CA2029015C - Pharmaceutical compositions for treating gastrointestinal distress - Google Patents
Pharmaceutical compositions for treating gastrointestinal distressInfo
- Publication number
- CA2029015C CA2029015C CA002029015A CA2029015A CA2029015C CA 2029015 C CA2029015 C CA 2029015C CA 002029015 A CA002029015 A CA 002029015A CA 2029015 A CA2029015 A CA 2029015A CA 2029015 C CA2029015 C CA 2029015C
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical composition
- loperamide
- simethicone
- accordance
- antidiarrheal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- 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
- A61K31/695—Silicon compounds
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
-
- 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
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/12—Magnesium silicate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
Abstract
This invention relates to a pharmaceutical composition for treating gastrointestinal distress comprising an effective amount of an antidiarrheal composition, e.g. loperamide, and an antiflatulent effective amount of simethicone and methods of treating gastrointestinal distress comprising administering such pharmaceutical compositions.
Description
PHARMACEUTICAL COMPOSITIONS FOR TREATING
GASTROINTESTINAL DISTRESS
Field of the Invention This invention relates to a pharmaceutical composition for treating gastrointestinal distress comprising an effective amount of an antidiarrheal composition and an antiflatulent effective amount of simethicone and methods of its use.
Background of the Invention Gastrointestinal distress for the purposes of the present invention is defined as discomfort associated with an intestinal disorder characterized by symptoms of diarrhea and flatulence or gas. Diarrhea is the abnormally frequent passage of watery stool.
Diarrhea may have a variety of causes including bacteria or viral induced diarrhea. Travelers diarrhea, for e~ample, is also believed to be of microbial origin.
Diarrhea may also be a side effect of drug administration, particularly antibiotics. Diarrhea may be induced by food intolerance which is caused by allergy or the ingestion of foods that are excessively fatty, spicy, or contain a high degree of fermentable carbohydrate, roughage or a large number of seeds. Food intolerance may also be brought on by a preformed toxin in the food thus causing focd .,, - -2- 202~01 5 poisoning. Other conditions and diseases can also cause diarrhea, and diarrhea may only be one of many symptoms associated with a major illness.
s Diarrhea is thus a symptom of an intestinal disorder or other bodily function and symptomatic relief can be accomplished by the use of various prescription and nonprescription products. The active ingredients in these products include loperamide, attapulgite, bismuth subsalicylate, diphenoxylate HCl, polycarbophil, calcium polycarbophil and mixtures thereof.
Flatulence or intestinal gas is another intestinal disorder which contributes to gastrointestinal distress.
Such gas e~ists as trapped gas bubbles which manifest feelings of pain, bloating and cramping in the abdominal area. It has been surprisingly found in a study of people complaining of diarrhea that about 67% of the population study also complained of accompanying gas.
While various products e~ist for separately treating diarrhea and gas, no product has heretofore been proposed for treating the combination of the symptoms of both diarrhea and gas which has been defined herein as gastrointestinal distress. It is therefore an object of the present invention to provide a composition for the treatment of gastrointestinal distress in response to a long felt need which has now been recognized by the above-mentioned study.
Summary of the Inventlon The foregolng ob~ect of fulfllling a long felt need for a pharmaceutlcal compositlon whlch can relleve the symptoms of gastrolntestlnal dlstress, l.e. dlarrhea and flatulence has now been accompllshed in accordance wlth the composltlons and methods of the present lnventlon.
In one aspect of the lnventlon, the lnvention comprlses a pharmaceutlcal composltlon for treatlng gastrolntestlnal dlstress comprlslng an effectlve amount of an antldlarrheal composltlon and an antlflatulent effectlve amount of slmethlcone.
In another aspect of the lnventlon, the lnventlon comprlses a pharmaceutlcal composltlon for treatlng gastrolntestlnal dlstress comprlslng an antldlarrheal effectlve amount of loperamlde and an antlflatulent amount of slmethlcone.
In a further aspect of the lnventlon, there ls provlded a use for treatment of gastrolntestlnal dlstress ln a patlent of a comblnatlon pharmaceutlcal composltlon comprlslng an effectlve amount of an antldlarrheal composltlon and an antlflatulent effectlve amount of slmethicone.
In preferred embodlments the antldlarrheal composltlon ls selected from the group conslstlng of loperamlde, attapulglte, blsmuth subsallcylate, dlphenoxylate HCl, polycarbophll, calclum polycarbophll and mlxtures thereof. In more preferred embodlments the antldlarrheal composltlon ls loperamlde.
As embodled and broadly descrlbed hereln, the ~ 74137-1 ,~
202qO1 5 inventlon further comprlses a method for treatlng gastrolntestlnal dlstress comprlslng admlnlstering a comblnatlon pharmaceutlcal composltlon to a patlent comprlslng an effectlve amount of an antldlarrheal composltlon and an antlflatulent effectlve amount of slmethlcone. In preferred embodlments of the method of the lnventlon, the antldiarrheal composltlon is selected from those described above wlth loperamlde being particularly preferred.
- 3a -. 74137-1 20290 ~ 5 Detailed Description of Preferred Embodiments of the Invention Reference will now be made in detail to preferred embodiments of the invention, e~amples of which are illustrated in the following e~amples section.
To achieve the object of the invention of providing a pharmaceutical composition for treatinq gastrointestinal distress, an effective amount of an antidiarrheal composition is combined with an antiflatulent effective amount of simethicone.
The preferred antiflatulent composition combined with effective amounts of an antidiarrheal composition in accordance with the invention is simethicone, also known as polydimethylsilo~ane. Simethicone is a surface active agent which acts as a defoamer or dispersent of gas bubbles by changing the surface tension of the bubbles to enable them to coalesce. The defoaming action of simethicone relieves flatulence by dispersing and preventing the formation of mucous surrounded gas pockets in the gastrointestinal tract. By reducing the size of the gas bubbles, the gas is free to travel through the gastrointestinal tract for release by belching or passing flatus. This release thus relieves the pain and pressure commonly associated with the presence of gas in the gastrointestinal tract.
