Title of Invention	"A PROCESS FOR PREPARING CASTED GELATIN CONTAINING COMPOSITION"
Abstract	The invention relates to a process for preparation of a novel synergistic composition of an improved gelatin having resistance to pellicle formation, improved dissolution, by incorporating an amino acid or its salt, a monomeric carboxylic acid or its salts, at least a preservative, water into the basic gelatin, also the invention provides the use of improved gelatin for obtaining gelatin films, sheets, ribbons, soft and hard gelatin capsules, sugar coated tablets or any other preparations involving gelatin with resistance to pellicle formation and having enhanced dissolution.

Title of Invention

"A PROCESS FOR PREPARING CASTED GELATIN CONTAINING COMPOSITION"

Abstract

The invention relates to a process for preparation of a novel synergistic composition of an improved gelatin having resistance to pellicle formation, improved dissolution, by incorporating an amino acid or its salt, a monomeric carboxylic acid or its salts, at least a preservative, water into the basic gelatin, also the invention provides the use of improved gelatin for obtaining gelatin films, sheets, ribbons, soft and hard gelatin capsules, sugar coated tablets or any other preparations involving gelatin with resistance to pellicle formation and having enhanced dissolution.

Full Text	A PROCESS FOR PREPARING AN IMPROVED GELATIN COMPOSITION FIELD OF INVENTION The present invention relates to a process for preparing an improved synergistic composition of gelatin based preparation having resistance to pellicle formation and an improved dissolution, the invention also relates to the composition and its use for obtaining gelatin film, sheets, ribbons, soft and hard gelatin capsules, sugar-coated tablets and any other preparations involving gelatin resistant to pellicle formation. BACKGROUND Gelatin is widely used in the pharmaceutical industry. Unfortunately, it undergoes pellicle formation on storage or on exposure to chemical catalysts. The pellicle formation results in retardation in dissolution behavior in formulations containing gelatin in the outer layer (hard and soft gel capsules and sugar coated tablets) and due to it there is always a risk in marketed preparations failing in the dissolution tests. To stabilize the gelatin preparations and dosage forms against pellicle formation due to cross linking, there are different approaches: to utilize the fill which is devoid of detrimental cross linking influence on the film; using gelatin which is most resistant to cross linking; and/or using stabilizers in the capsule fill or in the film, thus minimizing the impact of environmental conditions or chemical catalysts especially carbonyl compounds and more specifically formaldehyde, on the dissolution of films, ribbons or sheets, sugar-coated tablets and release of contents from the filled soft or hard gelatin capsules. The present invention relates to the discovery that the pellicle formation in the gelatin preparations is reduced or eliminated by the incorporation of an effective cross linking-reducing amount of a combination of at least one amino acid and at least one carboxylic acid during the preparation of the film mass or solution, instead of incorporation of the same substances in the fill of hard gel capsules, which is a known prior art (Adesunloye and Stach, Drug. Dev. Ind. Pharm. 24(6), 493-500,1998; Adesunloye and Stach, Patent No. WO 9733568). OBJECT OF THE INVENTION The main object of the present invention is to provide a process for the preparation of casted gelatin preparation containing synergistic composition of gelatin having resistance to pellicle formation, improved dissolution, Another objective of the present invention is to provide a gelatin film or any other gelatin preparation that incorporates gelatin in any other form to be used in food and pharmaceutical applications. Another objective of the present invention is to provide a gelatin film with reduced or devoid pellicle formation. Another objective of the present invention is to provide the use of stabilizer in much less quantities in preparing the gelatin composition. Another objective of the present invention provides a gelatin film, dissolution of which remains within acceptable limits on exposure to accelerated conditions of temperature, humidity and/or light. Another objective of the present invention provides a synergistic formulation, which minimizes the interaction of stabilizers with other ingredients used for filling. Another objective of the present invention provides easy and economical process for the preparation of stable gelatin film. Another objective of the present invention provides improved dissolution for the gelatin film or any other form of gelatin. Summary of the Invention Accordingly, the present invention provides a process for preparing an improved synergistic composition of gelatin based preparation having resistance to pellicle formation and an improved dissolution, the invention also relates to the composition and its use for obtaining gelatin film, sheets, ribbons, soft and hard gelatin capsules, sugar-coated tablets and any other preparations involving gelatin resistant to pellicle formation. Particularly this invention relates to a method of reducing pellicle formation in preparations made of gelatin film or those incorporating gelatin in any other form by incorporating an amino acid and a carboxylic acid into the gel mass or gelatin solution during its preparation. The inventive gelatin based preparations possess improved dissolution, relative to those, which do not contain either both or one among the amino acid and the carboxylic acid. The invention applies to all preparations where gelatin is the key or functional component, including films, sheets, ribbons, soft & hard gelatin capsules, and sugarcoated tablets. LIMITATIONS OF THE PRIOR ART The prior art of stabilization of gelatin capsules through addition of stabilizers in the fill, however, is associated with several limitations, which are as follows: i. High concentration of glycine and citric acid is needed to build up the required concentration in the entire fill. ii. The portion of stabilizers in the fill in immediate contact with the inner surface of the capsules can be said to have a functional role, whereas the remaining portion in the core of the fill is not expected to help in stabilization. iii. The method cannot be applied to soft gelatin capsules, as both glycine and citric acid are insoluble in non-aqueous solvents and oils, which are used to dispense drugs in soft gel dosage forms. The prior art, therefore, finds major application to hard gelatin capsules only. In reverse, the crosslinking problem is more serious with soft gel capsules and unfortunately no example has been covered in the previous patent (Adesunloye and Stach, Patent No. WO 9733568) on how the prior art applies to filled soft gel capsules and sugar-coated tablets. iv. Further, the prior art cannot be used to stabilize other presentations of gelatin, like films, sheets and ribbons, where there is no encapsulation and no fill. v. Another disadvantage of the prior art is that concentration of stabilizers would vary with the type of drug and ingredients enclosed as a fill in the capsules. This is because drugs containing keto or aldehydic groups themselves act as catalysts towards crosslinking. The same is expected of other ingredients that form part of capsule fill. It is expected that the amino acid, which also contain primary amino group, may be neutralized or become less effective in presence of other additives requiring larger quantities of stabilizer combination in the fill. a. mixing with cooling in an ice bath basic gelatin, an amino acid or its salt, a monomeric carboxylic acid, or its salt, propyl paraben, methyl paraben and water b. stirring with cooling in an ice bath the mixture of step (a) with a low speed for a time period of 0.5 h to 4 h. c. replacing the ice by water used in step (b) raising the temperature to a range of 40° C - 90° C, maintained for a period of Ih to 8 h, d. transferring the mixture of step (c), to an another container for maturation by maintaining the temperature in the range of 40 ° C to 80 ° C for a period of 2 h to 8 h to obtain improved gelatin, and e. Casting the improved gelatin of step (d) by cooling at a termperature range of 2 ° C to 10° C for a period of 5 h to 15 h to obtain the required casted gelatin preparation. Still another embodiment of the present invention provides a process such that the basic gelatin used is selected from either type A, B or any other type having 90 to 99% purity by its weight, bloom strength between 1 to 300 grams, viscosity between 1 to 100 and molecular weight ranging between 500 to 30,000 and further the gelatin material constitutes 1 to 60% in the film and the pH of its solution in water ranges between 3 and 10. Yet another embodiment of the present invention provides a process in which the weight percentage of gelatin is in the range of 1.0 to 60.0% and material that promotes pellicle formation in gelatin is a pharmaceutical active ingredient or a pharmaceutically acceptable excipient, or a combination thereof. Yet another embodiment of the present invention provides a process such that the aqueous solution of base gelatin has a pH in the range of 3 to 10. Yet another embodiment of the present invention provides a process for an improved gelatin resistant to materials that promote pellicle formation in gelatin. Still yet another embodiment of the present invention provides a process in which the material is a pharmaceutically active ingredient or a pharmaceutically acceptable excipient or its combination thereof. Yet still another embodiment of the present invention provides a process in which the Pharmaceutically active ingredient is a pharmaceutical amount of a drug or combination of drugs belonging to therapeutic categires like Antimicrobials and Anti- Infectives (like Beta-lactam Antibiotics, Macrolides and Clindamycin, Tetracyclines, Quinolones, Sulfonarnides, Antivirals, Antimalarials and Antiprotozoals, Antifungals, Anti-infectives, Antituberculars, Miscellaneous), Antineoplastics and Iminunosuppressants, Neurological Drugs, Cardiovascular Agents (Anti-arrhythmics and Cardiac Glycosides, Diuretics, Potassium Replacement, Beta Blockers, Calcium Channel Blockers, ACE Inhibitors, Angiotensin II Receptor Blockers, Centrally Acting Agents, Alpha-I Blockers, Antihypertensives, Vasodilators, Anti-Anginals, Antilipidemics), Pain and Inflammatory Diseases (NSAID Analgesics, Opioids, Drugs sued in Rheumatoid, Osteoarthritis and Gout), Psychiatric Drugs (Depression, Bipolar Disorders, Psychoses, Attention Deficit Disorder, Anxiety, Insomnia, Narcolepsy, Alcohol Deterrents); Gastrointestinal Drugs (Diarrhea, Pancreatic Enzymes, Emesis, Ulcers, Reflux (GERD), Spasm, Inflammatory Bowel Disease, Other Miscellaneous Gastrointestinal Drugs), Oral anti-diabetics, Oral Contraceptives, Menopausal drugs, Drugs against Osteoporosis and Vaginal Infections, Hormonal drugs (Adrenal Corticosteroids, Antithyroid and Thyroid Replacement, Androgens, Growth