Anti-ulcer composition

Abstract: In accordance with the present invention a novel oral composition and method of using same for the treatment of ulcers and other gastrointestinal disorders is disclosed. The composition comprises an agent capable of forming an ulcer-adherent protective complex in an acid environment combined with one or more alkaline materials in a total amount sufficient to substantially prevent the formation of such a complex in the mouth and adherence of such a complex to the buccal mucosa .

Description: The present invention relates to an improved pharmaceutical composition for anti-ulcer agents, and is particularly concerned with such compositions for anti-ulcer agents which form an ulcer-adherent protective complex in acidic environments. In accordance with the present invention a novel oral composition and the use thereof for the manufacture of a medicament for the treatment of ulcers and other gastrointestinal disorders is disclosed. The composition comprises an agent capable of forming an ulcer-adherent protective complex in an acid environment combined with one or more alkaline materials generally in an amount sufficient to substantially prevent the formation of such a complex in the mouth and adherence of such a complex to the buccal mucosa . More specifically the invention provides a pharmaceutical composition in tablet form comprising a therapeutically effective amount of an agent capable of forming an ulcer-adherent protective complex in an acid environment, and one or more alkaline materials, wherein said agent is sucralfate and wherein said one or more alkaline materials are present in an amount sufficient to provide between 0.5 and 10 milliequivalents of acid neutralizing capacity per tablet. The present invention provides an improved composition for ulcer curative/ulcer therapy agents capable of forming an ulcer-adherent protective complex, in particular sucralfate. Sucralfate, an aluminum salt of sucrose sulfate ester, is an excellent duodenal ulcer curative agent. Although sucralfate has negligible acid neutralizing capacity, its anti-ulcer activity is apparently the result of the formation of an ulcer-adherent complex that covers the ulcer site and protects it from further attack by acid, pepsin and bile salts. This complex is a gummy, gel-like bioadhesive which forms in acidic environments, e.g., the stomach, and which binds bile salts and inhibits pepsin activity in gastric juices. The complex actually favors adherence to ulcerated or inflamed mucosa. In a preferred embodiment, the composition of the present invention is in the form of a chewable tablet. The present composition in chewable tablet form is not of a gritty, uncomfortable consistency but rather is of a soft; freely flowing powder when broken up by chewing. This renders the present chewable composition easy to swallow and provides adherence of the preparation to inflammatory sites caused by regurgitational esophagitis, as well as to the duodenal ulcer sites, ulcer sites in the stomach and other ulcer sites. Therefore, the compositions of the present invention, especially the chewable tablet formulation, is useful in the treatment of stomach ulcers, duodenal ulcers, regurgitational esophagitis, hiatal hernia, and symptoms of upset stomach or dyspepsia, e.g., indigestion, "acid stomach", "sour stomach", "full stomach", heartburns and "burning". A potential disadvantage with taking an agent such as sucralfate by mouth is premature formation of the gummy complex in the mouth. Although the mouth is generally pH neutral, this premature gumming and adherence of the complex to the buccal mucosa can take place when the pH of the mouth is slightly acidic and/or when the mouth is ulcerated. This problem is potentially more prevalent in a chewable formulation. Since sucralfate forms the ulcer-adherent complex in an acidic environment, formulating sucralfate with alkaline materials might be expected to deter the formation of this gummy bioadhesive substance at the ulcer sites to be treated. Surprisingly, however, it has been found that combining such an anti-ulcer agent with one or more alkaline materials can provide a composition which will not prematurely "gum" or "gel" in the mouth, but which still provides highly effective anti-ulcer activity. This is so even with the chewable tablet formulation of the present invention. As stated above, the one or more alkaline materials are generally present in an amount sufficient to substantially prevent premature formation of the ulcer-adherent complex. The amount used for sucralfate compositions is between 0.5 and 10 milliequivalents of acid neutralizing capacity. Acid neutralizing capacity