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WO2006121521A2 - Implants pour tissus mous, agents prevenant la formation de cicatrices et compositions therapeutiques - Google Patents

Implants pour tissus mous, agents prevenant la formation de cicatrices et compositions therapeutiques Download PDF

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Publication number
WO2006121521A2
WO2006121521A2 PCT/US2006/011690 US2006011690W WO2006121521A2 WO 2006121521 A2 WO2006121521 A2 WO 2006121521A2 US 2006011690 W US2006011690 W US 2006011690W WO 2006121521 A2 WO2006121521 A2 WO 2006121521A2
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
agent
implant
antagonist
polymer
Prior art date
Application number
PCT/US2006/011690
Other languages
English (en)
Other versions
WO2006121521A3 (fr
Inventor
William L. Hunter
Philip M. Toleikis
David M. Gravett
Arpita Maiti
Richard T. Liggins
Aniko Takacs-Cox
Rui Avelar
Pierre E. Signore
Troy A.E. Loss
Anne Hutchinson
Gaye Mcdonald-Jones
Fara Lakhani
Original Assignee
Angiotech International Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Angiotech International Ag filed Critical Angiotech International Ag
Publication of WO2006121521A2 publication Critical patent/WO2006121521A2/fr
Publication of WO2006121521A3 publication Critical patent/WO2006121521A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings

Definitions

  • the present invention relates generally to soft tissue implants for use in cosmetic or reconstructive surgery, and more specifically, to compositions and methods for preparing and using such medical implants to make them resistant to overgrowth by inflammatory, fibrous scar tissue.
  • a soft tissue implant (aesthetic and reconstructive) is common in breast augmentation, breast reconstruction after cancer surgery, craniofacial procedures, reconstruction after trauma, congenital craniofacial reconstruction and oculoplastic surgical procedures to name a few.
  • the clinical function of a soft tissue implant depends upon the implant being able to effectively maintain its shape over time. In many instances, for example, when these devices are implanted in the body, they are subject to a "foreign body" response from the surrounding host tissues. The body recognizes the implanted device as foreign, which triggers an inflammatory response followed by encapsulation of the implant with fibrous connective tissue.
  • Encapsulation of surgical implants complicates a variety of reconstructive and cosmetic surgeries, and is particularly problematic in the case of breast reconstruction surgery where the breast implant becomes encapsulated by a fibrous connective tissue capsule that alters the anatomy and function.
  • Scar capsules that harden and contract are the most common complication of breast implant or reconstructive surgery.
  • Capsular (fibrous) contractures can result in hardening of the breast, loss of the normal anatomy and contour of the breast, discomfort, weakening and rupture of the implant shell, asymmetry, infection, and patient dissatisfaction.
  • fibrous encapsulation of any soft tissue implant can occur even after a successful implantation if the device is manipulated or irritated by the daily activities of the patient.
  • Scarring and fibrous encapsulation can also result from a variety of other factors associated with implantation of a soft tissue implant.
  • unwanted scarring can result from surgical trauma to the anatomical structures and tissue surrounding the implant during the implantation of the device. Bleeding in and around the implant can also trigger a biological cascade that ultimately leads to excess scar tissue formation.
  • the surrounding tissue can be inadvertently damaged from the resulting inflammation, leading to loss of function, tissue damage and/or tissue necrosis.
  • implantable prostheses such as breast implants
  • gel fillers e.g., silicone
  • the characteristics of the implant- tissue interface degrade, the subcutaneous tissue can harden and contract and the device can become disfigured.
  • the effects of unwanted scarring in the vicinity of the implant are the leading cause of additional surgeries to correct defects, break down scar tissue, or remove the implant.
  • the present invention discloses pharmaceutical agents that inhibit one or more aspects of the production of excessive fibrous (scar) tissue.
  • the present invention provides compositions for delivery of selected therapeutic agents via medical implants, as well as methods for making and using these implants and devices.
  • Compositions and methods are described for coating soft tissue implants with drug-delivery compositions such that the pharmaceutical agent is delivered in therapeutic levels over a period sufficient to prevent the implant from being encapsulated in fibrous tissue and to allow normal function of the implant to occur.
  • compositions e.g., topicals, injectables, liquids, gels, sprays, microspheres, pastes, wafers
  • an inhibitor of fibrosis e.g., an inhibitor of fibrosis
  • numerous specific soft tissue implants are described that produce superior clinical results as a result of being coated with agents that reduce excessive scarring and fibrous tissue accumulation as well as other related advantages.
  • drug-coated or drug- impregnated soft tissue implants are provided which reduce fibrosis in the tissue surrounding the implant, or inhibit scar development on the implant surface, thus enhancing the efficacy of the procedure.
  • fibrosis is inhibited by local or systemic release of specific pharmacological agents that become localized to the adjacent tissue.
  • the repair of tissues following a mechanical or surgical intervention, such as the implantation of a soft tissue implant involves two distinct processes: (1) regeneration (the replacement of injured cells by cells of the same type and (2) fibrosis (the replacement of injured cells by connective tissue).
  • fibrosis There are five general components to the process of fibrosis (or scarring) including: infiltration and activation of inflammatory cells (inflammation), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), the formation of new blood vessels (angiogenesis), deposition of extracellular matrix (ECM), and remodeling
  • inhibitors should be understood to refer to agents or compositions which decrease or limit the formation of fibrous or scar tissue (i.e., by reducing or inhibiting one or more of the processes of inflammation, connective tissue cell migration or proliferation, angiogenesis, ECM production, and/or remodeling).
  • numerous therapeutic agents described in this invention will have the additional benefit of also reducing tissue regeneration where appropriate.
  • a soft tissue implant is adapted to release an agent that inhibits fibrosis through one or more of the mechanisms cited herein.
  • medical devices comprising a soft tissue implant, wherein the implant or device releases an agent that inhibits fibrosis in vivo.
  • methods are provided for manufacturing a medical device or implant, comprising the step of coating (e.g., spraying, dipping, wrapping, or administering drug through) a soft tissue implant.
  • the implant or medical device can be constructed so that the device itself is comprised of materials that inhibit fibrosis in or around the implant.
  • Soft tissue implants may be utilized within the context of the present invention, depending on the site and nature of treatment desired.
  • the soft tissue implant is further coated with a composition or compound, which delays the onset of activity of the fibrosis-inhibiting agent for a period of time after implantation.
  • a composition or compound which delays the onset of activity of the fibrosis-inhibiting agent for a period of time after implantation.
  • agents include heparin, PLGA/MePEG, PLA, and polyethylene glycol.
  • the fibrosis-inhibiting implant or device is activated before, during, or after deployment (e.g., an inactive agent on the device is first activated to one that reduces or inhibits an in vivo fibrotic reaction).
  • the tissue surrounding the implant or device is treated with a composition or compound that contains an inhibitor of fibrosis.
  • Locally administered compositions e.g., topicals, injectables, liquids, gels, sprays, microspheres, pastes, wafers
  • compounds containing an inhibitor of fibrosis are described that can be applied to the surface of, or infiltrated into, the tissue adjacent to the device, such that the pharmaceutical agent is delivered in therapeutic levels over a period sufficient to prevent the soft tissue implant from being encapsulated in fibrous tissue. This can be done in lieu of coating the implant with a fibrosis-inhibitor, or done in addition to coating the device or implant with a fibrosis-inhibitor.
  • a soft tissue implant is coated in one aspect with a composition which inhibits fibrosis, as well as being coated with a composition or compound that promotes scarring on another aspect of the device (i.e., to affix the body of the device into a particular anatomical space).
  • agents that promote fibrosis and scarring include silk, silica, bleomycin, neomycin, talcum powder, metallic beryllium, retinoic acid compounds, growth factors, and copper, as well as analogues and derivatives thereof.
  • Also provided by the present invention are methods for treating patients undergoing surgical, endoscopic or minimally invasive therapies where a soft tissue implant is placed as part of the procedure.
  • inhibits fibrosis refers to a statistically significant decrease in the amount of scar tissue in or around the device or an improvement in the interface between the device and the tissue and not to a permanent prohibition of any complications or failures of the device/implant.
  • the pharmaceutical agents and compositions are utilized to create novel drug-coated soft tissue implants that reduce the foreign body response to implantation and limit the growth of reactive tissue on the surface of, or around in the tissue surrounding the implant, such that performance is enhanced.
  • the present invention is directed to medical devices that comprise a soft tissue implant and at least one of (i) an anti-scarring agent and (ii) a composition that comprises an anti-scarring agent.
  • the agent is present so as to inhibit scarring that may otherwise occur when the implant is placed within an animal.
  • the present invention is directed to methods wherein both a soft tissue implant and at least one of (i) an anti-scarring agent and (ii) a composition that comprises an anti-scarring agent, are placed into an animal, and the agent inhibits scarring that may otherwise occur.
  • the present invention provides a device, comprising a soft tissue implant and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring.
  • the agent may be present in a composition along with a polymer.
  • the polymer is biodegradable.
  • the polymer is non-biodegradable.
  • the present invention also provides methods.
  • the present invention provides methods whereby a specified soft tissue implant is implanted into an animal, and a specified agent associated with the implant inhibits scarring that may otherwise occur.
  • a specified soft tissue implant is implanted into an animal, and a specified agent associated with the implant inhibits scarring that may otherwise occur.
  • Each of the soft tissue implants identified herein may be a "specified implant”
  • each of the anti-scarring agents identified herein may be an "anti-scarring (or fibrosis-inhibiting) agent” where the present invention provides, in independent embodiments, for each possible combination of the implant and the agent.
  • the agent may be associated with the soft tissue implant prior to, during and/or after placement of the soft tissue implant within the animal.
  • the agent or composition comprising the agent
  • the agent may be coated onto an implant, and the resulting device then placed within the animal.
  • the agent may be independently placed within the animal in the vicinity of where the soft tissue implant is to be, is being, or has been placed within the animal.
  • the agent may be sprayed or otherwise placed onto, adjacent to, and/or within the tissue that will be contacting the medical implant or may otherwise undergo scarring.
  • the present invention provides placing a soft tissue implant and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring.
  • the agent may be present in a composition along with a polymer.
  • the polymer is biodegradable.
  • the polymer is non-biodegradable.
  • the anti-fibrotic agent may be one or more of the following: 1) an anti-fibrotic agent that inhibits cell regeneration, 2) an anti-fibrotic agent that inhibits angiogenesis, 3) an anti-fibrotic agent that inhibits fibroblast migration, 4) an anti-fibrotic agent that inhibits fibroblast proliferation, 5) an anti-fibrotic agent that inhibits deposition of extracellular matrix, 6) an anti-fibrotic agent inhibits tissue remodeling, 7) an adensosine A2A receptor antagonist, 8) an AKT inhibitor, 9) an alpha 2 integrin antagonist, wherein the alpha 2 integrin antagonist is Pharmaprojects No.
  • an alpha 4 integrin antagonist an alpha 4 integrin antagonist
  • an alpha 7 nicotinic receptor agonist 12) an angiogenesis inhibitor selected from the group consisting of AG-12,958 (Pfizer), ATN-161 (Attenuon LLC), neovastat, an angiogenesis inhibitor from Jerina AG (Germany), NM-3 (Mercian), VGA-1155 (Taisho), FCE-26644 (Pfizer), FCE-26950 (Pfizer), FPMA (Meiji Daries), FR-111142 (Fujisawa), GGTI-298, GM-1306 (Ligand), GPA-1734 (Novartis), NNC-47-0011 (Novo Nordisk), herbamycin (Nippon Kayaku), lenalidomide (Celegene), IP-10 (NIH) 1 ABT-828 (Abbott), KIN-841 (Tokushima University, Japan), SF-1126 (Semafore Pharmaceutical
  • a KDR inhibitor from LG Life Sciences, CT-6685 and CT-6729 (UCB), KRN-633 and KRN-951 (Kirin Brewery), OSI-930 (OSI Pharmaceuticals), SP-5.2 (Supratek Pharma), SU-11657 (Pfizer), a Tie-2 antagonist (Hybrigenics), SU 1498 (a VEGF-R inhibitor), a VEGFR-2 kinase inhibitor (Bristol-Myers Squibb), XL-647 (Exelixis), a KDR inhibitor from Abbott Laboratories, sorafenib tosylate, and an analogue or derivative thereof, 39) an endotoxin antagonist, 40) an epothilone and tubulin binder, 41) an estrogen receptor antagonist, 42) an FGF inhibitor, 43) a farnexyl transferase inhibitor, 44) a fa rnesy transferase inhibitor selected from the group of A-197574 (Abbott
  • an FLT-3 kinase inhibitor 46a) an FGF receptor kinase inhibitor, 47) a fibrinogen antagonist selected from the group consisting of AUV-201 (Auvation), MG-13926 (Sanofi-Aventis), plasminogen activator (CAS No. 105913-11-9) (from Sanofi-Aventis or UCB), plasminogen activator-2 (tPA-2) (Sanofi-Aventis), pro-urokinase (CAS No.
  • a heat shock protein 90 antagonist selected from the group consisting of SRN-005 (Sirenade), geldanamycin, NSC-33050 (17-allylaminogeldanamycin; 17-AAG), 17- dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG), rifabutin (rifamycin XIV, 1',4-didehydro-1-deoxy-1 ,4-dihydro-5'-(2-methylpropyl)-1-oxo-), radicicol from Humicola fuscoatra (CAS No.
  • an atherosclerosis therapeutic from Lipid Sciences, ATI-16000 (ARYx Therapeutics), KS-01-019 (Kos Pharmaceuticals), Pharmaprojects No. 2197 (Sanofi-Aventi), RP 61969 (Sanofi-Aventis), cerivastatin Na (CAS No.
  • an immunosuppressant selected from the group consisting of teriflunomide (Sanofi Aventis), chlorsulfaquinoxalone (NSC-339004), chlorsulfaquinoxalone sulfate, CS-712 (Sankyo), ismomultin alfa (CAS No.
  • microtubule poisons from Cambridge Enterprise paclitaxel such as LOTAX from Aphios (CAS No. 33069-62-4), Genexol-PM from Samyang, Pharmaprojects No. 6383 (Tapestry Pharmaceuticals), RPR-112378 (Sanofi- Aventis), SGN-75 (Seattle Genetics), SPL-7435 (Starpharma), SSR-250411 (Sanofi-Aventis), trastuzumab-DM1 (Genentech), vinorelbine, dolastatin 15 (CAS No.
  • paclitaxel such as LOTAX from Aphios (CAS No. 33069-62-4), Genexol-PM from Samyang, Pharmaprojects No. 6383 (Tapestry Pharmaceuticals), RPR-112378 (Sanofi- Aventis), SGN-75 (Seattle Genetics), SPL-7435 (Starpharma), SSR-250411 (Sanofi-Aventis), trastuzumab
  • NK neurokinin
  • anthrotainin CAS No. 148084-40-6
  • an IBS thereapeutic from ArQuIe
  • MDL-105212A CAS No. 167261-60-1
  • Pharmaprojects No. 2744, 3258 CAS No. 139167-47-8
  • Pharmaprojects No. 2744, 3258 CAS No. 139167-47-8
  • Pharmaprojects No. 2744, 3258 CAS No. 139167-47-8
  • RP 67580 CAS No. 135911-02-3
  • SR-144190 CAS No.
  • a palmitoyl-protein thioesterase inhibitor 80) a PDGF receptor kinase inhibitor selected from the group consisting of AAL-993, AMN-107, or ABP-309 (Novartis), AMG-706 (Amgen), BAY-57-9352 (Bayer), CDP-860 (UCB), E-7080 (Eisai), imatinib (CAS No.
  • a peroxisome proliferators-activated receptor agonist selected from the group consisting of (-)- halofenate (Metabolex), AMG-131 (Amgen), antidiabetics from Japan Tobacco, AZD-4619, AZD-8450, AZD-8677 (AstraZeneca), DRF-10945, balaglitazone (Dr Reddy's), CS-00088, CS-00098 (Chipscreen Biosciences), E-3030 (Eisai), etalocib (CAS No.
  • 122320-73-4 or 155141-29-0) (GlaxoSmithKline), rosiglitazone maleate/glimepir (CAS No. 155141-29-0 and 93479-97-1), AVANDARYL, rosiglitazone maleate/metformin extend (CAS No. 155141-29-0 and 657-24-9), AVANDAMET, rosiglitazone maleate+metformin, AVANDAMET (GlaxoSmithKline), tesaglitazar (AstraZeneca), LBM642, WY-14,643 (CAS No. 50892-23-4), GW7647, fenofibric acid (CAS No.
  • MCC-555 (CAS No. 161600-01-7), GW9662, GW1929, GW501516, L-165,041 (CAS No. 79558-09-1), and an analogue or derivative thereof, 82) a phosphatase inhibitor, 83) a phosphodiesterase (PDE) inhibitor selected from the group consisting of avanafil (Tanabe Seiyaku), dasantafil (CAS No. 569351-91-3) (Schering-Plough), A-906119 (CAS No.
  • PDE phosphodiesterase
  • papverine hydrochloride CAS No. 61-25-6
  • quercetin dehydrate CAS No. 6151-25-3
  • YM 976 CAS No. 191219- 80-4
  • irsogladine CAS No.
  • a phosphodiesterase III inhibitor enoximone, a phosphodiesterase IV inhibitor, fosfosal, Atopik (Barrier Therapeutics), triflusal, a phosphodiesterase V inhibitor, and an analogue or derivative thereof
  • a PKC inhibitor 85) a platelet activating factor antagonist, 86) a platelet-derived growth factor receptor kinase inhibitor, 87) a prolyl hydroxylase inhibitor, 88) a polymorphonuclear neutrophil inhibitor, 89) a protein kinase B inhibitor, 90) a protein kinase C stimulant, 91) a purine nucleoside analogue, 92) a purinoreceptor P2X antagonist, 93) a Raf kinase inhibitor, 94) a reversible inhibitor of ErbB1 and ErbB2, 95) a ribonucleoside triphosphate reductase inhibitor, 96
  • TNF ⁇ antagonist or TACE inhibitor selected from the group consisting of adalimumab (CAS No. 331731-18-1) (Cambridge Antibody Technology), AGIX-4207 (AtheroGenics), AGT-1
  • TNF antagonists form ProStrakan, and Synergen, TNF inhibitors (Amgen), TNF-alpha antagonists from Dynavax Technologies and Jerina AG (Germany), TNF-alpha inhibitors from IBFB Pharma and Xencor (Xencor), torbafylline (CAS No.
  • brompheniramine (CAS No. 980-71-2), fexofenadine hydrochloride, promethazine hydrochloride, loratadine, ketotifen fumarate salt, and acrivastine), methylxanthines (e.g., theophylline, theobromine, and caffeine), cimetidine (available under the tradename TAGAMET from SmithKline
  • H3 receptor antagonists e.g., thioperamide and thioperamide maleate salt
  • anti-histamines e.g., tricyclic dibenozoxepins, ethanolamines, ethylenediamines, piperizines, piperidines, and pthalazinones
  • 131 an alpha adrenergic receptor antagonist
  • 132) an anti-psychotic compound
  • 133) a CaM kinase Il inhibitor
  • 134) a G protein agonist 135) an antibiotic selected from the group consisting of apigenin (Cas No. 520-36-5), ampicillin sodium salt (CAS No.
  • a DNA topoisomerase inhibitor selected from the group consisting of ⁇ -lapachone (CAS No. 4707-32- 8), (-)-arctigenin (CAS No. 7770-78-7), aurintricarboxylic acid, and an analogue or derivative thereof, 138) a thromboxane A2 receptor inhibitor selected from the group consisting of BM-531 (CAS No. 284464-46-6), ozagrel hydrochloride (CAS No.
  • a D2 dopamine receptor antagonist 140) a Peptidyl-Prolyl Cis/Trans lsomerase Inhibitor, 141) a dopamine antagonist, an anesthetic compound, 142) a clotting factor, 143) a lysyl hydrolase inhibitor, 144) a muscarinic receptor inhibitor, 145) a superoxide anion generator, 146) a steroid, 147) an antiproliferative agent selected from the group consisting of silibinin (CAS No. 22888-70-6), silymarin (CAS No.
  • temozolomide temozolomide
  • procarbazine HCI and an analogue or derivative thereof
  • 157) a DNA methylation inhibitor 158) a NSAID agent, 159) a peptidylglycine alpha- hydroxylating monooxygenase inhibitor, 160) an MEK1/MEK 2 inhibitor, 161) a NO synthase inhibitor, 162) a retinoic acid receptor antagonist selected from isotretinoin (CAS No.
  • an ACE inhibitor 164) a glycosylation inhibitor, 165) an intracellular calcium influx inhibitor, 166) an anti-emetic agent, 167) an acetylcholinesterase inhibitor, 168) an ALK-5 receptor antagonist, 169) a RAR/RXT antagonist, 170) an elF-2a inhibitor, 171) an S-adenosyl-L-homocysteine hydrolase inhibitor, 172) an estrogen agonist, 173) a serotonin receptor inhibitor, 174) an anti-thrombotic agent, 175) a tryptase inhibitor, 176) a pesticide, 177) a bone mineralization promoter, 178) a bisphosphonate compound selected from risedronate and an analogue or derivative thereof, 179) an anti-inflammatory compound, 180) a DNA methylation promoter, 181) an anti-spasmodic agent, 182) a protein synthesis inhibitor, 183) an ⁇ -glucosidase inhibitor
  • Figure 1A schematically depicts the transcriptional regulation of matrix metalloproteinases.
  • Figure 1 B is a blot that demonstrates that IL-1 stimulates AP-1 transcriptional activity.
  • Figure 1C is a graph that shows that IL-1 induced binding activity decreased in lysates from chondrocytes which were pretreated with paclitaxel.
  • Figure 1 D is a blot which shows that IL-1 induction increases collagenase and stromelysin in RNA levels in chondrocytes, and that this induction can be inhibited by pretreatment with paclitaxel.
  • Figures 2A-H are blots that show the effect of various anti- microtubule agents in inhibiting collagenase expression.
  • Figure 3 is a graph showing the results of a screening assay for assessing the effect of paclitaxel on smooth muscle cell migration.
  • Figure 4 is a bar graph showing the area of granulation tissue in carotid arteries exposed to silk coated perivascular polyurethane (PU) films relative to arteries exposed to uncoated PU films.
  • PU perivascular polyurethane
  • Figure 5 is a bar graph showing the area of granulation tissue in carotid arteries exposed to silk suture coated perivascular PU films relative to arteries exposed to uncoated PU films.
  • Figure 6 is a bar graph showing the area of granulation tissue in carotid arteries exposed to natural and purified silk powder and wrapped with perivascular PU film relative to a control group in which arteries are wrapped with perivascular PU film only.
  • Figure 7 is a bar graph showing the area of granulation tissue (at
  • Medical device “implant,” “device,” “medical device,” “medical implant,” “implant/device,” and the like are used synonymously to refer to any object that is designed to be placed partially or wholly within a patient's body for one or more therapeutic or prophylactic purposes such as for tissue augmentation, contouring, restoring physiological function, repairing or restoring tissues damaged by disease or trauma, and/or delivering therapeutic agents to normal, damaged or diseased organs and tissues.
  • medical devices are normally composed of biologically compatible synthetic materials (e.g., medical- grade stainless steel, titanium and other metals; exogenous polymers, such as polyurethane, silicon, PLA, PLGA), other materials may also be used in the construction of the medical implant.
  • Specific medical devices and implants that are particularly useful for the practice of this invention include soft tissue implants for cosmetic and reconstructive surgery.
  • Soft tissue implant refers to a medical device or implant that includes a volume replacement material for augmentation or reconstruction to replace a whole or part of a living structure. Soft tissue implants are used for the reconstruction of surgically or traumatically created tissue voids, augmentation of tissues or organs, contouring of tissues, the restoration of bulk to aging tissues, and to correct soft tissue folds or wrinkles (rhytides). Soft tissue implants may be used for the augmentation of tissue for cosmetic
  • tissue implants include breast implants, chin implants, calf implants, cheek implants and other facial implants, buttocks implants, and nasal implants.
  • Fibrosis or “scarring” refers to the formation of fibrous (scar) tissue in response to injury or medical intervention.
  • Therapeutic agents which inhibit fibrosis or scarring can do so through one or more mechanisms including inhibiting inflammation, inhibiting angiogenesis, inhibiting migration or proliferation of connective tissue cells (such as fibroblasts, smooth muscle cells, vascular smooth muscle cells), reducing ECM production or encouraging ECM breakdown, and/or inhibiting tissue remodeling.
  • numerous therapeutic agents described in this invention will have the additional benefit of also reducing tissue regeneration (the replacement of injured cells by cells of the same type) when appropriate.
  • Inhibit fibrosis “inhibit scar,” “reduce fibrosis,” “reduce scar,” “fibrosis-inhibitor,” “anti-scarring,” “anti-fibrotic” and the like are used synonymously to refer to the action of agents or compositions which result in a statistically significant decrease in the formation, deposition and/or maturation of fibrous tissue that may be expected to occur in the absence of the agent or composition.
  • Encapsulation refers to the formation of a fibrous connective tissue capsule (containing fibroblasts, myofibroblasts, inflammatory cells, relatively few blood vessels and a collagenous extracellular matrix) encloses and isolates an implanted prosthesis or biomaterial from the surrounding body tissue.
  • This fibrous tissue capsule which is the result of unwanted scarring in response to an implanted prosthesis or biomaterial, has a tendency to progressively contract, thereby tightening around the implant/biomaterial and causing it to become very firm and disfigured. Further implications of encapsulation and associated contracture include tenderness of the tissue, pain, erosion of the adjacent tissue as well as other complications.
  • Constant refers to permanent or non- permanent scar tissue formation in response to an implanted prosthesis or biomaterial.
  • condition of contracture involves a fibrotic response that may involve inflammatory components, both acute and chronic.
  • Unwanted scarring in response to an implanted prosthesis or biomaterial can form a fibrous tissue capsule around the area or implantable prosthesis or biomaterial that encloses and isolates it from the surrounding body tissue (as described for encapsulation). Contracture occurs when fibrous tissue capsule matures and starts to shrink (contract) forming a tight, hard capsule around the implant/biomaterial that can alter the anatomy, texture, shape and movement of the implant.
  • contracture also draws the overlying skin in towards the implant and leads to dimpling of the skin and disfuguration. Contracture and chronic inflammation can also contribute to tenderness around the implant, pain, and erosion of the adjacent tissue. Fibrotic contractures related to implantation of soft tissue implant/biomaterials may be caused by a variety of factors including surgical trauma and complications, revisions or repeat procedures (the incidence is higher if implantation is being attempted where contractures have occurred previously), inadequate hemostasis (bleeding control) during surgery, aggressive healing processes, underlying or pre-existent conditions, genetic factors (people prone to hypertrohic scar or keloid formation), and immobilization.
  • “Host,” “person,” “subject,” “patient,” and the like are used synonymously to refer to the living being (human or animal) into which a soft tissue implant of the present invention is implanted.
  • “Implanted” refers to having completely or partially placed a device within a host. A device is partially implanted when some of the device reaches, or extends to the outside of, a host.
  • Release of an agent refers to a statistically significant presence of the agent, or a subcomponent thereof, which has disassociated from the device/implant.
  • Analogue refers to a chemical compound that is structurally similar to a parent compound but differs slightly in composition (e.g., one atom or functional group is different, added, or removed).
  • An analogue may or may not have different chemical or physical properties than the original compound and may or may not have improved biological and/or chemical activity.
