MXPA96004298A

MXPA96004298A - Solid dose forms containing bism

Info

Publication number: MXPA96004298A
Application number: MXPA/A/1996/004298A
Authority: MX
Inventors: Bernard Chapura Francis; Louis Barone Daniel
Original assignee: The Procter & Gamble Company
Priority date: 1994-03-24
Filing date: 1996-09-23
Publication date: 1998-09-18

Abstract

The present invention relates to a composition in swallowable solid dosage form for treating discomfort of the upper gastrointestinal tract, characterized in that it comprises by weight of the composition: (a) from about 2% to about 25% carbonate or bicarbonate salt (b) from about 0.5% to about 15% disintegrating agent; (c) from about 5% of about 70% bismuth subsalicylate; (d) from about 0.1% to about 35 anionic surfactant or nonionic, (e) from about 15% to about 50% microcrystalline cellulose, wherein the composition is designed for rapid absorption of the bismuth subsalicylate in the bloodstream

Description

FOR SOLID DOSES CONTAINING BISMUTO BACKGROUND OF THE INVENTION Fl Liquid Pepto-bismolR pink, which has (Its active ingredient subsal bismuth nitrate is common among consumers for the immediate relief of acidosis, indigestion, upset stomach, diarrhea and nausea.) However, for some consumers, the taste and sensation of said liquid in the mouth It is not pleasant, nor does it like to chew * a tablet with a similar taste.A swallowable tablet * would be ideal for those consumers, but it is technically difficult to formulate and make a tablet that can be swallowed and that contains bismuth that is a relief In order for consumers to appreciate it, such a tablet must dissolve quickly in the stomach until the active ingredient is absorbed into the bloodstream quickly enough to provide immediate release.A particularly preferred form of bismuth-based solid dose that can be swallowed is one that provides relief of symptoms in approximately the same period of time that the Pepto-bi srnolR liquid takes. gone in giving livio. U.S. Patent 5, 725,197, Bolt et al., Issued July 5, 1993, discloses an inasti cable tablet that includes a drug in a non-tacky base such as mannitol and the effervescent element such as citric acid sodium bicarbonate. U.S. Patent 5,096,714, Khurts, issued March 17, 1992, discloses a prolonged dose composition consisting essentially of a dietary fiber in the form of a gel, a biologically absorbable medicine or other therapeutic agent, and certain disintegrators, especially an acid physiologically acceptable edible and a mineral salt that releases a physiologically acceptable gas when it is i geri a.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to swallowable solid dosage form compositions for the treatment of discomfort of the upper gastrointestinal tract *, which includes, by weight of the composition: (a) from about "from?% To about 25% salt of bicarbonate cro ates, (b) about 0.5% about 15% of a disintegrating agent, (o) from about 5% to about 70% bismuth subsalicylate, (d) about 0.1% to about 3% ammonium or non-limeo surfactant, and (e) from about 15% to about 50% cellulose rnicrocp stali na.

The invention further relates to a method for the treatment of acidosis, indigestion, upset stomach, diarrhea and / or nausea in humans or other mammals, the method which includes administering to a human or other mammal in need of such treatment a safe and effective amount of a pharmaceutical composition according to the present invention.

DESCRIPTION OF THE INVENTION The swallowable solid dosage form compositions are even composed of (hi) carbonate salt, disintegrating agent, bismuth subsalt bilet, ammonium or nonionic surfactant, and cellulose cellulose, which are described below. The present compositions additionally include mannitol, silica, pol ivi mlpyrrole, and other ingredients, which are also described below, the percentages given below being by weight of the composition unless otherwise indicated. The ingested, dose-effective form compositions (eg, non-chewable) preferably do not include a dietary fiber in the form of a gel such as psylliurn, or an effervescent element such as sodium bicarbonate citric acid, or a physiologically acceptable edible acid and mineral salt that releases a physiologically acceptable gas at the time ingestion. The present compositions are not prolonged dose compositions; on the contrary, they are designed for rapid dissolution in the stomach and absorption in the bloodstream. It is not necessary to include calcium chloride in the present compositions.

