CA2030449A1 - Prolonged release drug tablet formulations - Google Patents
Prolonged release drug tablet formulationsInfo
- Publication number
- CA2030449A1 CA2030449A1 CA 2030449 CA2030449A CA2030449A1 CA 2030449 A1 CA2030449 A1 CA 2030449A1 CA 2030449 CA2030449 CA 2030449 CA 2030449 A CA2030449 A CA 2030449A CA 2030449 A1 CA2030449 A1 CA 2030449A1
- Authority
- CA
- Canada
- Prior art keywords
- weight
- composition
- gel
- drug
- forming
- 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.)
- Abandoned
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE INVENTION
A prolonged-release unit dosage formulation or pharmaceutical composition, preferably in tablet form, is described. The composition consists essentially of a gel-forming dietary fiber, a biologically-absorbable drug or other active therapeutic agent, and certain specific disintegrants, namely, a physiologically-acceptable edible acid and a mineral salt which releases a physiologically-acceptable gas upon inges-tion, preferably carbon dioxide, e.g., a mineral carbonate or bicarbonate, and advantageously dextrose or like soluble sugar. The dietary fiber-containing composition, when compressed into a tablet together with the drug and the specific disintegrants, provides a unique and efficient prolonged-action drug-delivery system.
HK 5/dlk
A prolonged-release unit dosage formulation or pharmaceutical composition, preferably in tablet form, is described. The composition consists essentially of a gel-forming dietary fiber, a biologically-absorbable drug or other active therapeutic agent, and certain specific disintegrants, namely, a physiologically-acceptable edible acid and a mineral salt which releases a physiologically-acceptable gas upon inges-tion, preferably carbon dioxide, e.g., a mineral carbonate or bicarbonate, and advantageously dextrose or like soluble sugar. The dietary fiber-containing composition, when compressed into a tablet together with the drug and the specific disintegrants, provides a unique and efficient prolonged-action drug-delivery system.
HK 5/dlk
Description
-2 ~J ll'f ''U~ ' f.'. 3 DELIVERY SYSTEM CONTAINING A GEL-FORMING DIETARY
FIBE~ AND A DRUG
BACKGROUND OF THE INVENTION
Field of the Invention and Prior Art The present invention relates to novel prolonged release formulations or compositions, e.g.,tablet, granule, lozenge, capsule, or like formulations, containing a gel-forming dietary fiber and a drug or other active therapeutic agent plus certain essential disintegrants.
Many drugs and vitamins must be released in a uniform and/or continuous manner over a period of time.
Water-soluble vitamins, for example, unless placed into a time-release form, are almost immediately released into the blood stream once they dissolve in the stomach. Aspirin is frequently coated to minimize gastric upset and release the drug over a period of time. Sustained-release dosage forms also avoid the necessity of frequent administration of the drug while, at the same time, achieving a desired blood level of active ingredient.
Various cellulose derivatives have been used to prov~de rapid disintegration of tablets, such as in U.S. Patent 3,266,992, which describes the use of methylcellulose, sodium carboxymethylcellulose and hydroxyethylcellulose for such purpose. However, in contrast, hydroxypropylmethylcellulose in enteric coatings has been disclosed in U.S. Patent 2,887,~40 to prevent disintegration of a tablet core and delay release of the active ingredients.
- 1 - H-K 5fdlk 2 5; ;v -U.S. Patent 3,870,790 discloses a method of preparing a long-acting buccal composition for admini-stering a therapeutic agent using an effective amount of hydroxypropylmethylcellulose which has been sub-jected to controlled humidity. Other processes for treating cellulose derivatives are described in U.S.
Patents 4,226,849, 4,357,469, 4,369,172, 4,389,393, 4,540,566, 4,795,327, and 4,849,229, the treated cellulose derivatives then being used in a solid drug dosage unit form to produce a controlled and prolonged-release pattern of a drug upon administration thereof.
For purposes of definition in this specification, the term "dietary fiber" is defined as "remnants of plant cells resistant to hydrolysis by the alimentary enzymes of man, the group of substances that remain in the ileum but are partly hydrolyzed by bacteria in the colon", according to JAMA 262, No. 4, 542-546 (July 28, 1989) in the Council Report entitled "Dietary Fiber and Health", at page 542. This article, moreover, gives considerably information as to what constitutes a "dietary fiber" and is accordingly incorporated herein by reference.
Gel-forming dietary fibers include mucillages, plant gums, pectins or pectic substances, and lignin, all of which are endogenous compounds of plant mater-ials which are resistant to digestion by enzymes in the monogastric stomach o~ small intestine. Chemically, nearly all of these plant materials are carbohydrates composed of repeating monosaccharide (sugar) units.
Disaccharides have two sugar units, oligosaccharides three to twelve, and polysaccharides may contain a million or more. The water-soluble fractions of these substances form gels in the stomach and intes-tinal tract and are known to lower serum cholesterol.
FIBE~ AND A DRUG
BACKGROUND OF THE INVENTION
Field of the Invention and Prior Art The present invention relates to novel prolonged release formulations or compositions, e.g.,tablet, granule, lozenge, capsule, or like formulations, containing a gel-forming dietary fiber and a drug or other active therapeutic agent plus certain essential disintegrants.
Many drugs and vitamins must be released in a uniform and/or continuous manner over a period of time.
Water-soluble vitamins, for example, unless placed into a time-release form, are almost immediately released into the blood stream once they dissolve in the stomach. Aspirin is frequently coated to minimize gastric upset and release the drug over a period of time. Sustained-release dosage forms also avoid the necessity of frequent administration of the drug while, at the same time, achieving a desired blood level of active ingredient.
Various cellulose derivatives have been used to prov~de rapid disintegration of tablets, such as in U.S. Patent 3,266,992, which describes the use of methylcellulose, sodium carboxymethylcellulose and hydroxyethylcellulose for such purpose. However, in contrast, hydroxypropylmethylcellulose in enteric coatings has been disclosed in U.S. Patent 2,887,~40 to prevent disintegration of a tablet core and delay release of the active ingredients.
- 1 - H-K 5fdlk 2 5; ;v -U.S. Patent 3,870,790 discloses a method of preparing a long-acting buccal composition for admini-stering a therapeutic agent using an effective amount of hydroxypropylmethylcellulose which has been sub-jected to controlled humidity. Other processes for treating cellulose derivatives are described in U.S.
Patents 4,226,849, 4,357,469, 4,369,172, 4,389,393, 4,540,566, 4,795,327, and 4,849,229, the treated cellulose derivatives then being used in a solid drug dosage unit form to produce a controlled and prolonged-release pattern of a drug upon administration thereof.
For purposes of definition in this specification, the term "dietary fiber" is defined as "remnants of plant cells resistant to hydrolysis by the alimentary enzymes of man, the group of substances that remain in the ileum but are partly hydrolyzed by bacteria in the colon", according to JAMA 262, No. 4, 542-546 (July 28, 1989) in the Council Report entitled "Dietary Fiber and Health", at page 542. This article, moreover, gives considerably information as to what constitutes a "dietary fiber" and is accordingly incorporated herein by reference.
Gel-forming dietary fibers include mucillages, plant gums, pectins or pectic substances, and lignin, all of which are endogenous compounds of plant mater-ials which are resistant to digestion by enzymes in the monogastric stomach o~ small intestine. Chemically, nearly all of these plant materials are carbohydrates composed of repeating monosaccharide (sugar) units.
Disaccharides have two sugar units, oligosaccharides three to twelve, and polysaccharides may contain a million or more. The water-soluble fractions of these substances form gels in the stomach and intes-tinal tract and are known to lower serum cholesterol.
