Title of Invention	"NOVEL COMPOSITION FOR STABILIZATION OF PHARMACEUTICALLY ACTIVE CHEMICAL/BIOLOGICAL AGENTS"
Abstract	A novel composition to stabilize pharmaceutically active chemical/biological agents which are unstable even in solid state is provided which comprises the active chemical/biological agents along with polyhydric alcohols or their derivatives as a stabilizer in a ratio of from 100: 0.1 to 0.1: 100 w/w.

Full Text

Introduction The present invention relates to a novel composition to stabilize pharmaceutically active chemicals/biologicals which are unstable even in solid state. Such instability in the pharmaceutically active chemicals/biologicals may be due to following causes such as : 1. Environmental factors such as (a) Humidity (b) Oxygen (c) Microbial attack 2. Chemical incompatibility 3. Loss of biological activity as in the case of live microbial spores due to presence of other anti microbial/antibiotic agents in the composition. To combat the above disclosed problems of instability in the pharmaceutically active chemicals/biologicals, the inventors in the present invention have developed a novel technology whereby the instability of the pharmaceutically active chemicals/biologicals can be countered satisfactorily. The invention comprises using solid polyhydric alcohols in particular solid polyethylene glycol. The expression "solid" wherever employed in the description should be understood as having melting point higher than 35° C. Background of the invention On affecting a search, the inventors were unable to locate any prior patents, which disclose the use of polyethylene glycol as a stabilizer for unstable drugs. Although some publications were found in the pharmaceutical extracts, which related to use of polyethylene glycol with dextrose, vitamin-D, urokinase, Tetracycline and Aspirin, in all these publications polyethylene glycol has been used as a solubilizer/plasticizer. Moreover none of the prior publications in the pharmaceutical abstracts disclose use of solid polyethylene glycol has a stabilizer for the pharmaceutically active chemical/biological agents as disclosed in our invention. Detailed description of the invention In accordance with the present invention the pharmaceutically active chemicals/biologicals could be selected from the group comprising: Cycloserine Clavulanic acid and its pharmaceutically acceptable salts Ranitidine Lactobacillus and/or antibiotics and combinations thereof with other pharmaceutically active agents. Cephalosporin The instability problems associated with the pharmaceutically active chemicals/biologicals disclosed above which the present invention intends to combat our discussed here in after: Cvcloserine Cycloserine is an antitubercular drug, which is prone to degradation by hydrolysis and autoaminolysis even in the solid state. (Reported in Analytical profiles of Drug substances. Vol. 18, Ed. K. Florey, P. 567 - 597, Academic press Inc.,) Clavulanic Acid and derivatives thereof Clavulanate is a beta-lactamase enzyme inhibitor, which is used in combination with beta-lactum antibiotics to combat infections. This group of drugs undergo rapid degradation on exposure to light, moisture and temperature even in the solid state. Ranitidine Ranitidine is a H-2-receptor antagonist having anti-ulcer activity. It undergoes rapid degradation upon exposure to light and moisture even in the solid state (Ref.: The Pharmaceutical Codex, 12th edition, P-1035, ed. Walter Lund, The Pharmaceutical Press, 1994). Lactobacillus and Antibiotics formulated together Lactobacillus spores are administered as an adjunct therapy along with antibiotics to alleviate the diarrhoel conditions caused by the antibiotics. However when lactobacillus spores are formulated together with antibiotics, it has been observed that a major portion of the spores undergo mortality due to the antibiotics resulting in the formulation being unstable. In accordance with the present invention the polyhydric alcohol is polyethylene glycol and/or poly (ethylene oxide). Polyethylene glycol is known to be a solvent, plasticizer and solubilizer in pharmaceutical preparations. The present invention employs polyethylene glycol and that too in a solid form as a stabilizer. In accordance with the present invention the composition comprises pharmaceutically active chemicals/biologicals and polyethylene glycol in a ratio of from 100 : 0.1 to 0.1 : 100 w/w. More preferably the ratio of pharmaceutically active chemicals/biologicals and polyethylene glycol is from 10 : 1 to 1 :10 w/w. Still more preferably the ratio may be 2 : 1 to 1 : 2 w/w. The process/technique of applying polyethylene glycol on solid substrate of pharmaceutically active chemicals/biologicals could be by any of the following processes/techniques known in the art: 1. Embedment of pharmaceutically active chemicals/biologicals in a molten mass of polyethylene glycol followed by solidification and size reduction to have a solid granular powder. 2. Hot melt spraying : the pharmaceutically active chemicals/biologicals are coated with a spray of molten polyethylene glycol using fluidized bed coating technology. 