CA2073561C - Polyanhydrides of the oligomerized unsaturated aliphatic acids - Google Patents

Abstract

A polyanhydride suitable for use as a matrix material in controlled delivery devices polymerized from monomers of general formula (I), wherein R, R', and R" are the same or a different aliphatic chain of C1 to C20 or hydrogen; m, n, and p are integers from 0 and 20; y is 0 or 1; and, if y is 0, one of R or R' is not H.

Description

~U-l~~b~.

Polyanhydrides of Oligomerized Unsaturated Aliphatic Acids Background of the ~nveation This invention is in the area of polymers for controlled delivery of substances, and is specifically a polyanhydride prepared from oligomerized unsaturated aliphatic acids.
There has been extensive research in the area of biodegradable controlled release systems for bioactive compounds. Biodegradable, biocompatible matrices for drug delivery are useful because they obviate the need to remove the drug-depleted device.
The most desirable polymeric matrix for drug delivery is one that is hydrophobic, stable, strong, flexible, soluble in organic solution, has a low melting goint, and degrades linearly over time. The polymer must be hydrophobic so that it retains its integrity for a sufficient time when placed in an aqueous environment, such as the body, to effect controlled release. The polymer must be stable to storage for an extended period before use. The polymer must be strong, yet flexible enough that it does not crumble or fragment during use.
Controlled release devices are typically prepared in one of several ways. In one method, the polymer is melted, mixed with the substance to be delivered, and then cooled. Melt fabrication~requires that the polymer have a melting point that is below the temperature at which the substance to be delivered and polymer degrade..or become reactive.
Alternatively,. the device. can be prepared by solvent casting,~in which the polymer is dissolved in_a solvent, and thew.:the substance'.to':be delivered is dissolved or dispersedvin ahe solution:' The solvent is then evaporated; leaving..the substance in the polymeric-matrix. .Solvent casting.requires that the polymer be soluble in organic solvents.

-2-For controlled drug delivery, the polymer must degrade by surface erosion and not by bulk erosion.
Surface erosion occurs when the rate of hydrolytic degradation on the surface of the polymeric structure is faster than the rate of degradation in the interior of the polymeric structure. Bulk erosion occurs when the polymer incorporates water into the center of the matrix, rendering the polymer sponge--like with hole, or channels in the matrix. When bulk erosion occurs, the material to.be delivered is released through the channels in a rapid, uncontrolled fashion.
Many polymers have been evaluated for use as controlled drug delivery matrices, including polyesters, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles, and polyphosphazenes. None of these polymers have exhibited the desired combination of characteristics for use in the controlled delivery of substances.
Polyanhydrides have also been studied for use in controlled delivery devices.. See, for example, U.S.
Patent 4,891,225 to Langer, et.al., U.S. Patent 4,886,870 to D'Amore, et al., Leong, et al., J. Med.
Biomed. Mater. Res. 19, 941 (1985); and Leong, et al., J. Med. Biomed. Mater. Res. 20, 51 (1986). One of the first polyanhydrides studied with respect: to controlled release characteristics was poly(bis(p-carboxyphenoxy)methane anhydride), as described by Rosen, et al., ~i~omaterials 4, 131 (1983). The aromatic polyanhydride exhibited near zero order (linear)_erosiow and.release kinetics.at 37°C and 60°C, in'vitro.
--Shortly ~thereafter;~-three related::
poly~anhydrides, poly_1,3-(bis(p-carbophenoxy)propane anhydride:-(p-CPP)~ .(an aromatic polyanhydride) , the polymer farmed.from.-the.copolymerization of CPP with sebacic acid (a copolymer of an aromatic diacid and an ~n735fi1 . WO 91 / 10696 PCT/ LJS91 /00126

