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WO2009149537A1 - Mélange polymère-lipide injectable - Google Patents

Mélange polymère-lipide injectable Download PDF

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Publication number
WO2009149537A1
WO2009149537A1 PCT/CA2008/002172 CA2008002172W WO2009149537A1 WO 2009149537 A1 WO2009149537 A1 WO 2009149537A1 CA 2008002172 W CA2008002172 W CA 2008002172W WO 2009149537 A1 WO2009149537 A1 WO 2009149537A1
Authority
WO
WIPO (PCT)
Prior art keywords
blend
wsc
chitosan
epc
fatty acid
Prior art date
Application number
PCT/CA2008/002172
Other languages
English (en)
Inventor
Christine Allen
Justin Grant
Jeapyoung Cho
Patrick Lim Soo
Micheline Piquette-Miller
Original Assignee
Christine Allen
Justin Grant
Jeapyoung Cho
Patrick Lim Soo
Micheline Piquette-Miller
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
Priority claimed from PCT/CA2008/001128 external-priority patent/WO2008151433A1/fr
Application filed by Christine Allen, Justin Grant, Jeapyoung Cho, Patrick Lim Soo, Micheline Piquette-Miller filed Critical Christine Allen
Publication of WO2009149537A1 publication Critical patent/WO2009149537A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/736—Chitin; Chitosan; Derivatives thereof
    • 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
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

  • the present invention relates in general to biodegradable, biocompatible systems.
  • the present invention relates more particularly to injectable polymer- lipid blend systems, including for localized drug delivery.
  • Material blends have been employed in the preparation of advanced drug delivery systems by combining the favorable properties of excipients to produce hybrid composites with enhanced characteristics.
  • injectable blends in the form of pastes and gels have been prepared which allow for easy administration directly to a targeted site and avoid prevalent toxicities that occur via systemic administration.
  • sustained release of drug from a blend formulation over an extended period can increase the overall efficacy of the drug by several means including: higher drug content at the treatment site, prolonged exposure for cell cycle specific drugs, increased tumor penetration, reduced drug resistance and improved patient compliance.
  • injectable blend systems are effective for localized delivery of anticancer agents, growth factors, proteins, antisense oligonucleotides, and scaffolds.
  • biocompatible, biodegradable injectable systems that can be administered in liquid form and remain as a semi-solid depot system over an extended period of time are clinically desirable.
  • the formation of a semi-solid implant allows for a targeted localized drug delivery system that may be more effective than current medical therapies.
  • localized drug delivery devices may require a lower drug dosage to achieve therapeutic concentrations as the drug is released at a specific site which in turn will reduce the prevalence of systemic side effects.
  • its ease of application by syringe injection may replace surgical procedures required for implanting medical devices. Patients with cancer, particularly solid tumors, diabetes, addiction disorders and wounds are ideal candidates for this drug therapy approach.
  • in situ precipitation is a method in which the injectable system solidifies in the body by precipitation of the material due to environmental changes such as temperature, pH, and solvent removal.
  • water insoluble polymers such as poly(lactide) (PLA), poly(lactide-co-glycolide (PLGA), and poly(lactide)-co-poly(caprolactone) (PLA-co-PCL) may be dissolved in a physiologically compatible water-miscible solvent and injected into an aqueous environment to precipitate the polymer.
  • polyesters such as PLA, PCL, or PLGA may be injected into the body as a melt and solidify upon cooling to body temperature of 37 0 C. These polymers also contain a low intrinsic viscosity below 0.8 dl/g in order to be easily injected via 22 gauge syringe.
  • high temperatures are often required for thermoplastic pastes at the time of injection and the degradation of polyester-based materials produces acid byproducts that may compromise the biocompatibility of the implant. Therefore, there is a need for new biomaterials to be employed in the preparation of implantable drug delivery systems.
  • Chitosan-based polymer blends have been found to be useful for controlled drug delivery because they degrade uniformly into non-toxic molecules that are non-mutagenic, non-cytotoxic, and non-inflammatory.
  • Chitosan is a natural, biodegradable cationic polysaccharide, which has previously been described as a promoter of wound healing.
  • Chitosan is a commercially available inexpensive polymer which is mainly composed of D-glucosamine units that are generated through catalyzed N-deacetylation of chitin, a natural material extracted from fungi, shellfish exoskeletons and algae. Chitosan has excellent tissue compatibility and biodegradability which renders it ideal for injection.
  • Various acids such as lactic acid, acetic acid and hydrochloric acid may be used to dissolve chitosan to formulate various drug delivery systems.
  • chitosan may be conjugated with glycidyltrimethylammonium chloride (“GTMAC”) in order to increase the biopolymer's water solubility.
  • GTMAC glycidyltrimethylammonium chloride
  • This chitosan derivative has high water solubility, up to 25 g/dL, without use of any acid.
  • WSC Water soluble chitosan
  • WSC Water soluble chitosan
  • the water solubility and biological properties of WSC grants an excellent polymer candidate, which can be used to formulate drug delivery systems, and serve as a polymer matrix for the drug to provide a controlled release drug delivery platform. Furthermore, its biodegradability allows the delivery system to completely degrade in vivo.
  • Fatty acids are known to be involved in a number of biological processes, including metabolism, energy storage, immune response, blood clotting, blood pressure regulation, formation of biological structures such as membranes, and formation in the body of compounds such as prostaglandins. Fatty acids are currently approved for use as inactive excipients in sublingual, oral, topical and vaginal formulations in the form of films, capsules, sprays, ointments, emulsions and creams. N-acetlyated chitosan derivatives have been prepared using fatty acid chlorides to produce a hydrophobic matrix in tablets for the sustained release of acetaminophen. (Le Tien, C, et al., Journal of Controlled Release, 2003. 93(1): p.
  • the initial chitosan component is achieved by dissolving it in acetic acid to ensure total solubility of the chitosan derivative, which is then modified using fatty acid chlorides.
  • the use of an acidic solution to prepare the derivative can cause toxicity and drug degradation in the blend.
  • Phospholipids due to their excellent biocompatibility, have been commonly used in preparation of drug delivery systems in the form of liposomes, emulsions, and films.