A. Carbonate or bicarbonate salt. The compositions even consist of from about 2% to about 25%, preferably from about 5% to about 20%, more preferably from about 8% to about 15%, by weight of the composition, of carbonate salt and / or bicarbonate. Preferred are calcium, sodium, potassium and / or magnesium carbonate salts (more preferred) and / or bicarbonate. More preferred is calcium carbonate. Without having to stick to the theory, it is believed that calcium carbonate at this level is acting as a processing aid and is not included in order to impart effervescence to this dosage form.

B. DISINTEGRATING AGENT The compositions even consist of about Ll.5% to about 10%, preferably from about 1% to about 20%, more preferably from about 2% to about 10%, by * the weight of the composition, of the agent in disintegration "Fl The disintegrating agent is preferably selected from a group consisting of sodium starch, modified polyvinylpyrrolidone, croscarmellose-sodium (an interlaced cellulose), polyacillin-potassium (an ion exchange resin), alginic acid, starch and mixtures thereof. The disintegrating agent is preferably preferably sodium starch glycolate or degraded polyvinylpyrrolidone (available as crospovir), and is more preferably sodium starch glycolate (available as Explotal from Edwar Mendel 1 Oo.) " C. Bismuth Subsalicylate The compositions herein consist of from about 5% to about 70%, preferably from about 10% to about 60%, more preferably from about 30% to about 50%, by the weight of the composition, of bismuth subsalicylate. The average particle size of the subsurface bismuth icylate (before incorporation with the remaining ingredients into the final form) is preferably about 50, more preferably from about 7 to about 30, more preferably about 3 to approximately 10, nicronos. Without being limited by theory, this small particle size is believed to contribute to the efficacy of solid dose forms even by facilitating the dissolution of the solid dose form in the stomach and allowing a more rapid absorption in the blood. Therefore, the relief of symptoms is experienced rapidly, with more preference in a period comparable to that of the Pepto-Bismarin liquid.

D. ANIONIC OR NON-IONIC TENSITIVE AGENT The compositions herein consist of from about 0.1% to about 3%, preferably from about 0.2 to about 1%, more preferably from about 0.4 to about 0.6%, by weight of the composition of ammonium and / or nonionic surfactant. Any ammonium and nonionic surfactant, including synthetic, suitable for use in the form of swallowable solid dose can be used * in the present compositions. The non-ionic surfactants for use in the present also include compounds produced by the condensation of alkylene oxide groups (essentially hydrophilic) with an organic hydrophobic compound, which may be uiphatic or aromatic alkyl in essence. The surfactant is preferably a surfactant agent and is preferably chosen from a group consisting of polyethylene oxide condensates of alkylphenols; the products derived from the condensation of ethanol with the resulting product for the reaction of propylene oxide and products of ethylene diamine; the condensation product of aliphatic alcohols containing from 8 to 10 carbon atoms with ethylene oxide; long chain tertiary amine oxides corresponding to the following general formula L Ri R3 N I > O I F? 2 wherein Ri contains an alkyl, alkenyl or rnononohydroxyalkyl radical of from about 8 to 18 carbon atoms, from 0 to about 10 portions of ethylene oxide, and from 0 to 1 glycemic portion, and R2 and R3. they contain from 1 to about 3 carbon atoms and from 0 to about a hydroxyl group; tertiary phosphide oxides in long chain; long chain dialkyl sulfoxides containing a short chain alkyl or hydroxyalkyl radical of L to about 3 carbon atoms and a hydrophobic l chain which contains alkyl, alkenyl, hydroxyalkyl or ketoalkyl radicals containing from about 8 percent. carbon atoms, from 0 to approximately 10 portions of ethylene oxide, and from 0 to 1 glycemic portion; and mixtures of this. F: Most preferred surfactant for use herein is polyoxyethylene sorbitan rnononoleate. The unique surfactants for use herein include the alkali metal salts of organic sulfuric reaction products containing in their structure "nolecul" an alkyl radical containing from 8-22 carbon atoms and an acid radical sul phonic or acid ester sul fup co.