3~
- 2 - , H-K 5/dlk 3 . ?~
Gums and mucillages have no common structure but are polysaccharides containing several sugars with alternating monomer structures and may or may not contain uronic acids. There are many gums found in plants and cereal grains. Guar and locust bean gums are galactomannans, whereas g~m arabic i~ an acidic polymer of galactose and rhammose. Oat and barley contain gums, but are not practical for use in the present application because of the low percentage of active gum per weight volume. Most of the gums in the present application are effective at much lower dosages. Suitable gums include, inter alia, besides guar gum, the following: locust bean gum, acacia gum, gum arabic, xanthan gum, carregeenan gum, karaya gum, tragacanth gum, and ghatti gum.
Pectin substances or pectins are mixtures of polysaccharides of partially methylated and 1,4-D
galacturonic acid units with side chains containing arabinose, galactose, xylose, and rhammose. They are contained in many fruits and vegetables as well as other plants.
Other suitable gel-forming dietary fibers include psyllium husks, algal polysaccharides, glucomannan, and agar, to name a few. Lignin is a non-carbohydrate polymer of aromatic plant alcohols comprisinq oxy-genated phenylpropane units. As a plant matures, more lignin is produced, which acts as a sort of cement as it hardens and holds together other plant cell wall constituents. Lignin passes through the digestive tract with very little change.
As already mentioned, a recent review of dietary fiber which mentions these substances is contained in the following reference: Dietary Fiber and Health, JAMA 262: No. 4, 542-546 (1989), from the Council on Scientific Affairs, American ~edical Association.
- 3 - H-K 5/dlk ~.,J 1:~3 Some gel-forming fibers such as guar gum are used as binders and disintegrators for compressed tablets, but at fairly low levels. At higher levels, these gel-forming fibers and gums are known not to dissolve properly when compressed into tablets.
Various unsuccessful attempts have been made to solve the problem of improper and incomplete dissolu-tion of guar gum tablets. EPA 0080673 describes these problems in detail, and discloses the use of 5 to 30%
of highly-dispersed silica gel in guar tablets.
Normally used tablet disintegrants or additives such as polyvinylpyrrolidone (crosslinking agent), sodium carboxymethyl-starch, cornstarch, microcrystalline cellulose, and so on, do not lead to satisfactory results. Hard tablets are produced which do not swell properly, and which form an impenetrable layer of gel around a powder core which may pass through the gastrointestinal tract undissolved.
U.S. Patent 4,824,672 describes the use of mineral carbonates to enhance dispersion of gel-forming dietary fibers in orally-administrable pharmaceutical composi-tions for use in reducing serum cholesterol levels.
Such compositions have proved to be very effective in use for their intended purpose, but do not provide a satisfactory matrix for providing a prolonged-release unit dosage formulation of a biologically-absorbable therapeutic agent or drug.
The foregoing EPO 0080673 mentions the employmént of citric acid with guar gum tablets. The citric acid and sweeteners were used, according to that disclosure, to improve the acceptability of the tablets if they were to be chewed. Accordingly, the citric acid was there used only to provide flavor and an aromatic quality to the product. Such formulations did not contain any mineral carbonate or bicarbonate and, - 4 - H-K 5/dlk moreover, when a carboxylic acid such as citric acid was employed in the compositions of that invention, "the acid is coated with 1 to 20% of a water-repellent agent based on the weight of the acid", reportedly to provide increased storage stability of the product.
It is.apparent that the prior art has not provided any suitable prolonged-release unit dosage formulation for the prolonged release of an effective dose of a biologically-absorbable therapeutic agent or drug, much 10 less such a prolonged-release unit dosage formulation which employs or embodies a gel-forming dietary fiber as an essential part of the matrix, fundamentally because of the fact that the swelling and balling and plug formation of such gel-forming dietary fibers has 15 heretofore been considered an insurmountable disadvant-age, insofar as the acid of the stomach does not readily or uniformly dissolve dietary fiber formula-tions, especially when in unit dosage form such as a tablet, granule, capsule, lozenge, or the like, for 20 which reason release of any therapeutic agent or drug which may have been combined therewith was unpredict-able and non-uniform and generally insufficiently rapid to cause or permit release of all of the drug or other therapeutic agent content thereof while the unit dosage 25 formulation was present in the gastrointestinal tract.
According to the present invention, however, excellent prolonged-release unit dosage formulations are provided, which consist essentially of an effective dose of the selected biologically-absorbable therapeu-30 tic agent or drug, a gel-forming dietary fiber, and a physiologically-acceptable edible acid, preferably a food-grade organic acid or phosphoric acid, and a mineral salt which releases a physiologically-accept-able gas upon ingestion, preferably a mineral carbonate 35 or bicarbonate which releases carbon dioxide upon - 5 - ' H-~ 5/dlk 2 ~ ~; ? r ingestion. According to the invention, when a bio-logical liquid begins to penetrate or wick into the prolonged-release unit dosage formulation, it dissolves the acid and mineral salt present therein, which react together to cause a rapid evolution of gas, e.g., carbon dioxide, which cannot be effected using either stomach acid alone or the mineral salt alone. This rapid evolution of gas breaks up the prolonged-release unit dosage form, e.g., tablet, granule, capsule, lozenge, or the like, before a surface layer of gel can form around the unit dosage form, especially a tablet, from the normal reaction of the gel-forming dietary fiber, which surface layer of gel would seal the unit dosage form off from further hydration and disintegra-tion. As already stated, stomach acid alone is not sufficiently rapid acting and is furthermore outside of the unit dosage form, so that it is necessary to have both the physiologically-acceptable edible acid and the mineral salt which releases a physiologically-accept-able gas upon ingestion, inside the tablet, granule, capsule, lozenge, or the like, or dispersed throughout the tablet,granule, capsule, lozenge, or other unit dosage form, to increase the speed of hydration of the drug or other therapeutic agent contained in the unit dosage formulation. According to the invention, the gel produced by the gel-forming dietary fiber modulates the release of the drug, but does not prevent the drug from being biologically absorbed, inhibition of disin-tegration by formation of a gel coating around the unit dosage formulation by the gel-forming dietary fiber being prevented by the evolution of a physiologically-acceptable gas by virtue of the combined action of the acid and mineral salt within the unit dosage formula-tion itself upon contact with biological fluids, e.g., those of the gastrointestinal tract.
- 2 - , H-K 5/dlk 3 . ?~
Gums and mucillages have no common structure but are polysaccharides containing several sugars with alternating monomer structures and may or may not contain uronic acids. There are many gums found in plants and cereal grains. Guar and locust bean gums are galactomannans, whereas g~m arabic i~ an acidic polymer of galactose and rhammose. Oat and barley contain gums, but are not practical for use in the present application because of the low percentage of active gum per weight volume. Most of the gums in the present application are effective at much lower dosages. Suitable gums include, inter alia, besides guar gum, the following: locust bean gum, acacia gum, gum arabic, xanthan gum, carregeenan gum, karaya gum, tragacanth gum, and ghatti gum.
Pectin substances or pectins are mixtures of polysaccharides of partially methylated and 1,4-D
galacturonic acid units with side chains containing arabinose, galactose, xylose, and rhammose. They are contained in many fruits and vegetables as well as other plants.
Other suitable gel-forming dietary fibers include psyllium husks, algal polysaccharides, glucomannan, and agar, to name a few. Lignin is a non-carbohydrate polymer of aromatic plant alcohols comprisinq oxy-genated phenylpropane units. As a plant matures, more lignin is produced, which acts as a sort of cement as it hardens and holds together other plant cell wall constituents. Lignin passes through the digestive tract with very little change.
As already mentioned, a recent review of dietary fiber which mentions these substances is contained in the following reference: Dietary Fiber and Health, JAMA 262: No. 4, 542-546 (1989), from the Council on Scientific Affairs, American ~edical Association.
