WO1992000082A1 - Antidiarrheal compositions and methods - Google Patents
Antidiarrheal compositions and methods Download PDFInfo
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- WO1992000082A1 WO1992000082A1 PCT/US1991/003770 US9103770W WO9200082A1 WO 1992000082 A1 WO1992000082 A1 WO 1992000082A1 US 9103770 W US9103770 W US 9103770W WO 9200082 A1 WO9200082 A1 WO 9200082A1
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- bismuth
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- antidiarrheal
- loperamide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/245—Bismuth; Compounds thereof
Definitions
- Liquid oral dosage forms include aqueous and/or alcoholic solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring, and flavoring agents.
- Liquid oral composition typically comprise water and suspending agents, such as magnesium aluminum silicate (e.g., Veegum, manufactured by R. T. Vanderbilt Company Inc.), as part of the pharmaceutically-acceptable carrier.
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
Compositions and methods for treating diarrhea, especially travelers' diarrhea, by concurrently administering bismuth-containing antidiarrheal agent and antimotility agents selected from the group consisting of loperamide-derived antidiarrheal agent, diphenoxylate-derived antidiarrheal agent, and mixtures thereof.
Description
ANTIDIARRHEAL COMPOSITIONS AND METHODS
BACKGROUND OF THE INVENTION
The present invention relates to compositions and methods useful for treating diarrhea, especially travelers' diarrhea.
Diarrhea is a major health problem, especially in and when traveling to developing countries. Treatment of diarrhea, especially travelers' diarrhea, typically include fluid replacement, symptomatic relief with absorbants and antimotility agents, and antimicrobial agents used for 3 to 5 days.
The article "Travelers' Diarrhea - Consensus Conference" (JAMA. May 10, 1985, 235(18), pages 2700-4) does not recommend antimicrobial agents for prevention of travelers' diarrhea in view of the potential for many .side effects from such widespread usage. The recommendation is rapid institution of effective treatment that can shorten the disease to 30 hours or less. For mild diarrhea, this publication recommends loperamide or diphenoxylate, and, alternatively, bismuth subsalicylate. Use of antimicrobial drugs, such as trimethoprim-sulfamethoxazole, trimethoprim alone, and doxycycline, are recommended for the more severe diarrhea cases. Oral rehydration is recommended when necessary.
In R. Longe, "Antidiarrheal and Other Gastrointestinal
Products" (Handbook of Nonprescription Drugs. Eiohth Edition. Chapter 5, pages 59-74, 1986; incorporated by reference herein in its entirety), types of diarrhea as well as various treatment methods are discussed. Pharmacologic agents described therein for use against diarrhea include opiates, polycarbophil, adsorbents, and anticholinergics. Combinations of agents, including bismuthcontaining agents, are known and are described therein (at pages
73-74), and include: paregoric/bismuth subsalicylate ("Corrective
Mixture with Paregoric", manufactured by Beecham Labs); opium/ bismuth subsalicylate ("Infantol Pink", manufactured by Scherer); bismuth subgallate/pepsin and other actives ("Digestalin", manufactured by Vortech); and bismuth subnitrate/caldum hydroxide
("Percy Medicine", manufactured by Merrick).
In spite of the efforts devoted to the problem of diarrhea, there continues to be a need for alternative safe, quick and effective methods and compositions for treating diarrhea.
The object of the present invention is therefore to provide compositions and methods useful for treating diarrhea, especially diarrhea generally characterized as travelers' diarrhea. Another object is to provide compositions and methods for treating diarrhea which reduce the duration and/or severity and/or reoccurrence of diarrhea in humans or lower animals.
These and other objects will become readily apparent from the detailed description which follows.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions useful for treating diarrhea, especially travelers' diarrhea. These compositions comprise a bismuth-containing antidiarrheal agent (e.g., bismuth subsalicylate) and an antimotility agent selected from the group consisting of a loperamide-derived antidiarrheal agent, diphenoxylate-derived antidiarrheal agent, and mixtures thereof.
