Biodegradable Polymer Composition

Europaisches Patentamt J European Patent Office © Publication number: 0 539 751 A1 Office europeen des brevets

® Priority: 28.10.91 US 783512 © Applicant: ATRIX LABORATORIES, INC. 2579 Midpoint Drive @ Date of publication of application: Fort Collins, Colorado 80525(US) 05.05.93 Bulletin 93/18 @ Inventor: Dunn, Richard L. © Designated Contracting States: 5021 Kitchell Drive Fort Collins AT BE CH DE DK ES FR GB IE IT LI LU NL SE Colorado 80524(US) Inventor: Tipton,Arthur J. 412 Garfield Street Fort Collins Colorado 80524(US) Inventor: Southard, George L. 1512 Brentford Lane Fort Collins Colorado 80525(US)

© The invention is directed to a composition composed of a thermoplastic or thermosetting polymer which is capable of forming a biodeg - radable and/or bioerodible microporous, solid or gelatinous polymer matrix. The matrix is useful as an implant in animals for enhancing regeneration of cells and tissue, such as bone and nerve cells, or for delivery of biologically -active substances to tissue or organs. The composition is administered to an implant site as a liquid. The invention also includes a ^" method of preventing and treating disorders and ^ diseases, such as bone or nerve growth disorders, or ^- of altering body functions such as birth control, using W the compositions and implants of the invention. o> CO

Rank Xerox (UK) Business Services (3. 10/3.6/3.3. 1) 1 EP 0 539 751 A1 2

Background of the Invention implant. Yet another object is to provide an implant which is capable of delivery of a drug or other Polymeric implants are useful as delivery sys - medicament over a desired period of time. A fur- terns and/or as mechanical barriers. Implants such ther object is to provide an implant for providing as preformed membranes or films have been de - 5 controlled release delivery of at least one scribed. However, many of these implants have biologically -active agent for stimulation and/or limited properties and produce inferior results ei - enhancement of physiological or biological activity ther as mechanical barriers or delivery systems. in an animal. Several implant techniques have been used in medical and dental applications. One application of w Summary of the Invention interest is the use of implants in treatment of periodontal disease. Surgery alone does not result These and other goals are achieved by the in restoration of lost periodontium. Successful present invention which is directed to a composi - periodontal restoration is known to occur if tion for providing in situ a biodegradable or periodontal ligament cells are allowed to colonize 75 bioerodible microporous matrix. The matrix may be root surfaces preferentially over gingival epithelial used to deliver biologically -active substances cells, gingival fibroblasts or osteoblasts. Micro - and/or for selective enhancement of cell growth porous membranes, such as the Millipore® filter and tissue regeneration in animals. and GORE -TEX® membranes, have been used The composition is a liquid formulation of a for periodontal tissue regeneration. Typically, the 20 biocompatible and biodegradable or bioerodible periodontal flap is cut, and the membrane is sur- thermoplastic or thermoset polymer or copolymer gically inserted to cover the surface of the tooth which is substantially insoluble in aqueous media root and to physically occlude epithelial cells from and body fluids. The composition may include a apically migrating along the root surface. separate pore -forming agent which is capable of Those membranes, however, have several 25 generating additional pores within the polymer drawbacks. Besides variable results, a second matrix. When a biologically -active agent is to be surgical entry is needed to remove the membrane released by the matrix, the agent is dissolved in after tissue regeneration has been achieved be- the composition to form a homogenous solution or cause the membranes are not biodegradable. dispersed in the composition to form a suspension. There is also a higher incidence of infection in 30 The invention also provides a method of using connection with their use. the composition for preventing and treating dis- To preclude surgical removal of the implant, eases and disorders, such as diseases of the bone membranes made of bioabsorbable material, such and connective tissue, infectious diseases, cancer, as microfibrillar collagen, polylactic acid, and metabolic disorders and allergies. The invention polygalactin (Vicryl®) mesh have been used. Re- 35 also provides a method of using the composition sults have been variable, and the therapeutic effect for tissue regeneration useful in wound and organ of these membranes has been unpredictable. In repair, nerve regeneration, periodontium regen - addition, fitting and positioning these membranes eration, and bone regeneration. The invention also to the implant site is time-consuming and cum- provides a method of using the composition for bersome. The degradation time of membranes 40 altering the physiological or biological activity of an composed of collagen has been variable, and the animal such as reproductive function. risk of adverse immunological reaction to this for- eign protein material in the body presents a major Thermoplastic polymer compositions concern. Therefore, an object of the invention is to pro - 45 According to a first embodiment of the inven - vide a composition comprising a biodegradable or tion, the composition is a liquid formulation of a bioerodible polymer for use as an implant in an thermoplastic polymer and a pharmaceutically ac - animal including a human. Another object is the ceptable organic solvent. The composition is ad - development of an implant that will eliminate the ministered as a liquid to an implant site, whereupon need for its surgical removal after its purpose has 50 the solvent diffuses or dissipates into the sur- been achieved. Another object is to provide a rounding aqueous tissue fluids. The thermoplastic composition which may be administered to an im - polymer is not soluble in these aqueous fluids so plant site in liquid form and which is capable of that it coagulates or solidifies to form a micro - solidifying in situ to form an implant. A further porous solid or gelatinous matrix. The matrix pref- object of the invention is to provide a biodeg - 55 erably has a two - layered pore structure com - radable implant which may be used to enhance posed of a core portion and an outer surface layer connective cell or tissue growth and deter growth or skin. The polymer matrix is suitable for use as of epithelial cells and tissue into the core of the an in situ formed implant in an animal, including

