Claims for Patent: 4,079,125

Summary for Patent: 4,079,125

Title:	Preparation of enteric coated digestive enzyme compositions
Abstract:	Improved enteric coated digestive enzyme-containing compositions which are capable of withstanding hours of exposure to gastric fluids while protecting the biological activity of the enzymes and thereafter releasing the digestive enzymes in their biologically active state within 5 to 30 minutes after being exposed to intestinal fluids, these compositions comprising (a) an enzyme concentrate in (b) a binder system comprising at least about 0.5 wt. %, preferably about 1 to about 10 wt. % (based on the weight of the binder system plus enzymes) of (i) a binder, preferably selected from the group consisting of polyvinylpyrrolidone, microcrystalline cellulose (Avicel), cellulose acetate phthalate, methylcellulose and alginic acid, and preferably (ii) from about 0.1 to about 10 wt. % of a stabilizer, preferably selected from the group consisting of calcium carbonate, polyvinylpyrrolidone, cellulose acetate phthalate, methylcellulose, alginic acid, starch and modified starches, e.g., carboxymethyl starch (Primojel); and (c) from about 0.1% to about 30 wt. %, based on the weight of the total composite (enzyme plus binder system plus disintegrant) of a disintegrant, preferably selected from the group consisting of citric acid, sodium carbonate, sodium bicarbonate, calcium carbonate and other suitable carbonates, alginic acid, starch and modified starches, e.g., carboxymethyl starch (Primojel) are prepared by a process in which the presence of water is avoided and which includes the step of blending enzyme, binder and disintegrant in the presence of a selected inert solvent as well as the subsequent coating of the resulting enzyme/binder/disintegrant composite with from about 2.5% to about 10% by weight, based on the weight of the enzyme/binder/disintegrant composite, of a gastric juice insoluble, intestinal juice soluble, non-porous, pharmaceutically acceptable enteric coating polymer.
Inventor(s):	Sipos; Tibor (Lebanon, NJ)
Assignee:	Johnson & Johnson (New Brunswick, NJ)
Application Number:	05/744,902
Patent Claims:	1. In a process for preparing a digestive enzyme composition for treating enzyme deficient mammals, said composition comprising (a) a concentrate of an enzyme from the group consisting of the pancreatic proteases, lipases, nucleases and amylase, the plant-derived digestive enzymes and the digestive enzymes derived from microbial sources in (b) a binder system comprising (i) at least about 0.5 wt. % (based on the weight of the binder system plus enzymes) of a binder selected from the group consisting of polyvinylpyrrolidone, microcrystalline cellulose, cellulose acetate phthalate, methylcellulose and alginic acid, and (ii) from zero to about 10 wt. % (based on the weight of the binder system plus enzymes) of a stabilizer selected from the group consisting of calcium carbonate, polyvinylpyrrolidone, cellulose acetate phthalate, methylcellulose, starch and modified starches and alginic acid; and (c) from about 0.1% to about 30 wt. %, based on the weight of the total composite (enzyme plus binder system plus disintegrant), of a disintegrant selected from the group consisting of citric acid, sodium carbonate, sodium bicarbonate, calcium carbonate, starch and modified starches, microcrystalline cellulose, and alginic acid; said process including the steps of blending said enzyme with said binder system and said disintegrant to form a composite and thereafter coating said enzyme/binder system/disintegrant composite with a non-porous, pharmaceutically acceptable enteric coating which is insoluble in the pH range of from about 1.5 to about 5 but is soluble in the pH range of from about 6 to about 9, the improvement consisting of carrying out said process while avoiding the presence of water and said blending step being performed in the presence of a single liquid phase comprising an inert organic enzyme-compatible solvent. 2. The process of claim 1 wherein said enzyme is selected from the group consisting of Trypsin, Chymotrypsin, Chymotrypsin B, Pancreatopeptidase, Carboxypeptidase A, Carboxypeptidase B, Glycerol ester hydrolase, Phospholipase A.sub.2, Sterol ester hydrolase, Ribonuclease, Deoxyribonuclease, .alpha.-Amylase, Papain, Chymopapain, Bromelain, Ficin, .beta.-Amylase, Cellulase, .beta.-Galactosidase, Subtilopeptidase A, and Aspergillopeptidase A. 3. The process of claim 1 wherein said enzyme concentrate comprises an enzyme mixture, each milligram of which contains at least about 75 N.F. units of protease activity, at least about 75 N.F. units of amylase activity, at least about 10 N.F. units of lipase activity, and an effective amount of co-lipase. 4. The process of claim 3 wherein said enzyme mixture further contains at least about 5 International Units of ribonuclease activity per milligram. 