The present invention further relates to methods for treating diarrhea in humans or lower animals. These methods comprise concurrently administering to a human or lower animal in need of such treatment a safe and effective amount of a bismuth-containing antidiarrheal agent and an antimotility agent selected from the group consisting of a loperamide-derived antidiarrheal agent, diphenoxylate-derived antidiarrheal agent, and mixtures thereof.
DETAILED DESCRIPTION OF THE INVENTION
(1) Antidiarrheal Compositions:
The antidiarrheal compositions of the present invention comprise one or more bismuth-containing antidiarrheal agents and one or more antimotility agents selected from the group consisting of loperamide-derived antidiarrheal agents, diphenoxylate-derived antidiarrheal agents, and mixtures thereof. Optionally, these compositions also comprise pharmaceutically-acceptable carrier materials suitable for the particular aesthetics and dose
form desired. Preferred are compositions in the form of liquid suspensions, and chewable or swallowable tablets or capsules. It is to be further recognized that such compositions may consist of simple admixtures or, depending on the agents utilized, may involve physical interaction between the agents such as a complexation material either preformed for use or formed in situ.
While both the bismuth-containing agents and the antimotility agents useful herein are known antidiarrheal agents, they are generally recognized as producing this result by different physiological mechanisms. The goal is to create an interactive effect by this combination whereby there is further enhancement of the effectiveness of each agent through their combination. This enhanced effectiveness may be observed as including faster action, reduced relapse, reduced dosing levels, and/or further enhanced safety profile.
The particular agents preferred for use herein, as well as the levels and amounts preferred therefor, are described in greater detail hereinafter,
(a) Bismuth-Containing Antidiarrheal Aoents:
The pharmaceutical compositions and methods of the present invention comprise a bismuth-containing antidiarrheal agent, preferably in the form of a pharmaceutically-acceptable salt. Such bismuth-containing antidiarrheal agents include, for example, bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicylate, bismuth subnitrate, bismuth subgallate, and mixtures thereof. Preferred compositions comprise bismuth subsalicylate, bismuth subnitrate, bismuth subgallate, and mixtures thereof. Most preferred compositions of the present invention comprise bismuth subsalicylate.
The pharmaceutical compositions of the present invention typically comprise, by weight, from about 0.1% to about 99.9% of the bismuth-containing antidiarrheal agent, preferably from about 0.1% to about 75%, and most preferably from about 0.5% to about 50%.
(b) Antimotility Agents:
In addition to the bismuth-containing antidiarrheal agents described hereinbefore, the pharmaceutical compositions and methods of the present invention further comprise an antimotility agent selected from the group consisting of loperamide-derived antidiarrheal agent, diphenoxylate-derived antidiarrheal agent, and mixtures thereof.
The term "loperamide-derived antidiarrheal agent", as used herein, means those compounds of the class of 2, 2-diaryl-4-(4'-aryl-4'-hydroxy-piperidino) butyramides, active metabolities thereof, and the pharmaceutically-acceptable salts thereof (including bismuth-containing salt complexes formed by a bismuth-containing antidiarrheal agent with a loperamide-derived antidiarrheal agent), which are effective as antidiarrheal agents, disclosed and described in detail in U.S. Patent 3,714,159, issued January 30, 1973 and U.S. Patent 3,884,916, issued May 20, 1975, both to Janssen et al., and U.S. Patent 4,824,853, issued April 25, 1989, to Wals et al., the disclosures of all these patents being incorporated by reference herein in their entirety. Preferred compounds are loperamide and the N-oxide of Toperamide, and most preferred is loperamide and/or the pharmaceutically-acceptable salt thereof (especially the hydrochloride salt thereof, as described in The Merck Index. 10th Ed., No. 5396, 1983, incorporated by reference in its entirety herein).