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humans and other mammals. The composition may The addition of a pore -forming agent to the be administered to tissue, to a surgical incision, or thermoplastic polymer composition and the use of to a void space in tissue such as a periodontal a pore -forming agent as part of the thermoset pocket, and the like. polymer composition will produce a matrix having 5 about the same diameter pores throughout the core Thermoset polymer compositions and skin. The size and/or quantity of a pore- forming agent included in the polymer matrix, and According to a second embodiment of the in - the distribution of the pore -forming agent within vention, the composition is a liquid formulation of a the polymer matrix, among other factors, may also thermoset prepolymer or copolymer, preferably an io influence pore size and porosity of the polymer acrylic ester -terminated biodegradable matrix. prepolymer, which is capable of cross - linking in Where the implant is employed for the purpose situ to form a polymeric or copolymeric solid or of tissue regeneration, as for example, to promote gelatinous matrix. The composition preferably is a guided tissue regeneration of periodontal tissue, it neat liquid but may include a pharmaceutically is is preferred that the diameter of the pores in the acceptable organic solvent that is miscible with matrix be effective to deter growth of epithelial water and body fluids. cells into the polymer matrix of the implant, and When the thermoset polymer composition is enhance growth of connective tissue cells into the cross -linked in situ, the resulting matrix is ren- matrix. It is further preferred that the size of the dered microporous by one of several means. Use 20 pores and porosity of the matrix of the implant of a small but suitable amount of organic solvent facilitate diffusion of nutrients and other growth - will produce pores as described above for the promoting substances such as growth factors, to thermoplastic polymer. The prepolymer ingredients cells which have grown into the matrix. Preferably, may release a pore -forming moiety such as car- the size of the pores in the polymer matrix is about bon dioxide and the like, or a separate pore- 25 3-500 microns, more preferably about 3-200 forming agent may be included. The pore -forming microns, and most preferably about 75-150 agent may be any suitable organic or inorganic microns. substance which is soluble or substantially miscible It is further preferred that the degree of po- in water and tissue fluids, and substantially mis- rosity of the matrix provides an implant which is cible or dispersible in the thermoset polymer 30 capable of substantially maintaining structural in - composition. tegrity for the desired period of time without The thermosetting polymer composition may breakage or fracturing during use. include a curing agent, such as a catalyst, which is capable of enhancing the cross - linking reaction of Biologically -active Agent prepolymers. The curing agent is biocompatible. 35 Preferred catalysts include benzoyl peroxide and The composition may further contain at least azobisisobutyronitrile. one biologically -active agent which is capable of providing a biological, physiological or therapeutic Porosity of the polymer matrices effect in an animal. For example it may enhance 40 cell growth and tissue regeneration, act for birth Several factors influence the size, or diameter, control, cause nerve stimulation or bone growth. of the pores formed in the polymer matrix of the The agent may also stimulate other desired bio- implant. In the polymer matrices formed from the logical or physiological activity within the animal. thermoplastic polymer composition and from the Accordingly, the invention provides an in situ thermoset polymer composition containing solvent 45 formed implant capable of functioning as a delivery or pore -forming moiety, the action of the solvent system of drugs, medicaments and other (or pore -forming moiety), as it diffuses out of the biologically - active agents to tissues adjacent to or coagulating or solidifying polymer matrix and into distant from the implant site. The biologically — the surrounding tissue fluids, generates pores in active agent is preferably incorporated into the the matrix and produces a two - component struc - 50 polymer matrix, and subsequently released into ture. The outer component is a surface skin which surrounding tissue fluids and to the pertinent body surrounds the inner component or core. The core tissue or organ. contains pores of diameter from about 10 to 1000 M. while the skin is functionally nonporous in Administration of the Composition comparison with the core. In fact, the skin has pores which are significantly smaller in diameter The composition may be administered to the than those of the core. implant site by any suitable method for applying a liquid, as for example, by means of a syringe,

3 5 EP 0 539 751 A1 6 needle, cannula, catheter, pressure applicator, and gelatinous matrix suitable for use as an implant in the like. In one embodiment, the composition may an animal. be administered by means of a syringe directly into The kinds of thermoplastic polymers suitable integral tissue or into a void or hole such as a for the present composition generally include any periodontal pocket or surgical incision, wherein the 5 having the foregoing characteristics. Examples are mixture in situ forms a solid implant conforming to polylactides, polyglycolides, polycaprolactones, the shape or the contour of the site. Advanta- polyanhydrides, polyamides, polyurethanes, geously, the composition of the invention is useful polyesteramides, polyorthoesters, polydioxanones, in overcoming placement difficulties inherent with polyacetals, polyketals, polycarbonates, polyor- solid forms of implants. io thocarbonates, polyphosphazenes, polyhydrox- The invention further provides a method of ybutyrates, polyhydroxyvalerates, polyalkylene altering a biological or physiological activity in an oxalates, polyalkylene succinates, poly(malic animal. The method involves administering to an acid), poly(amino acids), poly(methyl vinyl ether), animal, one of the foregoing compositions in an poly(maleic anhydride), chitin, chitosan, and amount effective to form a solid microporous matrix is copolymers, terpolymers, or combinations or mix- implant in the animal. The matrix, optionally con - tures therein. Polylactides, polycaprolactones, taining at least one biologically -active agent, is polyglycolides and copolymers thereof are highly capable of enhancing cell growth and/or tissue preferred thermoplastic polymers. formation such as bone or nerve formation, or The thermoplastic polymer is combined with a altering a biological or physiological activity in an 20 suitable organic solvent to form a solution. The animal such as reproductive function and the like. solubility or miscibility of a polymer in a particular solvent will vary according to factors such as Detailed Description of the Invention crystallinity, hydrophilicity, capacity for hydrogen - bonding and molecular weight of the polymer. The composition of the invention may be used 25 Consequently, the molecular weight and the con - to provide a biodegradable or bioerodible micro - centration of the polymer in the solvent are ad - porous in situ formed implant in animals. The justed to achieve desired miscibility. Highly pre- composition is composed of either a thermoplastic ferred thermoplastic polymers are those which polymer or copolymer in combination with a suit- have a low degree of crystallization, a low degree able solvent, or a thermosetting polymer or 30 of hydrogen - bonding, low solubility in water, and copolymer containing or combined with a pore- high solubility in organic solvents. forming means. The polymers or copolymers are substantially insoluble in water and body fluids, Thermoset polymer compositions biocompatible, and biodegradable and/or bioerodi - ble within the body of an animal. The compositions 35 The composition of the invention may as well are administered as a liquid to tissue wherein the be a liquid formulation of a thermosetting implant is formed in situ. The composition is oligomeric pre -polymer or copolymer which is biocompatible and the polymer matrix does not capable of cross - linking or hardening to provide a cause substantial tissue irritation or necrosis at the microporous gelatinous or solid matrix suitable for implant site. The implant has a variety of uses, as 40 use as an implant in an animal, including a human. for example, for enhancing cell growth and tissue The thermosetting pre -polymers and resulting regeneration, and delivery of biologically -active cross -linked polymers and copolymers are agents such as drugs and medicaments. biocompatible, and biodegradable and/or bioerodi - ble. Thermoplastic polymer composition 45 The pre - polymers are preferably low molec - ular weight polymers or oligomers having end Thermoplastic polymers useful in the com - functional groups that are reactive with acryloyl position of the invention include pharmaceutically chloride to produce acrylic ester -terminated pre- compatible polymers that are bioerodible by eel - polymers. Acrylic pre -polymers for use in the lular action, are biodegradable by action of non - 50 compositions may be synthesized according to a living body fluid components, soften when exposed variety of methods including, but not limited to, to heat but return to the original state when cooled reaction of a carboxylic acid, such as acrylic or and are capable of substantially dissolving or dis - methacrylic acid, with an alcohol; reaction of a persing in a water -miscible carrier or solvent to carboxylic acid ester, such as methyl acrylate or form a solution or dispersion. Upon contact with an 55 methyl methacrylate, with an alcohol by trans - aqueous fluid and the dissipation of the solvent esterification; and reaction of an isocyanatoalkyl component, the thermoplastic polymers are ca- acrylate, such as isocyanatoethyl methacrylate, pable of coagulating or solidifying to form a solid or with an alcohol.