-3-aliphatic diacid), and polyterephthalic acid (an aromatic anhydride) were prepared and studied, as described by Leong, et al., J. Med. l3iomed. Mater.
Res. 19, 941 (1985).
Tt was found that aromatic polyanhydrides have unacceptably long degradation rates. For example, it was estimated that a delivery device prepared from p-CPP would require more than three years to completely degrade in vivo. Further, anhydride homopolymers of aromatic or linear aliphatic dicarboxylic acids were found to be highly crystalline and have poor film forming properties. Aromatic polyanhydrides also have high melting points and low solubility in organic solvents.
As described in U.s. Patent 4,757,128 to Domb and Langer, high molecular weight copolymers of aliphatic dicarboxylic acids with aromatic diacids are less crystalline than aromatic or linear aliphatic polyanhydrides, and they form flexible films.
Degradation rates are also increased by copolymerizing an aromatic dicarboxylic acid with an aliphatic diacid; however, bulk erosion occurs because areas of the polymer containing aliphatic anhydride linkages erode faster than aromatic anhydride linkages,~leaving channels in the matrix through which the substance to be delivered is released in an uncontrolled fashion.w.For example, in the p-CPP
sebacic acid copolymer.,. the aliphatic anhydride bands are cleaved and all drug released in ten days, while the aromatic.ragions remained intact for.over.five months. :y Further,: the:.copolymers have inferior mechanical properties; they become brittle and crumble into flakes on exposure to moisture.
Polymers prepared.from linear aliphatic diacids are hydrophilic solids~~that degrade by. bulk erosion, resulting in a rapid release of the drug from the WO 91/10696 ~ ~ ~ ~ PCT/US91/0012G
_4_ polymeric matrix. Hydrophobicity is increased by copolymerizing the linear aliphatic diacids with aromatic diacids, however this approach results in an increase in the polymer melting temperature and a decrease in organic solvent solubility. Furthermore, it does not improve the drug release profile but increases the degradation and the elimination time of the polymer both in vivo and in vitro. Since both homopolymers and copolymers of linear aliphatic diacids are very sensitive to moisture, they require extremely anhydrous. and low temperature storage conditions.
Several attempts have been made to improve the cantrolled release characteristics of polyanhydrides by altering the method of synthesis or the molecular weight. See, for example, U.S. Patent 9:,857,311 to Domb and Langer, describing polyanhydrides with-a uniform distribution of aliphatic and aromatic residues in the chain, prepared by polymerizing a dicarboxylic acid with an aromatic end and an aliphatic end; U.S. Patent 4,888,176 to Langer, et al., describing the preparation of high molecular weight polyanhydride controlled delivery devices; and U.S. Patent 4,789,724 to Domb and Langer describing the preparation of very pure anhydride copolymers of aromatic and aliphatic diacids.
There remains is a strong need for a polymer havingwthe desired.characteristics of hydrophobicity, stability, strength, flexibility, organic solubility, low melting. point, and appropriate degradation profile; ,for. use as: the. matrix: for a controlled delivery device.
It is therefore :an object of the present invention to-provide°a biodegradable polymer that is highly hydrophobic, and-that degrades by: surface V1'O 91 / 10695 erosion to release an incorporated substance in a controlled manner.
It is another object of the present invention to provide a polymer that is thermodynamically and hydrolytically stable and that requires mild storage conditions.
It is yet another object of the present invention to provide a strong and flexible polymer film that degrades in vivo into a soft material that can be gradually eliminated from the body.
It is a further object of the present invention to provide a controlled delivery device that is suitable for intraperitoneal implantation.
8umanary of the Invention The present invention is a polyanhydride suitable for use as a matrix material in controlled delivery devices. The polyanhydride is synthesized from monomers prepared by linking two or more unsaturated aliphatic carboxylic acids to form a non-linear aliphatic di- or polyorganic acid of the general formula:
R R° R"
I I i Ho2c(cxa)a--c (cH2)= co2H
y H ~ H
( IH2)I~
COZH
wherein R, R', and R" are the same or different aliphatic chain of C~ to C2o or hydrogen; m, n, and p are integers from 0 and 20; y is 0 or 1; and, if y is 0, one of R or R' is not H.

~~ ~'3~~
°6-Suitable monomers include the dimers and trimers of naturally occurring unsaturated fatty acids or non°
naturally occurring unsaturated carboxylic acids.
Naturally occurring and synthetic unsaturated acids can also be coupled to form a mixed oligomer that is polymerized. The oligomerized monomer is typically a hydrophobic liquid.
Films made from these polymers are highly flexible (can be bent 180° at room temperature without breaking) and strong (between 1-20 megaPascal), yet degrade into a soft film that gradually disappears without forming harmful sharp flakes. The polymers are soluble in organic solvents and have melting points in the range of 25° to 65°C. The polymers degrade without significant bulk erosion over a period of days. The polymers release incorporated substance at a rate corresponding to their degradation rate (zero order release).
Brief Description of thn Figures Figure d is a graph comparing the percent release of methotrexate (MTX) from goly(FAD-SA) (6:4, weight/weight) over time (hours) in phosphate buffer, pH 7.4, at ~7°C.
Figure 2 is a graph comparing the percent release of methotrexate from poly(FAT-SA) (6:4, weightjweight) over time (hours) in phosphate buffer, pH 7.4, at 3°7°C.
Figure 3 is a graph comparing the percent release of gentamicin from poly(FAD-SA) (6:4, ~eight/raeight) over time (hours) in phosphate buffer, pH 7.4, at ~7°C~.

