Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Patent
1994-11-29
1998-06-09
Lesmes, George F.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
73 40, 73 6447, 424422, 424423, 43524022, A61K 948, G01M 302
Patent
active
057629595
DESCRIPTION:
BRIEF SUMMARY
This invention relates to polysaccharide gels, and to compositions and methods for encapsulating functional cores such as biologically active materials. More specifically, the present invention relates to processes for encapsulating functional materials for successful in vivo transplantation. Encapsulation compositions and methods defined by functional parameters and assays relating to the capsule core, capsule membrane and capsule biocompatibility properties have been identified which are critical for successful in vivo immunoprotectivity and for functioning in the large animal model and in discordant xenografts. Compositions of matter, articles of manufacture prepared therefrom, and methods for the use thereof are described to achieve these critical functional parameters, essential for successful in vivo application.
BACKGROUND OF THE INVENTION
Diabetes Mellitus is a life-threatening disease affecting over 100 million people worldwide. Multiple insulin injections given periodically throughout the day cannot duplicate the precise feedback of insulin secretion from the pancreas. A potential method of treatment is to extract the insulin-producing cells (islets) from a pancreas and to inject these cells into the diabetic patient, thus effecting a cure.
Microencapsulated islets as a bioartificial endocrine pancreas was By implanting islets encapsulated in calcium alginate coated with poly-L-lysine (PLL), they were able to maintain normal blood sugar levels in diabetic rats for 2-3 weeks. Due to the very gentle, simple and rapid immobilization procedure, alginate/polycation entrapment is still the most promising method for islet encapsulation and an extensive volume of literature has been devoted to this capsule. Notwithstanding the substantial body of literature and experimentation and patent art in this area, to date there have been no reports of successful long-term in vivo transplantation of encapsulated islets in large animal (canine) models by the methods of encapsulation taught in the literature or in the patent prior art. Only until viable, long term function is demonstrated in large animal models can this technology proceed to application in insulin-dependent diabetic patients.
More than a decade has passed since Lim and Sun described this technology, and successful reversal of diabetes in large mammalian models by transplantation of encapsulated islets has eluded all investigators in this field. As recently as March, 1992, in the Journal of the American Society for Artificial Internal Organs, Califiore reported that intraperitoneal graft of microencapsulated islet reversed diabetes in mice, but "this approach was less successful in large diabetic mammals (canines)" (ASAIO Journal 38:36-37 (1992). In order to overcome this deficiency in prior art capsules, Calafiore resorted to developing a vascular prosthesis, comprised of two coaxial tubes, creating a vascular chamber for encapsulated islets. This required a vascular anastomoses of the device and eliminated a major advantage of microencapsulated islets, namely, the simplicity and safety of injecting encapsulated cells, free floating, into the abdominal cavity without a major surgical procedure such as vascular anastomoses.
Thus, it is clear that difficulties in prior art capsules exist which have prevented successful long term application of alginate--PLL encapsulated islets in large animals, despite earlier success in small animal (rat and mice) trials.
Many attempts have been made to optimize or improve the performance of the as hormone delivery system. CRC Critical review in therapeutic drug carrier system 4:1-12; and Goosen et al. (1984) Optimization of microencapsulation parameters: Semipermeable microcapsules as a bioartificial pancreas. Biotechnol. Bioeng. 27:146-150!. Despite these attempts, the methods and materials critical for successful in vivo implantation in large animals have not been elucidated.
Although some attempts have been made to optimize the performance of the example, Sun et al., (1987), supra!, relatively little has been
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Heintz Roswitha E.
Skjak-Braek Gudmund
Soon-Shiong Patrick
Harrison Robert H.
Lesmes George F.
Reiter Stephen E.
Vivorx Inc.
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