- 3 - H-K 5/dlk ~.,J 1:~3 Some gel-forming fibers such as guar gum are used as binders and disintegrators for compressed tablets, but at fairly low levels. At higher levels, these gel-forming fibers and gums are known not to dissolve properly when compressed into tablets.
Various unsuccessful attempts have been made to solve the problem of improper and incomplete dissolu-tion of guar gum tablets. EPA 0080673 describes these problems in detail, and discloses the use of 5 to 30%
of highly-dispersed silica gel in guar tablets.
Normally used tablet disintegrants or additives such as polyvinylpyrrolidone (crosslinking agent), sodium carboxymethyl-starch, cornstarch, microcrystalline cellulose, and so on, do not lead to satisfactory results. Hard tablets are produced which do not swell properly, and which form an impenetrable layer of gel around a powder core which may pass through the gastrointestinal tract undissolved.
U.S. Patent 4,824,672 describes the use of mineral carbonates to enhance dispersion of gel-forming dietary fibers in orally-administrable pharmaceutical composi-tions for use in reducing serum cholesterol levels.
Such compositions have proved to be very effective in use for their intended purpose, but do not provide a satisfactory matrix for providing a prolonged-release unit dosage formulation of a biologically-absorbable therapeutic agent or drug.
The foregoing EPO 0080673 mentions the employmént of citric acid with guar gum tablets. The citric acid and sweeteners were used, according to that disclosure, to improve the acceptability of the tablets if they were to be chewed. Accordingly, the citric acid was there used only to provide flavor and an aromatic quality to the product. Such formulations did not contain any mineral carbonate or bicarbonate and, - 4 - H-K 5/dlk moreover, when a carboxylic acid such as citric acid was employed in the compositions of that invention, "the acid is coated with 1 to 20% of a water-repellent agent based on the weight of the acid", reportedly to provide increased storage stability of the product.
It is.apparent that the prior art has not provided any suitable prolonged-release unit dosage formulation for the prolonged release of an effective dose of a biologically-absorbable therapeutic agent or drug, much 10 less such a prolonged-release unit dosage formulation which employs or embodies a gel-forming dietary fiber as an essential part of the matrix, fundamentally because of the fact that the swelling and balling and plug formation of such gel-forming dietary fibers has 15 heretofore been considered an insurmountable disadvant-age, insofar as the acid of the stomach does not readily or uniformly dissolve dietary fiber formula-tions, especially when in unit dosage form such as a tablet, granule, capsule, lozenge, or the like, for 20 which reason release of any therapeutic agent or drug which may have been combined therewith was unpredict-able and non-uniform and generally insufficiently rapid to cause or permit release of all of the drug or other therapeutic agent content thereof while the unit dosage 25 formulation was present in the gastrointestinal tract.
According to the present invention, however, excellent prolonged-release unit dosage formulations are provided, which consist essentially of an effective dose of the selected biologically-absorbable therapeu-30 tic agent or drug, a gel-forming dietary fiber, and a physiologically-acceptable edible acid, preferably a food-grade organic acid or phosphoric acid, and a mineral salt which releases a physiologically-accept-able gas upon ingestion, preferably a mineral carbonate 35 or bicarbonate which releases carbon dioxide upon - 5 - ' H-~ 5/dlk 2 ~ ~; ? r ingestion. According to the invention, when a bio-logical liquid begins to penetrate or wick into the prolonged-release unit dosage formulation, it dissolves the acid and mineral salt present therein, which react together to cause a rapid evolution of gas, e.g., carbon dioxide, which cannot be effected using either stomach acid alone or the mineral salt alone. This rapid evolution of gas breaks up the prolonged-release unit dosage form, e.g., tablet, granule, capsule, lozenge, or the like, before a surface layer of gel can form around the unit dosage form, especially a tablet, from the normal reaction of the gel-forming dietary fiber, which surface layer of gel would seal the unit dosage form off from further hydration and disintegra-tion. As already stated, stomach acid alone is not sufficiently rapid acting and is furthermore outside of the unit dosage form, so that it is necessary to have both the physiologically-acceptable edible acid and the mineral salt which releases a physiologically-accept-able gas upon ingestion, inside the tablet, granule, capsule, lozenge, or the like, or dispersed throughout the tablet,granule, capsule, lozenge, or other unit dosage form, to increase the speed of hydration of the drug or other therapeutic agent contained in the unit dosage formulation. According to the invention, the gel produced by the gel-forming dietary fiber modulates the release of the drug, but does not prevent the drug from being biologically absorbed, inhibition of disin-tegration by formation of a gel coating around the unit dosage formulation by the gel-forming dietary fiber being prevented by the evolution of a physiologically-acceptable gas by virtue of the combined action of the acid and mineral salt within the unit dosage formula-tion itself upon contact with biological fluids, e.g., those of the gastrointestinal tract.
- 6 - . H-K 5/dlk 2alrJ ' ~j OBJECTS OF THE INVENTION
It is an object of the invention to provide a novel and advantageous prolonged-release unit dosage formulation and a method for prolonging the release of a drug or other active therapeutic agent upon administration to a human being involving the employ-ment of such improved and advantageous prolonged-release unit dosage -formulation of the invention.
Another object of the invention is to provide such formulation and method which involve the employment of a prolonged-release unit dosage formulation consist-ing essentially of an effective dose of a biologically-absorbable drug or other therapeutic agent, a gel-forming dietary fiber, a physiologically-acceptable edible acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion. A
further object of the invention is the provision of such formulation and method wherein the disadvan-tageous characteristics of the gel-forming dietary fiber matrix are offset by the inclusion therein of a combination of a physiologically-acceptable edible acid, preferably a food-grade organic acid or phos-phoric acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion, prefer-ably a mineral carbonate or bicarbonate which releases carbon dioxide upon ingestion. Still an additional object is the provision of such a formulation and method wherein the unit dosage formulation also con-tains a soluble sugar, which greatly enhances the controllable disintegration of the unit dosage formula-tion upon ingestion in addition to providing a more generally acceptable flavor. Still other objects will be apparent to one skilled in the art and additional objects will become obvious as this specification proceeds.
It is an object of the invention to provide a novel and advantageous prolonged-release unit dosage formulation and a method for prolonging the release of a drug or other active therapeutic agent upon administration to a human being involving the employ-ment of such improved and advantageous prolonged-release unit dosage -formulation of the invention.
Another object of the invention is to provide such formulation and method which involve the employment of a prolonged-release unit dosage formulation consist-ing essentially of an effective dose of a biologically-absorbable drug or other therapeutic agent, a gel-forming dietary fiber, a physiologically-acceptable edible acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion. A
further object of the invention is the provision of such formulation and method wherein the disadvan-tageous characteristics of the gel-forming dietary fiber matrix are offset by the inclusion therein of a combination of a physiologically-acceptable edible acid, preferably a food-grade organic acid or phos-phoric acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion, prefer-ably a mineral carbonate or bicarbonate which releases carbon dioxide upon ingestion. Still an additional object is the provision of such a formulation and method wherein the unit dosage formulation also con-tains a soluble sugar, which greatly enhances the controllable disintegration of the unit dosage formula-tion upon ingestion in addition to providing a more generally acceptable flavor. Still other objects will be apparent to one skilled in the art and additional objects will become obvious as this specification proceeds.
