CN101484145A

CN101484145A - Compositions and method for the reduction of post-operative pain

Info

Publication number: CN101484145A
Application number: CNA2006800230204A
Authority: CN
Inventors: R·L·克罗恩瑟尔
Original assignee: ORTHOCON LLC
Current assignee: ORTHOCON LLC
Priority date: 2005-07-25
Filing date: 2006-07-25
Publication date: 2009-07-15
Also published as: EP1912630A4; JP2009502928A; AU2006272663A1; CA2616384A1; AU2006272663C1; WO2007014210A2; AU2011200355A1; AU2006272663B2; KR20080055782A; WO2007014210A3; EP1912630A2; NZ563557A

Abstract

At least three component, body-implantable, absorbable, biocompatible, putty, and non-putty pain-relieving compositions for use in surgery comprising in intimate admixture: an analgesic having local pain-relieving activity for internal relief of pain, a finely powdered bulking material, preferably less than 50 microns, e.g. the metal salts of fatty acid, hydroxyapatite, DBM, polyglycolide, polylactide, polycaprolactones, absorbable glasses, gelatin, collagens, mono, and polysaccharides starches. An organic liquid capable of solubilizing, dispensing or suspending the analgesic, such as esters of monohydric alcohols with aliphatic monocarboxylic acids; C2-C18 monohydric alcohols with polycarboxylic acids; C8-C30 monohydric alcohols; tocopherol and esters thereof with mono or polycarboxylic acids; free carboxylic acids such as oleic, capric, and lauric; dialkyl ethers and ketones; polyhydroxy compounds and esters and ethers thereof; random or block copolymers of ethylene oxide and propylene oxide.

Description

Be used to alleviate the compositions and the method for postoperative pain

The cross reference of related application

[0001] the application requires to enjoy the rights and interests of following application: the sequence number of JIUYUE in 2003 submission on the 23rd is 60/504, the sequence number that 978 U.S. Provisional Application, on July 25th, 2005 submit to is 60/702, the sequence number that 226 provisional application, on January 12nd, 2006 submit to is 60/758, the sequence number of 300 provisional application and JIUYUE in 2004 submission on the 16th is 10/941,890 U.S. Patent application, all incorporate them into this paper by reference, ground proposes in this article as every word is unchanged with them.

About the research of federal funding or the statement of exploitation

(inapplicable)

About sequence table, form, the computer program table appendix of submitting to laser disc

(referring to 37CFR1.52 (e) (5))

(inapplicable)

[0002] the application is that the name of JIUYUE in 2004 application on the 16th is called the part continuation application that " absorbable implant and they are used to stop blooding and treat the method for bony defect ", sequence number are 10/941,890 U.S. Patent application.

Background of invention

Invention field

[0003] surgical operation that the present invention relates to the compositions of implantable health is sent, and is used to manage postoperative pain, and described compositions comprises one or more to be had local pain and alleviate active anesthetis or analgesic.Exchange in this article and use term " analgesic " and " anesthetis ".

[0004] alleviating postoperative pain is the importance of surgical operation pain management.Known systemic medication such as NSAIDs, opioid and other analgesic or anesthetis have significant clinical shortcoming.Used to reach this purpose additive method, for example pass through the external pump of the transdermal conduit of percutaneous, but they have not been considered to acceptable fully the aqueous solution input surgical incision zone of local anesthetic.

[0005] in the surgery operative process and after it, often with the solubility local anesthetic with around the form input surgery location of aqueous solution or its, to alleviate the pain relevant with operation wound.Regrettably, in that they are short-lived relatively aspect their effect.

[0006] be alkalescence because of most of local anesthetics owing to there being the amino part, and their easy and sour water soluble salts that forms, it is possible therefore obtaining water solublity.But the anesthetis of free alkali form is normally water-fast basically, and with this form, can not use conventional aqueous system to come administration.Relate to and use the exception of free alkali to comprise local anesthesia, wherein anesthetis alkali is dissolved in the non-water ointment carrier (for example, vaseline) and former state is coated on the surface of skin.

[0007] time of the acting duration of local anesthetic and itself and nervous tissue's actual contact is proportional.Local anesthetic is the conduction of impulse in the block nerves tissue reversibly, thereby produces temporary transient sensory deprivation in the localized area of health.Therefore, local anesthetic can be used to prevent the pain in the surgical procedures process.In order to prolong the effect of local anesthetic, often vasoconstriction medicine (for example norepinephrine) is added in the anesthetic solution.In general, constant pain alleviation for a long time is not often to realize after surgical procedures finishes.

[0008], they can be divided into two classes: micro-soluble compound and soluble compound according to the dissolubility of local anesthetic in water.Micro-soluble compound only is used for local anesthesia and has the relatively long persistent period.On the other hand, have only solubility anesthetis can be used to infiltration anesthesia.Local anesthetic can further be classified according to their chemical constitution, for example has the local anesthetic of the part that connects by ester bond or amido link.Usually, the toxicity of described esters is bigger and act on of short durationly, and amide-type anesthetis has long acting duration.

[0009] a kind of difficulty that is used for the art methods of postoperative pain alleviation is: can not kept lasting one suitable period at surgery location usually by the analgesic of infusion.The present invention relates to this one side of described art methods.That is, the present invention aims to provide a kind of implantable, compositions that can slowly absorb, and said composition is released into the pain relieving material in the surgery location after operation.

[0010] at the inventor's of JIUYUE in 2004 application on the 16th U.S. Patent application 10/941; 890; in the disclosed present U.S. Patent Publication on March 24th, 1 2005-0065214-A1 number (incorporating it into this paper by reference) for all purposes; describe and claimed absorbable system for example putty sample and non-putty sample material, be used for the treatment of the damaged and control of bone by the bone of incised wound or wound and soft tissue cause hemorrhage.A key character in the many features of described system is: they are anhydrous and have organic component that the free alkali of local anesthetic is soluble in this organic component.

[0011] described ' 890 applications (the application require enjoy its priority) disclose and have mixed analgesic regulate pain in excipient.Usually, can be with the acid-addition salts of local anesthetic, hydrochlorate for example mixes with suitable medium (for example, putty).Think that water-soluble hydrochloride salt will (be compared) eluting relatively apace with the microsolubility free alkali from described excipient in the aqueous environment of health and it will reduce longer effectiveness.

[0012] submit on January 12nd, 2006, sequence number is 60/758, in 300 the provisional application (the application requires to enjoy its priority), the combination that the present inventor discloses identical or different narcotic organic soluble free alkali and water-soluble hydrochloride salt (or other acid-addition salts) will form implantable, the absorbable combination of surgical operation, it provides the pain management that prolongs, wherein water-soluble component will be relatively apace eluting be used for early stage pain relief, and the water-insoluble free alkali component eluting pain relief that is used to prolong more lentamente.Basic conception of the present invention is that narcotic water soluble salt (for example hydrochlorate) and its corresponding free alkali (or free alkali form of another kind of analgesic) are incorporated in a kind of anhydrous in fact, non-aqueous composition, implants said composition then and is used for pain relief.Narcotic hydrochlorate part (for example, lidocaine hydrochloride) is considered to eluting from described system relatively apace, and the described free alkali (for example, lignocaine) that is dissolved in the nonaqueous carrier is incited somebody to action eluting more lentamente, to prolong the effectiveness of regulating pain.Because described carrier compositions is absorbable in vivo, so along with described implant is absorbed, any insoluble free alkali residue will be exhausted from implantation position.Therefore, use the anesthesia effect of the prolongation that water-bearing media can not realize to be considered to easily realize so far.

The invention brief overview

[0013] has now found that, according to the present invention, can from the property implanted compositions, provide and have the analgesic that surgery surgery location in vivo provides the ability of (intraoperative) pain relief in the average of operation periods, described compositions comprises the broken form of fine powder and the solid material organic liquid intimate mixing, and anesthetis in greater detail hereinafter.Described compositions is absorbable, anhydrous or anhydrous basically implant, when wherein comprising suitable on-aqueous liquid dispersibility excipient and having local pain and alleviate active anesthetis, the pain relief this implant provides surgical operation in one section reasonable time after.

[0014] therefore, key element that we can say anhydrous or anhydrous basically compositions of the present invention comprises following three primary categories in uniform homogeneous blend:

Component 1.The solid material implantable health, biocompatible, that fine powder is broken.

Component 2.Can disperse or the organic liquid of suspending components A.

Component A.Have local pain and alleviate the mixture of active narcoticness chemical compound or chemical compound.

B component.Available or can (choose wantonly) eluting controlling agent can add it to help to control the speed that described anesthetis discharges from described implant.

[0015] if the expectation final compound is anhydrous, each in the then described component all should be anhydrous.If final compositions is anhydrous basically, then each component self can be a band water.Can anhydrous components be used with the optional extra water that adds after the described component of fusion or the random time during the described component of fusion.

[0016] described component is when being blended in a time-out, produce anhydrous composition of the present invention or anhydrous basically compositions, character and ratio that this depends on described component obtain (amounts that depends on liquid component 2) such as various physical form such as putty, lotion, gel, emulsifiable pastes.Described compositions is preferably aseptic.

[0017] when implanted inner surgical site, but compositions of the present invention provides the analgesic source of eluting.Effectively analgesic usually can be during about 0 to 8 day behind the surgical operation eluting, in this time, discharge pain relief and effectively measure.

[0018] to influence the important feature of described compositions of the rate of release of analgesic be described compositions denseness or viscosity.Usually, more low viscous compositions trends towards more full-bodied compositions and discharges described product quickly.Described viscosity can change, at lower limit from being the liquid of the shape on container border under free flowable liquid (for example lotion) and other are allowing its expedite situation rapidly, and in that allow will be by the liquid of gravity flow container under its effusive situation, but the liquid to sluggish flow (for example has thick shampoo, Mel, the liquid of the viscosity of molasses etc.) viscosity higher, to the semisolid material example gel, paste and emulsifiable paste (its under environmental condition normally illiquidity), arrive for example putty of moldable material, wax and other these class materials are (when being applied to a position, it trends towards keeping in position), up to hard, solid material (it is not moldable under environmental condition), for example preformed, the material such as the clava that are shaped, button etc.

[0019] type of adjusting component 2 and amount also will have effect to the eluting of analgesic from finished product.For example, hydrophobic material is tocopherols for example, and for example Tocopherol acetate ester trends towards the discharge rate that slows down.

[0020] can expect that different anesthetis produces different elution rates, and, if particularly they exist with particle form.Therefore, suspensible or dispersible anesthetis should be and has relatively the broken form of fine powder of particle size distribution uniformly, with comparing of will obtaining with big or polydispersion granule, more reliable elution rate characteristic is provided.

[0021] optimal way of the described compositions of preparation is with described anesthetis compound dissolution, is dispersed or suspended in the described liquid component 2, randomly mix with the eluting controlling agent, to form solution, dispersion or suspension, then it is mixed with solid phase components 1 to form the admixture of all components.The physical form of described product, promptly putty, gel, lotion etc. depend on the physical characteristic of described component and relative amount.The most preferred form that is used for surgical procedures is so-called putty form.Therefore, implantable health, biocompatible, anhydrous, aseptic, the absorbable compositions of health basically of the invention provides that is its preferred form, it comprises component 1,2 and A, optional B component and any other optional component (will be described below), and this optional component is decided by the judgement of user and the special applications of looking for.

[0022] in case be implanted in the body of surgery patients, the anesthetis of interior envelope will be from the tissue around implant be diffused into, and the pain signal from the local nerve tip of wound to brain in the tissue around this is interrupted.Described compositions can contain the slightly water-soluble anesthetis of acid-addition salts form or free alkali form or these two kinds of forms, and the flexible and variation of the availability of pain relief is provided with the foundation situation.Under this class situation, in advance described salt is dispersed in the whole component 1 or alternately is dispersed in the component 2, after this with dispersion and solid phase components 1 intimate mixing to form dispersion.If also use the free alkali be dissolvable in water in the organic medium, it still is dissolved in the organic medium, its with described solid phase fusion and with described salt by eluting, but the speed difference of their eluting.