Hormones, Gonadotropin Inhibitors), Respiratory Drugs (COPD, Asthma, Antitussives and Expectorants, Antihistamines), Drugs against Urologic Disorders (Benign Prostatic Hypertrophy, Urinary Incontinence), Supplements, Other Miscellaneous Drugs. Still another embodiment of the present invention provides a process in which the excipients are inert materials belonging to different categories like Starches (corn starch, maize starch, potato starch, etc.); Sugars (glucose, lactose, mannitol, etc.); Stearates (including stearic acid, metallic stearates, etc.); Silicones (including silicon oil, silicon dioxide, etc.); Inorganic salts (calcium carbonate, magnesium oxide, etc.); Celluloses (microcrystalline cellulose, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, etc.); Glycols (Polyethylene glycols, etc.); Glycol esters; Glycerides; Talc; Bentonite; Silica gels; Polymers; Aromatic hydrocarbons; Chlorinated hydrocarbons; High molecular weight alcohols, esters, and organic acids; Vegetable oils (soyabean oils); Mineral oils; Fish oils; Nonionic surface active agents (polysorbate 80); Waxes etc. Still another embodiment of the present invention provides a process in which the weight percentage of amino acid or its salts is in the range of 0.01 to 25.0. Still in yet another embodiment of the present invention provides a process in which amino acid used is selected from the group consisting of glycine, tryptophan, lysine, leucine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, cysteine, phenylalaninc, tyrosine, histidine, acetylcysteine, valine, alanine, isoleucine, ormthine, p-aminoben/oic acid and nicotinic acid, or its salt thereof Yet another embodiment of the present invention provides in a process of the use of using the amino acid, glycine. Yet another embodiment of the present invention provides a process in which the weight percentage of monomeric carboxylic acid or its salt is in the range of 0.1 to 10.0. Still in another embodiment of the present invention the carboxylic acid used is a C4-C20 carboxylic acid with two or three -COOH groups or its salt thereof. Yet another embodiment of the present invention provides a process in which the carboxylic acid used is selected from the group consisting of benzoic acid, fumaric acid, maleic acid, citric acid, ascorbic acid, edetic acid, lactic acid, sorbic acid, tartaric acid, adipic acid, succinic acid and gluconic acid, or its salt thereof. Another embodiment of the present invention provides a process in which the carboxylic acid used is citric acid. Yet another embodiment of the present invention provides a process in which the preservative used is selected from a group consisting of propyl paraben, methyl paraben, benzoic acid , benzyl acid, benzalkonium chloride, cetrimide, chlorobutanol, butyl paraben or mixtures thereof or mixtures thereof. Still in another embodiment of the present invention the improved gelatin preparation obtained has a dissolution period within 30% of the initial dissolution of the film after exposure to environmental conditions of temperature, humidity and/or light, and to intentional or circumstantial exposure to chemical catalysts at various concentrations. Yet another embodiment of the present invention provides a process for obtaining improved gelatin which has resistance to environmental conditions may be natural environment at any time of the year at any place or accelerated conditions of temperature (above ambient to 45°C), and/or humidity (60%-95%RH) and/or light (>1.2 million lux hour exposure of fluorescent light and a minimum 200W h/m2 UVA light), created with artificial devices and the light is created using xenon, metal halide or a combination of white fluorescent and black UV lamps. Yet another embodiment of the present invention provides a process for obtaining gelatin which has resistance to chemical catalysts, a carbonyl compound, selected from ketones, aldehydes, furfural, acrolein, formaldehyde, glutaraldehyde, glyceryl aldehyde; imines, Saccharides selected from glucose and aldose; sugars; dyes (FD&C red No. 3 or 40 and blue No. 1); calcium carbonate, hydrogen peroxide, aliphatic and aromatic sulfonic acids; carbodiimides selected from 1-ethylene 3-(3-dimethylamino propyl); carbodiimide hydrochloride, guanidine hydrochloride; benzene, terephthaloyl chloride and/or derivatives thereof generated in the hard gel or soft gel capsule, either in situ in the capsule fill or used externally in the form of solution or vapors, and are present in the environment surrounding the film and preparations made thereof. Still yet another embodiment of the present invention provides a process in which the use of an amino acid or its salt, a monomeric carboxylic acid or its salt provides an effective cross-linking reducing combination. In an embodiment of the present invention, the seal coat refers to a step in the process of sugar-coating of tablets where a gelatin solution is applied as a seal coat on the tablet before sugar coating. In an embodiment of the present invention the term "Pellicle formation" refers to delayed dissolution. In yet another embodiment of the present invention cross linking refers to cross linking between the polypeptide chains of the gelatin employed as the backbone material for making films. In still another embodiment of the present invention, the chemical catalysts, which promote pellicle formation in the gelatin, include any material that promotes crosslinking between the polypeptide chains of the gelatin film or slows dissolution by any other mechanism. Still another embodiment of the present invention provides the use of an effective stabilizer against pellicle formation that is intended to mean an amount which is effective to achieve the specified dissolution requirements even when the gelatin preparations are subjected to normal/accelerated environmental conditions or exposed to chemical catalysts, either externally or when they are formed in situ within the formulation. Any preparation made out of gelatin as a key or functional component is expected to remain suitable for use if stabilized by the present method. The present method is also suitable for stabilizing formulations, for example, sugar-coated tablets, soft and hard gelatin capsules, containing pharmaceutically_active ingredient(s), acceptable excipients and their combinations. Yet another embodiment of the present invention provides preferably the stabilizer composition is made of about 0.01 to about 25 percent by weight of the amino acid and about 0.01 to about 10 percent by weight of the carboxylic acid, most preferably from 0.1 to 2.5 percent by weight of the amino acid and from 0.1 to 0.9 percent by weight of the carboxylic acid, the percentage by weight with respect to the total amount of gelatin used in making film or the preparations made thereof, including ribbons, sheets, sugar-coated tablets and soft and hard gelatin capsules or any other type of preparation. Still yet another embodiment of the present invention, provides the use of water-soluble monomeric carboxylic acid or its salts. Yet another embodiment of the present invention provides useful salts, which include those containing any pharmaceutically acceptable cation, especially alkali metal, alkaline earth metal and ammonium salts. Another embodiment of the present invention provides a composition and its preparation wherein the stabilizers are included in the film instead of the fill. One more embodiment of the present invention provides a synergistic composition of an improved gelatin having resistance to pellicle formation, with an improved dissolution, the said composition comprising: INGREDIENTS wt.% Basic gelatin 0.01 to 60.0 Amino acid or its salt 0.01 to 25.0 Monomeric carboxylic acid or its salts 0.10 to 10.0 Preservative - Propyl paraben 0.01 to 2.00 Preservative - Methyl paraben 0.01 to 2.00 Water 0.01 to 98.67 In an embodiment, the preservatives used are selected from parabens. Other than parabens, the other water-soluble preservatives are benzoic acid, benzyl alcohol, benzalkonium chloride, cetrimide, chlorobutanol, butyl paraben, etc. may be used as preservatives. Still another emobidment embodiment of the present invention provides a composition wherein the basic gelatin is selected from either type A, B or any other type, has 90 to 99% purity by its weight, bloom strength is between 1 to 300 grams, viscosity between 1 to 100 cps and molecular weight lies between 500 to 30,000. Yet another embodiment of the present invention provides a composition, having weight percentage of basic gelatin material in the range of 1.0 to 60. Still another embodiment of the present invention provides a solution of basic gelatin in water having a pH in the range of 3 to 10. In yet still another embodiment of the present invention the material that promotes pellicle formation in gelatin is a pharmaceutical active ingredient or a pharmaceutical excipient or combination thereof. In yet embodiment of the invention, the pharmaceutical active ingredient is a pharmaceutically effective amount of a drug or combination of drugs belonging to any therapeutic class, selected from a group consisting of Antimicrobials, Anti-Infectives, Antivirals, Antimalarials, Antiprotozoals, Antifungals, Anti-infectives, Antituberculars, Antineoplasties and Immunosuppressants, Neurological Drugs, Cardiovascular Agents, Pain and anti-Inflammatory agents, Psychiatric Drugs, Gastrointestinal Drugs, Oral anti-diabetics, Oral Contraceptives, Menopausal drugs, Drugs against Osteoporosis and Vaginal Infections, Hormonal drugs, Respiratory Drugs, Drugs against Urologic Disorders, Supplements, and Other Miscellaneous Drugs. Yet another embodiment, the antimicrobials and anti-infectives drug used is selected from a group consisting of like Beta-lactam Antibiotics, Macrolides and Clindamycin, Tetracyclines, Quinolones and Sulfonamides. Yet another embodiment, the cardiovascular agent used is selected from a group consisting of Anti-arrhythmics, Cardiac Glycosides, Diuretics, Potassium Replacement, Beta Blockers, Calcium Channel Blockers, ACE Inhibitors, Angiotensin II Receptor Blockers, Centrally Acting Agents, Alpha-I Blockers, Antihypertensives, Vasodilators, Anti-Anginals and Antilipidemics, Yet another embodiment, the pain and anti-Inflammatory drug used is selected from a group consisting of NSAID Analgesics, Opioids, and the drugs used in Rheumatoid, Osteoarthritis and Gout. Yet another embodiment, the psychiatric drug used is selected from a group consisting of such as Depression, Bipolar Disorders, Psychoses, Attention Deficit Disorder, Anxiety, Insomnia, Narcolepsy, Alcohol Deterrents; Yet another embodiment, the gastrointestinal drug used is selected from a group consisting of anti-diarrheal drug, Pancreatic Enzymes, Emesis, Ulcers, Reflux (GERD), Spasm, Inflammatory Bowel Disease and other Miscellaneous Gastrointestinal Drugs, Yet another embodiment, the hormonal drugs used is selected from a group consisting of Adrenal Corticosteroids, Antithyroid and Thyroid Replacement, Androgens, Growth Hormones, Gonadotropin Inhibitors, Yet another embodiment, the respiratory drugs used is selected from a group consisting