  • Phosphatidylcholine lipids are the major membrane phospholipids found in eukaryotic cells.
  • Egg phosphatidylcholine (“ePC”) consists of a mixture of phosphatidylcholine lipids having hydrocarbon chains of different lengths and degrees of saturation.
  • a blend prepared from two distinct families of materials, namely the biopolymer chitosan and the lipid ePC (“PoLi”), for use as an implantable film for localized drug delivery has been disclosed in United States Patent Application No. 2005/0208122 to Allen et al.
  • the implant provides a sustained release of a hydrophobic drug over an extended period in physiological solutions and in vivo.
  • acid is used to dissolve chitosan.
  • the PoLi implant system demonstrates both biocompatibility and efficacy in vitro and in vivo, it requires a long processing time and surgical implantation at a tumour resection site to provide controlled release of an anticancer agent or other drug.
  • an injectable biodegradable, biocompatible controlled drug delivery system comprising a chitosan based material in combination with a fatty acid and ePC, and the use of this system in the delivery of pharmaceutically active agents, are desirable. It would also be desirable if said injectable system could be prepared without the use of an acid for dissolving the chitosan based material.
  • an injectable composition comprising a semi-solid blend of at least three carrier materials: a chitosan-based material; one or more fatty acids having an acyl chain length of C8-C16, preferably C10-C14, most preferably C12; and one or more phospholipids.
  • the fatty acid may be a fatty acid chloride or a fatty acid aldehyde, preferably laurinaldehyde.
  • the chitosan-based material may be a water soluble chitosan derivative prepared by conjugating a chitosan-based material with GTMAC.
  • the phospholipid may be selected from the group consisting of phosphatidylcholines, phosphatidylethanolamine, ePC and phosphatidylglycerol.
  • the injectable composition may be formulated for injection through a syringe needle.
  • a method of manufacture of the injectable composition comprising the steps of preparing water soluble chitosan from a chitosan-based material; and forming a complex of the water soluble chitosan with a fatty acid and a phospholipid to form an injectable material.
  • a chitosan-based material a fatty acid, and a phospholipid in the manufacture of an injectable substance for cosmetic use.
  • a composition comprising a chitosan-based material, a fatty acid, and a phospholipid as a cosmetic substance.
  • one embodiment of the present invention is an injectable drug delivery composition for the controlled release of a pharmaceutically active agent, the injectable drug delivery composition comprising a semi-solid blend of at least three carrier materials which have favorable properties for drug delivery: a chitosan-based material; one or more fatty acids having an acyl chain length of C8-C16, preferably C10-C14, most preferably C 12; and one or more phospholipids, loaded with at least one pharmaceutically active agent.
  • the fatty acid may be a fatty acid chloride or a fatty acid aldehyde, preferably laurinaldehyde.
  • the composition is for the delivery of at least one pharmaceutically active agent to provide controlled release when administered to a target site in a mammal.
  • the blend includes a chitosan derivative which is water soluble chitosan.
  • the water soluble chitosan may be produced by conjugating a chitosan material with
  • GTMAC for example.
  • Other forms of water soluble chitosan are also within the scope of the present invention.
  • the viscosity of the drug delivery blend is related to the fatty acid selected and the pharmaceutically active agent.
  • the size of the acyl chain of the fatty acid is therefore selected to achieve an appropriate viscosity for injectability.
  • the phospholipid may be selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, egg phophatidylcholine and phosphatidylglycerol.
  • the pharmaceutically active agent may be selected from the group consisting of carmustine, methotrexate, carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, 5- fluorouridine, cytarabine, leuprolide acetate, cyclophosphamide, vinorelbine, pilocarpine, paclitaxel, mitomycin, camptothecin, doxorubicin, daunorubicin and docetaxel.
  • the pharmaceutically active agent may be an oligonucleotide, a peptide or a protein.
  • the injectable drug delivery composition may be formulated for injection through a syringe needle.
  • one embodiment of the present invention is a drug delivery platform for the loading, delivery and controlled release of a pharmaceutically active agent, comprising a water soluble chitosan; a fatty acid having an acyl chain length of C12; and a phospholipid selected from the group consisting of phosphatidylcholines, phosphatidylethanolamine, ePC and phosphatidyl lycan
  • a method of manufacturing a composition comprising preparing a water soluble chitosan from a chitosan-based material; and forming a complex of the water soluble chitosan with a fatty acid and a phospholipid to form an injectable material.
  • Water soluble chitosan may be prepared, for example, by conjugating a chitosan-based material with GTMAC.
  • a method of manufacturing a drug delivery composition for controlled release in a mammal comprising preparing a water soluble chitosan from a chitosan-based material; and forming a complex of the water soluble chitosan with a fatty acid and a phospholipid to form an injectable material for providing the controllable release of at least one pharmaceutically active agent.
  • Water soluble chitosan may be prepared, for example, by conjugating a chitosan-based material with GTMAC.
  • a method of treating, preventing or inhibiting disease comprising administering a therapeutically effective amount of an injectable drug delivery composition for the controlled release of a pharmaceutically active agent.
  • the disease may be any disease which is treatable at localized areas of the body, for example, a cancer.
  • a chitosan-based material a fatty acid, a phospholipid, and at least one pharmaceutically active agent in the manufacture of a drug delivery system to treat disease.
  • An object of one aspect of one embodiment of the present invention is to provide improved injectable polymer-lipid blends of pharmaceutically active agents as a method to provide sustained, local delivery of individual drugs or drug combinations.
  • Advantages of the present invention include the protection of drugs from degradation, the maintenance of effective concentrations of drugs, a decrease in the frequency of administration of drugs, a decrease in the dosage of therapeutic agents administered to patients, and a decrease in toxicities or side-effects that may result following systemic administration of drugs.
  • Fig. 1 illustrates the chemical structures of components of possible drug delivery blends in accordance with one embodiment of the present invention.
  • the letter 'm' represents an acyl chain length of from C10 to C16.
  • X is Cl
  • the fatty acid is a fatty acid chloride.