as used herein is determined by the "acid neutralizing capacity test" outlined in 21 C.F.R. 331.26. The most preferred amount for the one or more alkaline materials with sucralfate has been found to exist when the range of acid neutralizing capacity is greater than 0.5 and less than 5 milliequivalents. The alkaline materials for use in the present invention can be any convenient pharmaceutically acceptable substances and are preferably selected from magnesium hydroxide, aluminum hydroxide, sodium bicarbonate, magaldrate, calcium carbonate, hydrotalcite, dihydroxy aluminum sodium carbonate, magnesium oxide, magnesium trisilicate and combinations thereof. Most preferred is magnesium hydroxide. In addition to the anti-ulcer agent and alkaline materials, the composition of the present invention may further comprise one or more ingredients from each of the following categories: a) sugars b) sweeteners c) natural and artificial flavors d) flavor enhancers e) diluents f) diluent/sweetness enhancers g) lubricants h) preservatives. For example, in one embodiment the composition of the present invention comprises up to 30 percent by weight each of one or more diluent/sweetness enhancers provided that the total diluent/sweetness enhancers do not exceed 60 percent by weight of the composition; up to 50 percent by weight of one or more sugars; up to 10 percent by weight of one or more artificial or natural flavors; up to 5 percent by weight of one or more sweeteners; up to 5 percent by weight of one or more lubricants; sucralfate and the one or more alkaline materials. The diluent/sweetness enhancers can be of any such material known in the art, e.g., mannitol, sorbitol, xylitol, aspartame, lycasin, glycerin or ammoniated glycyrhizin. Likewise, any of the various sugars, flavors, sweeteners, flavor enhancers, diluents and preservatives known in the art of oral pharmaceutical compositions, especially chewable tablets, may be employed. Similarly any convenient lubricants may be utilized, e.g., magnesium stearate, stearic acid, talc, calcium stearate, sodium stearate, sterotex, sodium stearyl fumarate, stearowet or carbowax. The compositions of the present invention should contain a pharmaceutically effective amount of the complex forming anti-ulcer agent and may typically include 500 mg to 1 g of sucralfate in a tablet form. A preferred chewable tablet formulation in accordance with the present invention comprises sucralfate; an amount of alkaline materials, e.g., magnesium hydroxide, to provide between 0.5 and 5 milliequivalents of acid neutralizing capacity; between 10 and 20 percent by weight of a first diluent/sweetness enhancer such as sorbitol; between 10 and 20 percent by weight of a second diluent/sweetness enhancer such as mannitol; between 20 and 30 percent by weight of sugar; between about 0.1 and 1.5 percent by weight of a flavor; less than 1 percent by weight of a sweetener (e.g. Magnasweet 165 available from MacAndrews and Forbes Co.); and between 1 and 2 percent by weight of a lubricant such as magnesium stearate. The compositions of the present invention, whether as tablets for swallowing whole or chewable tablets, can be prepared as is known in the art. For example, using standard equipment known in the art, the sucralfate and one or more alkaline materials can be blended with a portion, for example 25 percent by weight, of the desired lubricant until uniform. The so-formed mixture can thereafter be compacted to the desired density followed by screening of the so-compacted material. After milling of this material, the sugars, sweeteners, flavors and diluent/sweetness enhancers can be added thereto and blended until a uniform mixture results. Finally, the balance of the lubricant can be blended into the mixture. Tableting can be accomplished using known techniques. The present invention will now be further described by the following example. EXAMPLE Sucralfate Chewable Tablet A sucralfate chewable tablet was prepared from the ingredients below using the methodology which follows: Ingredient Mg/Tablet Sugar, Baker's Special Crystalline 338.0 Sucralfate 500.0 Artificial Creme de Vanilla (flavoring; #11489, Food Materials Corp.) 2.0 Natural & Artificial Orange Flavor (flavoring; #23330, Food Materials Corp.) 2.0 Magnasweet 165 (sweetener) 2.6 Mannitol USP (diluent/sweetness enhancer) 200.0 Sorbitol NF (diluent/sweetness enhancer) 200.0 Magnesium Hydroxide USP (alkaline material) (about 1.72 milliequivalents of acid neutralizing capacity) 50.0 Magnesium Stearate NF (lubricant) 18.0 1312.6 m g The sucralfate and magnesium hydroxide were blended with 25 percent of the total amount of magnesium stearate to be added until a uniform mixture resulted. This blend was compacted, screened and milled. The milled material was thereafter blended with the mannitol, sorbitol, sugar, flavors and magnasweet until uniform. The remainder of the magnesium stearate was screened in and this mixture was again blended until uniform. The so-formed mixture was thereafter compressed into tablets.