Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-07-12
2003-03-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C426S490000, C426S492000, C426S496000, C426S497000, C426S499000, C426S500000
Reexamination Certificate
active
06531156
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel microcapsules having an anisotropic salt membrane encapsulating an aqueous or substantially aqueous core which may comprise various active agents. The microcapsules are prepared by the interfacial reaction, in aqueous medium, of Lewis acid and base wall-forming reactants.
BACKGROUND OF THE INVENTION
Microencapsulation is a process by which a relatively thin coating can be applied to dispersions of small particles of solids or droplets of liquids, thus providing a means for converting liquids to solids, altering colloidal and surface properties, providing environmental protection, and controlling the release characteristics or availability of coated materials. Several of these properties can be attained by macropackaging techniques; however, the uniqueness of microencapsulation is the smallness of the coated particles and their subsequent use and adaptation to a wide variety of dosage forms and product applications. Heretofore, known feasible methods for producing microcapsules on an industrial scale have often involved the use of organic solvents. However, the use of organic solvents may present environmental and safety problems. In addition, it is often difficult to remove all the organic solvent from the microcapsules, thus leaving organic contaminants.
It has been proposed to use microcapsules as a means of delivering vaccine. Two broad types of antigen delivery systems have been studied for their capacity to enhance immunity: solid (or porous) microcapsules and microcapsules with a core region surrounded by a physically distinct wall. Solid is microcapsules may be prepared by a variety of processes including coacervation of colloids (Kwok, K. K., et al., 1991,
Pharm. Res.,
8: 341-344), precipitation of proteins by physical means (e.g., phase separation) or chemical agents (e.g., acid chlorides) (Levy, M. C., et al., 1991,
J. Pharm. Sci.,
80: 578-585), or solvent evaporation techniques that surround aqueous dispersions with polyester films (Singh, M. et al., 1991,
Pharm. Res.,
8: 958-961). Wall/core systems shown useful for antigen delivery include liposomes (Gerlier, D. et al., 1983,
J. Immunol.,
131: 490), ISCOMS (Claasen, I., and Osterhaus, A., 1992,
Res. Immunol.,
143: 531-541) and proteosomes (Gould-Fogerite, S. and Mannino, R., 1992,
Liposome Technology, Volume III,
Gregoriadis, G., (ed.), CRC Press, Boca Ration, Fla.; Miller, M. D. et al., 1992,
J. Exp. Med.,
176: 1739-1744).
Perhaps the best studied of the antigen delivery systems are those derived from the linear polymeric esters of lactic acid and glycolic acid (i.e., poly (DL-lactide-co-glycolide)) (PLCG) (Edelman, R. et al., 1993,
Vaccine,
11: 155-158; Eldridge, J. H. et al., 1989,
Curr. Top. Microbiol. Immunol.,
146: 59-66; Eldridge, J. H. et al., 1990,
J. Controlled Release,
11: 205-214; Eldridge, J. H. et al., 1989,
Adv. Exp. Med. Biol.,
251: 191-202; Eldridge, J. H. et al., 1991,
Mol. Immunol.,
28: 287-294; Eldridge, J. H. et al., 1991,
Infect. Immun.,
59: 2978-2986; Marx, P. A. et al., 1993,
Science,
260: 1323-1327; Moldoveanu, Z. et al., 1993,
J. Infect. Dis.,
167: 84-90; O'Hagan, D. T. et al.,
Vaccine,
11: 149-154; O'Hagan, D. T. et al., 1991,
Immunology,
73: 239-242; Ray, R. et al., 1993,
J. Infect. Dis.,
167: 752-755; Reid, R. et al., 1993,
J. Immunol.,
150: 323A; Reid, R. H. et al., 1993,
Vaccine,
11: 159-167). Encapsulation of putative antigens into PLCG microcapsules affords a number of advantages. First, microcapsules are easily degraded by hydrolysis to form lactic acid and glycolic acid. Second, PLCG microcapsules less than 5 &mgr;m in size readily penetrate Peyer's patches, mesenteric lymph nodes and spleen after oral inoculation of mice. Third, oral intraperitoneal, intranasal or subcutaneous inoculation of mice with PLCG microencapsulated antigens including influenza virus, parainfluenza virus, simian immunodeficiency virus, Staph. aureus enterotoxin B toxoid, and ovalbumin induces a greater immune response than that induced in animals inoculated with the same dose of free virus or protein. In addition, oral inoculation of mice with inactivated viruses induces an enhanced antigen-specific IGa response at mucosal surfaces. Lastly, PLCG microcapsules have been administered orally to adult volunteers without adverse effects.
