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| PATENT DESCRIPTION |
These high molecular weight polyanhydrides have many useful applications in the biomedical area including the manufacture of sutures, protective coverings, and as absorbable bone replacements. The high molecular weight polyanhydrides are particularly useful for controlled drug delivery devices. The controlled drug delivery devices according to the present invention are suitable for subcutaneous implantation to deliver a suitable drug, implanting in the fluid of the eye for treatment of glaucoma, subdermal implant for delivering contraceptive steroids, and implanting in the mouth for delivering fluoride. The novel drug delivery devices are also suitable for transdermal drug delivery, for example in the treatment of motion sickness, immunizations and treatment of angina. Any biologically active substance can be utilized in conjunction with the polyanhydride so long as it is capable of being intimately admixed with the polyanhydride and subsequently formed into a desired shape without affecting the bioavailability of the drug. The active substance can be a protein or it can be non-proteinaceous; it can be a macromolecule ##EQU1## or a relatively low molecular weight molecule; and it can be soluble or insoluble in water. Examples of suitable active substances are interferon, anti-angiogenesis factors, antibodies, antigens, polysaccharides, growth factors, hormones including insulin, glucogen, parathyroid and pituitary hormones, calcitonin, vasopressin, renin, prolactin, growth hormones, thyroid stimulating hormone, corticotrophin, follicle stimulating hormone, luteinizing hormone, and chorionic gonadotropins; enzymes, including soybean trypsin inhibitor, lysozyme, catalase, tumor angiogenesis factor, cartilage factor, transferases, hydrolases, lysases, isomerases, proteases, ligases and oxidoreductases such as esterases, phophatases, glycosidases, and peptidases; enzyme inhibitors such as leupeptin, antipain, chymostatin and pepstatin; and drugs such as steroids, anti-cancer drugs or antibiotics. The improved effectiveness and desirable characteristics of the novel controlled drug delivery devices are due primarily to the employment of the above high molelcular weight polyanhydrides previously described rather than the low molecular weight polyanhydrides used in the prior art methods. The high molecular weight polyanhydrides in combination with the novel method of forming the controlled drug release devices result in a device which exhibits zero order release of the drug, a polymer which degrades at a constant rate and a device which is not subject to the drug/polymer interactions commonly encountered in the prior art devices. A significant advantage of using these high molecular weight polyanhydrides is that they exhibit superior film forming qualities compared to the low molecular weight polyanhydrides of the prior art. These film forming characteristics permit solvent casting of the polymer drug matrix at room temperature. By being able to form the bioerodible devices at room temperature, the undesirable interaction between the polymer and the drug and degradation of the polymer or drug is avoided which commonly occurs in compression and melt casting techniques. The superior film forming qualities of the high molecular weight polyanhydrides is in part attributed to the high intrinsic viscosity. The prior art polyanhydrides which had molecular weight approaching 20,000 had relatively low intrinsic viscosities (below 0.3 dl/g) while those polymers having the greater viscosities had comparatively low molecular weights. It has been found that the superior film forming qualities of the high molecular weight polyanhydrides result from both the high molecular weight (greater than 20,000) and the greater intrinsic viscosity (greater than 0.3 dl/g). In the preferred embodiment the bioerodible controlled drug release devices are prepared by a solvent casting technique. This technique dissolves the high molecular weight polyanhydride in powder form in a 20 percent solution of 1.0 gram of polymer in methylene chloride which is then placed in a 20 ml scintillation vial. The substance to be added to the polymeric matrix, for example a drug, is then placed in the solution at the desired polymer to drug ratio. The solution is then placed in a 0 degree freezer for 15 minutes during which time a heavy glass mold is prechilled on a metal platform immersed in a water/liquid nitrogen bath. At the time of molding, the viscous polymer or polymer/drug solution is mixed and poured into the glass mold where it will freeze immediately. The resulting film is cut into uniform disks which are then dried under