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The thermosetting prepolymers are also short may be used to produce a trifunctional polymer. chain polyol derivatives of the thermoplastic poly - Further, the molecular weight of the polymer or mers described herein. The polyol terminated de- co - polymer may be varied according to the con - rivatives are converted to acrylic ester terminated centration of the chain initiator in the composition. prepolymers by any suitable method. Examples are 5 For example, a high concentration of a bifunctional short chain polyol derivatives of polylactides, chain initiator may make available an initiator mol - polyglycolides, polycaprolactones, polyanhydrides, ecule for each polymer chain, while a low con - polyamides, polyurethanes, polyesteramides, centration may contain one initiator molecule for polyorthoesters, polydioxanones, polyacetals, every two polymer chains. polyketals, polycarbonates, polyorthocarbonates, 10 Following the addition of the curing agent, the polyphosphazenes, polyhydroxybutyrates, poly - pre -polymer polymer mixture preferably remains hydroxyvalerates, polyalkylene oxalates, polyal - in liquid form for a period of time effective to allow kylene succinates, poly(malic acid), poly(amino administration of the composition to the implant acids), poly(methyl vinyl ether), poly(maleic anhy - site. Thereafter, the cross - linking reaction prefer - dride), chitin, chitosan, and copolymers, ter- 15 ably continues until a solid or gelatinous polymer polymers, or combinations or mixtures therein. matrix is produced. Accordingly, the pre -polymer A preferred polymer matrix and implant pre- mixture cures, or solidifies, in situ to form a poly - pared with thermosetting prepolymers is composed mer matrix which is capable of biodegradation of poly(DL - lactide - co - caprolactone) (DL- and/or bioabsorption over time. PLC). To prepare the DL-PLC polymer matrix, 20 The thermoset polymer composition contains DL - lactide or L - lactide and y - caprolactone are one or more materials to form the microporous co - polymerized in the presence of a multifunc- matrix. The polymer itself can contain moieties that tional polyol initiator and a curing agent to produce are released as volatile substances during cross - hydroxy -terminated PLC prepolymers. This linking to cause pore -formation. Alternatively, the polyol -terminated pre -polymer is then converted 25 composition can contain a minimum amount of to an acrylic ester -terminated pre -polymer by suitable, biocompatible organic solvent as de- any suitable method, as for example, by acylation scribed below, or can contain a separate pore- of the alcohol terminus with acryloyl chloride by forming agent as discussed below. The thermoset means of, for example, a Schotten - Baumann polymers containing releaseable moieties are technique (reaction of acyl halide with alcohol). 30 known in the art. Optionally, a curing agent, such as a catalyst, may be added to the acrylic pre - polymer mixture Solvents to enhance cross - linking of the pre -polymers and the subsequent coagulation or solidification of Solvents suitable for the thermoplastic polymer the resulting polymer to form a matrix. For exam - 35 composition are those which are biocompatible, pie, the acrylic pre -polymer, in an amount of preferably pharmaceutically acceptable, miscible about 5 grams, may be added to a solution of with the polymer component and water, and ca- benzoyl peroxide (BP) in about 1 ml of CH2CI2. pable of diffusing into tissue fluids surrounding the Optionally, other acrylic monomers may be added implant site. Preferably, the solvent has a Hil - to the acrylic pre -polymer mixture before adding 40 debrand (HLB) solubility ratio of from about 9- the curing agent. The acrylic pre - polymer mixture (cal/cm3)* to 1 3(cal/cm3)*. The degree of polarity of may be cured in air at room temperature, or in a the solvent should be effective to provide at least preheated vacuum oven. about 10% solubility in water, and to dissolve or Preferred catalysts for the preparation of the disperse the polymer component into solution. PLC prepolymers are basic or neutral ester - in- 45 According to the invention, the composition is terchange (transesterification) catalysts, as for ex - administered to the implant site in liquid form, ample, metallic esters of carboxylic acids contain - whereupon the solvent diffuses into the adjacent ing up to 18 carbon atoms, formic, acetic, lauric, tissue fluids. Upon contact with the surrounding stearic, and benzoic acid. Preferred catalysts in - aqueous fluids, the polymer moiety coagulates or elude, for example, stannous octoate and stannous 50 solidifies to form a solid or gelatinous matrix fitting chloride. the usually irregular shape of the incision or void of A multi-functional polyol chain initiator may the implant site. Preferably, the solvent quickly be included in the thermosetting polymer com - diffuses into the surrounding tissue fluids to en - positions to vary the molecular weight and com - hance formation of the polymer matrix following position of the polymer. For example, a bifunctional 55 administration of the composition to the implant chain initiator such as ethylene glycol, may be site. Preferably, the polymer matrix is capable of included to produce a bifunctional polymer, or a adhering to the adjacent tissue by mechanical trifunctional initiator, such as trimethylolpropane, forces to at least partially bond or attach the im -