  • the analogue may be more hydrophilic, or it may have altered reactivity as compared to the parent compound.
  • the analogue may mimic the chemical and/or biological activity of the parent compound (i.e., it may have similar or identical activity), or, in some cases, may have increased or decreased activity.
  • the analogue may be a naturally or non-naturally occurring (e.g., recombinant) variant of the original compound.
  • an analogue is a mutein (i.e., a protein analogue in which at least one amino acid is deleted, added, or substituted with another amino acid).
  • Other types of analogues include isomers (enantiomers, diasteromers, and the like) and other types of chiral variants of a compound, as well as structural isomers.
  • the analogue may be a branched or cyclic variant of a linear compound.
  • a linear compound may have an analogue that is branched or otherwise substituted to impart certain desirable properties (e.g., improve hydrophilicity or bioavailability).
  • Derivative refers to a chemically or biologically modified version of a chemical compound that is structurally similar to a parent compound and (actually or theoretically) derivable from that parent compound.
  • a “derivative” differs from an “analogue” in that a parent compound may be the starting material to generate a "derivative,” whereas the parent compound may not necessarily be used as the starting material to generate an “analogue.”
  • An analogue may have different chemical or physical properties of the parent compound. For example, the derivative may be more hydrophilic or it may have altered reactivity as compared to the parent compound.
  • Derivatization i.e., modification
  • a hydrogen may be substituted with a halogen, such as fluorine or chlorine, or a hydroxy! group (- OH) may be replaced with a carboxylic acid moiety (-COOH).
  • derivative also includes conjugates, and prodrugs of a parent compound (i.e., chemically modified derivatives which can be converted into the original compound under physiological conditions).
  • the prodrug may be an inactive form of an active agent. Under physiological conditions, the prodrug may be converted into the active form of the compound.
  • Prodrugs may be formed, for example, by replacing one or two hydrogen atoms on nitrogen atoms by an acyl group (acyl prodrugs) or a carbamate group (carbamate prodrugs).
  • prodrugs More detailed information relating to prodrugs is found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; or H. Bundgaard, Drugs of the Future 16 (1991) 443.
  • derivative is also used to describe all solvates, for example hydrates or adducts (e.g., adducts with alcohols), active metabolites, and salts of the parent compound.
  • the type of salt that may be prepared depends on the nature of the moieties within the compound.
  • acidic groups for example carboxylic acid groups
  • alkali metal salts or alkaline earth metal salts e.g., sodium salts, potassium salts, magnesium salts and calcium salts
  • physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines such as, for example, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine.
  • Basic groups can form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
  • Compounds that simultaneously contain a basic group and an acidic group for example a carboxyl group in addition to basic nitrogen atoms, can be present as zwitterions. Salts can be obtained by customary methods known to those skilled in the art, for example by combining a compound with an inorganic or organic acid or base in a solvent or diluent, or from other salts by cation exchange or anion exchange.
  • “Inhibitor” refers to an agent that prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process.
  • the process may be a general one such as scarring or refer to a specific biological action such as, for example, a molecular process resulting in release of a cytokine.
  • “Antagonist” refers to an agent that prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process. While the process may be a general one, typically this refers to a drug mechanism by which the drug competes with a molecule for an active molecular site or prevents a molecule from interacting with the molecular site. In these situations, the effect is that the molecular process is inhibited.
  • Antist refers to an agent that stimulates a biological process or rate or degree of occurrence of a biological process.
  • the process may be a general one such as scarring or refer to a specific biological action such as, for example, a molecular process resulting in release of a cytokine.
  • Anti-microtubule agent should be understood to include any protein, peptide, chemical, or other molecule that impairs the function of microtubules, for example, through the prevention or stabilization of polymerization.
  • Compounds that stabilize polymerization of microtubules are referred to herein as "microtubule stabilizing agents.”
  • a wide variety of methods may be utilized to determine the anti-microtubule activity of a particular compound, including for example, assays described by Smith et al. (Cancer Lett. 79(2):213-219, 1994) and Mooberry et al., (Cancer Lett. 96(2):261-266, 1995).
  • any concentration ranges, percentage range, or ratio range recited herein are to be understood to include concentrations, percentages or ratios of any integer within that range and fractions thereof, such as one tenth and one hundredth of an integer, unless otherwise indicated.
  • any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
  • the terms “a” and “an” as used above and elsewhere herein refer to “one or more" of the enumerated components.
  • a polymer refers to either one polymer or a mixture comprising two or more polymers.
  • the term “about” means ⁇ 15%.
  • the present invention provides compositions, methods and devices relating to cosmetic and reconstructive devices and implants, which greatly increase their ability to inhibit the formation of reactive scar tissue on, or around, the surface of the implant.
  • the present invention provides for the combination of an anti-scarring agent and a soft tissue implant for use in cosmetic or reconstructive surgery.
  • soft tissue implants are provided that can reduce the development of surrounding scar capsules that harden and contract (also referred to herein as capsular or fibrous contracture), discomfort, leakage of fluid from the implant, infection, asymmetry, and patient dissatisfaction. Described in more detail below are methods for constructing soft tissue implants, compositions and methods for generating medical implants that inhibit fibrosis, and methods for utilizing such medical implants.
  • the present invention provides for soft tissue implants that include an agent that inhibits the formation of scar tissue to minimize or prevent encapsulation (and associated fibrous contracture) of the soft tissue implant.
  • Soft tissue implants are used in a variety of cosmetic, plastic, and reconstructive surgical procedures and may be delivered to many different parts of the body, including, without limitation, the face, nose, jaw, breast, chin, buttocks, chest, lip, and cheek. Soft tissue implants are used for the reconstruction of surgically or traumatically created tissue voids, augmentation of tissues or organs, contouring of tissues, the restoration of bulk to aging tissues, and to correct soft tissue folds or wrinkles (rhytides). Soft tissue implants may be used for the augmentation of tissue for cosmetic (aesthetic) enhancement or in association with reconstructive surgery following disease or surgical resection.
  • soft tissue implants that can be coated with, or otherwise constructed to contain and/or release fibrosis- inhibiting agents provided herein, include, e.g., saline breast implants, silicone breast implants, triglyceride-filled breast implants, chin and mandibular implants, nasal implants, cheek implants, lip implants, and other facial implants, pectoral and chest implants, malar and submalar implants, and buttocks implants.
  • Soft tissue implants have numerous constructions and may be formed of a variety of materials, such as to conform to the surrounding anatomical structures and characteristics.
  • soft tissue implants suitable for combining with a fibrosis-inhibitor are formed from a polymer such as silicone, poly(tetrafluoroethylene), polyethylene, polyurethane, polymethylmethacrylate, polyester, polyamide and polypropylene.
  • Soft tissue implants may be in the form shell (or envelope) that is filled with a fluid material such as saline.
  • soft tissue implants include or are formed from silicone or dimethylsiloxane. Silicone implants can be solid, yet flexible and very durable and stable.
  • silicone-based implants e.g., chin implants
  • silicone-based implants may be affixed to the underlying bone by way of one or several titanium screws.
  • Silicone implants can be used to augment tissue in a variety of locations in the body, including, for example, breast, nasal, chin, malar (e.g., cheek), and chest/pectoral area. Silicone gel with low viscosity has been primarily used for filling breast implants, while high viscosity silicone is used for tissue expanders and outer shells of both saline- filled and silicone-filled breast implants.
  • breast implants are manufactured by both lnamed Corporation (Santa Barbara, CA) and Mentor Corporation (Santa Barbara, CA).
  • soft tissue implants include or are formed from poly(tetrafluoroethylene) (PTFE).
  • the poly(tetrafluoroethylene) is expanded polytetrafluoroethylene (ePTFE).
  • PTFE used for soft tissue implants may be formed of an expanded polymer of solid PTFE nodes with interconnecting, thin PTFE fibrils that form a grid pattern, resulting in a pliable, durable, biocompatible material.
  • Soft tissue implants made of PTFE are often available in sheets that may be easily contoured and stacked to a desired thickness, as well as solid blocks. These implants are porous and can become integrated into the surrounding tissue that aids in maintaining the implant in its appropriate anatomical location.
  • PTFE implants generally are not as firm as silicone implants.
  • Soft tissue implants composed of PTFE may be used to augment tissue in a variety of locations in the body, including, for example, facial, chest, lip, nasal, and chin, as well as the mandibular and malar region and for the treatment of nasolabial and glabellar creases.
  • GORE-TEX W.L. Gore & Associates, Inc., Newark, DE
  • GORE-TEX is an expanded synthetic PTFE that may be used to form facial implants for augmentation purposes.
  • soft tissue implants include or are formed from polyethylene.
  • Polyethylene implants are frequently used, for example in chin augmentation.
  • Polyethylene implants can be porous, such that they may become integrated into the surrounding tissue, which provides an alternative to using titanium screws for stability.
  • Polyethylene implants may be available with varying biochemical properties, including chemical resistance, tensile strength, and hardness.
  • Polyethylene implants may be used for facial reconstruction, including malar, chin, nasal, and cranial implants.
  • Porex Surgical Products Group (Newnan, GA) makes MEDPOR, which is a high-density, porous polyethylene implant that is used in facial reconstruction. The porosity allows for vascular and soft tissue ingrowth for incorporation of the implant.
  • soft tissue implants include or are formed from polypropylene.
  • Polypropylene implants are a loosely woven, high density polymer having similar properties to polyethylene. These implants have good tensile strength and are available as a woven mesh, such as PROLENE (Ethicon, Inc., Sommerville, NJ) or MARLEX (CR. Bard, Inc., Billerica, MA). Polypropylene implants may be used, for example, as chest implants.
  • soft tissue implants include or are formed from polyamide.
  • Polyamide is a nylon compound that is woven into a mesh that may be implanted for use in facial reconstruction and augmentation. These implants are easily shaped and sutured and undergo resorption over time.
  • SUPRAMID and SUPRAMESH are nylon- based products that may be used for augmentation; however, because of their resorptive properties, their application is limited.
  • soft tissue implants include or are formed from polyester.
  • Nonbiodegradable polyesters such as MERSILENE Mesh (Ethicon, Inc.) and DACRON (available from Invista, Wichita, KS), may be suitable as implants for applications that require both tensile strength and stability, such as chest, chin and nasal augmentation.
  • soft tissue implants include or are formed from polymethylmethacrylate. These implants have a high molecular weight and have compressive strength and rigidity even though they have extensive porosity. Polymethylmethacrylate, such as Hard Tissue Replacement (HTR) polymer made by U.S. Surgical Corporation (Norwalk, CT), may be used for chin and malar augmentation as well as craniomaxillofacial reconstruction.
  • soft tissue implants include or are formed from polyurethane. Polyurethane may be used as a foam to cover breast implants. This polymer promotes tissue ingrowth resulting in low capsular contracture rate in breast implants.
  • Examples of commercially available polymeric soft tissue implants suitable for use in combination with a fibrosis-inhibitor include silicone implants from Surgiform Technology, Ltd. (Columbia Station, OH); ImpIantTech
  • Saline filled breast implants are made by both lnamed and Mentor and may also benefit from implantation in combination with a fibrosis inhibitor.
  • Commercially available poly(tetrafluoroethylene) soft tissue implants suitable for use in combination with a fibrosis-inhibitor include poly(tetrafluoroethylene) cheek, chin, and nasal implants from W. L. Gore & Associates, Inc. (Newark, DE).
  • Commercially available polyethylene soft tissue implants suitable for use in combination with a fibrosis-inhibitor include polyethylene implants from Porex Surgical Inc.
  • MEDPOR Biomaterial is composed of porous, high-density polyethylene material with an omni-directional latticework of interconnecting pores, which allows for integration into host tissues. Upon implantation, excessive scar tissue growth can occur around the all or parts of the implant, which can lead to a reduction in the performance of these devices (as described previously). Soft tissue implants that release a therapeutic agent for reducing scarring at the implant-tissue interface can be used to enhance the appearance, increase the longevity, reduce the need for corrective surgery or repeat procedures, decrease the incidence of pain and other symptoms, and improve the clinical function of implant. Accordingly, the present invention provides soft tissue implants that are coated or otherwise incorporate an anti-scarring agent or a composition that includes an anti-scarring agent.
  • the soft tissue implant suitable for use in combination with a fibrosis-inhibitor is a breast implant.
  • Breast implant placement for augmentation or breast reconstruction after mastectomy is one of the most frequently performed cosmetic surgery procedures. For example, in 2002 alone, over 300,000 women had breast implant surgery. Of these women, approximately 80,000 had breast reconstructions following a mastectomy due to cancer. An increased number of breast implant surgeries is highly likely given the incidence of breast cancer and current trends in cosmetic surgery.
  • breast augmentation or reconstructive surgery involves the placement of a commercially available breast implant, which consists of a capsule filled with either saline or silicone, into the tissues underneath the mammary gland.
  • a commercially available breast implant which consists of a capsule filled with either saline or silicone.
  • incision sites have historically been used for breast implantation: axillary (armpit), periareolar (around the underside of the nipple), inframamary (at the base of the breast where it meets the chest wall) and transumbilical (around the belly button).
  • the tissue is dissected away through the small incision, often with the aid of an endoscope (particularly for axillary and transumbilical procedures where tunneling from the incision site to the breast is required).
  • a pocket for placement of the breast implant is created in either the subglandular or the subpectorial region.
  • the tissue is dissected to create a space between the glandular tissue and the pectoralis major muscle that extends down to the inframammary crease.
  • the fibres of the pectoralis major muscle are carefully dissected to create a space beneath the pectoralis major muscle and superficial to the rib cage. Careful hemostasis is essential (since it can contribute to complications such as capsular contractures), so much so that minimally invasive procedures (axillary, transumbilical approaches) must be converted to more open procedures (such as periareolar) if bleeding control is inadequate.
  • the breast implant is often deflated and rolled up for placement in the patient. After accurate positioning is achieved, the implant can then be filled or expanded to the desired size.
  • capsular contracture Encapsulation of a breast prosthesis that creates a periprosthetic shell (called capsular contracture) is the most common complication reported after breast enlargement, with up to 50% of patients reporting some dissatisfaction. Calcification can occur within the fibrous capsule adding to its firmness and complicating the interpretation of mammograms. Multiple causes of capsular contracture have identified including: foreign body reaction, migration of silicone gel molecules across the capsule and into the tissue, autoimmune disorders, genetic predisposition, infection, hematoma, and the surface characteristics of the prosthesis.
  • Implant malposition, hardness and unfavorable shape are the most frequently sited complications and are most often attributed to capsular contracture.
  • the surrounding scar capsule begins to harden and contract, it results in discomfort, weakening of the shell, asymmetry, skin dimpling and malpositioning.
  • True capsular contractures will occur in approximately 10% of patients after augmentation, and in 25% to 30% of reconstruction cases, with most patients reporting dissatisfaction with the aesthetic outcome.
  • Scarring leading to asymmetries occurs in 10% of augmentations and 30% of reconstructions and is the leading cause of revision surgery.
  • Skin wrinkling due to the contracture pulling the skin in towards the implant) is a complication reported by 10% to 20% of patients ' .
  • Correction can involve several options including removal of the implant, capsulotomy (cutting or surgically releasing the capsule), capsulectomy (surgical removal of the fibrous capsule), or placing the implant in a different location (i.e., from subglandular to subpectoral).
  • additional surgery revisions, capsulotomy, removal, re-implantation
  • scar formation and capsular contracture being far and away the most common cause.
  • Procedures to break down the scar may not be sufficient, and approximately 8% of augmentations and 25% of reconstructions ultimately have the implant surgically removed.
  • a fibrosis-inhibiting agent or composition delivered locally from the breast implant, administered locally into the tissue surrounding the breast implant, or administered systemically to reach the breast tissue can minimize fibrous tissue formation, encapsulation and capsular contracture.
  • An ideal fibrosis-inhibiting agent will target only the components of the fibrous capsule and not harm the surrounding soft tissues.
  • Incorporation of a fibrosis-inhibiting agent onto a breast implant may minimize or prevent fibrous contracture in response to gel or saline- containing breast implants that are placed subpectorally or subglandularly.
  • breast implants may be composed of a flexible soft shell filled with a fluid, such as saline solution, polysiloxane, or silicone gel.
  • the breast implant may be composed of an outer polymeric shell having a cavity filled with a plurality of hollow bodies of elastically deformable material containing a liquid saline solution.
  • the breast implant may be composed of an envelope of vulcanized silicone rubber that forms a hollow sealed water impermeable shell containing an aqueous solution of polyethylene glycol. See, e.g., U.S. Patent No. 6,312,466.
  • the breast implant may be composed of an envelope made from a flexible non-absorbable material and a filler material that is a shortening composition (e.g., vegetable oil). See, e.g., U.S. Patent No. 6,156,066.
  • the breast implant may be composed of a soft, flexible outer membrane and a partially-deformable elastic filler material that is supported by a compartmental internal structure.
  • the breast implant may be composed of a non-biodegradable conical shell filled with layers of monofilament yarns formed into resiliently compressible fabric. See, e.g., U.S. Patent No. 6,432,138.
  • the breast implant may be composed of a shell containing sterile continuous filler material made of continuous yarn of polyolefin or polypropylene. See, e.g., U.S. Patent No. 6,544,287.
  • the breast implant may be composed of an envelope containing a keratin hydrogel. See, e.g., U.S. Patent No. 6,371 ,984.
  • the breast implant may be composed of a hollow, collapsible shell formed from a flexible, stretchable material having a base portion reinforced with a resilient, non- deformable member and a cohesive filler material contained within. See, e.g., U.S. Patent No. 5,104,409.
  • the breast implant may be composed of a smooth, non-porous, polymeric outer envelope with an affixed non-woven, porous outer layer made of extruded fibers of polycarbonate urethane polymer, which has a soft filler material contained within. See, e.g., U.S. Patent No. 5,376,117.
  • the breast implant may be configured to be surgically implanted under the pectoral muscle with a second prosthesis implanted between the pectoral muscle and the breast tissue. See, e.g., U.S. Patent No. 6,464,726.
  • the breast implant may be composed of a homogenous silicone elastomer flexible shell of unitary construction with an interior filling and a rough-textured external surface with randomly formed interconnected cells to promote tissue ingrowth to prevent capsular contracture. See, e.g., U.S. Patent No. 5,674,285.
  • the breast implant may be a plastic implant with a covering of heparin, which is bonded to the surface to prevent or treat capsule formation and/or shrinkage in a blood dry tissue cavity. See, e.g., U.S.
  • the breast implant may be a sealed, elastic polymer envelope having a microporous structure that is filled with a viscoelastic material (e.g., salt of chondroitin sulfate) to provide a predetermined shape.
  • a viscoelastic material e.g., salt of chondroitin sulfate
  • breast implant implants include those from INAMED Corporation (Santa Barbara, CA) that sells both Saline-Filled and Silicone-Filled Breast Implants.
  • INAMED's Saline-Filled Breast Implants include the Style 68 Saline Matrix and Style 363LF as well as others in a variety of models, contours, shapes and sizes.
  • INAMED's Silicone-Filled Breast Implants include the Style 10, Style 20 and Style 40 as well as others in a variety of shapes, contours and sizes.
  • INAMED also sells breast tissue expanders, such as the INAMED Style 133 V series tissue expanders, which are used to encourage rapid tissue adherence to maximize expander immobility.
  • the breast implant is combined with a fibrosis-inhibiting agent or composition containing a fibrosis- inhibiting agent.
  • Ways that this can be accomplished include, but are not restricted to, incorporating a fibrosis-inhibiting agent into the polymer that composes the shell of the implant (e.g., the polymer that composes the capsule of the breast implant is loaded with an agent that is gradually released from the surface), surface-coating the breast implant with an anti-scarring agent or a composition that includes an anti-scarring agent, and/or incorporating the fibrosis-inhibiting agent into the implant filling material (for example, saline, gel, silicone) such that it can diffuse across the capsule into the surrounding tissue.
  • a fibrosis-inhibiting agent into the polymer that composes the shell of the implant
  • the polymer that composes the capsule of the breast implant is loaded with an agent that is gradually released from the surface
  • an anti-scarring agent or a composition that includes an anti-scarring agent e.g., a composition that includes an anti-scarring agent
  • Methods for incorporating fibrosis-inhibiting compositions onto or into a breast implant include (a) directly affixing to, or coating, the surface of the breast implant with a fibrosis-inhibiting composition (e.g., by either a spraying process or dipping process, with or without a carrier); (b) directly incorporating the fibrosis-inhibiting composition into the polymer that composes the outer capsule of the breast implant (e.g., by either a spraying process or dipping process, with or without a carrier); (c) by coating the breast implant with a substance such as a hydrogel which will in turn absorb the fibrosis-inhibiting composition, (d) by inserting the breast implant into a sleeve or mesh which is comprised of, or coated with, a fibrosis-inhibiting composition, (e) constructing the breast implant itself (or a portion of the implant) with a fibrosis-inhibiting composition, or (f) by covalently binding the fibrosis
  • the fibrosis-inhibiting agent or composition can be incorporated into the central core of the implant.
  • the most common design of a breast implant involves an outer capsule (in a variety of shapes and sizes), which is filled with an aqueous or gelatinous material.
  • Most commercial devices employ either saline or silicone as the "filling" material.
  • numerous materials have been described for this purpose including, but not restricted to, polysiloxane, polyethylene glycol, vegetable oil, triglycerides, monofilament yarns (e.g., polyolefin, polypropylene), keratin hydrogel and chondroitin sulfate.
  • the fibrosis inhibiting agent or composition can be incorporated into the filler material and then can diffuse through, or be actively transported across, the capsular material to reach the surrounding tissues and prevent capsular contracture.
  • Methods of incorporating the fibrosis-inhibiting agent or composition into the central core material of the breast implant include, but are not restricted to: (a) dissolving a water soluble fibrosis-inhibiting agent into an aqueous core material (e.g., saline) at the appropriate concentration and dose; (b) using a solubilizing agent or carrier (e.g., micelles, liposomes, EDTA, a surfactant etc.) to incorporate an insoluble fibrosis-inhibiting agent into an aqueous core material at the appropriate concentration and dose; (c) dissolving a water-insoluble fibrosis-inhibiting agent into an organic solvent core material (e.g., vegetable oil, polypropylene etc.) at the appropriate concentration and dose; (d) incorporating the
  • an implant may be prepared which has a coating, where the coating is, e.g., uniform, non-uniform, continuous, discontinuous, or patterned.
  • the coating may directly contact the implant, or it may indirectly contact the implant when there is something, e.g., a polymer layer, that is interposed between the implant and the coating that contains the fibrosis-inhibiting agent.
  • Sustained release formulations suitable for incorporation into the core of the breast implant are described herein.
  • a composition that includes an anti-scarring agent can be infiltrated into the space (surgically created pocket) where the breast implant will be implanted.
  • the fibrosis-inhibiting agent with or without a polymeric, non-polymeric, or secondary carrier either directly (during an open procedure) or via an endoscope: (a) to the breast implant surface (e.g., as an injectable, paste, gel or mesh) during the implantation procedure; (b) to the surface of the tissue (e.g., as an injectable, paste, gel, in situ forming gel or mesh) of the implantation pocket immediately prior to, or during, implantation of the breast implant; (c) to the surface of the breast implant and/or the tissue surrounding the implant (e.g., as an injectable, paste, gel, in situ forming gel or mesh) immediately after to the implantation of the soft tissue implant; (d) by topical application of the anti-fibrosis agent into the anatomical space where the soft tissue implant will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids
  • certain polymeric carriers themselves can help prevent the formation of fibrous tissue around the breast implant.
  • These carriers are particularly useful for infiltration into the tissue surrounding the breast implant (as described in the previous paragraph), either alone, or in combination with a fibrosis inhibiting composition.
  • Numerous carriers suitable for the practice of this embodiment are described herein, but the following implantables are particularly preferred for infiltration into the vicinity of the implant-tissue interface and include: (a) sprayable collagen- containing formulations such as COSTASIS and crosslinked derivatized poly(ethylene glycol) -collagen compositions (described, e.g., in U.S. Patent Nos.
  • CT3 both from Angiotech Pharmaceuticals, Inc., Canada
  • sprayable PEG-containing formulations such as COSEAL or ADHIBIT (Angiotech Pharmaceuticals, Inc.), FOCALSEAL (Genzyme Corporation, Cambridge, MA), SPRAYGEL or DURASEAL (both from Confluent Surgical, Inc., Boston, MA), either alone, or loaded with a fibrosis-inhibiting agent, applied to the breast implantation site (or the breast implant surface);
  • fibrinogen-containing formulations such as FLOSEAL or TISSEAL (both from Baxter Healthcare Corporation, Fremont, CA), either alone, or loaded with a fibrosis-inhibiting agent, applied to the breast implantation site (or the breast implant surface);
  • hyaluronic acid-containing formulations such as RESTY
  • All of the above have the advantage of also acting as a temporary (or permanent) barrier (particularly formulations containing PEG, hyaluronic acid, and polysaccharide gels) that can help prevent the formation of fibrous tissue around the breast implant.
  • formulations containing PEG, collagen, or fibrinogen e.g., formulations containing PEG, collagen, or fibrinogen such as COSEAL, CT3, ADHIBIT, COSTASIS, FOCALSEAL, SPRAYGEL, DURASEAL, TISSEAL AND FLOSEAL
  • a preferred polymeric matrix which can be used to help prevent the formation of fibrous tissue around the breast implant, either alone or in combination with a fibrosis inhibiting agent/composition is formed from reactants comprising either one or both of pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG, which includes structures having a linking group(s) between a sulfhydryl group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents.
  • reactants comprising either one or both of pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4-armed thio
  • Another preferred composition comprises either one or both of pentaerythritol poly(ethylene glycol)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking group(s) between an amino group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents.
  • Chemical structures for these reactants are shown in, e.g., U.S. Patent 5,874,500.
  • collagen or a collagen derivative is added to the poly(ethylene glycol)-containing reactant(s) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a standalone composition to help prevent the formation of fibrous tissue around the breast implant.
  • collagen or a collagen derivative e.g., methylated collagen
  • the breast implant is coated on one aspect with a composition which inhibits fibrosis, as well as being coated with a composition or compound which promotes scarring on another aspect of the device (i.e., to affix the breast implant into the subglandular or subpectoral space).
  • implant malposition movement or migration of the implant after placement
  • implant malposition can lead to a variety of complications such as asymmetry and movement below the inframammary crease, and is a leading cause of patient dissatisfaction and revision surgery.
  • the breast implant is coated on the inferior surface (i.e., the surface facing the pectoralis muscle for subglandular breast implants or the surface facing the chest wall for subpectoral breast implants) with a fibrosis- promoting agent or composition, and the coated on the other surfaces (i.e., the surfaces facing the mammary tissue for subglandular breast implants or the surfaces facing the pectoralis muscle for subpectoral breast implants) with an agent or composition that inhibits fibrosis.
  • This embodiment has the advantage of encouraging fibrosis and fixation of the breast implant into the anatomical location into which it was placed (preventing implant migration), while preventing the complications associated with encapsulation on the superficial aspects of the breast implant.