WO 91/10696 Q ~ PCT/US91/00126 Detai3ed Dnsoription of th~ Invention The disclosed invention is a polyanhydride suitable for use as a matrix material in controlled delivery devices. The polyanhydride is prepared from oligomerized, unsaturated, naturally occurring or synthetic aliphatic organic acids: The monomers are prepared by linking two or more unsaturated aliphatic carboxylic acids to form a non-linear aliphatic di- or polyorganic acid of the general formula:
R R° R°°
HOZC ( CHZ ) n C C C ( CHZ )'---~ COZH
y H H
(iH2)P

wherein R, R°, and R°' are the same or.a different aliphatic chain of Cl to Czo or hydrogen; m, n; and p are integers from 0 and 20; y is 0 or 1; and, if y is 0, one of R or R° is not H.
If the polymer is used for medical applications, monomers should be chosen that are biocompatible and biodegradable. Suitable monomers include the dimers and trimers of naturally occurring unsaturated fatty acids, such as: oleic, erucic, lauroleic-, myristoleic, gadoleic, ricinoleic, palmitoleic, linoleic, linolenic,.. and:.-arachidonic:.acids.- These fatty-acid derivatives should be=_readily eliminated:=from the body through :the. normal:-metabolic. pa~ways. 'for' fatty acids .
:Diacids.-or.triacids can. also: be-:synthesized from non-naturally occurring carboxylic acids, such'as ~ '-=
acrylic, methacrylic,'fumaric;:~crotanic; vinyl acetic (3-butenoic),'-isocrotonic,-allylacetic (4-pentenoic), WO 91/10696 PCf/US91/00126 hexenoic and undecylenic acids. Naturally occurring and synthetic unsaturated acids can be coupled to form a mixed oligomer. The oligomerized monomers are typically hydrophobic liquids.
Dimers and trimers of oleic acid are available from commercial sources. Unichema Chemicals, Inc.
(Chicago, Illinois) sells the dimer as PripoIT"" 1009 (99% diacids; molecular weight 556). It sells the trimer as PripoIT"' 1025 (containing 25% by weight of trimer and 75% dimer) and PripoIT"" 1040 (78% trimer and 22% dimer). Henkel Corporation (LaGrange, Illinois) sells the following oligomerized oleic acid monomers:
VersadymeT"" 213 (50-70% trimer, 25-40% dimer) ; VersadymeT"~
288, 58, and 52 (97% dimer) ; VersadymeT"" 204 (83% dimer, 17 % monomer ) ; and Versadyme T"" 216 and 2 2 8 ( 8 8 % d imer ) .
The oligomerized unsaturated carboxylic acid monomers can also be synthesized from the corresponding unsaturated acids by methods known to those skilled in the art. See for example Advanced organic Chemistrv J. March, editor, 3rd ed., John Wiley & Sons, New York, New York 1985.
Oligomerized unsaturated aliphatic acids can be polymerized by methods known in the art, including melt polycondensation and solution polymerization. In the method of melt polycondensation, described by Domb, et al., in J. Poly. Sci 25, 3373 (1987), a prepolymer is prepared by heating the diacid with acetic anhydride to form a diacetyldianhydride. The prepolymer is then heated neat under vacuum to form the polymer. Mixtures of diacetyldianhydrides can also be polymerized with this method.
Solution polymerization is described in U.S. Patent No. 4,933,431, entitled "One Step Preparation of Poly(amide-anhydride)" to Domb et al., issued on June 12, 1990. Solution PC.'T/iJS91 /00126 _g_ polymerization involves the coupling of diacids with phosgene in an organic solvent. Poly(4-vinylpyridine) is added to remove the HC1 from solution. For example, diphosgene (0.5 equivalents) is added dropwise to a stirred mixture of diacid (1.0 equivalent) and poly(4-vinylpyridine) (2.5 equivalents) in 20 ml of chloroform. The solution is stirred for 3 hours at 25°C. The insoluble PVP~HC1 is removed by filtration. The solvent is then removed and the precipitate is isolated, washed with ethyl ether, and then dried at 25°C for 24 hours in a vacuum oven.
The physical properties of the polyanhydride are often improved by copolymerizing the oligomerized unsaturated aliphatic acid with another dicarboxylic acid, for example, sebacic acid (SA), isophthalic acid (ISO), adipic acid (AA), 1,10-dodecanoic acid (DID), or 1,3 bis(p-carboxyphenoxypropane) (CPP).
Biodegradable biocompatible polyanhydride films prepared as described herein can be used as a physical barrier for adhesion prevention using the method of Linsky, et al., J. Reprod. Med. 32, 17 (1987)); or for targeted release of drugs to specific organ surfaces.
Examples are films containing heparin fox the prevention of blood clotting, and films releasing dexamethasone or cyclosporin to prevent organ transplant rejection. Biodegradable films can also be used in. guided tissue regeneration in periodontal disease using the method reported by Nyman et al., J.
Clin: Perio. 9, 290 (1982); Nyman~ et al., J. Clin.
Perio...T3, 604 (1986); Nyman et al., J. Clin. Perio.
14,.. 618 (1987) , ~ Nyman:~et a.l. , J. Clan. Perio. ~ 15; 288 (1988), or as tubes~for guided'nerve'regeneration using the method ~f 'U. S. Patent- No. ',-4, 870, 966 to Dellon L: and Mackinnon~ S~E..