[0023], finds that further the composition of described implantable compositions can change, so that different medicament elution speed to be provided on concentration according to the present invention.For example, in comprising the putty sample compositions of lignocaine free alkali, calcium stearate and liquid triethyl citrate, discharge the free alkali of lignocaine in during three days.If the liquid component of putty is changed into Pluronic by triethyl citrate

L-35 (liquid block copolymer of oxirane and expoxy propane) and Tocopherol acetate ester, then during eight days in the free alkali of lignocaine by eluting.Liquid Pluronics

With solid Pluronics

Mixture will prolong elution time and surpass single liquid Pluronic that uses

Situation.We studies show that, Tocopherol acetate ester reduces elution rate, and tricalcium phosphate and hydroxyapatite increase elution rate.Free alkali is faster than acid-addition salts eluting, and in free alkali/salt mixture, free alkali eluting unexpectedly gets faster.Can use other nontoxic, on-aqueous liquid components similarly, as the mixable ethers of anesthetis free alkali (for example polyalkylene glycols) as described in therein.

[0024] preparation of the present invention is to have the compositions of different viscosity and adhesion strength and comprise putty and non-putty preparation denseness.Term used herein " putty " is employed in the prior art the same with it, and normally known to one skilled in the art.The example of the denseness of proper product has the putty (depending on explanation and final purposes) of the different viscosities of dough (for example pasty state dough), mold pressing clay and glazing human.The putty that can be used for the different viscosities among the present invention comprises the putty that can adhere to bone.Usually, putty is the suitable consistency that is used for putty sample compositions of the present invention, putty is soft, moldable (preferably stiff, agglutinating) mixture, prepare by fine-powdered material (component 1), and have the shape that to be out of shape in any direction with organic liquid (component 2) intimate mixing.But as said, the compositions with adhesion strength lower than above-mentioned putty and can be used in the specific application also within the scope of the invention, in this is used more viscosity, more the putty of high bond strength is more improper.

[0025] for the purposes of the present invention, putty of the present invention be not considered to putty (non-putty herein), but its still the main difference between within the scope of the invention the material be, non-putty has the adhesion strength lower than the adhesion strength of putty preparation, and may have even the adhesion strength higher in some cases, than putty.Be characterised in that in the of the present invention independent non-putty class of adhesion strength scope lower limit have emulsifiable paste, the adhesion strength of paste, ointment, lotion, foams, gel etc.By providing grid that non-putty can be employed or structure and overall structure to be used to surgery location, can promote of the application of non-putty as implant.Preferably, non-putty only has the part of the adhesion strength of putty of the present invention, trends towards can stretching easily or be torn off easily under little stress, and as a rule, this stress should not have same effect to putty.In the upper limit, promptly under the viscosity higher than putty, described compositions can be in state more rigidity, shaping, non-deformation, and is required as their final use.Ensuing explanation mainly provides in the related content of putty of the present invention, but it is interpreted as, the material of other less adhesion strengths if desired, for realizing same purpose, those skilled in the art will only change the ratio of component or add other materials.

[0026] the present invention includes and in fact use any solid phase to form medically useful absorbable putty sample and non-putty sample compositions, described solid phase is biocompatible and can be carefully splitted, to produce required denseness with compositions 2 liquid-carrier fusion the time.

[0027] except their pain management aspect, many compositionss of the present invention still are aseptic, absorbable bone hemorrhage.That is, they will provide surgical operation hemostasis in fact at once, will absorb in vivo after short relatively a period of time and will not damage hemostasia effect, and will allow analgesic is spread around surgery location.They suppress osteogenesis and knitting subsequently with minimally.Therefore with respect to present available material, they will have significant medical advantage.And, can in described preparation, add knitting auxiliary agent (as somatomedin, particularly for example platelet-derived somatomedin (PDGF) and/or bone morphogenetic protein (BMPs) and other), since stimulate the knitting process.And then substance such as collagen, demineralized bone substrate (DBM) and/or hydroxyapatite can make that hemostasis/the pain management material is of value to bone conduction or bone is induced.Adding suitable anti-infective is that the antibiotic of representative or bacteriostatic and germ-resistant material such as iodine, silver salt, triclosan, collargol etc. are used for reducing and infect with tobramycin and gentamycin for example, particularly contaminated open wound if any the wound fracture in possibility of infection.The interpolation coloring agent will help the visuality in the operative process.Adding radiopaque material makes and can observe postoperative sequela with radiography.Adding chemotherapeutant or radionuclide is useful when using putty in the bone cavity that is for example being caused by tumor resection.Although the analgesic compounds that is used to ease the pain is formed the component A of compositions, being used to reduce hemorrhage vasoconstrictor and/or hemopexis derivant is useful additive.

Detailed Description Of The Invention

[0028] compositions of the present invention comprises and contains at least three kinds, but also may contain the compositions of four kinds or more kinds of components, and wherein at least a is the combination with partial, the active analgesic of alleviating pain or this class analgesic.They most preferably are that health is absorbable and biocompatible.They have putty sample denseness in many embodiments.In one embodiment, described compositions is the filling of mechanical hemostatic, and it is useful by putty sample compositions is applied to affected zone stopping aspect the osteorrhagia, also has the ability that discharges analgesic simultaneously." mechanical hemostatic filling " means described compositions and stops hemorrhage playing a role by the hemorrhage zone of mechanically pushing down bone, this with play a role opposed by chemical hemostatic mode (for example, use chemical means or reagent stops hemorrhage whole or in part).In at least three kinds of components in first of this section, mentioning, component 1 is the vehicle excipients or filling (bulking) the property material of fine-powdered, it has enough little mean diameter, to form required denseness with second component (promptly wherein having dissolved, disperseed or suspended the organic liquid component 2 of the present invention of analgesic) intimate mixing the time.

[0029] example of component 1 is that hydroxyapatite is (as employed in this article, hydroxyapatite is general to the form of ownership of the calcium sulfate that comprises tricalcium phosphate), carboxylate (preferred fat hydrochlorate such as calcium stearate or its homologue, calcium laurate for example) or other fine-powdered reagent (as synthetic absorbable polymer, the copolymer of for example poly-Acetic acid, hydroxy-, bimol. cyclic ester, polylactide, lactide and Acetic acid, hydroxy-, bimol. cyclic ester, gather dioxanone (polydioxanone), polycaprolactone) and absorbable glass (for example based on phosphorus pentoxide those or the like).Special component 1 solid phase is not subjected to particular restriction, and can be actually any solid, and this solid is biocompatible and can be divided into fine powder, so that can form the compositions with suitable consistency.Certainly, component 1 is insoluble to component 2.

[0030] component 2 dispersion excipient are organic liquids, and it is worked as and analgesic component A, during again with component 1 intimate mixing, makes it possible to form putty sample or non-putty sample implant.

[0031] although three components compositions of the present invention provides the fundamental characteristics of suitable lenitive material, as described in this article, in the described lenitive material some can be hemorrhages, if desired, they also may (but is not required to) contain those illustrational optional members as follows.For example, optional component 3 is absorption enhancers, and optional component 4 is materials of induction of bone growth.As will being explained in more detail hereinafter, can add other components provides extra attribute for putty sample of the present invention and non-putty sample compositions.

[0032] below the detailed description of various components.

Component 1

Component 1 is by (preferably micronized) of fine-powdered, water-fast (preferably anhydrous (except the water that absorbs)), biocompatible, the absorbable material of health constitute basically, it is when when mixing, forming compositions of the present invention with organic liquid (component 2 that contains analgesic).When the mean diameter of component 1 material is about 100 microns or more hour, obtain suitable compositions, but preferred average particle size range is about 3 to about 50 microns, and most preferably is about 6 to about 25 microns, particularly when expecting to obtain putty sample compositions.If desired, the particle diameter of non-putty compositions can change in higher scope than the particle diameter of putty compositions.

[0033] one group of examples of material that is applicable to purposes of the present invention is the salt with one or more carboxylic acids of carboxylate anion and metal cation, wherein some are well known in the art (United States Patent (USP) the 4th, 439, No. 420 and 4, in 568, No. 536 description is arranged).Suitable is that described salt can be calcium, magnesium, zinc, aluminum, lithium or the barium salt that contains the saturated or unsaturated carboxylic acid of have an appointment 6 to 22 carbon atoms and preferred 8 to 20 carbon atoms on the chain.Provide the preferred saturated carboxylic acid of carboxylate anion can be selected from aliphatic acid such as sad, capric acid, lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid and be positioned at intermediary homologue, but most preferred acid is higher fatty acids such as lauric acid, myristic acid, Palmic acid and stearic acid, most preferably stearic acid.Palmic acid and stearic calcium and aluminum salt are preferred salt, because the characteristic of the excellent security feature of calcium stearate and formation putty, most preferably calcium stearate.Yet aluminium stearate, aluminum palmitate or Aluminum trilaurate also are suitable.

[0034] can be used to the example of the cationic suitable unsaturated aliphatic acid of carboxylate radical is provided is oleic acid and linoleic acid, uses aforesaid identical cation for oleic acid and linoleic acid.

Have now found that [0035] the thin material crushed (for example mean diameter is about 100 microns, preferably less than 50 microns or littler) beyond the carboxylate can be as effective component 1 material.For example, find unexpectedly that the hydroxyapatite of fine-powdered (particularly when mean diameter less than about 25 microns time) forms the putty of excellence, particularly with Tocopherol acetate ester or triethyl citrate during as liquid dispersant (component 2).

[0036] and then, other materials (wherein some being discussed in conjunction with component 4) when providing with the fine-powdered form, can be used as component 1.Gelatin, monosaccharide and polysaccharide that example in these is demineralized bone substrate (DBM), mineralising bone matrix (MBM), insoluble absorbable collagen, obtained by collagen.Now think and when being converted into very little particle diameter, will be formed for medically useful compositions of the present invention by any bio-soluble material.During compositions of the present invention, having following component will not be uncommon in preparation: for example as about 20～30 microns hydroxyapatite (or any calcium phosphate or tricalcium phosphate) of component 1, suitable component 2 as described below, suitable component A with as the GUSUIPIAN of component 4 (for example having about 0.5 demineralized bone substrate or mineralising bone matrix to about 1 millimeter or bigger particle diameter).

[0037] other examples of component 1 material are synthetic absorbable homopolymer and copolymers of fine grinding, and (for example the cellulose of carboxymethyl cellulose and oxidation (is typically for copolymer, gelatin, monosaccharide (for example glucose and maltose) and the polysaccharide of the copolymer of for example poly-Acetic acid, hydroxy-, bimol. cyclic ester, polylactide, lactide and Acetic acid, hydroxy-, bimol. cyclic ester, poly-dioxanone, polycaprolactone, dioxanone and caprolactone and carbonic acid trimethylene ester ), starch, sucrose (being fit to be the form of refining thin sugar), alginic acid, hyaluronic acid, chitosan and acetyl derivative thereof or the like) and absorbable glass etc.In addition, some bioactive materials biological example glass (more going through in conjunction with component 4 hereinafter) (it may not be considered to absorbable on ordinary meaning) can be with the fine-powdered form as component 1.For example, when mixing with the Tocopherol acetate ester of No. the 4th, 439,420, United States Patent (USP) for example or triglyceride oil (especially Oleum Ricini), the absorbable polymer with about 25 microns mean diameters will be formed with usefulness, stable absorbable hemostasis putty.Therefore, if with suitable ratio and suitable, compatible component 2 mixed with excipients, that any natural or synthetic absorbable polymer that can be reduced to enough small particle diameter will form will be stable, absorbable putty and non-putty.