of COPD, Asthma, Antitussives and Expectorants, Antihistamines, Yet another embodiment, the drugs against urologic disorders used is selected from a group consisting of Benign Prostatic Hypertrophy, Urinary Incontinence, Supplements, Other Miscellaneous Drugs. In yet another embodiment of the present invention, the pharmaceutically active ingredient is a Pharmaceutically effective amount of a drug or combination of drugs belonging to different therapeutic categories, like Antimicrobials and Anti-Infectives (like Beta-lactam Antibiotics, Macrolides and Clindamycin, Tetracyclines, Quinolones, Sulfonamides, Antivirals, Antimalarials and Antiprotozoals, Antifungals, Anti-infectives, Antituberculars, Miscellaneous), Antineoplasties and Immunosuppressants, Neurological Drugs, Cardiovascular Agents (Anti-arrhythmics and Cardiac Glycosides, Diuretics, Potassium Replacement, Beta Blockers, Calcium Channel Blockers, ACE Inhibitors, Angiotensin II Receptor Blockers, Centrally Acting Agents, Alpha-I Blockers, Antihypertensives, Vasodilators, Anti-Anginals, Antilipidemics), Pain and Inflammatory Diseases (NSAID Analgesics, Opioids, Drugs sued in Rheumatoid, Osteoarthritis and Gout), Psychiatric Drugs (Depression, Bipolar Disorders, Psychoses, Attention Deficit Disorder, Anxiety, Insomnia, Narcolepsy, Alcohol Deterrents); Gastrointestinal Drugs (Diarrhea, Pancreatic Enzymes, Emesis, Ulcers, Reflux (GERD), Spasm, Inflammatory Bowel Disease, Other Miscellaneous Gastrointestinal Drugs), Oral anti-diabetics, Oral Contraceptives, Menopausal drugs, Drugs against Osteoporosis and Vaginal Infections, Hormonal drugs (Adrenal Corticosteroids, Antithyroid and Thyroid Replacement, Androgens, Growth Hormones, Gonadotropin Inhibitors), Respiratory Drugs (COPD, Asthma, Antitussives and Expectorants, Antihistamines), Drugs against Urologic Disorders (Benign Prostatic Hypertrophy, Urinary Incontinence), Supplements, Other Miscellaneous Drugs. In yet another embodiment of the present invention, excipients are inert materials belonging to different categories like Starches (corn starch, maize starch, potato starch, etc.); Sugars (glucose, lactose, mannitol, etc.); Stearates (including stearic acid, metallic stearates, etc.); Silicones (including silicon oil, silicon dioxide, etc.); Inorganic salts (calcium carbonate, magnesium oxide, etc.); Celluloses (microcrystalline cellulose, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, etc.); Glycols (Polyethylene glycols, etc.); Glycol esters; Glycerides; Talc; Bentonite; Silica gels; Polymers; Aromatic hydrocarbons; Chlorinated hydrocarbons; High molecular weight alcohols, esters, and organic acids; Vegetable oils (soyabean oils); Mineral oils; Fish oils; Nonionic surface active agents (polysorbate 80); Waxes etc. In yet another embodiment of the present invention, the weight percentage of amino acid or its salts is in the range of 0.01 to 25.0. Still in yet another embodiment of the present invention, the amino acid is selected from the group consisting of glycine, tryptophan, lysine, leucine, threonine, aspartic acid, glutamic acid, Asparagine, glutamine, lysine, arginine, cysteine, phenylalanine, tyrosine, histidine, acetylcysteine, valine, alanine, isoleucine, ornithine, p-aminobenzoic acid and nicotinic acid, or its salt thereof Yet in another embodiment of the present invention, the amino acid used is glycine. Still another embodiment of the present invention provides the weight percentage of monomeric carboxylic acid or its salt in the range of 0.1 to 10.0. In still another embodiment of the present invention, the carboxylic acid used is C4-C20 carboxylic acid with two or three -COOH groups or its salt. Another embodiment of the present invention provides a carboxylic acid selected from the group consisting of benzoic acid, fumaric acid, maleic acid, citric acid, ascorbic acid, edetic acid, lactic acid, sorbic acid, tartaric acid, adipic acid, succinic acid and gluconic acid, or its salt. Yet another embodiment of the present invention provides that the carboxylic acid used is citric acid. Still yet in another embodiment of the present invention the improved gelatin film obtained has a dissolution period within 30% of the initial dissolution of the film after exposure to environmental conditions of temperature, humidity and/or light, and to intentional or circumstantial exposure to chemical catalysts at various concentrations. In still another embodiment of the present invention, the environmental conditions may be natural environment at any time of the year at any place or accelerated conditions of temperature (above ambient to 45°C) and/or, humidity (60%-95%RH) and light (>1.2 million lux hour exposure of fluorescent light and a minimum 200W h/m2 UVA light), created with artificial devices using xenon, metal halide or a combination of white fluorescent and black UV lamps. Another embodiment of the present invention provides a chemical catalysts as a carbonyl compound, selected from ketones, aldehydes, furfural, acrolein, formaldehyde, glutaraldehyde, glyceryl aldehyde; imines, saccharides selected from glucose and aldose; sugars; dyes (FD&C red No. 3 or 40 and blue No. 1); calcium carbonate, hydrogen peroxide, aliphatic and aromatic sulfonic acids; carbodiimides selected from 1-ethylene 3-(3-dimethylamino propyl); carbodiimide hydrochloride, guanidine hydrochloride; benzene, terephthaloyl chloride and/or derivatives thereof generated in the hard gel or soft gel capsule, either in situ in the capsule fill or used externally in the form of solution or vapors, and are present in the environment surrounding the film and preparations made thereof. Another embodiment of the present invention provides at least one amino acid or its salt, and atleast a monomeric carboxylic acid or its salt that forms a cross-linking reducing combination. Still in yet another embodiment of the present invention, the improved gelatin obtained is used as a film, ribbon, sugar coated tablets, hard gelatin capsules, soft gelatin capsules or any other gelatin based preparation. The following examples illustrate, but do not limit, the present invention. All percentages are by weight unless otherwise indicated. EXAMPLES Example 1 Process for the preparation of gelatin film. All the materials were weighed according to the formulae in Table 1 and transferred to 1000 ml round bottom flask, which was connected to a rotary film evaporator, with its bath filled with ice. The flask was stirred at a low speed under mild vacuum for 1 h. Chilling facilitated the swelling of gelatin mass and removal of the air bubbles. Subsequently, the ice was removed and the bath was filled with fresh water. The temperature was increased to 75°C and maintained under vacuum for 4 h under constant stirring to facilitate appropriate mixing of the ingredients. The mass thus prepared was transferred to a beaker and kept in a constant water bath at 60°C for 4 h to allow maturation and transfer of entrapped air to the surface. The film casting was done using laboratory coating device on a glass plate. After casting the plate was kept in the refrigerator for 12 h to allow hardening of the film. The hardened film was removed from the plate with the help of a spatula and stored under ambient conditions. TableRemove: Composition a of gelatin film The films prepared according to Example 1 were exposed to formaldehyde vapors in the range of 39p,g to 190u,g in squat bottles for 12 hours. The films were cut into rings of size of 11 rnm i.d. x 14mm o.d. and the dissolution time of the rings was determined in water and also in simulated gastric fluid, described in USP (USP 24/NF 19, United States Pharmacopeia! Convention, Rockville, MD, 1999, p. 2696, Venugopal and Singh. Pharm. Technol, Drug Delivery Supplement, 32-37, 2001). The dissolution studies were done in triplicate. The films prepared in Example 1 were stored in a photostability chamber controlled at 40°C and 75% relative humidity for 8 days (S. Singh, R. Manikandan, and S. Singh. Pharm. Technol., 24 (5), 58-72, 2000). The films were cut into rings of size of 11 mm i.d. x 14mm o.d and the dissolution time of the rings was determined in water and also in simulated gastric fluid, described in USP (USP 24/NF 19, United States Pharmacopeial Convention, Rockville, MD, 1999, p. 2696). The dissolution studies were done in triplicate. Table 2 shows mean dissolution time of gelatin rings before exposure and after exposure to accelerated environmental conditions in a photostability chamber and also to different concentrations of formaldehyde. TableRemove: Mean dissolution time (minutes) of gelatin rings before addition of either glycine or citric acid Example 2 Process for preparation of gelatin film stabilized with glycine and citric acid. All the materials were weighed according to the formulae in Table 3 and transferred to 1000 ml round bottom flask, which was connected to a rotary film evaporator, with i:.s bath filled with ice. The flask was stirred at a low speed under mild vacuum for 1 h. Chilling facilitated the swelling of gelatin mass and removal of the air bubbles. Subsequently, the ice was removed and the bath was filled with fresh water. The temperature was increased to 75°C and maintained under vacuum for 4 h under constant stirring to facilitate appropriate mixing of the ingredients. The mass thus prepared was transferred to a beaker and kept in a constant water bath at 60°C for 4 h to allow maturation and transfer of entrapped air to the surface. The film casting was finally done using laboratory coating device on a glass plate. After casting, the plate was kept in the refrigerator for 12 h to allow hardening of the film. The hardened film was removed from the plate with the help of a spatula and stored under ambient conditions. Table 3: Formulae for preparation of gelatin films (Ingredients are expressed in terms of weight percentage) (Table Rewmove)The films prepared according to Example 2 were exposed to formaldehyde vapors in the range of 39u,g to 190u,g in squat bottles for 12 hours. The films were cut into rings of size of 11 mm i.d. x 14mm o.d. and the dissolution time of the rings was determined in water and also in simulated gastric fluid, described in USP (USP 24/NF 19, United States Pharmacopeial Convention, Rockville, MD, 1999, p. 2696). The dissolution studies were done in triplicate. The films prepared in Example 2 were stored in a photostability chamber controlled at 40°C and 75% relative humidity for 8 days (S. Singh, R. Manikandan, and S. Singh, Pharm. Technol., 24 (5), 58-72, 2000). The films were cut into rings of size of 11 mm i.d. x 14mm o.d. and the dissolution time of the rings was determined in water and also in simulated gastric fluid, described in USP (USP 24/NF 19, United States Pharmacopeial Convention, Rockville, MD, 1999, p. 2696). The dissolution studies were done in triplicate. Table 4 shows mean dissolution time of gelatin rings before exposure and after exposure to accelerated environmental conditions in a photostability chamber and also to different concentrations of formaldehyde. Table 4: Effect of glycine and citric acid on dissolution time (minutes) of gelatin