The term "diphenoxylate-derived antidiarrheal agent", as used herein, means diphenoxylate, active metabolites thereof (e.g., difenoxine), and the pharmaceutically-acceptable salts thereof (including bismuth-containing salt complexes formed by a bismuth-containing antidiarrheal agent with a diphenoxylatederived antidiarrheal agent), which are effective as antidiarrheal agents, disclosed and described in detail in U.S. Patent 2,898,340, issued August 4, 1959 to Janssen, and U.S. Patent 3,646,207, issued February 29, 1972 to Soudyn et al., the disclosures of both these patents being incorporated by reference herein in their entirety. Preferred compounds are diphenoxylate,
difenoxine, and the pharmaceutically-acceptable salts thereof (especially the hydrochloride salts thereof, as described in The Merck Index. 10th ed., Nos. 3325 and 3122, 1983, incorporated by reference in their entirety herein).
The pharmaceutical compositions of the present invention typically comprise, by weight, from about 0.001% to about 99.9% of the antimotility agents useful herein, preferably from about 0.001% to about 10%, and most preferably from about 0.005% to about 5%.
(c) Pharmaceutically-Acceptable Carrier Materials:
In addition to the bismuth-containing antidiarrheal agent and the antimotility agents as described hereinbefore, the pharmaceutical compositions of the present invention also preferably contain one or more pharmaceutically-acceptable carrier materials. The term "pharmaceutically-acceptable carrier materials", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the pharmaceutical composition are capable of being commingled with the bismuthcontaining antidiarrheal agent and the antimotility agent, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.
A variety of pharmaceutically-acceptable carriers may be included, depending on the particular dosage form to be used. Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, wetting agents,
coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous and/or alcoholic solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring, and flavoring agents. Liquid oral composition typically comprise water and suspending agents, such as magnesium aluminum silicate (e.g., Veegum, manufactured by R. T. Vanderbilt Company Inc.), as part of the pharmaceutically-acceptable carrier.
Some examples of substances which can serve as pharmaceutically-acceptably carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; ethanol; and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants such as sodium laryl sulfate, as well as coloring agents, flavoring agents, excipients, tableting agents, stabilizers, anti-oxidants, and preservatives can also be present. Other compatible pharmaceutical additives and actives (e.g., NSAI drugs; pain killers; muscle relaxants) may be included in the pharmaceutically-acceptable carrier for use in the compositions of the present invention. Techniques and compositions for making dosage forms useful herein are described in the following references, all incorporated by reference herein in their entirety; 7 Modern Pharmaceuticals. Chapters 9 and 10 (Banker and Rhodes, Ed., 1979); Lieberman, et al., Pharmaceutical Dosaoe Forms: Tablets (1981); and Ansel, Introduction to. Pharmaceutical Dosaoe Forms (2nd Edition, 1976).
The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the bismuth-containing antidiarrheal agent and antimotility agent combination of the present invention is basically determined by the way the composition is to be administered. The preferred mode of administering the compositions of the present invention is orally. The preferred unit dosage form is therefore tablets, capsules, and the like, as well as liquids and suspensions, comprising a safe and effective amount of the bismuth-containing antidiarrheal agent and the antimotility agent combination of the present invention. Pharmaceutically- acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Their selection will depend on secondary considerations like taste, cost, shelf stability, bioavailability, etc. which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art.
The pharmaceutically-acceptable carrier employed in conjunction with the bismuth-containing antidiarrheal agent and the antimotility agent combination of the present invention is used at a concentration sufficient to provide a practical size to dosage relationship. The pharmaceutically-acceptable carriers, in total, may comprise from about 0.1% to about 99.9%, by weight, of the pharmaceutical compositions of the present invention, preferably from about 25% to about 99.9%, and most preferably from about 50% to about 99.5%.
(2) Methods for Treating Diarrhea:
Another aspect of the present invention is methods for treating diarrhea. Such methods comprise concurrently administering, to a human or lower animal in need of such treatment, a safe and effective amount of a bismuth-containing antidiarrheal agent and safe and effective amount of an antimotility agent selected from the group consisting of loperamide-derived antidiarrheal agent, diphenoxylate-derived antidiarrheal agent, and mixtures thereof.