5 9 EP 0 539 751 A1 10 plant to the adjacent tissue, and/or mechanically polymer composition hardens to form a micro- bond two tissues together. The concentration of porous solid matrix. In either variation, pores may polymer in solvent for the composition will gen - be formed within the matrix by several means. erally accomplish rapid and effective dissipation of Dissipation, dispersement or diffusion of the solvent the solvent and coagulation of the polymer. This 5 or released moiety (thermoset polymer) out of the concentration may range from 0.01 g of polymer solidifying polymer matrix or hardening polymer per ml of solvent to a saturated concentration, matrix (thermoset polymer) and into the adjacent preferably from 0.1 g per ml to saturation. tissue fluids may generate pores, including pore Solvents which may be used in the thermo- channels, in the polymer matrix. plastic polymer composition of the invention in - 10 Diffusion of the solvent or released moiety elude, for example, N- methyl -2 - pyrrolidone, produces a thermoplastic or thermoset polymer 2 - pyrrolidone, C2 to Cg alkanols, propylene gly- matrix having a two component structure, that is, col, acetone, alkyl esters such as methyl acetate, an inner core portion or layer, and an outer surface ethyl acetate, ethyl lactate, alkyl ketones such as portion or skin. The pores of the core are sub- methyl ethyl ketone, dialkylamides such as 15 stantially uniform while by comparison with the dimethylformamide, dimethyl sulfoxide, dimethyl porous nature of the core, the skin is essentially sulfone, tetrahydrofuran, cyclic alkyl amides such non - porous. In fact, the skin has pores with di - as caprolactam, decylmethylsulfoxide, oleic acid, ameters significantly smaller in size than those in propylene carbonate, aromatic amides such as the core. N,N -diethyl - m -toluamide, and 1- 20 dodecylazacycloheptan - 2 - one. Preferred sol - Pore - forming agent vents according to the invention include N - methyl -2 -pyrrolidone, 2 - pyrrolidone, dimethyl In either the thermoplastic or thermoset poly - sulfoxide, acetone, and propylene carbonate. mer composition, a pore -forming agent may be A mixture of solvents may be used to increase 25 included to generate additional pores in the poly- the coagulation rate of polymers which exhibit a mer matrix. The pore -forming agent is biocom- slow coagulation or setting rate. For example, the patible, and soluble in body fluids and water as polymer may be combined with a coagulant -pro- well as in the organic solvents. The pore -forming moting solvent system composed of a mixture of a agent is further capable of diffusing or dispersing good solvent and a poorer solvent or a non - 30 out of the coagulating polymer matrix and into the solvent for the polymer component. It is preferred adjacent fluids, whereupon pores are generated in that the solvent mixture contain an effective amount the polymer matrix. of the two solvents such that the polymer will The pore -forming agent, when combined with remain soluble in the mixture but coagulate upon the thermoplastic polymer and solvent or with the dissipation or diffusion of the solvents into sur- 35 thermoset polymer optionally containing a minimal rounding tissue fluids at the implant site. amount of solvent, preferably forms a uniform The same solvents can also be combined with mixture with the polymer either as a dispersion or the thermoset polymer composition. In this vari - suspension, or as a solution. When the mixture is ation, the solvent does not form the liquid character administered to an implant site, the solvent and/or of the composition. The prepolymer itself is liquid. 40 pore -forming agent preferably dissipate or diffuse Instead the solvent acts to produce the two com - into surrounding tissue fluids causing the formation ponent porous matrix discussed below. The solvent of microporous channels within the coagulating concentration is at a minimum for such purpose polymer matrix. Optionally, the pore -forming and is preferably inert toward the cross - linking agent may become incorporated into the polymer reaction. The solvent diffuses as the prepolymer 45 matrix, and dissipate into the surrounding tissue hardens to form the solid implant matrix. The or- fluids at a rate slower than that of the solvent, or be ganic solvent is included in the thermosetting released from the matrix by biodegradation or polymer composition in an amount suitable to form bioerosion. The porous matrices formed through pores but not high enough to substantially dilute the inclusion of a pore -forming agent have a pore the pre - polymer ingredient to a condition where it 50 structure in which the pores are substantially simi - only lightly cross -links. lar in size throughout the matrix structure. Preferably, the pore -forming agent is com- Pore -formation and porosity bined with the thermoplastic polymer and solvent, or the thermoset pre -polymer or copolymer mix- Upon contact with an aqueous body fluid or 55 ture before the matrix is formed. The pore -for- water, the thermoplastic polymer composition co - ming agent may form a mixture solution or dis- agulates or solidifies to form a microporous gelat- persion with the polymer. inous or solid matrix. Similarly, the thermoset

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Pore -forming agents include, any pharma- be measured according to any suitable method, as ceutically acceptable organic or inorganic water- for example, mercury intrusion porosimetry, spe- soluble substance that is substantially miscible in cific gravity or density comparisons, calculation water and body fluids and will dissipate from the in from scanning electronic microscopy photographs, situ formed matrix into body fluids. The pore- 5 and the like. Additionally, porosity may be cal - forming agent may also be a water -immiscible culated according to the proportion or percent of substance that rapidly degrades to a water - solu - water-soluble material included in the polymer ble substance. In the thermoplastic polymer com - composition. For example, a composition which position of the invention, it is further preferred that contains about 30% polymer and about 70% sol - the pore -forming agent is miscible or dispersible io vent and/or other water-soluble components will in the organic solvent to form a uniform mixture generate a polymer matrix having about 70% po - with the polymer moiety. Suitable pore -forming rosity. agents include, for example, sugars such as su - Preferably, the pore -forming agent is dis- crose and dextrose, salts such as sodium chloride sipated immediately from the polymer matrix to and sodium carbonate, and polymers such as is generate a matrix having a porosity and pore hydroxylpropylcellulose, carboxymethylcellulose, structure effective to perform the particular purpose polyethylene glycol, and polyvinylpyrrolidone. of the implant, as for example, a tissue regenera- The concentration of pore -forming agent rel- tion site or a matrix for timed - release of a drug or ative to polymer in the composition will vary ac- medicament. cording to the degree of pore -formation desired. 20 Generally, this concentration will range from 0.01 g Implant for tissue regeneration of pore -forming agent per gram of polymer to about 1g per gram. The composition may be administered to an The size or diameter of the pores formed in the implant site, as for example, whole tissue or tissue matrix may be modified by the size and/or dis- 25 with a void such as a periodontal pocket, a soft- tribution of the pore -forming agent within the tissue defect, a surgical incision, and the like. polymer matrix. For example, pore -forming agents When the composition is administered to a tissue which are relatively insoluble in the polymer mix- regeneration site, it is preferred that the implant ture, may be selectively included in the composi - provides a surface to facilitate the growth of re- tion according to particle size to generate pores 30 generative tissue. For example, to enhance regen - having a diameter which corresponds to the size of eration of hard tissue such as bone tissue, it is the pore -forming agent. Pore -forming agents preferred that the polymer matrix will provide a which are soluble in the polymer mixture may vary support for new bone cell growth which will replace the pore size and porosity of the polymer matrix the matrix as it is gradually absorbed or eroded by according to the pattern of distribution and/or ag - 35 body fluids. gregation within the mixture and resulting polymer The microporous polymer matrix is capable of matrix. biodegradation and/or bioabsorption within the im - The concentration of water-soluble compo- plant site. According to the invention, the particular nents, such as the solvent and/or pore -forming polymer and the molecular weight of the polymer agent, in the composition may vary the porosity of 40 may vary in the composition according to a desired the polymer matrix. For example, a composition duration or time interval of the degradation or having a high concentration of water-soluble bioerosion of the polymer matrix, as for example, a substances may produce a polymer matrix having few weeks or several years. When the implant is a high degree of porosity. used to enhance cell growth and tissue regenera- To provide an effective implant for bone cell 45 tion, it is preferred that the matrix disintegrate at a regrowth and tissue regeneration, it is preferred rate effective to allow replacement of the matrix by that the diameter of the pores be about 3-500 cell growth from the adjacent cells or tissue. microns, more preferably about 3-200 microns, and most preferably 75-150 microns. It is further Biologically -active agent preferred that the matrix has a porosity of about 5-95%, preferably about 25-85% in order to The in situ formed implants may also provide a provide optimum cell and tissue ingrowth into the delivery system for biologically -active agents to matrix and optimum structural integrity. adjacent or distant body tissues and organs. Pore diameter and distribution within the poly - Biologically -active agents which may be used mer matrix may be measured, as for example, 55 alone or in combination in the present composi - according to scanning electron microscopy meth - tions and implants include medicaments, drugs, or ods by examination of cross - sections of the any suitable biologically-, physiologically- or polymer matrix. Porosity of the polymer matrix may pharmacologically - active substance which is ca-