  • X is H
  • the fatty acid is a fatty aldehyde.
  • Fig. 3 illustrates (a) DSC thermograms of WSC, ePC and C12 FA (b) WSC-FA blends (1 :1 , w/w) with varying FA acyl chain length; and (c) WSC-FA- ePC blends (1 :4:1 , w/w/w) with varying FA acyl chain length.
  • Fig. 4 illustrates Fourier transform infra-red spectra of (a) WSC, lauroyl chloride (C12 FA), WSC-FA(C12) blend, WSC-ePC blend and 1 :4:1 (w/w/w) WSC-FA-ePC, and (b) 1 :4:1 (w/w/w) WSC-FA-ePC blends varying in FA acyl chain length from C10 to C16.
  • Fig. 5 illustrates optical micrographs of the WSC:FA(C12):ePC blends (a) 1 :0:1 (w/w/w) (b) 1 :4:0 (w/w/w) and (c) 1 :4:1 (w/w/w).
  • Fig. 6 illustrates fluorescence confocal microscopy of 1 :4:1 (w/w/w) WSC- FA-ePC blends containing (a) C10 FA 1 (b) C12 FA, and (c) C16 FA where regions of lipid and/or fatty acid are in the top left image, WSC is in the top right image and the overlay of the WSC and FA-ePC regions is in the bottom left.
  • Fig. 7 illustrates a comparison of viscosity as a function of shear stress for
  • Fig. 9 illustrates the drug release profile of (a) the WSC-FA C12-ePC 1 :4:1 (w/w/w) blend fitted to different kinetic models and (b) the 1 :4:1 (w/w/w) WSC- FA-ePC blends varying in FA acyl chain length modeled by the Peppas-Sahlin equation.
  • Fig. 10 illustrates the ratio of Case Il transport to Fickian diffusion
  • Fig. 11 illustrates cell viability for blend compositions in which the FA is lauroyl chloride.
  • Fig. 12 illustrates turbidity data for blend compositions in which the FA is laurinaldehyde.
  • Fig. 13 illustrates turbidity data for additional blend compositions in which the FA is laurinaldehyde.
  • Fig. 14 illustrates partition coefficients for high and low molecular weight chitosan compositions.
  • Fig. 15 illustrates cumulative release of paclitaxel from a blend composition.
  • Fig. 16 illustrates experimental data and data predicted by the Ritger- Peppas and Peppas-Sahlin models for paclitaxel release.
  • Fig. 17 illustrates cell viability for blend compositions including laurinaldehyde.
  • Fig. 18 illustrates a comparison of docetaxel release from fatty acid chloride and laurinaldehyde blend compositions.
  • Figs. 19A and 19B illustrate release of varying loads of docetaxel from laurinaldehyde blend compositions.
  • Figure 20 illustrates plasma alanine aminotransferase (ALT) levels in CD- 1 mice between 2 days and 4 weeks after injection of drug-free or docetaxel- loaded blend compositions.
  • ALT alanine aminotransferase
  • Figure 21 illustrates average plasma concentration levels of docetaxel ( ⁇ g/mL) in CD-1 mice at times between 2 days and 7 weeks after injection of docetaxel-loaded blend compositions.
  • Polymer indicates a molecule composed of a number of identical repeating units.
  • Chitosan indicates any compound or composition which is a derivative or analogue of chitin. This term also includes chitin and various derivatives of chitosan such as carboxymethylchitosan, oleoyl chitosan and pegylated chitosan (Carbomer, Inc., Westborough, Mass.)
  • composition as used herein should be understood to indicate a combination of multiple substances into an aggregate mixture.
  • Controlled release indicates the release of therapeutically active agents or pharmaceutically active agents into the surrounding media or body over an extended time period.
  • the time period may be from approximately a few hours to several months.
  • Drug “Drug”, “therapeutic agent” and “therapeutic” each indicates any molecule that has a significant effect on the body to treat or prevent conditions or diseases.
  • Fatty acid (“FA”) includes, without limitation, fatty acid chloride and fatty aldehyde of any acyl chain length.
  • “Pharmaceutically active agent” means any of a drug, a therapeutic agent, a pro-drug or a diagnostic.
  • Hydrophilic Drug means any pharmaceutically active agent that is only soluble in water at less than 50 mg/L at 25 0 C.
  • Antiproliferative agent means a molecule that acts to inhibit proliferative events.
  • anti-proliferative agents include, but are not limited to, paclitaxel, carboplatin, cisplatin. Detailed Description
  • the drug may be combined with a carrier or vehicle that is biocompatible and biodegradable.
  • Suitable carriers for drug incorporation range in size from small molecules to macromolecules, including high molecular weight polymers.
  • Polymer-based devices can be used to release a drug at a specific location at a controlled release rate over an extended period of time.
  • the most desirable polymeric means for drug delivery is one that is inexpensive, biocompatible, and biodegradable, and provides uniform, controlled release of the drug in an aqueous environment.
  • the polymer-lipid blend of the present invention may be used as a local drug delivery device that is applied to a targeted site and allows prolonged controlled release of a drug or other active agent over an extended period, which may range from several days to several months.
  • the blend can be administered in a variety of ways, but is particularly suited as an injectable drug delivery means.
  • the blend may also be administered without a drug or other active agent.
  • an injectable drug delivery composition for the controlled release of a pharmaceutically active agent, the injectable drug delivery composition comprising a semi-solid blend of at least three carrier materials which have favorable properties for drug delivery: a chitosan-based material; one or more fatty acids having an acyl chain length of C8-C16, preferably C10-C14, most preferably C12; and one or more phospholipids, loaded with at least one pharmaceutically active agent.
  • the fatty acid may be a fatty acid chloride or a fatty acid aldehyde, preferably laurinaldehyde.
  • the composition is for the delivery of at least one pharmaceutically active agent to provide controlled release when administered to a target site in a mammal.
  • the unique formulation provides controlled release of hydrophilic agents, hydrophobic agents or combinations of hydrophilic and hydrophobic agents.
  • the polymer-lipid blend of the present invention may also be used without drug loading as a cosmetic substance. Such a drug-free polymer-lipid blend may be injected in a desired amount in a desired location of the body for cosmetic purposes.