The term "administering", as used herein, refers to any method which, in sound medical practice, delivers the bismuthcontaining agent and the antimotility agent to the subject to be
treated in such a manner so as to be effective in the treatment of the diarrhea. Preferably, both these agents are administered orally, either separately or as compositions or complexes according to the present invention.
The term "safe and effective amount", as used herein, means an amount of a bi smuth-containing antidiarrheal agent and antimotility agent, when used according to the compositions and methods of the present invention, high enough to significantly positively modify the diarrhea condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of the agents of the present invention will vary with the age and physical condition of the patient being treated, the etiology and severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific agents employed, the particular pharmaceutically-acceptable carrier materials utilized, and like factors within the knowledge and expertise of the attending physician.
The methods of the present invention typically involve administering the bismuth-containing antidiarrheal agent in an amount of from about 100 mg to about 5000 mg of bismuth per day, and preferably in an amount of from about 50 mg to about 1500 mg per dose. (As used herein, the quantity of the bismuth-containing antidiarrheal agents to be administered is indicated by the weight of elemental bismuth present in the dose of the bismuth-containing antidiarrheal agent. Thus, the actual weight of a dose of a bismuth-containing antidiarrheal agent will be greater than the amount of bismuth indicated.) Preferably, from about 250 mg to about 2500 mg of bismuth are administered per day, and from about 250 mg to about 1500 mg of bismuth are administered per dose. Most preferably, the bismuth-containing antidiarrheal agent is bismuth subsalicylate.
The methods of the present invention also typically involve administering the antimotility agent in an amount of from about 0.1 mg to about 20 mg per day, and from about 0.1 mg to about 5 mg per dose. Preferably from about 1 mg to about 20 mg are administered per day, and from about 0.5 mg to about 5 mg are
administered per dose. The preferred antimotility agents are the N-oxide of l operamide, l operamide, di phenoxyl ate, di fenoxine, the pharmaceutically-acceptable salts thereof, and mixtures thereof.
The methods of the present invention comprise administering the bismuth-containing antidiarrheal agent and the antimotility agent concurrently. The term "concurrently", as used herein, means that both types of agents are administered to the human or lower animal in need of treatment over the course of the same diarrheal episode, and preferably one or more doses of one type of agent is administered within one day of administration of one or more doses of the other type of agent. Also preferred is at least one dose of each type of agent being administered within about 60 minutes or less of each other, and more preferably within about five minutes of each other, and includes co-administration of the agent, e.g. by administering a composition or complex of the present invention.
The methods of the present invention in which the agents are administered concurrently comprise any dosing regimen in which part or all of the dosing of the agents is performed concurrently. Thus, for example, methods comprising concurrent dosing of the agents include:
(1) 2 days of a pharmaceutical composition of the present invention taken after each loose stool;
(2) 4 tablets of a bismuth subsalicylate-containing composition and 1 tablet of a 2 milligram loperamidecontaining composition administered within 5 minutes of each other QID.
For the methods of the present invention, the duration of administration of the agents will typically vary according to the severity of the diarrhea being treated, but usually will be within the range of from about 1 to about 3 days, and may require as few as one dose of a pharmaceutical composition according to the present invention.
The following examples further describe and demonstrate the preferred embodiments within the scope of the present invention.
The examples are given solely for the purpose of illustration, and
are not to be construed as limitations of the present invention since many variations thereof are possible without departing from its spirit and scope.
EXAMPLE 1
Liquid Pharmaceutical Composition
A composition of the present invention in liquid form suitable for oral administration is prepared using conventional methods and having the following components.
Components Weight %
Veegum1 0.985
Methylcellulose2 1.079
Bismuth subsalicylate 1.75
Loperamide HCl 0.0066
FD&C red #3 0.0364
FD&C red #40 0.00539
Sodium saccharin 0.06081
Sodium salicylate 0.05983
Salicylic acid 0.07062
Methyl salicylate 0.060
Peppermint oil 0.005
Purified water Q.S.