Simethicone acts largely in the stomach but is also believed to have gas relieving effect in the intestine~.
Since simethicone is not absorbed or metaboli~ed by the body, if released in the stomach area, it will proceed through the gastrointestinal tract into the il~ts~tines.
In preferred embodiments of the compositivn o~ t~.e invention, simethicone is presented in an immediate release form that is released in the stomach area.
Enteric coated simethicones or a combination of immediate release and enteric coated simethicones may be included in accordance with the present invention to release the simethicone in the intestines.
The preferred dosage ranges for simethicone is in the range of about 20 to 125 mg. per dosage unit, generally not to exceed 500 mg/day. The dosage ranges may vary for age and weight of a patient as well as the severity of symptoms.
Effective amount of antidiarrheal compositions combined with effective amounts of simethicone vary with the particular antidiarrheal composition selected. The preferred antidiarrheal compositions and their preferred dosage ranges as a component of the composition in accordance with the invention are as follows: loperamide with a dosage range from about O.S mg. to 8.0 mg.;
attapulgite with a dosage range from about 300 mg. to 1600 mg.; bismuth subsalicylate with a dosage range from about 120 mg. to 1200 mg; dipheno~ylate HCl with a preferred dosage range from about 0.7 mg. to 10 mg.; polycarbophil with a preferred dosage range of about 150 to 2000 mg.;
and calcium polycarbophil with a preferred dosage range of about 150 to 2000 mg. Compatible mi~tures of these antidiarrheal compositions and their pharmaceutically acceptable salts can also be included in a pharmaceutical composition of the invention.
Loperamide is the most preferred antidiar~heal active for use in the pharmaceutical composition of the invention.
Loperamide as a component of the present ~nvention includes pharmaceutically acceptable salts o loperamide 202~0 1 5 such as loperamide HCl. Loperamide acts by slowing intestinal motility and by normalizing water and electrolyte movement through the bowel. Further, loperamide inhibits peristaltic activity by a direct effect on circular and longitudinal muscles of the intestinal walls. Loperamide in man thus prolongs the transit time of the intestinal contents and reduces the daily fecal volume and increases the viscosity and bulk density and thus diminishes loss of foods and electrolytes.
Dosage ranges chosen for the loperamide component of the composition of the present invention depend upon the age and weight of the patient. A preferred adult dose given initially for the treatment of gastrointestinal distress is 4 mg. followed by 2 mg. after each unformed stool until diarrhea is controlled. A preferred ratio of simethicone to loperamide is in the range of from about 100 to 1 to about 10 to 1. Loperamide acts in the intestines and is therefore preferably enteric coated so that it will pass through the stomach and be released in the small intestines. While enteric coating is preferred, it is not essential since loperamide will not be absorbed or metabolized in the stomach but will eventually pass through into the small intestines in any event.
Other ingredients both active and inactive can be added to the combination antidiarrheal~antiflatulence compositions of the invention. For esample, flavoring compositions are desirably added to chewable and liquid dosage forms. The composition of the invention can also be provided in an oral solid dosage form.
Antispasmodic and anticholinergic compositions and their pharmaceutically acceptable salts may, for e~ample, be added to the compositions of the invention. E~amples of 202~01 5 antlspasmodlcs lnclude phenobarbltal, dlcyclomlne HCl, belladonna alkalolds, and atroplne. Further varlous dlgestlve enzymes such as llpase, amylase and protease may also be provlded as addltlonal components ln comblnatlon wlth the composltlons of the lnventlon to reduce and relleve gastrolntestlnal dlstress.
A method of treatlng gastrolntestlnal dlstress ls also provlded ln accordance wlth the present lnventlon. The method comprlses admlnlsterlng a comblnatlon pharmaceutlcal composltlon ln accordance wlth the lnventlon to a patlent havlng the symptoms of gastrolntestlnal dlstress whlch ls a comblnatlon of dlarrhea and flatulence, lncludlng dlscomforts assoclated wlth flatulence whlch may lnclude bloatlng, paln, and uncomfortable fullness. The method comprlses treatlng the patlent wlth an effectlve amount of an antldlarrheal composltlon and an antlflatulent effectlve amount of slmethlcone. The antldlarrheal ls preferably selected from the group conslstlng of loperamlde, attapulglte, blsmuth subsallcylate, polycarbophll, calclum polycarbophll and mlxtures thereof. More preferably, the antldlarrheal composltlon ls loperamlde ln a dosage range of about 0.5 to 8.0 mg. comblned wlth from about 20 to 125 mg. of slmethlcone.
ExamPles The lnventlon wlll now be lllustrated by examples.
The examples are not lntended to be llmltlng of the scope of the present lnventlon but read ln con~unctlon wlth the detalled and general descrlptlon above, provlde further s 74137 1 20290~ 5 understanding of the present lnventlon and an outllne of a process for preparin~ the composltlons of the lnventlon.
-~- 20290 1 5 Esample I. Bi-layer Loperamide HCl 2 mg./Simethicone 80 mg., Chewable Tablet Ingredients mg/tablet SIMETHICONE LAYE~
dicalcium phosphate, NF 784.000 collodial silicon dioxide, NF 40.000 simethicone, USP 80.000 aspartame, NF 5.000 flavors 16.056 stearic acid, NF 18.879 Layer Total943.935 hOPERAMID~ ~AXER
loperamide HCl, USP 2.000 sucrose, NF 12.000 mannitol, USP S65.120 aspartame, NF 2.820 flavors 9.060 stearic acid, NF 6.000 colloidal silicon dioside, NF 3.000 Layer Total600.000 Bi-layer Tablet Total 1541.935 Manufacturing Instructions A. Simethicone Granulation Combine dicalcium phosphate, colloidal silicon dioside, simethicone, aspartame, flav~rs and stearic acid. Mis using an appropriate mixer (e.g., PK
Blender) for 10 minutes.