  • Chitosan is a linear polysaccharide composed of two monosaccharides linked by glycoside bonds and is manufactured by deacylation of chitin.
  • Chitosan is a mucoadhesive, biocompatible polymer that is commercially available in a range of molecular weights and degrees of deacylation. As the molecule has a protonable primary amine on a side chain, chitosan has weak cationic properties.
  • Chitosan is a naturally occurring biodegradable, biocompatible polysaccharide that has been investigated for use in a variety of biomedical applications including wound dressings, sutures, artificial skin, tissue engineering and drug delivery.
  • Chitosan is typically not soluble in water but may be dissolved in weak acids such as a 2% acetic acid solution, and the chitosan degrades in vivo under the action of enzymes such as lysozymes.
  • Various acids i.e. lactic acid, acetic acid and hydrochloric acid
  • lactic acid, acetic acid and hydrochloric acid are normally used to dissolve chitosan in order to formulate various drug delivery systems.
  • residual acid may remain within the drug formulation and in turn reduce the biocompatibility or non-toxicity of the delivery system as well as accelerate the degradation of some drugs.
  • chitosan can be conjugated with glycidyltrimethylammonium chloride ("GTMAC”) in order to increase the biopolymer's water solubility.
  • GTMAC glycidyltrimethylammonium chloride
  • WSC water soluble chitosan
  • WSC has high water solubility of up to 25 g/dL without the use of any acid.
  • WSC is also known to have antimicrobial activity and the quaternary ammonium group in GTMAC has been found to inhibit the proliferation of various cancer cell lines.
  • WSC also acts as a surfactant for the fatty acid component as it prevents phase separation that occurs when the fatty acid is in contact with distilled water.
  • WSCs biodegradability allows the delivery system to completely degrade in vivo.
  • Fatty acids are known to be involved in a number of biological processes and in forming biological structures and compounds within the body.
  • a fatty acid may be mixed with WSC and phospholipids to develop a stable injectable blend for drug delivery.
  • the fatty acids used in the blend may include, without limitation, fatty acid chlorides or fatty aldehydes such as laurinaldehyde.
  • the fatty acid acyl chain length may vary, for example, from C8 to C16.
  • the phospholipid or lipid components may include phosphatidylcholines, phosphatidylserines, phosphatidylinositols, phosphatidylethanolamines, phosphatidylglycerols, or a mixture thereof.
  • the source of phospholipids may be a commercially available egg yolk extraction primarily comprised of phosphatidylcholine (>60%) and other phospholipids (40%).
  • Phosphatidylcholine is the principle membrane phospholipid found in human and animal cells and is commonly used in pharmaceutical liposome formulations.
  • the pharmaceutically active agents of the present invention can be any of those agents which are generally required to be frequently administered in order to maintain an effective blood concentration or an effective concentration of the pharmaceutically active agent content locally.
  • pharmaceutically active agents may include various anticancer or anti-proliferative agents, including, without limitation, carmustine, methotrexate, carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, 5-fluorouridine, cytarabine, leuprolide acetate, cyclophosphamide, vinorelbine, pilocarpine, paclitaxel, mitomycin, camptothecin, doxorubicin, and daunorubicin.
  • Other examples of pharmaceutically active agents include oligonucleotides, peptides and proteins.
  • the stability of polymer-lipid blends is known to be related to the ratio of the components and the acyl chain length of the fatty acid employed.
  • the effect of fatty acyl chain lengths, ranging from C6-C16, is to alter the viscosity of the final blend.
  • the viscosity and yield stress values increase.
  • the rheological properties of injectable systems are important for drug formulations as a blend with low viscosity may not exhibit a controlled drug release profile.
  • the viscosity in a polymeric system increases when there are more interactions between macromolecules, such as entanglement, physical interaction (i.e. van der waals, hydrophobic and hydrogen bonding interactions) and cross-linking. These interactions between macromolecules can be used to trap the drug in a polymer matrix. Thus, the more interactions present in a polymer system, the slower the rate of drug release.
  • the solubility of the drug in a formulation can also strongly influence the drug release performance. Accordingly, depending on the specific treatment that is required, the drug release can be controlled by modifying either the type of fatty acid used or the specific concentrations of each of the individual components in the blend.
  • a C12 fatty acid blend is an optimal chain length for preparation of a stable semi-solid injectable blend system for paclitaxel ("PTX"). Furthermore, PTX release from the blend systems shows Fickian diffusion for C12 FA and C14 FA blends.
  • the C16 FA blend involves Case Il transport mechanisms.
  • compositions of the present invention can be prepared as injectable drug delivery systems for intraperitoneal, intraarticular, intraocular, intratumoral, perivascular, subcutaneous, intracranial, intramuscular, intravenous, periophthalmic, inside the eyelid, intraortal, intranasal, intrabladder, intravaginal, intraurethral, or intrarectal delivery.
  • the compositions can be formulated to be injected through a syringe needle, though mode of administration need not be limited to injection.
  • the subject or patient can be a human or other mammal.
  • Advantages of the present invention should be understood to include: protection of therapeutic agents from degradation; maintenance of effective concentrations of the therapeutic either locally or systemically, decrease of the frequency of administration of the therapeutic agent; decrease of the amount of therapeutics administered to patients per dose; and decrease of the toxicities or side effects that usually result following systemic administration.
  • a controlled release drug delivery composition comprising a chitosan-based material, a fatty acid, at least one phospholipid component and at least one pharmaceutically active agent to provide controllable release of the at least one pharmaceutically active agent when administered to a mammalian subject or patient.
  • the methods of manufacture may produce a solution having desirable viscosity for use as a stable semi-solid injectable blend.
  • the preparation of a blend may include an initial step of modifying chitosan, chitin or a mixture thereof to a WSC derivative using GTMAC. This is achieved by generating a mixing GTMAC and chitosan in a ratio of 3:1 mol/mol, for example, following by a suitable purification procedure.
  • the WSC derivative is then weighed and dissolved in distilled water.