1 Magnesium aluminum silicate manufactured by R.T. Vanderbilt
Company, Inc.
2 Methocel A®, supplied by The Dow Chemical Company.
This composition may be prepared by first mixing the Veegum in chilled water, and then adding to this mixture a warm aqueous slurry of methylcellulose followed by FD&C red #3, bismuth subsalicylate slurry, FD1C red #40, sodium saccharin, sodium salicylate, peppermint oil, and a slurry of salicylic acid and methyl salicylate. Finally, the loperamide hydrochloride salt is added followed by sufficient water to dilute the composition to the desired final weight, and the composition is mixed to homogeneity.
Ingestion of 2 tablespoonfuls (approximately 30ml containing about 525 mg of bismuth subsalicylate and 2 mg of loperamide) of this liquid four times per day is effective for treating diarrhea. Similarly, an effective composition may also be prepared and orally administered by using the N-oxide of loperamide, diphenoxylate hydrochloride, or difenoxine hydrochloride in place of the loperamide hydrochloride salt in the above formulation at the .same concentration.
EXAMPLE 2
Method for Treating Diarrhea
A human subject experiencing diarrhea is treated according to the following regimen. Initially, the patient is treated with four teaspoonfuls (20 ml) of a loperamide hydrochloride-containing liquid composition (Imodium® A-D, sold by McNeil Consumer Products Company; 1 mg loperamide HC1 per teaspoonful) and, within about 5 minutes thereof, two tablespoonfuls (30 ml) of a bismuth subsalicylate-containing liquid composition (Pepto-Bismol®, sold by The Procter & Gamble Company; 262.5 mg bismuth subsalicylate per tablespoon). Thereafter, 2 teaspoonfuls (10 ml) of the loperamide-containing composition is taken after every loose stool to a maximum of 8 teaspoonfuls per day; and 2 tablespoonfuls (30 ml) of the bismuth subsalicylate-containing composition is taken every 30 minutes to a maximum of 8 times per day. Within 2 days the patient's diarrhea is stopped and does not recur following cessation of treatment. Similar results may be obtained by using diphenoxylate-containing liquid product (Lomotil®, sold by Searle & Company; 2.5 mg diphenoxylate HCl per teaspoonful) at a dose level of two teaspoonfuls (10 ml) initially and thereafter after every loose stool to a maximum of 8 teaspoonfuls per day.
Claims
1. Pharmaceutical compositions comprising:
(a) one or more bismuth-containing antidiarrheal agents; and
(b) one or more antimotility agents selected from the group consisting of loperamide-derived antidiarrheal agents, diphenoxylate-derived antidiarrheal agents, and mixtures thereof.
2. Pharmaceutical compositions according to Claim 1 wherein the antimotility agent is selected from loperamide-derived antidiarrheal agents.
3. Pharmaceutical compositions according to Claim 2 comprising:
(a) from 0.1% to 99.9% of bismuth-containing antidiarrheal agents selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicylate, bismuth subnitrate, bismith subgallate, and mixtures thereof; and
(b) front 0.001% to 99.9% of loperamide-derived antidiarrheal agents selected from the group consisting of loperamide N-oxide, loperamide and the pharmaceutically-acceptable salts thereof, and mixtures thereof.
4. Pharmaceutical compositions according to Claim 1 wherein the antimotility agent is selected from diptaenoxylate-derived antidiarrheal agents.
5. Pharmaceutical compositions according to Claim 4 comprising:
(a) from 0.1% to 99.9% of bismuth-containing antidiarrheal agents selected from the group consisting of bismuth alurrάnate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicylate, bismuth subnitrate, bismuth subgallate, and mixtures thereof; and
(b) from 0.001% to 99.9% of diphenoxylate-derived antidiarrheal agents selected from the group consisting of diphenoxylate, difenoxine, the pharmaceutically- acceptable salts thereof, and mixtures thereof.