If the surfactant is an ammonium surfactant, it is preferably chosen from a group consisting of: sodium alkyl, ammonium, potassium otp tanoelamine, sulfates and sulfonates of sodium fatty acid and coconut oil onglycolates. , potassium or sodium salts of sulfuric acid esters of the reaction product of 1 mole of a more fatty alcohol and of the 1? moles of ethylen oxide, sodium or potassium salts of alkyl phenoethylene oxide per molecule and in which the alkyl radicals contain from 3 to 12 carbon atoms, alkyl glyceroic sodium ether sulfonates, the reaction products of fatty acids containing from 10 to 12 carbon atoms esterified with acid iodide and neutralized with sodium hydroxide, soluble water salts of condensation products of fatty acids with sarcosm, and mixtures thereof.

E. Microcrystalline cellulose Compositions also comprise from about 15% to about 50%, preferably from about 20% to about 40%, more preferably from about 25% to about 35%, by weight of the composition, of microcrystalline cellulose. The preferred cellulose is the NF Flickr PH102 cellulose from FMC Corp. (Phi ladelphia, PA). Preferably, the average particle size of the microcrystalline cellulose at 1 to about 20 to about 200 millimeters, with more than about 80 to about 120 millons.

F. Optional ingredients The compositions even preferably consist of, by weight of the composition: (a) from about 2% to about 25%, preferably from about 5% to about 20%, more preferably from about 8% to about 15% soluble sugars and / or sugar alcohols, more preferably nanitol; (b) from about 0.02% to about 0.5%, preferably from about 0.05% to about 0.2%, more preferably from about 0.08% to about 0.15%, of silica, more preferably Cab-oS? lR from Cabot Corp; (c) from about 0.1% to about 5%, preferably from about .5% to about 7%, with preferably from about 0.6% to about 1.5%, of this magnesium; and (d) from about 0.5% to about 10%, preferably from about 1% to about 5%, more preferably from about * 1.5% to about 3%, from pol ivi to myself. rrolidone, more preferably Pov? doneR Soluble sugars are preferably chosen from a group consisting of dextrose, sucrose, glucose, xylose, pbose, mannose, galactose, fructose, maltose and mixtures thereof, and sugar alcohols are preferably chosen from a group consisting of silitol, rhamtol, sorbitol, and mixtures thereof. The most preferred is ma tol.

Conventional ingredients of swallowable solid dosage forms, such as dye, may also be included here. A preferred composition herein comprises, by weight of the composition: (a) from about 8% to about 15% calcium carbonate (b) from about 2% to about 10% sodium starch glycolate; (c) from about 3% to about 50% bismuth subsalicylate; (d) from about 0.4% to about 0.6% ammonium or nonionic surfactant; and (e) from about * 25% to about 35% microcpstalin cellulose. In addition, preferably it comprises by weight of the composition: (a) from about * 5% to about 20% by weight (b) from about 0.05% to about 2% if free; (c) from about 0.1% to about 5% of this magnesium, and (d) from about 1% to about 5% polyvinylpyrrolidone; G. METHODS The present invention also relates to a method for the treatment of acidosis, indigestion, upset stomach, diarrhea and / or nausea in humans or other mammals, the method including administration to a human-being or other mammal in the need for said treatment of a safe and effective amount of a pharmaceutical composition according to the present invention.

H. FORM The composition is preferably in the form of a tablet or capsule, more preferably in the form of a capsule-shaped tablet. The procedures for making conventional tablets / capsules are employed. The hardness of the tablet should be * low enough to provide integrity and stability, but not very high. The composition is even preferably self-administered orally by humans and is preferably used to treat the same symptoms that the Pepto-Bi Smol® Liquid is accustomed to treating. The tablets / capsules are preferably ingested by the mouth for the relief of heartburn, indigestion, upset stomach, diarrhea and / or nausea in humans or other mammals. An even composition is preferably orally administered to treat acid indigestion, preferably, two tablets 1e approximately 675 rngs per tablet (including approximately 752 mg of bismuth subsalicylate per tablet). They are ingested with water every half to one hour as needed up to a maximum of 8 doses in a period of 24 hours (adult dose). The recommended dose for children 9 to 12 years of age is a tablet, for children from 6 to 9 years of age it is two thirds 5 of tablet, for children from 3 to 6 years of age it is one third of tablet. Children under 3 years of age should consult a doctor. The examples given below illustrate the compositions and methods of the present inventions. They are presented only by means of examples and should not be construed to limit the application of these inventions. It will seem to those skilled in the art when reviewing the modifications described herein, that several related additional modifications may be made. Said modifications are intended to be made * within the application of this invention. L5 All parts, percentages and proportions herein are by weight unless otherwise indicated; All the references cited here are expressly incorporated by reference.