  • the ePC is then solubilized with fatty acids (varying in acyl chain length) and added to the WSC solutions in specific weight ratios.
  • WSC acts as a surfactant for FA as it prevents phase separation that occurs when FA is in contact with distilled water.
  • the WSC-FA-ePC blend may be vortexed, e.g., for two minutes, and stored at room temperature.
  • the injectable delivery system of the present invention may be advantageous as a treatment strategy for various diseases, including cancers of the prostate, breast, ovarian, bladder, brain, liver, gastric, head and neck.
  • the drug delivery composition of the present invention affords a method of delivering by controlled release at least one pharmaceutically active agent.
  • various cancers in which the current invention could be utilized.
  • the current invention could also be utilized as a drug delivery system in the treatment of diseases other than cancer, particularly where a localized method of drug delivery is optimal for favourable health outcomes.
  • the drug-free polymer lipid blend of the present invention may be used as an injectable cosmetic substance.
  • the drug-free blend may be used as an injectable filler in soft tissue augmentation procedures, involving injection of the polymer-lipid blend into the skin to fill and smooth wrinkles.
  • WSC and ePC to develop a stable injectable blend for drug delivery.
  • Thermal analysis was used to determine the stability of the blend components at body temperature.
  • FTIR measurements were employed to investigate the interactions present between the components in order to optimize the stability of the blend.
  • Morphological examination provided an indication of the functionality of each of the components within the formulation at a microscale level.
  • rheological and stability measurements were required.
  • release of the anticancer agent PTX from the WSC-FA-ePC blends was evaluated in physiological solution. Relationships between the composition of the WSC-FA-ePC blend and its properties were identified in order to optimize the performance of the blends for pharmaceutical applications.
  • Chitosan (90%) was purchased from Marinard Biotech Inc. (Riviere-au- Renard, QC, Canada).
  • ePC (>99%) was obtained from Northern Lipids Inc. (Vancouver, BC, Canada).
  • Unlabelled PTX (>99%) and C 14 -PTX were purchased from Hande Tech Development Co. (Houston, TX) and Moravek (Brea, CA), respectively.
  • the fluorescent probe 3-phosphoethanolamine-N-(7- nitro-2-1 ,3-benzoxadiazol-4-yl) (NBD-DPPE) was purchased from Avanti Polar Lipids Inc. (Alabaster, AL).
  • Glycidyltrimethylammonium chloride 1 acetone, ethanol, methanol, acetic acid (AcOH), fatty acid chlorides (i.e. capryloyl chloride (C8), decanoyl chloride (C10), lauroyl chloride (C12), myristoyl chloride (C14) and palmitoyl chloride (C16)) and all other chemicals were purchased from Sigma-Aldrich Chemical Co. (Oakville, ON, Canada). All chemicals were reagent grade and used without further modification.
  • the WSC derivative composed of GTMAC and chitosan in a ratio of 3:1 mol/mol was synthesized using a previously established method. (Cho, J., et al., Biomacromolecules, 2006. 7(10): p. 2845-2855; Seong, H. S., H. S. Whang, and S.W. Ko, Journal of Applied Polymer Science, 2000. 76(14): p. 2009-2015.)
  • the WSC derivative was weighed and then dissolved in distilled water.
  • the lipid ePC was solubilized with FA varying in acyl chain length and added to the WSC solutions in specific weight ratios.
  • the WSC-FA-ePC blend was vortexed for two minutes and stored at room temperature.
  • 5 ⁇ Ci of the C 14 -PTX in ethyl acetate was added to 10 mg of PTX and dried under nitrogen to form a thin film of drug.
  • a FA-lipid solution containing C12, C14 or C16 FA and ePC was used to resuspend the PTX film prior to mixing with WSC to achieve a
  • the stability of the samples was measured as a function of turbidity, which is the amount of light that a sample scatters.
  • turbidity is the amount of light that a sample scatters.
  • Approximately 300 ⁇ L of the WSC- FA-ePC blend was injected into a vial containing 0.01 M PBS and 0.2% lysozyme since chitosan degrades in the presence of lysozyme in vivo.
  • an aliquot of the solution was added to a cuvette and analyzed using UV- vis spectroscopy (CaryTM 50 UV-vis spectrophotometer, Varian Inc., Palo Alto, CA) at 700 nm (no absorption occurred for the blend at this wavelength). The aliquot was then transferred back into the vial containing the blend for subsequent analysis.
  • the stability of the WSC-FA-ePC blends was also visually inspected during preparation and following injection into 0.01 M PBS over a 72 hour period at 37°C.
  • chitosan was modified to a WSC derivative using GTMAC.
  • GTMAC Previously, FTIR analysis revealed that the lower the degree of substitution of GTMAC onto chitosan chains, the greater the interaction between ePC and the NH 2 groups of WSC. From the series of WSC synthesized, the 56% DS WSC was the most suitable polymer for preparing the blend formulations. Different concentrations and chain lengths of FA were mixed with WSC and ePC to increase the overall hydrophobicity and subsequently the stability of the formulation in aqueous environments. In addition, WSC acts as a surfactant for FA as it prevents phase separation that occurs when FA is in contact with distilled water.
  • the chemical structures of each of the components within the blend, namely WSC, FA and ePC are shown in Fig. 1.
  • the stability of the WSC-FA-ePC blend was found to be dependent on the acyl chain length of the FA employed and the ratio of the three components. Specifically, the WSC-FA-ePC blend containing the C12 FA was unstable in buffer solution when the amount of WSC was below 1 :4:1 and above 1.5:4:1 (w/w/w) blend ratios. At low concentrations of WSC, there were insufficient reactive groups to stabilize the blend; whereas, at high concentrations of WSC, the viscosity of the blend was increased and the miscibility of the components was reduced. The stability of the blend was also found to be dependent on the amount of ePC, as a mixture of WSC and FA dissolved in the presence of buffer.
  • ePC e.g. 1 :4:0.5
  • ePC e.g. 1 :4:0.5
  • the amount of FA was crucial to the stability of the blend, since a formulation containing only WSC-ePC would dissolve rapidly in an aqueous environment as discussed above.