6. Pharmaceutical compositions according to any of Claims 1-5 wherein the bi smuth-containing antidiarrheal agents are selected from the group consisting of bismuth subsalicylate, bismuth subnitrate, bismuth subgallate, and mixtures thereof.
7. Pharmaceutical compositions according to any of Claims 1-6 wherein the bi smuth-containing antidiarrheal agent is bismuth subsalicylate.
8. Pharmaceutical compositions according to Claim 3 wherein the composition comprises a bi smuth-containing salt complex of loperamide formed with the bi smuth-containing antidiarrheal agent.
9. Pharmaceutical compositions according to Claim 5 wherein the ccnpositions comprise a bi smuth-containing salt complex of diphenoxylate formed with the bi smuth-containing antidiarrheal agent.
10. Pharmaceutical compositions according to Claim 5 wherein the compositions comprise a bi smuth-containing salt complex of difenoxine formed with the bi smuth-containing antidiarrheal agent.
11. Pharmaceutical compositions comprising:
(a) from 0.1% to 75% of bi smuth-containing antidiarrheal agent selected from bismuth subsalicylate, bismuth subnitrate, bismuth subgallate, and mixtures thereof;
(b) from 0.001% to 10% of an antimotility agent selected from loperamide N-oxide, diphenoxylate, difenoxine, loperamide, the pharmaceutically-acceptable salts thereof, and mixtures thereof; and
(c) from 25% to 99.9% of pharmaceutically-acceptable carrier material.
12. Pharmaceutical compositions comprising:
(a) from 0.5% to 50% bismuth subsalicylate;
(b) from 0.005% to 5% of antimotility agent selected from the group consisting of loperamide, loperamide N-oxide, diphenoxylate, difenoxine, the pharmaceυtically- acceptable salts thereof, and mixtures thereof; and
(c) from 50% to 99.5% of a pharmaceutically-acceptable carrier material.
13. Pharmaceutical compositions according to Claim 12 wherein the loperamide-derived antidiarrheal agent is selected from loperamide, the pharmaceutically-acceptable salts thereof, and mixtures thereof.
14. Methods for treating diarrhea in humans or lower animals, said methods comprising concurrently administering to a human or lower animal in need of such treatment a safe and effective amount of one or more bismuth-containing antidiarrheal agents and one or more antimotility agents selected from the group consisting of loperamide-derived antidiarrheal agents, diphenoxylate derived antidiarrheal agents, and mixtures thereof.
15. Mathods far treating diarrhea according to Claim 14 wherein the bismuth-containing antidiarrheal agent is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicylate, bismuth subnitrate, bismuth subgallate, and mixtures thereof; and the antimotility agent is selected from the group consisting of loperamide N-oxide, loperamide, diphenoxylate, difenoxine, the pharmaceutically-accept able salts thereof, and mixtures thereof.
16. Methods for treating diarrhea according to Claim 15 wherein the bismuth-containing antidiarrheal agent is selected from the group consisting of bismuth subsalicylate, bismuth subnitrate, bismuth subgallate, and mixtures thereof.
17. Methods for treating diarrhea according to Claim 14 wherein the bismuth-containing antidiarrheal agent is bismuth subsalicylate.
18. Methods for treating diarrhea according to Claim 17 wherein the loperamide-derived antidiarrheal agent is selected from loperamide, the pharmaceutically-acceptable salts thereof, and mixtures thereof.
19. Methods for treating diarrhea according to Claim 17 wherein the loperamide-derived antidiarrheal agent is selected from loperamide N-oxide, the pharmaceutically-acceptable salts thereof, and mixtures thereof.
20. Methods for treating diarrhea according to Claim 17 wherein the diphenoxylate-derived antidiarrheal agent is selected from άliphenoxylate, the pharmaceutically-acceptable salts thereof, and mixtures thereof.