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE A pharmaceutical composition in tablet form comprising a therapeutically effective amount of an agent capable of forming an ulcer-adherent protective complex in an acid environment, and one or more alkaline materials, wherein said agent is sucralfate and wherein said one or more alkaline materials are present in an amount sufficient to provide between 0.5 and 10 milliequivalents of acid neutralizing capacity per tablet. The pharmaceutical composition of claim 1 wherein said one or more alkaline materials are present in an amount sufficient to provide acid neutralizing capacity in the range greater than 0.5 and less than 5 milliequivalents. The pharmaceutical composition of claim 1 or 2 wherein said one or more alkaline materials are selected from magnesium hydroxide, aluminum hydroxide, sodium bicarbonate, magaldrate, calcium carbonate, hydrotalcite, dihydroxy aluminum sodium carbonate, magnesium oxide and magnesium trisilicate. The pharmaceutical composition of any preceding claim, which is a chewable tablet formulation and said agent and said one or more alkaline materials are in a pharmaceutically acceptable carrier comprising one or more ingredients selected from sugar, sweeteners, natural and artificial flavors, flavor enhancers, diluents, diluent/sweetness enhancers, lubricants and preservatives. The chewable tablet formulation of claim 4 comprising up to 30 percent by weight each of one or more diluent/sweetness enhancers provided that the total diluent/sweetness enhancers are not more than 60 percent by weight of said formulation; up to 50 percent by weight of one or more sugars; up to 10 percent by weight of one or more artificial and natural flavors; up to 5 percent by weight of one or more sweeteners; and, up to 5 percent by weight of one or more lubricants. The chewable tablet formulation of claim 5 wherein said one or more diluent/sweetness enhancers are selected from mannitol, sorbitol, xylitol, aspartame, lycasin, glycerin and ammoniated glycyrhizin. The chewable tablet formulation of claim 5 or 6 wherein said one or more lubricants are selected from magnesium stearate, stearic acid, talc, calcium stearate, sodium stearate, sterotex, sodium stearyl fumarate, stearowet and carbowax. A chewable tablet formulation comprising a therapeutically effective amount of sucralfate; one or more alkaline materials in a total amount sufficient to provide between 0.5 and 10 milliequivalents of acid neutralizing capacity; between 10 and 20 percent by weight of sorbitol; between 10 and 20 percent by weight of mannitol; between 20 and 30 percent by weight of sugar; between 0.1 and 1.5 percent by weight of natural and artificial flavors; less than 1 percent by weight of sweeteners; and between 1 and 2 percent by weight of lubricants. The chewable tablet formulation of claim 8 wherein said one or more alkaline materials are present in an amount sufficient to provide acid neutralizing capacity in the range greater than 0.5 and less than 5 milliequivalents. The chewable tablet formulation of claim 8 or 9 wherein said one or more alkaline materials are selected from magnesium hydroxide, aluminum hydroxide, sodium bicarbonate, magaldrate, calcium carbonate, hydrotalcite, dihydroxy aluminum sodium carbonate, magnesium oxide and magnesium trisilicate. The chewable tablet formulation of claim 10 wherein said alkaline material is magnesium hydroxide A pharmaceutical composition or chewable tablet formulation according to any one of claims 1-11 for the treatment of stomach ulcers, duodenal ulcers or regurgitational esophagitis. Use of a pharmaceutical composition or chewable tablet formulation according to any one of claims 1-11 for the manufacture of a medicament for the treatment of stomach ulcers, duodenal ulcers or regurgitational esophagitis. Use of a pharmaceutical composition or chewable tablet formulation according to any one of claims 1-11 for the manufacture of a medicament for the treatment of symptoms of upset stomach or dyspepsia. Use of a pharmaceutical composition or chewable tablet formulation according to any one of claims 1-11 for the manufacture of a medicament for the treatment of hiatal hernia. A process for preparing a pharmaceutical composition in tablet form comprising a therapeutically effective amount