[0038] has been found that, based on phosphorus pentoxide (not being silicon dioxide) and contain alkali metal oxide or alkaline earth oxide (for example sodium oxide, potassium oxide, calcium oxide and magnesium oxide) can slowly dissolve in aqueous medium as the absorbable glass of network polymers, and can use as component 1.In addition, such chemical compound can be used as absorption enhancer, in this case, they can, but not necessarily, with them during as component 1 such fine-powdered form use.United States Patent (USP) the 4th, 612 is mentioned for No. 923 about the prior art of the preparation of these glass and their being used for the application of synthetic absorbable surgical operating instrument as the additive that is used to strengthen intensity and increase hardness.When with United States Patent (USP) the 4th, 612, when 325 order glass described in No. 923 the embodiment 1 further are crushed to less than 50 microns mean diameter, resulting fine powder is worked as and United States Patent (USP) the 4th, 439, during mixed with excipients described in No. 420 (incorporating this paper by reference into) and this description, form medically useful absorbable putty.Can increase water dissolution (absorption) speed of this class glass by the ratio that increases alkali metal oxide, and it be reduced by the ratio that increases alkaline earth oxide.

[0039] this new method discussed above, promptly be formed with the absorbable putty and the non-putty of usefulness by the particle diameter that significantly reduces fillibility excipient component 1, a lot of difficulties of prior art have been overcome, particularly for example as the difficulty of the synthetic absorbable polymer of bone hemorrhage.

Component 2

[0040] as second component, it is described organic liquid, may mention several classes as an example and also not be used as the material that disperse medium is used to prepare medicinal compositions (as putty or non-putty) so far, yet should be emphasized that and to use even known material as disperse medium.Component 2 is as disperseing or the medium of suspending components A (analgesic), and in this aspect of the invention, and component 2 is biocompatible, anhydrous organic liquids basically, and it promotes and the mixing with formation putty or non-putty material of component 1.Although be not preferred, comprise the organic liquid medium (liquefied reagent will be discussed hereinafter more comprehensively) that provides separately as fruit component 2, then component 2 can be a solid.Term " component 2 " also means this situation that is applied to.

[0041] although normally water can not be miscible for component 2, it also can be that water is mixable.Important consideration be that component 2 is anhydrous or anhydrous basically, so that prepare anhydrous or anhydrous basically final pain relief compositions.From this on the one hand, illustrating " anhydrous basically " is that what implication is suitable in this.Preferred compositions of the present invention is anhydrous, except might be by absorbing from atmosphere the water exist.Therefore, the every kind of component itself that is preferred for preparing final composition is anhydrous.

[0042] still in some cases, owing to a variety of causes can allow, even wish to exist a spot of water in component or final composition.Therefore, the most about 10% the water yield that accounts for the weight of whole compositions will be an acceptable.The compositions that contains 0 percent water (except the water that absorbs) will be considered to anhydrous, and the compositions that contains about at the most 10% water will be considered to anhydrous basically in the present invention.To such an extent as to should not containing so many water, component do not produce the final composition that has above about 10% water.Preferably, compositions of the present invention has water that is less than 5% and the interpolation water that most preferably has 0 percent (except the water that absorbs).Under one situation of back, they will be considered to " anhydrous ", as this term is normally used in the art.

[0043] in order to help to understand the term that uses in this article, and the aspect of this one side of the present invention and prior art is distinguished in help, may emphasize the essence of the chemical entities of indication in this description in this by the relevant classical technical terms of chemistry of brief review, to guarantee that it is useful understanding suitable chemistry differentiation.

[0044] carboxylic acid is can be connected the material that define by covalent bond with the carbonyl official by the OH group.The result is, carboxylic acid has the physics and the chemical property of the material (alcohol) that is different from the material (for example aldehyde, ketone) that contains the carbonyl functionality or hydroxy functionality fully.Contain simultaneously not directly by the carbonyl of covalent bond connection and the material of hydroxyl, for example hydroxypropanone-also has identical difference, and it shows ketone and the two performance of alcohol, but does not show the carboxylic acid feature.Carboxylic acid always makes up carbonyl and OH base, and has acidic character, but the OH base does not have the feature of alcoholic extract hydroxyl group.Therefore, monocarboxylic acid is not described as monohydroxy compound.For this point is described, consider all to be acetic acid and the ethanol that contains the c2 compounds of OH base.In acetic acid, the hydrogen atom of OH base is released as ion in water, and in ethanol, the hydrogen atom in the hydroxyl is not so discharged.Therefore, carboxylic acid disassociation also forms carboxylate with alkali, calcium stearate for example, a kind of OH base that makes carboxylic acid obviously be different from do not dissociate with the character of the salifiable alcoholic extract hydroxyl group of alkali shape.Therefore, it is incorrect fully that carboxylic acid is characterized by alcohol, monohydric alcohol or certain this term, because it is not an alcohol on chemical sense.Only because it comprises carboxylic acid OH base, so also polybasic carboxylic acid is not called polyhydric alcohol or many alkyl compounds or polyhydric alcohol (polyol).These groups are not characterized by alcohol.The example of these differences illustrates by considering the molecule citric acid of knowing.This material has three carboxyls and a hydroxyl on a part.Citric acid is monohydroxy (monobasic) alcohol, also is polybasic carboxylic acid.Citric acid comprises three carboxylic acid OH bases and this monohydroxy compound is not classified as many alkyl compounds.Because the main difference aspect reactive, synthetic and reaction, in every kind of organic chemistry textbook, the chemistry of alcohol always is being considered in the chapters and sections of carboxylic acid chemistry separately.

[0045] alcohol can be thought the hydroxy derivatives of hydrocarbon or the alkyl derivative of water.They are feature with the R-OH structure, and wherein R is an alkyl.Distinct with the hydrogen atom of easy ionized carboxylic acid hydroxyl is that the R-OH hydrogen atom is unionization in fact in water.On this basis, think that aliphatic alcohol is neutral rather than tart.One or more hydroxyls can be appended to the hydrocarbon part, make that for example propane can have a hydroxyl (propanol), two hydroxyls (propylene glycol or propylene glycol) or three hydroxyls (glycerol or glycerol).Propylene glycol and glycerol are the simplified example of polyhydric alcohol.Polysaccharide, for example hyaluronic acid comprises many hydroxyls on monomeric unit separately, and correctly is called polyhydric alcohol.Alcohol can have short alkyl chain, for example methanol, ethanol, propanol etc., and perhaps they can have longer alkyl chain, for example lauryl alcohol, myristyl alcohol etc.Though it is highly important that and it is also noted that lauric acid (C ₁₁H ₂₃COOH, a kind of fatty acid) and lauryl alcohol (C ₁₂H ₂₅OH, a kind of aliphatic alcohol) all comprise 12 carbon atoms, but they are diverse molecules aspect oxidation state and degree of functionality.

[0046] ester is normally produced by the reaction of carboxylic acid and alcohol, and can to transform back by hydrolysis be original carboxylic acid and alcohol.Therefore, acetic acid and ethanol are merged in esterification process to form ethyl acetate and water.Term fat (or vegetable oil or animal oil) is limited to the ester (glyceride) of various long-chains saturated or unsaturated fatty acid and glycerol.The oil that is cited as the excipient of preparation putty sample material in the prior art specially refers to glyceride, for example Oleum Ricini, Oleum sesami, Fructus Canarii albi wet goods, and simple fatty acid ester, for example ethyl laurate.Never propose in the prior art as the excipient of preparation putty sample material be the free fluid aliphatic carboxylic acid, for example saturated sad and unsaturated oleic acid.The most important thing is, use the ester of aliphatic alcohol and low-molecular-weight monobasic or polybasic carboxylic acid, for example lauryl acetate (ester of lauryl alcohol and acetic acid) is new for preparation putty sample material fully, and is different from the ethyl laurate (lauric acid and alcoholic acid ester) that prior art is quoted aspect chemical.

[0047] returning to describe component of the present invention now, more specifically is component 2, and described key element more specifically is described below:

[0048] in the organic liquid of many types that can be used as component 2, can mention following organic liquid:

[0049], there are one or more absorbable C as first kind component 2 ₈-C ₁₈Monohydric alcohol and C ₂-C ₆The monocarboxylic ester of aliphatic.Monohydric alcohol can be selected from C ₈-C ₁₈Alcohol, for example capryl alcohol, decanol, lauryl alcohol, myristyl alcohol, stearyl alcohol and between intermediary homologue.Preferred alcohol is senior aliphat alcohol, for example lauryl alcohol, myristyl alcohol and stearyl alcohol.With C ₂-C ₆The example of the useful este that monocarboxylic acid forms is lauryl acetate and propanoic acid myristin.

[0050], there are one or more absorbable C as the second class component 2 ₂-C ₁₈The ester of monohydric alcohol and polybasic carboxylic acid.C ₂-C ₁₈Monohydric alcohol is except at the C described in the first kind ester ₈-C ₁₈Outside the alcohol, also comprise lower aliphatic C ₂-C ₈Alcohol, for example ethanol, propanol, butanols, amylalcohol, enanthol, hexanol and capryl alcohol, their produce corresponding ethyl, propyl group, butyl, amyl group, heptyl, hexyl and octyl group part.Polybasic carboxylic acid can be selected from the ester of the hydroxyl-functional (if any) of malonic acid, succinic acid, 1,3-propanedicarboxylic acid, adipic acid, 1,5-pentanedicarboxylic acid., suberic acid, Azelaic Acid, decanedioic acid, maleic acid, fumaric acid, glutaconate, citric acid, malic acid and esterification polybasic carboxylic acid (particularly acetyl group citric acid and acetyl-malic acid).Be apparent that to one skilled in the art; many combinations of alcohol/acid esters can be selected from above material, but from monohydric alcohol/polybasic ester be preferred for of the present invention for diethyl succinate; dioctyl succinate; triethyl citrate; tributyl citrate and their senior and lower homologue; acetyl triethyl citrate; acetyl tributyl citrate and their senior and lower homologue; the bytyry triethyl citrate; diethyl malate; two-amyl group malate and acetyl group diethyl malate and their senior and lower homologue.

[0051] the another kind of material that is suitable as component 2 is senior C ₈-C ₁₂, about at the most C ₃₀, and preferred liquid or liquable monohydric alcohol, for example capryl alcohol and decanol.Especially the unexpected suitable embodiment of this class is the aromatic alcohol tocopherol (vitamin E) of arbitrary form in its optical activity or racemic form and α, β, γ or the δ form, and and C ₂-C ₁₀The liquid Renascin of aliphatic monocarboxylic acid, polybasic carboxylic acid or its mixture (this paper is called Renascin sometimes).Renascin usefully, for example acetas, butyrate, alkyl caproate, caprylate, decanoin and between intermediary homologue and and the multi-carboxylate, for example those that mentioned in the paragraph in front, the particularly ester of succinic acid, citric acid and malic acid, preferred succinate.Tocopherol acetate ester also is useful as eluting controlling agent (B component).

[0052] being suitable for the another kind of material of making component 2 is the hydrocarbon with about 10-14 carbon atom.For example decane and dodecane are suitable.

[0053] the another kind of material that can be used as component 2 is liquid or liquable saturated or undersaturated, free carboxylic acid, for example non-esterified fatty acid, oleic acid, linoleic acid, sad, capric acid and lauric acid.At this apoplexy due to endogenous wind, liquids in general, satisfied fatty acid suit, but because they have offensive odour, so may not be ideal.Some forms at room temperature and also suits for the saturated free fatty of the low melting point than the low melting point eutectic mixture of liquid.An advantage of saturated free fatty is that they have the stability to radiation sterilization of raising, and undersaturated acid, for example oleic acid may radiation sterilization in oxygen-free container.The higher homologue of solid acid also can mix use with component 1 in the presence of liquefaction medium or other suitable component.Can use any compatible liquid, as long as it is guaranteed component 2 liquefaction and also is biocompatible.

[0054] being suitable for the another kind of material of making component 2 is the cyclic polymer of the ethers of simple dialkyl ether and alkylaryl ethers and the aklylene glycol (as ethylene glycol) that is called as crown ether, they all have and are higher than about 80 ℃ boiling point, di-n-butyl ether for example, di-n-hexyl ether, di-n-octylether and asymmetric ether are (as ethylhexyl ether, ethylphenyl ether and analog), or the random copolymer of oxirane and expoxy propane, but preferably have the oxirane of the oxirane of different proportion and expoxy propane and different molecular weight (preferred 1000 to 10,000) and block (non--random) copolymer of expoxy propane (

).They can obtain with the liquid or solid form.Being used for preferred form of the present invention is liquid

Their manufacturer (seeing below) characterizes it with prefix " L ".Be characterized as being " F " or be characterized by " P " for lamellar for powdery Solid form can dissolve, disperse or be suspended in liquid

In or if desired, use with another kind of liquefier.Suitably examples of material is those shown in following examples.Except they appropriatenesses as component 2, they also can be used as absorption enhancer.They can be with trade name

From BASF AG, Mt.Olive, New Jersey 07828 obtains.