EXAMPLE I DEGLUTIBLE TABLET A swallowable tablet composition of the present invention is the ingredient M111 gram / abl ta bismuth subsalicylate 262.5 Cellulose starch, NFi 213.3 Calcium carbonate 67.5 Mannitol 67.5 Sodium starch glycolate2 40.5 PoLivim lpirroli dona3 13.5 Magnesium stearate, NF 5.4 Poly orbate 8 * 3.4 111 ees 0. Colorant 0.7 Total 675.0 i Available as Av? celR PH107 from FMC Corp. Available as Ex-lotabR from Edward Mendell Co. 3 Available as Pov? doneR Available as Tween 80 5 Available as Cab-o-Sil from Cabot Corp. Preferably, the ingredients are added to a mixer, preferably a Processall (made by Processal of Cincinnati, Ohio) or a Littieford (made by Littieford de Kentuc and) in the following order: part of the cellulose my crocrystal, the calcium carbonate, of the glycolate of sodium starch, poly sorbate 80, the dye and the bismuth subsalt ici lato. After adding the bismuth subsalicylate and mixing at high strength, the mixture is dried at 86 ° C in the Processall at less than 2% humidity. Additional powders (microcrystalline cellulose, sodium starch glycolate, anitol and polyvinylpyrrolidone) are added, and granules are formed by spraying water (approximately 10% by weight of the composition) to the high-strength mixture in the Processall. After further drying, even in the Processall, at less than 3% humidity, the silica (deslizer) and the magnesium stearate (lubricant) are admixed and mixed for approximately one minute. The tablets are then formed into a rotary tablet press. Two tablets of approximately 675 mg per tablet are ingested with water every half to one hour as needed until a maximum of 8 doses in a period of 74 hours (adult dose). This composition can alternatively be compressed in the form of a tablet or capsule, the alternative ingredients set forth in the specification can be replaced by the above ingredients. The amounts of these ingredients can be varied within the limits specified here.

EXAMPLE II DEGLUTIBLE TABLET A swallowable tablet axis composition of the present invention is as follows.

In retentive Milligram / tablet Bismuth subsalicylate 262.5 Cellulose rni c roe psta lina 186.5 Calcium carbonate 15.0 Croscarrnelosa-sodium 10.0 Polypropylene idona 20.0 Magnesium stearate 5.0 Polysorbate 80 1.0 The ingredients are mixed at a high strength according to Example I. The disintegrating agent here is croscarrnelosa-sodium. Tablets are formed using a rotary tablet press.