  • agents that promote fibrosis and are suitable for delivery from the inferior (deep) surface of the breast implant include silk, wool, silica, bleomycin, neomycin, talcum powder, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, cytokines (e.g., wherein the cytokine is selected from the group consisting of bone morphogenic proteins, demineralized bone matrix, TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-1, IL-1- ⁇ , IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (e.g., wherein the agent that stimulates cell proliferation is selected from the group consisting of dexamethasone, isotretinoin, 17- ⁇ -estradiol, estradiol, 1- ⁇ -25 dihydroxyvitamin D 3, diethylstibesterol, cyclosporine A, N(
  • a composition that includes a fibrosis-inducing agent can be infiltrated into the space (the base of the surgically created pocket) where the breast implant will be apposed to the underlying tissue.
  • the breast implant may include a fibrosis- inhibiting agent and/or an anti-microbial agent.
  • Evidence of infection particularly from skin flora such as S. aureus and S. epidermidis, is a common histological finding in cases of capsular contracture. Overt implant infection (occurs in about 1-4% of cases) resulting from wound infections, contaminated saline in the implant, contamination of the breast implant at the time of surgical implantation and other causes necessitates the removal of the implant.
  • an anti-microbial agent e.g., antibiotics, micocycline, rifamycin, 5- FU, methotrexate, mitoxantrone, doxorubicin
  • Delivery of an anti-microbial agent may reduce the incidence of breast implant infections and help prevent the formation of infection-induced capsular contracture.
  • an anti-microbial agent e.g., antibiotics, micocycline, rifamycin, 5- FU, methotrexate, mitoxantrone, doxorubicin
  • analogues and derivatives thereof have the added benefit of also preventing fibrosis (as described herein).
  • embodiments of the present invention will create a breast implant with improved clinical outcomes and a lower incidence of common complications of breast augmentation surgery.
  • Administration of a fibros ⁇ s-inhibitor can reduce the incidence of capsular contracture, asymmetry, skin dimpling, hardness and repeat surgical interventions (e.g., capsulotomy, capsulectomy, revisions, and removal) and improve patient satisfaction with the procedure.
  • Administration of a fibrosis-inducing agent can reduce the incidence of migration, asymmetry and repeat surgical interventions (e.g., revisions and removal) and improve patient satisfaction.
  • administration of an anti- infective agent can reduce the incidence of infection and capsular contracture.
  • the soft tissue implant is a facial implant, including implants for the malar-midface region or submalar region (e.g., cheek implant).
  • Malar and submalar augmentation is often conducted when obvious changes have occurred associated with aging (e.g., hollowing of the cheeks and ptosis of the midfacial soft tissue), midface hypoplasia (a dish-face deformity), posttraumatic and post-tumor resection deformities, and mild hemifacial microsomia. Malar and submalar augmentation may also be conducted for cosmetic purposes to provide a dramatic high and sharp cheek contour. Placement of a malar-submalar implant often enhances the result of a rhytidectomy or rhinoplasty by further improving facial balance and harmony.
  • the facial implant may be a thin teardrop-shaped profile with a broad head and a tapered narrow tail for the mid- facial or submalar region of the face to restore and soften the fullness of the cheeks. See, e.g., U.S. Patent No. 4,969,901.
  • the facial implant may be composed of a flexible material having a generally concave-curved lower surface and a convex-curved upper surface, which is used to augment the submalar region. See, e.g., U.S. Patent No. 5,421 ,831.
  • the facial implant may be a modular prosthesis composed of a thin planar shell and shims that provide the desired contour to the overlying tissue.
  • the facial implant may be composed of moldable silicone having a grid of horizontal and vertical grooves on a concave bone-facing rear surface to facilitate tissue ingrowth. See, e.g., U.S. Patent No. 5,876,447.
  • the facial implant may be composed of a closed-cell, cross-linked, polyethylene foam that is formed into a shell and of a shape to closely conform to the face of a human. See, e.g., U.S. Patent No. 4,920,580.
  • the facial implant may be a means of harvesting a dermis plug from the skin of the donor after applying a laser beam for ablating the epidermal layer of the skin thereby exposing the dermis and then inserting this dermis plug at a site of facial skin depression. See, e.g., U.S. Patent No. 5,817,090.
  • the facial implant may be composed of silicone- elastomer with an open-cell structure whereby the silicone elastomer is applied to the surface as a solid before the layer is cured. See, e.g., U.S. Patent No. 5,007,929.
  • the facial implant may be a hollow perforate mandibular or maxillary dental implant composed of a trans osseous bolt receptor that is secured against the alveolar ridge by contiguous straps. See, e.g., U.S. Patent No. 4,828,492.
  • facial implants suitable for the practice of this invention include: Tissue Technologies, Inc. (San Francisco, CA) sells the ULTRASOFT-RC Facial Implant which is made of soft, pliable synthetic e-PTFE used for soft tissue augmentation of the face. Tissue Technologies, Inc. also sells the ULTRASOFT, which is made of tubular e-PTFE indicated for soft tissue augmentation of the facial area and is particularly well suited for use in the lip border and the nasolabial folds.
  • a variety of facial implants are available from ImplanTech Associates including the BINDER SUBMALAR facial implant, the BINDER SUBMALAR Il FACIAL IMPLANT, the TERINO MALAR SHELL, the COMBINED SUBMALAR SHELL, the FLOWERS TEAR TROUGH implant; solid silicone facial and malar implants from Allied Biomedical; the Subcutaneous Augmentation Material (S.A.M.), made from microporous ePTFE which supports rapid tissue incorporation and preformed TRIMENSIONAL 3-D Implants from W. L. Gore & Associates, Inc.
  • S.A.M. Subcutaneous Augmentation Material
  • Facial implants such as these may benefit from release of a therapeutic agent able to reduce scarring at the implant-tissue interface to minimize the occurrence of fibrous contracture.
  • Incorporation of a fibrosis- inhibiting agent into or onto a facial implant e.g., as a coating applied to the surface, incorporated into the pores of a porous implant, incorporated into the implant, incorporated into the polymers that compose the outer capsule of the implant and/or incorporated into the polymers that compose the inner portions of the implant
  • the fibrosis-inhibiting agent can reduce the incidence of capsular contracture, asymmetry, skin dimpling, hardness and repeat surgical interventions (e.g., capsulotomy, capsulectomy, revisions, and removal) and improve patient satisfaction with the procedure.
  • a composition that includes an anti-scarring agent can be infiltrated into the space where the implant will be surgically implanted.
  • the implant must be accurately positioned within the body. Facial implants can migrate following surgery and it is important to achieve attachment of the implant to the underlying periosteum and bone tissue.
  • Facial implants have been described that have a grid of horizontal and vertical grooves on a concave bone-facing rear surface to facilitate tissue ingrowth.
  • the facial implant is coated on one aspect with a composition which inhibits fibrosis, as well as being coated with a composition or compound which promotes scarring on another aspect of the device (i.e., to affix the facial implant to the underlying bone).
  • Facial implant malposition movement or migration of the implant after placement
  • the facial implant is coated on the inferior surface (i.e., the surface facing the periosteum and bone) with a fibrosis-inducing agent or composition, and coated on the other surfaces (i.e., the surfaces facing the skin and subcutaneous tissues) with an agent or composition that inhibits fibrosis.
  • a fibrosis-inducing agent or composition i.e., the surface facing the periosteum and bone
  • the other surfaces i.e., the surfaces facing the skin and subcutaneous tissues
  • agents that promote fibrosis and are suitable for delivery from the inferior (deep) surface of the facial implant include silk, wool, silica, bleomycin, neomycin, talcum powder, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, cytokines (e.g., wherein the cytokine is selected from the group consisting of bone morphogenic proteins, demineralized bone matrix, TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-1 , IL-1- ⁇ , IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (e.g., wherein the agent that stimulates cell proliferation is selected from the group consisting of dexamethasone, isotretinoin, 17- ⁇ -estradiol, estradiol, 1- ⁇ -25 dihydroxyvitamin D 3 , diethylstibesterol, cyclosporine A
  • a composition that includes a fibrosis-inducing agent can be infiltrated onto the surface or space (e.g., the surface of the periosteum) where the facial implant will be apposed to the underlying tissue.
  • the facial implant may include a fibrosis- inhibiting agent and/or an anti-microbial agent.
  • Delivery of an anti-microbial agent e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • an anti-microbial agent e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • an anti-microbial agent e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • Four of the above agents (5-FU, methotrexate, mitoxantrone, doxorubicin) have the added benefit of also preventing fibrosis (as are described herein).
  • the soft tissue implant is a chin or mandibular implant. Incorporation of a fibrosis-inhibiting agent into or onto the chin or mandibular implant, or infiltration of the agent into the tissue around a chin or mandibular implant, may minimize or prevent fibrous contracture in response to implants placed for cosmetic or reconstructive purposes.
  • the chin implant may be a solid, crescent-shaped implant tapering bilaterally to form respective tails and having a curved projection surface positioned on the outer mandible surface to create a natural chin profile and form a build-up of the jaw. See, e.g., U.S. Patent No. 4,344,191.
  • the chin implant may be a solid crescent with an axis of symmetry of forty-five degrees, which has a softer, lower durometer material at the point of the chin to simulate the fat pad. See, e.g., U.S. Patent No. 5,195,951.
  • the chin implant may have a concave posterior surface to cooperate with the irregular bony surface of the mandible and a convex anterior surface with a protuberance for augmenting and providing a natural chin contour. See, e.g., U.S. Patent No. 4,990,160.
  • the chin implant may have a porous convex surface made of polytetrafluoroethylene having void spaces of size adequate to allow soft tissue ingrowth, while the concave surface made of silicone is nonporous to substantially prevent ingrowth of bony tissue. See, e.g., U.S. Patent No. 6,277,150.
  • chin or mandibular implants examples include: the TERINO EXTENDED ANATOMICAL chin implant, the GLASGOLD WAFER, the FLOWERS MANDIBULAR GLOVE, MITTELMAN PRE JOWL- CHIN, GLASGOLD WAFER implants, as well as other models from ImplantTech Associates; and the solid silicone chin implants from Allied Biomedical.
  • a fibrosis-inhibiting agent into or onto a chin or mandibular implant (mandibular implant (e.g., as a coating applied to the surface, incorporated into the pores of a porous implant, incorporated into the implant, incorporated into the polymers that compose the outer capsule of the implant and/or incorporated into the polymers that compose the inner portions of the implant) may minimize or prevent fibrous contracture in response to implants that are placed in the chin or mandible for cosmetic or reconstructive purposes.
  • mandibular implant e.g., as a coating applied to the surface, incorporated into the pores of a porous implant, incorporated into the implant, incorporated into the polymers that compose the outer capsule of the implant and/or incorporated into the polymers that compose the inner portions of the implant
  • the fibrosis-inhibiting agent can reduce the incidence of capsular contracture, asymmetry, skin dimpling, hardness and repeat surgical interventions (e.g., capsulotomy, capsulectomy, revisions, and removal) and improve patient satisfaction with the procedure.
  • a composition that includes an anti-scarring agent can be infiltrated into the space where the implant will be implanted.
  • a chin or mandibular implant for a chin or mandibular implant to be effective in cosmetic or reconstructive procedures, the implant must be accurately positioned on the face. Chin or mandibular implants can migrate following surgery and it is important to achieve attachment of the implant to the underlying periosteum and bone tissue. Chin or mandibular implant malposition (movement or migration of the implant after placement) can lead to asymmetry and is a leading cause of patient dissatisfaction and revision surgery.
  • the chin or mandibular implant is coated on one aspect with a composition which inhibits fibrosis, as well as being coated with a composition or compound which promotes scarring (or fibrosis) on another aspect of the device (i.e., to affix the implant to the underlying mandible).
  • the chin or mandibular implant is coated on the inferior surface (i.e., the surface facing the periosteum and the mandible) with a fibrosis-inducing agent or composition, and coated on the other surfaces (i.e., the surfaces facing the skin and subcutaneous tissues) with an agent or composition that inhibits fibrosis.
  • This embodiment has the advantage of encouraging fibrosis and fixation of the chin or mandibular implant to the underlying mandible (preventing implant migration), while preventing the complications associated with encapsulation on the superficial aspects of the implant.
  • agents that promote fibrosis and are suitable for delivery from the inferior (deep) surface of the chin or mandibular implant include silk, wool, silica, bleomycin, neomycin, talcum powder, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, inflammatory cytokines (e.g., wherein the inflammatory cytokine is selected from the group consisting of bone morphogenic proteins, demineralized bone matrix, TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-1 , IL-1- ⁇ , IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (e.g., wherein the agent
  • a composition that includes a fibrosis-inducing agent can be infiltrated onto the surface or space (e.g., the surface of the periosteum) where the implant will be apposed to the underlying tissue.
  • the chin or mandibular implant may include a fibrosis-inhibiting agent and/or an anti-microbial agent.
  • Delivery of an anti-microbial agent e.g., antibiotics, minocycline, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • an anti-microbial agent e.g., antibiotics, minocycline, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • an anti-microbial agent e.g., antibiotics, minocycline, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • Four of the above agents (5- FU, methotrexate, mitoxantrone, doxorubicin) have the added benefit of also preventing fibrosis (as described herein).
  • the soft tissue implant for use in the practice of the invention is a nasal implant. Incorporation of a fibrosis-inhibiting agent into or onto the nasal implant, or infiltration of the agent into the tissue around a nasal implant, may minimize or prevent fibrous contracture in response to implants placed for cosmetic or reconstructive purposes.
  • the nasal implant may be elongated and contoured with a concave surface on a selected side to define a dorsal support end that is adapted to be positioned over the nasal dorsum to augment the frontal and profile views of the nose.
  • the nasal implant may be composed of substantially hard-grade silicone configured in the form of an hourglass with soft silicone at the tip. See, e.g., U.S. Patent No. 5,030,232.
  • the nasal implant may be composed of essentially a principal component being an aryl acrylic hydrophobic monomer with the remainder of the material being a cross-linking monomer and optionally one or more additional components selected from the group consisting of UV-light absorbing compounds and blue- light absorbing compounds. See, e.g., U.S. Patent No. 6,528,602.
  • the nasal implant may be composed of a hydrophilic synthetic cartilaginous material with pores of controlled size randomly distributed throughout the body for replacement of fibrous tissue. See, e.g., U.S. Patent No. 4,912,141.
  • Nasal implants such as these may benefit from release of a therapeutic agent able to reduce scarring at the implant-tissue interface to minimize the occurrence of fibrous contracture.
  • Incorporation of a fibrosis- inhibiting agent into or onto a nasal implant e.g., as a coating applied to the surface, incorporated into the pores of a porous implant, incorporated into the implant, incorporated into the polymers that compose the outer capsule of the implant and/or incorporated into the polymers that compose the inner portions of the implant
  • the fibrosis-inhibiting agent can reduce the incidence of capsular contracture, asymmetry, skin dimpling, hardness and repeat surgical interventions (e.g., capsulotomy, capsulectomy, revisions, and removal) and improve patient satisfaction with the procedure.
  • a composition that includes an anti-scarring agent can be infiltrated into the space where the implant will be implanted.
  • the implant must be accurately positioned on the face.
  • Nasal implants can migrate following surgery and it is important to achieve attachment of the implant to the underlying cartilage and/or bone tissue in the nose.
  • Nasal implant malposition movement or migration of the implant after placement
  • the nasal implant is coated on one aspect with a composition which inhibits fibrosis, as well as being coated with a composition or compound which promotes scarring on another aspect of the device (i.e., to affix the implant to the underlying cartilage or bone of the nose).
  • the nasal implant is coated on the inferior surface (i.e., the surface facing the nasal cartilage and/or bone) with a fibrosis-inducing agent or composition, and coated on the other surfaces (i.e., the surfaces facing the skin and subcutaneous tissues) with an agent or composition that inhibits fibrosis.
  • a fibrosis-inducing agent or composition coated on the other surfaces (i.e., the surfaces facing the skin and subcutaneous tissues) with an agent or composition that inhibits fibrosis.
  • agents that promote fibrosis and are suitable for delivery from the inferior (deep) surface of the nasal implant include silk, wool, silica, bleomycin, neomycin, talcum powder, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, inflammatory cytokines (e.g., wherein the inflammatory cytokine is selected from the group consisting of bone morphogenic proteins, demineralized bone matrix, TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-1 , IL-1- ⁇ , IL-S, IL-6, and growth hormone), agents that stimulate cell proliferation (e.g., wherein the agent that stimulates cell proliferation is selected from the group consisting of dexamethasone, isotretinoin, 17- ⁇ -estradiol, estradiol, 1- ⁇ -25 dihydroxyvitamin D 3, diethylstibesterol, cyclo
  • a composition that includes a fibrosis-inducing agent can be infiltrated onto the surface or space (e.g., the surface of the nasal cartilage or bone) where the implant will be apposed to the underlying tissue.
  • the nasal implant may include a fibrosis- inhibiting agent and/or an anti-microbial agent.
  • Delivery of an anti-microbial agent e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • an anti-microbial agent e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • an anti-microbial agent e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • Four of the above agents (5-FU, methotrexate, mitoxantrone, doxorubicin) have the added benefit of also preventing fibrosis (as will be described herein).
  • the soft tissue implant suitable for combining with a fibrosis-inhibiting agent is a lip implant. Incorporation of a fibrosis-inhibiting agent into or onto the lip implant, or infiltration of the agent into the tissue around a lip implant, may minimize or prevent fibrous contracture in response to implants placed for cosmetic or reconstructive purposes.
  • the lip implant may be composed of non-biodegradable expanded, fibrillated polytetrafluoroethylene having an interior cavity extending longitudinally whereby fibrous tissue ingrowth may occur to provide soft tissue augmentation.
  • the lip implant may comprise soft, malleable, elastic, non-resorbing prosthetic particles that have a rough, irregular surface texture, which are dispersed in a non-retentive compatible physiological vehicle. See, e.g., U.S. Patent No. 5,571,182.
  • lip implants suitable for use in the present invention include SOFTFORM from Tissue Technologies, Inc. (San Francisco, CA), which has a tube-shaped design made of synthetic ePTFE; ALLODERM sheets (Allograft Dermal Matrix Grafts), which are sold by LifeCell Corporation (Branchburg, NJ) may also be used as an implant to augment the lip. ALLODERM sheets are very soft and easily augment the lip in a diffuse manner. W. L. Gore and Associates (Newark, DE) sells solid implantable threads that may also be used for lip implants.
  • Lip implants such as these may benefit from release of a therapeutic agent able to reduce scarring at the implant-tissue interface to minimize the occurrence of fibrous contracture.
  • Incorporation of a fibrosis- inhibiting agent into or onto a lip implant e.g., as a coating applied to the surface, incorporated into the pores of a porous implant, incorporated into the implant, incorporated into the polymers that compose the outer capsule of the implant, incorporated into the threads or sheets that make up the lip implant and/or incorporated into the polymers that compose the inner portions of the implant
  • the fibrosis- inhibiting agent can reduce the incidence of asymmetry, skin dimpling, hardness and repeat interventions and improve patient satisfaction with the procedure.
  • a composition that includes an anti-scarring agent can be injected or infiltrated into the lips directly.
  • the lip implant is coated on one aspect with a composition that inhibits fibrosis, as well as being coated with a composition or compound that promotes fibrous tissue ingrowth on another aspect.
  • This embodiment has the advantage of encouraging fibrosis and fixation of the lip implant to the adjacent tissues, while preventing the complications associated with fibrous encapsulation on the superficial aspects of the implant.
  • agents that promote fibrosis and are suitable for delivery from the inferior (deep) surface of the lip implant include silk, wool, silica, bleomycin, neomycin, talcum powder, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, inflammatory cytokines (e.g., wherein the inflammatory cytokine is selected from the group consisting of bone morphogenic proteins, demineralized bone matrix, TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF 1 GM-CSF, IGF-1 , IL-1- ⁇ , IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (e.g., wherein the agent that stimulates cell proliferation is selected from the group consisting of dexamethasone, isotretinoin, 17- ⁇ -estradiol, estradiol, 1- ⁇ -25 dihydroxy vitamin D 3 , diethylstibesterol, cyclo
  • a composition that includes a fibrosis-inducing agent can be injected directly into the lip where the implant will be placed.
  • the lip implant may include a fibrosis- inhibiting agent and/or an anti-microbial agent. Delivery of an anti-microbial agent (e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin) as a coating, from the surface, from the implant, and/or injected into the surrounding tissue at the time of implantation, may reduce the incidence of lip implant infections.
  • an anti-microbial agent e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • the soft tissue implant suitable for combining with a fibrosis-inhibitor is a pectoral implant. Incorporation of a fibrosis-inhibiting agent into or onto the pectoral implant, or infiltration of the agent into the tissue around a lip implant, may minimize or prevent fibrous contracture in response to implants placed for cosmetic or reconstructive purposes.
  • the pectoral implant may be composed of a unitary rectangular body having a slightly concave cross-section that is divided by edges into sections. See, e.g., U.S. Patent No. 5,112,352.
  • the pectoral implant may be composed of a hollow shell formed of a flexible elastomeric envelope that is filled with a gel or viscous liquid containing polyacrylamide and derivatives of polyacrylamide. See, e.g., U.S. Patent No. 5,658,329.
  • pectoral implants suitable for use in the present invention include solid silicone implants from Allied Biomedical. Pectoral implants such as these may benefit from release of a therapeutic agent able to reduce scarring at the implant-tissue interface to minimize the incidence of fibrous contracture.
  • the pectoral implant is combined with a fibrosis-inhibiting agent or composition containing a fibrosis- inhibiting agent.
  • Ways that this can be accomplished include, but are not restricted to, incorporating a fibrosis-inhibiting agent into the polymer that composes the shell of the implant (e.g., the polymer that composes the capsule of the pectoral implant is loaded with an agent that is gradually released from the surface), surface-coating the pectoral implant with an anti-scarring agent or a composition that includes an anti-scarring agent, and/or incorporating the fibrosis-inhibiting agent into the implant filling material (saline, gel, silicone) such that it can diffuse across the capsule into the surrounding tissue.
  • a composition that includes an anti- scarring agent can be infiltrated into the space where the pectoral implant will be implanted.
  • the pectoral implant is coated on one aspect with a composition which inhibits fibrosis, as well as being coated with a composition or compound which promotes scarring on another aspect of the device (i.e., to affix the pectoral implant into the subpectoral space).
  • implant malposition movement or migration of the implant after placement
  • can lead to a variety of complications such as asymmetry, and is a leading cause of patient dissatisfaction and revision surgery.
  • the pectoral implant is coated on the inferior surface (Ae., the surface facing the chest wall) with a fibrosis-promoting agent or composition, and the coated on the other surfaces (i.e., the surfaces facing the pectoralis muscle) with an agent or composition that inhibits fibrosis.
  • This embodiment has the advantage of encouraging fibrosis and fixation of the pectoral implant into the anatomical location into which it was placed (preventing implant migration), while preventing the complications associated with encapsulation on the superficial aspects of the pectoral implant.
  • agents that promote fibrosis and are suitable for delivery from the inferior (deep) surface of the pectoral implant include silk, wool, silica, bleomycin, neomycin, talcum powder, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, cytokines (e.g., wherein the cytokine is selected from the group consisting of bone morphogenic proteins, demineralized bone matrix, TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-1, IL-1- ⁇ , IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (e.g., wherein the agent that stimulates cell proliferation is selected from the group consisting of dexamethasone, isotretinoin, 17- ⁇ -estradiol, estradiol, 1- ⁇ -25 dihydroxyvitamin D 3 , diethylstibesterol, cyclosporine
  • a composition that includes a fibrosis-inducing agent can be infiltrated into the space (the base of the surgically created subpectoral pocket) where the pectoral implant will be apposed to the underlying tissue.
  • the pectoral implant may include a fibrosis-inhibiting agent and/or an anti-microbial agent.
  • an antimicrobial agent e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • Delivery of an antimicrobial agent may reduce the incidence of pectoral implant infections and help prevent the formation of infection-induced capsular contracture.
  • an antimicrobial agent e.g., antibiotics, 5-FU, methotrexate, mitoxantrone, doxorubicin
  • analogues and derivatives thereof have the added benefit of also preventing fibrosis (as will be described herein).
  • the soft tissue implant suitable for use with a fibrosis-inhibitor is an autogenous tissue implant, which includes, without limitation, adipose tissue, autogenous fat implants, dermal implants, dermal or tissue plugs, muscular tissue flaps and cell extraction implants.
  • Adipose tissue implants may also be known as autogenous fat implants, fat grafting, free fat transfer, autologous fat transfer/transplantation, dermal fat implants, liposculpture, lipostructure, volume restoration, micro-lipoinjection and fat injections.
  • Autogenous tissue implants have been used for decades for soft tissue augmentation in plastic and reconstructive surgery.
  • Autogenous tissue implants may be used, for example, to enlarge a soft tissue site (e.g., breast or penile augmentation), to minimize facial scarring (e.g., acne scars), to improve facial volume in diseases (e.g., hemifacial atrophy), and to minimize facial aging, such as sunken cheeks and facial lines (e.g., wrinkles).
  • These injectable autogenous tissue implants are biocompatible, versatile, stable, long-lasting and natural-appearing.
  • Autogenous tissue implants involve a simple procedure of removing tissue or cells from one area of the body (e.g., surplus fat cells from abdomen or thighs) and then re-implanted them in another area of the body that requires reconstruction or augmentation.
  • Autogenous tissue is soft and feels natural.
  • Autogenous soft tissue implants may be composed of a variety of connective tissues, including, without limitation, adipose or fat, dermal tissue, fibroblast cells, muscular tissue or other connective tissues and associated cells.
  • An autogenous tissue implant is introduced to correct a variety of deficiencies, it is not immunogenic, and it is readily available and inexpensive.
  • autogenous tissue implants may be composed of fat or adipose.
  • adipose tissue involves the aspiration of fat from the subcutaneous layer, usually of the abdominal wall by means of a suction syringe, and then injected it into the subcutaneous tissues overlying a depression.
  • Autologous fat is commonly used as filler for depressions of the body surface (e.g., for bodily defects or cosmetic purposes), or it may be used to protect other tissue (e.g., protection of the nerve root following surgery).
  • Fat grafts may also be used for body prominences that require padding of soft tissue to prevent sensitivity to pressure.
  • fat padding When fat padding is lacking, the overlying skin may be adherent to the bone, leading to discomfort and even pain, which occurs, for example, when a heel spur or bony projection occurs on the plantar region of the heel bone (also known as the calcaneous).
  • fat grafting may provide the interposition of the necessary padding between the bone and the skin.
  • U.S. Patent No. 5,681,561 describes, for example, an autogenous fat graft that includes an anabolic hormone, amino acids, vitamins, and inorganic ions to improve the survival rate of the lipocytes once implanted into the body.
  • autogenous tissue implants may be composed of pedicle flaps that typically originate from the back (e.g., latissimus dorsi myocutaneous flap) or the abdomen (e.g., transverse rectus abdominus myocutaneous or TRAM flap).
  • Pedicle flaps may also come from the buttocks, thigh or groin. These flaps are detached from the body and then transplanted by reattaching blood vessels using microsurgical procedures. These muscular tissue flaps are most frequently used for post-mastectomy closure and reconstruction.
  • Some other common closure applications for muscular tissue flaps include coverage of defects in the head and neck area, especially defects created from major head and neck cancer resection; additional applications include coverage of chest wall defects other than mastectomy deformities.
  • the latissimus dorsi may also be used as a reverse flap, based upon its lumbar perforators, to close congenital defects of the spine such as spina bifida or meningomyelocele.
  • U.S. Patent No. 5,765,567 describes methodology of using an autogenous tissue implant in the form of a tissue flap having a cutaneous skin island that may be used for contour correction and enlargement for the reconstruction of breast tissue.