[0055] being suitable for the another kind of material of making component 2 is that boiling point is higher than about 80 ℃ symmetry and asymmetric dialkyl group ketone and alkylaryl ketone, for example methyl propyl ketone, metacetone, methyl butyl ketone, ethyl propyl ketone, methyl amyl ketone and methyln-hexyl ketone, methyl n-heptyl ketone, 2-decanone and acetophenone.

[[0056] is suitable for member and the fatty acid ester that the another kind of material make component 2 is selected from the group that solution by polyol, polyol ester, polyol and composition thereof forms.Preferably be selected from the liquid polyol chemical compound of the group of forming by no cyclopolyol, poly alkylene glycol and composition thereof in these materials.The object lesson of above-mentioned material is ethylene glycol, diethylene glycol, 2,2'-ethylenedioxybis(ethanol)., 1, the liquid solution of the fatty-acid monoester of 2-propylene glycol, trimethylolethane, trimethylolpropane, erithritol, tetramethylolmethane, Polyethylene Glycol, glycerol (for example glyceryl monolaurate).Solid in the above-mentioned material can be dissolved or dispersed in the appropriate solvent medium (for example propylene glycol, glycerol, monoacetin, diacetin, liquid macrogol and composition thereof).As glyceride type, can mention monoglyceride class (for example acetin, tristerin, their homologue etc.), di-glycerides (for example diacetine, two caprins, two glycerol monobutyraltes, GLYCERYL DILAURATE etc.) and triglyceride (for example olive oil, Oleum Ricini, almond oil, Oleum sesami, Oleum Gossypii semen, Semen Maydis oil, cod liver oil, safflower oil and soybean oil).It should be noted, if desired, also can be with above-mentioned polyol as absorption enhancer.

[0057], it should be noted that it at room temperature is that the material of component 2 of liquid is component 2 preferred materials, and, do not need liquefied reagent because they are liquid as the statement of the common suitability.Can also be at room temperature to be solid chemical compound as component 2 materials.Since it is so, particularly when wishing to obtain putty, by using the liquefier of compatible liquefaction therein, solubilize, dispersion or suspending components A of absorbable biological, solid constituent 2 is preferably with before component A and component 1 are mixed in succession, also can the time mix, or be converted into liquid form afterwards.Represent a kind of reagent by " liquefier " as used herein, for example suitable organic solvent, it can solubilize, dispersion or suspending components A, and then mixes with solid constituent 2.Can also use other reagent, although described reagent may not be considered to organic " solvent " on the ordinary meaning of this term, the described solid reagent (for example heating) that maybe can liquefy helps to form even putty, emulsifiable paste or pasty mixture thereby maybe described solid can be separated into dispersion in liquid.Certainly, the special reagent that is used will be according to the component 2 that is used for special preparation and component A and is changed.Suitable reagent is the material similar to component 2, does not singly describe clearly as component 2 at this.

[0058] idea of aforementioned novelty and compositions, the particularly above-mentioned compositions of utilizing the ester of monohydric alcohol and monocarboxylic acid or polybasic carboxylic acid provides the absorbable hemostatic implant of bone with releasable analgesic.The novelty of having found lower molecular weight, simple ester (for example diethyl succinate and triethyl citrate) nontoxic and capable of being fast degraded is utilized as the excellent replacement that component 2 provides the fatty acid triglycercide (for example Oleum Ricini) much higher to molecular weight.Therefore if desired, this aspect of the present invention allows not use the form of component 2 known in the art, be esters hydrophobic, that slowly absorb, as being the triglyceride of representative with castor oil acid triglyceride, Oleum Ricini and fatty acid ester (for example isopropyl myristate).

[0059] still, (for example United States Patent (USP) 4 to comprise component 2 materials known in the art, 439, material in 420) these putty compositions known in the art, in any situation but particularly in according to the skeletonization bone hemostatic material aspect following of the present invention, can be used to obtain the useful pain relief compositions of the present invention.Found when wishing to obtain having the bone hemostatic composition of skeletonization character, though have slower absorption characteristic, can be by adding hereinafter with the skeletonization material of describing, for example demineralized bone substrate (DBM), mineralising bone matrix (MBM), hydroxyapatite, tricalcium phosphate or somatomedin, for example bone morphogenetic protein (BMP) and platelet-derived somatomedin (PDGF)) improve compositions known in the art.

[0060] it is as follows to be used as the preferred material of component 2 in specific embodiment: Tocopherol acetate ester, triethyl citrate, molecular weight be about 1900 to about 8000 oxirane and expoxy propane liquid block copolymer (special preferred molecular weight 1900

L-35) and

L-35 and F-68 (

Sheet form) admixture.

Component A

[0061] component A is a key component of the present invention, is applicable to as mentioned above that just the local pain that has of inner pain relief is alleviated active analgesic.Whether described anesthetis is generally the analgesic of injectable or whole body use, and this is unimportant, as long as it has part (part) pain relief activity when implanted surgical site.In the embodiment of this and back, sometimes they are called " pain relieving component ".The analgesic that useful analgesic preferably exists with free alkali form (it comprises the analgesic with the part that connects by ester bond or amido link) and exists with its acid-addition salts form among the present invention.Their example is the analgesic with " caine " suffix, comprising benzocaine, bupivacaine, Cinchocaine, lignocaine, mepivacaine, prilocaine, procaine, chloroprocaine, Etidocaine, tetracaine, lidocaine and propipocaine (propivacaine).As acid-addition salts, can use hydrohalide, for example hydrochlorate, hydrobromate etc.Preferably lignocaine and lidocaine hydrochloride.

[0062] can also use many other to have local pain and alleviate active analgesic, for example nonsteroidal anti-inflammatory compound (as ibuprofen, aspirin, acetaminophen, naproxen etc.), non-opium material (for example fentanyl) and pain relief prostaglandins.The actual drug of using is not subjected to particular restriction, as long as they have the local pain mitigation and are biocompatible at described position, does not promptly have insupportable toxicity under used dosage.

B component

[0063] can add the material that changes analgesic elution rate from putty.For example, have been found that and add hydrophobic, biocompatible, absorbable material, for example ester of fatty acid or aliphatic alcohol (for example ethyl laurate or lauryl acetate) and tocopherols (for example Tocopherol acetate ester) have delayed the eluting of anesthetic compound from putty.On the other hand, add the increase that more hydrophobic additive (for example tricalcium phosphate, hydroxyapatite DBM or lecithin) can cause anesthetis elution rate from putty.Can add hydrophobic compound up to about 20% concentration, and 40% hydrophilic additive is being effective increasing aspect the elution rate at the most.

Component 3-chooses wantonly

[0064] optionally comprise component 3 as absorption enhancer, and itself in addition can be used to assist the disintegrate of implanted material to control the kinetics of absorption by physics.If the promoter that Shi Yongs is not toxic or is not biological inconsistent in others in the prior art, then can use them.These prior art chemical compounds as

(referring to the discussion under the component 2 above and discussion hereinafter) and a kind of or combination of glycerol, propylene glycol, lecithin, betanin and polyol (for example hyaluronic acid, carboxymethyl cellulose and chitosan and acetyl derivative thereof) can be used as absorption enhancer in compositions of the present invention, points for attention as above.

[0065] still preferably uses other materials for this purpose, this material is expandable or soluble and absorbable, for example soluble or insoluble natural or synthetic polypeptide (for example purification, the insoluble fibrous but expandable collagen of powdery), can faster absorption solubility procollagen (for example ) and the soluble polypeptide of cold-peace hot water (for example gelatin) that can faster absorption.Lecithin and octyl phenyl ethoxylate are (for example X-100) can be used as biocompatible surfactant to help dilatancy.Polyvinylpyrrolidone is soluble with other, absorbable polymer (for example oxirane of above discussing in conjunction with component 2 and the block copolymer of expoxy propane) also is functional with relative hydrophilic polypeptide (for example poly-aspartate, polyglutamic acid and their salt) in the case.Compositions of the present invention (for example can comprise (as component 3) insoluble fibre shape collagen, soluble collagen, gelatin, octyl phenyl ethoxylate X-100), the block of oxirane and expoxy propane or random copolymer, polyvinylpyrrolidone or absorbable glass or aforesaid stabilized mixture based on phosphorus pentoxide.

[0066] although according to terminal use's expectation, can use greater or lesser particle diameter, the particle diameter in about 200-500 micrometer range produces suitable result.Gelatin, PVP and other copolymers have been used as the thickening additive but have not been to be used for the demineralized bone technical field as absorption enhancer.The upright Blume number (Bloomnumber) that connects along with gelatin of the thickening property of gelatin changes.Gelatin with Blume number in the 100-300 scope is suitable for compositions of the present invention, if but the product that obtains is acceptable for the terminal use, then also can use the value that is higher or lower than those numbers.

[0067] aforementioned preparation has the example following (based on the weight of final composition) of some suitable ratios of component of the compositions of above-mentioned character:

Component 1. is from about 5 to 80%, preferred about 20 to 60%.

Component 2. from about 5 to about 70%, preferred about 20 to 60%.

Component A. pharmacy effective dose, suitable is about by weight 5 to 25%, preferred about 10 to 20%.

B component. 0 to about 40%.

Water 0 is to about 10%.

[0068] although the discussion of front mainly is provided, may wish to have less relatively viscosity or less close-burning compositions in some applications in the scope of the material with putty consistency, perhaps even more viscosity, more close-burning compositions.For example may wish with compositions of the present invention put into bone the space (brill or otherwise form, as finedraw shape fracture) in, have only painstakingly and may in this space, put into full-bodied putty.The putty compositions of the present invention of less viscosity form will be ideal substitute.All need be made is to change in this ratio that provides to allow higher or lower strength of fluid, and the liquid diluting that perhaps adds the compatibility is to achieve this end.Make in this way, also can obtain the injectable forms of described material.Can prepare other less adhesion strengths, non-putty compositions in a like fashion, for example the emulsifiable paste of front indication, ointment, gel, lotion etc.

Component 4-chooses wantonly

What [0069] comprise in the above-mentioned product is the lenitive product that suits, and it also allows the osteogenesis of bone injury oral area position.Therefore, they are bone conductibility.The aspect of an expectation of the present invention also makes described product become osteoinductive, and the product of the component 4 (a kind of bone growth inducing material) of the amount that comprises effective induction of bone growth promptly is provided.Therefore, comprise osteogenic materials, for example somatomedin such as platelet-derived somatomedin (PDGF), transforming growth factor (TGF-β), the growth factor-I (IGF-I) that insulin is relevant, growth factor-I I (IGF-II), fibroblast growth factor (FGF), beta-2-microglobulin (BDGF II), bone morphogenetic protein (BMP) and the combination thereof that insulin is relevant stimulate osteogenesis to some extent.Other bone growth inducing material, for example demineralization bone matrix (DBM), bone connect albumen, osteocalcin, osteogenin and combination thereof, mineralising bone matrix (MBM) tricalcium phosphate and bioactivity glass that hemostasia products is suitably are osteogenic.

[0070] in use, be added to the suitable amount of the osteogenic materials in the present composition, according to material, its scope is about 0.001 to about 60wt%, and preferably approximately 0.001 to about 40wt%.When as component 4, during promptly as osteogenic materials, preferably use some reagent, for example the DBM or the mineralising bone of big mean diameter form.The scope of suitable big mean diameter is about 0.05-10mm, 0.1-5mm preferably approximately, most preferably about 0.5-1mm.But, if satisfy end user's needs, use less or greater particle size or component 4 higher or low quantity also are suitable.