. Loperamide Granulation Granulate loperamide HCl with sucrose and a portion of the mannitol using an appropriate fluid bed granulator (i.e., Glatt GPCG-3).
Dry blend stearic acid, colloidal silicon dio~ide, aspartame, flavors and the remaining mannitol with the above granulation. Mi~ for 10 minutes in an appropriate mixer (e.g., PK Blender).
C. Compression Compress the loperamide and simethicone granulations as separate layers using a bi-layer tablet press (e.g., Stokes Versa Press).
E~ample II. Bi-layer Loperamide HCl 2 mg./Simethicone 80mg. Swallowable Caplet Ingredients mg/tab SIMETHICONE LAYER
dicalcium phosphate, NF 784.000 collodial silicon dio~ide, NF 40.000 simethicone, USP 80.000 sodium starch glycolate, NF 80.360 stearic acid, NF 20.090 Layer Total1004.450 ~f 3 ~J
LOPERAMIDE LAYER
loperamide HCl, USP 2.000 mannitol, USP 101.000 5 sucrose, NF 12.000 microcrystalline cellulose, NF 6.460 sodium starch glycolate, NF 3.880 stearic acid, NF 1.290 colloidal silicon dioxide, NF 0.646 Layer Total129.276 Bi-layer Caplet Total1133.7260 Manufacturing Instructions A. Simethicone Granulation Combine dicalcium phosphate, colloidal silicon dioside, simethicone, sodium ætarch glycolate and stearic acid. Mis using an appropriate miser (e.g., PK Blender) for 10 minutes.
B. Loperamide Granulation Granulate loperamide HCl with sucrose and a portion of the mannitol using an appropriate fluid bed granulator (e.g., Glatt GPCG-3).
Dry blend stearic acid, colloidal silicon dio~ide, microcrystalline cellulose and sodium starch glycolate with the above granulation and mi~ for 10 minutes using an appropriate mi~er (e.g., PK
Blender).
; ", C. Compression Compress the loperamide and simethicone granulations as separate layers using an appropriate bi-layer tablet press (e.g., Stokes Versa Press).
Example III. Loperamide 2 mg./Simethicone 80 mg. Emulsion Ingredients mg/tab sucrose, NF 35.00 sorbitol, USP (70%) 20.00 15 sodium benzoate, NF 0.10 benzoic acid, USP 0.10 citric acid, USP (Anydrous) 0.032 propylene glycol, USP 15.00 glycerin, USP 15.00 20 carbosy polymethylene, NF 0.20 loperamide HCl, USP 0.02 30% simethicone emulsion 0.80 10% sodium hydroside solution 0.80 purified water, USP, qs to: lO0.00 ml Manufacturing Instructions Combine the above ingredients (escept 10% sodium hydroside solution) with mising.
Add with gentle mising, 10% sodium hydroside solution.
QS to final volume with purified water and mis (e.g.
IKA-Werk miser at low speed).
Example IV. Bismuth Subsalicylate 300 mg/Simethicone 80mg Emulsion~Suspension Esample IV is carried out using the same ingredients and procedure as used for the emulsion of Example III
except that 3.00 gm% bismuth subsalicylate is substituted for 0.02gm% loperamide.
Example V. Loperamide 2mg/Bismuth Subsalicylate 300 mg./Simethicone 80 mg. Emulsion/Suspension Esample V is carried out using the same ingredients and procedure as used for the emulsion of Esample III
escept that 3.00 gm% bismuth subsalicylate is added to the emulsion.
Method of Treating Patients with Gastrointestinal Distress A patient eshibiting the symptoms of gastrointestinal distress, i.e. diarrhea and escess gas or flatulence, is treated by the administration of two caplets of the loperamide/simethicone composition in accordance with Esample II whereby each caplet contains 2 mg. of loperamide and 80 mg. of simethicone as an initial dose followed by administering an additional caplet after each unformed stool not to esceed 8 mg loperamide per day (4 caplets), one caplet being a dosage of 2 mg. of loperamide and 80 mg. of simethicone.
The scope of the present invention is not limited by the description, esamples, and suggested uses herein, and modifications can be made without departi~ rom the MC~-24 spirit of the invention. For example, the combined antidiarrheal and antiflatulent compositions of the invention may be provided in a sustained release formulation for treatment of chronic gastrointestinal distress.
Application of the compositions and methods of the present invention for medical and pharmaceutical uses can be accomplished by any clinical, medical and pharmaceutical method and technique as are presently or prospectively known to those skilled in the art. Thus it is intended that the present invention cover the modifications and variations of this invention provided that they come within the scope of the appended claims and their equivalents.
r
GASTROINTESTINAL DISTRESS
Field of the Invention This invention relates to a pharmaceutical composition for treating gastrointestinal distress comprising an effective amount of an antidiarrheal composition and an antiflatulent effective amount of simethicone and methods of its use.
Background of the Invention Gastrointestinal distress for the purposes of the present invention is defined as discomfort associated with an intestinal disorder characterized by symptoms of diarrhea and flatulence or gas. Diarrhea is the abnormally frequent passage of watery stool.
Diarrhea may have a variety of causes including bacteria or viral induced diarrhea. Travelers diarrhea, for e~ample, is also believed to be of microbial origin.