7 13 EP 0 539 751 A1 14 pable of providing local or systemic biological or the implant. To enhance selective cell growth into physiological activity in an animal, including a hu - the matrix, for example, it is preferred that the man, and which is capable of being released from bioactive agent is released from the polymer matrix the polymer matrix into an adjacent or surrounding at a rate corresponding to that of cell migration and aqueous fluid. The biologically -active agent may 5 growth into newly formed pores of the matrix. be miscible The biologically -active agent may also be a in the polymer and/or solvent to provide a substance, or metabolic precursor thereof, which is homogenous mixture with the polymer, or insoluble capable of promoting growth and survival of cells in the polymer and/or solvent to form a suspension and tissues, or augmenting the activity of func- or dispersion with the polymer. It is highly pre- io tioning cells, as for example, blood cells, neurons, ferred that the biologically - active agent be com - muscle, bone marrow, bone cells and tissues, and bined with the thermosetting polymer composition the like. For example, the biologically -active agent almost immediately prior to administration of the may be a nerve growth promoting substance, as composition to the implant site. It is further pre- for example, a ganglioside, phosphatidylserine, a ferred that the bioactive agent will not contain is nerve growth factor, brain - derived neurotrophic functional groups which will interfere with the factor, a fibroblast growth factor, and the like. In cross - linking reaction of the thermoset polymer. particular, the in situ implants are capable of en - These conditions are readily determined by those hancing regeneration of the periodontium by pro - of skill in the art simply by comparing the structure viding an outer surface having a porosity which of the bioactive agent and the reacting moieties of 20 serves as a physical barrier between an exposed the thermoset polymer. root surface and encroaching epithelial cells to Upon administration of the composition to the promote guided tissue regeneration. implant site, the biologically -active agent prefer- To promote tissue growth, the biologically — ably becomes incorporated into the polymer matrix. active agent may be either a hard or soft tissue As the matrix biodegrades and/or bioerodes, the 25 promoting substance or combinations thereof. biologically -active agent may be released from Suitable tissue growth promoting agents include, the matrix into the adjacent tissue fluids. Prefer- for example, fibronectin (FN), endothelial cell ably, the biologically -active agent is released into growth factor (ECGF), cementum attachment ex- the surrounding tissue fluids at a controlled rate. tracts (CAE), human growth hormone (HGH), a For example, the polymer matrix may be formu - 30 Periodontal ligament cell growth factor, fibroblast lated to degrade after an effective and/or substan - growth factor (FGF), animal growth hormones, tial amount of the biologically -active agent is re- platelet derived growth factor (PDGF), epidermal leased from the matrix. Release of a biologically - growth factor (EGF), protein growth factor active agent having a low solubility in water, as for interleukin - 1 (IL-1), transforming growth factor example a peptide or protein, may require the 35 (TGF/3-2), insulin -like growth factor II (ILGF- degradation of a substantial part of the polymer II), human alpha thrombin (HAT), osteoinductive matrix to expose the agent directly to the sur- factor (OIF), bone morphogenetic protein (BMP) or rounding tissue fluids. Thus, the release of the protein derived therefrom, demineralized bone biologically -active agent from the matrix may be matrix, and releasing factors thereof. varied by, for example, the solubility of the 40 Further, the agent may be a bone growth pro - biologically -active agent in water, the distribution moting substance such as hydroxyapatite, trical - of the biologically -active agent within the matrix, cium phosphate, a di - or polyphosphonic acid, an or the size, shape, porosity, solubility and biodeg - anti -estrogen, a sodium fluoride preparation, a radability of the polymer matrix, among other fac - substance having a phosphate to calcium ratio tors. 45 similar to natural bone, and the like. A bone growth The composition and in situ formed implant promoting substance may be in the form, as for contain the biologically -active agent in an amount example, of bone chips, bone crystals or mineral effective to provide a desired biological, phys- fractions of bone and/or teeth, a synthetic hydrox- iological, pharmacological and/or therapeutic effect, yapatite, or other suitable form. The agent may optionally according to a desired release profile, 50 further be capable of treating metabolic bone dis - and/or time duration of release. It is further pre- orders such as abnormal calcium and phosphate ferred that the biologically - active agent is in - metabolism by, for example, inhibiting bone re- eluded in the polymer composition in an amount sorption, promoting bone mineralization, or inhibit- effective to provide an acceptable solution or dis - ing calcification. persion viscosity. 55 See, for example, U.S. Patent No. 4,939,131 to In addition, the biologically -active agent may Benedict et al., U.S. Patent No. 4,942,157 to Gall et act as a pore -forming agent, or substance ca- al., U.S. Patent No. 4,894,373 to Young, U.S. Pat- pable of generating pores in the polymer matrix of ent No. 4,904,478 to Walsdorf et al., and U.S.