of an agent capable of forming an ulcer-adherent protective complex in an acid environment, and one or more alkaline materials in a total amount sufficient to substantially prevent formation of said complex in the area of the mouth and adherence of said complex to the buccal mucosa, wherein said agent is sucralfate, wherein said one or more alkaline materials are present in an amount sufficient to provide between 0.5 and 10 milliequivalents of acid neutralizing capacity per tablet, and wherein said process comprises mixing said agent capable of forming an ulcer-adherent protective complex with one or more alkaline materials. The process of claim 16 wherein said composition is according to any one of claims 2-12. Claims for the following Contracting States : ES, GR A process for preparing a pharmaceutical composition in tablet form comprising a therapeutically effective amount of an agent capable of forming an ulcer-adherent protective complex in an acid environment, and one or more alkaline materials, wherein said agent is sucralfate, wherein said one or more alkaline materials are present in an amount sufficient to provide between 0.5 and 10 milliequivalents of acid neutralizing capacity per tablet, and wherein said process comprises mixing said agent capable of forming an ulcer-adherent protective complex with one or more alkaline materials. The process of claim 1 wherein said one or more alkaline materials are present in an amount sufficient to provide acid neutralizing capacity in the range greater than 0.5 and less than 5 milliequivalents. The process of claim 1 or 2 wherein said one or more alkaline materials are selected from magnesium hydroxide, aluminum hydroxide, sodium bicarbonate, magaldrate, calcium carbonate, hydrotalcite, dihydroxy aluminum sodium carbonate, magnesium oxide and magnesium trisilicate. The process of any preceding claim, wherein the composition is a chewable table formulation and said agent and said one or more alkaline materials are in a pharmaceutically acceptable carrier comprising one or more ingredients selected from sugar, sweeteners, natural and artificial flavors, flavor enhancers, diluents, diluent/sweetness enhancers, lubricants and preservatives. The process of claim 4 comprising up to 30 percent by weight each of one or more diluent/sweetness enhancers provided that the total diluent/sweetness enhancers are not more than 60 percent by weight of said formulation; up to 50 percent by weight of one or more sugars; up to 10 percent by weight of one or more artificial and natural flavors; up to 5 percent by weight of one or more sweeteners; and, up to 5 percent by weight of one or more lubricants. The process of claim 5 wherein said one or more diluent/sweetness enhancers are selected from mannitol, sorbitol, xylitol, aspartame, lycasin, glycerin and ammoniated glycyrhizin. The process of claim 5 or 6 wherein said one or more lubricants are selected from magnesium stearate, stearic acid, talc, calcium stearate, sodium stearate, sterotex, sodium stearyl fumarate, stearowet and carbowax. A process for preparing a chewable tablet formulation comprising a therapeutically effective amount of sucralfate; one or more alkaline materials in a total amount sufficient to provide between 0.5 and 10 milliequivalents of acid neutralizing capacity; between 10 and 20 percent by weight of sorbitol; between 10 and 20 percent by weight of mannitol; between 20 and 30 percent by weight of sugar; between 0.1 and 1.5 percent by weight of natural and artificial flavors; less than about 1 percent by weight of sweeteners; and between 1 and 2 percent by weight of lubricants, characterised by mixing said sucralfate, said one or more alkaline materials and the other specified ingredients. The process of claim 8 wherein said one or more alkaline materials are present in an amount sufficient to provide acid neutralizing capacity in the range greater than 0.5 and less than 5 milliequivalents. The process of claim 8 or 9 wherein said one or more alkaline materials are selected from magnesium hydroxide, aluminum hydroxide, sodium bicarbonate, magaldrate, calcium carbonate, hydrotalcite, dihydroxy aluminum sodium carbonate, magnesium oxide and magnesium trisilicate. The process of claim 10 wherein said alkaline material is magnesium hydroxide.

Inventors: DEGROOF ROBERT C, FOO LUKE T H, HARWOOD RICHARD J, HENRY EDWARD V, RHEINGOLD JAY L, SONK JOSEPH S, DEGROOF, ROBERT C., FOO, LUKE T.H., HARWOOD, RICHARD J., HENRY, EDWARD V., RHEINGOLD, JAY L., SONK, JOSEPH S.
Applicants: SQUIBB & SONS INC, E.R. SQUIBB & SONS, INC.
Application year: 1990
Main classification: A61K31
IPC codes: A61K45, A61K33, A61K31, A61K9, A61K47, A61P1