WO 91/10696 2 0'~ 3 5 G..1 P~'T/1JS91/00126 Other medical applications for the polyanhydride films described here including coatings for implantable devices, i.e. stents, catheters, artificial vascular grafts, and pacemakers. The coating can incorporate antibiotics, anti-inflammatories, or anti-clotting agents for release at a predetermined rate, to decrease complications caused by the implanted devices. Controlled delivery devises prepared from these polyanhydrides can also be used as ocular inserts for extended release of drugs to the eye.
The polyanhydrides of the present invention are described in greater detail in the following non-limiting working examples using dimers and trimers of oleic acid, a naturally occurring fatty acid, for ease of illustration.
Oleic acid dimer (referred to below as F~1D) and trimer (referred to below as FAT) were obtained from Unichema Chemicals, Inc. (Pripol 1009 and Pripol 1025, respectively). Both are liquids at room temperature.
Infrared spectroscopy was performed on a Perkin-Elmer 1310 spectrophotometer (Perkin-Elmer, CT.).
Polymeric samples were film cast onto NaCl plates from a solution of the polymer in chloroform. Acids and prepolymer samples were either pressed into KBr pellets or dispersed in nujol onto NaCl plates. A
Perkin Elmer DSC 7 Differential. Scanning Calorimeter calibrated with indium was, used to determine the glass transition temperature;.(Tg), the-melting temperature , (Tm),.and the heat of fusion.of the-polymers. The_:..
standard heating rate,.for all; polymerswas-10°C/min under,nitrogen atmosphere. The decomposition.
temperatures: were determined on a Dupont 951-Thermogravimetric Analyzer (TGA).ata.heating rate-of.
20°C/min. in a nitrogen atmosphere. The molecular WO 91/10696 ~ ~ ~ '~ ~ PC'Jf/US91/00126 _11_ weights of the polymers were estimated on a Waters GPC
system (Waters, MA) consisting of a Waters 510 pump and Waters programmable multiwavelength detector at 254 nm wavelength. Samples were eluted in dichloromethane through two Styrogel(TM) columns (Waters, Linear and a 10a A pore sizes) in series at a flow rate of 1.0 mL/min. Molecular weights of polymers were determined relative to polystyrene standards (Polysciences, P.A., molecular weight range, 400 to 1,500,000) using Maxima 840 computer programs (Waters, M.A.). 1H NMR spectra were obtained on a Varian 250 MHz spectrophotometer using deuterated chloroform containing tetramethylsilane (TMS) as the solvent for the pplymers and prepolymers. UV
absorbencies were determined on a Lambda 3B
spectrophotometer (Perkin Elmer, CT). Degradation studies were performed at 37°C, using melt molded or film cast samples containing drug placed in a 20om1 solution of phosphate buffer at pH 7.40. The release of drug to the medium was determined by the W
absorption or HPLC (high pressure liquid chromatography) of the drug.
Eacample Z - Bseparation of lPsepolymess of Oligomessized oleic Aoid.
The fatty, acid FAD and FAT oligomers were separately purified by extraction of a dichloromethane solution of the oligomer (50% w/v) with deionized water. The purified monomers were then separately refluxed in acetic anhydride (100..8 in 500 ml) for one hour and. evaporated.to~dryness.
The infrared spectra for both grepolymers included the_..following absorbances: (cm-1, film cast) 1800,, 1740 (sharp) . The proton NMI2 for the prepolymers contained the following chemical shifts:

20?35~~~

0.9(m,6H), 1.3(s,52H), 1.7(m,2H), 2.2(s,4H), 2.4(m,4H).
Prepolymers of sebacic acid, isophthalic acid, adipic acid, 1,10-dodecanoic acid, and 1,3 bis(p-carboxyphenoxypropane) were prepared as described by A. Domb and R. Langer in f. Polym. Sci. 25, 3373 (1987).
Exampl~ a - Polyaaerization of the Prepolymers Polymers of varying combinations of oligomers and aliphatic diacids were synthesized by melt polycondensation of diacetyldianhydride prepolymers or by solution polymerization of the diacids.
The melting point, molecular weight, and appearance of the polyanhydrides prepared by melt polycondensation are provided in Table 1. The melting point, molecular weight, and appearance of polyanhydrides prepared by solution polymerization are provided in Table 2. The ratio of monomers was calculated on a weight/weight basis. The following abbreviations are used in the.tables: SA, sebacic acid; CPP, 1,3-bis(p-carboxyphenoxy)propane; DD, 1,10-dodecanoic acid; and rSO, isophthalic acid.
Polyanhydrides prepared according to this method have low melting temperatures, in the range of 25°C to 65°C, and high solubility in chloroform, dichloromethane, tetrahydrofuran, ethyl acetate and methyl ethyl ketone. These characteristics allow the polymer to be easily fabricated into controlled delivery devices. High molecular weight polymers, in the range of 18,300 to 243,100, were obtained by melt polymerisation:
All polymers displayed the typical.IR-absorbances for aliphatic polyanhydrides (2910, 2860, 1810, and 1750 c~ i). Copolymers containing an aromatic unit or fumaric acid had an additional sharp peak at 1600 c~ 1. The H-NMR spectra of the polymers were consistent with their polymeric structures.
None of the polyanhydrides prepared had a glass transition temperature (Tg) in the temperature range of -50 to +50°C. In addition, all had a law heat of fusion (<5 Jouls/gram), indicating low crystallinity (<5%). P(FAD-SA) (50:50) and P(FAD-DD) (50:50) decamposed at 292°C and 296°C, respectively.