[0071] about the relative populations of the osteogenic materials that is used for the present composition, can use the bone growth inducing effective dose, it means in amount and the material that is fit in form is osteoinductive in compositions.Used amount can change according to the effectiveness of skeletonization agent and the mean diameter of solid material.For example, somatomedin such as BMP, platelet-derived somatomedin (PDGF) etc. are effective under the part weight percent concentration, and the effective dose of DBM and mineralising bone matrix is generally higher percetage by weight concentration, for example about 10% to about 50% or higher, preferred mean diameter is bigger slightly than mean diameter used in the component 1.

[0072] adding of bone growth inducing material not only improves compositions of the present invention, and the agent for stanching that improves prior art is to produce new compositions with it.This class is added also makes these agent for stanching also can be for osteogenic.Think that the existence of osteogenic materials also will improve the bone conduction performance, because big relatively granule is tending towards " opening " putty structure, thus the space that provides inductive bone can hypertrophy to enter.

[0073] type of improved especially prior art agent for stanching is to be disclosed in United States Patent (USP) 4,439 by this interpolation, the type in 420 and 4,568,536, and each in them piece is introduced into to be provided with the reference of all purposes at this paper.Therefore, should word-for-word be reproduced as whole description of above-mentioned patent and claim and read this description and claim herein.Be purpose easily, usually the preparation of those patents can be characterized by and comprise the absorbable hemostatic composition that is used to control osteorrhagia, it comprises: the component that contains biocompatible soap, the component that the cation of described soap is selected from calcium, magnesium, zinc, aluminum, lithium and barium and contains the absorbable biocompatible substrate of health, described substrate is selected from ethylene oxide/propylene oxide block copolymer, polyol, Polyethylene Glycol and methoxy poly (ethylene glycol), triglyceride and fatty acid ester, and optional absorption enhancer.Therefore, at this respect of the present invention, bone growth inducing material is added to above prior art preparation to produce skeletonization hemostatic material and the damaged packing material of osteoinductive bone.

Other optional ingredients

[0074] can in following any compositions, add effective dose pharmaceutically separately or with the bonded anti-infective of substrate to slow down its release.The example of these infection materials is for example tetracycline, vancomycin, cephalosporins and an aminoglycoside of antibiotic, for example tobramycin and gentamycin, it combines with collagen separately or for example, and triclosan (Tricolsan), separately or as the iodine of PVP complex, collargol, silver salt, separately or and carrier, for example combination such as gelatin, collagen.

[0075] other material, for example two sulfate (double-sulfates) of vasoconstrictor and blood clot derivant such as epinephrine, tannic acid, ferrous sulfate and trivalent metal and monovalence metal, for example aluminum potassium sulfate and aluminum ammonium sulfate; Antitumor agent, for example methotrexate, cisplatin, amycin and combination thereof, radionuclide, for example strontium 89 etc.; As the analgesic of hereinafter being mentioned, for example benzocaine, lignocaine, tetracaine, fentanyl (a kind of potent non-opium material) etc., anti-inflammatory substance, for example non-specific ibuprofen and aspirin, perhaps COX-2 specific inhibitor, for example celecoxib (celeboxib); Radiopaque material, iodine compound for example, for example can with

The iodo ethyl stearte that (Savage Laboratories) obtains, and barium salt such as barium stearate can be added in the preparation with the amount of their treatment of effective realization or diagnostic purpose.According to the feature of selected coloring agent, coloring agent, for example Gentian Violet, D﹠amp; C Violet#2 and D﹠amp; C Green #6 is suitable.

[0076] in certain embodiments of the invention, may expect water and compositions intimate mixing of the present invention.Up to 10% or the existence of the low amounts of water of the more order of magnitude assist in many ways, wherein its changes the tactile properties of compositions.At this on the one hand, the compositions of gained has generally been given the sensation (with comparing of may existing in the compositions that does not add entry) that roughness reduces.In some cases, need provide putty sample preparation or the adhesion strength more not condensed non-putty preparation less than putty, aforesaid other this class material of emulsifiable paste, paste or this paper for example is based on water or other waterborne liquid rather than based on more hydrophobic excipient.Filler is metal fatty acid salt for example, and for example calcium stearate and other non-wetable filler as herein described are not moistening by water, and aqueous putty sample (denseness is less) compositions is not provided.But we find to use a small amount of surface active material, lecithin for example,

Pluronic for example

Handle filler, make non-wetable filler moistening fully can when component 2 is the aqueous excipient, prepare suitable soap-water formulation.Suitable aqueous excipient is water, saline, different biocompatible buffers, different body fluid for example blood, serum, blood constitutent concentrate etc.

[0077] if the narcotic salt of water solublity is used for described preparation, then can be in being added to other components of preparation before, they are dissolved in the minimum water.Although compare with the putty that uses more hydrophobic material preparation, the anti-washability of above putty is less, and they have application in the bone defect repair, wherein expect the quicker disintegrate of implant.Nonionic, cationic and surfactant anionic are suitable, though any in fact biocompatible surfactant can use, for example the smooth lauric acid salt of Dodecyl trimethyl ammonium chloride, sodium lauryl sulfate, Nonoxynol-9, tween such as polyoxyethylene Pyrusussuriensis, Tergitol-7 are heptadecyl sodium sulfate and antimicrobial surfactant, 1-lauryl-3-ethyl benzo-triazole (triazolium) bromide etc.Non-putty sample compositions, for example emulsifiable paste, paste etc. can prepare by water or the component A that uses additional amount.This is useful especially when needs form putty sample or emulsifiable paste shape compositions with for example blood rather than water in the surgery operative process.

[0078] the above discussion that relates to the use of blood clot derivant among the present invention understands that for example compositions in use can chemical hemostatic embodiment.That is to say,, hemostatic material is added to the compositions that obtains in the compositions of the present invention having as the ability of chemical hemostatic material no matter whether machinery stops blooding those compositionss.Therefore, by adding the blood clot induced material mechanical hemostatic putty is more effectively stopped blooding.Similarly, can make the emulsifiable paste or the paste of the low adhesion strength that may lack obvious mechanical anthemorrhagic performance become hemostatic by adding the hemopexis material.The latter's example is in the buttocks surgical operation paste of the vasoconstriction of the present invention improvement of skim to be applied to hemorrhage acetabular bone.

[0079] above-mentioned component is adding fashionable obtaining at useful, putty sample that has multiple favorable characteristics in varying degrees and non-putty sample reagent together with suitable ratio.In order to produce putty sample feature, combination of components different in preparation process may need different time and temperature.For example, the broken hydroxyapatite of some material such as fine powder may need the time longer than other component to obtain putty sample state.Usually, putty sample compositions of the present invention is absorbable in the rational time, usually in 30-60 days, though soak time may extend to several months or longer time for some is used.They be at ambient temperature hand-mouldable or be shaped, in the presence of blood, can handle well, and the acceptable salts water washing.They contact sometimes is clamminess, but is not bonded on the wet or dried surgical glove on any big degree.Under the situation that does not have radiosensitivity material such as DBM or certain micro-organisms agent, they can be by radiation sterilization.

[0080] actual ratio of Xuan Ding material will be according to the terminal applies of the expectation of the quantity of material itself, component utilized and final putty compositions.The user will be subjected to guide about the demand of desired viscosity, adhesion strength and the denseness that obtains at first, it is the consistency range of compositions is changed to emulsifiable paste, paste, ointment, gel etc. from flowable liquid consistency denseness, and be changed to more agglutinating putty sample denseness, keep the final further feature of expecting in the component that uses simultaneously.For example, to many operations, can guarantee that the position that analgesic compositions arrival pain takes place is important.In plastic surgery operations, provide compositions to adhere to the surface of bone, because it discharges analgesic in local environment.But in common surgical procedures, usually there is not the putty sample or even more the compositions of viscosity can adherent hard surface.This embodiment has solved this class difficulty.Particularly, find to sieve the material that shape or textile-like or felted or non-woven constructions can enough this classes contain analgesic and flooded equably, contained the fabric-putty laminate of analgesic with generation.Certainly, can for example antimicrobial, antiinflammatory and anticarcinogen and growth stimulant (as PDGF etc.) be admixed in the apparatus of this embodiment of the present invention with other drug material as herein described.

[0081] although solid constituent of the present invention is general absorbable to avoid the long-term existence of solid exotic, according to operating needs, described fabric component can be absorbable or non--absorbable.For example, by using hobnail to sew up or staple is connected to fabric component in the adjacent tissue, fabric-putty laminate is used to provide the medicine of per unit area normalized quantity and is used to guarantee that described apparatus is the device in needs zone (if organizationally or wherein simple to place laminate of the present invention be unsuitable).

[0082] for the operation of the needs that relate to lasting support or reinforcement, for example hernia reparation, non--absorbable fabric may be fit to.Therefore, at the operation after-stage, because analgesic is depleted and described putty absorbs, so that remaining non--absorbable fabric is used for strengthening enduringly repairing is damaged.Fabric is for example by knitting polyester, polypropylene or polyethylene fibre, or the fabric of nonwoven or felted textile is the example of useful materials, because they at present and be successfully used to the operation that other can be compatible with health.Therefore, if described fabric with carry out specially operatingly requiring compatiblely, the present invention can use with the fabric (absorbable or non--absorbable) of any kind.In fact, described substrate needs not be " fabric " on the ordinary meaning that makes word " fabric " usually.For example, described substrate can be adhesive-bonded fabric or felted fabric, and described compositions is applied thereon or is impregnated into wherein.

[0083] for not needing the lasting operation of strengthening, absorbable fabric, for example those that made by synthetic absorbable polymer (for example polyglycolic acid) and natural absorbable polymer (for example collagen, alginate etc.) are applicatory.In this case, after its medicine delivery functions was finished, whole apparatus was absorbed.

[0084] emulsifiable paste and putty are not only used as the analgesic vehicle excipients in this aspect of the present invention, and use other compositionss, said composition can be applied in the substrate and support thereon.Spendable in the present invention analgesic can be for example foregoing in this article analgesic of analgesic of any inner tolerance.The example of other analgesic that can be used be non-steroidal class anti-inflammatory compound (for example

Ibuprofen, aspirin, acetaminophen etc.).

[0085] for many application, the substrate of net, gauze, fabric, felt or non-woven constructions form is suitable.As described operation wish or need like that, described form can be inflexible, flexible, flat or arc.Can imagine that it is made by suitable material with for example shape of gauze shape substrate form, can use one deck thereon, resemble very much with one deck in compositions as herein described

Be applied to the mode on the cotton yarn.It does not have particular restriction for substrate, as long as can support described analgesic compositions and can be compatible with health.

[0087] therefore the composite or the laminate of this aspect of the present invention are suitable for being applied in the multiple operation, and wherein following is typical, but only is illustrational:

A) with containing the collagen substrate that the putty of ibuprofen as analgesic covers, be applied to orthopedics, for example in knee joint, hip and the shoulder displacement;

B) load has the absorbable polymer screen cloth of putty compositions (as the compositions of carrying analgesic), said composition contains any " caine " analgesic compounds of free alkali or acid-addition salts or their combining form, be applied to the incised wound bone to stop blooding and to provide postoperative pain to alleviate, for example in the hernia operation;

C) absorbable material (for example

) knit goods, its load has the coating of the dipping of the of the present invention dense and burned or antiperspirant cream compositions that comprises analgesic, wherein described fabric can be adhered to or be applied to, or cover the tissue of surgical exposure.

[0088] when when surgery uses, the described compositions of description must be aseptic.The 25kGy radiation sterilization that all compositionss all can be used standard cobalt-60 radiation source for example and demarcate dosage except following those.Exception is to contain radiosensitive additive, for example demineralized bone substrate, bone morphogenetic protein, some antibiotic, unsaturated molecule, for example preparation of oleic acid etc.When using these materials, can also sterilely add aseptic radiosensitive additive by putty sample or the radiation sterilization of non-putty sample material that will fill, carry out aseptic packaging then and realize aseptic.

