Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Carbohydrate or lignin – or derivative
Reexamination Certificate
1999-02-12
2002-02-05
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Carbohydrate or lignin, or derivative
C514S054000, C514S055000, C424S422000, C424S423000
Reexamination Certificate
active
06344488
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a temperature-controlled pH-dependant formation of ionic polysaccharide gels, such as chitosan/organo-phosphate aqueous systems, and methods of preparation thereof.
BACKGROUND OF THE INVENTION
Chitosan is a commercially available inexpensive polymer, a derivative of chitin or poly(N-acetyl-glu-cosamine) materials. Chitosan is mainly composed of D-glucosamine units that are generated through catalyzed N-deacetylation of chitin, an insoluble biopolymer extracted from hard shells of marine living animals (fishes, crustaceans, shrimps, crabs . . . ) or synthesized by natural organisms (zygomycete, fungi . . . ). Chitosan is expected to have good viscoelastic properties, and has adequate tissue compatibility and biodegradability which renders it ideal for bioactive and resorbable implants. Poly-D-glucosamine chains are also known to potentially attach a large number of proteoglycan molecules and coexist with fibrous collagens to form aqueous gels. It is believed that the role of proteoglycans within the gel is to retain water and supply appropriate viscoelasticity. Resulting extracellular matrices are expected to offer compatible environments for cellular proliferation and tissue formation, especially for skin, ligament, bone and cartilage cells. As a consequence, chitosan attracts great interest for scaffolding or supporting materials of bioengineered artificial tissues.
Moreover, chitin and partially-acetylated chitosan derivatives have been extensively investigated for therapeutic substances or implantable materials. Biocompatibility of chitosan-based materials has been evaluated specifically for blood, wounds and bone. Immunological and genotoxic activities as well as stimulatory effects on macrophagic action have been also studied with various chitosan materials.
Chitosan and its derivatives has been widely explored for drug delivery system through gels (Ohya Y. et al. (1993)
J. Micro-encapsulation,
10(1):1-9). Peptides delivery with chitosan was proposed to be effected nasally. Cationic colloidal drug carriers were proposed from chitosan-polycaprolactone systems. Wound healing and reconstructive devices made of chitosan materials have been proposed for open or corneal wounds, periodontal tissues and skin. Chitosan was specially evaluated in bone and dura matter and as an hemostatic.
Entrapment of living biologicals (cells, enzymes, etc . . . ) have been investigated with different chitosan products, however, in nearly all cases, living cells have been encapsulated within alginate/chitosan microbeads. Encapsulation of chondrocytes (cartilage cells) were proposed within calcium-alginate/chitosan beads.
Gelation of chitosan through polyphosphates has been promoted for encapsulating cells such as neural or musculo-squeletal tissues. Generally, chitosan in an acid/water medium was loaded with cell suspensions, and the resulting mixture was dropped in a buffered penta-sodium tri-polyphosphates so as to form cell-loaded chitosan beads and capsules. Entrapment of neural cells within polyphosphate-gelated chitosan beads has led to good cellular viability but low proliferation rate (Zielinski B. A. et al. (1994)
Biomaterials,
15(13) :1049-1056). No large or specific three-dimensional shaped materials were proposed (Zielinski B. A. et al. (1994)
Biomaterials,
15(13) :1049-1056). Polysaccharide capsules have been proposed for entrapping physiologically active cells such as Langerhans Islets (U.S. Pat. No. 4,391,909). Chitosan/hydrochloride cisplatin mixture were cross-linked and proposed as drug delivery systems.
Chitosan derivatives have been incorporated in numerous carrier composition or drug formulation. Chitosan materials such as wound filling materials or contraceptive products were also proposed (U.S. Pat. Nos. 4,956,350 and 4,474,769). Chitosan gels were again reported as supports for immobilizing and encapsulating living biomaterials such as cells, bacteria and fungi (U.S. Pat. No. 4,647,536). Ophthalmic drug delivery systems made of chitosan were also proposed for in situ gelating and forming (U.S. Pat. No. 5,422,116).
In U.S. Pat. No. 4,659,700, chitosan gels were prepared from glycerol/acid/water systems as biodegradable carriers for drug delivery. The resulting chitosan gels were reported to remain quite stable, keeping intact their three-dimensional shape for long periods and over a wide range of temperatures, particularly between 4 and 40° C. Gels and gel-like materials were processed by dissolving 1.0 to 4.0% w/v chitosan within acid-water-glycerol solutions wherein acetic, formic or propionic acid and 10-90% glycerol proportions are used preferentially, and by neutralizing with liquid bases such the sodium, ammonium and potassium hydroxides or ammonia vapors. The pH of the resulting chitosan-glycerol gel materials is about pH 7.0. After neutralization, the resultant mixtures turn into gels upon standing, such gels resulting apparently from the interaction of chitosan, glycerol and water. No free glycerol or water were reported as being apparent. It must be noted, however, that such three-dimensionally shaped chitosan-glycerol gels will occur only when the solution is previously neutralized with a base. One-piece three-dimensional gels can be molded easily as well as gel-like membranes. The role of the glycerol component and chitosan-glycerol interactions is not elucidated.
In situ formed gels were also proposed with ionic polysaccharides in U.S. Pat. No. 5,587,175. A composition can be used as a medical device for drug delivery, the application of a diagnostic agent, or the prevention of post-operative adhesions, and is composed an aqueous liquid vehicle which is capable of being gelled in situ. It includes at least one ionic polysaccharide, at least one film forming polymer, and a medicament or pharmaceutical agent, water, and optionally, a counter-ion capable of gelating the ionic polysaccharide (U.S. Pat. No. 5,587,175). However, the gelation is reached by interaction between the ionic polysaccharide and the film-forming polymer, or by counter-ion induced cross-linking of the ionic polysaccharide. Other in situ forming gels are based upon polyoxyalkylene composition (U.S. Pat. No. 4,185,618) or polyoxyalkylene/polysaccharide mixture (U.S. Pat. No. 5,126,141) or alginate/cation mixture in situ (U.S. Pat. Nos. 4,185,618 and 5,266,326).
It would be highly desirable to be provided with a temperature-controlled pH-dependant formed polysaccharide gel which could be used to encapsulate cells and cellular material while retaining their biological activity.
It would be highly desirable to be provided with such a polysaccharide gel which would retain its solid or gel state at the physiological temperature or 37° C.
SUMMARY OF THE INVENTION
One aim of the present invention is to provide a temperature-controlled pH-dependant formed polysaccharide gel which could be used to encapsulate cells and cellular material while retaining their biological activity.
Another aim of the present invention is to provide a polysaccharide gel which would retain its solid or gel state at the physiological temperature or 37° C.
Another aim of the present invention is to provide a method for the preparation of such a polysaccharide gel.
In accordance with the present invention there is provided a polysaccharide based gel which comprises:
a) 0.1 to 5.0% by weight of chitosan or a chitosan derivative; and
b) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar;
wherein said gel is induced and stable within a temperature range from 20 to 70° C. and is adapted to be formed and/or gelated in situ within a tissue, organ or cavities of an animal or a human.
The salt may be any of the following or in any of the following combination:
a) a mono-phosphate dibasic salt selected from the group consisting of glycerol, comprising glycerol-2-phosphate, sn-glycerol 3-phosphate and L-glycerol-3-phosphate salts;
b) a mono-pho
Chaput Cyril
Chenite Abdellatif
Combes Christele
Jalal Fayrouze
Selmani Amine
Bio Syntech
Nixon & Peabody LLP
Travers Russell
Wang Shengjun
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