WO 91/10696 ~. , PCT/CJ891/00126 Table 1: Analxsis of Polygnhgdridea Prepared by Melt Condensation.
Polymer Melting Molecular Weight Physical Point (°C) Mn Mw Appearance P(FAD) 25-35 18,600 88,700 soft clear sticky P(FAD-SA)50:50 60-65 18,200 243,100 clear flexible P(FAD-SA)33:66 42-47 16,900 175,200 soft clear rubbery P(FAD-CPP)50:50 35-40 8,900 18,300 Sticky Soft white P(FAD-CPP)80:20 30-35 9,100 23,600 sticky soft white P(FAD-ISO)50:50 38 -42 15,700 48,800 sticky clear soft P(FAD-SA-CPP) 55-60 10,300 86,200 strong 45:45:10 flexible P(FAD-DD)50:50 38-42 20,100 123,700 clear flexible P(FAD-AA)50:50 25-30 9,300 24,600 sticky clear semisolid P(FAD-FA)50:50 25-30 10,400 26,300 sticky dark semisolid P(FAT) a insoluble insoluble clear rubbery P(FAT-SA)50:50 58-63 15,300 85,900 flexible hard solid .
P(FAT-SA)33:66 56-60 1.1,200 74,700 flexible hard solid P(FAT-CPP)50:50 a insoluble insoluble rubbery P(FAT-CPP)80:20 a insoluble insoluble rubbery P(FAT-SA-CPP) 54-58 10,700 55,700 flexible 40:50:10 hard solid P(FAT-SA-CPP) 61-64 10,400 53,700 flexible 40:40:20 hard rubber P(FA~-FAD-SA) 4i-44 15,700 88,800 sticky hard 3:1:1 rubber P(FAT-DD)50:50 41-45 8,500 35,200 soft breakable rubbery a: melting temperature in excess of 200oC

WO 9t/10696 PCT/1US91/00126 ~o~~:~s~~

Table 2. Analysis of Polyanhydrides Prepared by Solution Condensation.
Polymer Melting Molecular WeightPhysical Point (C) Mn Mw Appearance P(FAD) 25-355,600 13,400soft clear stic3~y P(FAD-SA)50:50 60-658,600 24,300soft f lexible P(FAD-SA-CPP) 52-606,700 17,400strong 45:45:10 flexible P(FAD-DD)50:50 38-427,900 26,500clear flexible a. The polymers were synthesized in dichloromethane solution using phosgene as coupling agent and pyridine as an acid acceptor.
Exampl~ 3 - Preparation of Polyanhydrids Films Polyanhydride films were.prepared by melt or solvent casting using the following methods.
sole~at castings The polyanhydrides were dissolved in dichloromethane (1 g dissolved in 5 ml) and cast on a Teflon(TM) coated Petri dish. When drug was incorporated into the film, the drug powder was dissolved or dispersed in the polymer solution prior to casting. On solvent evaporation,, transparent strong films were obtained from most of the polymer.
compositions described in Table 1.
Malt Casting: 200 Milligrams. of polymer were compressed between two hot plates heated to the melting point of trie compressed polymer. Partially crosslinked polymers based on trimer fatty acids prepared from Pripol 1025 (example 2, polymers 12-19) formed flexible and strong films ~xsing_the melt technique.