rings (Table Remove) (Table Remove)Gelatin films without glycine/citric acid (Table 2) show an increased mean dissolution time as compared to films containing the stabilizers (Table 4). Moreover, the mean dissolution times after exposure are within 30% of initial (without exposure) both in case of stability chamber and formaldehyde exposure at 78 ju,g (Table 4) for Formula E and much lower than the normal acceptable dissolution time of 45 min or even 20 min for some drug preparations. ADVANTAGES OF THE PRESENT INVENTION i. In the present invention an approach is provided for the stabilization of all kinds of preparations or formulations made out of gelatin film or mass. It is expected to be useful to prevent pellicle formation in gelatin films, sheets, ribbons, sugar-coated tablets and soft as well as hard gelatin capsules. ii. In the present invention the stabilizer added into the gelatin layer provides the intervention to pellicle formation or cross linking in a more efficient manner. iii. In the present invention much lesser quantities of the stabilizer are needed. iv. In the present invention there is no requirement of differential amounts of stabilizer concentrations, which is the case when the stabilizer is added to the capsule fill. Incorporation of a specific amount of stabilizer in the gelatin layer, as shown above in the examples, takes care of all possible catalytic challenges, whether due to in-situ generated catalyst(s) or an external exposure to chemical catalysts. v. In the present invention the addition of stabilizers in the gelatin film neutralizes very effectively the pellicle formation and cross linking caused by exposure to accelerated conditions of temperature and/or humidity and/or light. The addition of stabilizers in the fill is not expected to give the same stabilizing effect because influence of environmental factors is an external surface phenomenon, and the same can be better tackled if the stabilizer combination is present in the film itself. vi. In the present invention, the chances of interaction of stabilizers with fill of the Formulations is minimized due to very low concentration of stabilizers and also the same would not happen unless there is leaching of stabilizers from the gelatin film, which is unlikely especially in solid dosage forms I / We Claims 1. A process for the preparation of an improved synergistic composition gelatin preparation namely casted gelatin preparation containing synergistic composition of gelatin having resistance to pellicle formation and improved dissolution, the said process comprising steps of: a. mixing a basic gelatin, an amino acid or its salt, a monomeric carboxylic acid or its salt, at least a preservatiye_jind water at a temperature ranging between 1°C and 8°C in an ice bath; b. stirring the mixture of step (a) with a low speed for a time period of 0.5 hour to 4 hour, c. raising the temperature of the mixture of step (b) to a temperature range of 60°C to 80°C by replacing the ice bath by hot water maintaining the temperature for a period of Ihour to 8 hour, d. transferring the mixture of step (c), to an another container for maturation by maintaining the temperature in the range of 40°C to 80°C for a period of 2h to 8h to obtain an improved gelatin, and e. casting the improved gelatin of step (d) by cooling to a temperature range of 2°C to 10°C for a period of Shows to IShours to obtain the required casted gelatin preparation. 2. A process of claim 1, wherein in step (a), basic gelatin used is selected from either type A, B or any other type having 90 to 99% purity by its weight, bloom strength between 1 to 300 grams, viscosity between 1 to 100 cps and molecular weight ranging between 500 to 30,000. 3. A process of claim 1, wherein in step (a) the weight percentage of gelatin used, is in the range of 1.0 to 60.0. 4. A process of claim 1, wherein in step (a) the preservative used is selected from a group consisting of propyl paraben, methyl paraben, benzoic acid, benzyl alcohol, benzalkonium chloride, cetrimide, chlorobutanol, butyl paraben or mixtures thereof. 5. A process of claim 1, wherein the aqueous solution of basic gelatin has a pH in the range of 3 to 10. 6. A process of claim 1 provides an improved gelatin resistant to material that promotes pellicle formation in gelatin. 7. A process of claim 6, wherein the material which promotes the pellicle formation is a pharmaceutical active ingredient or a pharmaceutical acceptable excipient or combination thereof. 8. A process of claim 7, wherein the pharmaceutical active ingredient is a pharmaceutically effective amount of a drug or combination of drugs belonging to any therapeutic class, selected from a group consisting of Antimicrobials, Anti- Infectives, Antivirals, Antimalarials, Antiprotozoals, Antifungals, Anti-infectives. Antituberculars, Antineoplastics and Immunosuppressants, Neurological Drugs. Cardiovascular Agents, Pain and anti-Inflammatory agents, Psychiatric Drugs, Gastrointestinal Drugs, Oral anti-diabetics, Oral Contraceptives, Menopausal drugs. Drugs against Osteoporosis and Vaginal Infections, Hormonal drugs, Respirator) Drugs, Drugs against Urologic Disorders, Supplements, and Other Miscellaneous Drugs. 9. A process of claim 8, wherein antimicrobials and anti-infectives drug used is selected from a group consisting of like Beta-lactam Antibiotics, Macrolides and Clindamycin, Tetracyclines, Quinolones and Sulfonamides, 10. A process of claim 8, wherein the cardiovascular agent used is selected from a group consisting of Anti-arrhythmics, Cardiac Glycosides, Diuretics, Potassium Replacement, Beta Blockers, Calcium Channel Blockers, ACE Inhibitors, Angiotensin II Receptor Blockers, Centrally Acting Agents, Alpha-I Blockers. Antihypertensives, Vasodilators, Anti-Anginals and Antilipidemics, 11. A process of claim 8, wherein the pain and anti-Inflammatory drug used is selected from a group consisting of NSAID Analgesics, Opioids, and the drugs used in Rheumatoid, Osteoarthritis and Gout. 12. A process of claim 8, wherein the psychiatric drug used is selected from a group consisting of such as Depression, Bipolar Disorders, Psychoses, Attention Deficit Disorder, Anxiety, Insomnia, Narcolepsy, Alcohol Deterrents; 13. A process of claim 8, wherein the gastrointestinal drug used is selected from a group consisting ofDiarrhea, Pancreatic Enzymes, Emesis, Ulcers, Reflux (GERD). Spasm, Inflammatory Bowel Disease and other Miscellaneous Gastrointestinal Drugs, 14. A process of claim 8, wherein the hormonal drugs used is selected from a group consisting of Adrenal Corticosteroids, Antithyroid and Thyroid Replacement, Androgens, Growth Hormones, Gonadotropin Inhibitors, 15. A process of claim 8, wherein the. respiratory drugs used is selected from a group consisting of COPD, Asthma, Antitussives and Expectorants, Antihistamines, 16. A process of claim 8, wherein the drugs against urologic disorders used is selected from a group consisting of Benign Prostatic Hypertrophy, Urinary Incontinence, Supplements, Other Miscellaneous Drugs. 17. A process of claim 7, wherein the excipients used are inert materials selecetd from a group consisting of Starches (corn starch, maize starch, potato starch, etc.); Sugars (glucose, lactose, mannitol, etc.); Stearates (including stearic acid, metallic stearates, etc.), Silicones (including silicon oil, silicon dioxide, etc.); Inorganic salts (calcium carbonate, magnesium oxide, etc.); Celluloses (microcrystalline cellulose, hydroxyl propyl cellulose, hydroxy propyl methyl cellulose, etc.); Glycols (Polyethylene glycols, etc.); Glycol esters; Glycerides; Talc; Bentonite; Silica gels; Polymers; Aromatic hydrocarbons, chlorinated hydrocarbons; High molecular weight alcohols, esters and, organic acids; Vegetable oils (soyabean oils); Minerals oils, Fish oils; Nonionic surface active agents (polysorbate 80); and waxes. 18. A process of claim 1, wherein in step (a) the weight percentage of amino acid or its salts is in the range of 0.01 to 25.0. 19. A process of claim 18, wherein the amino acid used is selected from the group consisting of glycine, tryptophan, lysine, leucine, threonine, aspartic acid, glutamic acid, asparagine glutamine, lysine, arginine, cysteine, phenylalanine, tyrosine, histidine, acetylcysteine, valine, alanine, isoleucine, ornithine, p-aminobenzoic acid and nicotinic acid, or its salt thereof. 20. A process of claim 1, wherein the amino acid used is glycine. 21. A process of claim 1, wherein in step (a) the weight percentage of monomeric carboxylic acid or its salt is in the range of 0.1 to 10.0. 22. A process of claim I, wherein the carboxylic acid is a €4-020 aliphatic or aromatic carboxylic acid with one to three -COOH groups or its salt thereof. 23. A process of claim 22, wherein the carboxylic acid is selected from the group consisting of benzoic acid, furnaric acid, maleic acid, citric acid, ascorbic acid, edetic acid, lactic acid, sorbic acid, tartaric acid, adipic acid, succinic acid and gluconic acid or its salt thereof. 24. A process of claim 1, wherein the carboxylic acid used is citric acid. 25. A process of claim 1, wherein the improved gelatin preparation obtained has a dissolution period within 30% of the initial dissolution of the film after exposure to environmental conditions of temperature, humidity and/or light, and to intentional or circumstantial exposure to chemical catalysts at various concentrations. 26. A process of claim 25, wherein the environmental conditions may be natural environment at any time of the year at any place or accelerated conditions of temperature (above ambient to 45°C), humidity (60%-95%RH) and light (>1.2 million lux hour exposure of fluorescent light and a minimum 200W h/m2 UYA light), created with artificial devices created using xenon, metal halide or a combination of white fluorescent and black UV lamps. 27. A process of claim 25, wherein the chemical catalysts is a carbonyl compound, selected from ketones, aldehydes, furfural, acrolein, formaldehyde, glutaraldehyde, glyceryl aldehyde; imines, Saccharides selected from glucose and aldose; sugars; dyes (FD&C red No. 3 or 40 and blue No. 1); calcium carbonate, hydrogen peroxide, aliphatic and aromatic Sulfonic acids; carbodiimides selected from 1- ethylene 3-(3-dimethylamino propyl); Carbodiimide hydrochloride, guanidine hydrochloride; benzene, terephthaloyl chloride and/or derivatives thereof generated in the hard gel or soft gel capsule, either in situ in the capsule fill or used externally in the form of solution or vapors, and are present in the environment surrounding the film and preparations made thereof. 28. A process of claim 1, wherein an amino acid or its salt, and a monomeric carboxylic acid or its salt used provides an effective cross-linking reducing combination. 29. A process as claimed in claim 1, wherein the improved gelatin obtained provides its use as a film, ribbon, sugar coated tablets, hard gelatin capsules, soft gelatin capsules or any other gelatin based preparation. 30. A process for the preparation of synergistic composition substantially as herein described with reference to the given examples in the specification.