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Patent No. 4,911,931 to Baylink, U.S. Patent No. Growth factors such as colony stimulating fac - 4,916,241 to Hayward et al., U.S. Patent No. tor, epidermal growth factor, erythropoietin, 4,921,697 to Peterlik et al., U.S. Patent No. fibroblast growth factor, neural growth factor, hu - 4,902,296 to Bolander et al., U.S. Patent No. man growth hormone, platelet derived growth fac - 4,294,753 to Urist, U.S. Patent No. 4,455,256 to 5 tor, insulin - like growth factor, and the like. Urist, U.S. Patent No. 4,526,909 to Urist, U.S. Pat- Hormones such as progesterone, estrogen, ent No. 4,563,489 to Urist, U.S. Patent No. testosterone, follicle stimulating hormone, chorionic 4,596,574 to Urist, U.S. Patent No. 4,619,989 to gonadotrophin, insulin, endorphins, somatotropins Urist, U.S. Patent No. 4,761,471 to Urist, U.S. Pat- and the like. ent No. 4,789,732 to Urist, U.S. Patent No. io Antihistamines such as diphenhydramine, 4,795,804 to Urist, and U.S. Patent No. 4,857,456 chlorpheneramine, chlorcyclizine, promethazine, to Urist, the disclosures of which are incorporated cimetidine, terfenadine, and the like. by reference herein. Cardiovascular agents such as verapamil hy- Suitable biologically -active agents also in- drochloride, digitalis, streptokinase, nitroglycerine clude substances useful in preventing infection at is papaverine, disopyramide phosphate, isosorbide the implant site, as for example, antiviral, anti - dinitrate, and the like. bacterial, antiparasitic, antifungal substances and Anti - ulcer agents such as cimetidine hydro - combinations thereof. The agent may further be a chloride, isopropamide iodide, propantheline bro- substance capable of acting as a stimulant, seda - mide, and the like. tive, hypnotic, analgesic, anticonvulsant, and the 20 Bronchodilators such as metaproternal sulfate, like. aminophylline, albuterol, and the like. The delivery system can contain a large num - Vasodilators such as theophylline, niacin, ber of biologically -active agents either singly or in nicotinate esters, amylnitrate, minoxidil, diazoxide, combination. Examples of these biologically -ac- nifedipine, and the like. tive agents include, but are not limited to: 25 The biologically -active agent may be included Anti - inflammatory agents such as hydrocor - in the compositions in the form of, for example, an tisone, prednisone, fludrotisone, triamcinolone, uncharged molecule, a molecular complex, a salt, dexamethasone, betamethasone and the like. an ether, an ester, an amide, or other form to Anti - bacterial agents such as penicillins, provide the effective biological or physiological cephalosporins, vancomycin, bacitracin, poly- 30 activity. mycins, tetracyclines, chloramphenicol, eryth - Administration of the composition of the in - romycin, streptomycin, and the like. vention ultimately will be accomplished according Antiparasitic agents such as quinacrine, to the wisdom and protocol of the patient's at- chloroquine, quinine, and the like. tending health care professional such as a physi - Antifungal agents such as nystatin, gentamicin, 35 cian, or if appropriate, a dentist. Choice of the miconazole, tolnaftate, undecyclic acid and its particular composition will depend upon the mal - salts, and the like. condition or condition to be treated, which choice Antiviral agents such as vidarabine, acyclovir, will be made by the attending health care profes - ribarivin, amantadine hydrochloride, iododeox- sional. Application by syringe, or other means for yuridine, dideoxyuridine, interferons and the like. 40 applying a liquid to or into a tissue may be em - Antineoplastic agents such as methotrexate, ployed. Without a bioactive agent, the composition 5 -fluorouracil, bleomycin, tumor necrosis factor, can function as a structure for promotion of cell tumor specific antibodies conjugated to toxins, and growth and tissue repair. With a bioactive agent, the like. the composition will not only function in such ca- Analgesic agents such as salicylic acid, sali - 45 pacity but will also adopt the properties of the cylate esters and salts, acetaminophen, ibuprofen, bioactive agent. morphine, phenylbutazone, indomethacin, sulindac, The amounts and concentrations of composi - tolmetin, zomepirac, and the like. tion administered to the patient will generally be Local anaesthetics such as cocaine, ben - sufficient to accomplish the task intended. If that zocaine, novocaine, lidocaine, and the like. 50 task is void space filling, enough composition will Vaccines such as hepatitis, influenza, measles, be administered to accomplish this task. For ad - mumps, rubella, hemophilus, diphtheria, tetanus, ministration of bioactive agent, the amounts and rabies, polio, and the like. release rates will follow recommendations of the Central nervous system agents such as tran - manufacturer of the bioactive agent. Generally, the quilizers, sedatives, anti - depressants, hypnotics, 55 concentration of bioactive agent in the liquid poly - B- adrenergic blocking agents, dopamine, and the mer mixture will be from 0.01 mg per g of mixture like. to 400mg per g of mixture.

9 17 EP 0 539 751 A1 18

Advantageously, the polymer compositions EXAMPLE 5 may be administered to an implant site, as for example, by injection with a syringe, whereupon In this example, a mixture was prepared com - the composition will solidify in situ. The resulting prising about 50% of two different molecular implant may thus be administered to an implant 5 weights of DL-PLA and about 50% NMP. A site without the need for surgical incision. water-soluble, low molecular weight DL-PLA The invention will be described with reference (molecular weight of about 2000 daltons) was to various specific and preferred embodiments and mixed with a higher molecular weight DL-PLA techniques. However, it should be understood that with an inherent viscosity of 0.38 dL/g (molecular many variations and modifications may be made w weight of about 30,000 daltons). The DL-PLA while remaining within the spirit and scope of the mixture was dissolved in NMP to provide a mixture invention. comprised of about 38% low molecular weight DL-PLA, about 12% higher molecular weight DL- EXAMPLE 1 PLA, and about 50% NMP. This mixture was then is precipitated, incubated and dried according to Ex- A mixture comprising about 5% equimolar ample 1. A porous article was producing having mixture of sodium carbonate and citric acid, about pores of about 10 -50m in diameter, and about 34.8% poly(DL- lactide) (DL-PLA) and about 50% porosity. 60.2% N- methyl pyrrolidone (NMP) was prepared by suspending sodium carbonate and citric acid in 20 EXAMPLE 6 the polymer solution. The DL-PLA polymer had a molecular weight of about 30,000 daltons (inherent A mixture comprising about 5% ethox- viscosity of 0.38 dL/g). ydihydrosanguinarine (SaOEt), 27.5% DL-PLA One drop of the mixture was precipitated into a and 67.5% NMP was prepared according to Ex- vial containing phosphate - buffered saline (PBS) or 25 ample 1 . SaOEt is an antimicrobial agent derivable water. The vial was placed in a 37° C shaker bath from benzophenanthridine alkaloids. A porous arti - for about 48 hours. The sample was then removed cle was produced having pores of about 15 -30m from the bath, and dried in vacuo prior to exami - in diameter and about 70% porosity. nation by Scanning Electron Microscopy (SEM). The resulting article was porous with pores of 30 EXAMPLE 7 about 5m. in diameter, and a porosity of about 65%. A mixture comprising about 5% SaOEt, 27.5% EXAMPLE 2 DL-PLA and 67.5% NMP was prepared according to Example 1, the DL-PLA component having a A mixture comprising about 5% sucrose, about 35 molecular weight of about 10,000 daltons. A porous 34.8% DL-PLA and about 60.2% NMP was pre- article was produced having pores of about 4 -8m pared according to Example 1. A porous article in diameter. A wet sample of the article was ex- was produced having pores of about 3m. in diam - amined by X-ray tomography by scanning at in- eter and a porosity of about 65%. tervals of about 0-25 mm. The articles showed 40 porosity throughout with about 70% porosity. EXAMPLE 3 EXAMPLE 8 A mixture comprising about 5% polyvinyl pyrrolidone)(PVP), about 34.8% DL-PLA and An implant comprising about 5.0% san - about 60.2% NMP was prepared according to Ex- 45 guinarine chloride (SaCI), about 47.5% DL-PLA, ample 1. A porous article was produced having and about 47.5% NMP was administered to a pores of about 5 -10m in diameter and a porosity periodontal pocket of a human patient. SaCI is an of about 65%. antimicrobial and anti - inflammatory agent derivable from benzophenanthridine alkaloids. After 28 EXAMPLE 4 50 days, the implant was removed, dried in vacuo and examined by SEM. Pores having a diameter of A mixture comprising about 10% PVP, about about 1 -2m and of about 10 -20m were detected. 33.0% DL-PLA, and about 57.0% NMP was pre- Approximately 50% of the pores were 10 -20m. pared according to Example 1. A porous article The implant had a total porosity of about 50%. was produced having pores of about 5 -20m in 55 diameter and a porosity of about 65%.