Claims

NOVELTY OF THE INVENTION CLAIMS A composition in the form of a swallowable solid dose for treating discomfort of the upper gastrointestinal tract, including, by weight of the composition: (a) from about 2% to about 25% carbonate or bicarbonate salt; (b) from about * 0.5% to about 15% disintegrating agent; (c) from about 5% to about 70% bismuth subsalicylate; (d) from about 0.1% to about 3% ammonium or nonionic surfactant; and (e) from about 15% to about 50% cellulose microsomal ina.
2. A composition according to claim 1, further characterized in that the disintegrating agent is chosen from a group consisting of sodium starch glycollate, interlaced poly ivi lpirroli dona, oroscapnelosa-sodium, pol lacp lato-potassium, algid acid, starch and mixtures thereof.
3. A composition according to claim 1, further characterized in that it includes about 0.02% to about 5% by weight of the composition, silica.
4. A composition according to claim 2, further characterized in that the surfactant agent is a nonionic surfactant chosen from a group consisting of polyethylene oxide condensates of alkyl Lophenols; products derived from the condensation of ethylene oxide with the resulting product form the reaction of products of propylene oxide and ethylene diamine; the condensation product of aliphatic alcohols having from 8 to 18 carbon atoms with ethylene oxide; oxides of ami to tertiary in long chain corresponding to the following general formula: Ri in don < Ri contains an alkyl, alkenyl or nonohydroxyalkyl radical of from about 8 to about 18 carbon atoms from 0 to about 10 portions of ethylene oxide, and from 0 to glycemic portion, and R2 and R3 contain from 1 to about 3 carbon atoms and from 0 to about a hydroxyl group; Tertiary phosphine oxides on Long chain; and dialkyl long chain sulphides containing a short chain alkyl or hydroxyalkyl radical of 1 to about 3 carbon atoms and a long phfoic hydrocarbon chain containing alkyl radicals, wherein the hydroxyalkyl or ketoalerjuyl containing from about 8 to about 20 carbon atoms, from 0 to about 10 portions of ethylene oxide and from 0 to L portion of glycol; v mixtures thereof. GO 5. - A composition according to claim 2, characterized in that the composition is in the form of a tablet or capsule. 6. A composition according to claim 5, further characterized in that the composition is in the form of a tablet in the form of a capsule. 7. A composition according to claim 6, further characterized in that the composition is administered orally for treatment of acid indigestion, acidosis or stomach acid. 8. A composition according to claim 7, further characterized in that it includes from about * 10% to about 60% of bismuth subsalicylate. 9. An axis composition according to the rei indication 8, further characterized because it includes about 1% to about 70%, by weight of the composition, of sodium starch glycolate. 10. A composition according to claim 9, further characterized in that it includes from about 0.4% to about 0.6%, by weight of the composition, < polioxie rnonoleate + ilensorbitan. 1-A composition according to claim 10, further characterized in that it includes uncle about 70% to about 40%, by weight of the composition, of microcp cellulose stan i na. 12. - A composition in accordance with claim 11, further characterized in that it includes from about 2% to about 25%, by weight of the composition, of soluble sugar chosen from a group consisting of pink elex., sucrose, glucose, xylose, ribose, monosa, galactose, fructose, maltose and mixtures thereof. 13. A composition according to claim 11, further characterized in that it includes from 0.5% to approximately 10%, by weight of the composition, poly-axis and vimlpyrrolidone. 14. A composition according to claim 13, further characterized in that it includes from about 7% to about 25%, by weight of the composition, sugar alcohols chosen from a group consisting of xylitol, narutol, sorbitol and mixtures thereof. 15. A composition that rapidly dissolves in the stomach axis according to claim 7, further characterized in that the composition includes, by weight, the composition: (a) from about 8% to about 15% calcium carbonate axis; (b) Approximately 2% Approximately 10% sodium starch glycolate; (c) from about 3% to approximately 50% bismuth subsalicylate; (d) the round < 0.4% to about 0.6% ammonium or nonionic surfactant; and (e) from about 25% to about 35% cellulose my crocrystal. 16. A composition according to claim 13, further characterized in that the composition further includes, by the weight of the composition: (a) from about 5% to about 20% mannitol salt; (b) < about 0.05% to about 0.2% silica; (c) from about 0.1% to about 5% magnesium stearate; and (d) from about L% to about 5% polyvinylpyrrolidone; 17. A composition according to claim 1, further characterized because it does not include a dietary fiber in the form of goal. 18. A composition according to claim 11, further characterized in that the disintegrating agent is sodium starch glycol or poi i or Ipi rroli dona in re l azada. 19. A method for treating acidosis, indigestion, upset stomach, diarrhea and / or nausea in humans or other mammals, the method includes administering to a human * or mammal in need of said treatment a safe and effective amount of a pharmaceutical composition according to claim 1. 20.- A method for treating asidosis, indigestion, upset stomach, diarrhea and / or nausea in humans or other mammals, the method includes administering to a human or other mammal or in The treatment must, therefore, be a safe and effective quantity of a pharmaceutical composition in accordance with the requirement.