The major disadvantage of PLCG microcapsules is the requisite use of organic solvents. Contact with organic solvents tends to inactivate the infectivity of viral and bacterial pathogens, and, in addition, may alter the immunogenicity of surface proteins critical to induction of humoral or cellular immune responses. In fact, large quantities of viral proteins have been required to induce an antigen-specific immune response with PLCG microcapsules.
U.S. Pat. No. 3,137,631 relates to encapsulation of water insoluble organic liquids by cross-linking synthetic resins through the application of heat or catalysts or both. The capsule shells are described as formed from covalently linked non-ionic materials or from heat denaturable proteins. The resultant capsules benefit from secondary treatment with cross-linking agents to impart increased stability to the capsule.
U.S. Pat. No. 4,205,060 discloses microcapsules comprising a core containing a water soluble salt formed by reaction between a polymeric ionic resin and a medicament, formed either by reaction of an acidic polymer with a basic medicament or, conversely, a basic polymer with an acidic drug. The walls of the microcapsules are formed from water-insoluble film-forming polymers. The water-insoluble film-forming polymers identified as suitable sheathing agents are all neutral non-ionized polymers. The capsules of that invention are made by preparing an aqueous solution of a salt made by reacting a medicament and a core polymer; preparing a solution of a water-insoluble sheath-forming polymer in a first water-immiscible organic liquid; dispersing the aqueous solution in the organic solution; and adding to the dispersion a second water-immiscible liquid which is a non-solvent for the sheath-forming polymer to precipitate the film around droplets of the dispersed aqueous phase.
U.S. Pat. No. 4,606,940 discloses the preparation of microcapsules by coacervation to precipitate the encapsulating material. A single colloid is dispersed in water and the water of salvation is removed from around the colloid by addition of chemical compounds which have a greater affinity for water than the colloid. This causes the colloid chains to come closer together and form the coacervate. Temperature changes are needed to facilitate the encapsulation by coacervation.
U.S. Pat. No. 3,959,457 discloses microcapsules comprised of the reaction product produced in a finely dispersed emulsion of a water-immiscible solution of (a) an organic polyfunctional Lewis base, in a (b) low boiling point, polar, organic solvent, and an aqueous solution of a (c) partially hydrophilic, partially lipophilic, polyfunctional Lewis acid. The capsules of that invention have lipophilic cores.
U.S. Pat. No. 5,132,117 discloses microcapsules that consist of aqueous or substantially aqueous cores surrounded by capsular anisotropic Lewis salt membranes. These aqueous-core microcapsules are prepared by dispersing an aqueous solution of a suitable Lewis-acid wall-forming reactant and a core material in a suitable non-aqueous solvent, adding an additional amount of non-aqueous solvent containing a suitable Lewis-base wall-forming reactant, and harvesting the microcapsules formed by the interfacial reaction. Alternatively, the aqueous-core microcapsules of that patent may be prepared by dispersing an aqueous solution of a suitable Lewis-acid wall-forming reactant and a core material in a suitable non-aqueous solvent containing a suitable Lewis-base wall-forming reactant and harvesting the microcapsules formed by the interfacial reaction.
F. Lim, in Belgium Patent No. 882,476, (1980), describes a process in which calcium alginate microspheres are first formed, then su
Clark Fred M.
Offit Paul A.
Speaker Tully J.
Di Nola-Baron Liliana
Nixon & Vanderhye PC
Page Thurman K.
Temple University
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