| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | August 15, 1989 |
| PATENT TITLE |
Polyanhydrides with improved hydrolytic degradation properties |
| PATENT ABSTRACT |
Polyanhydrides with uniform distribution of alkyl and aromatic residues are prepared by melt polycondensation or solution polymerization of p-carboxyphenoxyalkanoic acids or p-carboxyphenylalkanoic acids. These polymers are soluble in common organic solvents and have low melting points, generally in the range of 40.degree.-100.degree. C. The polyanhydrides are especially well suited for forming bioerodible matrices in controlled bioactive compound delivery devices. A polymeric matrix formed according to the method described here degrades uniformly during drug release, preventing the wholescale channeling of the bioactive compound into the environment, and eliminating the problem of the presence of the polymer matrix at the site long after drug release. The polymer displays zero-order kinetic degradation profiles over various periods of time (days to months), at a rate useful for controlled drug delivery. Furthermore, a desired degradation rate may be obtained by choosing the appropriate length of the aliphatic moiety. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | July 31, 1987 |
| PATENT REFERENCES CITED |
K. W. Leong et al., 1985, J. of Biomed. Materials, vol. 19, 941-955. Encyclopedia of Polymer Sci. & Tech., vol. 10 (1969), pp. 630-653. Leong, et al., J. Biomed., Mater. Res. 20, 51 (1986). Hill, J.A.C.S., 52, 4110, (1930). Hill, J.A.C.S., 54, 1569, (1932). Rosen, et al., Biomaterials 4, 131 (1983). Leong, et al., Macromolecules 20(4), 705-712, (Apr. 1987). |
| PATENT CLAIMS |
We claim: 1. A polyanhydride having the general formula ##STR4## wherein X is selected from the group consisting of O and CH.sub.2, n is an integer between 2 and 25, and y is at least 2, and wherein the polyanhydride is soluble in organic solvents and has a melting point of approximately 100.degree. C. or less. 2. The polymer of claim 1 further comprising a bioactive compound for use in a controlled bioactive compound delivery device. 3. The polymers of claim 1 which have a melting point between 40.degree. C. and 100.degree. C. 4. The polymers of claim 1 which display zero order kinetic degradation profiles past 60% degradation. 5. The polymers of claim 1 formed by the polymerization of monomers selected from the group consisting of p-carboxyphenoxyvaleric acid, and p-carboxyphenoxyoctanoic acid. 6. The polymers of claim 5 further comprising a bioactive compound for use in a controlled drug delivery device. 7. The polymers of claim 5 which have a melting point between 40.degree. C. and 100.degree. C. 8. The polymers of claim 5 which display zero order kinetic degradation profiles past 60% degradation. 9. A method of preparing a controlled bioactive compound delivery device comprising selecting monomers having both aromatic and aliphatic moieties which may be polymerized into a polyanhydride with a uniform distribution of aliphatic and aromatic residues in the polymer chain, having the general formula ##STR5## wherein X is selected from the group consisting of O and CH.sub.2, n is an integer between 2 and 25, and y is at least 2, and wherein the polyanhydride is soluble in organic solvents and has a melting point of approximately 100.degree. C. or less. 10. The method of claim 15 further comprising polymerizing the monomers to form a polymer having the formula ##STR6## wherein X is selected from the group consisting of O and CH.sub.2, n is an integer between 2 and 25, and y is at least 2. 11. The method of claim 10 further comprising: providing a bioactive compound selected from the group consisting of proteins, drugs, saccharides, nucleic acid sequences, and combinations thereof. 12. The method of claim 9 further comprising polymerizing monomers selected from the group consisting of p-carboxyphenoxyalkanoic acids. 13. The method of claim 12 wherein the monomers are selected from the group consisting of p-carboxyphenoxyvaleric acid, and p-carboxyphenoxyoctanoic acid. 14. The method of claim 9 further comprising polymerizing the monomers to form a polymeric matrix, providing a bioactive compound, and embedding the bioactive compound in the polymeric matrix. 15. The method of claim 14 further comprising implanting the bioactive compound delivery device. 16. The method of claim 11 further comprising polymerizing the monomers with a bioactive compound. 17. The method of claim 16 further comprising implanting the controlled bioactive compound delivery device. 18. A polyanhydride with the general formula ##STR7## wherein X is selected from the group consisting of O and CH.sub.2, Y is an aromatic, Z is an aliphatic having between 2 and 25 carbon molecules in the backbone, and y is at least 2, and wherein the polyanhydride is soluble in organic solvents and has a melting point of approximately 1000.degree. C. or less. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION This invention is in the area of organic synthetic chemistry and is in particular a method of preparing a polyanhydride polymer which contains a uniform distribution of aliphatic and aromatic residues for use as a bioerodible matrix material for controlled bioactive compound delivery systems. Biodegradable controlled release systems for bioactive compounds have an advantage over the other controlled release systems in obviating the need to surgically remove the drug depleted device. The device is implanted under the skin, and degrades during bioactive compound release. Drug loaded devices are generally fabricated by solvent casting, injection molding or compression molding. Injection molding is conducted at temperatures above the melting point of the polymer, and so it is important to construct a polymer which has a melting point lower than the temperature at which drugs begin to degrade or react with the matrix. Properties of the polymer matrix material other than melting point are very important to obtaining the proper release of the drug. To be useful as a matrix for controlled release of a biologically active substance, the polymer composition must undergo surface erosion in the in vivo environment, rather than bulk erosion. Surface erosion occurs when the rate of hydrolytic degradation on the surface is much faster than the rate of water penetration into the bulk of the matrix. This deters whole scale permeation of the drug molecules into the environment. Bulk erosion occurs when the polymers incorporate water in the center of the matrix, rendering the entire polymer composition sponge like. This results in the break up of the matrix, and creates a channeling effect in which the bioactive compound is released from the matrix. Bulk erosion is directly related to the sensitivity of the polymer composition to hydrolysis. The matrix degrades heterogeneously when it erodes from the surface, and homogeneously when it erodes evenly from the surface and the interior. Polymers which undergo bulk erosion (homogeneous degradation) include polylactic acid, polyglutamic acid, polycaprolactone and lactic/glycolic acid copolymers. The ideal polymer must have a hydrophobic backbone, but with a water labile linkage. Many classes of polymers, including polyesters, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles, and polyphosphazenes, have been studied for controlled delivery applications, but few, except for polyorthoesters, have been designed with these considerations in mind. Leong, K. W., Brott, B. C. and Langer, R., J. Biomed. Mater. Res. 19, 941, 942 (1985). Polyorthoesters, furthermore, erode from the surface only if additives are included in the matrix. Taking advantage of the pH dependence of the rate of orthoester cleavage, preferential hydrolysis at the surface is obtained by either addition of basic substances to suppress degradation in the bulk, or incorporation of acidic catalysts to promote degradation on the surface. Polyanhydrides are well suited as a biodegradable system because they erode in a heterogeneous manner without requiring any such additives. The degradation products of polyanhydrides are nonmutagenic, noncytotoxic and have a low teratogenic potential, Leong, K. W., D'Amore, P. D., Marletta, M., and Langer, R., J. Biomed. Mater. Res. 20, 51 (1986), which further confirms the utility of these compound for in vivo use. Polyanhydrides were initially proposed by Hill and Carothers in the 1930s to be a substitute for polyesters in textile applications. Hill, J. J.A.C.S. 52, 4110 (1930); Hill, J.; and Carothors, W. H. J.A.C.S. 54, 1569 (1932). The idea was later rejected because of their hydrolytic instability. It is this property, however, that renders polyanhydrides appealing for controlled release applications. The hydrophilic anhydride linkage ensures biodegradability and may be synthesized with a variety of backbones. It was earlier shown that a model polyanhydride, poly[bis(p-carboxyphenoxy) methane anhydride], displayed near zero-order erosion and release kinetics at 37.degree. and 60.degree. C. Rosen, H. B.; Chang, J.; Wnek, G. E.; Linhardt, R. J.; Langer, R., Bioerodible polyanhydrides for controlled drug delivery, Biomaterials 4, 131 (1983). Later, three other related compounds, poly 1,3-[bis(p-carboxyphenoxy)propane anhydride] (p(CPP)), the polymer formed from copolymerization 1,3-bis(p-carboxyphenoxy)propane with sebacic acid (p(CPP-SA)), and polyterephthalic acid anyhydride were synthesized and tested for their drug matrix properties. Leong, K. W.; Brott, B. C.; Langer, R., Bioerodible polyanhydrides as drug carrier matrices; J. Biomed. Mater. Res. 19, 941 (1985). The hydrophobic polymers of p(CPP) and p(CPP-SA) (in a 85:15 ratio) displayed constant erosion kinetics over several months, and by extrapolation it was estimated that p(CPP) would completely degrade in over three years. Degradation rates in the range of 10.sup.-1 to 10.sup.