Diarrhea may also be a side effect of drug administration, particularly antibiotics. Diarrhea may be induced by food intolerance which is caused by allergy or the ingestion of foods that are excessively fatty, spicy, or contain a high degree of fermentable carbohydrate, roughage or a large number of seeds. Food intolerance may also be brought on by a preformed toxin in the food thus causing focd .,, - -2- 202~01 5 poisoning. Other conditions and diseases can also cause diarrhea, and diarrhea may only be one of many symptoms associated with a major illness.
s Diarrhea is thus a symptom of an intestinal disorder or other bodily function and symptomatic relief can be accomplished by the use of various prescription and nonprescription products. The active ingredients in these products include loperamide, attapulgite, bismuth subsalicylate, diphenoxylate HCl, polycarbophil, calcium polycarbophil and mixtures thereof.
Flatulence or intestinal gas is another intestinal disorder which contributes to gastrointestinal distress.
Such gas e~ists as trapped gas bubbles which manifest feelings of pain, bloating and cramping in the abdominal area. It has been surprisingly found in a study of people complaining of diarrhea that about 67% of the population study also complained of accompanying gas.
While various products e~ist for separately treating diarrhea and gas, no product has heretofore been proposed for treating the combination of the symptoms of both diarrhea and gas which has been defined herein as gastrointestinal distress. It is therefore an object of the present invention to provide a composition for the treatment of gastrointestinal distress in response to a long felt need which has now been recognized by the above-mentioned study.
Summary of the Inventlon The foregolng ob~ect of fulfllling a long felt need for a pharmaceutlcal compositlon whlch can relleve the symptoms of gastrolntestlnal dlstress, l.e. dlarrhea and flatulence has now been accompllshed in accordance wlth the composltlons and methods of the present lnventlon.
In one aspect of the lnventlon, the lnvention comprlses a pharmaceutlcal composltlon for treatlng gastrolntestlnal dlstress comprlslng an effectlve amount of an antldlarrheal composltlon and an antlflatulent effectlve amount of slmethlcone.
In another aspect of the lnventlon, the lnventlon comprlses a pharmaceutlcal composltlon for treatlng gastrolntestlnal dlstress comprlslng an antldlarrheal effectlve amount of loperamlde and an antlflatulent amount of slmethlcone.
In a further aspect of the lnventlon, there ls provlded a use for treatment of gastrolntestlnal dlstress ln a patlent of a comblnatlon pharmaceutlcal composltlon comprlslng an effectlve amount of an antldlarrheal composltlon and an antlflatulent effectlve amount of slmethicone.
In preferred embodlments the antldlarrheal composltlon ls selected from the group conslstlng of loperamlde, attapulglte, blsmuth subsallcylate, dlphenoxylate HCl, polycarbophll, calclum polycarbophll and mlxtures thereof. In more preferred embodlments the antldlarrheal composltlon ls loperamlde.
As embodled and broadly descrlbed hereln, the ~ 74137-1 ,~
202qO1 5 inventlon further comprlses a method for treatlng gastrolntestlnal dlstress comprlslng admlnlstering a comblnatlon pharmaceutlcal composltlon to a patlent comprlslng an effectlve amount of an antldlarrheal composltlon and an antlflatulent effectlve amount of slmethlcone. In preferred embodlments of the method of the lnventlon, the antldiarrheal composltlon is selected from those described above wlth loperamlde being particularly preferred.
- 3a -. 74137-1 20290 ~ 5 Detailed Description of Preferred Embodiments of the Invention Reference will now be made in detail to preferred embodiments of the invention, e~amples of which are illustrated in the following e~amples section.
To achieve the object of the invention of providing a pharmaceutical composition for treatinq gastrointestinal distress, an effective amount of an antidiarrheal composition is combined with an antiflatulent effective amount of simethicone.
The preferred antiflatulent composition combined with effective amounts of an antidiarrheal composition in accordance with the invention is simethicone, also known as polydimethylsilo~ane. Simethicone is a surface active agent which acts as a defoamer or dispersent of gas bubbles by changing the surface tension of the bubbles to enable them to coalesce. The defoaming action of simethicone relieves flatulence by dispersing and preventing the formation of mucous surrounded gas pockets in the gastrointestinal tract. By reducing the size of the gas bubbles, the gas is free to travel through the gastrointestinal tract for release by belching or passing flatus. This release thus relieves the pain and pressure commonly associated with the presence of gas in the gastrointestinal tract.
Simethicone acts largely in the stomach but is also believed to have gas relieving effect in the intestine~.
Since simethicone is not absorbed or metaboli~ed by the body, if released in the stomach area, it will proceed through the gastrointestinal tract into the il~ts~tines.
In preferred embodiments of the compositivn o~ t~.e invention, simethicone is presented in an immediate release form that is released in the stomach area.
Enteric coated simethicones or a combination of immediate release and enteric coated simethicones may be included in accordance with the present invention to release the simethicone in the intestines.
The preferred dosage ranges for simethicone is in the range of about 20 to 125 mg. per dosage unit, generally not to exceed 500 mg/day. The dosage ranges may vary for age and weight of a patient as well as the severity of symptoms.
Effective amount of antidiarrheal compositions combined with effective amounts of simethicone vary with the particular antidiarrheal composition selected. The preferred antidiarrheal compositions and their preferred dosage ranges as a component of the composition in accordance with the invention are as follows: loperamide with a dosage range from about O.S mg. to 8.0 mg.;
attapulgite with a dosage range from about 300 mg. to 1600 mg.; bismuth subsalicylate with a dosage range from about 120 mg. to 1200 mg; dipheno~ylate HCl with a preferred dosage range from about 0.7 mg. to 10 mg.; polycarbophil with a preferred dosage range of about 150 to 2000 mg.;
and calcium polycarbophil with a preferred dosage range of about 150 to 2000 mg. Compatible mi~tures of these antidiarrheal compositions and their pharmaceutically acceptable salts can also be included in a pharmaceutical composition of the invention.