[0089] compositions described in the description can be aseptic maybe can sterilizing, and can pack in a variety of forms.Described packing itself can be aseptic maybe can sterilizing.That described compositions can be used as is amorphous (be deformed or do not have definite shape) material, for example paste, emulsifiable paste or putty packing perhaps are the shape of its container.They can be shaped as parallelepiped or conventional circle usually, and the former example is little brick shapes or sheet (shape of chewing gum rod), and the latter's example is columniform, avette or spheric product.As alternative selection, when use allowing and viscosity when suitable, described product can be packaged in the syringe-like or the auxiliary allotter of piston that can extrude by the hole of suitable cross section and shape or extrude.Can comprise and be similar to the mechanical assistant device that is used for joint filling.Another kind of be included in squeezable, deformable pipe, for example toothpaste type pipe or folding pipe for example are used for the product in the pipe of underfill applications, wherein are shaped and design the hole so that any suitable shape is dispensed to pending surface.Described packing can comprise ES as outer package, and for example strippable blister is delivered to aseptic area to allow described package.

[0090] the present invention also considers the using method of compositions of the present invention.For example, an embodiment is the method for coming machinery control osteorrhagia by the compositions any of the present invention of using effective dose for hemorrhage bone, and wherein said compositions has sufficient dense denseness, for example is in the putty compositions of the present invention.In this case, described compositions is mechanical hemostatic filling.

[0091] another embodiment of using method of the present invention is the method for coming the Chemical Control osteorrhagia by of the present invention any compositions of using effective dose, and wherein said compositions comprises above-mentioned blood clot derivant.Under the situation of putty, described compositions is chemical hemostatic filling.Also comprising clot induces the mechanicalness hemostatic tamponade of the present invention of reagent will be as mechanical hemorrhage and chemical styptic.

[0092] another kind of method of the present invention is to be applied to the method that the osteogenesis of bone in damaged induced in affected bone zone by the of the present invention any compositions that comprises the bone growth inducing agent with effective dose, especially comprise bone growth inducing material when described compositions, for example DBM, mineralising bone matrix, bone morphogenetic protein, hydroxyapatite etc. the time.Another kind method be by to treated in the bone by any compositions of the present invention who comprises anti-infective of the affected bone area applications effective dose of being treated or bone around the method for infection.

[0093] another kind of method be by destroy in the bone to the of the present invention any compositions that contains antitumor agent of the affected bone area applications effective dose that contains cancerous cell or bone around the method for this cell.

[0094] another kind of method is to alleviate from the bone or the method for pain around the bone by the of the present invention any compositions that contains analgesic to affected area applications effective dose.

[0095] another kind of method be by control in the bone to the of the present invention any compositions that contains antiinflammatory of affected area applications effective dose or bone around the method for inflammation.

[0096] another kind of method is the method that has been employed the bone inner region state of implant by the following steps evaluation: to the of the present invention any compositions that contains radiopaque material of affected area applications effective dose, then through the radiography described zone of developing, and determine the state in described zone.

[0097] another kind of method is to make any moistening method of filler of the present invention (it can be hydrophobic) that is used for as follows: the surfactant with cationic, anionic or nonionic is handled, use any fluid supply then, for example water itself, saline or body fluid as blood, serum etc. by as described in processing fill out agent preparation putty based on water.

[0098] additive method is above-mentionedly to be used for the treatment of or to manage in the method for postoperative pain each, and wherein said compositions comprises analgesic.

[0099] one skilled in the art will know that mode and the amount thereof of using described compositions.In some applications, can use a large amount of fillings, and in other is used, only need or requires on a small quantity.

[0100] method that provides below and embodiment are intended to more fully describe the preferred embodiments of the invention, and prove its advantage and practicality.

[0101] following embodiment for example understands particular of the present invention.

Embodiment 1

In this embodiment and all embodiment subsequently, unless otherwise noted, otherwise prepare described compositions by the following method: all exsiccant reagent of at first mechanical fusion, add any liquid reagent then gradually.Described compositions is with spatula (spatula) at room temperature " processing ", until obtaining required denseness.In some cases,, then add described material if the additional composition of described material require improves denseness, and continuously the kneading or " processing " mixture until obtaining required putty sample denseness.Component presents with weight portion.

Component 1 calcium stearate 4 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Described sample produces the putty sample material with fabulous resistance to water, physical characteristic and hemostasis feature and water-fast character, and promptly it resists the trial of under mobile tap water strength it being washed off consumingly.

Embodiment 1a)

By changing the ratio of liquid component, can make compositions of the present invention become the state of lower (promptly having more liquid) or higher (promptly having more inflexible) viscosity.The example of low viscosity preparation is as follows: the putty preparation to embodiment 1 adds 3 gram CitroflexA-2s.Resulting product has emulsifiable paste shape denseness, and can be under adapt circumstance be applied to bone as hemostasis agents or the delivery of agents that is used for various additives such as medicine.

Embodiment 2

Partly substitute calcium stearate with the bone growth inducing material

A) component 1 calcium stearate 3 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Component 4 hydroxyapatite (6-12 micron grain size) 1 gram

Resulting product be have with embodiment 1 in the putty sample material of the suitable character of product.When being enough to give differentiated shallow violaceous a small amount of Gentian Violet when being added in the above preparation, obtain having coloured product of the feature of embodiment 1 product.

B) substitute calcium stearate fully with hydroxyapatite

Component 1 hydroxyapatite (6-12 micron grain size) 2 grams

Component 2 Tocopherol acetate esters 2.5 grams

Component 3 gelatin 2 grams

Allow described compositions at room temperature leave standstill 72 hours, produce the product of feature with embodiment 1 product.

Embodiment 3

Component 1 aluminum palmitate 5 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Resulting product is to have the putty sample material that is similar to about the described performance of product among the embodiment 1.

Embodiment 3a), 3c 3b))

By following change embodiment 3 preparations, make the putty sample preparation of embodiment 3 become the less compositions of viscosity:

Embodiment 3 Embodiment 3a Embodiment 3b Embodiment 3c

Component 1 aluminum palmitate 5555

Component 2 Tocopherol acetate esters 3468

Component 3 gelatin 3000

Preparation 3a has the denseness of consistent lubricant ash.

Preparation 3b has the denseness of the ropy milk cream that resembles very much cake loaf sugar frost.

But preparation 3c has the denseness of the compositions of the sluggish flow that resembles very much cold Mel.

In them each can be applied to bone as hemorrhage.

Embodiment 4

Component 1 calcium stearate 5 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Component 4 DBM 3 grams

Resulting product also has the additional character of bone conductibility except the anthemorrhagic performance with embodiment 1 product.

Embodiment 5

5a. 5b.

Component 1 calcium stearate 2 grams 1.3

Component 2 triethyl citrates 1.6 grams 0.98

Component 3

X-100 0 0.02

Resulting product 5a is that putty sample and having is similar to those physical features of embodiment 1.Product 5b also be the putty sample and more can absorb apace than 5a.

X-100 can be from Dow Chemical Co., Midland, and Michigan obtains.

Embodiment 6

Component 1 calcium stearate 4 grams

Component 2 triethyl citrates 3 grams

Component 3 gelatin 3 grams

Resulting product is the putty sample, and has the physical features that can be used as hemorrhage, but when comparing with the product of embodiment 5, it is not preferred.

Embodiment 7

Component 1 calcium stearate 2 grams

Component 2 CitroflexA-2s 2 grams

Resulting product has fabulous putty sample feature and physical features, and those of itself and embodiment 1 are suitable.

Embodiment 8

Component 1 calcium stearate 0.5 gram

Component 2 triethyl citrates 1 gram

Component 4 hydroxyapatite 2 grams

Obtain a kind of injectable compositions of low viscosity with anthemorrhagic performance.

Embodiment 9

Component 1 calcium stearate .5 gram

Component 2 Tocopherol acetate esters 2 grams

Component 4 hydroxyapatite 2 grams

Obtain a kind of have fabulous putty sample feature and water-proof compositions.

Embodiment 10

Component 1 hydroxyapatite 2 grams

Component 2 triethyl citrates 2.5 grams

Obtain a kind of thick bone surface that is applied to easily, have good adhesion and fill the combination of features thing.

Embodiment 11

Component 1 calcium stearate 3 grams

Component 2 Tocopherol acetate esters 1.0 grams

Component 2 triethyl citrates 1.5 grams

Component 3 gelatin 2 grams

Resulting product be a kind of have be similar to those putty sample physical features of embodiment 1, and the good material more sticking slightly than the product of embodiment 1.

Embodiment 12

Component 1 calcium stearate 4 grams

Component 2 lauric acids 4 grams

Component 2 Tocopherol acetate ester .5 gram

With the lauric acid fusion of calcium stearate and fusing, and form good putty, the cooling after fixing.Obtain good putty then with described solid crushing, and with the tocopherol fusion.

Resulting product has putty sample denseness under body temperature, and at room temperature has hard slightly denseness.

Embodiment 13

Component 1 calcium stearate 4 grams

Component 2 triethyl citrates 4 grams

Component 2 lauric acids 4 grams

Resulting product is the putty sample, and has and be similar to those physical features of embodiment 1, and its caking property is slightly little.

Embodiment 14

Component 1 calcium stearate 2 grams

Component 2 dodecanes 1 gram

Resulting product has excellent water tolerance, and viscosity is lower, and has good comparability with other physical features of embodiment 1.

Embodiment 15

Component 1 calcium stearate 2 grams

Component 2 capryl alcohol-1 1 gram

Resulting product viscosity is lower, and has and be similar to those physical features of embodiment 14, but its caking property is slightly little.

Embodiment 16

Component 1 calcium stearate 2 grams

Component 2 diethyl succinates 2 grams

The resulting product of component 3 gelatin, 2 grams is the good putty that is similar to embodiment 1.

Embodiment 17

Component 1 calcium stearate 4 grams

Component 2 diethyl succinates 3 grams

Resulting product is good putty, compares the denseness with raising with embodiment 16 products.

Embodiment 18

Component 1 calcium stearate 4 grams

Component 2 CitroflexA-2s 3 grams

Component 3 gelatin 3 grams

Resulting product is equivalent to the product that obtains among the embodiment 1.

Embodiment 19

Component 1 aluminum palmitate 4 grams

Component 2 Tocopherol acetate ester .3 gram

Component 2 triethyl citrates 3 grams

Resulting product is a kind of softish, translucent slightly putty, has excellent water tolerance and good hemostasis feature.

Embodiment 20

Component 1 calcium stearate 3 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Component 4 demineralized bone substrate 1 gram

Resulting product is a kind of putty sample material, has the character of the product that is equivalent to embodiment 1 and has bone formation performance.

Embodiment 21

Component 1 hydroxyapatite 3 grams

Component 2 Tocopherol acetate esters 3.5 grams

Component 3 gelatin 3 grams

In this embodiment, described material is soft and buttery at first, and lacks caking property.But, after at room temperature leaving standstill 72 hours, form a kind of fabulous putty with good water resistance.Increase the Tocopherol acetate ester of other 3 gram amounts, obtain the having roughness paste of (causing) by gelatin.

Embodiment 22

Component 1 calcium stearate 3 grams

Component 2 two-n-hexyl ether 2.5 grams

Component 3 gelatin 2 grams

Resulting product is the putty sample, and has and be similar to those good water resistance and physical features of embodiment 1.

Embodiment 23

Component 1 calcium stearate 3 grams

Component 2 two-n-pentyl ketone 2.5 grams

Component 3 gelatin 2 grams

Resulting product is the putty sample, and has and be similar to those good water resistance and physical features of embodiment 22.

Embodiment 24

Component 1 calcium stearate 3 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 bovine collagens (Powdered) 3 grams

Resulting product is the putty sample, has to be similar to those good water resistance and physical features of embodiment 23.In addition, described putty have by as absorb that fiber dust shape collagen sponge additive that accelerator (component 3) exists produces fibrous quality.

Embodiment 25

Component 1 calcium stearate 3 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 ^*Bovine collagen (Powdered) 3 grams

Comprise gentamycin sulfate

^*CollatampG can derive from Europe

Obtain a kind of hemostatic putty with infection performance.