  • the tissue flap may be a free flap or a flap attached via a native vascular pedicle.
  • the autogenous tissue implant may be a suspension of autologous dermal fibroblasts that may be used to provide cosmetic augmentation.
  • a suspension of autologous dermal fibroblasts that may be used to provide cosmetic augmentation.
  • Typical defects that can be corrected by this method include rhytids, stretch marks, depressed scars, cutaneous depressions of non-traumatic origin, scaring from acne vulgaris, and hypoplasia of the lip.
  • the fibroblasts that are injected are histocompatible with the subject and have been expanded by passage in a cell culture system for a period of time in protein free medium.
  • the autogenous tissue implant may be a dermis plug harvested from the skin of the donor after applying a laser beam for ablating the epidermal layer of the skin thereby exposing the dermis and then inserting this dermis plug at a site of facial skin depressions.
  • This autogenous tissue implant may be used to treat facial skin depressions, such as acne scar depression and rhytides.
  • Dermal grafts have also been used for correction of cutaneous depressions where the epidermis is removed by dermabrasion.
  • autogenous tissue implants also have a tendency to migrate, extrude, become infected, or cause painful and deforming capsular contractures. Incorporation of a fibrosis-inhibiting agent into or onto an autogenous tissue implant may minimize or prevent fibrous contracture in response to autogenous tissue implants that are placed in the body for cosmetic or reconstructive purposes.
  • the implant includes, or is coated with, an anti-scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti-scarring agent can be injected or infiltrated into the space where the implant will be implanted.
  • Soft tissue implants that release a therapeutic agent for reducing scarring at the implant-tissue interface can be used to increase the efficacy and/or the duration of activity of the implant (particularly for fully-implanted, battery-powered devices).
  • the present invention provides soft tissue implants that include an anti-scarring agent or a composition that includes an anti-scarring agent. Numerous polymeric and non-polymeric delivery systems for use in soft tissue implants have been described above. These compositions can further include one or more fibrosis-inhibiting agents such that the overgrowth of granulation or fibrous tissue is inhibited or reduced.
  • therapeutic agents are potentially suitable to prevent fibrous tissue accumulation around soft tissue implants. These therapeutic agents can be used alone, or in combination, to prevent scar tissue build-up in the vicinity of the implant-tissue interface in order to improve the clinical performance and longevity of these implants. Such agents may be readily identified based upon in vitro and in vivo (animal) models, such as those provided in Examples 19-29, 31 , and 41. Agents that inhibit fibrosis can also be identified through in vivo models including inhibition of intimal hyperplasia development in the rat balloon carotid artery model (Examples 22 and 31). The assays set forth in Examples 21 and 29 may be used to determine whether an agent is able to inhibit cell proliferation in fibroblasts and/or smooth muscle cells.
  • the agent has an IC 50 for inhibition of cell proliferation within a range of about 10 "6 to about 10 "10 M. In certain embodiments, the agent may have an IC 50 for inhibition of cell proliferation of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM.
  • the assay set forth in Example 25 may be used to determine whether an agent may inhibit migration of fibroblasts and/or smooth muscle cells.
  • the agent has an IC 50 for inhibition of cell migration within a range of about 10 "6 to about 10 "9 M. In one aspect of the invention, the agent has an IC 50 for inhibition of cell migration within a range of about 10 "6 to about 10 "9 M.
  • the agent may have an IC 50 for inhibition of fibroblast or smooth muscle cell migration of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM.
  • Assays set forth herein may be used to determine whether an agent is able to inhibit inflammatory processes, including nitric oxide production in macrophages (Example 19), and/or TNF-alpha production by macrophages (Example 20), and/or IL-1 beta production by macrophages (Example 26), and/or IL-8 production by macrophages (Example 27), and/or inhibition of MCP-1 by macrophages (Example 28).
  • the agent has an IC 50 for inhibition of any one of these inflammatory processes within a range of about 10 "6 to about 10 "10 M. In certain embodiments, the agent may have an IC 50 for any one of these inflammatory processes of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM.
  • the assay set forth in Example 23 may be used to determine whether an agent is able to inhibit MMP production. In one aspect of the invention, the agent has an IC 50 for inhibition of MMP production within a range of about 10 "4 to about 10 "8 M.
  • the agent may have an IC 50 for inhibition of MMP production of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM.
  • the assay set forth in Example 24 (also known as the CAM assay) may be used to determine whether an agent is able to inhibit angiogenesis.
  • the agent has an IC 5 0 for inhibition of angiogenesis within a range of about 10 "6 to about 10 "10 M.
  • the agent may have an IC 50 for inhibition of angiogenesis of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM.
  • the assay set forth in Example 44 may be used to determine whether an agent is able to inhibit MMP-1.
  • the agent has an IC50 for inhibition of MMP-1 within a range of about 10 "6 to about 10 "10 M.
  • the agent may have an IC 50 for inhibition of MMP-1 of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM.
  • an agent which is useful for the compositions and methods described herein may exhibit different levels of effectiveness in different assays (e.g., effectiveness indicated by IC 50 values) and in different animal models described herein and practiced in the art.
  • an agent that is useful may exhibit activity in one assay or animal model or may exhibit activity in more than one, two, or three, etc., different assays and/or animal models.
  • Agents that reduce the formation of surgical adhesions may be identified through in vivo models including the rabbit surgical adhesions model and the rat caecal sidewall model. These pharmacologically active agents (described herein) can be delivered at appropriate dosages (described herein) into to the tissue either alone, or via carriers (formulations are described herein), to treat the clinical problems described previously (described herein).
  • Numerous therapeutic compounds may be identified as useful in the present invention including:
  • the fibrosis-inhibiting compound is an adensosine A2A receptor antagonist (e.g., Sch-63390 (Schering-Plough) or an A2A receptor antagonists from Almirall-Prodesfarma, SCH-58261 (CAS No. 160098-96-4), or an analogue or derivative thereof).
  • an adensosine A2A receptor antagonist e.g., Sch-63390 (Schering-Plough) or an A2A receptor antagonists from Almirall-Prodesfarma, SCH-58261 (CAS No. 160098-96-4), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an
  • AKT inhibitor e.g., PKB inhibitors from DeveloGen, AKT inhibitors from Array BioPharma, Celgene, Merck & Co, Amphora, NeoGenesis Pharmaceuticals, A- 443654 (Abbott Laboratories), erucylphosphocholine (AEterna Zentaris), KRX- 401 (Keryx), protein kinase B inhibitors from Astex Technology, PX-316 (ProlX), or an analogue or derivative thereof).
  • PKB inhibitors from DeveloGen AKT inhibitors from Array BioPharma, Celgene, Merck & Co, Amphora, NeoGenesis Pharmaceuticals, A- 443654 (Abbott Laboratories), erucylphosphocholine (AEterna Zentaris), KRX- 401 (Keryx), protein kinase B inhibitors from Astex Technology, PX-316 (ProlX), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an alpha 2 integrin antagonist (e.g., Pharmaprojects No. 5754 (Merck KGaA), or an analogue or derivative thereof).
  • an alpha 2 integrin antagonist e.g., Pharmaprojects No. 5754 (Merck KGaA), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an alpha 4 integrin antagonist (e.g., T-0047 (Tanabe Seiyaku), VLA-4 antagonists from Sanofi-Aventis, Merck & Co., Biogen personal, Uriach, and Molecumetics, alpha 4 integrin antagonists from Genentech), BIO-2421 (Biogen personal), cell adhesion inhibitors from Kaken Pharmaceuticals, CT-737 (Wyeth), CT-767 (Elan), CY-9652 (Epimmune), CY-9701 (Epimmune), fibronectin antagonists from Uriach, integrin alpha4 ⁇ 7 antagonists frin Wilex, Pharmaprojects No.
  • alpha 4 integrin antagonist e.g., T-0047 (Tanabe Seiyaku), VLA-4 antagonists from Sanofi-Aventis, Merck & Co., Biogen personal, and Molecumetics, alpha 4 integrin antagonists from Genentech), BIO
  • the fibrosis-inhibiting compound is an alpha 7 nicotinic receptor agonist (e.g., AZD-0328 (AstraZeneca), galantamine (CAS No. 357-70-0) (Synaptc), MEM-3454 or nicotinic alpha-7 agonist (Memory Pharmaceuticals and Critical Therapeutics), Pharmaprojects No. 4779 (AstraZeneca), PNU-282987 (Pfizer), SSR-180711 (Sanofi-Aventis), TC-1698 or TC-5280 (Targacept), or an analogue or derivative thereof).
  • Angiogenesis Inhibitors e.g., AZD-0328 (AstraZeneca), galantamine (CAS No. 357-70-0) (Synaptc), MEM-3454 or nicotinic alpha-7 agonist (Memory Pharmaceuticals and Critical Therapeutics), Pharmaprojects No. 4779 (AstraZeneca), PNU-282987
  • the fibrosis-inhibiting compound is an angiogenesis inhibitor (e.g., AG-12,958 (Pfizer), ATN-161 (Attention LLC), neovastat, an angiogenesis inhibitor from Jerina AG (Germany), NM-3 (Mercian), VGA-1155 (Taisho), FCE-26644 (Pfizer), FCE-26950 (Pfizer), FPMA (Meiji Daries), FR-111142 (Fujisawa), GGTI-298, GM-1306 (Ligand), GPA-1734 (Novartis), NNC-47-0011 (Novo Nordisk), herbamycin (Nippon Kayaku), lenalidomide (Celegene), IP-10 (NlH), ABT-828 (Abbott), KIN-841 (Tokushima University, Japan), SF-1126 (Semafore Pharmaceuticals), laminin technology (NIH), CHIR-258 (Chiron), NVP-AEW541 (Novar
  • the fibrosis-inhibiting compound is an apoptosis antagonist (e.g., didemnin B, RGB-286199 (GPC Biotech), 5F-DF- 203 (Cancer Research Technology), aplidine, bongkrekic acid, triammonium salt, [6]-gingerol (CAS No. 23513-14-6), or an analogue or derivative thereof).
  • apoptosis antagonist e.g., didemnin B, RGB-286199 (GPC Biotech), 5F-DF- 203 (Cancer Research Technology), aplidine, bongkrekic acid, triammonium salt, [6]-gingerol (CAS No. 23513-14-6), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an apoptosis activator (e.g., aplidine (CAS No. 137219-37-5) (PharmaMar), canfosfamide hydrochloride (CAS No. 58382-37-74 and 39943-59-6) (Telik), idronoxil (CAS No.
  • apoptosis activator e.g., aplidine (CAS No. 137219-37-5) (PharmaMar), canfosfamide hydrochloride (CAS No. 58382-37-74 and 39943-59-6) (Telik), idronoxil (CAS No.
  • Beta 1 lntegrin Antagonist in another embodiment, is a beta
  • Beta Tubulin Inhibitor e.g., ⁇ -1 integrin antagonists, Berkeley Lab, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a beta tubulin inhibitor (e.g., ZEN-017 (AEterna Zentaris), laulimalide (Kosan Biosciences), or an analogue or derivative thereof).
  • a beta tubulin inhibitor e.g., ZEN-017 (AEterna Zentaris), laulimalide (Kosan Biosciences), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an agent that blocks enzyme production in hepatitis C (e.g., merimepodib (Vertex Pharmaceuticals), or an analogue or derivative thereof).
  • hepatitis C e.g., merimepodib (Vertex Pharmaceuticals), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a
  • Bruton's tyrosine kinase inhibitor e.g., a Btk inhibitor from Cellular Genomics, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a calcineurin inhibitor (e.g., tacrolimus (LifeCycle Pharma), or an analogue or derivative thereof).
  • a calcineurin inhibitor e.g., tacrolimus (LifeCycle Pharma)
  • analogue or derivative thereof e.g., tacrolimus (LifeCycle Pharma)
  • the fibrosis-inhibiting compound is a caspase 3 inhibitor (e.g., NM-3 (Mercian), or an analogue or derivative thereof).
  • a caspase 3 inhibitor e.g., NM-3 (Mercian), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a CC chemokine receptor antagonist (e.g., a chemokine receptor 3 antagonist, a chemokine receptor 6 antagonist, and a chemokine receptor 7 antagonist).
  • a CC chemokine receptor antagonist e.g., a chemokine receptor 3 antagonist, a chemokine receptor 6 antagonist, and a chemokine receptor 7 antagonist.
  • CC chemokine receptor antagonists include chemokine antagonists such as the CCR7 antagonists from Neurocrine
  • the fibrosis-inhibiting compound is a CC chemokine receptor antagonist (CCR) 1 , 3, & 5 (e.g., peptide T (Advanced lmmuni T), a CCR3 antagonist from GlaxoSmithKline, a chemokine antagonist (Pharmaprojects No. 6322) from Neurocrine Biosciences or Merck & Co., an " HIV therapy agent from ReceptoPharm (Nutra Pharma), Pharmaprojects No. 6129 (Sangamo BioSciences), or an analogue or derivative thereof).
  • CCR CC chemokine receptor antagonist
  • the CCCR antagonist is a CCR2b chemokine receptor antagonist such as RS 102895 (CAS No. 300815-41-2).
  • the fibrosis-inhibiting compound is a cell cycle inhibitor (e.g., SNS-595 (Sunesis), homoharringtonine, or an analogue or derivative thereof).
  • a cell cycle inhibitor e.g., SNS-595 (Sunesis), homoharringtonine, or an analogue or derivative thereof.
  • the cell cycle inhibitor is an anti- microtubule agent (e.g., synthadotin, or an analogue or derivative thereof).
  • cell cycle inhibitor is a microtubule stimulant (e.g., KRX-0403, or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a cathepsin B inhibitor (e.g., AM-4299A (Asahi Kasei Pharma), BDI-7800 (Biopharmacopae), a cathepsin B inhibitor from Axys (Celera Genomics), MDL- 104903 (CAS No. 180799-56-8) (Sanofi-Aventis), NC-700 (Nippon Chemiphar), Pharmaprojects No. 2332 (Hoffmann-La Roche), Pharmaprojects No. 4884 (Takeda), Pharmaprojects No. 5134 (Nippon Chemiphar), or an analogue or derivative thereof).
  • a cathepsin B inhibitor e.g., AM-4299A (Asahi Kasei Pharma), BDI-7800 (Biopharmacopae), a cathepsin B inhibitor from Axys (Celera Genomics), MDL- 104903 (CAS No. 180799-56-8) (
  • the fibrosis-inhibiting compound is a cathepsin K inhibitor (e.g., 462795 (GlaxoSmithKline), INPL-022-D6 (Amura Therapeutics), or an analogue or derivative thereof).
  • Cathepsin L Inhibitor e.g., 462795 (GlaxoSmithKline), INPL-022-D6 (Amura Therapeutics), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a cathepsin L Inhibitor (e.g., a cathepsin L inhibitor from Takeda, INPL-022-E10 (Amura Therapeutics), Pharmaprojects No. 5447 (Taiho), or an analogue or derivative thereof).
  • a cathepsin L Inhibitor e.g., a cathepsin L inhibitor from Takeda, INPL-022-E10 (Amura Therapeutics), Pharmaprojects No. 5447 (Taiho), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a CD40 antagonists (e.g., 5D12 (Chiron), ABI-793 (Novartis), an anticancer antibody from Chiron, anti-CD40 MAb-2 (Kirin Brewery), anti-CD40 (EIi Lilly), anti-CD40L antibody (UCB), a CD40 inhibitor from Apoxis, CD40 ligand inhibitor from Millennium Pharmaceuticals, a CD40/CAP inhibitor from Snow Brand, CGEN-40 (Compugen), CHIR-12.12 (Chiron), Pharmaprojects No.
  • CD40 antagonists e.g., 5D12 (Chiron), ABI-793 (Novartis), an anticancer antibody from Chiron, anti-CD40 MAb-2 (Kirin Brewery), anti-CD40 (EIi Lilly), anti-CD40L antibody (UCB), a CD40 inhibitor from Apoxis, CD40 ligand inhibitor from Millennium Pharmaceuticals, a CD40/CAP inhibitor from Snow Brand, CGEN-40 (Compugen
  • the fibrosis-inhibiting compound is a chemokine receptor agonist (e.g., a chemokine agonist from NeuroTarget, or an analogue or derivative thereof).
  • a chemokine receptor agonist e.g., a chemokine agonist from NeuroTarget, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a chymase inhibitor (e.g., BL-3875 (Dainippon), LEX-043 (SuperGen), NK-3201 (CAS No. 204460-24-2) (Nippon Kayaku), or an analogue or derivative thereof).
  • a chymase inhibitor e.g., BL-3875 (Dainippon), LEX-043 (SuperGen), NK-3201 (CAS No. 204460-24-2) (Nippon Kayaku), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a collagenase (interstitial) antagonist (e.g., IBFB-212543 (IBFB Pharma), Pharmaprojects No. 3762 (Sanofi-Aventis), S-0885 (CAS No. 117517-22-3) (Sanofi-Aventis), SC-40827 (CAS No. 101470-42-2) (Pfizer), or an analogue or derivative thereof).
  • IBFB-212543 IBFB Pharma
  • Pharmaprojects No. 3762 Sanofi-Aventis
  • S-0885 CAS No. 117517-22-3
  • SC-40827 CAS No. 101470-42-2
  • the fibrosis-inhibiting compound is a CXCR (2, 4) antagonist (e.g., SB-656933 (GlaxoSmithKline), AMD3100 octahydrochloride (CAS No. 155148-31-5), or an analogue or derivative thereof).
  • CXCR (2, 4) antagonist e.g., SB-656933 (GlaxoSmithKline), AMD3100 octahydrochloride (CAS No. 155148-31-5), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a cyclin dependent kinase (CDK) inhibitor.
  • the cyclin dependent kinase inhibitor is a CDK-1 inhibitor.
  • the cyclin dependent kinase inhibitor is a CDK-2 inhibitor.
  • the cyclin dependent kinase inhibitor is a CDK- 4 inhibitor.
  • the cyclin dependent kinase inhibitor is a CDK-6 inhibitor.
  • Representative examples of cyclin dependent kinase inhibitors include CAK1 inhibitors from GPC Biotech and Bristol-Myers Squibb, RGB-286199 (GPC Biotech), or an analogue or derivative thereof.
  • Additional exemplary cyclin dependent protein kinase inhibitors include an anticancer agent from Astex Technology, a CAK1 inhibitor from GPC Biotech, a CDK inhibitor from Sanofi-Aventis, a CDK1/CDK2 inhibitor from Astex Technology, a CAK1 inhibitor from GPC Biotech, a CDK inhibitor from Sanofi-Aventis, a CDK1/CDK2 inhibitor from Astex Technology, a CAK1 inhibitor from GPC Biotech, a CDK inhibitor from Sanofi-Aventis, a CDK1/CDK2 inhibitor from
  • the fibrosis-inhibiting compound is a cyclooxygenase inhibitor (e.g., NS-398 (CAS No. 123653-11-2), ketoprofen, or an analogue or derivative thereof).
  • the cyclooxygenase inhibitor is a COX-1 inhibitor such as triflusal, or an analogue or derivative thereof).
  • DHFR Dihydroorotate Dehydrogenase Inhibitor
  • DHFR inhibitor e.g., PDX (Allos Therapeutics), SC12267, sulfamerazine (CAS No. 127-79-7), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a dual integrin inhibitor (e.g., R411 (Roche Pharmaceuticals), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is an elastase inhibitor (e.g., orazipone, depelestat (CAS No. 506433-25-6) (Dyax), AE-3763 (Dainippon), or an analogue or derivative thereof).
  • elastase inhibitor e.g., orazipone, depelestat (CAS No. 506433-25-6) (Dyax), AE-3763 (Dainippon), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an elongation factor-1 alpha inhibitor (e.g., aplidine, or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is an endothelial growth factor (EGF) antagonist (e.g., neovastat, NM-3 (Mercian), or an analogue or derivative thereof).
  • EGF endothelial growth factor
  • the fibrosis-inhibiting compound is an endothelial growth factor receptor (EGF-R) kinase inhibitor (e.g., sorafenib tosylate (Bayer), AAL-993 (Novartis), ABP-309 (Novartis), BAY-57-9352 (Bayer), BIBF-1120 (Boehringer Ingelheim), E-7080 (Eisai), EG-3306 (Ark Therapeutics), EXEL-2880 (Exelixis), GW-654652 (GlaxoSmithKline), lavendustin A (CAS No.
  • EGF-R endothelial growth factor receptor
  • a KDR inhibitor from LG Life Sciences, CT-6685 or CT-6729 (UCB), KRN-633 or KRN-951 (Kirin Brewery), OSI-930 (OSI Pharmaceuticals), SP-5.2 (Supratek Pharma), SU-11657 (Pfizer), a Tie-2 antagonist (Hybrigenics), a VEGF-R inhibitor such as SU 1498, a VEGFR-2 kinase inhibitor (Bristol-Myers Squibb), XL-647 (Exelixis), a KDR inhibitor from Abbott Laboratories, or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is an endothelial growth factor receptor 2 kinase inhibitor (e.g., sorafenib tosylate, or an analogue or derivative thereof).
  • an endothelial growth factor receptor 2 kinase inhibitor e.g., sorafenib tosylate, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an endotoxin antagonist (e.g., E5564 (Eisai Pharmaceuticals), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is an epothilone or tubulin binder (e.g., ixabepilone (BMS), or an analogue or derivative thereof).
  • BMS ixabepilone
  • the fibrosis-inhibiting compound is an estrogen receptor antagonist (e.g., ERB-041 (Wyeth), or an analogue or derivative thereof). 36) FGF Inhibitors
  • the fibrosis-inhibiting compound is a FGF inhibitor (e.g., IDN-5390 (Indena), or an analogue or derivative thereof).
  • FGF inhibitor e.g., IDN-5390 (Indena), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an inhibitor of farnexyl transferase (FTI).
  • FTI farnexyl transferase
  • the FTI inhibits the RAS oncogene family.
  • FTI's include SARASAR (from Schering Corporation, Kenilworth, NJ), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a farnesyltransferase inhibitor (e.g., A-197574 (Abbott), a farnesyltransferase inhibitor from Servier, FPTIII (Strathclyde Institute for Drug R), LB-42908 (LG Life Sciences), Pharmaprojects No. 5063 (Genzyme), Pharmaprojects No. 5597 (Ipsen), Yissum Project No. B-1055 (Yissum), or an analogue or derivative thereof).
  • a farnesyltransferase inhibitor e.g., A-197574 (Abbott), a farnesyltransferase inhibitor from Servier, FPTIII (Strathclyde Institute for Drug R), LB-42908 (LG Life Sciences), Pharmaprojects No. 5063 (Genzyme), Pharmaprojects No. 5597 (Ipsen), Yissum Project No. B-1055 (Yissum), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a FLT- 3 kinase inhibitor (e.g., Amphora, or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a FGF receptor kinase inhibitor (e.g., MED-A300 (Gerolymatos), SSR-128129 (Sanofi- Aventis), TBC-2250 (Encysive Pharmaceuticals), XL-999 (Exelixis), or a FGF receptor kinase inhibitor from Paradigm Therapeutics, or an analogue or derivative thereof).
  • FGF receptor kinase inhibitor e.g., MED-A300 (Gerolymatos), SSR-128129 (Sanofi- Aventis), TBC-2250 (Encysive Pharmaceuticals), XL-999 (Exelixis), or a FGF receptor kinase inhibitor from Paradigm Therapeutics, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a fibrinogen antagonist (e.g., AUV-201 (Auvation), MG-13926 (Sanofi-Aventis), plasminogen activator (CAS No. 105913-11-9) (from Sanofi-Aventis or UCB), plasminogen activator-2 (tPA-2) (Sanofi-Aventis), pro-urokinase (CAS No.
  • AUV-201 Alvation
  • MG-13926 Sanofi-Aventis
  • plasminogen activator CAS No. 105913-11-9
  • tPA-2 plasminogen activator-2
  • pro-urokinase CAS No.
  • the fibrosis-inhibiting compound is a heat shock protein 90 antagonist (e.g., SRN-005 (Sirenade), geldanamycin or a derivative thereof, such as NSC-33050 (17-allylaminogeldanamycin; 17-AAG) or 17-dimethylaminoethylamino-17-demethoxy-geIdanamycin (17-DMAG), rifabutin (rifamycin XIV, 1',4-didehydro-1-deoxy-1 ,4-dihydro-5'-(2-methylpropyl)- 1-OXO-), radicicol, Humicola fuscoatra (CAS No. 12772-57-5), or an analogue or derivative thereof).
  • SRN-005 Serenade
  • geldanamycin or a derivative thereof such as NSC-33050 (17-allylaminogeldanamycin; 17-AAG) or 17-dimethylaminoethylamino-17-demeth
  • the fibrosis-inhibiting compound is a histone deacetylase inhibitor (e.g., FK228 (Gloucester), trichostatin A from Streptomyces sp. (CAS No. 58880-19-6), or an analogue or derivative thereof).
  • a histone deacetylase inhibitor e.g., FK228 (Gloucester), trichostatin A from Streptomyces sp. (CAS No. 58880-19-6), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an
  • HMGCoA reductase inhibitor e.g., an atherosclerosis therapeutic from Lipid Sciences, ATI-16000 (ARYx Therapeutics), KS-01-019 (Kos Pharmaceuticals), Pharmaprojects No. 2197 (Sanofi-Aventi), RP 61969 (Sanofi-Aventis), cerivastatin Na) CAS No. 143201-11-0), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is an ICAM inhibitor (e.g., alicaforsen (CAS No. 185229-68-9) (ISIS Pharmaceuticals), an ICAM-5 modulator (such as ICAM-4 from ICOS), or an analogue or derivative thereof).
  • ICAM inhibitor e.g., alicaforsen (CAS No. 185229-68-9) (ISIS Pharmaceuticals), an ICAM-5 modulator (such as ICAM-4 from ICOS), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an IL- 1 , ICE & IRAK antagonist (e.g., CJ-14877 or CP-424174 (Pfizer), NF-61 (Negma-Lerads), or an analogue or derivative thereof).
  • ICE & IRAK antagonist e.g., CJ-14877 or CP-424174 (Pfizer), NF-61 (Negma-Lerads), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an IL-2 inhibitor (e.g., AVE 8062 (Sanofi-Aventis), or an analogue or derivative thereof).
  • IL-2 inhibitor e.g., AVE 8062 (Sanofi-Aventis), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an immunosuppressant (e.g., teriflunomide (Sanofi Aventis), chlorsulfaquinoxalone (NSC-339004), chlorsulfaquinoxalone sulfate, CS-712 (Sankyo), ismomultin alfa (CAS No. 457913-93-8) (Akzo Nobel), antiallergics from GenPat77, anti- inflammatories or AT-005 (Androclus Therapeutics), autoimmune disease therapeutics from EpiVax, BN-007 (Bone), budesonide (CAS No.
  • an immunosuppressant e.g., teriflunomide (Sanofi Aventis), chlorsulfaquinoxalone (NSC-339004), chlorsulfaquinoxalone sulfate, CS-712 (Sankyo), ismomultin alfa (CAS No. 457913-93-8) (
  • the fibrosis-inhibiting compound is IMPDH (inosine monophosphate) (e.g., ribavirin (Hoffmann-La Roche) or an analogue or derivative thereof).
  • IMPDH inosine monophosphate
  • ribavirin Hoffmann-La Roche
  • the fibrosis-inhibiting compound is an integrin antagonist (e.g., 683699 from Glaxo Smith Kline, integrin antagonists from Jerina AG (Germany), or an analogue or derivative thereof).