-4 mg/h/cm2 were obtained. Degradation rates were increased significantly by the addition of a compound with more labile anhydride linkages, such as sebacic acid. The compounds which hydrolyze more easily, however, tend to have channeling problems at a stage of about 60% degradation. Channeling occurs when sufficient anhydride bonds are cleaved in the same region of the matrix that wholescale permeation of the bioactive compound into the environment occurs. For example, in the CPP-SA copolymer, the aliphatic anhydride bonds are cleaved and all drug is released in 10 days (60% degradation), yet the aromatic anhydride regions of the matrix remain for another 51/2 months. See FIG. 1. The problem that has arisen to date with the use of polyanhydride copolymers as a biodegradable matrix is that if the matrix is very sensitive to hydrolysis, the device absorbs water promoting degradation in the interior of the matrix (homogeneous degradation), which results in a channeling effect. Aliphatic anhydrides in these polymer compositions are more sensitive to hydrolysis than aromatic anhydrides. When aromatic and aliphatic diacids are randomly copolymerized, a non uniform chain structure is obtained which contains regions of aliphatic character, resulting in non uniform degradation and breakup of the matrix. The problem of bioactive compound channeling in the past was exacerbated by the low molecular weights of the polymers. In Co-pending patent application Ser. No. 892,809, filed Aug. 1, 1986, entitled "Synthesis and Application of High Molecular Weight Polyanhydrides," by Abraham J. Domb and Robert S. Langer, high molecular weight polyanhydrides were formed by melt polycondensation of highly pure isolated prepolymers under optimized reaction conditions, with the optimal inclusion of a catalyst. These higher molecular weight polyanhydrides have improved physico-mechanical properties, however, regions of aliphatic anhydride still present problems of premature release of the drug. If the polyanhydride is aromatic, although a zero order hydrolytic degradation profile is displayed, the rate of degradation is so slow that the compounds are limited to long-term applications (years). Furthermore, they cannot be fabricated into microspheres or films from solutions because they have low solubility in common organic solvents and have high melting points, which results in the destruction of the drug on preparation of the controlled release device. It is therefore an object of this invention to provide a method of preparing a polyanhydride polymer composition which degrades uniformly over time in an aqueous medium, and at a rate useful for controlled bioactive compound delivery. It is another object of this invention to provide a method of preparing a polymer which is soluble in organic solvents and has a low melting point, generally in the range of 40.degree.-100.degree. C., in order to be able to fabricate the controlled release drug device into microspheres or films from solution, or to prepare such compositions by injection molding. SUMMARY OF THE INVENTION The present invention is a method of preparing polyanhydrides with a uniform distribution of aliphatic and aromatic residues in the chain, which property imparts valuable characteristics to the polymer for use as a bioerodible matrix material in controlled bioactive compound delivery devices. In the preferred mode, the polyanhydrides are synthesized by melt polycondensation or solution polymerization of p-carboxyphenoxyalkanoic acids, as defined by the formula ##STR1## wherein n=2 to 25 and X=0 or p-carboxyphenylalkanoic acids, (X=CH.sub.2, n=2 to 25). Because of the fine distribution of aliphatic and aromatic groups in the polymer matrix, the matrix degrades uniformly. Aliphatic anhydrides hydrolyze more rapidly than aromatic anhydrides. However, because there are no more than two aliphatic moieties linked together, the aliphatic hydrolysis results in many fine breaks (or pores) in the matrix, limiting bioactive compound release during the later period in which the aromatic anhydride bonds are being cleaved. Hydrolytic degradation of these polyanhydrides display zero-order kinetics, indicative of surface erosion of the matrix. Integrity of the matrix is maintained during hydrolysis, as indicated by the fact that drug release rates closely follow, polymer degradation rates. The matrix does not degrade homogeneously before 60% heterogeneous degradation, and more usually, not until greater than 90% heterogeneous degradation has taken place. Furthermore, degradation rates are accomplished which typify the time frames needed for drug release (days-months). The rate of degradation is dependent on the length of the aliphatic residue in the monomer unit. As an example, poly (p-carboxyphenoxyvaleric anhydride), with four alkyl carbons per monomer, completely degrades in less than 20 days, whereas poly (p-carboxyphenoxyoctanoic anhydride), with seven alkyl carbons, degrades in less than 120 days. The utility of these polyanhydrides for bioerodible matrix materials is further demonstrated by their low melting points (in the range of 40.degree.-100.degree. C.), and their solubility in organic solvents. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. is a graph of the release of model drug (p-nitroaniline from the matrix material comprised of p(CPP-SA)(1:1) versus time, along with the percentage degradation of the matrix material itself over time. FIG. 2. is a graph of the percentage of hydrolytic degradation of three p-carboxyphenoxyalkanoic polyanhydrides over time in phosphate buffer (0.1 M, pH 7.40) at 37.degree. C. FIG. 3. is a graph of the release of p-nitroaniline (PNA) from the matrix material comprised of poly p-carboxyphenoxyvaleric anhydride [p(CPV)] versus time, along with the percentage degradation of the matrix material itself [p(CPV)] over time. FIG. 4. is a graph of the release of p-nitroaniline (PNA) from the matrix material comprised of poly p-carboxyphenoxyacetic anhydride [p(CPA)] over time, along with the percentage degradation of the matrix material itself [p(CPA)] over time. FIG. 5. is a graph of the degradation of copolymers p(CPV/CPA), p(CPO/CPA), and p(CPV/CPO) over time. DETAILED DESCRIPTION OF THE INVENTION The present invention is a method for synthesizing polyanhydride polymers which have a uniform distribution of aliphatic and aromatic residues, are soluble in organic solvents, have low melting points (in the range of 40.degree.