- 7 - H-X 5/dlk , t ~ 7 SUMMARY OF THE INVENTION
The invention, then, comprises the following, inter alia, singly or in combination:
A prolonged-release unit dosage formulation or composition which consists essentially of an effective dose of a biologically-absorbable therapeutic agent or drug, a gel-forming dietary fiber, a physiologically-acceptable acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion, the combination of the fiber, acid, and salt providing prolonged release of the drug or therapeutic agent upon exposure of the composition to biological fluids;
such a composition wherein the gas released is carbon dioxide; such a composition wherein the mineral salt is a mineral carbonate or bicarbonate; such a composition wherein the mineral salt is calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbon-ate, or potassium bicarbonate; such a composition wherein the acid is a food-grade organic acid or phosphoric acid.
composition wherein, in addition to the previ-ously-recited ingredients, the composition contains a soluble sugar; such a composition wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight of the composition; such a composition wherein the gel-forming dietary fiber comprises about 50% by weight of the composition;
such a composition wherein the physiologically-acceptable acid comprises about 2% to about 50% by weight of the composition; such a - 8 - H-X 5/dlk .
2 ~ r t3 ~3 composition wherein the physiologically-acceptable acid comprises about 5% by weight of the composition;
such a composition wherein the mineral salt comprises : 5 about 5~ to about 75% by weight of the composition;
such a composition wherein the mineral salt comprises about 15% by weight of.the composition; such a composition wherein the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5;
such a composition wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physio-logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5;
such a composition wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about l,OOO:Q.5 and 1:1.5; such a composition whereir, a soluble sugar is also present in an amount between about 1% and about 30% by weight of the composition; such a composition wherein a soluble sugar is present in an amount between about 3% and about 12% by weight of the composition; such a composition wherein the gel-forming dietary fiber comprises about 25% to about 85~ by weight, the physio-- 9 - HK 5/dl~
~ ~ ? ,.,,' ., IJ ! 1. ~
logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of soluble sugar; such a - composition wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physio-logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5~ to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5, and also containing between about 3% and about 12% by weight of a soluble sugar; such a composition wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5~ by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of a soluble sugar; such a composition wherein the drug or therapeutic agent is niacin.
composition wherein niacin is present in granular form, with a cellulose coating about the granules thereof; such a composition wherein the niacin is present in amount between about 100 and about 200 mg/per unit dosage form; such a composition in tablet form.; such a prolonged-release unit dosage formulation or composition consisting essentially of an effective dose - 10 - ~ HK S/dlk of niacin, a gel-forming dietary fiber in an amount between about 25~ to about 85~ by weight of the compo-sition, a physiologically-acceptable edible acid in an amount of about 2% to about 50% by weight, and a mineral salt which releases a physiologically-accept-able gas upon ingestion in an amount of between about 5% and about 75% by weight; such a composition in tablet form; such a composition wherein the amount of the niacin is between about 100 mg and about 200 mg per tablet;
such a composition wherein the niacin is present in granular form, the granules being coated with a cellu-lose coating; such a composition wherein the coating is a combination of a carboxymethylcellulose coating and an ethylcellu-lose coating; such a composition wherein the gel-forming fiber is psyllium husk powder or guar gum; such a composition wherein the acid is a food-grade organic acid or phosphoric acid; such a composition wherein the acid is citric acid;
such a composition wherein the mineral salt is a carbon-ate or bicarbonate; and such a composition wherein the mineral salt is calcium carbonate.
Moreover, a method for prolonging the release of a drug or other active therapeutic agent, comprising the step of preparing a prolonged-release unit dosage formulation or composition which consists essentially of an effective dose of a biologically-absorbable drug or other therapeutic agent, a gel-forming dietary fiber, a physiologically-acceptable acid, and a mineral - 11 - HK 5/dlk salt which releases a physiologically-acceptable gas upon ingestion, the combination of the fiber, acid, and salt providing prolonged release of the drug or thera-peutic agent upon exposure of the composition to biological fluids; such a method wherein the gas released is carbon dioxide;
such a method wherein the mineral salt is a mineral carbonate or bicarbonate; such a method wherein the mineral salt is calcium carbon-ate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate; such a method wherein the acid is a food-grade organic acid or phosphoric acid; such a method wherein, in addition to the previously-recited ingredients, the composition contains a soluble :~ sugar such a method wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight of the ; composition; such a method wherein the gel-forming dietary fiber comprises about 50% by weight of the composition;
such a method wherein the physiologically-acceptable acid comprises about 2% to about 50% by weight of the composition; such a method wherein the physiologically-acceptable acid comprises about 5% by weight of the composition;
such a method wherein the mineral salt comprises about 5%
to about 75% by weight of the composition; such a method wherein the mineral salt comprises about 15% by weight of the composition; such a method wherein the ratio of the weight of the - 12 - HK 5/dlk S ~
gel-forming fiber to the weight of the drug or thera-peutic agent is between about l,OOO:O.S and 1:1.5;
such a method wherein the gel-forming dietary fiber 5 comprises about 25~ to about 85% by weight, the physio-logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5;
such a method wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent i5 between about 1,000:0.5 and 1:1.5; such a method wherein a soluble sugar is also present in an amount between about 1% and about 30% by weight of the composition; such a method wherein a soluble sugar is present in an amount between about 3% and about 12% by weight of the composition; such a method wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physio-logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.S, and containing also between about 1% and about 30% by weight of soluble sugar; such a method wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physio-- 13 - H~ 5/dlk 2 ~? r~ J 1.. 1 .
logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 3% and about 12% by weight of soluble sugar; such a method wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about ; 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of a soluble sugar; such a method wherein the drug or therapeutic agent is niacin; such a method wherein niacin is present in granular form, with a cellulose coating about the granules thereof;
such a method wherein the niacin is presPnt in amount between about 100 and about 200 mg/per unit dosage form; such a method wherein the dosage unit is a tablet;
such a prolonged-release unit dosage formulation con-sisting essentially of an effective dose of niacin, a gel-forming dietary fiber in an amount of about 25% to about 85% by weight of the composition, a physiologi-cally-acceptable edible acid in an amount between about 2% and about 50% by weight, and a mineral salt which releases a physiologically-acceptable gas upon inges-tion in an amount of between about 5% and about 75% by . weight; such a - 14 - HK 5~dlk ~ ,r3,;? ~ ,J
formulation wherein the dosage unit is a tablet;
such a - formulation wherein the amount of the niacin is between about 100 mg and about 200 mg per tablet; such a . formulation wherein the niacin is present in gran-ular form, the granules being coated with a cellulose coating; such a ; formulation wherein the coating is a combination of a carboxymethylcellulose coating and an ethylcellu-lose coating; such a formulation wherein the gel-forming fiber is psyl-lium husk powder or guar gum; such a formulation wherein the acid is a food-grade or-ganic acid or phosphoric acid; such a formulation wherein the acid is citric acid; such a formulation wherein the mineral salt is a carbon-ate or bicarbonate; such a formulation wherein the mineral salt is calcium carbonate and, finally, such a composition whe~ein the drug or therapeutic agent is an analgesic, an antihypercholesterolemic, a vita-min, a stimulant, an appetite suppressant, or a mineral supplement and such a method wherein the drug or therapeutic agent is an analgesic, an antihypercholesterolemic, a vitamin, a stimulant, an appetite suppressant, or a mineral supplement.
The invention, then, comprises the following, inter alia, singly or in combination:
A prolonged-release unit dosage formulation or composition which consists essentially of an effective dose of a biologically-absorbable therapeutic agent or drug, a gel-forming dietary fiber, a physiologically-acceptable acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion, the combination of the fiber, acid, and salt providing prolonged release of the drug or therapeutic agent upon exposure of the composition to biological fluids;
such a composition wherein the gas released is carbon dioxide; such a composition wherein the mineral salt is a mineral carbonate or bicarbonate; such a composition wherein the mineral salt is calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbon-ate, or potassium bicarbonate; such a composition wherein the acid is a food-grade organic acid or phosphoric acid.
composition wherein, in addition to the previ-ously-recited ingredients, the composition contains a soluble sugar; such a composition wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight of the composition; such a composition wherein the gel-forming dietary fiber comprises about 50% by weight of the composition;
such a composition wherein the physiologically-acceptable acid comprises about 2% to about 50% by weight of the composition; such a - 8 - H-X 5/dlk .