  • an integrin antagonist e.g., 683699 from Glaxo Smith Kline, integrin antagonists from Jerina AG (Germany), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an interleukin antagonist (e.g., dersalazine, or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is an interleukin 1 antagonist (e.g., NPI-1302a-3, or an analogue or derivative thereof).
  • an interleukin 1 antagonist e.g., NPI-1302a-3, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an inhibitor of type III receptor tyrosine kinase such as FLT3, PDGRF and c-KIT (e.g., MLN518 (Millenium Pharmaceuticals), or an analogue or derivative thereof).
  • type III receptor tyrosine kinase such as FLT3, PDGRF and c-KIT
  • FLT3, PDGRF and c-KIT e.g., MLN518 (Millenium Pharmaceuticals), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an irreversible inhibitor of enzyme methionine aminopeptidase type 2 (e.g., PPI- 2458 (Praecis Pharmaceuticals), or analogue or derivative thereof).
  • methionine aminopeptidase type 2 e.g., PPI- 2458 (Praecis Pharmaceuticals), or analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an isozyme-selective delta protein kinase C inhibitor (e.g., KAI-9803 (Kai Pharmaceuticals), or an analogue or derivative thereof).
  • KAI-9803 Kai Pharmaceuticals
  • the fibrosis-inhibiting compound is a JAK3 enzyme inhibitor (e.g., CP-690,550 (Pfizer), or an analogue or derivative thereof).
  • a JAK3 enzyme inhibitor e.g., CP-690,550 (Pfizer), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a JNK inhibitor (e.g., BF-67192 (BioFocus), XG-101 or XG-102 (Xigen), or an analogue or derivative thereof).
  • a JNK inhibitor e.g., BF-67192 (BioFocus), XG-101 or XG-102 (Xigen), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a kinase inhibitor (e.g., a kinase inhibitors from EVOTEC, or an analogue or derivative thereof).
  • a kinase inhibitor e.g., a kinase inhibitors from EVOTEC, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a kinesin antagonist (e.g., SB-715992 and an antifungal from Cytokinetics, or an analogue or derivative thereof).
  • a kinesin antagonist e.g., SB-715992 and an antifungal from Cytokinetics, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a leukotriene inhibitor or antagonist (e.g., ambicromil (CAS No. 58805-38-2) (Sanofi-Aventis), amelubant (CAS No. 346735-24-8) (Boehringer Ingelheim), DW-1141 (Dong Wha), ebselen (Daiichi Pharmaceutical), ibudilast (Kyorin), Ieucotriene inhibitors from Sanofi-Aventis, lymphotoxin -beta receptor (LT- ⁇ ) from Biogen pou, Pharmaprojects No. 1535 or 2728 (CAS No.
  • the fibrosis-inhibiting compound is a MAP kinase inhibitor (e.g., SRN-003-556 (Sirenade), AEG-3482 (AEgera), ARRY- 142886 (Array BioPharma), CDP-146 (UCB) or analogue or derivative thereof).
  • MAP kinase inhibitor e.g., SRN-003-556 (Sirenade), AEG-3482 (AEgera), ARRY- 142886 (Array BioPharma), CDP-146 (UCB) or analogue or derivative thereof.
  • MMPI Matrix Metalloproteinase Inhibitors
  • the fibrosis-inhibiting compound is a matrix metalloproteinase inhibitor.
  • a variety of MMPI's may be used in the practice of the invention.
  • the MMPI is a MMP-1 inhibitor.
  • the MMPI is a MMP-2 inhibitor.
  • the MMPI is a MMP-4, MMP-5, MMP-6, MMP-7, or MMP-8 inhibitor.
  • Representative examples of MMPI's include glucosamine sulfate, neovastat, GM1489 (CAS No.
  • the fibrosis-inhibiting compound is a MCP-CCR2 inhibitor (e.g., MLN1202 (Millennium Pharmaceuticals) , or an analogue or derivative thereof).
  • MCP-CCR2 inhibitor e.g., MLN1202 (Millennium Pharmaceuticals) , or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an mTOR inhibitor (e.g., temsirolimus (CAS No. 162635-04-3) (Wyeth), or an analogue or derivative thereof).
  • mTOR inhibitor e.g., temsirolimus (CAS No. 162635-04-3) (Wyeth), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an mTOR kinase inhibitor (e.g., ABT-578 (Abbott), temsirolimus (Wyeth), AP- 23573 (Ariad), or an analogue or derivative thereof).
  • ABT-578 Abbott
  • temsirolimus Wyeth
  • AP- 23573 Ariad
  • the fibrosis-inhibiting compound is a microtubule inhibitor (e.g., antibody-maytansinoid conjugates from Biogen pouez, colchicines (MantiCore Pharmaceuticals), anticancer immunoconjugates from Johnson & Johnson, DIME from Octamer, gni-1f (GNI), huC242-DM4 or huMy9- 6-DM1 (ImmunoGen), IDN-5404 (Indena), IMO-098 or IMOderm (Imotep), mebendazole (Introgen Therapeutics), microtubule poisons from Cambridge Enterprise, paclitaxel such as LOTAX from Aphios (CAS No.
  • microtubule inhibitor e.g., antibody-maytansinoid conjugates from Biogen pou, colchicines (MantiCore Pharmaceuticals), anticancer immunoconjugates from Johnson & Johnson, DIME from Octamer, gni-1f (GNI), huC242-DM4
  • the microtubule inhibitor is a microtubule polymerization inhibitor such as vincamine, or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a MIF inhibitor (e.g., AVP-13546 (Avanir), an MIF inhibitor from Genzyme, migration stimulation factor D, or an analogue or derivative thereof).
  • MIF inhibitor e.g., AVP-13546 (Avanir)
  • Genzyme a MIF inhibitor from Genzyme
  • migration stimulation factor D a MIF inhibitor from Genzyme
  • an analogue or derivative thereof e.g., a MIF inhibitor from Genzyme, migration stimulation factor D, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a MMP (stromolysin) inhibitor (e.g., anticancer tetracycline from Tetragenex, rhostatin (BioAxone), TIMP's from Sanofi-Aventis (CAS No. 86102-31-0), and MMP inhibitors form Cognosci and Tetragenex, or an analogue or derivative thereof).
  • MMP stromolysin
  • the fibrosis-inhibiting compound is a neurokinin (NK) antagonist (e.g., anthrotainin (CAS No. 148084-40-6) (Sanofi- Aventis), an IBS thereapeutic such as SLV-332 from ArQuIe, MDL-105212A (CAS No. 167261-60-1) (Ssanofi-Aventis), Pharmaprojects No. 2744, 3258 (CAS No. 139167-47-8) 4006, 4201 , or 5986 (Sanofi-Aventis), RP 67580 (CAS No. 135911-02-3), SR-144190 (CAS No.
  • NK neurokinin
  • SSR-240600 or SSR- 241586 (Sanofi-Aventis), TKA-457 (Novartis), vestipitant mesylate (CAS No. 334476-64-1) (GlaxoSmithKline), Win-64821 (Sanofi-Aventis), PRX-96026 (Predix Pharmaceuticals), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a NF kappa B (NFKB) inhibitor (e.g., emodin (CAS No. 518-82-1), AVE-0545 or AVE- 0547 (Sanofi-Aventis), bortezomib (CAS No. 179324-69-7) (Millennium Pharmaceuticals), dexanabinol (CAS No. 112924-45-5) (Pharmos), dexlipotam (Viatris), Pharmaprojects No. 6283 (INDRA) (OXiGENE), IPL-576092 (CAS No.
  • the fibrosis-inhibiting compound is a nitric oxide agonist (e.g., Acclaim, Angx-1039 or Angx-3227 (Angiogenix), CAS-1609 (CAS No. 158590-73-9) (Sanofi-Aventis), GCI-503 (Spear Therapeutics), HCT- 3012 (CAS No. 163133-43-5) (NicOx), hydralazine + ISDN (NitroMed), isosorbide dinitrate, Diffutab (CAS No. 87-33-2) (Eurand), isosorbide mononitrate (CAS No.
  • a nitric oxide agonist e.g., Acclaim, Angx-1039 or Angx-3227 (Angiogenix), CAS-1609 (CAS No. 158590-73-9) (Sanofi-Aventis), GCI-503 (Spear Therapeutics), HCT- 3012 (CAS No. 163133-43-5) (NicOx),
  • nitroglycerin in the form of a nitroglycerin patch such as DERMATRANS from (Rottapharm), nitroglycerin (CAS No. 55-63-0) (from Cellegy Pharmaceuticals, Forest Laboratories, NovaDel, Schwarz Pharma, and Watson), NO-releasing prodrugs (Inotek), OM-294DP (OM PHARMA), oxdralazine (CAS No.
  • the fibrosis-inhibiting compound is an ornithine decarboxylase inhibitor (e.g., aplidine, or an analogue or derivative thereof).
  • an ornithine decarboxylase inhibitor e.g., aplidine, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a p38 MAP kinase inhibitor (e.g., AZD-6703 (AstraZeneca), JX-401 (Jexys Pharmaceuticals), BMS-2 (Bristol-Myers Squibb), a p38 MAP kinase inhibitor from Novartis, a p38-alpha MAP kinase inhibitor from Amphora, Pharmaprojects No. 5704 (Pharmacopeia), SKF86002 (CAS No. 72873-74-6), RPR-200765A (Sanofi-Aventis), SD-282 (Johnson & Johnson), TAK-715 (Takeda), or an analogue or derivative thereof).
  • a p38 MAP kinase inhibitor e.g., AZD-6703 (AstraZeneca), JX-401 (Jexys Pharmaceuticals), BMS-2 (Bristol-Myers Squibb), a p38
  • the fibrosis-inhibiting compound is a palmitoyl-protein thioesterase inhibitor (e.g., aplidine, or an analogue or derivative thereof).
  • a palmitoyl-protein thioesterase inhibitor e.g., aplidine, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a
  • PDGF receptor kinase inhibitors e.g., AAL-993, AMN-107, or ABP-309 (Novartis), AMG-706 (Amgen), BAY-57-9352 (Bayer), CDP-860 (UCB), E-7080 (Eisai), imatinib (CAS No. 152459-95-5) (Novartis), OSI-930 (OSI Pharmaceuticals), RPR-127963E (Sanofi-Aventis), RWJ-540973 (Johnson & Johnson), sorafenib tosylate (Bayer), SU-11657 (Pfizer), tandutinib (CAS No. 387867-13-2) (Millennium Pharmaceuticals), vatalanib (Novartis), ZK-CDK (Schering AG), or an analogue or derivative thereof).
  • AAL-993, AMN-107, or ABP-309 Novartis
  • AMG-706 Amgen
  • the fibrosis-inhibiting compound is a peroxisome proliferator-activated receptor (PPAR) agonists (e.g., (-)-halofenate (Metabolex), AMG-131 (Amgen), antidiabetics from Japan Tobacco, AZD-4619, AZD-8450, or AZD-8677 (AstraZeneca), DRF-10945 or balaglitazone (Dr Reddy's), CS-00088 or CS-00098 (Chipscreen Biosciences), E-3030 (Eisai), etalocib (CAS No.
  • PPAR peroxisome proliferator-activated receptor
  • rosiglitazone maleate/glimepir (CAS No. 155141-29-0 and 93479-97-1), such as AVANDARYL or rosiglitazone maleate/metformin extend (CAS No. 155141-29- 0 and 657-24-9) such as AVANDAMET, or rosiglitazone maleate+metformin, such as AVANDAMET (GlaxoSmithKline), tesaglitazar (AstraZeneca), LBM642, WY-14,643 (CAS No. 50892-23-4), or an analogue or derivative thereof).
  • the PPAR Agonist is a PPAR ⁇ agonist such as GW7647 or fenofibric acid (CAS No. 42017-89-0), a PPAR ⁇ agonist such as MCC-555 (CAS No. 161600-01-7), GW9662 or GW1929, a PPAER ⁇ agonist such as GW501516, a PPAR ⁇ and PPAR ⁇ agonist such L-165,041 (CAS No. 79558-09-1), or an analogue or derivative thereof.
  • a PPAR ⁇ agonist such as GW7647 or fenofibric acid (CAS No. 42017-89-0)
  • MCC-555 CAS No. 161600-01-7
  • GW9662 or GW1929 a PPAER ⁇ agonist
  • GW501516 a PPAR ⁇ and PPAR ⁇ agonist
  • L-165,041 CAS No. 79558-09-1
  • the fibrosis-inhibiting compound is a phosphatase inhibitor (e.g., diabetes thereapy such as SQMO3, SQDM38, SQDM60 from Sequenom, Pharmaprojects No. 4191 (Sanofi-Aventis), PRL-3 inhibitors from Genzyme, WIP1 inhibitors from Amgen, or an analogue or derivative thereof).
  • a phosphatase inhibitor e.g., diabetes thereapy such as SQMO3, SQDM38, SQDM60 from Sequenom, Pharmaprojects No. 4191 (Sanofi-Aventis), PRL-3 inhibitors from Genzyme, WIP1 inhibitors from Amgen, or an analogue or derivative thereof.
  • PDE Phosphodiesterase
  • the fibrosis-inhibiting compound is a phosphodiesterase (PDE) inhibitor (e.g., avanafil (Tanabe Seiyaku), dasantafil (CAS No. 569351-91-3) (Schering-Plough), A-906119 (CAS No. 134072-58-5) or DL-850 (Sanofi-Aventis), GRC-3015, GRC-3566, or GRC-3886 (Glenmark), HWA-153 (CAS No.
  • PDE phosphodiesterase
  • the phosphodiesterase inhibitor is a phosphodiesterase III inhibitor (e.g., enoximone, or an analogue or derivative thereof).
  • the phosphodiesterase inhibitor is a phosphodiesterase IV inhibitor (e.g., fosfosal, Atopik (Barrier Therapeutics), triflusal, or an analogue or derivative thereof).
  • the phosphodiesterase inhibitor is a phosphodiesterase V inhibitor.
  • the fibrosis-inhibiting compound is a PKC inhibitor (e.g., HMR-105509 or P-10050 (Sanofi-Aventis), JNJ-10164830 (Johnson & Johnson), Ro-31 -8425 (CAS No. 131848-97-0), NPC-15437 dihydrochloride (CAS No. 136449-85-9), or an analogue or derivative thereof).
  • the PKC inhibitor is an inhibitor of PKC beta (e.g., ruboxistaurin (EIi Lilly), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a platelet activating factor antagonist (e.g., dersalazine, or an analogue or derivative thereof).
  • a platelet activating factor antagonist e.g., dersalazine, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a platelet-derived growth factor receptor kinase inhibitor (e.g., sorafenib tosylate, Raf or Ras inhibitors such as sorafenib tosylate from Bayer and Onyx Pharmaceuticals, or an analogue or derivative thereof).
  • a platelet-derived growth factor receptor kinase inhibitor e.g., sorafenib tosylate, Raf or Ras inhibitors such as sorafenib tosylate from Bayer and Onyx Pharmaceuticals, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a prolyl hydroxylase inhibitor (e.g., FG-2216 (CAS No. 11096-26-7) or HIF agonists from FibroGen, or an analogue or derivative thereof).
  • FG-2216 CAS No. 11096-26-7
  • HIF agonists from FibroGen or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a polymorphonuclear neutrophil inhibitor (e.g., orazipone, or an analogue or derivative thereof).
  • a polymorphonuclear neutrophil inhibitor e.g., orazipone, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a protein kinase B inhibitor (e.g., Akt-1 inhibitors from Amphora, or an analogue or derivative thereof).
  • Akt-1 inhibitors from Amphora, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a protein kinase C stimulant (e.g., bryostatin-1 , or analogue or derivative thereof).
  • a protein kinase C stimulant e.g., bryostatin-1 , or analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a purine nucleoside analogue (e.g., cladrinbine and formulations thereof, such as MYLINAX from Serone SA and IVAX Research Inc. (Miami, FL), or an analogue or derivative thereof).
  • a purine nucleoside analogue e.g., cladrinbine and formulations thereof, such as MYLINAX from Serone SA and IVAX Research Inc. (Miami, FL), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a purinoreceptor P2X antagonist (e.g., AZD-9056 (AstraZeneca), R-1554 (Hoffmann-La Roche), AR-C118925XX (AstraZeneca), suramin (CAS No. 129- 46-4), P2Y4 receptor from Euroscreen, or an analogue or derivative thereof).
  • AZD-9056 AstraZeneca
  • R-1554 Hoffmann-La Roche
  • AR-C118925XX AstraZeneca
  • suramin CAS No. 129- 46-4
  • P2Y4 receptor from Euroscreen, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a Raf kinase inhibitor (e.g., sorafenib tosylate, or an analogue or derivative thereof).
  • a Raf kinase inhibitor e.g., sorafenib tosylate, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a reversible inhibitor (e.g., lapatinib (GSK), or an analogue or derivative thereof).
  • GSK lapatinib
  • the fibrosis-inhibiting compound is a cytoplasmic tyrosine kinase inhibitor such as a SRC inhibitor (e.g., SRN-004 (Sirenade), gallium maltolate (Titan Pharmaceutcals), or an analogue or derivative thereof), or an analogue or derivative thereof).
  • SRC inhibitor e.g., SRN-004 (Sirenade), gallium maltolate (Titan Pharmaceutcals), or an analogue or derivative thereof), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a SDF-1 antagonist (e.g., CTCE-9908 (Chemokine Therapeutics), or an analogue or derivative thereof).
  • SDF-1 antagonist e.g., CTCE-9908 (Chemokine Therapeutics), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a sheddase inhibitor (e.g., INCB-7839 (Incyte Corporation), or an analogue or derivative thereof).
  • a sheddase inhibitor e.g., INCB-7839 (Incyte Corporation), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a SRC inhibitor (e.g., SRN-004 (Sirenade), or an analogue or derivative thereof).
  • the SRC inhibitor is a SRC kinase inhibitor (e.g., AZD0530 (AstraZeneca), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a stromelysin inhibitor (e.g., glucosamine sulfate, or an analogue or derivative thereof).
  • a stromelysin inhibitor e.g., glucosamine sulfate, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a syk kinase inhibitor (e.g., R406 (Rigel), or an analogue or derivative thereof).
  • a syk kinase inhibitor e.g., R406 (Rigel), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a telomerase inhibitor (e.g., AS-1410 (Antisoma), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a TGF beta inhibitor (e.g., pirfenidone (CAS No. 53179-13-8) (MARNAC), tranilast (CAS No. 53902-12-8) (Kissei), IN-1130 (ln2Gen), mannose-6-phosphate (BTG), TGF- ⁇ antagonists from Inflazyme (Pharmaprojects No. 6075), TGF- ⁇ antagonists (e.g., 1090 and 1091 from Sydney; non-industrial source), TGF- ⁇ I receptor kinase inhibitors from EIi Lilly, TGF- ⁇ receptor inhibitors from Johnson & Johnson, or an analogue or derivative thereof).
  • TGF beta inhibitor e.g., pirfenidone (CAS No. 53179-13-8) (MARNAC), tranilast (CAS No. 53902-12-8) (Kissei), IN-1130 (ln2Gen), mannose-6-phosphate (BTG), TGF- ⁇ antagonists from Inflazy
  • the fibrosis-inhibiting compound is a TNF ⁇ antagonist or TACE inhibitors (e.g., adalimumab (CAS No. 331731-18-1) (Cambridge Antibody Technology), AGIX-4207 (AtheroGenics), AGT-1 (Advanced Biotherapy), an anti-inflammatory from Borean Pharma, Cellzome, or Paradigm Therapeutics, anti-inflammatory vaccine (TNF-alpha kinoid) from Neovacs, humanized anti-TNF antibody or an anti-TNF MAb (CB0006) Celltech (UCB), apratastat (CAS No.
  • TNF ⁇ antagonist or TACE inhibitors e.g., adalimumab (CAS No. 331731-18-1) (Cambridge Antibody Technology), AGIX-4207 (AtheroGenics), AGT-1 (Advanced Biotherapy), an anti-inflammatory from Borean Pharma, Cellzome, or Paradigm Therapeutics, anti-inflammatory vaccine (TNF-alpha ki
  • TNF antagonists form ProStrakan, and Synergen, TNF inhibitors (Amgen), TNF-alpha antagonists from Dynavax Technologies and Jerina AG (Germany), TNF-alpha inhibitors from IBFB Pharma and Xencor (Xencor), torbafylline (CAS No.
  • the fibrosis-inhibiting compound is a tumor necrosis factor (TNF) antagonist (e.g., anti-inflammatory compounds from Biota Inc., or an analogue or derivative thereof).
  • TNF tumor necrosis factor
  • the fibrosis-inhibiting compound is a Toll receptor antagonist (e.g., E5564 (Eisai Pharmaceuticals), or an analogue or derivative thereof).
  • a Toll receptor antagonist e.g., E5564 (Eisai Pharmaceuticals), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a tubulin antagonist (e.g., synthadotin, KRX-0403 (Keryx Biopharmaceuticals), or an analogue or derivative thereof).
  • a tubulin antagonist e.g., synthadotin, KRX-0403 (Keryx Biopharmaceuticals), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a tyrosine kinase inhibitor (e.g., SU-011248 (e.g., SUTENT from Pfizer Inc. (New York, NY), BMS-354825, PN-355 (Paracelsian Pharmaceuticals), AGN-199659 (Allergan), (e.g., AAL-993 or ABP-309 (Novartis), adaphostin (NIH), AEE-788 (Novartis), AG-013736 (OSI Pharmaceuticals), AG-13736 (Pfizer), ALT-110 (Alteris Therapeutics), AMG-706 (Amgen), anticancer MAbs from Xencor, anti- EGFrvlll MAbs from Abgenix, anti-HER2 MAb from Abiogen, AZD-2171 or AZD-9935 (AstraZeneca), BAY-57-9352 (Bayer), BIBF-1120 (Boehringer Ingelheim),
  • the tyrosine kinase inhibitor is an EGFR tyrosine kinase inhibitor such as EKB-569 (Wyeth), or an analogue or derivative thereof).
  • the fibrosis-inhibiting compound is a VEGF Inhibitor (e.g., AZD2171 (AstraZeneca), or an analogue or derivative thereof).
  • a VEGF Inhibitor e.g., AZD2171 (AstraZeneca), or an analogue or derivative thereof.
  • Vitamin D Receptor Agonists in another embodiment, is a vitamin D receptor agonist (e.g., BXL-628, BXL-922 (BioXell), or an analogue or derivative thereof).
  • a vitamin D receptor agonist e.g., BXL-628, BXL-922 (BioXell), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an histamine receptor antagonist.
  • the histamine receptor antagonists such as H1 , H2, and H3 histamine receptor antagonists, block the production of pro-inflammatory cytokines such as TNFa and IL-1 (e.g., IL- 1 ⁇ ).
  • the histamine receptor antagonist inhibit NFkB activation.
  • H1 histamine receptor antagonists include phenothiazines, such as promethazine, and alkylamines, such as chlorpheniramine (CAS No. 7054-11-7), brompheniramine (CAS No.
  • histamine receptor antagonists include broad spectrum histamine receptor antagonists such as methylxanthines (e.g., theophylline, theobromine, and caffeine).
  • H2 receptor antagonists include those with a histamine-like structure including cimetidine (available under the tradename TAGAMET from SmithKline Beecham Phamaceutical Co., Wilmington, DE), ranitidine (available under the tradename ZANTAC from Warner Lambert Company, Morris Plains, NJ), famotidine (available under the tradename PEPCID from Merck & Co., Whitehouse Station, NJ), nizatidine (available under the tradename AXID from Reliant Pharmaceuticals, Inc., Liberty Corner, NJ), nizatidine, and roxatidine acetate (CAS No. 78628-28-1).
  • cimetidine available under the tradename TAGAMET from SmithKline Beecham Phamaceutical Co., Wilmington, DE
  • ranitidine available under the tradename ZANTAC from Warner Lambert Company, Morris Plains, NJ
  • famotidine available under the tradename PEPCID from Merck & Co., Whitehouse Station, NJ
  • nizatidine available under the tradename AXID from Reliant Pharmaceutical
  • H3 receptor antagonists e.g., thioperamide and thioperamide maleate salt
  • anti-histamines such as tricyclic dibenozoxepins, ethanolamines, ethylenediamines, piperizines, piperidines, and pthalazinones.
  • the fibrosis-inhibiting compound is an alpha adrenergic receptor antagonist.
  • Alpha adrenergic receptor antagonists may inhibit the production of pro-inflammatory cytokines such as TNFa.
  • the alpha adrenergic receptor antagonist may be an alpha-1 and/or an alpha-2 adrenergic receptor antagonist.
  • Representative examples of alpha-1 /alpha-2 antagonists include phenoxybenzamine.
  • the alpha adrenergic receptor antagonist is a haloalkylamine compound or a catecholamine uptake inhibitor.
  • Representative examples of alpha-1 adrenergic receptor antagonists include phenoxybenzamine hydrochloride and prazosin, a piperizinyl quinazoline.
  • alpha-2 adrenergic receptor antagonists include imadazole based compounds such as idazoxan (CAS No. 79944-56-2), idazoxan hydrochloride, and loxapine succinate salt (CAS No. 27833-64-3). Additional examples of alpha adrenergic receptor antagonists include prazosin hydrochloride. 106) Anti-Psychotic Compounds
  • the fibrosis-inhibiting compound is an anti-psychotic compound, such as a phenothiazine compound or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a phenothiazine derivative capable of suppressing the production of proinflammatory cytokines such as TNFa and/or IL-1.
  • phenothiazine compounds include chlorpromazine, fluphenazine, trifluorphenazine, mesoridazine, thioridazine, and perphenazine.
  • anti-psychotic compounds include thioxanthines such as chlorprothixene and thiothixene, clozapine, loxapine succinate, and olanzapine.
  • the fibrosis-inhibiting compound is CaM kinase Il inhibitor, such as a lavendustin C, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is CaM kinase Il inhibitor, such as a lavendustin C, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is G protein agonist, such as aluminum fluoride, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an antibiotic, such as apigenin (Cas No. 520-36-5), ampicillin sodium salt (CAS
  • the fibrosis-inhibiting compound is an anti-microbial agent, such as brefeldin A (CAS No. 20350-15-6), terbinafine, benzoyl peroxide, pentamidine, ornidazole, tinidazole, ketocanazole, sulconazole nitrate salt, or an analogue or derivative thereof.
  • brefeldin A CAS No. 20350-15-6
  • terbinafine benzoyl peroxide
  • pentamidine ornidazole
  • tinidazole ketocanazole
  • sulconazole nitrate salt or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is DNA topoisomerase I inhibitor, such as ⁇ -lapachone (CAS No. 4707-32-8), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is DNA topoisomerase Il inhibitor, such as (-)-arctigenin (CAS No. 7770-78-7), aurintricarboxylic acid, or an analogue or derivative thereof.
  • DNA topoisomerase Il inhibitor such as (-)-arctigenin (CAS No. 7770-78-7), aurintricarboxylic acid, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is thromboxane A2 receptor inhibitor, such as BM-531 (CAS No. 284464-46-6), ozagrel hydrochloride (CAS No. 78712-43-3), or an analogue or derivative thereof.
  • thromboxane A2 receptor inhibitor such as BM-531 (CAS No. 284464-46-6), ozagrel hydrochloride (CAS No. 78712-43-3), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a D2 dopamine receptor antagonist, such as clozapine (CAS No. 5786-21-0), mesoridazine benzenesulfonate, or an analogue or derivative thereof.