2.~17;3~5 61 WO 91/10696 PCfJUS91/00126 Polyanhydride films prepared as described above are useful as laminates for degradable or nondegradable fabrics. FAD°SA copolymers are particularly useful for this purpose. As an example, poly(FAD-SA) (50:50) was laminated onto a biodegradable oxidized cellulose (Surgicell TM) by solvent casting or melt compression (0.5 gram on 2 gram of fabric) to form a solid nonporous sheet. The sheet can be used as a degradable physical barrier for adhesion prevention.
Erample 4 ~ Release of Metlhotrexate (MTg) groin Polyanhydrides.
Methotrexate (MTX; x.00 mg) was uniformly dispersed in a molten sample of poly(FAD-SA) (6:4 weight/weight) (0.9 g) and separately in a molten sample of poly(FAT-SA) (6:4 weight/weight) (0.9:g).
The samples were cast to tough yellow slabs (6 x 10 x 1 mm, about 200 mg). The ~n vitro release of methotrexate from the polyanhydride was determined in phosphate buffer (pH 7.4) at 37°C by HPLC analysis (C18 column, mobile phase: ammonium persulphate pH
3.5, ~. ml/min). The rate of release of MTX from poly(FAD-SA) (6:4) and poly(FAT°SA) (6:4) as well as the degradation rates of the polymers, are illustrated in Figures 1 and 2, respectively.
As shown, MTX is released from the polymers at a linear rate approximately corresponding to the degradation rates of the polymers. - Over 80% ~of the drug was released from poly(FAD-SA) (6:4) in 250 hours, ~ and over 95%~-of the drug was released from poly (FAT-SA) ( 6 4 ) 'in tlie~ same time period o Bxampl~ 5~ - Rehaaae of Gentamici~ from P~lga~hydrides.
Gentamiciri sixlphate (200 mg) was uniformly distributed in a-'molten sample of poly(FAD-SA) (1:1) Pcrms9lioolz (1.8 g). The sample was cast to tough but flexible off-white rods (3 X 25 mm). The rods were cut into 200 mg samples. The in vitro release of gentamicin was determined in phosphate buffer at pH 7.4 and 37aC, by radioimmunoassay (RTA). The degradatian rate of the polymer was determined from the weight loss of the sample. The rate of release of gentamicin from poly(FAD-sA) (1:1) as well as the degradation rate of the polymers is illustrated in Figure 3.
As shown, gentamicin was consistently released from the polyanhydride over a period of approximately days. After 15 days, the polymer was completely degraded, leaving the water insoluble FAD as a semi-liquid mass.
To investigate whether the polymer was eroding predominately from the surface, at various time intervals, polymer samples were removed from the gentamicin containing slab and cut in the middle for observation. The samples were found to have a solid core, containing anhydride bonds,,that decreased in size with time, leaving a soft shale of the FAD
degradation products (as determined by IR and H-Nit spectroscopy) indicative of surface erosion.
Exmmple 6 -.Release ~~ cisplatin and carbgplatin from Polym~ra.
Poly(FAD-SA). (50:50) samples containing the anti-cancer agent Cisplatin or Carboplatin (3 mg in a 30 mg circular tablet, ~3 x 3 mm) were prepared by melt casting. The in vitro, release rates were determined as described in Example 5. The release of drug was I
monitored by at~mic absorption:spectroscopy. The drugs were released at a linear rate. approximately corresponding to the degradation..rates of the polymers, over a period of 14 days:

2~ 4'~ 3 5 G
CVO 91/10696 - P~CT/US91/00126 _18-E$ampie 7 - Films containing Heparin.
Heparin containing films were prepared by mixing heparin powder (121 units/mg, particle size less than 65 microns) into molten polymer (300 mg, Poly(FAD:SA) (1:1) weight/weight) and then melt pressing the mixture to form films (0.1 mm thick and 12 cm2 wide) containing 2, 5, 10, and 15 units per mg of film. The mechanical properties of the film, i.e., flexibility and strength, were not affected by drug incorporation.
The release of heparin from these films was determined in vitro by immersing a film sample in 0.1 M phosphate buffer at pH 7.4. The amount of heparin released into the buffer was determined by increasing inhibition of blood clotting. Thirty percent of the heparin was released from films containing 5 units/mg in one hour; 55% was released in six hours; 78% in 18 hours; 85% in 24 hours and 100% in 48 hours. No~drug remained in the polymer after 48 hours.
The rate of release of heparin from the films can be manipulated by compressing heparin loaded films between two drug free films or by varying the drug concentration or thickness of the film. Films that release heparin over a period of 4 days were obtained using these methods.
To obtain drug release from one side of the film only, the drug loaded film was compressed with a drug free filmwon one side. These films were effective in vivo to prevent adhesions and clotting prevention.
EHaynple ~ - Hydrolytic Stability of' ~olyanby~iride 8ilms vThe hydrolytic: stability of: the polyanhydride films . ( o . 1. mw. thickness) - were tested. by. storing the polymers at 25°C under 70%: relative humidity,-and monitoring the changes in the film properties over time. The results are summarized in Table 3.

-'~x'091/10696 ~ ;~., _ PC1'/US91/00126 _19_ Polyanhydrides of fatty acid oligomers (films 5-11) are flexible and strong when prepared, and remain flexible and relatively strong after 5 days at room temperature exposed to air. For comparison, under similar conditions, films of linear aliphatic homopolymers and copolymers with aromatic diacids became brittle and fragmented after 2~ hours.
Polymers prepared from fatty acid oligomers remained stable when stored in an aluminum foil pouch under dry argon at 5°C for at least 2 months.