2 ~ r t3 ~3 composition wherein the physiologically-acceptable acid comprises about 5% by weight of the composition;
such a composition wherein the mineral salt comprises : 5 about 5~ to about 75% by weight of the composition;
such a composition wherein the mineral salt comprises about 15% by weight of.the composition; such a composition wherein the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5;
such a composition wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physio-logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5;
such a composition wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about l,OOO:Q.5 and 1:1.5; such a composition whereir, a soluble sugar is also present in an amount between about 1% and about 30% by weight of the composition; such a composition wherein a soluble sugar is present in an amount between about 3% and about 12% by weight of the composition; such a composition wherein the gel-forming dietary fiber comprises about 25% to about 85~ by weight, the physio-- 9 - HK 5/dl~
~ ~ ? ,.,,' ., IJ ! 1. ~
logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of soluble sugar; such a - composition wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physio-logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5~ to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5, and also containing between about 3% and about 12% by weight of a soluble sugar; such a composition wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5~ by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of a soluble sugar; such a composition wherein the drug or therapeutic agent is niacin.
composition wherein niacin is present in granular form, with a cellulose coating about the granules thereof; such a composition wherein the niacin is present in amount between about 100 and about 200 mg/per unit dosage form; such a composition in tablet form.; such a prolonged-release unit dosage formulation or composition consisting essentially of an effective dose - 10 - ~ HK S/dlk of niacin, a gel-forming dietary fiber in an amount between about 25~ to about 85~ by weight of the compo-sition, a physiologically-acceptable edible acid in an amount of about 2% to about 50% by weight, and a mineral salt which releases a physiologically-accept-able gas upon ingestion in an amount of between about 5% and about 75% by weight; such a composition in tablet form; such a composition wherein the amount of the niacin is between about 100 mg and about 200 mg per tablet;
such a composition wherein the niacin is present in granular form, the granules being coated with a cellu-lose coating; such a composition wherein the coating is a combination of a carboxymethylcellulose coating and an ethylcellu-lose coating; such a composition wherein the gel-forming fiber is psyllium husk powder or guar gum; such a composition wherein the acid is a food-grade organic acid or phosphoric acid; such a composition wherein the acid is citric acid;
such a composition wherein the mineral salt is a carbon-ate or bicarbonate; and such a composition wherein the mineral salt is calcium carbonate.
Moreover, a method for prolonging the release of a drug or other active therapeutic agent, comprising the step of preparing a prolonged-release unit dosage formulation or composition which consists essentially of an effective dose of a biologically-absorbable drug or other therapeutic agent, a gel-forming dietary fiber, a physiologically-acceptable acid, and a mineral - 11 - HK 5/dlk salt which releases a physiologically-acceptable gas upon ingestion, the combination of the fiber, acid, and salt providing prolonged release of the drug or thera-peutic agent upon exposure of the composition to biological fluids; such a method wherein the gas released is carbon dioxide;
such a method wherein the mineral salt is a mineral carbonate or bicarbonate; such a method wherein the mineral salt is calcium carbon-ate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate; such a method wherein the acid is a food-grade organic acid or phosphoric acid; such a method wherein, in addition to the previously-recited ingredients, the composition contains a soluble :~ sugar such a method wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight of the ; composition; such a method wherein the gel-forming dietary fiber comprises about 50% by weight of the composition;
such a method wherein the physiologically-acceptable acid comprises about 2% to about 50% by weight of the composition; such a method wherein the physiologically-acceptable acid comprises about 5% by weight of the composition;
such a method wherein the mineral salt comprises about 5%
to about 75% by weight of the composition; such a method wherein the mineral salt comprises about 15% by weight of the composition; such a method wherein the ratio of the weight of the - 12 - HK 5/dlk S ~
gel-forming fiber to the weight of the drug or thera-peutic agent is between about l,OOO:O.S and 1:1.5;
such a method wherein the gel-forming dietary fiber 5 comprises about 25~ to about 85% by weight, the physio-logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5;
such a method wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent i5 between about 1,000:0.5 and 1:1.5; such a method wherein a soluble sugar is also present in an amount between about 1% and about 30% by weight of the composition; such a method wherein a soluble sugar is present in an amount between about 3% and about 12% by weight of the composition; such a method wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physio-logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.S, and containing also between about 1% and about 30% by weight of soluble sugar; such a method wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physio-- 13 - H~ 5/dlk 2 ~? r~ J 1.. 1 .
logically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or thera-peutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 3% and about 12% by weight of soluble sugar; such a method wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about ; 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of a soluble sugar; such a method wherein the drug or therapeutic agent is niacin; such a method wherein niacin is present in granular form, with a cellulose coating about the granules thereof;
such a method wherein the niacin is presPnt in amount between about 100 and about 200 mg/per unit dosage form; such a method wherein the dosage unit is a tablet;
such a prolonged-release unit dosage formulation con-sisting essentially of an effective dose of niacin, a gel-forming dietary fiber in an amount of about 25% to about 85% by weight of the composition, a physiologi-cally-acceptable edible acid in an amount between about 2% and about 50% by weight, and a mineral salt which releases a physiologically-acceptable gas upon inges-tion in an amount of between about 5% and about 75% by . weight; such a - 14 - HK 5~dlk ~ ,r3,;? ~ ,J
formulation wherein the dosage unit is a tablet;
such a - formulation wherein the amount of the niacin is between about 100 mg and about 200 mg per tablet; such a . formulation wherein the niacin is present in gran-ular form, the granules being coated with a cellulose coating; such a ; formulation wherein the coating is a combination of a carboxymethylcellulose coating and an ethylcellu-lose coating; such a formulation wherein the gel-forming fiber is psyl-lium husk powder or guar gum; such a formulation wherein the acid is a food-grade or-ganic acid or phosphoric acid; such a formulation wherein the acid is citric acid; such a formulation wherein the mineral salt is a carbon-ate or bicarbonate; such a formulation wherein the mineral salt is calcium carbonate and, finally, such a composition whe~ein the drug or therapeutic agent is an analgesic, an antihypercholesterolemic, a vita-min, a stimulant, an appetite suppressant, or a mineral supplement and such a method wherein the drug or therapeutic agent is an analgesic, an antihypercholesterolemic, a vitamin, a stimulant, an appetite suppressant, or a mineral supplement.
- 15 - HK 5/dlk TH E I NVENT I ON
It has now been discovered that unit dosage formulations, especially tablets, consisting essen-tially of a gel-forming fiber, especially guar gum, and a drug, vitamin, dietary food supplement, or other active therapeutic agent, produce a unique, prolonged-action and advantageous delivery system, when combined with certain essential disintegrants, as hereinafter described. The problem which needed to be overcome was a proper disintegration of the tablet, so that the gel produced by the fiber could modulate the release of the drug. Otherwise a solid tablet containing the drug would start to hydrate, but stop abruptly when a film of gel sealed off the rest of the tablet and inhibited its full disintegration, thereby preventing release of the active drug or other therapeutic agent. The discovery of the present invention is therefore two-fold. It provides both a delivery system for therapeutic compounds wherein the delivery vehicle is a gel-forming dietary fiber which, when dissolved in the fluids of the gastrointestinal tract, forms a gel which modulates but does not stop the release of the therapeutic agent, and a solution to the problem of a proper and complete dissolution of tablets in the stomach with release of the drug or other active therapeutic agent.