Embodiment 26

Component 1 calcium stearate 4 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

120 milligrams of anti-infective gentamycin sulfate

Repeat embodiment 1,, add Tocopherol acetate ester then with the preparation putty except 120 milligrams of gentamycin sulfate and dried ingredients are merged.This embodiment has proved the preparation of the putty with infection character.

Embodiment 27

Component 1 calcium stearate 4 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Repeat embodiment 1, in 2% silver nitrate aqueous solution, soaked 2 hours, wash with twice distilled water and an acetone, then dried overnight except at room temperature making gelatin.This preparation is owing to existing silver/gelatin-compounded thing to have infection character.

Embodiment 28

Component 1 calcium stearate 4 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Repeat embodiment 1, (BMP-2 in aqueous solution Sigma-Aldrich) is incubated overnight 10 milligrams of gelatin, then air dried overnight except the lyophilizing people bone morphogenetic protein that contains 10 micrograms at 1 milliliter.Removing residual moisture content, and merge the putty that has skeletonization and anthemorrhagic performance with preparation with the wet gelatin of washing with acetone with remaining gelatin.

Embodiment 29

Component 1 calcium stearate 4 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Repeat embodiment 1, except with 0.5 milliliter (polyvidone-iodine, 10%; Be equivalent to 1% available iodine) sneak in the formation putty of 10 gram embodiment 1.Described material overstrike, and have the infection performance.

Embodiment 30

Component 1 micronization polylactic acid 3 grams

Component 2 Tocopherol acetate esters 1.5 grams

Described mixture forms a kind of fabulous putty, has the good water resistance and the performance that are equivalent to embodiment 1 product.

Embodiment 31

United States Patent (USP) 4,439 as the preferred composition of about 40% calcium stearate, 30% dextran and 30% Oleum Ricini, has been described following compositions in 420.If add entry, preferred compositions is 38% calcium stearate, 28% dextran, 27% Oleum Ricini and 7% water (all weight are weight percentage).To avoid the degraded of possible heat sensitivity component, prepare described compositions by mechanical mixture at ambient temperature.

Calcium stearate 4 grams

Oleum Ricini 3 grams

Dextran 3 grams

The dry fusion in 50 milliliters of glass beakers with calcium stearate and dextran under agitation uses spatula to add Oleum Ricini.At room temperature with spatula with mixture " processing " after several minutes, denseness changes gradually.Described mixture becomes frangible, becomes the putty sample after further handling.Adding low amounts of water (about 1 gram) has reduced the gravel character of dextran.

Embodiment 32

Preparation among the change embodiment 31 as follows is to prepare a kind of new putty sample inventive compositions.This material is effective hemorrhage, and is the damaged filler of a kind of effective skeletonization bone.

Calcium stearate 2 grams

Oleum Ricini 1.5 grams

Dextran 1 .5 gram

DBM (demineralized bone substrate) 1.5 grams

The purpose of this embodiment is to show, DBM can be added to United States Patent (USP) the 4th, 439, in the compositions described in No. 420, to obtain a kind of putty sample material with bone formation performance.

Embodiment 33

Component 1 aluminum palmitate 5 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Additive methotrexate .2 gram

After the surgical resection bone tumor, with this chemotherapy putty be filled into bone damaged in.

Embodiment 34

Component 1 aluminum palmitate 5 grams

Component 2 Tocopherol acetate esters 3 grams

Component 3 gelatin 3 grams

Additive strontium 89 (form of salt)

Above preparation obtains the radiotherapy putty described in the embodiment 33 when the strontium 89 with the radioactivity effective dose provides together.

Embodiment 35

Absorbable phosphate glass 3 grams that component 1 is pulverized

Component 2 Tocopherol acetate esters 1 gram

The crucible that will contain the biphosphate sodium hydrate heated 4 hours cooling fast then down at about 800 degrees centigrade.With hammer the absorbable phosphorus glass material of gained is smashed then, and in the screw grinding machine, handled about 72 hours and segment is ground to form fine powder.The glass that fine powder is broken (3 gram) stirs with Tocopherol acetate ester (1.0 gram), has good physical behavior and water-proof putty sample material until formation.

Embodiment 36

Component 1 calcium stearate 3 grams

Component 2 ethyl laurates 3 grams

Component 4 demineralized bone substrate 1 gram

The purpose of this embodiment is to show, DBM can be added to United States Patent (USP) the 4th, 439, in the compositions described in No. 420 to obtain a kind of putty sample material with skeletonization character.

Embodiment 37

Component 1 hydroxyapatite 3 grams

Component 2 isopropyl palmitates 3.5 grams

Component 3 gelatin 3 grams

After at room temperature leaving standstill 72 hours, obtain a kind of fabulous putty with the good water resistance that is equivalent to embodiment 2.

Embodiment 38

Component 1 calcium stearate 5 grams

Component 2 glycerol (American Pharmacopeia) 15 grams

3 gram calcium stearates are mixed with the glycerol of 3 gram increments, present emulsifiable paste shape denseness (15 gram glycerol altogether) until described mixture.In this stage, other 2 gram calcium stearates are mixed mixture with the denseness of the Ovum Gallus domesticus album that obtains having beating property good (well-beaten) and the compositions of outward appearance.

Embodiment 39

Component 1 calcium stearate 1 gram

Component 2 Tocopherol acetate esters 1 gram

Component 3 glycerol .25 gram

Obtain a kind of softer putty, have fabulous resistance to water.

Embodiment 40

Component 1 sucrose (refining Saccharum Sinensis Roxb.) 3 grams

Component 2 olive oil 2 grams

This produces hard relatively putty, and it is very easy to wash off and is useful under the low water-proof situation of needs.

Embodiment 41

With 3 grams from the product of above embodiment 38 and 0.75 milliliter of deionized water mixing that contains 30ppm collargol (Scotts Valley, CA 98006 for Source Naturals, Inc.).The color of resulting hemostasis emulsifiable paste becomes canescence, because there is antimicrobial silver, and it is smaller slightly than the viscosity of initial emulsifiable paste.

Embodiment 42

Component 1 calcium stearate 4 grams

Component 2

L-35 ^*0.2 gram

(molecular weight 1900)

Component 12 water 2 grams

^*Pluronic?588310，Lot?WPAW-502B，BASF，Corp.Mt.Olive，NJ07828-1234

Under agitation described composition is merged, until producing putty sample material.Described material is dispersed in the excessive water easily.

Embodiment 43

Component 1 calcium stearate 12.0 grams

Component 2 d, l-alpha tocopherol acetas 7.5 grams

Component 3 soybean lecithin granules 1.3 grams

With calcium stearate and lecithin (Archer-Daniels-Midland Ultralec P) dry mixed, under vigorous stirring, add Tocopherol acetate ester then.Form and a kind ofly have good water resistance and processing characteristics but the putty more sticking slightly than the corresponding preparation that contains gelatin rather than lecithin.

Embodiment 44

Component 1 calcium stearate 0.6 gram

Component 1 potato starch ^*3.8 gram

Component 2 d, l-alpha tocopherol acetas 1.6 grams

^＊-Razin?International，Inc.

6527?Route?9

Howell，New?Jersey?07731

Tocopherol acetate ester and calcium stearate are mixed, add starch then.Described mixture forms the soft white putty with good water resistance.In order to prevent to form postoperative adhesion, may need from the ionizing gamma-radiation of cobalt 60 source putty to be sterilized so that starch degradation with 25kGy.As alternative selection, described starch carries out radiation degradation before can be in being formulated into putty.

Following examples 45-52 has shown the putty compositions as embodiment 1 preparation, and it has excellent water tolerance and along with the quantity of the gelatin quantity with respect to calcium salt increases, and the absorbability slow trapping increment of postponing increases to more fast Absorption.

Umber Ca salt Umber component 2 Umber-gelatin-%

Embodiment 45 12 stearic acid Ca 7.5 Tocopherol acetate esters 00

Embodiment 46 12 stearic acid Ca 7.5 Tocopherol acetate esters 2.0 10

Embodiment 47 12 stearic acid Ca 7.5 Tocopherol acetate esters 3.5 15

Embodiment 48 12 stearic acid Ca 7.5 Tocopherol acetate esters 5.0 20

Embodiment 49 12 lauric acid Ca 7.5 Tocopherol acetate esters 4.5 20

Embodiment 50 12 stearic acid Ca 7.5 triethyl citrates 4.5 20

Embodiment 51 0.6 stearic acid Ca 1.6 Tocopherol acetate esters 5.0 70

A) umber-% of umber-%b)

Embodiment 52 components 1 stearic acid Ca 3.4 31 2.35 21

Component 2 Tocopherol acetate esters 3.2 29 2.2120

Component 3 gelatin (150 Blume) 4.4 40 3.0428

Component 4DBM 0 3.4031

Amount to 11.0 11.0

Resulting product has the feature of the putty that is similar to embodiment 53.

The gelatin of preparation in a) exists with 40wt%, and described compositions has good putty consistency and excellent water tolerance and absorbability.

When obtaining a kind of more condensed can be used as in orthopedics's operation, will follow closely or screw by needs, when for example the base of a fruit (pedicle) screw anchors to the preparation of the excipient on the bone, then can wherein comprise big particle diameter GUSUIPIAN and change previous formulations a) by making, and the bony site that is applied to suit.Therefore, when the DBM that is the 1-5 millimeter with 31 parts of particle diameters be added to 69 parts of preparations a) in the time, produce the preparation b comprise 31%DBM and 28% gelatin).Denseness is a kind of denseness of thick, close putty, wherein can insert nail or screw, and anchor in the adjacent bone.The one-tenth bone characteristics of described preparation can allow to carry out osteogenesis sooner or later around nail or screw, thereby permanently they is anchored on the adjacent bone structure.

Embodiment 53

Component 1 stearic acid Ca 3.0 grams

Component 2 Tocopherol acetate esters 0.4 gram

Component 2 tributyl citrate 2.3 grams

Component 3 gelatin 2.0 grams

Obtain a kind of putty that has very good hemostasis feature and absorb feature.

Embodiment 54

Component 1 stearic acid Ca 3.0

Component 2 Tocopherol acetate esters 0.4

Component 2 citroflex A-4s 2.3

Component 3 gelatin 2.0

Embodiment 55

Component 1 calcium stearate 2.0 grams

Component 2 Tocopherol acetate esters 1.5 grams

Component 3

F-38 ^*2.0 gram

(molecular weight 4700)

^*Product 583095, Lot WP1W-515B, BASF Corp., Mt.Olive, NJ07828-1234

Provide Pluronic with " lozenge " form, and be ground into powder, mix then.Described mixture forms fabulous putty.

Embodiment 56

Component 1 calcium stearate 4.0 grams

Component 2

L-35 3.0 grams

(molecular weight 1900)

Among this embodiment

Be a kind of viscous liquid, and form fabulous putty.Because it is this

Be water miscible, so do not need to add absorption enhancer.

[0204] all compositionss of following embodiment 57-63 have putty sample denseness and are used to incised wound bone or soft tissue easily.Unless otherwise indicated, they prepare by the following method: described analgesic component A is dissolved, suspends or is dispersed in liquid component 2 and the B component (if any), thereby form uniform admixture, then this admixture is mixed with solid constituent 1.The percentage ratio sign all is the percentage by weight of whole compositions.

[0205] compositions of considering by making experiences the evaluation that following processing obtains elution rate: a certain amount of compositions that will have 0.5 gram " button shape " form of 1 cm diameter is placed in 37 ℃ of phosphate buffers (pH7.4) of 500cc, and slowly stirs.The surface area that is exposed to described buffer is about 0.785 square centimeter.During first day working time, during 3 days, took out the buffer solution of 1 ml aliquots sample in per 2 hours, then at second day and sampling the 3rd day every day several.Analyze the lignocaine of every duplicate samples with HPLC-UV spectrophotography contrast lignocaine standard substance.The existence of lignocaine proves the analgesic that has discharged described pain relief amount in the supernatant during three days.Abide by same program and measure the eluting of marcaine free alkali and hydrochlorate.