5. The process of claim 1 wherein said stabilizer is present in an amount of from about 0.1% to about 10% by weight. 6. The process of claim 1 wherein said binder is present in an amount of from about 1% to about 5% by weight. 7. The process of claim 1 wherein said disintegrant is present in an amount of from about 2% to about 15% by weight. 8. The process of claim 1 wherein said binder is methyl cellulose. 9. The process of claim 1 wherein said binder is polyvinylpyrrolidone, which also acts as said stabilizer. 10. The process of claim 1 wherein said enteric coating is present in an amount of from about 2.5% to about 10% by weight of the entire composition. 11. The process of claim 1 wherein said enteric coating comprises cellulose acetate phthalate and diethyl phthalate. 12. The process of claim 1 wherein said binder and said disintegrant are first dissolved in said solvent and the resulting solution is then slowly added to said enzyme mixture. 13. The process of claim 1 wherein said solvent is isopropanol. 14. The process of claim 1, which includes the steps of granulating the resulting blend, extruding it into segments, screening the segments and subsequently tableting the resulting granules at a sufficiently low compression pressure that the temperature during compression is maintained in the range of from about 15.degree. to about 30.degree. C. 15. The process of claim 1 wherein said solvent is employed in an amount of from about 600 to about 700 ml. per kg. of blend of enzyme mixture plus binder plus disintegrant. 16. The process of claim 1 wherein said blend is granulated, extruded through a screen with uniform openings having a diameter in the range of between about 0.5 mm and about 2 mm, and thereafter formed into spheres having a size in the range of between about 8 and about 14 mesh by processing said extruded pellets on a Marumerizer for from about 30 seconds to about 75 seconds. 17. The process of claim 16 wherein said Marumerization is performed at a temperature not greater than about 20.degree. C. 18. The process of claim 1 wherein said blend is prepared by combining said disintegrant and said enzyme mixture in a suitable apparatus to form a uniform dry blend; said binder is separately dissolved in said solvent, and the composition is formed into spheres having a diameter in the range of from about 8 to about 14 mesh by dusting said dry blend over nonpareil seeds tumbling and flowing in a coating pan, said seeds having been wetted with said binder solution, with periodic addition of said solvent to maintain the particles in a wetted but free-flowing state, until the seeds have been built to uniform spherical particles having diameters predominantly in said range of from about 8 to about 14 mesh. 19. The process of claim 18 wherein said dusting operation is performed until said diameters of said spheres are predominantly in the range of from about 10 to about 12 mesh. 20. The process of claim 1 which further comprises applying an enteric coating to said tablets or spheres by spraying solutions of progressively lower concentrations of an enteric coating composition onto said tablets or spheres in a coating pan until the desired coating thickness is achieved. 21. The process of claim 20 wherein said enteric coating solution comprises cellulose acetate phthalate and diethyl phthalate in at least one solvent selected from the group consisting of acetone, methyl ethyl ketone, diacetone alcohol, ethylene glycol monoacetate, ethanol, chloroform, methanol, isopropanol, ethyl acetate, methylene chloride and benzene. 22. The process of claim 21 wherein said solvent is a mixture of equal parts by volume of chloroform and methanol, or of isopropanol and ethylacetate. 23. A digestive enzyme composition prepared by the process of claim 1. 24. A digestive enzyme composition prepared by the process of claim 14. 25. A digestive enzyme composition prepared by the process of claim 16. 26. A digestive enzyme composition prepared by the process of claim 18. 27. A method for treating digestive enzyme deficiency in mammals comprising feeding the mammal with each meal an effective amount of the composition of claim 25. 28. The method of claim 27, wherein from about 0.8 to about 1.5 grams of said composition are fed with each meal. 29. The method of claim 28 wherein said composition is in the form of spheres of a size in the range of from about 8 to about 14 mesh. 30. The method of claim 1 wherein said inert organic enzyme-compatible solvent is a member selected from the group consisting of isopropanol, methylene chloride, dioxane, tetrahydrofuran and acetone.

Details for Patent 4,079,125

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Discure Medical, Llc	CHYMODIACTIN	chymopapain	For Injection	018663	November 10, 1982		2040-04-01
Discure Medical, Llc	CHYMODIACTIN	chymopapain	For Injection	018663	August 21, 1984		2040-04-01