Full Text

A PROCESS FOR PREPARING AN IMPROVED GELATIN COMPOSITION
FIELD OF INVENTION
The present invention relates to a process for preparing an improved synergistic composition of gelatin based preparation having resistance to pellicle formation and an improved dissolution, the invention also relates to the composition and its use for obtaining gelatin film, sheets, ribbons, soft and hard gelatin capsules, sugar-coated tablets and any other preparations involving gelatin resistant to pellicle formation.
BACKGROUND
Gelatin is widely used in the pharmaceutical industry. Unfortunately, it undergoes pellicle formation on storage or on exposure to chemical catalysts. The pellicle formation results in retardation in dissolution behavior in formulations containing gelatin in the outer layer (hard and soft gel capsules and sugar coated tablets) and due to it there is always a risk in marketed preparations failing in the dissolution tests.
To stabilize the gelatin preparations and dosage forms against pellicle formation due to cross linking, there are different approaches: to utilize the fill which is devoid of detrimental cross linking influence on the film; using gelatin which is most resistant to cross linking; and/or using stabilizers in the capsule fill or in the film, thus minimizing the impact of environmental conditions or chemical catalysts especially carbonyl compounds and more specifically formaldehyde, on the dissolution of films, ribbons or sheets, sugar-coated tablets and release of contents from the filled soft or hard gelatin capsules. The present invention relates to the discovery that the pellicle formation in the gelatin preparations is reduced or eliminated by the incorporation of an effective cross linking-reducing amount of a combination of at least one amino acid and at least one carboxylic acid during the preparation of the film mass or solution, instead of incorporation of the same substances in the fill of hard gel capsules, which is a known prior art (Adesunloye and Stach, Drug. Dev. Ind. Pharm. 24(6), 493-500,1998; Adesunloye and Stach, Patent No. WO 9733568).

OBJECT OF THE INVENTION
The main object of the present invention is to provide a process for the preparation of casted gelatin preparation containing synergistic composition of gelatin having resistance to pellicle formation, improved dissolution,
Another objective of the present invention is to provide a gelatin film or any other gelatin preparation that incorporates gelatin in any other form to be used in food and pharmaceutical applications.
Another objective of the present invention is to provide a gelatin film with reduced or devoid pellicle formation.
Another objective of the present invention is to provide the use of stabilizer in much less quantities in preparing the gelatin composition.
Another objective of the present invention provides a gelatin film, dissolution of which remains within acceptable limits on exposure to accelerated conditions of temperature, humidity and/or light.
Another objective of the present invention provides a synergistic formulation, which minimizes the interaction of stabilizers with other ingredients used for filling.
Another objective of the present invention provides easy and economical process for the preparation of stable gelatin film.
Another objective of the present invention provides improved dissolution for the gelatin film or any other form of gelatin.
Summary of the Invention
Accordingly, the present invention provides a process for preparing an improved synergistic composition of gelatin based preparation having resistance to pellicle formation and an improved dissolution, the invention also relates to the composition and its use for obtaining gelatin film, sheets, ribbons, soft and hard gelatin capsules, sugar-coated tablets and any other preparations involving gelatin resistant to pellicle formation.
Particularly this invention relates to a method of reducing pellicle formation in preparations made of gelatin film or those incorporating gelatin in any other form by incorporating an amino acid and a carboxylic acid into the gel mass or gelatin solution during its preparation.

The inventive gelatin based preparations possess improved dissolution, relative to those, which do not contain either both or one among the amino acid and the carboxylic acid. The invention applies to all preparations where gelatin is the key or functional component, including films, sheets, ribbons, soft & hard gelatin capsules, and sugarcoated tablets.
LIMITATIONS OF THE PRIOR ART
The prior art of stabilization of gelatin capsules through addition of stabilizers in the fill, however, is associated with several limitations, which are as follows:
i. High concentration of glycine and citric acid is needed to build up the required concentration in the entire fill.
ii. The portion of stabilizers in the fill in immediate contact with the inner surface of the capsules can be said to have a functional role, whereas the remaining portion in the core of the fill is not expected to help in stabilization.
iii. The method cannot be applied to soft gelatin capsules, as both glycine and citric acid are insoluble in non-aqueous solvents and oils, which are used to dispense drugs in soft gel dosage forms. The prior art, therefore, finds major application to hard gelatin capsules only. In reverse, the crosslinking problem is more serious with soft gel capsules and unfortunately no example has been covered in the previous patent (Adesunloye and Stach, Patent No. WO 9733568) on how the prior art applies to filled soft gel capsules and sugar-coated tablets.
iv. Further, the prior art cannot be used to stabilize other presentations of gelatin, like films, sheets and ribbons, where there is no encapsulation and no fill.
v. Another disadvantage of the prior art is that concentration of stabilizers would vary with the type of drug and ingredients enclosed as a fill in the capsules. This is because drugs containing keto or aldehydic groups themselves act as catalysts towards crosslinking. The same is expected of other ingredients that form part of capsule fill. It is expected that the amino acid, which also contain primary amino group, may be neutralized or become less effective in presence of other additives requiring larger quantities of stabilizer combination in the fill.

a. mixing with cooling in an ice bath basic gelatin, an amino acid or its salt, a
monomeric carboxylic acid, or its salt, propyl paraben, methyl paraben and
water
b. stirring with cooling in an ice bath the mixture of step (a) with a low speed
for a time period of 0.5 h to 4 h.
c. replacing the ice by water used in step (b) raising the temperature to a range
of 40° C - 90° C, maintained for a period of Ih to 8 h,
d. transferring the mixture of step (c), to an another container for maturation
by maintaining the temperature in the range of 40 ° C to 80 ° C for a period
of 2 h to 8 h to obtain improved gelatin, and
e. Casting the improved gelatin of step (d) by cooling at a termperature range
of 2 ° C to 10° C for a period of 5 h to 15 h to obtain the required casted
gelatin preparation.
Still another embodiment of the present invention provides a process such that the basic gelatin used is selected from either type A, B or any other type having 90 to 99% purity by its weight, bloom strength between 1 to 300 grams, viscosity between 1 to 100 and molecular weight ranging between 500 to 30,000 and further the gelatin material constitutes 1 to 60% in the film and the pH of its solution in water ranges between 3 and 10.
Yet another embodiment of the present invention provides a process in which the weight percentage of gelatin is in the range of 1.0 to 60.0% and material that promotes pellicle formation in gelatin is a pharmaceutical active ingredient or a pharmaceutically acceptable excipient, or a combination thereof.
Yet another embodiment of the present invention provides a process such that the aqueous solution of base gelatin has a pH in the range of 3 to 10.
Yet another embodiment of the present invention provides a process for an improved gelatin resistant to materials that promote pellicle formation in gelatin.
Still yet another embodiment of the present invention provides a process in which the material is a pharmaceutically active ingredient or a pharmaceutically acceptable excipient or its combination thereof.

Yet still another embodiment of the present invention provides a process in which
the Pharmaceutically active ingredient is a pharmaceutical amount of a drug or
combination of drugs belonging to therapeutic categires like Antimicrobials and Anti-
Infectives (like Beta-lactam Antibiotics, Macrolides and Clindamycin, Tetracyclines,
Quinolones, Sulfonarnides, Antivirals, Antimalarials and Antiprotozoals, Antifungals,
Anti-infectives, Antituberculars, Miscellaneous), Antineoplastics and
Iminunosuppressants, Neurological Drugs, Cardiovascular Agents (Anti-arrhythmics and Cardiac Glycosides, Diuretics, Potassium Replacement, Beta Blockers, Calcium Channel Blockers, ACE Inhibitors, Angiotensin II Receptor Blockers, Centrally Acting Agents, Alpha-I Blockers, Antihypertensives, Vasodilators, Anti-Anginals, Antilipidemics), Pain and Inflammatory Diseases (NSAID Analgesics, Opioids, Drugs sued in Rheumatoid, Osteoarthritis and Gout), Psychiatric Drugs (Depression, Bipolar Disorders, Psychoses, Attention Deficit Disorder, Anxiety, Insomnia, Narcolepsy, Alcohol Deterrents); Gastrointestinal Drugs (Diarrhea, Pancreatic Enzymes, Emesis, Ulcers, Reflux (GERD), Spasm, Inflammatory Bowel Disease, Other Miscellaneous Gastrointestinal Drugs), Oral anti-diabetics, Oral Contraceptives, Menopausal drugs, Drugs against Osteoporosis and Vaginal Infections, Hormonal drugs (Adrenal Corticosteroids, Antithyroid and Thyroid Replacement, Androgens, Growth Hormones, Gonadotropin Inhibitors), Respiratory Drugs (COPD, Asthma, Antitussives and Expectorants, Antihistamines), Drugs against Urologic Disorders (Benign Prostatic Hypertrophy, Urinary Incontinence), Supplements, Other Miscellaneous Drugs.
Still another embodiment of the present invention provides a process in which the excipients are inert materials belonging to different categories like Starches (corn starch, maize starch, potato starch, etc.); Sugars (glucose, lactose, mannitol, etc.); Stearates (including stearic acid, metallic stearates, etc.); Silicones (including silicon oil, silicon dioxide, etc.); Inorganic salts (calcium carbonate, magnesium oxide, etc.); Celluloses (microcrystalline cellulose, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, etc.); Glycols (Polyethylene glycols, etc.); Glycol esters; Glycerides; Talc; Bentonite; Silica gels; Polymers; Aromatic hydrocarbons; Chlorinated hydrocarbons; High molecular weight alcohols, esters, and organic acids; Vegetable oils (soyabean oils); Mineral oils; Fish oils; Nonionic surface active agents (polysorbate 80); Waxes etc.