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1'°~ T~~'I ~ 1~'I f"I I p'~' r'I P') ,~. W ~ . ~w ~ r ~I is s1 ~~~o~t~J~ ~ ~ v~J~U~erAap v 1 1 I-t I f 1 ~ I 1 1 p, W ... ... 1 D H H ~f1 v7 E-~ H
W W ~ GI iaC Et,' ~ ~ ~ r~ ~ a;
C~ U !'P1 C5 CI5 i~ 6sr C~ O Gc, trr t:e v ..r wr v wr d. ~ v. w,s ~7 ~i al- a1 ~1 ~1 ~1 ~1 Q! ~ Ad pd ~1 ~a'~35~1 Example 9 - Hydrolytio Degradation ofi Polyanhydrides ' in Buffer solutions.
The hydrolytic degradation characteristics of polyanhydrides described in Table 3 were evaluated by immersing the films in buffer at pH 7.4 and 37°C, and monitoring the physical properties of the polymers over time.
Polyanhydrides prepared from olig0merized fatty acids (films 6-11) did not fragment after 5 days in buffer. At day one, the films were as flexible as at time zero, and they were relatively strong. After 2 days the films were still flexible and strong enough to be handled. After 5 days the films became weak and soft, and when mixed with a spatula formed a soft semi-solid mass.
In contrast, the films of linear aliphatic homopolymers and copolymers with aromatic diacids (films 1-5) became white and rigid after 1 day, and crumbled into sharp small flakes after two days.
Example to - Biocompatibility studies.
Twelve female Sprague-Dawley rats (250=300 gram weight, 8-14 weeks of age) were implanted with 200 mg melt molded polymer discs (1 mm thick; poly(FAD-SA) (l: l), poly(FAD-SA-CPP) (5:4.:1), and clinical grade poly(CPP-SA) (20:80)) using the following procedure.
After prepping and draping the rat under sterile conditions, an.8 cm midline incision was~made on the dorsum. Using fine tissue scissors, a pocket area was created 6 cm away from the midline incision. One 200 mg disc or no:disc°was implanted, and'the wound was then closed: using surgical' clips. w= Seven -days after implantation;:. the rats were: sacrificed -and- thewsite of implantation was°examined.
In Groups 1 (control animals) ,- 3/3 sites- were found to be~normal;-with no.swelling or'redness. In Group 2:(poly(FAD-SA):(1:3).disc), 3/3 sites were also sormal. Most of the film material remained in the WO 91/10696 2 ~ ~ 3 ~ 6 PCT/US91/00126 site of implantation as a waxy semi-solid. In Group 3 (poly(FAD-SA-CPP) (5:4:1) discs), 2/3 sites were normal, and one site showed some red foci. In Group 4 (poly(CPP-SA) (20:80} disc), 2J3 sites were normal, and one site had red foci.
Both poly(FAD-SA) (1:1) and poly(FAD-SA-CPP) (5:4:1) copolymers displayed similar or better biocompatibility than the reference biocompatible polymer, poly(CPP-SA) (20:80).
Example ii - =ntraperitoneal =mplaatation of the Polyanhydrides.
Films (1 x 1 cmZ, 0.12 mm) of poly(FAD-SA) (1:1), poly(FAD-SA-CPP) (5:4:1), and clinical grade poly(CPP-SA) (20:80) as reference, were implanted into the peritoneal cavity of rats as described in example 10. Animals were sacrificed and examined after one or five weeks. After one week, the reference films (poly(CPP-SA) (20:80)) had completely crumbled to white flakes and had spread out in the peritoneal cavity. In contrast, the fatty~acid based ffilms remained as saft materials somewhat stuck to the surface of the organ they had been placed. The site of implantation was clean with no tissue response, indicating that the polymers were highly biocompatible.
The animals sacrif iced after f five: :weeks showed no',inflammation at the site of implantation. Further, most of_ the;polymer had disappeared.by-this:time.
Ezampi~i ~x2. -, Tensile; Strength of polymer.: films.
The _tensile~ strength .ofsolvent casted= ors melt compressed: films ~af-_polymers prepared asp in vExample =~2-(numbers 2, 7, 8, 12, and 16)wwere:. ested:;..The.
results.are provided in.:Table 4:
Solvent:casted:films:were preparedrfrom l0% w/v solutions in dichloromethane:at room: temperature.

WO 91/10696 ~,. , ~.1 (; , ~~f~ :.. 1'~/US91/00,126 After drying, the films were stored under vacuum for 12 hours.
Alternatively, polymer samples (200 mg) were compressed between two Teflon coated hot plates to form films using a Carver laboratory press. Tensile measurements were made using an Instron Tensile Tester Model 1122 at room temperature according to ASTM D882-83. Tensile strength, tensile modules, elongation at yield and break were determined. The tensile values were calculated from the arithmetic average of at least four measurements obtained from four separate specimens per polymer sample.
As seen in Table 4, films made by melt compression are stronger than films prepared by solvent casting. All films were transparent and very flexible. Adding a trifunctional monomer (FAT) almost doubled the tensile strength of the films. Additional increase in the tensile strength can be achieved by incorporating small amounts of an aromatic monomer (CPP) in the polymer.
Table ~1. Meohanioal Prop~rties of Fatty Acid Polyanhydride Films Polymer Method' Tensile Tensile Elongation Strength Modules yield break (MPa) (MPa) (%) (%) 1-2.P(FAD-SA) A 4 45 14 85 1-2.P(FAD-SA) B 3 35 18 115 50:50 ...