21. Methods for treating diarrhea according to Claim 17 wherein the diphenoxylate-derived antidiarrheal agent is selected from difenoxine, the pharmaceutically-acceptable salts thereof, and mixtures thereof.
22. Methods for treating diarrhea according to Claim 18 wherein the bismuth subsalicylate and loperamide-derived antidiarrheal agent are administered within about 60 minutes or less of each other.
23. Methods for treating diarrhea according to Claim 19 wherein the bismuth subsalicylate and loperamide-derived antidiarrheal agent are administered within about 60 minutes or less of each other.
24. Methods for treating diarrhea according to Claim 20 wherein the bismuth subsalicylate and diphenoxylate-derived antidiarrheal agent are administered within about 60 minutes or less of each other.
25. Methods for treating diarrhea according to Claim 21 wherein the bismuth subsalicylate and diphenoxylate-derived antidiarrheal agent are administered within about 60 minutes or less of each other.
26. Methods for treating diarrhea in humans or lower animals, said methods comprising orally administering to a human or lower animal in need of such treatment a safe and effective amount of a pharmaceutical opposition according to Claim 1.
27. Methods for treating diarrhea in humans or lower animals, said methods comprising orally administering to a human or lower animal in need of such treatment a safe and effective amount of a pharmaceutical composition according to Claim 3.
28. Methods for treating diarrhea in humans or lower animals, said methods comprising orally administering to a human or lower animal in need of such treatment a safe and effective amount of a pharmaceutical composition according to Claim 13.
29. Methods for treating diarrhea in humans or lower animals, said methods comprising orally administering to a human or lower animal in need of such treatment a safe and effective amount of a pharmaceutical composition according to Claim 5.
30. Methods for treating diarrhea in humans or lower animals, said methods comprising orally administering to a human or lower animal in need of such treatment a safe and effective amount of a pharmaceutical composition according to Claim 7.
31. Methods for treating diarrhea in humans or lower animals, said methods comprising orally administering to a human or lower animal in need of such treatment a safe and effective amount of a pharmaceutical composition according to Claim 11.
32. Methods for treating diarrhea in humans or lower animals, said methods comprising orally administering to a human or lower animal in need of such treatment a safe and effective amount of a pharmaceutical composition according to Claim 12.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US54285590A | 1990-06-22 | 1990-06-22 | |
| US542,855 | 1990-06-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992000082A1 true WO1992000082A1 (en) | 1992-01-09 |
Family
ID=24165566
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1991/003770 WO1992000082A1 (en) | 1990-06-22 | 1991-05-31 | Antidiarrheal compositions and methods |
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| Country | Link |
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| WO (1) | WO1992000082A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2317110A (en) * | 1996-09-10 | 1998-03-18 | Ninh On | Anti-diarrhoeal compositions comprising loperamide |
| WO2004112810A1 (en) * | 2003-06-25 | 2004-12-29 | Dong Wha Pharm. Ind. Co., Ltd. | Pharmaceutical compositions for antidiarrhea |
-
1991
- 1991-05-31 WO PCT/US1991/003770 patent/WO1992000082A1/en unknown
Non-Patent Citations (1)
| Title |
|---|
| Chemical Abstracts, vol. 88, no. 7, 13 February 1978, (Columbus, Ohio, US), P. Kramer: "Effect of antidiarrheal and antimotility drugs on ileal excreta", see page 53, abstract 45095t, & Am. J. Dig. Dis. 1977, 22(4), 327-32 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2317110A (en) * | 1996-09-10 | 1998-03-18 | Ninh On | Anti-diarrhoeal compositions comprising loperamide |
| GB2317110B (en) * | 1996-09-10 | 2000-10-18 | Ninh Thuy On | Anti-diarrhoeal compositions comprising loperamide and an opioid |
| WO2004112810A1 (en) * | 2003-06-25 | 2004-12-29 | Dong Wha Pharm. Ind. Co., Ltd. | Pharmaceutical compositions for antidiarrhea |
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