vacuum to remove all traces of solvent. The resulting bioerodible devices are translucent, flexible and shelf stable. The improved film forming characteristics of the high molecular weight polyanhydrides are further related to the tensil strength of the polymer. As demonstrated in FIG. 3 the tensil strength of the polyanhydride film made of CPP polymers is a function of the molecular weight and as a function of the percent of CPP present in the copolymer. As the percent of CPP is increased in the copolymer and/or the molecular weight is increased the tensil strength is also increased. These studies demonstrate that the tensil strength of the high molecular weight polyanhydride copolymers are proportional to the percent of aromatic repeating units in the copolymer. As indicated in the graph of FIG. 3 the copolymer having 20% CPP and a molecular weight 116,800 produces in a film having a suitable tensil strength of 40-45 kg/cm.sup.2. Further studies have demonstrated that as low as 5% aromatic units in the copolymer chain produce beneficial film forming qualities necessary for solvent casting techniques. The high molecular weight polyanhydrides also have improved biocompatibility compared to the prior art low molecular weight polyanhydrides thereby contributing to their utility in biomedical applications. The improved biocompatibility is apparent by comparing normal subcutaneous rat tissue as shown in FIG. 17 with FIG. 18 showing the subcutaneous rat tissue after implantation with 1 disk of the high molecular weight polyanhydride revealing the presence of residual polymer and macrophages. The polyanhydride disk in the above and following examples as shown in FIG. 16 was a 200 mg wafer which when implanted into a rat represents 267 mg times the anticipated human dose on the basis of weight of polymer to body weight. A sample of subcutaneous rat tissue implanted with 3 high molecular weight polyanhydride disks is shown in FIG. 19. As can be seen, residual polymer appears in the upper portion of the photograph. Some of the polymer remaining is surrounded by a zone of macrophages and connective tissue. FIG. 20 shows the subcutaneous tissue of a rat implanted with 1 disk of the high molecular weight polyanhydride after the polymer has completely eroded. The resulting tissue in the vicinity of the polymer consists of fibroblasts and macrophages. Additional testing was carried out to further determine the effects of the high molecular weight polyanhydrides subcutaneously implanted in tissue. For example, as can be seen in FIG. 21 the subcutaneous tissue of a rat shows no residual polymer and the tissue consisting essentially of fibroblasts, microphages and an occasional lymphocyte. FIG. 22 shows the subcutaneous tissue of a rat after implantation with 3 high molecular weight disks. As can be seen some residual polymer is present in the lower portion of the photograph. The tissue consists essentially of fibroblasts, macrophages and an occasional lymphocyte. The low molecular weight polyanhydrides of the prior art were also examined to demonstrate the improved biocompatibility of the high molecular weight polymers. Referring to FIG. 23 the subcutaneous tissue of a rat implanted with 1 low molecular weight polyanhydride is shown. Throughout this sample residual polymer can be seen. The tissue after erosion of the polymer consisted of macrophages, lymphocytes, polymorphonuclear cells, foreign body giant cells and fibroblasts. In addition much of the general architecture of the subcutaneous tissue is no longer present. Second and third examples of subcutaneous tissue of a rat implanted with 1 disk of the low molecular weight polyanhydrides can be seen in FIG. 24 and FIG. 25 respectively. In these examples no residual polymer is present. The tissue after polymer erosion was hypercellular consisting of lymphocytes, polymorphonuclear cells, macrophages and fibroblasts. The prior art low molecular weight polyanhydrides generally tended to cause destruction of the underlying tissue as can be seen in a fourth sample as shown in FIG. 26. This destruction of tissue resulted from the implantation and erosion of low molecular weight polyanhydrides in the subcutaneous tissue of a rat. The above results demonstrate the high molecular weight polyanhydrides tended to preserve the local surrounding tissue while the prior art lower molecular weight polyanhydrides exhibited hypercellular tissue and destruction of the local surrounding tissue. Additionally the lower molecular weight polyahydrides produced a response which was primarily lymphocytic and resulted in destructive polymorphonuclear cells. Conversely the novel high molecular weight polyanhydrides induced a response which was via macrophages without the production of any significant amounts of polymorphonuclear cells. These results reveal a considerably milder response to the tissue with the implantation of high molecular weight polyanhydride copolymers than the response to the prior art low molecular weight polyanhydrides. The strong lymphocytic and polymorphonuclear response of the low molecular weight polyanhydrides in combination with the tissue destruction which are not present with the implantation of the high molecular weight polyanhydrides demonstrate improved benefits of using the high molecular weight polyanhydrides for controlled release of drugs. The bioerodible controlled drug release devices formed from high molecular weight polyanhydrides exhibit superior degradation characteristics. Referring to FIG. 4 the degradation rate of a low molecular weight (under 20,000) CPP:SA (9:91) copolymer containing 1 percent p-nitroanaline is shown. This graph demonstrates that for low molecular weight polyanhydrides no induction period for degradation occurs. In comparison with FIG. 5 a high molecular weight copolymer of CPP:SA (30:70) containing 5 percent colchicine demonstrates a considerable induction period prior to initial polymer degradation and drug release. This induction period is attributed primarily to the increased hydrophobicity of high molecular weight polyanhydrides. The high molecular weight polyanhydrides have fewer hydrophobic polymer chain end groups which lead to a more hydrophobic polymer and to a polymeric matrix of greater density. In addition, the polymeric matrices formed from the high molecular weight polyanhydrides have been found to possess a greater density when prepared by solvent casting techniques. The higher density of the polymeric matrix also serves to increase the hydrophobicity of the resulting matrix. This increased hydrophobicity compared to the lower molecular weight polyanhydrides of the prior art translate into an induction period before the polymer surface is sufficiently wetted for degradation to occur. Further examples comparing the induction period of the high molecular weight polyanhydrides to the low molecular weight polyanhydrides are disclosed in FIGS. 6 (high molecular weight) and 7 (low molecular weight). Further advantages of using the high molecular weight polyanhydrides for controlled drug release devices can be seen in the kinetics of the release of drugs. Referring to FIG. 8 a comparison of the rate of release of the drug to the rate of degradation of a high molecular weight CPP:SA (30:70) copolymer indicates the rate of release of the drug and degradation of the polymer occuring at nearly the same rate. In comparison with the low molecular weight polyanhydride of CPP:SA (9:91) as disclosed in FIG. 7 the rate of release of the drug far exceeds the rate of degradation of the polymer. The controlled drug delivery devices formed from the high molecular weight polyanhydrides have further been shown to exhibit improved release rates of high molecular weight (macromolecules) drugs. As shown in FIG. 9 a low molecular weight copolymer of CPP:SA (9:99) forms into a matrix containing 5 percent beta galacosidase shows a rate of release of the high molelcular weight drug much lower than the weight of degradation of the polymer. In comparison, a polymeric matrix formed from the high molecular weight polyanhydrides results in a rate of release of the high molecular weight drug to be greater than the rate of release from low molecular weight polymers as demonstrated in FIG. 10. This difference between the rate of degradation and rate of release of high molecular weight drug is believed to be due to the fabrication techniques required for low molecular weight polyanhydrides. In bioerodible controlled drug release devices it is desirable to have the rate of release of the drug correspond as closely as possible to the rate of degradation of the polymer. By correlating these rates it is possible to have the supply of drug depleted simultaneously with the complete erosion of the polyanhydride. Similarly, it is possible to avoid having an excess concentration of the drug released at the end of life-span of the polymer if the polyanhydride erodes faster than the release of the drug. Polymeric matrices prepared from high molecular weight polyanhydrides further have the advantage of being able to preserve the bioactivity of polypeptides when implanted in vivo unlike the low molecular weight polyanhydrides. This is most likely due to the fact that the interaction between the polypeptides and the polymer caused an inadequate release of the macromolecules and/or reduced activity of the macromolecules. |
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