  • D2 dopamine receptor antagonist such as clozapine (CAS No. 5786-21-0), mesoridazine benzenesulfonate, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a
  • Peptidyl-Prolyl Cis/Trans lsomerase Inhibitor such as juglone (CAS No. 481- 39-0), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a dopamine antagonist, such as thiothixene, thioridazine hydrochloride, or an analogue or derivative thereof. 116) Anesthetics
  • the fibrosis-inhibiting compound is an anesthetic compound, such as lidocaine (CAS No. 137-58-6), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a clotting factor, such as menadione (CAS No. 58-27-5), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a lysyl hydrolase inhibitor, such as minoxidil (CAS No. 38304-91-5), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a muscarinic receptor inhibitor, such as perphenazine (CAS No. 58-39-9), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a superoxide anion generator, such as plumbagin (CAS No. 481-42-5), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a steroid, such as prednisolone 21 -acetate (CAS No. 52-21-1), loteprednol etabonate, (CAS No. 82034-46-6), clobetasol propionate, or an analogue or derivative thereof. 122) Anti-Proliferative Agents
  • the fibrosis-inhibiting compound is an antiproliferative agent, such as silibinin (CAS No. 22888-70-6), silymarin (CAS No. 65666-07-1), 1 ,2-hexanediol, dioctyl phthalate (CAS No.
  • zirconium (IV) oxide zirconium (IV) oxide, glycyrrhizic acid, spermidine trihydrochloride or tetrahydrochloride, CGP 74514A, spermine tetrahydrochloride, NG-methyl-L- arginine acetate salt, galardin, halofuginone hydrobromide (HBr), fascaplysin, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a diuretic, such as spironolactone (CAS No. 52-01-7), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an anti-coagulant, such as fucoidan from Fucus vesiculosus (CAS No. 9072-19-9), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a cyclic GMP agonist, such as sinitrodil (CAS No. 143248-63-9), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an adenylate cyclase agonist, such as histamine (CAS No. 51-45-6), or an analogue or derivative thereof. 127) Antioxidants
  • the fibrosis-inhibiting compound is an antioxidant, such as morpholine, phytic acid dipotassium salt, (-)- epigallocatechin or (-)-epigallocatechin gallate from green tea (CAS Nos. 970- 74-1 and 1257-08-5, respectively), (-)-epigallocatechin gallate (CAS No. 989- 51-5), nobiletin (CAS No. 478-01-3), probucol (CAS No. 23288-49-5), phosphorous acid, hesperetin, L-ascorbyl-2-phosphate, magnesium salt (CAS No. 84309-23-9), catechin, ( ⁇ )-naringenin (CAS No. 67604-48-2), (-)- epicatechin, (-)-epicatechin gallate, 3-hydroxyflavone, and (-)-arctigenin, or an analogue or derivative thereof.
  • an antioxidant such as morpholine, phytic acid dipotassium salt, (-
  • the fibrosis-inhibiting compound is a nitric oxide synthase inhibitor, such as ammonium pyrrolidinedithiocarbamate (CAS No. 5108-96-3), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a reversible nitric oxide synthase inhibitor, such as NB-methyl-L-arginine acetate salt (L-NMMA) (CAS No. 53308-83-1), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an anti-neoplastic agent, such as tirapazamine (CAS No. 27314-97-2), fludarabine (CAS No. 21679-14-1), cladribine (CAS Number: 4291-63-8; Leustat®, Janssen-Ortho), imatinib mesilate, or an analogue or derivative thereof.
  • an anti-neoplastic agent such as tirapazamine (CAS No. 27314-97-2), fludarabine (CAS No. 21679-14-1), cladribine (CAS Number: 4291-63-8; Leustat®, Janssen-Ortho), imatinib mesilate, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a DNA synthesis inhibitor, such as S-(2-hydroxy-5-nitrobenyl)-6-thioguanosine or uracilfludarabine phosphate (CAS No. 75607-67-9), 6,11-dihydroxy-5,12- naphthacenedione, cladribine (CAS Number: 4291-63-8; Leustat®, Janssen- Ortho), or an analogue or derivative thereof. 131) DNA Alkylating Agents
  • the fibrosis-inhibiting compound is a DNA alkylating agent, such as dacarbazine (CAS No. 4342-03-4), temozolomide, procarbazine HCI, or an analogue or derivative thereof.
  • a DNA alkylating agent such as dacarbazine (CAS No. 4342-03-4), temozolomide, procarbazine HCI, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a DNA methylation inhibitor, such as decitabine (CAS No. 2353-33-5), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a
  • NSAID agent such as nabumetone, benzydamine hydrochloride, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a peptidylglycine alpha-hydroxylating monooxygenase inhibitor, such as trans- styrylacetic acid, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a MEK1/MEK 2 inhibitor, such as U0126 (CAS No. 109511-58-2), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an NO synthase inhibitor, such as L-NAME (CAS No. 53308-83-1), NG-Methyl-L- arginine acetate salt, or an analogue or derivative thereof.
  • NO synthase inhibitor such as L-NAME (CAS No. 53308-83-1), NG-Methyl-L- arginine acetate salt, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is retinoic acid receptor antagonist, such as isotretinoin (CAS No. 4759-48-2), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an ACE inhibitor, such as quinapril hydrochloride (CAS No. 85441-61-8), enalapril, or an analogue or derivative thereof.
  • ACE inhibitor such as quinapril hydrochloride (CAS No. 85441-61-8), enalapril, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a glycosylation inhibitor, such as aminoguanidine hydrochloride, castanospermine, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an intracellular calcium influx inhibitor, such as TAS-301 (CAS No. 193620-69-8), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an anti-emetic agent, such as amifostine (CAS No. 20537-88-6), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an acetylcholinesterase inhibitor, such as (-)-huperzine A (CAS No. 102518-79-6), or an analogue or derivative thereof. 143) ALK-5 Receptor Antagonists
  • the fibrosis-inhibiting compound is an ALK-5 receptor antagonist, such as SB 431542 (CAS No. 301836-41-9), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a RAR/RXT antagonist, such as 9-cis-retinoic acid, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a elF-
  • the fibrosis-inhibiting compound is a S- adenosyl-L-homocysteine hydrolase inhibitor, such as 3-deazaadenosine, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an estrogen agonist, such as coumestrol, bisphenol A, 1-linoleoyl-rac-glycerol (CAS No. 2277-28-3), daidzein (4,7-dihydroxy-iso-flavone), dihexyl phthalate, kaempferol, formononetin, , or an analogue or derivative thereof.
  • estrogen agonist such as coumestrol, bisphenol A, 1-linoleoyl-rac-glycerol (CAS No. 2277-28-3), daidzein (4,7-dihydroxy-iso-flavone), dihexyl phthalate, kaempferol, formononetin, , or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a serotonin receptor inhibitor, such as amitriptyline hydrochloride, or an analogue or derivative thereof. 149) Anti-Thrombotic Agents
  • the fibrosis-inhibiting compound is an anti-thrombotic agent, such as geniposidic acid, geniposide, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a tryptase inhibitors, such as 2-azetidinone, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a pesticide, such as allyl disulfide, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a bone mineralization promotor, such as glycerol 2-phosphate disodium salt hydrate, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a bisphosphonate compound, such as risedronate, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an anti-inflammatory compound, such as aucubin, cepharanthine, or an analogue or derivative thereof. 155) DNA Methylation Promotors
  • the fibrosis-inhibiting compound is a DNA methylation promotor, such as 5-azacytidine, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an anti-spasmodic agent, such as 2-hydroxy-4,6-dimethoxyacetophenone, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a protein synthesis inhibitor, such as oxytetracycline hydrochloride, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a ⁇ - glucosidase inhibitor, such as myricetin (CAS No. 529-44-2), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a calcium channel blocker, such as verapamil, nitrendipine, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a L- type calcium channel blocker, such as nifedipine (CAS No. 21829-25-4), (+)-cis- diltiazem hydrochloride, or an analogue or derivative thereof.
  • L- type calcium channel blocker such as nifedipine (CAS No. 21829-25-4), (+)-cis- diltiazem hydrochloride, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a T- type calcium channel blocker, such as penfluridol (CAS No. 26864-56-2), or an analogue or derivative thereof. 160) Pyruvate Dehydrogenase Activators
  • the fibrosis-inhibiting compound is a pyruvate dehydrogenase activator, such as dichloroacetic acid, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a prostaglandin inhibitor, such as betulinic acid, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a sodium channel inhibitor, such as amiloride hydrochloride hydrate, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a serine protease inhibitor, such as gabexate mesylate, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an intracellular calcium flux inhibitor, such as thapsigargin, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a JAK2 inhibitor (e.g., AG-490 (CAS No. 134036-52-5), or an analogue or derivative thereof). 166) Androgen Inhibitors
  • the fibrosis-inhibiting compound is an androgen inhibitor (e.g., tibolone (CAS No. 5630-53-5), or an analogue or derivative thereof).
  • an androgen inhibitor e.g., tibolone (CAS No. 5630-53-5), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an aromatase inhibitor (e.g., letrozole, or an analogue or derivative thereof).
  • an aromatase inhibitor e.g., letrozole, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an anti-viral agent, such as imiquimod, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a 5-HT inhibitor, such as ketanserin tartrate, amoxapine, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a FXR antagonist, such as guggulsterone (CAS No. 95975-55-6), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an actin polymerization and stabilization promotor, such as jasplakinolide, or an analogue or derivative thereof. 172) AXOR12 Agonists
  • the fibrosis-inhibiting compound is an AXOR12 agonist, such as metastin (KiSS-1 (112-121), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an angiotensin Il receptor agonist, such as losartan potassium, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a platelet aggregation inhibitor, such as clopidogrel, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a CB1/CB2 receptor agonist, such as HU-210 (CAS No. 112830-95-2), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a norepinephrine reuptake inhibitor, such as nortriptyline hydrochloride, or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is a selective serotonin reuptake inhibitor, such as paroxetine maleate, or an analogue or derivative thereof. 178) Reducing Agents
  • the fibrosis-inhibiting compound is a reducing agent such as WW-85 (Inotek), or an analogue or derivative thereof.
  • the fibrosis-inhibiting compound is an immunomodulators such as Bay 11-7085, (-)-arctigenin, idazoxan hydrochloride, or an analogue or derivative thereof.
  • compositions may further include a compound that acts to have an inhibitory effect on pathological processes in or around the treatment site.
  • additional therapeutically active agents include, by way of example and not limitation, anti-thrombotic agents, antiproliferative agents, antiinflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine kinase inhibitors, MMP inhibitors, p38 MAP kinase inhibitors, immunosuppressants, apoptosis antagonists, caspase inhibitors, and JNK inhibitors.
  • anti-thrombotic agents include, by way of example and not limitation, anti-thrombotic agents, antiproliferative agents, antiinflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine kinase inhibitor
  • the present invention also provides for the combination of a soft tissue implant (as well as compositions and methods for making soft tissue implants) that includes an anti-fibrosing agent and an anti- infective agent, which reduces the likelihood of infections.
  • Infection is a common complication of the implantation of foreign bodies such as, for example, medical devices.
  • Foreign materials provide an ideal site for micro- organisms to attach and colonize. It is also hypothesized that there is an impairment of host defenses to infection in the
  • the present invention provides agents (e.g., chemotherapeutic agents) that can be released from a composition, and which have potent antimicrobial activity at extremely low doses.
  • agents e.g., chemotherapeutic agents
  • a wide variety of anti-infective agents can be utilized in combination with the present compositions. Suitable anti-infective agents may be readily determined based the assays provided in Example 36.
  • agents that can be used: (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin).
  • anthracyclines e.g., doxorubicin and mitoxantrone
  • fluoropyrimidines e.g., 5-FU
  • C folic acid antagonists (e.g., methotrexate)
  • D podophylotoxins
  • E camptothecins
  • F hydroxyureas
  • platinum complexes e.g., cisplatin
  • Anthracyclines have the following general structure, where the R groups may be a variety of organic groups:
  • R groups are as follows: Ri is CH 3 or CH 2 OH; R 2 is daunosamine or H; R 3 and R 4 are independently one of OH, NO 2 , NH 2 , F, Cl, Br, I, CN, H or groups derived from these; R 5 is hydrogen, hydroxyl, or methoxy; and Re- ⁇ are all hydrogen. Alternatively, R 5 and R 6 are hydrogen and R 7 and Rs are alkyl or halogen, or vice versa.
  • Ri may be a conjugated peptide.
  • R 5 may be an ether linked alkyl
  • R 5 may be OH or an ether linked alkyl group.
  • Ri may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH 2 CH(CH 2 -X)C(O)-Ri, wherein X is H or an alkyl group (see, e.g., U.S. Patent 4,215,062).
  • R 3 may have the following structure:
  • Ri 0 may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903).
  • Ri 0 may be derived from an amino acid, having the structure -
  • Ri 2 may be H, alkyl, aminoalkyl, amino, hydroxyl, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105).
  • anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin.
  • Suitable compounds have the structures:
  • Doxorubicin OCH 3 C(O)CH 2 OH OH out of ring plane
  • Epirubicin (4' epimer of OCH 3 C(O)CH 2 OH OH in ring plane doxorubicin)
  • Daunorubicin OCH 3 C(O)CH 3 OH out of ring plane
  • Idarubicin H C(O)CH 3 OH out of ring plane
  • Pirarubicin OCH 3 C(O)CH 2 OH
  • Carubicin OH C(O)CH 3 OH out of ring plane
  • anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A 3 , and plicamycin having the structures:
  • anthracyclines include, FCE 23762, a doxorubicin derivative (Quaglia et al., J. Liq. Chromatogr. 17(18):3911 -3923, 1994), annamycin (Zou et al., J. Pharm. Sci. 82(11):1151-1154, 1993), ruboxyl (Rapoport et al., J. Controlled Release 58(2): 153-162, 1999), anthracycline disaccharide doxorubicin analogue (Pratesi et al., CHn. Cancer Res.
  • the therapeutic agent is a fluoropyrimidine analog, such as 5-fluorouracil, or an analogue or derivative thereof, including carmofur, doxifluridine, emitefur, tegafur, and floxuridine.
  • fluoropyrimidine analog such as 5-fluorouracil
  • an analogue or derivative thereof including carmofur, doxifluridine, emitefur, tegafur, and floxuridine.
  • Exemplary compounds have the structures:
  • fluoropyrimidine analogues include 5-FudR (5- fluoro-deoxyuridine), or an analogue or derivative thereof, including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).
  • 5-FudR 5- fluoro-deoxyuridine
  • an analogue or derivative thereof including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).
  • Exemplary compounds have the structures:
  • fluoropyrimidine analogues include N3-alkylated analogues of 5-fluorouracil (Kozai et ai, J. Chem. Soc, Perkin Trans. ?(19):3145-3146, 1998), 5-fluorouracil derivatives with 1 ,4- oxaheteroepane moieties (Gomez et al., Tetrahedron 54(43):13295-13312, 1998), 5-fluorouracil and nucleoside analogues (Li, Anticancer Res.
  • the therapeutic agent is a folic acid antagonist, such as methotrexate or derivatives or analogues thereof, including edatrexate, trimetrexate, raltitrexed, piritrexim, denopterin, tomudex, and pteropterin.
  • Methotrexate analogues have the following general structure:
  • R group may be selected from organic groups, particularly those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582.
  • R 1 may be N
  • R 2 may be N or C(CH 3 )
  • R 3 and R 3 ' may H or alkyl, e.g., CH 3
  • R 4 may be a single bond or NR, where R is H or alkyl group.
  • 6,8 may be H, OCH 3 , or alternately they can be halogens or hydro groups.
  • R 7 is a side chain of the general structure:
  • the carboxyl groups in the side chain may be esterified or form a salt such as a Zn 2+ salt.
  • R 9 and R-io can be NH 2 or may be alkyl substituted.
  • Exemplary folic acid antagonist compounds have the structures:
  • N-( ⁇ -aminoacyl) methotrexate derivatives Cheung et ai , Pteridines 3(1 -2): 101 -2, 1992
  • biotin methotrexate derivatives Fean et ai, Pteridines 3(1-2):131-2, 1992
  • D-glutamic acid or D-erythrou threo-4-fluoroglutamic acid methotrexate analogues
  • cysteic acid and homocysteic acid methotrexate analogues (4,490,529), ⁇ -tert-butyl methotrexate esters (Rosowsky et al., J. Med. Chem. 2S(5):660-7, 1985), fluorinated methotrexate analogues (Tsushima et al., Heterocycles 23(1):45-9, 1985), folate methotrexate analogue (Trombe, J. Bacteriol. 160(3): 849-53, 1984), phosphonoglutamic acid analogues (Sturtz & Guillamot, Eur. J. Med. Chem.-Chim. Ther.
  • the therapeutic agent is a podophyllotoxin, or a derivative or an analogue thereof.
  • exemplary compounds of this type are etoposide or teniposide, which have the following structures:
  • podophyllotoxins include Cu(II)- VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. ⁇ (7):1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al., Bioorg. Med. Chem. Lett. 7(5):607-612, 1997), 4 ⁇ -amino etoposide analogues (Hu, University of North Carolina Dissertation, 1992), ⁇ -lactone ring-modified arylamino etoposide analogues (Zhou et al., J. Med. Chem.
  • the therapeutic agent is camptothecin, or an analogue or derivative thereof.
  • Camptothecins have the following general structure.
  • X is typically O, but can be other groups, e.g., NH in the case of 21 -lactam derivatives.
  • R 1 is typically H or OH, but may be other groups, e.g., a terminally hydroxy lated Ci -3 alkane.
  • R 2 is typically H or an amino containing group such as (CH 3 ) 2 NHCH 2 , but may be other groups e.g., NO 2 , NH 2 , halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing these groups.
  • R 3 is typically H or a short alkyl such as C 2 H 5 .
  • R 4 is typically H but may be other groups, e.g., a methylenedioxy group with Ri
  • camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10- hydroxycamptothecin.
  • Exemplary compounds have the structures:
  • Camptothecins have the five rings shown here.
  • the ring labeled E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity.
  • Camptothecins are believed to function as topoisomerase I inhibitors and/or DNA cleavage agents.
  • the therapeutic agent of the present invention may be a hydroxyurea.
  • Hydroxyureas have the following general structure:
  • Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein R 1 is:
  • R 2 is an alkyl group having 1-4 carbons and R 3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.
  • R-i is a cycloalkenyl group, for example N-(3-(5-(4- fluorophenylthio)-furyl)-2-cyclopenten-1-yl)N-hydroxyurea;
  • R 2 is H or an alkyl group having 1 to 4 carbons and R 3 is H;
  • X is H or a cation.
  • Suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 4,299,778, wherein Ri is a phenyl group substituted with one or more fluorine atoms; R 2 is a cyclopropyl group; and R 3 and X is H.
  • n is 0-2 and Y is an alkyl group.
  • the hydroxyurea has the structure:
  • the therapeutic agent is a platinum compound.
  • suitable platinum complexes may be of Pt(II) or Pt(IV) and have this basic structure:
  • X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; Ri and R 2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups.
  • Ri and R 2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups.
  • Pt(II) complexes Zi and Z 2 are non-existent.
  • Pt(IV) Zi and Z 2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Patent Nos. 4,588,831 and 4,250,189.
  • Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897.
  • platinum compounds are cisplatin, carboplatin, oxaliplatin, and miboplatin having the structures:
  • platinum compounds include (CPA) 2 Pt(DOLYM) and (DACH)Pt(DOLYM) cisplatin (Choi et al., Arch. Pharmacal Res. 22(2): 151 -156, 1999), Cis-(PtCI 2 (4,7-H-5-methyl-7- oxo)1 , 2,4(thazolo(1 ,5-a)pyrimidine) 2 ) (Navarro et al., J. Med. Chem. 41(3):332- 338, 1998), (Pt(cis-1 ,4-DACH)(trans-CI 2 )(CBDCA)) • 1 /4Me0H cisplatin (Shamsuddin et al., Inorg.
  • the total dose of doxorubicin applied to the implant should not exceed 25 mg (range of 0.1 ⁇ g to 25 mg). In one embodiment, the total amount of drug applied should be in the range of 1 ⁇ g to 5 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated should fall within the range of 0.01 ⁇ g - 100 ⁇ g per mm 2 of surface area.
  • doxorubicin should be applied to the implant surface at a dose of 0.1 ⁇ g/mm 2 - 10 ⁇ g/mm 2 .
  • the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10 ⁇ - 10 "4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10 "4 M; although for some embodiments lower concentrations are sufficient).
  • doxorubicin is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months. In one embodiment the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).
  • the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 ⁇ g to 5 mg). In one embodiment, the total amount of drug applied should be in the range of 0.1 ⁇ g to 3 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated
  • mitoxantrone should be applied to the implant surface at a dose of 0.05 ⁇ g/mm 2 - 5 ⁇ g/mm 2 .
  • the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10 "4 - 10 "8 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the implant surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10 "5 M; although for some embodiments lower drug levels will be sufficient).
  • mitoxantrone is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).
  • the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 ⁇ g to 250 mg). In one embodiment, the total amount of drug applied should be in the range of 10 ⁇ g to 25 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated
  • 5-fluorouracil should be applied to the implant surface at a dose of 0.5 ⁇ g/mm 2 - 50 ⁇ g/mm 2 .
  • the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10 "4 - 10 ⁇ 7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10 "4 M; although for some embodiments lower drug levels will be sufficient).
  • 5-fluorouracil is released from the implant surface such that anti-infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5- fluorouracil is administered at twice the above parameters, etc.).
  • the total dose of etoposide applied should not exceed 25 mg (range of 0.1 ⁇ g to 25 mg). In one embodiment, the total amount of drug applied should be in the range of 1 ⁇ g to 5 mg.
  • the dose per unit area (Ae., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) should fall within the range of 0.01 ⁇ g - 100 ⁇ g per mm 2 of surface area.
  • etoposide should be applied to the implant surface at a dose of 0.1 ⁇ g/mm 2 - 10 ⁇ g/mm 2 .
  • the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a concentration of 10 "4 - 10 "7 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (Ae., are in excess of 10 "5 M; although for some embodiments lower drug levels will be sufficient).
  • etoposide is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week — 6 months.
  • anthracyclines e.g., doxorubicin or mitoxantrone
  • fluoropyrimidines e.g., 5-fluorouracil
  • folic acid antagonists e.g., methotrexate and/or podophylotoxins (e.g., etoposide)
  • podophylotoxins e.g., etoposide
  • an anti-infective agent e.g., anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide)
  • anthracyclines e.g., doxorubicin or mitoxantrone
  • fluoropyrimidines e.g., 5-fluorouracil
  • folic acid antagonists e.g., methotrexate and/or podophylotoxins (e.g., etoposide)
  • traditional antibiotic and/or antifungal agents e.g., doxorubicin or mitoxantrone
  • fluoropyrimidines e.g., 5-fluorouracil
  • folic acid antagonists e.g., methotrex
  • the anti-infective agent may be further combined with anti-thrombotic and/or antiplatelet agents (for example, heparin, dextran sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissue plasminogen activator) to enhance efficacy.
  • anti-thrombotic and/or antiplatelet agents for example, heparin, dextran sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone
  • one or more other pharmaceutically active agents can be incorporated into the present compositions and devices to improve or enhance efficacy.
  • additional therapeutically active agents include, by way of example and not limitation, anti-thrombotic agents, anti-proliferative agents, antiinflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine kinase inhibitors, MMP inhibitors, p38 MAP kinase inhibitors, immunosuppressants, apoptosis antagonists, caspase inhibitors, and JNK inhibitors.
  • anti-thrombotic agents include, by way of example and not limitation, anti-thrombotic agents, anti-proliferative agents, antiinflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine kinas
  • Soft tissue implants and compositions for use with soft tissue implants may further include an anti-thrombotic agent and/or antiplatelet agent and/or a thrombolytic agent, which reduces the likelihood of thrombotic events upon implantation of a medical implant.
  • a device is coated on one aspect with a composition which inhibits fibrosis (and/or restenosis), as well as being coated with a composition or compound that prevents thrombosis on another aspect of the device.
  • anti-thrombotic and/or antiplatelet and/or thrombolytic agents include heparin, heparin fragments, organic salts of heparin, heparin complexes (e.g., benzalkonium heparinate, tridodecylammonium heparinate), dextran, sulfonated carbohydrates such as dextran sulphate, Coumadin, coumarin, heparinoid, danaparoid, argatroban chitosan sulfate, chondroitin sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, acetylsalicylic acid, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost, streptokinase, factor Xa inhibitors, such as DXa inhibitor
  • Further examples include plasminogen, lys- plasminogen, alpha-2-antiplasmin, urokinase, aminocaproic acid, ticlopidine, clopidogrel, trapidil (triazolopyrimidine), naftidrofuryl, auriritricarboxylic acid and glycoprotein llb/llla inhibitors such as abcixamab, eptifibatide, and tirogiban.
  • agents capable of affecting the rate of clotting include glycosaminoglycans, danaparoid, 4-hydroxycourmarin, warfarin sodium, dicumarol, phenprocoumon, indan-1 ,3-dione, acenocoumarol, anisindione, and rodenticides including bromadiolone, brodifacoum, diphenadione, chlorophacinone, and pidnone.
  • compositions for use with soft tissue implants may be or include a hydrophilic polymer gel that itself has anti-thrombogenic properties.
  • the composition can be in the form of a coating that can comprise a hydrophilic, biodegradable polymer that is physically removed from the surface of the device over time, thus reducing adhesion of platelets to the device surface.
  • the gel composition can include a polymer or a blend of polymers.
  • the anti-thrombotic composition can include a crosslinked gel formed from a combination of molecules (e.g., PEG) having two or more terminal electrophilic groups and two or more nucleophilic groups.
  • Soft tissue implants and compositions for use with soft tissue implants may further include a compound that acts to have an inhibitory effect on pathological processes in or around the treatment site.
  • the agent may be selected from one of the following classes of compounds: anti-inflammatory agents (e.g., dexamethasone, cortisone, fludrocortisone, prednisone, prednisolone, 6 ⁇ -methylprednisolone, triamcinolone, betamethasone, and aspirin); MMP inhibitors (e.g., batimistat, marimistat, TIMP's representative examples of which are included in U.S. Patent Nos.
  • cytokine inhibitors chlorpromazine, mycophenolic acid, rapamycin, 1 ⁇ -hydroxy vitamin D 3
  • IMPDH inosine monophosplate dehydrogenase inhibitors
  • MAPK MAP kinase inhibitors
  • WO 00/63204A2 WO 01/21591 A1 , WO 01/35959A1 , WO 01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO 02/094842A2, WO 02/096426A1 , WO 02/101015A2, WO 02/103000A2, WO 03/008413A1 , WO 03/016248A2, WO 03/020715A1 , WO 03/024899A2, WO 03/031431 A1, WO 03/040103A1 , WO 03/053940A1 , WO 03/053941 A2, WO 03/063799A2, WO 03/079986A2, WO 03/080024A2, WO 03/082287A1 , WO 97/44467A1 , WO 99/01449A1 , and WO 99/58523A1), and immunomodulatory agents (
  • Patent No. 6,258,823 and everolimus and derivatives thereof (e.g., U.S. Patent No. 5,665,772).
  • Further representative examples of sirolimus analogues and derivatives include ABT-578 and those found in PCT Publication Nos.