Loperamide is the most preferred antidiar~heal active for use in the pharmaceutical composition of the invention.
Loperamide as a component of the present ~nvention includes pharmaceutically acceptable salts o loperamide 202~0 1 5 such as loperamide HCl. Loperamide acts by slowing intestinal motility and by normalizing water and electrolyte movement through the bowel. Further, loperamide inhibits peristaltic activity by a direct effect on circular and longitudinal muscles of the intestinal walls. Loperamide in man thus prolongs the transit time of the intestinal contents and reduces the daily fecal volume and increases the viscosity and bulk density and thus diminishes loss of foods and electrolytes.
Dosage ranges chosen for the loperamide component of the composition of the present invention depend upon the age and weight of the patient. A preferred adult dose given initially for the treatment of gastrointestinal distress is 4 mg. followed by 2 mg. after each unformed stool until diarrhea is controlled. A preferred ratio of simethicone to loperamide is in the range of from about 100 to 1 to about 10 to 1. Loperamide acts in the intestines and is therefore preferably enteric coated so that it will pass through the stomach and be released in the small intestines. While enteric coating is preferred, it is not essential since loperamide will not be absorbed or metabolized in the stomach but will eventually pass through into the small intestines in any event.
Other ingredients both active and inactive can be added to the combination antidiarrheal~antiflatulence compositions of the invention. For esample, flavoring compositions are desirably added to chewable and liquid dosage forms. The composition of the invention can also be provided in an oral solid dosage form.
Antispasmodic and anticholinergic compositions and their pharmaceutically acceptable salts may, for e~ample, be added to the compositions of the invention. E~amples of 202~01 5 antlspasmodlcs lnclude phenobarbltal, dlcyclomlne HCl, belladonna alkalolds, and atroplne. Further varlous dlgestlve enzymes such as llpase, amylase and protease may also be provlded as addltlonal components ln comblnatlon wlth the composltlons of the lnventlon to reduce and relleve gastrolntestlnal dlstress.
A method of treatlng gastrolntestlnal dlstress ls also provlded ln accordance wlth the present lnventlon. The method comprlses admlnlsterlng a comblnatlon pharmaceutlcal composltlon ln accordance wlth the lnventlon to a patlent havlng the symptoms of gastrolntestlnal dlstress whlch ls a comblnatlon of dlarrhea and flatulence, lncludlng dlscomforts assoclated wlth flatulence whlch may lnclude bloatlng, paln, and uncomfortable fullness. The method comprlses treatlng the patlent wlth an effectlve amount of an antldlarrheal composltlon and an antlflatulent effectlve amount of slmethlcone. The antldlarrheal ls preferably selected from the group conslstlng of loperamlde, attapulglte, blsmuth subsallcylate, polycarbophll, calclum polycarbophll and mlxtures thereof. More preferably, the antldlarrheal composltlon ls loperamlde ln a dosage range of about 0.5 to 8.0 mg. comblned wlth from about 20 to 125 mg. of slmethlcone.
ExamPles The lnventlon wlll now be lllustrated by examples.
The examples are not lntended to be llmltlng of the scope of the present lnventlon but read ln con~unctlon wlth the detalled and general descrlptlon above, provlde further s 74137 1 20290~ 5 understanding of the present lnventlon and an outllne of a process for preparin~ the composltlons of the lnventlon.
-~- 20290 1 5 Esample I. Bi-layer Loperamide HCl 2 mg./Simethicone 80 mg., Chewable Tablet Ingredients mg/tablet SIMETHICONE LAYE~
dicalcium phosphate, NF 784.000 collodial silicon dioxide, NF 40.000 simethicone, USP 80.000 aspartame, NF 5.000 flavors 16.056 stearic acid, NF 18.879 Layer Total943.935 hOPERAMID~ ~AXER
loperamide HCl, USP 2.000 sucrose, NF 12.000 mannitol, USP S65.120 aspartame, NF 2.820 flavors 9.060 stearic acid, NF 6.000 colloidal silicon dioside, NF 3.000 Layer Total600.000 Bi-layer Tablet Total 1541.935 Manufacturing Instructions A. Simethicone Granulation Combine dicalcium phosphate, colloidal silicon dioside, simethicone, aspartame, flav~rs and stearic acid. Mis using an appropriate mixer (e.g., PK
Blender) for 10 minutes.
. Loperamide Granulation Granulate loperamide HCl with sucrose and a portion of the mannitol using an appropriate fluid bed granulator (i.e., Glatt GPCG-3).
Dry blend stearic acid, colloidal silicon dio~ide, aspartame, flavors and the remaining mannitol with the above granulation. Mi~ for 10 minutes in an appropriate mixer (e.g., PK Blender).
C. Compression Compress the loperamide and simethicone granulations as separate layers using a bi-layer tablet press (e.g., Stokes Versa Press).
E~ample II. Bi-layer Loperamide HCl 2 mg./Simethicone 80mg. Swallowable Caplet Ingredients mg/tab SIMETHICONE LAYER
dicalcium phosphate, NF 784.000 collodial silicon dio~ide, NF 40.000 simethicone, USP 80.000 sodium starch glycolate, NF 80.360 stearic acid, NF 20.090 Layer Total1004.450 ~f 3 ~J
LOPERAMIDE LAYER
loperamide HCl, USP 2.000 mannitol, USP 101.000 5 sucrose, NF 12.000 microcrystalline cellulose, NF 6.460 sodium starch glycolate, NF 3.880 stearic acid, NF 1.290 colloidal silicon dioxide, NF 0.646 Layer Total129.276 Bi-layer Caplet Total1133.7260 Manufacturing Instructions A. Simethicone Granulation Combine dicalcium phosphate, colloidal silicon dioside, simethicone, sodium ætarch glycolate and stearic acid. Mis using an appropriate miser (e.g., PK Blender) for 10 minutes.