Still another embodiment of the present invention provides a process in which the weight percentage of amino acid or its salts is in the range of 0.01 to 25.0.
Still in yet another embodiment of the present invention provides a process in which amino acid used is selected from the group consisting of glycine, tryptophan, lysine, leucine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, cysteine, phenylalaninc, tyrosine, histidine, acetylcysteine, valine, alanine, isoleucine, ormthine, p-aminoben/oic acid and nicotinic acid, or its salt thereof
Yet another embodiment of the present invention provides in a process of the use of using the amino acid, glycine.
Yet another embodiment of the present invention provides a process in which the weight percentage of monomeric carboxylic acid or its salt is in the range of 0.1 to 10.0.
Still in another embodiment of the present invention the carboxylic acid used is a C4-C20 carboxylic acid with two or three -COOH groups or its salt thereof.
Yet another embodiment of the present invention provides a process in which the carboxylic acid used is selected from the group consisting of benzoic acid, fumaric acid, maleic acid, citric acid, ascorbic acid, edetic acid, lactic acid, sorbic acid, tartaric acid, adipic acid, succinic acid and gluconic acid, or its salt thereof.
Another embodiment of the present invention provides a process in which the carboxylic acid used is citric acid.
Yet another embodiment of the present invention provides a process in which the preservative used is selected from a group consisting of propyl paraben, methyl paraben, benzoic acid , benzyl acid, benzalkonium chloride, cetrimide, chlorobutanol, butyl paraben or mixtures thereof or mixtures thereof.
Still in another embodiment of the present invention the improved gelatin preparation obtained has a dissolution period within 30% of the initial dissolution of the film after exposure to environmental conditions of temperature, humidity and/or light, and to intentional or circumstantial exposure to chemical catalysts at various concentrations.
Yet another embodiment of the present invention provides a process for obtaining improved gelatin which has resistance to environmental conditions may be natural environment at any time of the year at any place or accelerated conditions of temperature (above ambient to 45°C), and/or humidity (60%-95%RH) and/or light (>1.2 million lux

hour exposure of fluorescent light and a minimum 200W h/m2 UVA light), created with artificial devices and the light is created using xenon, metal halide or a combination of white fluorescent and black UV lamps.
Yet another embodiment of the present invention provides a process for obtaining gelatin which has resistance to chemical catalysts, a carbonyl compound, selected from ketones, aldehydes, furfural, acrolein, formaldehyde, glutaraldehyde, glyceryl aldehyde; imines, Saccharides selected from glucose and aldose; sugars; dyes (FD&C red No. 3 or 40 and blue No. 1); calcium carbonate, hydrogen peroxide, aliphatic and aromatic sulfonic acids; carbodiimides selected from 1-ethylene 3-(3-dimethylamino propyl); carbodiimide hydrochloride, guanidine hydrochloride; benzene, terephthaloyl chloride and/or derivatives thereof generated in the hard gel or soft gel capsule, either in situ in the capsule fill or used externally in the form of solution or vapors, and are present in the environment surrounding the film and preparations made thereof.
Still yet another embodiment of the present invention provides a process in which the use of an amino acid or its salt, a monomeric carboxylic acid or its salt provides an effective cross-linking reducing combination.
In an embodiment of the present invention, the seal coat refers to a step in the process of sugar-coating of tablets where a gelatin solution is applied as a seal coat on the tablet before sugar coating.
In an embodiment of the present invention the term "Pellicle formation" refers to delayed dissolution.
In yet another embodiment of the present invention cross linking refers to cross linking between the polypeptide chains of the gelatin employed as the backbone material for making films.
In still another embodiment of the present invention, the chemical catalysts, which promote pellicle formation in the gelatin, include any material that promotes crosslinking between the polypeptide chains of the gelatin film or slows dissolution by any other mechanism.
Still another embodiment of the present invention provides the use of an effective stabilizer against pellicle formation that is intended to mean an amount which is effective to achieve the specified dissolution requirements even when the gelatin preparations are

subjected to normal/accelerated environmental conditions or exposed to chemical catalysts, either externally or when they are formed in situ within the formulation.
Any preparation made out of gelatin as a key or functional component is expected to remain suitable for use if stabilized by the present method. The present method is also suitable for stabilizing formulations, for example, sugar-coated tablets, soft and hard gelatin capsules, containing pharmaceutically_active ingredient(s), acceptable excipients and their combinations.
Yet another embodiment of the present invention provides preferably the stabilizer composition is made of about 0.01 to about 25 percent by weight of the amino acid and about 0.01 to about 10 percent by weight of the carboxylic acid, most preferably from 0.1 to 2.5 percent by weight of the amino acid and from 0.1 to 0.9 percent by weight of the carboxylic acid, the percentage by weight with respect to the total amount of gelatin used in making film or the preparations made thereof, including ribbons, sheets, sugar-coated tablets and soft and hard gelatin capsules or any other type of preparation.
Still yet another embodiment of the present invention, provides the use of water-soluble monomeric carboxylic acid or its salts.
Yet another embodiment of the present invention provides useful salts, which include those containing any pharmaceutically acceptable cation, especially alkali metal, alkaline earth metal and ammonium salts.
Another embodiment of the present invention provides a composition and its preparation wherein the stabilizers are included in the film instead of the fill.
One more embodiment of the present invention provides a synergistic composition of an improved gelatin having resistance to pellicle formation, with an improved dissolution, the said composition comprising:
INGREDIENTS wt.%
Basic gelatin 0.01 to 60.0
Amino acid or its salt 0.01 to 25.0
Monomeric carboxylic acid or its salts 0.10 to 10.0
Preservative - Propyl paraben 0.01 to 2.00
Preservative - Methyl paraben 0.01 to 2.00
Water 0.01 to 98.67

In an embodiment, the preservatives used are selected from parabens. Other than parabens, the other water-soluble preservatives are benzoic acid, benzyl alcohol, benzalkonium chloride, cetrimide, chlorobutanol, butyl paraben, etc. may be used as preservatives.
Still another emobidment embodiment of the present invention provides a composition wherein the basic gelatin is selected from either type A, B or any other type, has 90 to 99% purity by its weight, bloom strength is between 1 to 300 grams, viscosity between 1 to 100 cps and molecular weight lies between 500 to 30,000.
Yet another embodiment of the present invention provides a composition, having weight percentage of basic gelatin material in the range of 1.0 to 60.
Still another embodiment of the present invention provides a solution of basic gelatin in water having a pH in the range of 3 to 10.
In yet still another embodiment of the present invention the material that promotes pellicle formation in gelatin is a pharmaceutical active ingredient or a pharmaceutical excipient or combination thereof.
In yet embodiment of the invention, the pharmaceutical active ingredient is a pharmaceutically effective amount of a drug or combination of drugs belonging to any therapeutic class, selected from a group consisting of Antimicrobials, Anti-Infectives, Antivirals, Antimalarials, Antiprotozoals, Antifungals, Anti-infectives, Antituberculars, Antineoplasties and Immunosuppressants, Neurological Drugs, Cardiovascular Agents, Pain and anti-Inflammatory agents, Psychiatric Drugs, Gastrointestinal Drugs, Oral anti-diabetics, Oral Contraceptives, Menopausal drugs, Drugs against Osteoporosis and Vaginal Infections, Hormonal drugs, Respiratory Drugs, Drugs against Urologic Disorders, Supplements, and Other Miscellaneous Drugs.
Yet another embodiment, the antimicrobials and anti-infectives drug used is selected from a group consisting of like Beta-lactam Antibiotics, Macrolides and Clindamycin, Tetracyclines, Quinolones and Sulfonamides.
Yet another embodiment, the cardiovascular agent used is selected from a group consisting of Anti-arrhythmics, Cardiac Glycosides, Diuretics, Potassium Replacement, Beta Blockers, Calcium Channel Blockers, ACE Inhibitors, Angiotensin II Receptor

Blockers, Centrally Acting Agents, Alpha-I Blockers, Antihypertensives, Vasodilators, Anti-Anginals and Antilipidemics,
Yet another embodiment, the pain and anti-Inflammatory drug used is selected from a group consisting of NSAID Analgesics, Opioids, and the drugs used in Rheumatoid, Osteoarthritis and Gout.
Yet another embodiment, the psychiatric drug used is selected from a group consisting of such as Depression, Bipolar Disorders, Psychoses, Attention Deficit Disorder, Anxiety, Insomnia, Narcolepsy, Alcohol Deterrents;
Yet another embodiment, the gastrointestinal drug used is selected from a group consisting of anti-diarrheal drug, Pancreatic Enzymes, Emesis, Ulcers, Reflux (GERD), Spasm, Inflammatory Bowel Disease and other Miscellaneous Gastrointestinal Drugs,
Yet another embodiment, the hormonal drugs used is selected from a group consisting of Adrenal Corticosteroids, Antithyroid and Thyroid Replacement, Androgens, Growth Hormones, Gonadotropin Inhibitors,
Yet another embodiment, the respiratory drugs used is selected from a group consisting of COPD, Asthma, Antitussives and Expectorants, Antihistamines,
Yet another embodiment, the drugs against urologic disorders used is selected from a group consisting of Benign Prostatic Hypertrophy, Urinary Incontinence, Supplements, Other Miscellaneous Drugs.
In yet another embodiment of the present invention, the pharmaceutically active ingredient is a Pharmaceutically effective amount of a drug or combination of drugs belonging to different therapeutic categories, like Antimicrobials and Anti-Infectives (like Beta-lactam Antibiotics, Macrolides and Clindamycin, Tetracyclines, Quinolones, Sulfonamides, Antivirals, Antimalarials and Antiprotozoals, Antifungals, Anti-infectives, Antituberculars, Miscellaneous), Antineoplasties and Immunosuppressants, Neurological Drugs, Cardiovascular Agents (Anti-arrhythmics and Cardiac Glycosides, Diuretics, Potassium Replacement, Beta Blockers, Calcium Channel Blockers, ACE Inhibitors, Angiotensin II Receptor Blockers, Centrally Acting Agents, Alpha-I Blockers, Antihypertensives, Vasodilators, Anti-Anginals, Antilipidemics), Pain and Inflammatory Diseases (NSAID Analgesics, Opioids, Drugs sued in Rheumatoid, Osteoarthritis and Gout), Psychiatric Drugs (Depression, Bipolar Disorders, Psychoses, Attention Deficit