10 19 EP 0 539 751 A1 20

EXAMPLE 9 EXAMPLE 12

A mixture comprising about 33% PVP, about Terfenadine, an antiallergy medication, may be 33% 50/50 copolymer of DL - lactide and glycolide added to a solution of DL-PLA in NMP to provide (DL-PLG), and about 34% NMP was prepared 5 a liquid mixture containing about 10 wt.% ter- according to Example 1 . A porous article was pro - fenadine, about 33 wt.% DL-PLA and 57 wt.% duced having pores of about 3 -10m.. Examination NMP. The mixture can then be injected under the of the article showed that the pores were arranged skin of an animal where it coagulates to form a in an interconnecting network. The article had a solid microporous implant. The level of terfenadine porosity of about 65%. io in the blood can be measured over time. The efficacy of the implant in controlling allergy symp - EXAMPLE 10 toms can also be measured.

A lyophilized sample of fibronectin, a tissue EXAMPLE 13 growth and cell attachment factor, was added to a 15 solution of DL-PLA in NMP to provide a disper- Bone chips and bone morphogenetic protein sion comprising about 13.2% wt-% lyophilized can be added to form a liquid mixture containing fibronectin, about 30.4 wt-% DL-PLA, and about about 10 wt.% bone chips, about 1 wt.% bone 56.4 wt-% NMP. As a result of the lyophilization morphogenetic protein, about 5 wt.% PVP, about process, the lyophilized fibronectin contained var- 20 33 wt.% DL-PLA, and about 51 wt.% NMP. The ious salts with only about 0.89% active component. mixture can then be injected to fill in a bone defect This dispersion was added to a phosphate - buf - in a crushed cheekbone. The mixture coagulates in fered receiving solution wherein it coagulated into a situ, conforming to the shape of the site, and filling solid matrix. The receiving solution was maintained in the damaged tissue. Healing and regeneration of at 37 °C under agitation and changed periodically 25 bone tissue can be monitored over time. to preclude a high concentration of fibronectin within the receiving solution. The receiving solution EXAMPLE 14 was analyzed for total protein concentration by the Pierce BCA protein assay. The cumulative per- Ovine follicle stimulating hormone, an ovulation centage of fibronectin released from the matrix was 30 stimulatory agent, may be added to form a liquid calculated. About 12% of the fibronectin compo- mixture containing about 2 wt.% ovine follicle nent was released after one day, about 25% after 2 stimulating hormone, about 41 wt.% DL-PLA, and days, about 26% after 3 days, about 28% after 4 about 57 wt.% NMP. The solution can be injected days, 30% after 5 days, and 33% after 7 days. The subdermally into a cow to form a solid microporous porosity of the solid matrix of the implant was 35 implant. The ovulation rate can be measured 4-6 initially about 55%. The porosity level of the matrix days after oestrus. increased as the fibronectin component was released over time. The pores of greater than 3m in Claims diameter were produced by the dissolving fibronectin component. 40 1. A composition suitable for forming an in situ solid implant in an animal, comprising: a liquid EXAMPLE 11 formulation of a biodegradable, bioerodible thermoplastic polymer that is substantially in - Norethindrone and ethinylestradiol, birth control soluble in aqueous or body fluid, and an or- agents, may be added to a solution of DL-PLA in 45 ganic solvent that is miscible or dispersible in NMP to provide a liquid mixture containing about aqueous or body fluid, the composition being 10% wt.% norethindrone, about 1 wt.% capable of coagulating or solidifying to form a ethinylestradiol, about 33 wt.% DL-PLA and about solid microporous matrix upon its contact with 56 wt.% NMP. The mixture can then be injected an aqueous or body fluid, the matrix being a under the skin of an animal where it coagulates to 50 core surrounded by a skin. form a solid microporous implant. Levels of norethindrone and ethinylestradiol in the blood can 2. A composition according to claim 1, wherein be measured over time. The effect on rates of the core is porous and the skin is substantially pregnancy can also be measured. The implant nonporous in comparison to the porosity of the advantageously functions to release birth control 55 core. agents continuously over time and does not have to be removed by surgery. 3. A composition according to claim 1, wherein the core and skin are both substantially po-

11 21 EP 0 539 751 A1 22

rous. enhancing agents.