1-7.P(FAD-DD) A 5 50 13 77 50:50 1-8 . P (FAT-SA)A 7 . .. . 75 . 12 _8p .

50: 50 .. - .- _~. r ., .

. .. . .... _m _. ~ _~ _ .:. '.~
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15 88_ . . .

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. : .:: _:
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, a. Films prepared by melt compression (A) or by solvent casting (B).

Claims (35)

CLAIMS:

1. A polyanhydride polymerized from monomers selected from the group consisting of dimers and trimers of unsaturated aliphatic acids.

2. The polyanhydride of claim 1, wherein the monomer is selected from the group consisting of dimers and trimers of aleic, erucic, lauroleic, myristoleic, gadoleic, ricinoleic, palmitoleic, linoleic, linolenic, and arachidonic acids.

3. The polyanhydride of claim 1, wherein the monomer is selected from the group consisting of dimers and trimers of acrylic, methacrylic, fumaric, crotonic, vinyl acetic (3-butenoic), isocrotonic, allylacetic (4-pentenoic), hexenoic and undecylenic acids.

4. The polyanhydride of claim 1 comprising an aliphatic dicarboxylic acid selected from the group consisting of sebacic acid, isophthalic acid, adipic acid, 1,10-dodecanoic acid, or 1,3 bis(p-carboxyphenoxypropane).

5. The polyanhydride of claim 1 that is soluble in organic solvents.

6. The polyanhydride of claim 1 that has a melting point below 65°C.

7. The polyanhydride of claim 1 that is strong and flexible.

8. The polyanhydride of claim 1 prepared by melt polycondensation.

9. The polyanhydride of claim 1 prepared by solution polymerization.

10. The polyanhydride of claim 1 in the form of a film.

11. The polyanhydride of claim 10 prepared by solvent casting.

12. The polyanhydride of claim 10 prepared by melt casting.

13. The polyanhydride of claim 1 further comprising a substance to be delivered.

14. The polyanhydride of claim 13 wherein the substance is a bioactive compound.

15. The polyanhydride of claim 14 wherein the substance is selected from the group consisting of chemotherapeutic agents, antibiotics, antiinflammatories, and anticoagulants.

16. The polyanhydride of claim 1 in the form of a laminate for degradable or nondegradable fabrics.

17. The polyanhydride of claim 1 used as a coating for implantable devices.

18. A method for providing a biocompatible, biodegradable, polyanhydride comprising polymerizing monomers of dimers or trimers of unsaturated aliphatic acids.

19. The method of claim 18, further comprising selecting the monomer from the group consisting of dimers and trimers of oleic, erucic, lauroleic, myristoleic, gadoleic, ricinoleic, palmitoleic, linoleic, linolenic, and arachidonic acids.

20. The method of claim 18, further comprising selecting the monomer from the group consisting of dimers and trimers of acrylic, methacrylic, fumaric, crotonic, vinyl acetic (3-butenoic), isocrotonic, allylacetic (4-pentenoic), hexenoic and undecylenic acids.

21. The method of claim 18, further comprising polymerizing the monomers with an aliphatic dicarboxylic acid to form a copolymer, wherein the aliphatic dicarboxylic acid is selected from the group consisting of sebacic acid, isophthalic acid, adipic acid, 1,10-dodecanoic acid, and 1,3 bis(p-carboxyphenoxypropane).

22. The method of claim 18, wherein the method of polymerization is melt polycondensation.

23. The method of claim 18, wherein the method of polymerization is solution polymerization.

24. A method for providing a biocompatible, biodegradable, polyanhydride comprising polymerizing monomers of dimers or trimers of unsaturated aliphatic acids, and casting the polyanhydride as a film.

25. The method of claim 24, wherein the polyanhydride film is solvent cast.

26. The method of claim 24, wherein the polyanhydride film is melt cast.

27. The method of claim 18, further comprising incorporating into the polyanhydride a substance to be released.

28. The method of claim 27, wherein the substance is a bioactive compound.

29. The method of claim 28 further comprising selecting the substance form the group consisting of chemotherapeutic agents, antibiotics, antiinflammatories, and anticoagulants.

30. The method of claim 18, further comprising fabricating the polyanhydride into a laminate for degradable or nondegradable fabrics.

31. The method of claim 18, further comprising providing the polyanhydride as a barrier for adhesion prevention.

32. The method of claim 28, further comprising fabricating the polyanhydride for targeted release of drugs to a specific organ.

33. The method of claim 18, further comprising fabricating the polyanhydride for use in guided tissue regeneration on periodontal disease.

34. The method of claim 18, further comprising fabricating the polyanhydride for use as a tube for nerve generation.

35. The method of claim 18, further comprising applying the polyanhydride as a coating on implantable devices.