Disorder, Anxiety, Insomnia, Narcolepsy, Alcohol Deterrents); Gastrointestinal Drugs (Diarrhea, Pancreatic Enzymes, Emesis, Ulcers, Reflux (GERD), Spasm, Inflammatory Bowel Disease, Other Miscellaneous Gastrointestinal Drugs), Oral anti-diabetics, Oral Contraceptives, Menopausal drugs, Drugs against Osteoporosis and Vaginal Infections, Hormonal drugs (Adrenal Corticosteroids, Antithyroid and Thyroid Replacement, Androgens, Growth Hormones, Gonadotropin Inhibitors), Respiratory Drugs (COPD, Asthma, Antitussives and Expectorants, Antihistamines), Drugs against Urologic Disorders (Benign Prostatic Hypertrophy, Urinary Incontinence), Supplements, Other Miscellaneous Drugs.
In yet another embodiment of the present invention, excipients are inert materials belonging to different categories like Starches (corn starch, maize starch, potato starch, etc.); Sugars (glucose, lactose, mannitol, etc.); Stearates (including stearic acid, metallic stearates, etc.); Silicones (including silicon oil, silicon dioxide, etc.); Inorganic salts (calcium carbonate, magnesium oxide, etc.); Celluloses (microcrystalline cellulose, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, etc.); Glycols (Polyethylene glycols, etc.); Glycol esters; Glycerides; Talc; Bentonite; Silica gels; Polymers; Aromatic hydrocarbons; Chlorinated hydrocarbons; High molecular weight alcohols, esters, and organic acids; Vegetable oils (soyabean oils); Mineral oils; Fish oils; Nonionic surface active agents (polysorbate 80); Waxes etc.
In yet another embodiment of the present invention, the weight percentage of amino acid or its salts is in the range of 0.01 to 25.0.
Still in yet another embodiment of the present invention, the amino acid is selected from the group consisting of glycine, tryptophan, lysine, leucine, threonine, aspartic acid, glutamic acid, Asparagine, glutamine, lysine, arginine, cysteine, phenylalanine, tyrosine, histidine, acetylcysteine, valine, alanine, isoleucine, ornithine, p-aminobenzoic acid and nicotinic acid, or its salt thereof
Yet in another embodiment of the present invention, the amino acid used is glycine.
Still another embodiment of the present invention provides the weight percentage of monomeric carboxylic acid or its salt in the range of 0.1 to 10.0.
In still another embodiment of the present invention, the carboxylic acid used is C4-C20 carboxylic acid with two or three -COOH groups or its salt.

Another embodiment of the present invention provides a carboxylic acid selected from the group consisting of benzoic acid, fumaric acid, maleic acid, citric acid, ascorbic acid, edetic acid, lactic acid, sorbic acid, tartaric acid, adipic acid, succinic acid and gluconic acid, or its salt.
Yet another embodiment of the present invention provides that the carboxylic acid used is citric acid.
Still yet in another embodiment of the present invention the improved gelatin film obtained has a dissolution period within 30% of the initial dissolution of the film after exposure to environmental conditions of temperature, humidity and/or light, and to intentional or circumstantial exposure to chemical catalysts at various concentrations.
In still another embodiment of the present invention, the environmental conditions may be natural environment at any time of the year at any place or accelerated conditions of temperature (above ambient to 45°C) and/or, humidity (60%-95%RH) and light (>1.2 million lux hour exposure of fluorescent light and a minimum 200W h/m2 UVA light), created with artificial devices using xenon, metal halide or a combination of white fluorescent and black UV lamps.
Another embodiment of the present invention provides a chemical catalysts as a carbonyl compound, selected from ketones, aldehydes, furfural, acrolein, formaldehyde, glutaraldehyde, glyceryl aldehyde; imines, saccharides selected from glucose and aldose; sugars; dyes (FD&C red No. 3 or 40 and blue No. 1); calcium carbonate, hydrogen peroxide, aliphatic and aromatic sulfonic acids; carbodiimides selected from 1-ethylene 3-(3-dimethylamino propyl); carbodiimide hydrochloride, guanidine hydrochloride; benzene, terephthaloyl chloride and/or derivatives thereof generated in the hard gel or soft gel capsule, either in situ in the capsule fill or used externally in the form of solution or vapors, and are present in the environment surrounding the film and preparations made thereof.
Another embodiment of the present invention provides at least one amino acid or its salt, and atleast a monomeric carboxylic acid or its salt that forms a cross-linking reducing combination.
Still in yet another embodiment of the present invention, the improved gelatin obtained is used as a film, ribbon, sugar coated tablets, hard gelatin capsules, soft gelatin capsules or any other gelatin based preparation.

The following examples illustrate, but do not limit, the present invention. All percentages are by weight unless otherwise indicated.
EXAMPLES Example 1 Process for the preparation of gelatin film.
All the materials were weighed according to the formulae in Table 1 and transferred to 1000 ml round bottom flask, which was connected to a rotary film evaporator, with its bath filled with ice. The flask was stirred at a low speed under mild vacuum for 1 h. Chilling facilitated the swelling of gelatin mass and removal of the air bubbles. Subsequently, the ice was removed and the bath was filled with fresh water. The temperature was increased to 75°C and maintained under vacuum for 4 h under constant stirring to facilitate appropriate mixing of the ingredients. The mass thus prepared was transferred to a beaker and kept in a constant water bath at 60°C for 4 h to allow maturation and transfer of entrapped air to the surface. The film casting was done using laboratory coating device on a glass plate. After casting the plate was kept in the refrigerator for 12 h to allow hardening of the film. The hardened film was removed from the plate with the help of a spatula and stored under ambient conditions.
TableRemove: Composition a of gelatin film

The films prepared according to Example 1 were exposed to formaldehyde vapors in the range of 39p,g to 190u,g in squat bottles for 12 hours. The films were cut into rings of size of 11 rnm i.d. x 14mm o.d. and the dissolution time of the rings was determined in water and also in simulated gastric fluid, described in USP (USP 24/NF 19, United States

Pharmacopeia! Convention, Rockville, MD, 1999, p. 2696, Venugopal and Singh. Pharm. Technol, Drug Delivery Supplement, 32-37, 2001). The dissolution studies were done in triplicate.
The films prepared in Example 1 were stored in a photostability chamber controlled at 40°C and 75% relative humidity for 8 days (S. Singh, R. Manikandan, and S. Singh. Pharm. Technol., 24 (5), 58-72, 2000). The films were cut into rings of size of 11 mm i.d. x 14mm o.d and the dissolution time of the rings was determined in water and also in simulated gastric fluid, described in USP (USP 24/NF 19, United States Pharmacopeial Convention, Rockville, MD, 1999, p. 2696). The dissolution studies were done in triplicate.
Table 2 shows mean dissolution time of gelatin rings before exposure and after exposure to accelerated environmental conditions in a photostability chamber and also to different concentrations of formaldehyde.
TableRemove: Mean dissolution time (minutes) of gelatin rings before addition of either glycine or citric acid

Example 2
Process for preparation of gelatin film stabilized with glycine and citric acid.
All the materials were weighed according to the formulae in Table 3 and transferred to 1000 ml round bottom flask, which was connected to a rotary film evaporator, with i:.s bath filled with ice. The flask was stirred at a low speed under mild vacuum for 1 h. Chilling facilitated the swelling of gelatin mass and removal of the air bubbles. Subsequently, the ice was removed and the bath was filled with fresh water. The

temperature was increased to 75°C and maintained under vacuum for 4 h under constant stirring to facilitate appropriate mixing of the ingredients. The mass thus prepared was transferred to a beaker and kept in a constant water bath at 60°C for 4 h to allow maturation and transfer of entrapped air to the surface. The film casting was finally done using laboratory coating device on a glass plate. After casting, the plate was kept in the refrigerator for 12 h to allow hardening of the film. The hardened film was removed from the plate with the help of a spatula and stored under ambient conditions.
Table 3: Formulae for preparation of gelatin films (Ingredients are expressed in terms of weight percentage)

(Table Rewmove)The films prepared according to Example 2 were exposed to formaldehyde vapors in the range of 39u,g to 190u,g in squat bottles for 12 hours. The films were cut into rings of size of 11 mm i.d. x 14mm o.d. and the dissolution time of the rings was determined in water and also in simulated gastric fluid, described in USP (USP 24/NF 19, United States Pharmacopeial Convention, Rockville, MD, 1999, p. 2696). The dissolution studies were done in triplicate.
The films prepared in Example 2 were stored in a photostability chamber controlled at 40°C and 75% relative humidity for 8 days (S. Singh, R. Manikandan, and S. Singh, Pharm. Technol., 24 (5), 58-72, 2000). The films were cut into rings of size of 11 mm i.d. x 14mm o.d. and the dissolution time of the rings was determined in water and also in simulated gastric fluid, described in USP (USP 24/NF 19, United States Pharmacopeial Convention, Rockville, MD, 1999, p. 2696). The dissolution studies were done in triplicate.

Table 4 shows mean dissolution time of gelatin rings before exposure and after exposure to accelerated environmental conditions in a photostability chamber and also to different concentrations of formaldehyde. Table 4: Effect of glycine and citric acid on dissolution time (minutes) of gelatin rings

(Table Remove)
(Table Remove)Gelatin films without glycine/citric acid (Table 2) show an increased mean dissolution time as compared to films containing the stabilizers (Table 4). Moreover, the mean dissolution times after exposure are within 30% of initial (without exposure) both in case of stability chamber and formaldehyde exposure at 78 ju,g (Table 4) for Formula E and much lower than the normal acceptable dissolution time of 45 min or even 20 min for some drug preparations.
ADVANTAGES OF THE PRESENT INVENTION
i. In the present invention an approach is provided for the stabilization of all kinds of preparations or formulations made out of gelatin film or mass. It is expected to be useful to prevent pellicle formation in gelatin films, sheets, ribbons, sugar-coated tablets and soft as well as hard gelatin capsules.
ii. In the present invention the stabilizer added into the gelatin layer provides the intervention to pellicle formation or cross linking in a more efficient manner.
iii. In the present invention much lesser quantities of the stabilizer are needed.
iv. In the present invention there is no requirement of differential amounts of stabilizer concentrations, which is the case when the stabilizer is added to the capsule fill. Incorporation of a specific amount of stabilizer in the gelatin layer, as shown above in the examples, takes care of all possible catalytic challenges, whether due to in-situ generated catalyst(s) or an external exposure to chemical catalysts.
v. In the present invention the addition of stabilizers in the gelatin film neutralizes very effectively the pellicle formation and cross linking caused by exposure to accelerated conditions of temperature and/or humidity and/or light. The addition of stabilizers in the fill is not expected to give the same stabilizing effect because

influence of environmental factors is an external surface phenomenon, and the same can be better tackled if the stabilizer combination is present in the film itself. vi. In the present invention, the chances of interaction of stabilizers with fill of the Formulations is minimized due to very low concentration of stabilizers and also the same would not happen unless there is leaching of stabilizers from the gelatin film, which is unlikely especially in solid dosage forms