This is effected,-according to the present inven-tion, by the inclusion, in the unit dosage formulation of the invention, of a physiologically-acceptable edible acid and a mineral salt which releases a physio-logically-acceptable gas upon ingestion and while the unit dosage formulation is in the gastrointestinal tract, which gas penetrates and modulates the film of gel produced from the gel-forming dietary fiber and - 16 - HK S/dlk ~ J"-thus assists in the proper disintegration of the unit dosage form and the proper dissolution of all of the drug or other therapeutic agent present in the unit dosage formulation. The unit dosage form of the invention becomes activated upon contact with biologi-cal fluids, i.e., body fluids, e.g., saliva, gastroin-testinal fluids, or rectal fluids, and dissolves slowly, with the internally-contained acid and mineral salt cooperating to mechanically disperse the fiber in a slow and prolonged manner as it hydrates, the gas - released by the mineral salt and organic or other acid assisting in the slow disintegration of the unit dosage form. The present invention preferably employs a mineral carbonate or bicarbonate, a physiologically-acceptable organic acid or phosphoric acid, and prefer-ably also a soluble sugar such as dextrose, all of which aid in the proper disintegration and dissolution of the tablet.
The Physiologically-Acceptable Acid As physiologically-acceptable acid may be employed any non-toxic and preferably edible acid such as citric, malic, succinic, ascorbic, fumaric, phosphoric, tartaric, gluconic, acetic, tannic, lactic, glycollic, or the like. Food-grade organic acids are preferred and, of organic food-grade acids, citric, tartaric, and malic are preferred due to their introduction of a definite citrous, grape, and apple flavor into the composition, respectively.
The Gel-Forminq Dietary Fiber According to the invention, any of the foregoing enumerated gel-forming dietary fibers may be employed, with gums such as guar gum and the like and psyllium - 17 - HY 5/dlk 2 ~ 3 seed husks in powdered form being preferred, but pectin or a pectic substance, algal polysaccharides, gluco-mannan, agar, lignin, or the like, or combinations thereof, may generally be employed with essentially the same results.
The ~ineral Salt According to the invention, any mineral salt which releases a physiologically-acceptable gas upon ingestion may be employed. Such gas released is preferably carbon dioxide and the mineral salt is preferably a mineral carbonate or bicarbonate, with calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, and sodium bicarbonate, as well as the corresponding potassium carbonate and bicarbonate, being preferred.
Soluble Sugar As the optional but most preferred soluble sugar employed to assist disintegration according to the invention any of the following representative sugars may be employed: Dextrose, succrose, glucose, xylose, ribose, mannose, galactose, fructose, maltose, partially hydrolzyed starch, corn syrup solids, sugar alcohols such as sorbitol, xylitol, mannitol, and the like, with dextrose, xylose, and fructose being pre-ferred.
Tableting Pressures and Procedure According to the invention, in producing tablets, usual tableting procedure and practice is employed, with pressures ranging from about 4,000 to about 10,000 pounds per square inch being preferred. Due to the fact that the gel-forming dietary fibers become closely compacted and even more difficult to disinte-- 18 - HK 5~dlk ~ ~ J !~ 3 pressures above about 10,000 pounds per inch are employed care must be taken that the possibility of disintegration of the tablet is not impaired. To this end, cellulose flocked granules, microcrystalline cellulose, plain or chemically-modified starch, lac-tose, dextrose, mannitol, carboxymethylcellulose, methylcellulose, lubricants such as magnesium stearate or polyethylene glycols, or mineral excipients such as dicalcium phosphate, silicon dioxide, talc, and the like may be included singly or in combination in any desired ratio as a blend, but in any event only to the extent necessary and for the purpose of providing a tablet hardness sufficient for maximum tablet stability but not so great that the disintegration rate in water or gastric fluid is disadvantageously affected.
Ranges of Ingredients According to the invention, the range for the gel-forming dietary fiber comprising an essential part of the prolonged-release matrix of the present invention should be about 25% to 85% by weight, preferably about 50% by weight; the range of physio-logically-acceptable edible acid should be about 2%
to about 50% by weight, preferably about 5% by weight;
the range for the mineral salt should be about 5% to about 75% by weight, preferably about 15% by weight.
The gel-forming fiber to drug weight ratio should be between about 1,000:0.5 and 1:1.5. Therapeutic agents which are employed in microgram dosages fall at the higher end of the range and therapeutic agents which require relatively larger amounts for a therapeutically-effective dose fall at the lower ends of the range, as will be readily understood and as illustrated by the Examples herein. When present, the soluble sugar i5 - 19 - HK 5/dlk ~ ~1 C' ~ i J
preferably present in an amount between about 1 and about 30~ by weight, preferably between about 3 and about 12% by weight.
DETAILED DESC~IPTION OF PREFERRED EMBODIMENTS
The following Examples are given to illustrate the compositions and method of the present invention, but are not to be construed as limiting.
Example 1 Tablets were made according to the following formula:
Guar Gum 400 mg Aspirin 200 mg Calcium Carbonate 100 mg - Dextrose 50 mg Citric Acid 25 mg Microcrystalline-Cellulose (MCC) 25 mg The citric acid and calcium carbonate act to mechanically disintegrate the guar gum fiber so that it forms a sphere or plug of hydrated gel which coats the aspirin and from which the aspirin slowly leaches as the gel hydrates and passes through the gastrointes-tinal tract. The gel-forming fiber also assists in minimizing the caustic effect of the aspirin when it comes into full contact ~ith the stomach, because the "gel plug" or sphere of fiber-gel insulates the aspirin as well as modulates its release.
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
It has now been discovered that unit dosage formulations, especially tablets, consisting essen-tially of a gel-forming fiber, especially guar gum, and a drug, vitamin, dietary food supplement, or other active therapeutic agent, produce a unique, prolonged-action and advantageous delivery system, when combined with certain essential disintegrants, as hereinafter described. The problem which needed to be overcome was a proper disintegration of the tablet, so that the gel produced by the fiber could modulate the release of the drug. Otherwise a solid tablet containing the drug would start to hydrate, but stop abruptly when a film of gel sealed off the rest of the tablet and inhibited its full disintegration, thereby preventing release of the active drug or other therapeutic agent. The discovery of the present invention is therefore two-fold. It provides both a delivery system for therapeutic compounds wherein the delivery vehicle is a gel-forming dietary fiber which, when dissolved in the fluids of the gastrointestinal tract, forms a gel which modulates but does not stop the release of the therapeutic agent, and a solution to the problem of a proper and complete dissolution of tablets in the stomach with release of the drug or other active therapeutic agent.
This is effected,-according to the present inven-tion, by the inclusion, in the unit dosage formulation of the invention, of a physiologically-acceptable edible acid and a mineral salt which releases a physio-logically-acceptable gas upon ingestion and while the unit dosage formulation is in the gastrointestinal tract, which gas penetrates and modulates the film of gel produced from the gel-forming dietary fiber and - 16 - HK S/dlk ~ J"-thus assists in the proper disintegration of the unit dosage form and the proper dissolution of all of the drug or other therapeutic agent present in the unit dosage formulation. The unit dosage form of the invention becomes activated upon contact with biologi-cal fluids, i.e., body fluids, e.g., saliva, gastroin-testinal fluids, or rectal fluids, and dissolves slowly, with the internally-contained acid and mineral salt cooperating to mechanically disperse the fiber in a slow and prolonged manner as it hydrates, the gas - released by the mineral salt and organic or other acid assisting in the slow disintegration of the unit dosage form. The present invention preferably employs a mineral carbonate or bicarbonate, a physiologically-acceptable organic acid or phosphoric acid, and prefer-ably also a soluble sugar such as dextrose, all of which aid in the proper disintegration and dissolution of the tablet.
The Physiologically-Acceptable Acid As physiologically-acceptable acid may be employed any non-toxic and preferably edible acid such as citric, malic, succinic, ascorbic, fumaric, phosphoric, tartaric, gluconic, acetic, tannic, lactic, glycollic, or the like. Food-grade organic acids are preferred and, of organic food-grade acids, citric, tartaric, and malic are preferred due to their introduction of a definite citrous, grape, and apple flavor into the composition, respectively.
The Gel-Forminq Dietary Fiber According to the invention, any of the foregoing enumerated gel-forming dietary fibers may be employed, with gums such as guar gum and the like and psyllium - 17 - HY 5/dlk 2 ~ 3 seed husks in powdered form being preferred, but pectin or a pectic substance, algal polysaccharides, gluco-mannan, agar, lignin, or the like, or combinations thereof, may generally be employed with essentially the same results.
The ~ineral Salt According to the invention, any mineral salt which releases a physiologically-acceptable gas upon ingestion may be employed. Such gas released is preferably carbon dioxide and the mineral salt is preferably a mineral carbonate or bicarbonate, with calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, and sodium bicarbonate, as well as the corresponding potassium carbonate and bicarbonate, being preferred.
Soluble Sugar As the optional but most preferred soluble sugar employed to assist disintegration according to the invention any of the following representative sugars may be employed: Dextrose, succrose, glucose, xylose, ribose, mannose, galactose, fructose, maltose, partially hydrolzyed starch, corn syrup solids, sugar alcohols such as sorbitol, xylitol, mannitol, and the like, with dextrose, xylose, and fructose being pre-ferred.
Tableting Pressures and Procedure According to the invention, in producing tablets, usual tableting procedure and practice is employed, with pressures ranging from about 4,000 to about 10,000 pounds per square inch being preferred. Due to the fact that the gel-forming dietary fibers become closely compacted and even more difficult to disinte-- 18 - HK 5~dlk ~ ~ J !~ 3 pressures above about 10,000 pounds per inch are employed care must be taken that the possibility of disintegration of the tablet is not impaired. To this end, cellulose flocked granules, microcrystalline cellulose, plain or chemically-modified starch, lac-tose, dextrose, mannitol, carboxymethylcellulose, methylcellulose, lubricants such as magnesium stearate or polyethylene glycols, or mineral excipients such as dicalcium phosphate, silicon dioxide, talc, and the like may be included singly or in combination in any desired ratio as a blend, but in any event only to the extent necessary and for the purpose of providing a tablet hardness sufficient for maximum tablet stability but not so great that the disintegration rate in water or gastric fluid is disadvantageously affected.
Ranges of Ingredients According to the invention, the range for the gel-forming dietary fiber comprising an essential part of the prolonged-release matrix of the present invention should be about 25% to 85% by weight, preferably about 50% by weight; the range of physio-logically-acceptable edible acid should be about 2%
to about 50% by weight, preferably about 5% by weight;
the range for the mineral salt should be about 5% to about 75% by weight, preferably about 15% by weight.
The gel-forming fiber to drug weight ratio should be between about 1,000:0.5 and 1:1.5. Therapeutic agents which are employed in microgram dosages fall at the higher end of the range and therapeutic agents which require relatively larger amounts for a therapeutically-effective dose fall at the lower ends of the range, as will be readily understood and as illustrated by the Examples herein. When present, the soluble sugar i5 - 19 - HK 5/dlk ~ ~1 C' ~ i J
preferably present in an amount between about 1 and about 30~ by weight, preferably between about 3 and about 12% by weight.
DETAILED DESC~IPTION OF PREFERRED EMBODIMENTS
The following Examples are given to illustrate the compositions and method of the present invention, but are not to be construed as limiting.
Example 1 Tablets were made according to the following formula:
Guar Gum 400 mg Aspirin 200 mg Calcium Carbonate 100 mg - Dextrose 50 mg Citric Acid 25 mg Microcrystalline-Cellulose (MCC) 25 mg The citric acid and calcium carbonate act to mechanically disintegrate the guar gum fiber so that it forms a sphere or plug of hydrated gel which coats the aspirin and from which the aspirin slowly leaches as the gel hydrates and passes through the gastrointes-tinal tract. The gel-forming fiber also assists in minimizing the caustic effect of the aspirin when it comes into full contact ~ith the stomach, because the "gel plug" or sphere of fiber-gel insulates the aspirin as well as modulates its release.
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
- 20 - ~x 5/dlk 2 ~ .3 Example 2 Tablets were made by compression at usual pres-sures of 4,000 to 10,000 pounds per square inch according to the following formula:
Each Table Contains Locust Bean Gum150 mg Acacia Gum 50 mg Xaraya Gum 100 mg Tragacanth Gum50 mg Carrageenan 50 mg Vitamin C 250 mg Calcium Carbonate 100 mg Dextrose 25 mg Citric Acid 25 mg Microcrystalline-Cellulose 25 mg Polyvinylpyrrolidone (crosslinked)-(Povidone~)15 mg Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 3 Stimulant tablet Guar Gum 500 mg Caffeine 100 mg Calcium Carbonate 200 mg ;
Citric Acid 75 mg Lactose (Anhydrous) 50 mg Microcrystalline-Cellulose (MCC) 25 mg Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Each Table Contains Locust Bean Gum150 mg Acacia Gum 50 mg Xaraya Gum 100 mg Tragacanth Gum50 mg Carrageenan 50 mg Vitamin C 250 mg Calcium Carbonate 100 mg Dextrose 25 mg Citric Acid 25 mg Microcrystalline-Cellulose 25 mg Polyvinylpyrrolidone (crosslinked)-(Povidone~)15 mg Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 3 Stimulant tablet Guar Gum 500 mg Caffeine 100 mg Calcium Carbonate 200 mg ;
Citric Acid 75 mg Lactose (Anhydrous) 50 mg Microcrystalline-Cellulose (MCC) 25 mg Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
- 21 - HK 5/dlk Example 4 Weight-Loss tablet (Appetite Suppressant) Guar Gum 500 mg Phenylpropanolamine base 5 mg Calcium Carbonate 200 mg Citric Acid 75 mg Dextrose 50 mg ~ Microcrystalline-Cellulose (MCC) 30 mg The Guar Gum expands 3 to 4 times its original size in the stomach, and gives the subject a full feeling, while the phenylpropanolamine tends to shut off the hunger signal in the brain. These two princi-ple ingredients work together to produce a dual action on the two primary components of a weight loss product, satiety and hunger, while the guar gum also serves to modulate the absorption of the phenylpropanolamine, prolonging its action.
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 5 Tablets are made according to the following formula: A
Each Tablet Contains Psyllium seed husks - powdered 500 mg Niacin 100 mg Calcium carbonate 150 mg Dextrose 50 mg Citric acid 25 mg Microcrystalline cellulose [Avicel-TM)25 mg - 22 - HK 5/dlk The citric acid and calcium carbonate act to mechanically disperse the gel-forming psyllium fiber which acts as a drug delivery system for the niacin.
The psyllium fiber also serves to coat the niacin, minimizing its acidic effect on the stomach lining and intestines.
In the foregoing formulation, some or all of the psyllium seed husk powder may be replaced by another gel-forming dietary fiber, e.g., guar gum or one or more of the gums used in Example 6, pectin or a pectic ;- substance, algal polysaccharides, glucomannan, agar, lignin, or the like, or combinations thereof, with essentially the same result.
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 6 Tablets are made according to the following ; 20 formula:
Each Tablet Contains Locust bean gum 1 ao mg Acacia gum 100 mg Gum arabic 100 mg Xanthan gum 100 mg Karaya gum 50 mg Tragacanth gum 50 mg Niacin 100 mg Calcium carbonate 150 mg Dextrose 50 mg Citric Acid 25 mg Microcrystalline cellulose (Avicel-TM)25 mg - 23 - HR 5/dlk J~ ^3 In the foregoing formulation, one or more of the gums may be replaced by another gel-forming dietary fiber, e.g., psyllium seed husks, pectin or a pectic substance, algal polysaccharides, glucomannan, agar, lignin, or the like, or combinations thereof, with essentially the same result.