B. Loperamide Granulation Granulate loperamide HCl with sucrose and a portion of the mannitol using an appropriate fluid bed granulator (e.g., Glatt GPCG-3).
Dry blend stearic acid, colloidal silicon dio~ide, microcrystalline cellulose and sodium starch glycolate with the above granulation and mi~ for 10 minutes using an appropriate mi~er (e.g., PK
Blender).
; ", C. Compression Compress the loperamide and simethicone granulations as separate layers using an appropriate bi-layer tablet press (e.g., Stokes Versa Press).
Example III. Loperamide 2 mg./Simethicone 80 mg. Emulsion Ingredients mg/tab sucrose, NF 35.00 sorbitol, USP (70%) 20.00 15 sodium benzoate, NF 0.10 benzoic acid, USP 0.10 citric acid, USP (Anydrous) 0.032 propylene glycol, USP 15.00 glycerin, USP 15.00 20 carbosy polymethylene, NF 0.20 loperamide HCl, USP 0.02 30% simethicone emulsion 0.80 10% sodium hydroside solution 0.80 purified water, USP, qs to: lO0.00 ml Manufacturing Instructions Combine the above ingredients (escept 10% sodium hydroside solution) with mising.
Add with gentle mising, 10% sodium hydroside solution.
QS to final volume with purified water and mis (e.g.
IKA-Werk miser at low speed).
Example IV. Bismuth Subsalicylate 300 mg/Simethicone 80mg Emulsion~Suspension Esample IV is carried out using the same ingredients and procedure as used for the emulsion of Example III
except that 3.00 gm% bismuth subsalicylate is substituted for 0.02gm% loperamide.
Example V. Loperamide 2mg/Bismuth Subsalicylate 300 mg./Simethicone 80 mg. Emulsion/Suspension Esample V is carried out using the same ingredients and procedure as used for the emulsion of Esample III
escept that 3.00 gm% bismuth subsalicylate is added to the emulsion.
Method of Treating Patients with Gastrointestinal Distress A patient eshibiting the symptoms of gastrointestinal distress, i.e. diarrhea and escess gas or flatulence, is treated by the administration of two caplets of the loperamide/simethicone composition in accordance with Esample II whereby each caplet contains 2 mg. of loperamide and 80 mg. of simethicone as an initial dose followed by administering an additional caplet after each unformed stool not to esceed 8 mg loperamide per day (4 caplets), one caplet being a dosage of 2 mg. of loperamide and 80 mg. of simethicone.
The scope of the present invention is not limited by the description, esamples, and suggested uses herein, and modifications can be made without departi~ rom the MC~-24 spirit of the invention. For example, the combined antidiarrheal and antiflatulent compositions of the invention may be provided in a sustained release formulation for treatment of chronic gastrointestinal distress.
Application of the compositions and methods of the present invention for medical and pharmaceutical uses can be accomplished by any clinical, medical and pharmaceutical method and technique as are presently or prospectively known to those skilled in the art. Thus it is intended that the present invention cover the modifications and variations of this invention provided that they come within the scope of the appended claims and their equivalents.
r
Claims (20)
1. A pharmaceutical composition for treating gastrointestinal distress comprising an effective amount of an antidiarrheal composition and an antiflatulent effective amount of simethicone.
2. A composition according to claim 1 wherein the antidiarrheal composition is selected from the group consisting of loperamide, attapulgite, bismuth subsalicylate, diphenoxylate, polycarbophil, calcium polycarbophil, their pharmaceutically acceptable salts and mixtures thereof.
3. A composition according to claim 2 wherein the antiflatulent effective amount of simethicone is in the range of about 20 to 125 mg. per dose and the antidiarrheal composition and amount thereof is selected from the group consisting of: from about 0.5 to 8.0 mg. of loperamide; about 300 mg. to 1600 mg. of attapulgite; about 120 mg. to 1200 mg. of bismuth subsalicylate; about 0.7 mg. to 10 mg. of diphenoxylate HCl; about 150 mg. to 2000 mg. of polycarbophil; and about 150 to 2000 mg. of calcium polycarbophil per dose, and pharmaceutically acceptable salts thereof.
4. A pharmaceutical composition for treating gastrointestinal distress comprising an antidiarrheal effective amount of loperamide and an antiflatulent amount of simethicone.
5. A pharmaceutical composition according to claim 4 wherein the ratio of simethicone: loperamide is in the range of from about 100:1 to 10:1.
6. A pharmaceutical composition according to claim 4 wherein the antidiarrheal effectiveness amount of loperamide is in the range of 0.6 to 8.0 mg. of loperamide and 20 to 125 mg. of simethicone per dose.
7. A pharmaceutical composition according to claim 4 wherein the loperamide is 2 mg. and the simethicone 80 mg. per dose.
8. A pharmaceutical composition in accordance with claim 1 wherein the pharmaceutical composition is in an oral solid dosage form.
9. A pharmaceutical composition in accordance with claim 3 wherein the pharmaceutical composition is in an oral solid dosage form.
10. A pharmaceutical composition in accordance with claim 4 wherein the pharmaceutical composition is in an oral solid dosage form.
11. A pharmaceutical composition in accordance with claim 1 wherein the pharmaceutical composition is in liquid dosage form.
12. A pharmaceutical composition in accordance with claim 3 wherein the pharmaceutical composition is in liquid dosage form.
13. A pharmaceutical composition in accordance with claim 4 wherein the pharmaceutical composition is in liquid dosage form.
14. A pharmaceutical composition in accordance with claim 1 wherein the pharmaceutical composition is in chewable dosage form.
15. A pharmaceutical composition in accordance with claim 3 wherein the pharmaceutical composition is in chewable dosage form.