4. A composition according to claim 1, further 11. A composition suitable for forming an in situ comprising a pore -forming agent. solid implant in an animal, comprising: a liquid 5 formulation of a biodegradable, bioerodible 5. A composition according to claim 4, wherein thermoset polymer, the composition being the pore -forming agent is a sugar, salt, or capable of forming a solid microporous matrix, water-soluble polymer, or water -insoluble the matrix being a core surrounded by a skin. substance that rapidly degrades to a water soluble substance. 70 12. A composition according to claim 11, wherein the core is porous and the skin is substantially 6. A composition according to claim 1, wherein nonporous in comparison to the porosity of the the thermoplastic polymer is selected from the core. group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, 75 13. A composition according to claim 11, wherein polyamides, polyurethanes, polyesteramides, the core and skin are both substantially po- polyorthoesters, polydioxanones, polyacetals, rous. polyketals, polycarbonates, polyorthocar - bonates, polyphosphazenes, polyhydrox- 14. A composition according to claim 11 further ybutyrates, polyhydroxyvalerates, polyalkylene 20 comprising a pore -forming agent, an organic oxalates, polyalkylene succinates, polymalic solvent that is miscible or dispersible in aque- acid, polyamino acids, polymethyl vinyl ether, ous or body fluid or a combination thereof. chitin, chitosan, and copolymers, terpolymers, and any combination thereof. 15. A composition according to claim 14 wherein 25 the pore -forming agent is a sugar, salt, 7. A composition according to claim 1, wherein water-soluble polymer, or water -miscible the solvent is selected from the group con - organic solvent. sisting of N- methyl -2 -pyrrolidone, 2 -pyrrolidone, ethanol, propylene glycol, propylene 16. A composition according to claim 11, wherein carbonate, acetone, acetic acid, ethyl acetate, 30 the polymer is an acrylic ester -terminated ethyl lactate, methyl acetate, methyl ethyl ke - biodegradable prepolymer capable of cross - tone, dimethylformamide, dimethyl sulfoxide, linking to form a polymer matrix. dimethyl sulfone, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, N,N - 17. A composition according to claim 16, wherein diethyl - m -toluamide, and 1- 35 the acrylic ester -terminated biodegradable dodecylazacycloheptan-2-one, and any prepolymer is selected from the group con - combination thereof. sisting essentially of polylactides, polyglycolides, polycaprolactones, polyanhydrides, 8. A composition according to claim 1, further polyamides, polyurethanes, polyesteramides, comprising at least one biologically -active 40 polyorthoesters, polydioxanones, polyacetals, agent. polyketals, polycarbonates, polyorthocar - bonates, polyphosphazenes, polyhydrox- 9. A composition according to claim 8, wherein ybutyrates, polyhydroxyvalerates, polyalkylene the biologically -active agent is a polypeptide oxalates, polyalkylene succinates, polymalic or derivatives thereof derived from a natural, 45 acid, polyamino acids, polymethyl vinyl ether, synthetic, or recombinant DNA source. chitin, chitosan, and copolymers, terpolymers, and any combination thereof. 10. A composition according to claim 8, wherein the biologically -active agent is selected from 18. A composition according to claim 11, further a group consisting of anti - inflammatory 50 comprising a curing agent. agents, antibacterial agents, antiparasitic agents, antifungal agents, antiviral agents, 19. A composition according to claim 11, further anti - neoplastic agents, analgesic agents, an - comprising at least one biologically -active aesthetics, vaccines, central nervous system agent that is free of functional groups that agents, growth factors, hormones, antihista- 55 would interfere with the thermosetting reaction mines, osteoinductive agents, cardiovascular of the thermoset polymer. agents, anti - ulcer agents, bronchodilators, vasodilators, birth control agents, and fertility

12 23 EP 0 539 751 A1 24

20. A composition according to claim 19, wherein 27. A method of claim 25, wherein the the biologically -active agent is a polypeptide biologically -active agent alters the biological or derivatives thereof derived from a natural, or physiological action of the reproductive synthetic, or recombinant DNA source. system. 5 21. A composition according to claim 19, wherein 28. A method of forming an implant suitable for the biologically -active agent is selected from altering a biological or physiological activity in a group consisting of anti - inflammatory an animal, comprising: administering to the agents, antibacterial agents, antiparasitic animal a composition in an amount effective to agents, antifungal agents, antiviral agents, io form in situ a solid implant, the composition anti - neoplastic agents, analgesic agents, an - being a liquid formulation of a biodegradable, aesthetics, vaccines, central nervous system bioerodible thermoset polymer that is insoluble agents, growth factors, hormones, antihista- in aqueous or body fluid and the composition mines, osteoinductive agents, cardiovascular undergoing curing to form a microporous ma- agents, anti - ulcer agents, bronchodilators, 15 trix, the matrix being a core surrounded by a vasodilators, birth control agents and fertility skin. enhancing agents.

22. A method of forming an implant suitable for altering a biological or physiological activity in 20 an animal, comprising: administering to the animal a composition in an amount effective to form in situ a solid implant, the composition being a liquid formulation of a biodegradable, bioerodible thermoplastic polymer that is sub - 25 stantially insoluble in aqueous or body fluid, and an organic solvent that is miscible or dis - persible in aqueous or body fluid, and the composition undergoing coagulation or solidi - fication of the polymer and dispersion of the 30 solvent into body fluid to form a solid micro - porous matrix, the matrix being a core surrounded by a skin.

23. A method according to claim 22, wherein the implant is capable of enhancing tissue regen - eration.

24. A method according to claim 22, wherein the implant is capable of filling in defects in tissue. 40

25. A method according to claim 22, wherein the composition further comprises at least one biologically -active agent. 45 26. A method according to claim 25, wherein the biologically active agent is selected from the group consisting of anti - inflammatory agents, antibacterial agents, antiparasitic agents, an - tifungal agents, antiviral agents, anti - neo - so plastic agents, analgesic agents, anaesthetics, vaccines, central nervous system agents, growth factors, hormones, antihistamines, osteoinductive agents, cardiovascular agents, anti -ulcer agents, vasodilators, bronchodila- 55 tors, birth control agents, and fertility enhanc - ing agents.

13 European Patent PARTIAL EUROPEAN SEARCH REPORT Application Number Office which under Rule 45 of the European Patent Convention shall be considered, for the purposes of subsequent |EP 92 11 6802 proceedings, as the European search report DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document with indication, where appropriate, Relevant CLASSIFICATION OF THE of relevant passages to claim APPLICATION ant. CI. 5) EP-A-0 430 474 (THE PROCTER & GAMBLE 1-17, A61K9/00 COMPANY) 19-21 A61K9/16 claims 1,5 * A61K47/34 page 3, line 1 - line 4 * A61L27/00 page 3, line 34 - line 45 page 4, line 3 - line 8 * page 6, line 34 - line 40

TECHNICAL FIELDS SEARCHED (Int. CI. 5)

A61K A61L

INCOMPLETE SEARCH The Search Division considers that the present European patent application does not comply with the provisions of the European Patent Convention to such an extent that it is not possible to carry out a meaningful search into the state of the art on the basis of some of the claims Claims searched completely : Claims searched incompletely : Claims not searched : Reason for the limitation of the search:

see sheet C

Place of March Date of conpleUoa of the search Exantaer THE HAGUE 16 DECEMBER 1992 VENTURA AMAT A. CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons A : technological background O : non-written disclosure & : member of the same patent family, corresponding P : intermediate document document