  • biologically active agents which may be combined with soft tissue implants according to the invention include tyrosine kinase inhibitors, such as imantinib, ZK-222584, CGP-52411 , CGP-53716, NVP-AAK980-NX, CP-127374, CP-564959, PD-171026, PD-173956, PD- 180970, SU-0879, and SKI-606; MMP inhibitors such as nimesulide, PKF-241- 466, PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964, PNU- 171829, AG-3433, PNU-142769, SU-5402, and dexlipotam; p38 MAP kinase inhibitors such as include CGH-2466 and PD-98-59; immunosuppressants such as argyrin B, macrocyclic lactone, ADZ-62-826, CCI-779,
  • the soft tissue implants may further include an antibiotic (e.g., amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxicillin-clavulanate, cefprozil, cefuroxime, cefpodoxime, or cefdinir).
  • an antibiotic e.g., amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxicillin-clavulanate, cefprozil, cefuroxime, cefpodoxime, or cefdinir.
  • a composition comprising a fibrosis-inhibiting agent is combined with an agent that can modify metabolism of the agent in vivo to enhance efficacy of the fibrosis-inhibiting agent.
  • an agent that can modify metabolism of the agent in vivo to enhance efficacy of the fibrosis-inhibiting agent includes agents capable of inhibiting oxidation of the anti-scarring agent by cytochrome P450 (CYP).
  • compositions include a fibrosis-inhibiting agent (e.g., ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin-A4, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, lotepredn
  • CYP inhibitors include flavones, azole antifungals, macrolide antibiotics, HIV protease inhibitors, and anti-sense oligomers.
  • Devices comprising a combination of a fibrosis-inhibiting agent and a CYP inhibitor may be used to treat a variety of proliferative conditions that can lead to undesired scarring of tissue, including intimal hyperplasia, surgical adhesions, and tumor growth.
  • a device incorporates or is coated on one aspect, portion or surface with a composition which inhibits fibrosis (and/or restenosis), as well as with a composition or compound which promotes or stimulates fibrosis on another aspect, portion or surface of the device.
  • Compounds that promote or stimulate fibrosis can be identified by, for example, the in vivo (animal) models provided in Examples 34- 37.
  • agents that promote fibrosis include silk and other irritants (e.g., talc, wool (including animal wool, wood wool, and synthetic wool), talcum powder, copper, metallic beryllium (or its oxides), quartz dust, silica, crystalline silicates), polymers (e.g., polylysine, polyurethanes, poly(ethylene terephthalate), PTFE, poly(alkylcyarioacrylates), and poly(ethylene-co-vinylacetate); vinyl chloride and polymers of vinyl chloride; peptides with high lysine content; growth factors and inflammatory cytokines involved in angiogenesis, fibroblast migration, fibroblast proliferation, ECM synthesis and tissue remodeling, such as epidermal growth factor (EGF) family, transforming growth factor- ⁇ (TGF- ⁇ ), transforming growth factor- ⁇ (TGF- ⁇ -1 , TGF- ⁇ -2, TGF- ⁇ -3, platelet-derived growth factor (PDGF), fibroblast growth factor (acidic -
  • CTGF connective tissue growth factor
  • inflammatory microcrystals e.g., crystalline minerals such as crystalline silicates
  • bromocriptine methylsergide, methotrexate, chitosan, N-carboxybutyl chitosan, carbon tetrachloride, thioacetamide, fibrosin, ethanol, bleomycin, naturally occurring or synthetic peptides containing the Arg-Gly-Asp (RGD) sequence, generally at one or both termini (see, e.g., U.S. Patent No. 5,997,895), and tissue adhesives, such as cyanoacrylate and crosslinked poly(ethylene glycol) - methylated collagen compositions.
  • tissue adhesives such as cyanoacrylate and crosslinked poly(ethylene glycol) - methylated collagen compositions.
  • fibrosis-inducing agents include bone morphogenic proteins ⁇ e.g., BMP-2, BMP- 3, BMP-4, BMP-5, BMP-6 (VgM), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11 , BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16.
  • BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7 are of particular utility.
  • Bone morphogenic proteins are described, for example, in U.S. Patent Nos.
  • fibrosis-inducing agents include components of extracellular matrix (e.g., fibronectin, fibrin, fibrinogen, collagen (e.g., bovine collagen), including fibrillar and non-fibrillar collagen, adhesive glycoproteins, proteoglycans (e.g., heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan, secreted protein acidic and rich in cysteine (SPARC), thrombospondins, tenacin, and cell adhesion molecules (including integrins, vitronectin, fibronectin, laminin, hyaluronic acid, elastin, bitronectin), proteins found in basement membranes, and fibrosin) and inhibitors of matrix metalloproteinases, such as TIMPs (tissue inhibitors of matrix metalloproteinases) and synthetic TIMPs, such as, e.g., marimistat,
  • combretastatin A4 may be understood to refer to not only the common chemically available form of combretastatin, but analogues (e.g., combretastatin A2, A3, A5, A6, as noted above) and combretastatin conjugates.
  • analogues e.g., combretastatin A2, A3, A5, A6, as noted above
  • combretastatin conjugates e.g., combretastatin A2, A3, A5, A6, as noted above
  • the agents set forth above may be noted within the context of one class, many of the agents listed in fact have multiple biological activities. Further, more than one therapeutic agent may be utilized at a time (i.e., in combination), or delivered sequentially.
  • Drug dose can be calculated as a function of dose (i.e., amount) per unit area of the portion of the device being coated. Surface area can be measured or determined by methods known to one of ordinary skill in the art. Total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined.
  • Drugs are to be used at concentrations that range from several times more than to 50%, 10%, 5%, or even less than 1% of the concentration typically used in a single chemotherapeutic systemic dose application.
  • the drug is released in effective concentrations for a period ranging from 1 - 90 days.
  • the fibrosis- inhibiting agents used alone or in combination, may be administered under the following dosing guidelines:
  • soft tissue implants may be used in combination with a composition that includes an anti-scarring agent.
  • the total amount (dose) of anti-scarring agent in or on the device may be in the range of about 0.01 ⁇ g-10 ⁇ g, or 10 ⁇ g-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg.
  • the dose (amount) of anti-scarring agent per unit area of device surface to which the agent is applied may be in the range of about 0.01 ⁇ g/mm 2 - 1 ⁇ g/mm 2 , or 1 ⁇ g/mm 2 - 10 ⁇ g/mm 2 , or 10 ⁇ g/mm 2 - 250 ⁇ g/mm 2 , 250 ⁇ g/mm 2 - 1000 ⁇ g/mm 2 , or 1000 ⁇ g/mm 2 - 2500 ⁇ g/mm 2 .
  • the total dose typically should not exceed 200 mg (range of 0.1 ⁇ g to 200 mg) and preferably 1 ⁇ g to 100 mg; dose per unit area of 0.01 ⁇ g - 100 ⁇ g per mm 2 ; preferably 0.1 ⁇ g/mm 2 - 20 ⁇ g/mm 2 ; and minimum concentration of 10 ⁇ - 10 "4 M of agent should be maintained on the implant or barrier surface.
  • the total dose typically should not to exceed 500 mg (range of 1.0 ⁇ g to 500 mg) and preferably 1 ⁇ g to 200 mg; dose per unit area of 0.01 ⁇ g - 200 ⁇ g per mm 2 , preferably 0.1 ⁇ g/mm 2 - 40 ⁇ g/mm 2 .
  • the total dose typically should not exceed 1000 mg (range of 0.1 ⁇ g to 1000 mg), preferably 1 ⁇ g to 500 mg; dose per unit area of 0.01 ⁇ g - 500 ⁇ g per mm 2 ; preferably 0.1 ⁇ g/mm 2 - 100 ⁇ g/mm 2 .
  • soft tissue implants may be adapted to release an agent that inhibits one or more of the five general components of the process of fibrosis (or scarring), including: inflammation, migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), formation of new blood vessels (angiogenesis), deposition of extracellular matrix (ECM), and remodeling
  • the overgrowth of scar tissue may be inhibited or reduced.
  • the present invention provides a soft tissue implant an anti-fibrosing agent listed below in a dosage as set forth above: 1) an anti-fibrotic agent that inhibits cell regeneration, 2) an anti-fibrotic agent that inhibits angiogenesis, 3) an anti-fibrotic agent that inhibits fibroblast migration, 4) an anti-fibrotic agent that inhibits fibroblast proliferation, 5) an anti-fibrotic agent that inhibits deposition of extracellular matrix, 6) an anti-fibrotic agent inhibits tissue remodeling, 7) an adensosine A2A receptor antagonist, 8) an AKT inhibitor, 9) an alpha 2 integrin antagonist, wherein the alpha 2 integrin antagonist is Pharmaprojects No.
  • angiogenesis inhibitor selected from the group consisting of AG-12,958 (Pfizer), ATN-161 (Attenuon LLC), neovastat, an angiogenesis inhibitor from Jerina AG
  • laminin technology (NIH), CHIR-258 (Chiron), NVP-AEW541 (Novartis), NVP-AEW541 (Novartis), Vt16907 (Alchemia), OXI-8007 (Oxigene), EG-3306 (Ark Therapeutics), Maspin (Arriva), ABT-567 (Abbott), PPi-2458 (Praecis Pharmaceuticals), CC-5079, CC-4089 (Celgene), H1F-1 alpha inhibitors (Xenova), S-247 (Pfizer), AP-23573 (Ariad), AZD-9935 (Astra Zeneca), mebendazole (Introgen Therapeutics), MetAP-2 inhibitors (GlaxoSmithKline), AG-615 (Angiogene Pharmaceuticals), Tie-2 antagonists (Hybrigenics), NC- 381 , CYC-381 , NC-169, NC-219, NC-383, NC-384, NC-407 (Lorus Therapeutics
  • Inhibitors Ontogen, DIMI, Octamer (Octamer), ABR-215050 (Active Biotech), ABT-518 (Abbott), KDR inhibitors (Abbott), BSF-466895 (Abbott), SCH-221153 (Schering-Plough), DAC.antiangiogenic (ConjuChem), TFPI (EntreMed), AZD- 2171 (Astra-Zenaca), CDC-394 (Celgene), LY290293 (EIi Lilly), IDN-5390 (Indena), Kdr Kinase Inhibitors (Merck), CT-113020, CT-116433, CT-116563, CT-31890, CT-32228) (Cell Therapeutics), A-299620 (Abbott), TWEAK Inhibitor (Amgen), VEGF modulators (Johnson and Johnson), Tum-N53, tumstatin (Genzyme), Thios-1 , Thios-2 (Thios Pharmaceuticals), MV
  • cyclin dependent kinase inhibitor selected from the group consisting of a CDK-1 inhibitor, a CDK-2 inhibitor, a CDK- 4 inhibitor, a CDK-6 inhibitor, a CAK1 inhibitor from GPC Biotech and Bristol-Myers Squibb, RGB-286199 (GPC Biotech), an anticancer agent from Astex Technology, a CAK1 inhibitor from GPC Biotech, a CDK inhibitor from Sanofi-Aventis, a CDK1/CDK2 inhibitor from Amgen, a CDK2 inhibitor from SUGEN-2 (Pfizer), a hearing loss therapy agent (Sound Pharmaceuticals), PD-0332991 (Pfizer), RGB-286199 (GPC Biotech), Ro-0505124 (Hoffmann-La Roche), a Ser/Thr kinase inhibitor from Lilly (EIi Lilly), CVT-2584 (CAS No.
  • a KDR inhibitor from LG Life Sciences, CT-6685 and CT-6729 (UCB), KRN-633 and KRN-951 (Kirin Brewery), OSI-930 (OSI Pharmaceuticals), SP-5.2 (Supratek Pharma), SU-11657 (Pfizer), a Tie-2 antagonist (Hybrigenics), SU 1498 (a VEGF-R inhibitor), a VEGFR-2 kinase inhibitor (Bristol-Myers Squibb), XL-647 (Exelixis), a KDR inhibitor from Abbott Laboratories, sorafenib tosylate, and an analogue or derivative thereof, 39) an endotoxin antagonist, 40) an epothilone and tubulin binder, 41) an estrogen receptor antagonist, 42) an FGF inhibitor, 43) a famexyl transferase inhibitor, 44) a farnesyltransferase inhibitor selected from the group of A-197574 (Abbott), a
  • an FLT-3 kinase inhibitor 46a) an FGF receptor kinase inhibitor, 47) a fibrinogen antagonist selected from the group consisting of AUV-201 (Auvation), MG-13926 (Sanofi-Aventis), plasminogen activator (CAS No. 105913-11-9) (from Sanofi-Aventis or UCB), plasminogen activator-2 (tPA-2) (Sanofi-Aventis), pro-urokinase (CAS No.
  • a heat shock protein 90 antagonist selected from the group consisting of SRN-005 (Sirenade), geldanamycin, NSC-33050 (17-allylaminogeldanamycin; 17-AAG), 17- dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG), rifabutin (rifamycin XIV, 1',4-didehydro-1-deoxy-1 ,4-dihydro-5'-(2-methylpropyl)-1-oxo-), radicicol from Humicola fuscoatra (CAS No.
  • an atherosclerosis therapeutic from Lipid Sciences, ATI-16000 (ARYx Therapeutics), KS-01-019 (Kos Pharmaceuticals), Pharmaprojects No. 2197 (Sanofi-Aventi), RP 61969 (Sanofi-Aventis), cerivastatin Na (CAS No.
  • an immunosuppressant selected from the group consisting of teriflunomide (Sanofi Aventis), chlorsulfaquinoxalone (NSC-339004), chlorsulfaquinoxalone sulfate, CS-712 (Sankyo), ismomultin aifa (CAS No.
  • microtubule poisons from Cambridge Enterprise paclitaxel such as LOTAX from Aphios (CAS No. 33069-62-4), Genexol-PM from Samyang, Pharmaprojects No. 6383 (Tapestry Pharmaceuticals), RPR-112378 (Sanofi- Aventis), SGN-75 (Seattle Genetics), SPL-7435 (Starpharma), SSR-250411 (Sanofi-Aventis), trastuzumab-DM1 (Genentech), vinorelbine, dolastatin 15 (CAS No.
  • paclitaxel such as LOTAX from Aphios (CAS No. 33069-62-4), Genexol-PM from Samyang, Pharmaprojects No. 6383 (Tapestry Pharmaceuticals), RPR-112378 (Sanofi- Aventis), SGN-75 (Seattle Genetics), SPL-7435 (Starpharma), SSR-250411 (Sanofi-Aventis), trastuzumab
  • a neurokinin (NK) antagonist selected from the group consisting of anthrotainin (CAS No. 148084-40-6) (Sanofi-Aventis), an IBS thereapeutic from ArQuIe, MDL-105212A (CAS No. 167261-60-1) (Ssanofi-Aventis), Pharmaprojects No. 2744, 3258 (CAS No. 139167-47-8) 4006, 4201 , or 5986 (Sanofi-Aventis), RP 67580 (CAS No.
  • SR-144190 (CAS No. 201152-86-5), SSR-240600, SSR-241586 (Sanofi-Aventis), TKA-457 (Novartis), vestipitant mesylate (CAS No. 334476- 64-1) (GlaxoSmithKline), Win-64821 (Sanofi-Aventis), PRX-96026 (Predix Pharmaceuticals), and an analogue or derivative thereof, 75) an NF kappa B inhibitor selected from the group consisting of emodin (CAS No. 518-82-1), AVE-0545 or AVE-0547 (Sanofi-Aventis), bortezomib (CAS No.
  • a palmitoyl-protein thioesterase inhibitor 80) a PDGF receptor kinase inhibitor selected from the group consisting of AAL-993, AMN-107, or ABP-309 (Novartis), AMG-706 (Amgen), BAY-57-9352 (Bayer), CDP-860 (UCB), E-7080 (Eisai), imatinib (CAS No.
  • a peroxisome proliferators-activated receptor agonist selected from the group consisting of (-)- halofenate (Metabolex), AMG-131 (Amgen), antidiabetics from Japan Tobacco, AZD-4619, AZD-8450, AZD-8677 (AstraZeneca), DRF-10945, balaglitazone (Dr Reddy's), CS-00088, CS-00098 (Chipscreen Biosciences), E-3030 (Eisai), etalocib (CAS No.
  • 122320-73-4 or 155141-29-0 (GlaxoSmithKline), rosiglitazone maleate/glimepir (CAS No. 155141-29-0 and 93479-97-1), AVANDARYL, rosiglitazone maleate/metformin extend (CAS No. 155141-29-0 and 657-24-9), AVANDAMET, rosiglitazone maleate+metformin, AVANDAMET
  • a phosphatase inhibitor a phosphodiesterase (PDE) inhibitor selected from the group consisting of avanafil (Tanabe Seiyaku), dasantafil (CAS No.
  • a phosphodiesterase III inhibitor enoximone, a phosphodiesterase IV inhibitor, fosfosal, Atopik (Barrier Therapeutics), triflusal, a phosphodiesterase V inhibitor, and an analogue or derivative thereof
  • a PKC inhibitor 85) a platelet activating factor antagonist, 86) a platelet-derived growth factor receptor kinase inhibitor, 87) a prolyl hydroxylase inhibitor, 88) a polymorphonuclear neutrophil inhibitor, 89) a protein kinase B inhibitor, 90) a protein kinase C stimulant, 91) a purine nucleoside analogue, 92) a purinoreceptor P2X antagonist, 93) a Raf kinase inhibitor, 94) a reversible inhibitor of ErbB1 and ErbB2, 95) a ribonucleoside triphosphate reductase inhibitor, 96
  • TNF ⁇ antagonist or TACE inhibitor selected from the group consisting of adalimumab (CAS No.
  • TNF antagonists form ProStrakan, and Synergen, TNF inhibitors (Amgen), TNF-alpha antagonists from Dynavax Technologies and Jerina AG (Germany), TNF-alpha inhibitors from IBFB Pharma and Xencor (Xencor), torbafylline (CAS No. 105102-21-4) (Sanofi- Aventis), UR-1505 (Uriach), VT-346 (Viron Therapeutics), YSIL6 (Y's Therapeutics), YSTH2 (Y's Therapeutics), NPI-1302a-3 (Nereus
  • TNF antagonist from Jerina AG (Germany), dersalazine, and an analogue or derivative thereof, 104) a tumor necrosis factor antagonist, 105) a Toll receptor inhibitor, 106) a tubulin antagonist, 107) a tyrosine kinase inhibitor selected from the group consisting of SU-011248, SUTENT from Pfizer Inc.
  • brompheniramine (CAS No. 980-71-2), fexofenadine hydrochloride, promethazine hydrochloride, loratadine, ketotifen fumarate salt, and acrivastine), methylxanthines (e.g., theophylline, theobromine, and caffeine), cimetidine (available under the tradename TAGAMET from SmithKline Beecham Phamaceutical Co., Wilmington, DE), ranitidine (available under the tradename ZANTAC from Warner Lambert Company, Morris Plains, NJ), famotidine (available under the tradename PEPCID from Merck & Co., Whitehouse Station, NJ), nizatidine (available under the tradename AXID from Reliant Pharmaceuticals, Inc., Liberty Corner, NJ), nizatidine, and roxatidine acetate (CAS No.
  • H3 receptor antagonists e.g., thioperamide and thioperamide maleate salt
  • anti-histamines e.g., tricyclic dibenozoxepins, ethanolamines, ethylenediamines, piperizines, piperidines, and pthalazinones
  • 131 an alpha adrenergic receptor antagonist
  • 132) an anti-psychotic compound
  • 133) a CaM kinase Il inhibitor
  • 134) a G protein agonist 135) an antibiotic selected from the group consisting of apigenin (Cas No. 520-36-5), ampicillin sodium salt (CAS No.
  • a DNA topoisomerase inhibitor selected from the group consisting of ⁇ -lapachone (CAS No. 4707-32- 8), (-)-arctigenin (CAS No. 7770-78-7), aurintricarboxylic acid, and an analogue or derivative thereof, 138) a thromboxane A2 receptor inhibitor selected from the group consisting of BM-531 (CAS No. 284464-46-6), ozagrel hydrochloride (CAS No.
  • a D2 dopamine receptor antagonist 140) a Peptidyl-Prolyl Cis/Trans lsomerase Inhibitor, 141) a dopamine antagonist, an anesthetic compound, 142) a clotting factor, 143) a lysyl hydrolase inhibitor, 144) a muscarinic receptor inhibitor, 145) a superoxide anion generator, 146) a steroid, 147) an anti-proliferative agent selected from the group consisting of silibinin (CAS No. 22888-70-6), silymarin (CAS No.
  • temozolomide temozolomide
  • procarbazine HCI and an analogue or derivative thereof
  • 157) a DNA methylation inhibitor 158) a NSAID agent, 159) a peptidylglycine alpha- hydroxylating monooxygenase inhibitor, 160) an MEK1/MEK 2 inhibitor, 161) a NO synthase inhibitor, 162) a retinoic acid receptor antagonist selected from isotretinoin (CAS No.
  • an ACE inhibitor 164) a glycosylation inhibitor, 165) an intracellular calcium influx inhibitor, 166) an anti-emetic agent, 167) an acetylcholinesterase inhibitor, 168) an ALK-5 receptor antagonist, 169) a RAR/RXT antagonist, 170) an elF-2a inhibitor, 171) an S-adenosyl-L-homocysteine hydrolase inhibitor, 172) an estrogen agonist, 173) a serotonin receptor inhibitor, 174) an anti-thrombotic agent, 175) a tryptase inhibitor, 176) a pesticide, 177) a bone mineralization promoter, 178) a bisphosphonate compound selected from risedronate and an analogue or derivative thereof, 179) an anti-inflammatory compound, 180) a DNA methylation promoter, 181) an anti-spasmodic agent, 182) a protein synthesis inhibitor, 183) an ⁇ -glucosidase inhibitor
  • Angiogenesis inhibitors including alphastatin, ZD-6474, IDN-5390, SB-2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 ⁇ g to 200 mg); preferred 1 ⁇ g to 100 mg. Dose per unit area of 0.01 ⁇ g - 100 ⁇ g per mm 2 ; preferred dose of 0.1 ⁇ g/mm 2 - 20 ⁇ g/mm 2 .
  • mTOR inhibitors including AP-23573 and Temsirolimus, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 ⁇ g to 200 mg); preferred 1 ⁇ g to 100 mg. Dose per unit area of 0.01 ⁇ g - 100 ⁇ g per mm 2 ; preferred dose of 0.1 ⁇ g/mm 2 - 20 ⁇ g/mm 2 . Minimum concentration of 10 ⁇ - 10 "4 M of agent is to be maintained on the implant or barrier surface.
  • Minimum concentration of 10 ⁇ - 10 "4 M of agent is to be maintained on the implant or barrier surface.
  • TNF alpha antagonists including Etanercept, Humicade, Adalimumab and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 ⁇ g to 200 mg); preferred 1 ⁇ g to 100 mg.
  • Minimum concentration of 10 "8 - 10 "4 M of agent is to be maintained on the implant or barrier surface.
  • AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 ⁇ g to 200 mg); preferred 1 ⁇ g to 100 mg.
  • NF Kappa B Inhibitors including Bortezomib (an NF Kappa B inhibitor) and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 ⁇ g to 200 mg); preferred 1 ⁇ g to 100 mg. Dose per unit area of 0.01 ⁇ g - 100 ⁇ g per mm 2 ; preferred dose of 0.1 ⁇ g/mm 2 - 20 ⁇ g/mm 2 . Minimum concentration of 10 "8 - 10 "4 M of agent is to be maintained on the implant or barrier surface.
  • Minimum concentration of 10 ⁇ - 10 "4 M of agent is to be maintained on the implant or barrier surface.
  • anti-scarring agents which can be used include those having a high potency in selected assays described herein (approximately 1-10OnM IC 50 range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, and tacrolimus.
  • selected assays described herein such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, and tacrolimus.
  • the total dose typically should not exceed 200 mg (range of 0.1 ⁇ g to 200 mg) and preferably 1 ⁇ g to 100 mg; dose per unit area of 0.01 ⁇ g - 100 ⁇ g per mm 2 ; preferably 0.1 ⁇ g/mm 2 - 20 ⁇ g/mm 2 ; and minimum concentration of 10 ⁇ - 10 "4 M of agent should be maintained on the implant or barrier surface.
  • agents which can be used include those having a mid-potency in selected assays described herein (approximately 100-500 nM IC 50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate.
  • the total dose typically should not to exceed 500 mg (range of 1.0 ⁇ g to 500 mg) and preferably 1 ⁇ g to 200 mg; dose per unit area of 0.01 ⁇ g - 200 ⁇ g per mm 2 , preferably 0.1 ⁇ g/mm 2 - 40 ⁇ g/mm 2 ; and minimum concentration of 10 ⁇ - 10 "4 M of agent should be maintained on the implant or barrier surface.
  • agents which can be used include those having a low potency in selected assays described herein (approximately 500-1 OOOnm range IC 50 range) such as 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin.
  • the total dose typically should not exceed 1000 mg (range of 0.1 ⁇ g to 1000 mg), preferably 1 ⁇ g to 500 mg; dose per unit area of 0.01 ⁇ g - 500 ⁇ g per mm 2 ; preferably 0.1 ⁇ g/mm 2 - 100 ⁇ g/mm 2 ; and minimum concentration of 10 "8 - 10 "4 M of agent should to be maintained on the implant or barrier surface.
  • Fibrosis-lnhibiting Agent and for Delivering a Fibrosis-lnhibiting Agent
  • drug-coated or drug-impregnated soft tissue implants are provided which inhibit fibrosis in and around the soft tissue implant.
  • fibrosis is inhibited by local, regional or systemic release of specific pharmacological agents that become localized to the tissue adjacent to the implant.
  • There are numerous soft tissue implants where the occurrence of a fibrotic reaction will adversely affect the functioning or aesthetic appearance of the implant.
  • fibrotic encapsulation of the soft tissue implant or the growth of fibrous tissue between the implant and the surrounding tissue
  • fibrous contracture of tissue surrounding the implant can result in fibrous contracture of tissue surrounding the implant.
  • the fibrosis-inhibiting agent may be delivered via a carrier system to optimize dosage and allow sustained release of the agent into the target tissue for a period of time after implantation surgery.
  • a carrier system to optimize dosage and allow sustained release of the agent into the target tissue for a period of time after implantation surgery.
  • Soft tissue implants including facial implants, chin and mandibular implants, nasal implants, lip implants, pectoral implants, autogenous tissue implants and breast implants are described herein for combining with a fibrosis-inhibitor. Although available in a plethora of shapes and sizes, the majority of soft tissue implants are made for the same materials and similar design features. Specifically, many soft tissue implants feature an outer capsule filled with saline, silicone or other gelatinous material.
  • methods for incorporating fibrosis-inhibiting compositions onto or into these soft tissue implants include (a) directly affixing to, or coating, the surface of the soft tissue implant with a fibrosis-inhibiting composition ⁇ e.g., by either a spraying process or dipping process, with or without a carrier); (b) directly incorporating the fibrosis-inhibiting composition into the polymer that composes the outer capsule of the soft tissue implant (e.g., by either a spraying process or dipping process, with or without a carrier); (c) by coating the soft tissue implant with a substance such as a hydrogel which will in turn absorb the fibrosis-inhibiting composition, (d) by inserting the soft tissue implant into a sleeve or mesh which is comprised of, or coated with, a fibrosis-inhibiting composition, (e) constructing the soft tissue implant itself (or a portion of the implant) with a fibrosis-inhibiting composition, or (f) by covalent
  • the fibrosis-inhibiting agent or composition can be incorporated into the central core of the implant.