16. A pharmaceutical composition in accordance with claim 4 wherein the pharmaceutical composition is in chewable dosage form.
17. The use for treatment of gastrointestinal distress in a patient of a combination pharmaceutical composition comprising an effective amount of an antidiarrheal composition and an antiflatulent effective amount of simethicone.
18. The use of the combination pharmaceutical composition of claim 17 wherein the antidiarrheal composition is selected from the group consisting of loperamide, attapulgite, bismuth subsalicylate, diphenoxylate HCl, polycarbophil, calcium polycarbophil, their pharmaceutically acceptable salts and mixtures thereof.
19. The use of the combination pharmaceutical composition of claim 17 wherein the combination pharmaceutical composition comprises from about 20 to 125 mg. of simethicone and 0.5 to 8.0 mg. of loperamide.
20. The use of the combination pharmaceutical composition of claim 17 wherein the pharmaceutical composition comprises 80 mg. of simethicone and 2 mg. of loperamide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US43070789A | 1989-11-01 | 1989-11-01 | |
| US430,707 | 1989-11-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2029015A1 CA2029015A1 (en) | 1991-05-02 |
| CA2029015C true CA2029015C (en) | 1996-02-20 |
Family
ID=23708683
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002029015A Expired - Lifetime CA2029015C (en) | 1989-11-01 | 1990-10-31 | Pharmaceutical compositions for treating gastrointestinal distress |
Country Status (15)
| Country | Link |
|---|---|
| US (2) | US5248505A (en) |
| EP (1) | EP0428296B1 (en) |
| JP (1) | JP2856289B2 (en) |
| KR (1) | KR910009273A (en) |
| AT (1) | ATE106737T1 (en) |
| AU (1) | AU634833B2 (en) |
| CA (1) | CA2029015C (en) |
| DE (2) | DE19975006I2 (en) |
| ES (1) | ES2058815T3 (en) |
| GR (1) | GR1002091B (en) |
| IE (1) | IE62605B1 (en) |
| IN (1) | IN171919B (en) |
| NZ (1) | NZ235876A (en) |
| PT (1) | PT95752B (en) |
| ZA (1) | ZA908748B (en) |
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| JP2711759B2 (en) * | 1990-10-24 | 1998-02-10 | エスエス製薬 株式会社 | Antidiarrheal composition |
| JP2609022B2 (en) * | 1990-11-29 | 1997-05-14 | 北陸製薬株式会社 | Polycarbophil calcium-containing preparation |
| GR1002332B (en) * | 1992-05-21 | 1996-05-16 | Mcneil-Ppc Inc. | Novel simethicone containing pharmaceutical compositions. |
| DE4409357C2 (en) * | 1994-03-18 | 1996-10-17 | Upmeyer Hans Juergen | Use of Dimeticon to eradicate Heliobacter pylori |
| WO1995025525A1 (en) * | 1994-03-18 | 1995-09-28 | Alfred Schmidt | The use of dimeticone for the local antibacterial therapy and/or the prevention and therapy of helicobacter pylori (hp) associated syndromes and infectious diseases |
| US6190691B1 (en) | 1994-04-12 | 2001-02-20 | Adolor Corporation | Methods for treating inflammatory conditions |
| US5962477A (en) * | 1994-04-12 | 1999-10-05 | Adolor Corporation | Screening methods for cytokine inhibitors |
| US5534544A (en) * | 1994-08-19 | 1996-07-09 | New England Medical Center Hospitals, Inc. | Surfactants and emulsifying agents to inhibit Helicobacter |
| US6028062A (en) * | 1995-03-15 | 2000-02-22 | Upmeyer; Hans-Juergen | Use of dimeticone for the local antibacterial therapy and/or the prevention and therapy of helicobacter pylori (Hp) associated syndromes and infectious diseases |
| US5849761A (en) * | 1995-09-12 | 1998-12-15 | Regents Of The University Of California | Peripherally active anti-hyperalgesic opiates |
| US6573282B1 (en) | 1995-09-12 | 2003-06-03 | Adolor Corporation | Peripherally active anti-hyperalgesic opiates |
| US5908636A (en) * | 1996-06-28 | 1999-06-01 | Mcneil-Ppc, Inc. | Fill material for soft gelatin pharmaceutical dosage form containing an antiflatulent |
| US5997911A (en) * | 1996-08-27 | 1999-12-07 | Brinton Veterinary Supply, Inc. | Composition and method for reducing diarrhea in poultry and swine |
| JP3001440B2 (en) * | 1996-11-25 | 2000-01-24 | 日本電気通信システム株式会社 | Virtual LAN method |
| FR2759294B1 (en) * | 1997-02-07 | 1999-04-30 | Georges Serge Grimberg | OESOGASTROINTESTINAL COMPOSITION BASED ON COAL OF WHICH THE PORES ARE CLOGGED BY A COATING, AND WHICH CAN BE USED ALONE OR IN ASSOCIATIOIN WITH OTHER MOLECULES |
| US7101573B2 (en) * | 2001-09-28 | 2006-09-05 | Mcneil-Pcc, Inc. | Simethicone solid oral dosage form |
| US20030099699A1 (en) * | 2001-11-13 | 2003-05-29 | Hanshew Dwight D. | Storage stable thyroxine active drug formulations and methods for their production |
| US6645526B2 (en) * | 2001-11-13 | 2003-11-11 | Mylan Pharmaceuticals, Inc. | Storage stable thyroxine active drug formulations and methods for their production |