I / We Claims
1. A process for the preparation of an improved synergistic composition gelatin
preparation namely casted gelatin preparation containing synergistic composition of
gelatin having resistance to pellicle formation and improved dissolution, the said
process comprising steps of:
a. mixing a basic gelatin, an amino acid or its salt, a monomeric carboxylic acid
or its salt, at least a preservatiye_jind water at a temperature ranging between
1°C and 8°C in an ice bath;
b. stirring the mixture of step (a) with a low speed for a time period of 0.5 hour to
4 hour,
c. raising the temperature of the mixture of step (b) to a temperature range of 60°C
to 80°C by replacing the ice bath by hot water maintaining the temperature for
a period of Ihour to 8 hour,
d. transferring the mixture of step (c), to an another container for maturation by
maintaining the temperature in the range of 40°C to 80°C for a period of 2h to
8h to obtain an improved gelatin, and
e. casting the improved gelatin of step (d) by cooling to a temperature range of
2°C to 10°C for a period of Shows to IShours to obtain the required casted
gelatin preparation.
2. A process of claim 1, wherein in step (a), basic gelatin used is selected from either
type A, B or any other type having 90 to 99% purity by its weight, bloom strength
between 1 to 300 grams, viscosity between 1 to 100 cps and molecular weight
ranging between 500 to 30,000.
3. A process of claim 1, wherein in step (a) the weight percentage of gelatin used, is in
the range of 1.0 to 60.0.
4. A process of claim 1, wherein in step (a) the preservative used is selected from a
group consisting of propyl paraben, methyl paraben, benzoic acid, benzyl alcohol,
benzalkonium chloride, cetrimide, chlorobutanol, butyl paraben or mixtures thereof.
5. A process of claim 1, wherein the aqueous solution of basic gelatin has a pH in the
range of 3 to 10.

6. A process of claim 1 provides an improved gelatin resistant to material that
promotes pellicle formation in gelatin.
7. A process of claim 6, wherein the material which promotes the pellicle formation is
a pharmaceutical active ingredient or a pharmaceutical acceptable excipient or
combination thereof.
8. A process of claim 7, wherein the pharmaceutical active ingredient is a
pharmaceutically effective amount of a drug or combination of drugs belonging to
any therapeutic class, selected from a group consisting of Antimicrobials, Anti-
Infectives, Antivirals, Antimalarials, Antiprotozoals, Antifungals, Anti-infectives.
Antituberculars, Antineoplastics and Immunosuppressants, Neurological Drugs.
Cardiovascular Agents, Pain and anti-Inflammatory agents, Psychiatric Drugs,
Gastrointestinal Drugs, Oral anti-diabetics, Oral Contraceptives, Menopausal drugs.
Drugs against Osteoporosis and Vaginal Infections, Hormonal drugs, Respirator)
Drugs, Drugs against Urologic Disorders, Supplements, and Other Miscellaneous
Drugs.
9. A process of claim 8, wherein antimicrobials and anti-infectives drug used is
selected from a group consisting of like Beta-lactam Antibiotics, Macrolides and
Clindamycin, Tetracyclines, Quinolones and Sulfonamides,
10. A process of claim 8, wherein the cardiovascular agent used is selected from a
group consisting of Anti-arrhythmics, Cardiac Glycosides, Diuretics, Potassium
Replacement, Beta Blockers, Calcium Channel Blockers, ACE Inhibitors,
Angiotensin II Receptor Blockers, Centrally Acting Agents, Alpha-I Blockers.
Antihypertensives, Vasodilators, Anti-Anginals and Antilipidemics,
11. A process of claim 8, wherein the pain and anti-Inflammatory drug used is selected
from a group consisting of NSAID Analgesics, Opioids, and the drugs used in
Rheumatoid, Osteoarthritis and Gout.
12. A process of claim 8, wherein the psychiatric drug used is selected from a group
consisting of such as Depression, Bipolar Disorders, Psychoses, Attention Deficit
Disorder, Anxiety, Insomnia, Narcolepsy, Alcohol Deterrents;
13. A process of claim 8, wherein the gastrointestinal drug used is selected from a
group consisting ofDiarrhea, Pancreatic Enzymes, Emesis, Ulcers, Reflux (GERD).

Spasm, Inflammatory Bowel Disease and other Miscellaneous Gastrointestinal Drugs,
14. A process of claim 8, wherein the hormonal drugs used is selected from a group
consisting of Adrenal Corticosteroids, Antithyroid and Thyroid Replacement,
Androgens, Growth Hormones, Gonadotropin Inhibitors,
15. A process of claim 8, wherein the. respiratory drugs used is selected from a group
consisting of COPD, Asthma, Antitussives and Expectorants, Antihistamines,
16. A process of claim 8, wherein the drugs against urologic disorders used is selected
from a group consisting of Benign Prostatic Hypertrophy, Urinary Incontinence,
Supplements, Other Miscellaneous Drugs.
17. A process of claim 7, wherein the excipients used are inert materials selecetd from
a group consisting of Starches (corn starch, maize starch, potato starch, etc.);
Sugars (glucose, lactose, mannitol, etc.); Stearates (including stearic acid, metallic
stearates, etc.), Silicones (including silicon oil, silicon dioxide, etc.); Inorganic salts
(calcium carbonate, magnesium oxide, etc.); Celluloses (microcrystalline cellulose,
hydroxyl propyl cellulose, hydroxy propyl methyl cellulose, etc.); Glycols
(Polyethylene glycols, etc.); Glycol esters; Glycerides; Talc; Bentonite; Silica gels;
Polymers; Aromatic hydrocarbons, chlorinated hydrocarbons; High molecular
weight alcohols, esters and, organic acids; Vegetable oils (soyabean oils); Minerals
oils, Fish oils; Nonionic surface active agents (polysorbate 80); and waxes.
18. A process of claim 1, wherein in step (a) the weight percentage of amino acid or its
salts is in the range of 0.01 to 25.0.
19. A process of claim 18, wherein the amino acid used is selected from the group
consisting of glycine, tryptophan, lysine, leucine, threonine, aspartic acid, glutamic
acid, asparagine glutamine, lysine, arginine, cysteine, phenylalanine, tyrosine,
histidine, acetylcysteine, valine, alanine, isoleucine, ornithine, p-aminobenzoic acid
and nicotinic acid, or its salt thereof.
20. A process of claim 1, wherein the amino acid used is glycine.
21. A process of claim 1, wherein in step (a) the weight percentage of monomeric
carboxylic acid or its salt is in the range of 0.1 to 10.0.

22. A process of claim I, wherein the carboxylic acid is a €4-020 aliphatic or aromatic
carboxylic acid with one to three -COOH groups or its salt thereof.
23. A process of claim 22, wherein the carboxylic acid is selected from the group
consisting of benzoic acid, furnaric acid, maleic acid, citric acid, ascorbic acid,
edetic acid, lactic acid, sorbic acid, tartaric acid, adipic acid, succinic acid and
gluconic acid or its salt thereof.
24. A process of claim 1, wherein the carboxylic acid used is citric acid.
25. A process of claim 1, wherein the improved gelatin preparation obtained has a
dissolution period within 30% of the initial dissolution of the film after exposure to
environmental conditions of temperature, humidity and/or light, and to intentional
or circumstantial exposure to chemical catalysts at various concentrations.
26. A process of claim 25, wherein the environmental conditions may be natural
environment at any time of the year at any place or accelerated conditions of
temperature (above ambient to 45°C), humidity (60%-95%RH) and light (>1.2
million lux hour exposure of fluorescent light and a minimum 200W h/m2 UYA
light), created with artificial devices created using xenon, metal halide or a
combination of white fluorescent and black UV lamps.
27. A process of claim 25, wherein the chemical catalysts is a carbonyl compound,
selected from ketones, aldehydes, furfural, acrolein, formaldehyde, glutaraldehyde,
glyceryl aldehyde; imines, Saccharides selected from glucose and aldose; sugars;
dyes (FD&C red No. 3 or 40 and blue No. 1); calcium carbonate, hydrogen
peroxide, aliphatic and aromatic Sulfonic acids; carbodiimides selected from 1-
ethylene 3-(3-dimethylamino propyl); Carbodiimide hydrochloride, guanidine
hydrochloride; benzene, terephthaloyl chloride and/or derivatives thereof generated
in the hard gel or soft gel capsule, either in situ in the capsule fill or used externally
in the form of solution or vapors, and are present in the environment surrounding
the film and preparations made thereof.
28. A process of claim 1, wherein an amino acid or its salt, and a monomeric
carboxylic acid or its salt used provides an effective cross-linking reducing
combination.

29. A process as claimed in claim 1, wherein the improved gelatin obtained provides its
use as a film, ribbon, sugar coated tablets, hard gelatin capsules, soft gelatin
capsules or any other gelatin based preparation.
30. A process for the preparation of synergistic composition substantially as herein
described with reference to the given examples in the specification.

Documents:

1111-DEL-2002-Abstract-(03-03-2008).pdf

1111-del-2002-abstract.pdf

1111-DEL-2002-Claims-(03-03-2008).pdf

1111-del-2002-claims.pdf

1111-del-2002-correspondence-others.pdf

1111-DEL-2002-Description (Complete)-(03-03-2008).pdf

1111-del-2002-description (complete).pdf

1111-del-2002-form-1.pdf

1111-del-2002-form-18.pdf

1111-DEL-2002-Form-2-(03-03-2008).pdf

1111-del-2002-form-2.pdf

1111-del-2002-form-3.pdf

1111-del-2002-form-5.pdf

1111-del-2002-gpa.pdf

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Patent Number

215811

Indian Patent Application Number

1111/DEL/2002

PG Journal Number

12/2008

Publication Date

21-Mar-2008

Grant Date

03-Mar-2008

Date of Filing

06-Nov-2002

Name of Patentee

NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER)

Applicant Address

SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SARANJIT SINGH	NIPER, SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
2	VENKATA RAMA RAO KAMALA	NIPER, SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.

PCT International Classification Number

B22C 001/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA