Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active...
Reexamination Certificate
2000-04-21
2002-05-07
Pryor, Alton N. (Department: 1616)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Reexamination Certificate
active
06383478
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of pharmaceutical sciences, protein chemistry, polymer chemistry, colloid chemistry, immunology, and biomedical engineering. More specifically, the present invention relates to a novel delivery system for vascularization agents and other growth factors and drugs.
2. Description of the Related Art
Microparticulate systems are particles having diameter 1-2,000 &mgr;m (2 mm), more preferably 100-500 &mgr;m (microcapsules). Nanoparticles range from 1-1000 nm (1 &mgr;m=1,000 nm), preferably 10-300 nm. Alternatively, polymeric films of 0.5 to 5-mm thickness can be made. Also, absorbable or nonabsorbable polymers can be coated with a polymeric film. Collectively, these systems will be denoted as drug delivery vehicles. All these vehicles can be formed from variety of materials, including synthetic polymers and biopolymers (proteins and polysaccharides) and can be used as carriers for drugs and other biotechnology products, such as growth factors and genes.
In the scientific realm of controlled drug delivery, the drug delivery vehicles are formed in a mixture with the agent to be encapsulated for subsequent sustained release. A number of different techniques are used to make these vehicles from synthetic or natural polymers. These techniques include phase separation, precipitation, solvent evaporation, emulsification, spray drying, casting of polymers into a polymeric sheet, or any combination thereof [Desay, P. B. Microencapsulation of drugs by pan and air suspension technique. Crit. Rev. Therapeut. Drug Carrier Syst., 5: 99-139 (1988); Berthold, A., Cremer, K., Kreuter, J. Preparation and characterization of chitosan microspheres as drug carrier for prednisolone sodium phosphate as model antiinflammatory drugs. J. Controlled Release 39: 17-25 (1996); Watts, P. J., Davies, H. C., Melia, C. D. Microencapsulation using emulsification/solvent evaporation: An overview of techniques and applications. Crit. Rev. Therapeut. Drug Carrier Syst. 7: 235-159 (1990); Cowsar, D. R., Tice, T. R., Gilley, R. M., English, J. P. Poly(lactide-co-glycolide) microcapsules for controlled release of steroids. Methods Enzymol. 112: 101-116 (1985); Genta, I., Pavanetto, F., Conti, B., Ginnoledi, P., Conte, U. Spray-drying for the preparation of chitosan microspheres. Proc. Int. Symp. Controlled Release Mater. 21: 616-617 (1994)].
Polymeric vehicles can be prepared either from preformed polymers, such as polylactic acid, polylactic-glycolic acid [Cohen, S., Yoshioka, T., Lucarolli, M., Hwang, L. H., Langer, R. Controlled delivery systems for proteins based on poly(lactic/glycolic acid) microspheres. Pharm. Res. 8: 713-720 (1991)], or from a monomer during polymerization, such as polyalkylcyanoacrylates [Al-Khouri-Fallouh, N., Roblet-Trempel, L., Fessi, M, Devissaguet, J.-P., Puisieux, F. Development of new process for the manufacture of polyisobutylcyanoacrylate nanoparticles. Int. J. Pharm. 28: 125-132 (1986)]. Both of these technologies have limited application due to the use of organic solvents, which leave residual organic solvents in the final product. Although the polyalkylcyanoacrylate nanoparticulate technology is also available in a water-based system [Couvreur, P., Roland, M., Speiser, P. Biodegradable submicroscopic particles containing a biologically active substance and compositions containing them. U.S. Pat. No. 4,329,332 (1982)], animal studies demonstrated the presence of toxic degradation products [Cruz, T., Gaspar, R., Donato, A., Lopes, C. Interaction between polyalkylcyanoacrylate nanoparticles and peritoneal macrophages: MTT metabolism, NBT reduction, and NO production. Pharm. Res. 14: 73-79 (1997)].
Cell encapsulation [Chang, T. M. Hybrid artificial cells: Microencapsulation of living cells. ASAIO Journal 38: 128-130 (1992)] is a related technology that has also been explored for the purpose of making micro- and nanoparticles. Such particles can be formed either by polymer precipitation, following the addition of a non-solvent or by gelling, following the addition of a small inorganic ion (salt) and a complexing polymer (of an opposite charge). If a long enough time is allowed the particle interior (core) can be completely gelled. Usually, the inner core material is of a polyanionic nature (negatively charged polymer). The particle membrane (shell) is made from a combination of polycation (positively charged polymer) and polyanion. The core material is usually atomized (nebulized) into small droplets and collected in a receiving bath containing a polycationic polymer solution. The reciprocal structure is also possible. In this scenario, core material is polycationic and the receiving bath is polyanionic. Several binary polymeric encapsulation systems (resulting from two polymers) have been described [Prokop, A., Hunkeler, D., DiMari, S., Haralson, M. A., Wang, T. G. Water soluble polymers for immunoisolation. I. Complex caocervation and cytotoxicity. Advances in Polymer Science, 136: 1-51 (1998)]. These systems are inadequate due to the fact that the membrane parameters are governed by a single chemical complex resulting from the ionic interactions. The inability to adjust independently particle parameters hinders the success of these systems.
In an effort to overcome these severe limitations, new multicomponent polymeric micro- and nanoparticles were designed that permit independent modification of mechanical strength and permeability [Prokop, A., Hunkeler, D., Powers, A. C., Whitesell, R. R., Wang, T. G. Water soluble polymers for immunoisolation. II. Evaluation of multicomponent microencapsulation systems. Advances in Polymer Science, 136: 52-73 (1998)]. Over one thousand combinations of polyanions and polycations were examined as polymer candidates suitable for encapsulation of living cells. Thirty-three combinations were found to be usable. However, microcapsules are not always best suited as delivery vehicles because of their relatively large size. In addition, the composition and concentrations claimed in [Wang, T. G., Lacik, I., Brissova, M., Anilkumar, A. V., Prokop, A., Powers, A. C. Encapsulation system for the immunoisolation of living cells. U.S. Pat. No. 599,790, 1997] do not allow for the generation of small nanoparticles, suitable for injectable drug delivery. Such system has recently been described in a patent application [Prokop, A.: Micro- and nano-particulate polymeric delivery system, U.S. patent application, 1997].
Diabetes is a chronic disease, characterized by a high morbidity and mortality rate due to major complications (blindness, renal failure, and neuropathy) [The Diabetes Control and Complications Trial Research Group (DCCT). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus, New England J. Med. 329: 977-986 (1993)]. During the past 10 years it has become clear that none of the alternative treatment strategies (such as gene therapy, islet transplantation, beta cell bioartificial pancreas) provide a sufficient benefit to risk ratio. It is, nevertheless, difficult using current technologies to maintain normal blood sugar levels in individuals with diabetes. Considerable research has been devoted to the development of alternative methods for reestablishing normoglycemia. Pancreas and islet transplantation results have been disappointing, and the procedures are unlikely to receive widespread use [Lacy, P. E. Islet transplantation—The future, in:
Pancreatic Islet Cell Transplantation
, Ricordi, C., ed., R. G. Landes, Austin, pp. 394-399, 1992; Mintz, D. H. and Alejandro, R. Islet cell transplantation, In:
Pancreatic Islet Cell Transplantation
, Ricordi C, ed., R. G. Landes, Austin, pp. 1-6, 1992]. The use of non-human islets is limited by their immediate rejection and destruction by the recipient unless a potent immune suppressive the
Davidson Jeffrey M.
Dikov Mikhail M.
Prokop Ales
Williams Phillip
Adler Benjamin Aaron
Pryor Alton N.
Vanderbilt University
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