| EP1545516B1 (en) * | 2002-08-26 | 2008-09-03 | S.L.A. Pharma AG | Topical formulation comprising at least 10% of metronidazole in white petrolatum and its use in the anal and rectal region |
| CO5790164A1 (en) * | 2006-08-10 | 2007-08-31 | Procaps S A | SOLID PHARMACEUTICAL COMPOSITION THAT INCLUDES IN COMBINATION AN INTESTINAL MOTILITY REGULATING AGENT AND AN ANTIFLATULENT AGENT |
| WO2016130830A1 (en) * | 2015-02-11 | 2016-08-18 | The Fix, Llc | Compositions and methods for combination ingredient delivery |
| MA41620A (en) | 2015-05-14 | 2018-01-09 | Abdi Ibrahim Ilac Sanayi Ve Ticaret A S | PHARMACEUTICAL COMPOSITION CONSISTING OF SIMETHICONE AND OTILONIUM |
| US20180311201A1 (en) | 2015-06-12 | 2018-11-01 | Santa Farma ?Laç Sanay? A. ?. | Oral pharmaceutical composition comprising otilonium bromide and simethicone with certain bulk density and improved dissolution characteristics |
| BR112018013828A2 (en) * | 2016-01-13 | 2018-12-11 | Johnson & Johnson Consumer Inc. | improved composition comprising at least one cadotrilla |
| AU2019225236A1 (en) * | 2018-02-26 | 2020-09-10 | R.P. Scherer Technologies, Llc | Pharmaceutical dosage form for an emulsion of simethicone and loperamide |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2441098A (en) * | 1946-09-09 | 1948-05-04 | Corning Glass Works | Methyl siloxane polymers and method of preparation |
| US2951011A (en) * | 1956-12-17 | 1960-08-30 | Feinstone Wolffe Harry | Silicone composition for the relief of gastro-intestinal distress and method of using same |
| US2898340A (en) * | 1957-07-05 | 1959-08-04 | Paul A J Janssen | 2,2-diaryl-omega-(4'-phenyl-1'-piperidino) alkanonitriles |
| AU407324B2 (en) * | 1962-05-01 | 1970-10-28 | Smith, Kline & French Laboratories | Powdered silicone products and processes |
| DE2611979C3 (en) * | 1976-03-20 | 1981-02-26 | Alois 8400 Regensburg Mayer | Preparations for the treatment of flatulence and diarrhea in animals |
| US4588589A (en) * | 1983-10-13 | 1986-05-13 | Richardson-Vicks Inc. | Antidiarrheal compositions and use thereof |
| FR2565107B1 (en) * | 1984-05-30 | 1986-09-05 | Ucb Laboratoires | NOVEL MEDICINAL PRODUCT BASED ON ACTIVE CARBON AND ITS PREPARATION METHOD |
| US4676984A (en) * | 1985-08-14 | 1987-06-30 | American Home Products Corp. | Rehydratable antacid composition |
| US4786502A (en) * | 1986-10-06 | 1988-11-22 | The Procter & Gamble Company | Palatable solid pharmaceutical compositions |
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1990
- 1990-10-29 NZ NZ235876A patent/NZ235876A/en unknown
- 1990-10-29 IN IN908/CAL/90A patent/IN171919B/en unknown
- 1990-10-31 CA CA002029015A patent/CA2029015C/en not_active Expired - Lifetime
- 1990-10-31 ES ES90311930T patent/ES2058815T3/en not_active Expired - Lifetime
- 1990-10-31 AT AT90311930T patent/ATE106737T1/en active
- 1990-10-31 DE DE1999175006 patent/DE19975006I2/en active Active
- 1990-10-31 EP EP90311930A patent/EP0428296B1/en not_active Expired - Lifetime
- 1990-10-31 ZA ZA908748A patent/ZA908748B/en unknown
- 1990-10-31 DE DE69009684T patent/DE69009684T2/en not_active Expired - Lifetime
- 1990-10-31 IE IE393190A patent/IE62605B1/en not_active IP Right Cessation
- 1990-10-31 AU AU65691/90A patent/AU634833B2/en not_active Expired
- 1990-10-31 PT PT95752A patent/PT95752B/en not_active IP Right Cessation
- 1990-11-01 JP JP2293779A patent/JP2856289B2/en not_active Expired - Lifetime
- 1990-11-01 GR GR900100785A patent/GR1002091B/en not_active IP Right Cessation
- 1990-11-01 KR KR1019900017660A patent/KR910009273A/en not_active Application Discontinuation
-
1992
- 1992-03-17 US US07/852,355 patent/US5248505A/en not_active Expired - Lifetime
-
1995
- 1995-04-19 US US08/426,423 patent/US5612054A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE69009684D1 (en) | 1994-07-14 |
| PT95752B (en) | 1998-05-29 |
| US5248505A (en) | 1993-09-28 |
| DE19975006I2 (en) | 2006-02-02 |
| PT95752A (en) | 1991-09-30 |
| CA2029015A1 (en) | 1991-05-02 |
| GR900100785A (en) | 1992-04-17 |
| AU634833B2 (en) | 1993-03-04 |
| ATE106737T1 (en) | 1994-06-15 |
| IE62605B1 (en) | 1995-02-22 |
| GR1002091B (en) | 1995-12-28 |
| JP2856289B2 (en) | 1999-02-10 |
| AU6569190A (en) | 1991-05-09 |
| EP0428296A3 (en) | 1991-07-03 |
| ZA908748B (en) | 1992-07-29 |
| ES2058815T3 (en) | 1994-11-01 |
| NZ235876A (en) | 1992-06-25 |
| EP0428296B1 (en) | 1994-06-08 |
| US5612054A (en) | 1997-03-18 |
| KR910009273A (en) | 1991-06-28 |
| EP0428296A2 (en) | 1991-05-22 |
| DE69009684T2 (en) | 1994-10-06 |
| JPH03206048A (en) | 1991-09-09 |
| IE903931A1 (en) | 1991-05-08 |
| IN171919B (en) | 1993-02-06 |
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