3. The polyethylene glycols may be dissolved in a solvent and then sprayed on to pharmaceutically active chemicals/biologicals substrate. Combination of lactobacillus with polyethylene glycol In particular the spores of lactobacillus could be treated with polyethylene glycol employing any of the disclosed treatment techniques. The end product of this treatment has been coined the expression "STABIPORE" ™, "STABILAC" ™ and "PROBIO" ™ by the inventors. Combination of pharmaceutically active chemicals with polyethylene glycol The end result of the treatment of pharmaceutically active chemicals with polyethylene glycols employing the above disclosed treatment techniques has been coined the expression "STABICOAT" ™, "STABITAB" ™ and "PROBIO" ™ by the inventors. The STABIPORE'S and STABICOAT's materials may be further combined with standard usual pharmaceutical additives such as fillers, colouring agents, binders, antioxidants, preservatives and the like. The treated pharmaceutically chemical/biological agents which could either be STABIPORE or STABICOAT will be in the solid form such as granules, beads, pellets and powder which may in turn be dispersed/suspended in any pharmaceutical base which could be a liquid or a solid or a semi solid. The STABIPORE and STABICOAT formulations could be marketed in the form of a capsule- hard gelatin/soft gelatin, tablets, wafers, granules, powder, suppository, medicated patches, ointments, pastilles and suspensions. The invention will now be described in detail with reference to the foregoing examples. The examples should be taken by way of an illustration and should not in any way be interpreted to limit the scope of the invention. Example 1. Composition Cycloserine - 62.5% w/w Polyethylene glycol 6000 - 35.0% w/w Talc - 2.5% w/w Process : Sift Cycloserine through mesh no. 100 BSS. Melt Polyethylene glycol 6000 at upto 65°C. Add to the sifted drug with continuous mixing. Cool to room temperature. Pass through mesh no. 22 BSS. Mix the granules with Talc. Fill in Hard Gelatin Capsules. Example 2. Composition Lactobacillus spores - 30.0% w/w Polyethylene glycol 8000 - 60.0% w/w Polyethylene glycol 3350 - 10.0% w/w Process : Lactobacillus spores are fluidized in the fluidized bed coater and sprayed with molten Polyethylene glycol. Blend at 40° to 80°C. Example 3 Composition Clavulanate - 12.5% w/w (as Clavulanate potassium) Polyethylene glycol 8000 - 11.0% w/w Amoxicillin - 50.0% w/w (as Amoxicillin tri hydrate) Fumed silicon dioxide - 10.0% w/w Microcrystalline Cellulose - 15.0% w/w Magnesium Stearate - 1.5% w/w Process : Sift Clavulanate potassium through mesh no. 100 BSS. Melt Polyethylene glycol 8000 at upto 65°C. Add to the sifted drug with continuous mixing. Cool to room temperature. Pass through mesh no. 22 BSS. Mix the granules with Amoxicillin trihydrate, Fumed silicon dioxide, Microcrystalline cellulose and Magnesium stearate. Compress into tablets. Example 4 Composition Ranitidine - 40.0% w/w Polyethylene glycol 6000 - 30.0% w/w Microcrystalline cellulose - 23.0% w/w Sodium starch glycollate - 4.0% w/w Talc - 2.0% w/w Magnesium stearate - 1.0% w/w Isopropyl alcohol - q.s Process : Polyethylene glycol 6000 is dissolved in sufficient quantity of Isopropyl alcohol and sprayed on to fluidized Ranitidine in a fluidized bed coater. The resulting powder is sifted through mesh no. 30 BSS and blended with Microcrystalline cellulose, Sodium starch glycollate, Talc and Magnesium stearate. Compress into tablets. Example 5 Composition Cefoperazone - 60.0% w/w (as Cefoperazone Sodium) Polyethylene glycol 3350 - 25.0% w/w Polyethylene glycol 6000 - 15.0% w/w Process : Fluidize Cefoperazone sodium in a fluidized bed coater and the molten blend of polyethylene glycols is sprayed on it. The resulting granular powder is filled in vials and sealed. We Claim: 1. A novel composition to stabilize pharmaceutically active chemical/biological agents that are unstable even in solid state, which comprises the active chemical/biological agents alongwith polyhydric alcohols or their derivatives as a stabilizer in a ratio of from 100:0.1 to 0.1:100 w/w. 2. A composition as claimed in claim 1 wherein the pharmaceutically active chemical/biological agents are selected from the group comprising Cycloserine, Clavulanic Acid and its pharmaceutically acceptable salts, Ranitidine, Lactobacillus and/or antibiotics and combinations thereof with other pharmaceutically active agents, and Cephalosporin. 3. A composition as claimed in claim 1 wherein the polyhydric alcohol is polyethylene glycol. 4. A composition as claimed in claim 3 wherein the ratio of pharmaceutically active chemical/biological agents and polyethylene glycol is from 10:1 to 1:10 w/w. 5. A composition as claimed in claim 3 wherein the ratio of pharmaceutically active chemical/biological agents and Polyethylene glycol is from 2:1 to 1:2 w/w. 6. A composition as claimed in claim 3, wherein the polyethylene glycol is in the solid form. 7. A pharmaceutical composition for stabilizing pharmaceutically active chemical/ biological agents substantially as herein described with reference to the foregoing description and the accompanying examples.

Documents:

19-del-2000-abstract.pdf

19-del-2000-claims.pdf

19-del-2000-correspondence-others.pdf

19-del-2000-correspondence-po.pdf

19-del-2000-description (complete).pdf

19-del-2000-form-1.pdf

19-del-2000-form-13.pdf

19-del-2000-form-19.pdf

19-del-2000-form-2.pdf

19-del-2000-form-3.pdf

19-del-2000-petition-138.pdf