  • a soft tissue implant involves an outer capsule (in a variety of shapes and sizes) that is filled with an aqueous or gelatinous material.
  • Many commercial devices employ either saline or silicone as the "filling" material.
  • numerous materials have been described for this purpose including, but not restricted to, polysiloxane, polyethylene glycol, vegetable oil, monofilament yarns (e.g., polyolefin, polypropylene), keratin hydrogel and chondroitin sulfate.
  • the fibrosis inhibiting agent or composition can be incorporated into the filler material and then can diffuse through, or be actively transported across, the capsular material to reach the surrounding tissues and prevent capsular contracture.
  • Methods of incorporating the fibrosis- inhibiting agent or composition into the central core material of the soft tissue implant include, but are not restricted to: (a) dissolving a water soluble fibrosis- inhibiting agent into an aqueous core material (e.g., saline) at the appropriate concentration and dose; (b) using a solubilizing agent or carrier (e.g., micelles, liposomes, EDTA, a surfactant etc.) to incorporate an insoluble fibrosis- inhibiting agent into an aqueous core material at the appropriate concentration and dose; (c) dissolving a water-insoluble fibrosis-inhibiting agent into an organic solvent core material (e.g., vegetable oil, polypropylene etc.) at the appropriate concentration and dose; (d) incorporating the fibros
  • an implant may be prepared that has a coating, where the coating is, e.g., uniform, non-uniform, continuous, discontinuous, or patterned.
  • the coating may directly contact the implant, or it may indirectly contact the implant when there is something, e.g., a polymer layer, that is interposed between the implant and the coating that contains the fibrosis- inhibiting agent.
  • Sustained release formulations suitable for incorporation into the core of the breast implant are described herein.
  • the fibrosis-inhibiting agent may be delivered as a solution (e.g., in a saline filled implant).
  • the fibrosis-inhibiting agent can be incorporated directly into the solution to provide a homogeneous solution or dispersion.
  • the solution is an aqueous solution.
  • the aqueous solution may further include buffer salts, as well as viscosity modifying agents (e.g., hyaluronic acid, alginates, CMC, and the like).
  • the solution can include a biocompatible solvent, such as ethanol, DMSO, glycerol, PEG-200, PEG-300 or NMP.
  • the fibrosis-inhibiting agent can be incorporated into a biodegradable polymer (e.g., PLGA, PLA, PCL,
  • anti-scarring agent may be located within pores or voids of the soft tissue implant.
  • a soft tissue implant may be constructured to have cavities (e.g., divets or holes), grooves, lumen(s), pores, channels, and the like, which form voids or pores in the body of the implant. These voids may be filled (partially or completely) with a fibrosis- inhibiting agent or a composition that comprises a fibrosis-inhibiting agent.
  • a soft tissue implant may include a plurality of reservoirs within its structure, each reservoir configured to house and protect a therapeutic drug. The reservoirs may be formed from divets in the device surface or micropores or channels in the device body.
  • the reservoirs are formed from voids in the structure of the device.
  • the reservoirs may house a single type of drug or more than one type of drug.
  • the drug(s) may be formulated with a carrier (e.g., a polymeric or non-polymeric material) that is loaded into the reservoirs.
  • the filled reservoir can function as a drug delivery depot that can release drug over a period of time dependent on the release kinetics of the drug from the carrier.
  • the reservoir may be loaded with a plurality of layers. Each layer may include a different drug having a particular amount (dose) of drug, and each layer may have a different composition to further tailor the amount of drug that is released from the substrate.
  • the multi-layered carrier may further include a barrier layer that prevents release of the drug(s). The barrier layer can be used, for example, to control the direction that the drug elutes from the void.
  • Coating of Soft Tissue Implants with Fibrosis-lnhibitinq Agents As described above, a range of polymeric and non-polymeric materials can be used to incorporate the fibrosis-inhibiting agent onto or into a soft tissue implant. Coating the soft tissue implant with these fibrosis-inhibiting agent-containing compositions, or with the fibrosis-inhibiting agent only, is one process that can be used to incorporate the fibrosis-inhibiting agent into or onto the implant.
  • the anti-fibrosing agent can be coated onto the entire device or a portion of the device.
  • the agent is present as part of a coating on a surface of the soft tissue implant.
  • the coating may partially cover or may completely cover the surface of the soft tissue implant. Further, the coating may directly or indirectly contact the soft tissue implant.
  • the soft tissue implant may be coated with a first coating and then coated with a second coating that includes the anti-scarring agent.
  • Soft tissue implants may be coated using a variety of coating methods, including by dipping, spraying, painting, by vacuum deposition, or by any other method known to those of ordinary skill in the art.
  • Dip coating is an example of coating process that can be used to associate the anti-scarring agent with the soft tissue implant.
  • the fibrosis-inhibiting agent is dissolved in a solvent for the fibrosis-inhibiting agent and is then coated onto the soft tissue implant. Fibrosis-lnhibitinq Agent with an Inert Solvent
  • the solvent is an inert solvent for the soft tissue implant such that the solvent does not dissolve the medical implant to any great extent and is not absorbed by the implant to any great extent.
  • the soft tissue implant can be immersed, either partially or completely, in the fibrosis-inhibiting agent/solvent solution for a specific period of time. The rate of immersion into the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The implant can then be removed from the solution. The rate at which the implant is withdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated implant can be air-dried.
  • the dipping process can be repeated one or more times depending on the specific application, where higher repetitions generally increase the amount of agent that is coated onto the soft tissue implant.
  • the implant can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent being coated on the surface of the soft tissue implant.
  • the solvent is one that will not dissolve the soft tissue implant but will be absorbed by the implant. In certain cases, these solvents can swell the implant to some extent.
  • the implant can be immersed, either partially or completely, in the fibrosis-inhibiting agent/solvent solution for a specific period of time (seconds to days). The rate of immersion into the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The implant can then be removed from the solution. The rate at which the soft tissue implant is withdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated implant can be air-dried.
  • the dipping process can be repeated one or more times depending on the specific application.
  • the implant can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent being adsorbed into the soft tissue implant.
  • the fibrosis-inhibiting agent may also be present on the surface of the implant. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated implant into a solvent for the fibrosis-inhibiting agent, or by spraying the coated implant with a solvent for the fibrosis-inhibiting agent.
  • the solvent is one that will be absorbed by the soft tissue implant and that will not dissolve the implant.
  • the implant can be immersed, either partially or completely, in the fibrosis-inhibiting agent/solvent solution for a specific period of time (seconds to hours).
  • the rate of immersion into the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec).
  • the implant can then be removed from the solution.
  • the rate at which the implant is withdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec).
  • the coated implant can be air-dried.
  • the dipping process can be repeated one or more times depending on the specific application.
  • the implant can be dried under vacuum to reduce residual solvent levels.
  • the fibrosis-inhibiting agent being adsorbed into the soft tissue implant as well as being surface associated.
  • the exposure time of the implant to the solvent does not incur significant permanent dimensional changes to the implant.
  • the fibrosis- inhibiting agent may also be present on the surface of the implant.
  • the amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated implant into a solvent for the fibrosis-inhibiting agent or by spraying the coated implant with a solvent for the fibrosis-inhibiting agent.
  • the fibrosis-inhibiting agent and a polymer are dissolved in a solvent, for both the polymer and the fibrosis-inhibiting agent, and are then coated onto the soft tissue implant.
  • the soft tissue implant can be one that has not been modified or one that has been further modified by coating with a polymer, surface treated by plasma treatment, flame treatment, corona treatment, surface oxidation or reduction, surface etching, mechanical smoothing or roughening, or grafting prior to the coating process.
  • the surface of the soft tissue implant can be treated with a plasma polymerization method prior to coating of the fibrosis-inhibiting agent or fibrosis-inhibiting agent-containing composition, such that a thin polymeric layer is deposited onto the implant surface.
  • a plasma polymerization method prior to coating of the fibrosis-inhibiting agent or fibrosis-inhibiting agent-containing composition, such that a thin polymeric layer is deposited onto the implant surface.
  • Examples of such methods include the use of various monomers such hydrocyclosiloxane monomers.
  • Spray coating is another coating process that can be used in the practice of this invention.
  • a solution or suspension of the fibrosis-inhibiting agent, with or without a polymeric or non-polymeric carrier is nebulized and directed to the soft tissue implant to be coated by a stream of gas.
  • spray devices such as an air-brush (for example models 2020, 360, 175, 100, 200, 150, 350, 250, 400, 3000, 4000, 5000, 6000 from Badger Air-brush Company, Franklin Park, IL), spray painting equipment, TLC reagent sprayers (for example Part # 14545 and 14654, Alltech Associates, Inc. Deerfield, IL, and ultrasonic spray devices (for example those available from Sono-Tek, Milton, NY).
  • TLC reagent sprayers for example Part # 14545 and 14654, Alltech Associates, Inc. Deerfield, IL, and ultrasonic spray devices (for example those available from Sono-Tek, Milton, NY).
  • powder sprayers and electrostatic sprayers for
  • the fibrosis-inhibiting agent is dissolved in a solvent for the fibrosis agent and is then sprayed onto the soft tissue implant.
  • the solvent is an inert solvent for the soft tissue implant such that the solvent does not dissolve the medical implant to any great extent and is not absorbed to any great extent.
  • the implant can be held in place or mounted onto a mandrel or rod that has the ability to move in an X, Y or Z plane or a combination of these planes.
  • the soft tissue implant can be spray coated such that it is either partially or completely coated with the fibrosis-inhibiting agent/solvent solution.
  • the rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained.
  • the coated implant can be air-dried.
  • the spray coating process can be repeated one or more times depending on the specific application.
  • the implant can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis- inhibiting agent being coated on the surface of the soft tissue implant.
  • the solvent is one that will not dissolve the soft tissue implant but will be absorbed by it. These solvents can thus swell the implant to some extent.
  • the soft tissue implant can be spray coated, either partially or completely, in the fibrosis-inhibiting agent/solvent solution. The rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that a good coating of the fibrosis- inhibiting agent is obtained.
  • the coated implant can be air-dried. The spray coating process can be repeated one or more times depending on the specific application.
  • the implant can be dried under vacuum to reduce residual solvent levels.
  • the fibrosis-inhibiting agent may also be present on the surface of the implant.
  • the amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated implant into a solvent for the fibrosis-inhibiting agent, or by spraying the coated implant with a solvent for the fibrosis-inhibiting agent.
  • the solvent is one that will be absorbed by the soft tissue implant and that will dissolve it.
  • the soft tissue implant can be spray coated, either partially or completely, in the fibrosis-inhibiting agent/solvent solution.
  • the rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained.
  • the coated implant can be air-dried.
  • the spray coating process can be repeated one or more times depending on the specific application.
  • the implant can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent being adsorbed into the soft tissue implant as well as being surface associated.
  • the exposure time of the implant to the solvent may not incur significant permanent dimensional changes to it.
  • the fibrosis-inhibiting agent may also be present on the surface of the implant. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated implant into a solvent for the fibrosis-inhibiting agent, or by spraying the coated implant with a solvent for the fibrosis-inhibiting agent.
  • the soft tissue implant can be one that has not been modified as well as one that has been further modified by coating with a polymer, surface treated by plasma treatment, flame treatment, corona treatment, surface oxidation or reduction, surface etching, mechanical smoothing or roughening, or grafting prior to the coating process.
  • the fibrosis-inhibiting agent and a polymer are dissolved in a solvent, for both the polymer and the anti-fibrosing agent, and are then spray coated onto the soft tissue implant.
  • the solvent is an inert solvent for the soft tissue implant such that the solvent does not dissolve it to any great extent and is not absorbed by it to any great extent.
  • the soft tissue implant can be spray coated, either partially or completely, in the fibrosis-inhibiting agent/polymer/solvent solution for a specific period of time. The rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that a good coating of the fibrosis- inhibiting agent is obtained.
  • the coated implant can be air-dried.
  • the spray coating process can be repeated one or more times depending on the specific application.
  • the implant can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent/polymer being coated on the surface of the soft tissue implant.
  • the solvent is one that will not dissolve the soft tissue implant but will be absorbed by it. These solvents can thus swell the implant to some extent.
  • the soft tissue implant can be spray coated, either partially or completely, in the fibrosis-inhibiting agent/polymer/solvent solution. The rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained.
  • the coated implant can be air-dried. The spray coating process can be repeated one or more times depending on the specific application.
  • the implant can be dried under vacuum to reduce residual solvent levels.
  • This process will result in the fibrosis-inhibiting agent/polymer being coated onto the surface of the soft tissue implant as well as the potential for the fibrosis-inhibiting agent being adsorbed into the soft tissue implant.
  • the fibrosis-inhibiting agent may also be present on the surface of the implant.
  • the amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated implant into a solvent for the fibrosis-inhibiting agent or by spraying the coated implant with a solvent for the fibrosis-inhibiting agent.
  • the solvent is one that will be absorbed by the soft tissue implant and that will dissolve it.
  • the soft tissue implant can be spray coated, either partially or completely, in the fibrosis-inhibiting agent/solvent solution.
  • the rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained.
  • the coated implant can be air-dried.
  • the spray coating process can be repeated one or more times depending on the specific application.
  • the implant can be dried under vacuum to reduce residual solvent levels.
  • the exposure time of the implant to the solvent may not incur significant permanent dimensional changes to it (other than those associated with the coating itself).
  • the fibrosis-inhibiting agent may also be present on the surface of the implant. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated implant into a solvent for the fibrosis-inhibiting agent or by spraying the coated implant with a solvent for the fibrosis-inhibiting agent.
  • the soft tissue implant can be one that has not been modified as well as one that has been further modified by coating with a polymer, surface treated by plasma treatment, flame treatment, corona treatment, surface oxidation or reduction, surface etching, mechanical smoothing or roughening, or grafting prior to the coating process.
  • a suspension of the fibrosis-inhibiting agent in a polymer solution can be prepared.
  • the suspension can be prepared by choosing a solvent that can dissolve the polymer but not the fibrosis- inhibiting agent, or a solvent that can dissolve the polymer and in which the fibrosis-inhibiting agent is above its solubility limit.
  • the suspension of the fibrosis-inhibiting and polymer solution can be sprayed onto the soft tissue implant such that it is coated with a polymer that has a fibrosis-inhibiting agent suspended within it.
  • the anti-fibrosing agent can be coated onto the appropriate soft tissue implant using the polymeric coatings described above.
  • the coating compositions and methods described above there are various other coating compositions and methods that are known in the art. Representative examples of these coating compositions and methods are described in U.S. Patent. Nos.
  • the biologically active agent can be delivered with non-polymeric agents.
  • non-polymeric agents can include sucrose derivatives (e.g., sucrose acetate isobutyrate, sucrose oleate), sterols such as cholesterol, stigmasterol, beta-sitosterol, and estradiol; cholesteryl esters such as cholesteryl stearate; Ci 2 -C 24 fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; Ci 8 -C 36 mono-, di- and triacylglycerides such as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl
  • the fibrosis-inhibiting agent can further comprise a secondary carrier.
  • the secondary carrier can be in the form of microspheres (e.g., PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly(alkylcyanoacrylate), nanospheres (e.g., PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly(alkylcyanoacrylate)), liposomes, emulsions, microemulsions, micelles (e.g., SDS, block copolymers of the form X-Y, X-Y-X or Y-X-Y, R-(Y-X) n , R-(X-Y) worship where X is a poly(alkylene oxide) or alkyl ether thereof and Y is a polyester where the polyester can comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide
  • these fibrosis-inhibiting agent/secondary carrier compositions can be (a) incorporated directly into, or onto, the soft tissue implant, (b) incorporated into a solution (e.g., the saline within a soft tissue implant), (c) incorporated into a gel or viscous solution (e.g., the silicone or gelatinous filler of a soft tissue implant), (d) incorporated into the composition used for coating the soft tissue implant, or (e) incorporated into, or onto, the soft tissue implant following coating of the implant with a coating composition.
  • a solution e.g., the saline within a soft tissue implant
  • a gel or viscous solution e.g., the silicone or gelatinous filler of a soft tissue implant
  • fibrosis-inhibiting agent loaded PLGA microspheres may be incorporated into a polyurethane coating solution, which is then coated onto the soft tissue implant.
  • the soft tissue implant can be coated with a polyurethane and then allowed to partially dry such that the surface is still tacky.
  • a particulate form of the fibrosis-inhibiting agent or fibrosis-inhibiting agent/secondary carrier can then be applied to all or a portion of the tacky coating after which the device is dried.
  • the soft tissue implant can be coated with one of the coatings described above.
  • a thermal treatment process can then be used to soften the coating, after which the fibrosis-inhibiting agent or the fibrosis-inhibiting agent/secondary carrier is applied to the entire implant or to a portion of the implant (e.g., outer surface).
  • the coated soft tissue implant that inhibits or reduces an in vivo fibrotic reaction is further coated with a compound or compositions which delay the release of and/or activity of the fibrosis-inhibiting agent.
  • a compound or compositions which delay the release of and/or activity of the fibrosis-inhibiting agent include biologically inert materials such as gelatin, PLGA/MePEG film, PLA, polyurethanes, silicone rubbers, surfactants, lipids, or polyethylene glycol, as well as biologically active materials such as heparin (e.g., to induce coagulation).
  • the active agent on the soft tissue implant is top-coated with a physical barrier.
  • barriers can include non-degradable materials or biodegradable materials such as gelatin, PLGA/MePEG film, PLA, or polyethylene glycol among others.
  • the rate of diffusion of the therapeutic agent in the barrier coat is slower that the rate of diffusion of the therapeutic agent in the coating layer.
  • the MePEG will dissolve out of the PLGA, leaving channels through the PLGA to an underlying layer containing the fibrosis- inhibiting agent, which then can then diffuse into the tissue and initiate its biological activity.
  • a particulate form of the active agent may be coated onto the soft tissue implant using a polymer (e.g., PLG, PLA, polyurethane).
  • a second polymer that dissolves slowly or degrades e.g., MePEG-PLGA or PLG
  • MePEG-PLGA or PLG e.g., MePEG-PLGA or PLG
  • the top layer dissolves or degrades, it exposes the under coating which allows the active agent to be exposed to the treatment site or to be released from the coating.
  • the outer layer of the coating of a coated soft tissue implant that inhibits an in vivo fibrotic response is further treated to crosslink the outer layer of the coating.
  • This can be accomplished by subjecting the coated implant to a plasma treatment process.
  • the degree of crosslinking and nature of the surface modification can be altered by changing the RF power setting, the location with respect to the plasma, the duration of treatment as well as the gas composition introduced into the plasma chamber.
  • Protection of a biologically active surface can also be utilized by coating the implant surface with an inert molecule that prevents access to the active site through steric hindrance, or by coating the surface with an inactive form of the fibrosis-inhibiting agent, which is later activated.
  • the implant can be coated with an enzyme, which causes either release of the fibrosis-inhibiting agent or activates the fibrosis-inhibiting agent.
  • Another example of a suitable soft tissue implant surface coating includes an anticoagulant such as heparin, which can be coated on top of the fibrosis-inhibiting agent. The presence of the anticoagulant delays coagulation. As the anticoagulant dissolves away, the anticoagulant activity may stop, and the newly exposed fibrosis-inhibiting agent may inhibit or reduce fibrosis from occurring in the adjacent tissue or coating the implant.
  • the soft tissue implant can be coated with an inactive form of the fibrosis-inhibiting agent, which is then activated once the device is deployed. Such activation can be achieved by injecting another material into the treatment area after the device (as described below) is deployed or after the fibrosis- inhibiting agent has been administered to the treatment area (via, e.g., injections, spray, wash, drug delivery catheters or balloons).
  • the soft tissue implant can be coated with an inactive form of the fibrosis-inhibiting agent. Once the implant is deployed, the activating substance is injected or applied into or onto the treatment site where the inactive form of the fibrosis- inhibiting agent has been applied.
  • a soft tissue implant can be coated with a biologically active fibrosis-inhibiting agent and a first substance having moieties that capable of forming an ester bond with another material.
  • the coating can be covered with a second substance such as polyethylene glycol.
  • the first and second substances can react to form an ester bond via, e.g., a condensation reaction.
  • an esterase is injected into the treatment site around the outside of the soft tissue implant, which can cleave the bond between the ester and the fibrosis-inhibiting agent, allowing the agent to initiate fibrosis-inhibition.
  • the implants and compositions of the invention may include one or more additional ingredients and/or therapeutic agents, such as surfactants (e.g., PLURONICS, such as F-127, L-122, L-101 , L-92, L-81 , and L-61), antiinflammatory agents (e.g., dexamethasone or aspirin), antithrombotic agents (e.g., heparin, high activity heparin, heparin quaternary amine complexes (e.g., heparin benzalkonium chloride complex)), anti-infective agents (e.g., 5- fluorouracil (5-FU), triclosan, rifamycim, and silver compounds), preservatives, anti-oxidants and/ or anti-platelet agents.
  • surfactants e.g., PLURONICS, such as F-127, L-122, L-101 , L-92, L-81 , and L-61
  • antiinflammatory agents e.g.,
  • the implant or therapeutic composition can also comprise radio-opaque, echogenic materials and magnetic resonance imaging (MRI) responsive materials (i.e., MRI contrast agents) to aid in visualization of the composition under ultrasound, fluoroscopy and/or MRI.
  • MRI magnetic resonance imaging
  • a composition may be echogenic or radiopaque (e.g., made with echogenic or radiopaque with materials such as powdered tantalum, tungsten, barium carbonate, bismuth oxide, barium sulfate, metrazimide, iopamidol, iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol, iotrolan, acetrizoic acid derivatives, diatrizoic acid derivatives, iothalamic acid derivatives, ioxithalamic acid derivatives, metrizoic acid derivatives, iodamide, lypophylic agents, iodipamide and ioglycamic acid or, by the addition of microspheres or bubbles which present an acoustic interface).
  • materials such as powdered tantalum, tungsten, barium carbonate, bismut
  • contrast agents e.g., gadolinium (III) chelates or iron oxide compounds
  • a medical device may include radio-opaque or MRI visible markers (e.g., bands) that may be used to orient and guide the device during the implantation procedure.
  • the implants may, alternatively, or in addition, be visualized under visible light, using fluorescence, or by other spectroscopic means.
  • Visualization agents that can be included for this purpose include dyes, pigments, and other colored agents.
  • the composition may further include a colorant to improve visualization of the composition in vivo and/or ex vivo. Frequently, compositions can be difficult to visualize upon delivery into a host, especially at the margins of an implant or tissue.
  • a coloring agent can be incorporated into a composition to reduce or eliminate the incidence or severity of this problem. The coloring agent provides a unique color, increased contrast, or unique fluorescence characteristics to the composition.
  • a composition in one aspect, includes a colorant such that it is readily visible (under visible light or using a fluorescence technique) and easily differentiated from its implant site.
  • a colorant can be included in a liquid or semi-solid composition.
  • a single component of a two-component mixture may be colored, such that when combined ex-vivo or in-vivo, the mixture is sufficiently colored.
  • the coloring agent may be, for example, an endogenous compound (e.g., an amino acid or vitamin) or a nutrient or food material and may be a hydrophobic or a hydrophilic compound.
  • the colorant has a very low or no toxicity at the concentration used.
  • colorants that are safe and normally enter the body through absorption such as ⁇ - carotene.
  • Representative examples of colored nutrients include fat soluble vitamins such as Vitamin A (yellow); water soluble vitamins such as Vitamin B12 (pink-red) and folic acid (yellow-orange); carotenoids such as ⁇ -carotene (yellow-purple) and lycopene (red).
  • coloring agents include natural product (berry and fruit) extracts such as anthrocyanin (purple) and saffron extract (dark red).
  • the coloring agent may be a fluorescent or phosphorescent compound such as ⁇ -tocopherolquinol (a Vitamin E derivative) or L-tryptophan.
  • the implants and compositions of the present invention include one or more coloring agents, also referred to as dyestuffs, which may be present in an effective amount to impart observable coloration to the composition, e.g., the gel.
  • coloring agents include dyes suitable for food such as those known as F. D. & C.
  • a colorant such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and so forth.
  • Derivatives, analogues, and isomers of any of the above colored compound also may be used.
  • the method for incorporating a colorant into an implant or therapeutic composition may be varied depending on the properties of and the desired location for the colorant. For example, a hydrophobic colorant may be selected for hydrophobic matrices.
  • the colorant may be incorporated into a carrier matrix, such as micelles. Further, the pH of the environment may be controlled to further control the color and intensity.
  • the implants and compositions of the present invention include one or more preservatives or bacteriostatic agents present in an effective amount to preserve the composition and/or inhibit bacterial growth in the composition, for example, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, ethyl hydroxybenzoate, propyl hydroxybenzoate, erythromycin, chlorocresol, benzalkonium chlorides, and the like.
  • the preservative include paraoxybenzoic acid esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
  • the compositions of the present invention include one or more bactericidal (also known as bacteriacidal) agents.
  • the implant s and compositions of the present invention include one or more antioxidants, present in an effective amount.
  • the antioxidant include sulfites, alpha-tocopherol and ascorbic acid.
  • the therapeutic composition may be biocompatible, and release one or more fibrosis-inhibiting agents over a period of several hours, days, or, months.
  • release of an agent refers to any statistically significant presence of the agent, or a subcomponent thereof, which has disassociated from the compositions and/or remains active on the surface of (or within) the composition.
  • the compositions of the present invention may release the anti-scarring agent at one or more phases, the one or more phases having similar or different performance ⁇ e.g., release) profiles.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

On utilise des implants pour tissus mous (p. ex des implants pour la poitrine, pectoraux, pour le menton, faciaux, pour les lèvres) en combinaison avec un agent empêchant la formation de cicatrices susceptibles de se développer lorsque l'implant est placé dans l'animal.
PCT/US2006/011690 2005-05-10 2006-03-31 Implants pour tissus mous, agents prevenant la formation de cicatrices et compositions therapeutiques WO2006121521A2 (fr)

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US67929305P 2005-05-10 2005-05-10
US60/679,293 2005-05-10
US60/679,962 2005-05-10

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Cited By (4)

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US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
CN113423411A (zh) * 2018-10-19 2021-09-21 明尼苏达大学董事会 用碳二亚胺处理的耐受性疫苗诱导移植物耐受
US12029820B2 (en) 2015-09-29 2024-07-09 Acorda Therapeutics, Inc. Sustained release compositions of 4-aminopyridine

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Publication number Priority date Publication date Assignee Title
US12133930B2 (en) 2017-05-24 2024-11-05 Theramicro, Llc System and methods for soft-tissue augmentation

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US20050175703A1 (en) * 2003-11-20 2005-08-11 Angiotech International Ag Polymer compositions and methods for their use

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US20050175703A1 (en) * 2003-11-20 2005-08-11 Angiotech International Ag Polymer compositions and methods for their use

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12029820B2 (en) 2015-09-29 2024-07-09 Acorda Therapeutics, Inc. Sustained release compositions of 4-aminopyridine
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US12122833B2 (en) 2016-05-11 2024-10-22 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
CN113423411A (zh) * 2018-10-19 2021-09-21 明尼苏达大学董事会 用碳二亚胺处理的耐受性疫苗诱导移植物耐受

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