-100.degree. C.) and which hydrolytically degrade in periods of days to months without undergoing bulk erosion. These properties are essential to a useful bioerodible matrix material for controlled drug delivery devices. The method for preparing such polyanhydride polymers consists of choosing a monomer of the general chemical structure ##STR2## where X=O or CH.sub.2, and n=an integer between 2 and 25. When such monomers are polymerized according to the methods described below, namely by melt polycondensation of prepolymers or solution polymerization, polymers result which contain a uniform distribution of aliphatic and aromatic groups. The aliphatic-aromatic diacids are connected by an anhydride bond ##STR3## in the polymer. Since the monomer has a "head," the aromatic region, and a "tail," the aliphatic region, these monomers connect to form the polymer in three ways: tail to tail, head to head, and head to tail (or tail to head). Because of this, the largest aliphatic chain between two aromatic residues in the polymer consists of two units, which occurs when the the polymer in three ways: tail to tail, head to head, and head to tail (or tail to head). Because of this, the largest aliphatic chain between two aromatic residues in the polymer consists of two units, which occurs when the anhydride results from a "tail to tail" reaction between monomer units. This controls the problem found with the use of copolyanhydrides to date as a controlled drug delivery device; the wholesale channeling of bioactive compound from the matrix due to bulk erosion caused by regions of aliphatic moieties which are more sensitive to hydrolysis. The polymeric matrix degrades hydrolytically in a two phase process. Since aliphatic anhydrides hydrolyze faster than aromatic anhydrides, the first phase consists of the cleavage of the aliphatic bonds. Because there are no more than two aliphatic moieties linked together, the aliphatic hydrolysis result in many fine breaks (or pores) in the matrix. The integrity of the matrix is maintained, and the device continues to limit bioactive compound release. In the second phase, the aromatic anhydrides are hydrolyzed, resulting in the degradation of the matrix. The method of the present invention also consists of choosing monomers which will polymerize into polyanhydrides with low melting points (within the range of 40.degree.-100.degree. C.) and which are soluble in organic solvents. This solves the problem to date of the inability to fabricate long acting polymers into microspheres or films because of low solubility and high melting point of the product. By this method of preparing a polymer with uniform aliphatic and aromatic regions, a rate of degradation is obtained which is better suited to controlled release delivery devices than the rates obtained by the use of compounds less sensitive to hydrolysis, such as aromatic polymers. As stated above, these polyanhydride compositions are valuable as controlled bioactive compound delivery devices. A bioactive compound is any compound which has a direct or indirect biological effect. Examples are drugs, proteins, hormones, antibodies, nucleic acids and saccharides. The bioactive compound is embedded into the polymer and then implanted or controlled delivery, in vivo. I. Synthesis of the monomers The following provides the preferred method of synthesis of these uniform aliphatic-aromatic polymers. Infared spectroscopy of the monomers and polymers was performed on a Perkin-Elmer 1430 spectrophotometer. Polymeric samples were film cast onto NaCl plates from a solution of the polymer in chloroform. Monomer and prepolymer samples were either pressed into KBr pellets or dispersed in nujol onto NaCl plates. The melting points of prepolymers were determined on a Fisher Johns melting point apparatus. The molecular weights of the polymers and prepolymers were estimated on a Perkin-Elmer GPC system consisting of the series 10 pump and the 3600 Data Station with The LKB 214-rapid spectral detector at 254 nm wavelength. Samples were eluted in chloroform through two PL Gel columns (Polymer Laboratories; 100 A and 1000 A pore sizes) in series at a flow rate of 1.5 ml/min. Molecular weights of polymers were determined relative to polystyrene standards (Polysciences; polyanhydrides with molecular weights from 500 to 1,500,000) using CHROM 2 and GPC 4 computer programs (Perkin-Elmer, Mass.). .sup.1 H-NMR spectra were obtained on a Varian 250 MHz spectrophotometer, using deuterated chloroform as a solvent and tetramethylsilane as an internal reference. UV measurements were performed on a Perkin-Elmer 553 UV/VIS spectrophotometer. The methyl p-carboxyphenoxyalkanoate monomers were prepared according to the method of Izard. Izard, C. F.; Kworek, X. I. J. Am. Chem. Soc. 1951, 73, 1861, (1951) as follows: |
| PATENT PHOTOCOPY | Available on request |
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