  • blends that contained FA below the 1 :4:1 (WSC:FA:ePC, w/w/w) ratio were unstable following the incubation period.
  • the effect of acyl chain lengths of FA ranging from C6-C16 was investigated for the 1 :4:1 (w/w/w) WSC-FA-ePC blend.
  • the blend containing either the C6 FA or C8 FA easily solubilized ePC, yet the solution phase separated in the presence of WSC.
  • the blends containing FA of C10-C16 in chain length formed stable formulations, but differed in terms of their mechanical properties. Specifically, the blends containing C10-C12 FA were semi-solid, whereas the C14-C16 FA blends solidified upon mixing. However, following 24 hours at room temperature, the blends containing the C14-C16 FA formed a viscous solution with reduced mechanical properties.
  • the C12 FA was considered the optimal chain length for preparation of a stable semisolid injectable blend. This result was confirmed by analyzing the turbidity of the WSC-FA-ePC blends as a function of chain length in physiological solution (Fig. 2). From the results, the C10 FA blend disintegrated upon injection into buffer (data not shown). However, the C12-C16 blend formulations were stable as the turbidity was less than 0.1 after 1 hour. The C12 FA blend was the most stable formulation as the turbidity did not exceed 0.05 for 2 months. The C14 FA blend also remained stable as a low turbidity ( ⁇ 0.5) was observed for the duration of the experiment. However, the C16 FA blend was unstable as the turbidity increased to ca. 1 after 3 days of incubation.
  • a DSCTM Q100 (TA Instruments, New Castle, DE) was used to determine the thermal transitions of the WSC-FA-ePC blends. Samples of 5-7 mg were placed in hermetic pans and their transition temperatures were analyzed between -40 0 C to 8O 0 C at a temperature ramp speed of 5 0 C per minute under nitrogen purge. TA universal analysis software was used to analyze the second heating cycle of all samples.
  • fatty acids generally have a sharp transition that can vary from
  • the FA and ePC components were considered to be miscible as only a single peak was observed for these materials in the temperature range investigated. Similar to the WSC-FA blends, the peak position was found to increase in temperature from 28 to 58°C with increasing FA acyl chain length. However, the peak positions for WSC-FA- ePC blends were more comparable to the values obtained in the literature for C10-C14 fatty acids (Table 2). No significant changes in melting transition were observed for the C16 blends (i.e. WSC-FA and WSC-FA-ePC). Thus, WSC-FA- ePC blends containing FA greater than an acyl chain length of C10 had thermal transitions above body temperature. However, ePC may have less interaction with longer acyl chain length FA 1 which may explain the instability observed for the WSC-FA-ePC blend containing the C16 FA (Fig. 2).
  • the FTIR spectra of the WSC-FA-ePC blends and their individual components were obtained using a universal ATR Spectrum-one spectrophotometer (Perkin-Elmer, Wellesley, MA). A background spectrum of air was subtracted from the sample spectra using Perkin-Elmer's Spectrum software. All spectra were an average of 16 scans at a resolution of 2 cm '1 , repeated in triplicate.
  • FTIR spectra of the blends and the individual components that make up the blends were analyzed (Figs. 4a and 4b).
  • WSC 56% DS
  • the conjugation of GTMAC to chitosan was confirmed by the appearance of the peak at 1475 cm '1 , which represents the methyl band of GTMAC and the peak at 1564 cm "1 corresponds to the primary amine group of chitosan.
  • FTIR analysis established that an interaction exists between the WSC (56% DS) and ePC as the peak corresponding to the NH 2 groups of WSC shifted from 1564 to 1575 cm "1 with the addition of ePC.
  • the spectra of the- C12 FA contained a sharp peak at 1800 cm '1 which represents the acid chloride groups (COCI), and peaks at 1291 cm “1 and 717 cm '1 which correspond to C-O and C-Cl bonds, respectively (Fig. 4a).
  • the peak area at 1700 cm "1 was significantly decreased for only the C12 and C14 WSC-FA-ePC blends.
  • the stability found for the WSC-FA-ePC blend containing C12 and C14 FA may be related to the interactions present at the carboxylic acid groups of FA.
  • the red regions represent the WSC component of the film and the bright green fluorescent regions correspond to the lipid and/or FA.
  • the yellow regions represent areas of co-localization or interaction between the components of the blend, while the black regions may correspond to the unlabelled FA or the uneven surface of the blend.
  • the WSC-FA-ePC (1 :4:1 , w/w/w) blend containing C10 FA the domains for both WSC and the FA-ePC appear small and scattered throughout the blend with minimal areas of interaction (Fig. 6a). This morphology may provide an indication of the instability that was observed for this blend by turbidity measurements.
  • the blend containing the C12 FA has larger domains for both WSC and FA-ePC, as well as a higher degree of interaction between the components as evidenced by the large yellow regions (Fig. 6b).
  • the larger domains may be due to the increase in hydrophobicity of the FA employed within the blend. This morphology may explain the increase in rheological properties and stability for the blends containing longer FA chains.
  • a larger degree of phase separation was apparent for the WSC-FA-ePC blend containing the C16 FA as the lipid-FA domains appear disjointed with a distinct spatial arrangement (Fig. 6C). Therefore, the acyl chain length of the FA employed within the WSC-FA-ePC blend has a significant effect on molecular arrangement of the molecules.
  • the rheological properties of WSC-FA-ePC blends were characterized by a stress-controlled rheometer with a 2 cm cone and 4° angle plate geometry (AR- 2000, TA InstrumentsTM). The rheometer was calibrated and rotational mapping was performed according to instrument specifications. The viscosity was measured using a continuous ramping flow mode while increasing the shear stress from 1 to 500 Pa. The blend formulations were stored for 24 hours prior to mechanical testing. A 200 ⁇ l_ injection of each sample was placed on the rheometer plate for mechanical testing.
  • the rheological properties of injectable systems are important for drug formulations as a blend with low viscosity may not exhibit a sustained drug release profile. However, if the blend is too viscous, difficulties will be encountered when injecting the formulation, n order to determine the optimal rheological properties of the injectable system, the viscosities of the WSC-FA- ePC blends (1 :2:1 and 1 :4:1) were measured as a function of the FA chain length using steady shear tests (Fig. 7). From the results, as the hydrocarbon chain length of the FA increased within the blends, the viscosity and yield stress values increased.