[0206] in some cases, the component of similar quantity is applied to patient's arm partly, shows effective eluting of the analgesic of pain relief amount on three days phase intercycle ground with the numbness of the application site of needle-like rod test.

Embodiment 57

[0207] prepared following compositions:

Composition I. component 1. calcium stearates 55%

Component 2.a. triethyl citrate 24%

Component A. lignocaine free alkali 16%

B component. Tocopherol acetate ester 5%

II. component 1. calcium stearates 50%

Component 2.a.

L-35 29%

Component A.a. lignocaine free alkali 8%

B. lidocaine hydrochloride 8%

B component. Tocopherol acetate ester 5%

III. component 1. calcium stearates 47%

Component 2. triethyl citrates 37%

Component A. lidocaine hydrochloride 16%

IV. component 1. calcium stearates 55%

Component 2.a) Pluronic L-35 12%

b) Pluronic?F-68 12％

Component is lignocaine free alkali 8% A.1.

2. lidocaine hydrochloride 8%

B component. Tocopherol acetate ester 5%

[0208]

L-35 is liquid epoxy ethane/propylene oxide block copolymer, and molecular weight is about 1900, can obtain from BASF (Mt.Olive, New Jersey 07828).

[0209]

F-68 is solid (lamellar) ethylene oxide/propylene oxide block copolymer, and it is easy to be dissolved among the warm L-35.

(F-68) have 8,400 molecular weight, make

Component 2 mean molecule quantities are 4,500, are separately 1,900 than L-35.

[0210] in order to prepare the mixture of component 2 and component A, L-35 (liquid), F-68 (solid) and mixed being incorporated under the vortex of Tocopherol acetate ester are heated on hot plate, after this described solid dissolves rapidly.For fear of described mixture solidified, do not allow the liquid cools that obtains.

Mixture still temperature (not being hot) and when being liquid, add calcium stearate, and described mixture stirred with scraper in common mode, up to forming putty.It is stable that this putty at room temperature shows denseness through a couple of days, and anti-in high quality flushing.

V. prepared following compositions

Component 1. calcium stearates 2.0 grams

Component 2 a. Tocopherol acetate esters 1.5 grams

Component 2 b.

F-38 2.0 grams

Component A 1. lignocaine free alkali .65 gram

2. lidocaine hydrochloride .65g

Embodiment 58

Component 1 calcium stearate 47%

Component 2

L-35 28%

Component A. lidocaine hydrochloride 20%

B component. Tocopherol acetate ester 5%

Embodiment 59

[0212] bone conduction material, the admixture of the admixture of hydroxyapatite (HAP), tricalcium phosphate (TCP), HAP/TCP (40:60), HAP/TCP (20:80) for example, it has the particle diameter (permission bone conduction) between 0.5 and 1.5 millimeter, can be by commercially available acquisition (BerkeleyAdvanced Biomaterial), thereby and can be added and prepare arbitrary composition of the present invention and produce the bone conductibility compositions, for example, as follows:

I. component 1. calcium stearates 37%

Component 2. triethyl citrates 32%

Component A. lignocaine 16%

Component 4.TCP 15%

II. component 1. calcium stearates 32.04%

Component 2. triethyl citrates 24.665

Component A1. lignocaine free alkali 6.65%

2. lidocaine hydrochloride 6.65%

Component 4. hydroxyapatite 30.00%

III. component 1. calcium stearates 24.66%

Component 2.

L-35 32.04%

Component A 1. lignocaine free alkalis 6.65%

2. lidocaine hydrochloride 6.65%

Component 4. DBM 30.00%

Embodiment 60

Component 1. calcium stearates 60%

Component 2. triethyl citrates 27%

Component A 1. lignocaine free alkalis 6.5%

2. lidocaine hydrochloride 6.5%

Embodiment 61

Component 1. calcium stearates 49.00%

Component 2. triethyl citrates 37.70%

Component A. 1. lignocaine free alkalis 6.65%

2. lidocaine hydrochloride 6.65%

Embodiment 62

Component 1. calcium stearates 49.0

Component 2.

L-35 37.7

Component A. 1. lignocaine free alkalis 6.65

2. lidocaine hydrochloride 6.65

[0216] embodiment 58-62 produces the product that is suitable as implantable lenitive compositions.

Embodiment 63

[0217] can individually product of the present invention be applied to absorbable or non--absorbable knitting or non-woven constructions body or felted thing, the wound bracing means is provided, it will discharge local anesthetic and manage postoperative pain in soft tissue.But described fabric component based on synthetic absorption mesh is degraded fast in position and is absorbed.

[0218] for example, the product of embodiment 62 before implanting, can be deployed on the fabric web in the hernia prosthesis:

Component 1. calcium stearates 49.05

Component 2.

L-353 7.7%

Component A. 1. lignocaine free alkalis 6.65%

2. lidocaine hydrochloride 6.65%

[0219] although provides the foregoing description in conjunction with lignocaine free alkali and lidocaine hydrochloride, but will be appreciated that and to use the combination of any analgesic/narcotic free alkali/acid-addition salts, and the identical or different analgesic/narcotic combination that can use free alkali or acid-addition salts form when needing.In addition, any this class analgesic or their combination can be included in any compositions of the foregoing description, no matter whether described embodiment comprises analgesic.

[0220] the foregoing description comprises exemplary of the present invention.Other embodiments within the scope of the present invention can be prepared according to the content described in the above-mentioned description by those skilled in the art.

Claims

1. the compositions of an implantable health, said composition comprises the following component of intimate mixing:

Component 1, implantable health, this material comprises thin particulate solids,

Component 2, the organic liquid of the following component A that can dissolve, disperses or suspend, and

Component A has the mixture that local pain is alleviated active analgesic compounds or chemical compound, and wherein said analgesic compounds exists with effective, lenitive amount pharmaceutically.

2. the described compositions of claim 1, wherein said compositions is anhydrous.

3. the described compositions of claim 1, the wherein extra water that has about at the most 10 weight % in described compositions.

4. the described compositions of claim 1, wherein in described compositions, additionally there is B component, this B component comprises the water wetted material that can delay component A eluting from described compositions when implanted, or can increase the hydrophobic material of component A eluting from described compositions when implanted.

5. the described compositions of claim 1, wherein component 1 is water-fast in fact.

6. the described compositions of claim 1, wherein component 1 is can compatible with health, absorbable micronizing solid material.

7. the described compositions of claim 6, wherein component 1 is the slaine of fatty acid.

8. the described compositions of claim 1, wherein said compositions has the denseness of moldable putty.

9. the described compositions of claim 1, wherein component 1 comprises calcium stearate.

10. the described compositions of claim 1, wherein component 2 comprises one or more in the random or block copolymer of the liquid or solid of triethyl citrate, Tocopherol acetate ester, oxirane and expoxy propane.

11. the described compositions of claim 10, wherein said component 2 liquid comprise the liquid block copolymer of at least a oxirane and expoxy propane.

12. the described compositions of claim 11, wherein said component 2 liquid additionally comprise dissolving, suspend or are scattered in the solid copolymer of one or more polyalkylene oxides in the component 2.

13. the described compositions of claim 12, wherein said solid copolymer comprises the block copolymer of oxirane and expoxy propane.

14. the described compositions of claim 1, wherein said component A analgesic are to exist with its free alkali or acid-addition salts form, or exist with the combination of two kinds of forms of this analgesic.

15. the described compositions of claim 14, wherein said analgesic component comprises the annulus that links together by ester bond or amido link.

16. the described compositions of claim 15, wherein said free alkali form and acid-addition salts form exist jointly.

17. the described compositions of claim 16, wherein said free alkali form is all or part of to be dissolved in the component 2.

18. the described compositions of claim 1, wherein said analgesic comprise lignocaine or lidocaine hydrochloride or their combination.

19. the described compositions of claim 1, wherein component 1 comprises calcium stearate, and component 2 is selected from by triethyl citrate, Tocopherol acetate ester, Pluronic

L-35 and Pluronic

L-35 and solid Pluronic

The group formed of mixture, and component A comprises lignocaine, lidocaine hydrochloride or their mixture.

20. the described compositions of claim 19, wherein component 2 comprises triethyl citrate.

21. the described compositions of claim 4, wherein B component comprises Tocopherol acetate ester.

22. the described compositions of claim 19, wherein component 2 comprises Pluronic

L-35.

23. the described compositions of claim 19, wherein component 2 comprises Pluronic

L-35 and Pluronic

F-68.

24. having, the described compositions of claim 1, the granule of wherein said component 1 be 100 microns mean diameter to the maximum.

25. wherein additionally there is the granule of the material of induction of bone growth in the described compositions of claim 1.

26. the described compositions of claim 25, the granule of wherein said induction of bone growth are selected from the group of being made up of GUSUIPIAN or bone powder, demineralized bone, hydroxyapatite and tricalcium phosphate.

27. the described compositions of claim 26, wherein said compositions is anhydrous.

28. the described compositions of claim 26, the wherein extra water that has about at the most 10 weight % in described compositions.

29. the described compositions of claim 26, wherein in described compositions, additionally there is B component, this B component comprises the water wetted material that can delay component A eluting from described compositions when implanted, or can increase the hydrophobic material of B component eluting from described compositions when implanted.

30. the described compositions of claim 26, wherein component 1 is water-fast in fact.

31. the described compositions of claim 26, wherein component 1 is the slaine of fatty acid.

32. the described compositions of claim 26, wherein said compositions has the denseness of moldable putty.

33. the described compositions of claim 26, wherein component 1 comprises calcium stearate.

34. the described compositions of claim 26, wherein component 2 comprises one or more in the random or block copolymer of the liquid or solid of triethyl citrate, Tocopherol acetate ester, oxirane and expoxy propane.

35. the described compositions of claim 34, wherein said component 2 liquid comprise the liquid block copolymer of at least a oxirane and expoxy propane.

36. the described compositions of claim 35, wherein said component 2 liquid additionally comprise dissolving, suspend or are scattered in the solid copolymer of one or more polyalkylene oxides in the component 2.

37. the described compositions of claim 36, wherein said solid copolymer comprises the block copolymer of oxirane and expoxy propane.

38. the described compositions of claim 37, wherein said component A analgesic exists with its free alkali or acid-addition salts form, or exists with the combination of two kinds of forms of this analgesic.

39. the described compositions of claim 38, wherein said analgesic component comprises the annulus that links together by ester bond or amido link.

40. the described compositions of claim 39, wherein said free alkali form and acid-addition salts form exist jointly.

41. the described compositions of claim 40, wherein said free alkali form is all or part of to be dissolved in the component 2.

42. the described compositions of claim 41, wherein said analgesic comprise lignocaine or lidocaine hydrochloride or their combination.

43. a composite, it comprises supporting structure, on this supporting structure or have the compositions of claim 1 therein, wherein this supporting construction be implantable health, can be compatible with health material.

44. the described composite of claim 43, wherein said compositions is anhydrous.

45. the described composite of claim 43, the wherein extra water that has about at the most 10 weight % in described compositions.

46. the described composite of claim 43, wherein in described compositions, additionally there is B component, this B component comprises the water wetted material that can delay component A eluting from described compositions when implanted, or can increase the hydrophobic material of component A eluting from described compositions when implanted.

47. the described composite of claim 43, wherein component 2 comprises triethyl citrate.

48. the described composite of claim 46, wherein B component comprises Tocopherol acetate ester.

49. the described composite of claim 43, wherein component 2 comprises Pluronic

L-35.

50. the described composite of claim 43, wherein component 2 comprises Pluronic

L-35 and Pluronic

F-68.

51. be used for alleviating the method from the pain in the zone around bone or the bone, this method comprises to the described compositions of the claim 1 of affected area applications effective dose.

52. be used for inducing the damaged osteogenesis of bone and alleviate from described damaged in or the method for the pain in described zone around damaged, this method comprises the described compositions of claim 25 to the area applications effective dose of affected bone.

53. be used to prepare the described method for compositions of claim 1, at first component A is mixed with component 2 in the method, then with resulting mixture and component 1 intimate mixing.