  • the blend containing the C10 FA had the lowest viscosity and yield stress values, as well as a slight increase in viscosity ( ⁇ 1 * 10 2 Pa) was found for the blend containing the C12 FA (Fig. 7a).
  • a significant increase in viscosity to approximately 1 * 10 4 Pa was measured.
  • the amount of FA was increased within the WSC-FA-ePC blend to 1 :4:1 , a similar trend was observed at higher viscosity and yield stress values (Fig. 7b).
  • the blends containing the C14 and C16 FA had a viscosity of approximately 1 * 10 5 Pa, whereas the C12 and C10 FA blends were approximately 1 * 10 4 Pa. It is known that most injectable systems use a needle size no larger than 22 gauge, otherwise special equipment such as hydraulic syringes are employed. From these results, only the WSC-FA-ePC (1 :4:1) blends containing C10 and C12 FA were injectable via a 22 gauge needle; the C14 and C16 FA blends were too viscous. Thus, from the stability and rheological analyses, the optimal formulation ratio to produce a viscous injectable blend was found to be 1 :4:1 (w/w/w) WSC-FA-ePC containing the C12 FA.
  • Taxol paclitaxel in Cremophor ® EL (polyoxyethylated castor oil) and dehydrated alcohol
  • C14 FA blend the release reached ca. 70% after 35 days, and continued at a sustained release rate of 0.2 % per day for 3 months. Similar trends have been observed in other studies.
  • K 11 , K R p , K p S ⁇ and K P S 2 are empirical constants related to the release rate
  • M(t)/M(0) is the fraction of drug release
  • t is the time of release.
  • n is the diffusional exponent which indicates the main mechanism of drug release.
  • the first term represents a Fickian diffusion contribution and the second term is the effect of Case ll-transport on drug release.
  • the release of PTX from the C12 FA blend was fitted to the various kinetic models (Higuchi, Ritger-Peppas and Peppas-Sahlin) as shown in Fig. 9.
  • the specific contribution can be determined by plotting the ⁇ p S 2 t m I ⁇ p S i value as a function of time as shown in Fig. 10. Due to the large deviation in the fitting, release data greater than 28 days was not included in the plot. Fickian diffusion is dominant when ⁇ p S 2 t m i ⁇ p s ⁇ ⁇ 1 , but
  • the higher release rate (or large K value) observed for the C16 FA blend may be attributed to the greater immiscibility that was observed from the confocal images and turbidity results (Figs. 2 and 6).
  • the chain length of the FA was increased, the overall hydrophobicity of the blend was also increased.
  • the longer fatty acids aggregate into the hydrophilic environment (i.e. aqueous WSC solution), resulting in a phase separated blend. Phase separation causes a reduction in volume (or size) of the blend, which in turn may lead to an increased surface area and a reduced diffusion length for the drug.
  • the rheological properties of the blends may also explain the higher release rate of paclitaxel from the C16 blend.
  • the rheological properties were increased when a longer FA was used to formulate the blend system (i.e. ⁇ ⁇ 100 Pas and ⁇ ⁇ 10 5 for C14 and C16, respectively).
  • the viscosity increases when there are more interactions between macromolecules in a polymeric system such as entanglement, physical interaction (i.e. Van der Waals, hydrophobic and hydrogen bonding interactions) and cross-linking. These interactions between the macromolecules can be used to trap the drug in a polymer matrix.
  • the rate of drug release will be slower.
  • the C12 FA had the lowest viscosity among the three blends, indicating the lowest connectivity, resulting in an accelerated PTX release. It is known that the solubility of the drug in a formulation can also strongly influence the drug release performance.
  • the drug release from C12 FA was faster than C14 FA 1 since PTX was more soluble in the shorter FA acyl chains.
  • the slow drug release exhibited by C14 FA blend may also be due to high viscosity (high connectivity) and minimal phase separation between the hydrophilic and hydrophobic components in the matrix.
  • the drug release can be controlled by modifying either the type of FA used or the specific concentrations of each of the individual components in the blend.
  • An injectable polymer-lipid blend including lauroyl chloride was prepared to assess cell viability.
  • the composition included a low molar weight WSC, C12 Cl and ePC in ratios of 1 :3:1 and 1 :4:1.
  • the ePC was dissolved with lauroyl chloride (C12 Cl) and vortexed to dissolve.
  • Water soluble chitosan (WSC) was then added, and the blend was further vortexed and then transferred to a 1 cc syringe.
  • the composition in the syringe was then sterilized with UV sterilizer for 24 hours.
  • a composition was prepared including WSC (low MW), laurinaldehyde and ePC in ratios of 1 :2:1 , 1 :2:3, 2:2:3, 1 :3:1 and 1 :4:1.
  • the compositions were prepared by dissolving ePC with the laurinaldehyde and vortexed, followed by the addition of WSC and further vortexed to blend components, and then transferred to a 1 cc syringe.
  • compositions comprising WSC (low and high MW), laurinaldehyde and ePC in ratios of 1:3:1 and 1:4:1 along with 10 mg of paclitaxel.
  • the paclitaxel was added in ethanol and the solvent was fully evaporated.
  • the components were vortexed in stages before transferred to a 1 cc syringe. Partition coefficients (K v ) of paclitaxel according to the formula:
  • compositions also were prepared comprising WSC (high MW), laurinaldehyde and ePC in a ratio of 1 :4:1 , along with 10 mg of paclitaxel and
  • 14C-paclitaxel 14C-paclitaxel.
  • the 14C-paclitaxel (.14C-PTX) and paclitaxel were added in ethanol and the solvent fully evaporated.
  • Laurinaldehyde was used to dissolve ePC.
  • the components were vortexed in stages and then transferred to a 1 cc syringe.
  • the percent of cumulative release of 14C-PTX-labeled paclitaxel from various blend formulations incubated in 0.01 M phosphate buffer solution (pH 0.01 M phosphate buffer solution
  • compositions comprising WSC (low MW), laurinaldehyde and ePC in ratios of 1 :3:1 and 1 :4:1.
  • the ePC and laurinaldehyde were vortexed, and then WSC was added.
  • the blend was further vortexed and then transferred to a 1 cc syringe, and sterilized with UV sterilizer for 24 hours.
  • the in vitro biocompatibility of L929 cells in the presence of the blends (1 :3:1 and 1 :4:1) after 24 hours of incubation is shown in Fig. 17.
  • compositions comprising WSC (low MW), laurinaldehyde and ePC in a ratio of 1 :4:1.
  • the ePC and laurinaldehyde were vortexed, and then WSC was added.
  • the blend was further vortexed and then transferred to a 1 cc syringe, and sterilized with UV sterilizer for 24 hours.
  • compositions were prepared comprising WSC (high MW), C12CI or C12-
  • the drug release profile of 10 mg of 3 H-DTX from two different formulations is provided at Fig. 18.
  • In vitro drug release profiles for further formulations comprising C12-CHO and DTX illustrate the concentration effect of different amounts of loaded H-DTX in the CHO formulation, as shown in Figs. 19A and 19B.
  • This novel injectable system provided sustained release of DTX in vitro and in vivo with demonstrated in vivo biocompatibility. These studies indicate the potential use of this injectable blend for localized sustained intraperitoneal release of DTX in the treatment of disease, for example, advanced ovarian cancer.
  • the drug-free blend formulation consisted of water-soluble high molecular weight chitosan, egg phosphatidylcholine and laurinaldehyde in a 1 :4:1 weight ratio.
  • the drug-loaded blend formulation consisted of 30 mg of DTX per gram of blend formulation to create a final drug to matrix ratio of 1 :8 (w/w).
  • PBS phosphate-buffer solution
  • Plasma from control and treatment groups were analyzed for DTX by HPLC to determine in vivo release rate of drug from the blend formulation.
  • the mice in the treatment group received a DTX dose of 8mg/kg.
  • mice were assessed for the following biocompatibility endpoints: weight loss; post mortem examination for local inflammation and capsid formation; ALT measurements on plasma to assess liver toxicity; and hematoxylin and eosin staining on kidney, spleen, liver, and intestines.
  • mice Prior to sacrificing, mice appeared healthy without significant weight loss. Post-mortem examination did not show local peritoneal inflammation. Minimal to no capsid formation was observed.
  • ALT levels of treated mice injected with DTX-loaded formulation were within acceptable limits (10 - 35 units/L) ranging from 12.8 to
  • FIG. 21 depicts DTX plasma levels.

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Abstract

La présente invention concerne un mélange polymère-lipide injectable. Ledit mélange exempt de médicament peut être utilisé en tant que substance injectable à des fins cosmétiques ou thérapeutiques. Ce mélange peut être préparé à partir d'un matériau à base de chitosane, d'un acide gras et d'un phospholipide. Le matériau à base de chitosane peut être un dérivé de chitosane soluble dans l’eau. L’acide gras peut être un acide gras ou un aldéhyde gras, tel que le laurinaldéhyde, avec une longueur de chaîne acyle de C8 à C16. Les propriétés rhéologiques dudit mélange concernent le rapport des composants et la longueur de la chaîne acyle de l’acide gras. Le système injectable, lorsqu’il est chargé en médicament, est bien adapté à la libération à action retardée d’agents actifs pharmaceutiquement dans le traitement du cancer et d’autres maladies nécessitant l’administration localisée d’un médicament.
PCT/CA2008/002172 2008-06-12 2008-12-11 Mélange polymère-lipide injectable WO2009149537A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
PCT/CA2008/001128 WO2008151433A1 (fr) 2007-06-12 2008-06-12 Mélange polymère-lipide injectable permettant une délivrance localisée de médicament
CAPCT/CA2007/001128 2008-06-12
US12/138,141 2008-06-12
US12/138,141 US20080311223A1 (en) 2007-06-12 2008-06-12 Injectable polymer-lipid blend for localized drug delivery
US12/200,553 2008-08-12
US12/200,553 US20090324741A1 (en) 2007-06-12 2008-08-28 Injectable polymer-lipid blend

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3733173A4 (fr) * 2017-12-26 2021-10-27 Hirotaro Fukuoka Composition pharmaceutique destinée à être utilisée pour augmenter le volume des cheveux, modifier le cuir chevelu ou la peau, cicatriser les plaies, favoriser l'ostéogenèse ou modifier les cheveux

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002013782A1 (fr) * 2000-08-11 2002-02-21 Hyundai Pharmaceutical Ind. Co., Ltd Peptide a administration per os
WO2005087221A1 (fr) * 2004-03-15 2005-09-22 Christine Allen Implant biocompatible et biodegradable et procede de fabrication de cet implant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002013782A1 (fr) * 2000-08-11 2002-02-21 Hyundai Pharmaceutical Ind. Co., Ltd Peptide a administration per os
WO2005087221A1 (fr) * 2004-03-15 2005-09-22 Christine Allen Implant biocompatible et biodegradable et procede de fabrication de cet implant

Non-Patent Citations (3)

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Title
CHO, J. ET AL.: "Synthesis and physicochemical and dynamical mechanical properties of a water-soluble chitosan derivative as biomaterial", BIOMACROMOLECULES, vol. 7, 2006, pages 2845 - 2855 *
GRANT, J. ET AL.: "Influence of molecular organization and interactions on drug release for an injectable polymer-lipid blend", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 360, 2008, pages 83 - 90 *
LE TIEN, C. ET AL.: "N-acylated chitosan: hydrophobic matrices for controlled drug release", JOURNAL OF CONTROLLED RELEASE, vol. 93, 2003, pages 1 - 13 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3733173A4 (fr) * 2017-12-26 2021-10-27 Hirotaro Fukuoka Composition pharmaceutique destinée à être utilisée pour augmenter le volume des cheveux, modifier le cuir chevelu ou la peau, cicatriser les plaies, favoriser l'ostéogenèse ou modifier les cheveux

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