These tablets, as well as those of Example 6, are found to be effective ln lowering cholesteral levels at effective doses of niacin without the usual side effects of flushing, itching, and irritation.
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 7 A niacin granulate is produced in a fluid bed granulator (Glatt Air Techniques, Ramsey, New Jersey).
The niacin is first sprayed with NaCMC (Sodium Carboxy-methylcellulose) at 7.5% solids in solution level, and 3% by weight volume percentage. While still in the fluid bed granulator, the coated niacin is then sprayed with Surelease (TM) (Colorcon, West Point, PA), an ethyl cellulose preparation, at 15% solids in solution and 2% by weight volume percentage.
PrePare 95% Niacin Granulation In qranulator bowl - Niacin powder.
In solution - Spray first with NaCMC, 7.5% solids in solution, 3% by weight volume percentage. Spray second with Surelease (TM) (ethyl cellulose) 15% solids, 2% by weight volume percentage.
The 95% niacin granulate is then used in the following formula:
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 5 Tablets are made according to the following formula: A
Each Tablet Contains Psyllium seed husks - powdered 500 mg Niacin 100 mg Calcium carbonate 150 mg Dextrose 50 mg Citric acid 25 mg Microcrystalline cellulose [Avicel-TM)25 mg - 22 - HK 5/dlk The citric acid and calcium carbonate act to mechanically disperse the gel-forming psyllium fiber which acts as a drug delivery system for the niacin.
The psyllium fiber also serves to coat the niacin, minimizing its acidic effect on the stomach lining and intestines.
In the foregoing formulation, some or all of the psyllium seed husk powder may be replaced by another gel-forming dietary fiber, e.g., guar gum or one or more of the gums used in Example 6, pectin or a pectic ;- substance, algal polysaccharides, glucomannan, agar, lignin, or the like, or combinations thereof, with essentially the same result.
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 6 Tablets are made according to the following ; 20 formula:
Each Tablet Contains Locust bean gum 1 ao mg Acacia gum 100 mg Gum arabic 100 mg Xanthan gum 100 mg Karaya gum 50 mg Tragacanth gum 50 mg Niacin 100 mg Calcium carbonate 150 mg Dextrose 50 mg Citric Acid 25 mg Microcrystalline cellulose (Avicel-TM)25 mg - 23 - HR 5/dlk J~ ^3 In the foregoing formulation, one or more of the gums may be replaced by another gel-forming dietary fiber, e.g., psyllium seed husks, pectin or a pectic substance, algal polysaccharides, glucomannan, agar, lignin, or the like, or combinations thereof, with essentially the same result.
These tablets, as well as those of Example 6, are found to be effective ln lowering cholesteral levels at effective doses of niacin without the usual side effects of flushing, itching, and irritation.
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 7 A niacin granulate is produced in a fluid bed granulator (Glatt Air Techniques, Ramsey, New Jersey).
The niacin is first sprayed with NaCMC (Sodium Carboxy-methylcellulose) at 7.5% solids in solution level, and 3% by weight volume percentage. While still in the fluid bed granulator, the coated niacin is then sprayed with Surelease (TM) (Colorcon, West Point, PA), an ethyl cellulose preparation, at 15% solids in solution and 2% by weight volume percentage.
PrePare 95% Niacin Granulation In qranulator bowl - Niacin powder.
In solution - Spray first with NaCMC, 7.5% solids in solution, 3% by weight volume percentage. Spray second with Surelease (TM) (ethyl cellulose) 15% solids, 2% by weight volume percentage.
The 95% niacin granulate is then used in the following formula:
- 24 - HK 5/dlk r~
J ~ u; . .j Each Tablet Contains Psyllium husk powder 600 mg Niacin granulate (95~) 160 mg Calcium carbonate 100 mg Citric Acid 25 mg Microcrystalline cellulose (Avicel~) 25 mg In the foregoing formulation, some or all of the psyllium seed husk powder may be replaced by another gel-forming dietary fiber, e.g., guar gum or one or more of the gums used in Example 6, pectin or a pectic substance, algal polysaccharides, glucomannan, agar, lignin, or the like, or combinations thereof, with essentially the same result.
Other cellulose coatings may replace those used for preparation of the coated niacin granulate in the foregoing.
A much higher dose of niacin is found to be possible by granulating the niacin before tableting so that it is released more slowly. A subject can take two tablets of the above formula with virtually no side effects such as the severe flushing, itching, or gastric distress produced by normal niacin.
The tablet ingredients may also be formed into granules, if desired, and then may be taken alone, without tabletting, if desired, in effective dosages, but this is generally less convenient from the stand-; point of the user and less advantageous from the standpoint of prolonged time-release effect upon ingestion.
Dextrose or other soluble sugar may also be present in an amount up to about 100 mg if desired, to further assist in the tablets' disintegration upon ingestion.
J ~ u; . .j Each Tablet Contains Psyllium husk powder 600 mg Niacin granulate (95~) 160 mg Calcium carbonate 100 mg Citric Acid 25 mg Microcrystalline cellulose (Avicel~) 25 mg In the foregoing formulation, some or all of the psyllium seed husk powder may be replaced by another gel-forming dietary fiber, e.g., guar gum or one or more of the gums used in Example 6, pectin or a pectic substance, algal polysaccharides, glucomannan, agar, lignin, or the like, or combinations thereof, with essentially the same result.
Other cellulose coatings may replace those used for preparation of the coated niacin granulate in the foregoing.
A much higher dose of niacin is found to be possible by granulating the niacin before tableting so that it is released more slowly. A subject can take two tablets of the above formula with virtually no side effects such as the severe flushing, itching, or gastric distress produced by normal niacin.
The tablet ingredients may also be formed into granules, if desired, and then may be taken alone, without tabletting, if desired, in effective dosages, but this is generally less convenient from the stand-; point of the user and less advantageous from the standpoint of prolonged time-release effect upon ingestion.
Dextrose or other soluble sugar may also be present in an amount up to about 100 mg if desired, to further assist in the tablets' disintegration upon ingestion.
- 25 ~ 5/dlk 2 ~
Example 8 A capsule example is:
Guar Gum 500 mg Magnesium Carbonate 80 mg Niacin 80 mg Citric Acid (fine powder) 10 mg Other fibers, drugs, mineral salts, and acids ~may obviously replace those employed in the foregoing Example.
Example 9 Minimum Ratio Example (600:1) (small amount of drug) Guar Gum 300 mg Vitamin B-12 500 mcg Calcium Carbonate 100 mg Citric Acid 50 mg Dextrose 100 mg MCC 25 mg Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 10 Maximum Ratio Example (1:2) (large amount of drug) Each tablet contains:
Guar Gum 350 mg Ibuprofen 700 mg Calcium Carbonate 50 mg Citric Acid 50 mg Dextrose 50 mg MCC 25 mg - 26 - H-K 5/dlk C(.)~,3 1, ~
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 11 5Pharmacological Evaluation Dissolution Test The tablets from Example 2 are dissolved in a gastric simulator dissolution apparatus at 0.1 N HCl and are observed to take on the appearance of "cotton plugs" or balls of fiber-gel from which the Vitamin C
is slowly released. Samples are taken from each vessel --at 1, 4, and 6 hours and the Vitamin C content from each is analyzed. The results confirm that the Vitamin C is being slowly released over time from the fiber-gel matrix. Similar tests on other products of the invention likewise confirm the steady prolonged and efficient release of the drug or other therapeutic agent over a prolonged period but with ultimate release of substantially all of the active ingredient within the gastrointestinal tract.
Drugs or Therapeutic Agents Among drugs or therapeutic agents which may be incorporated according to this invention, but to which it should not be limited, are:
a. Antipyretics and analgesics such as acetamino-phen, aspirin and ibuprofen b~ Appetite suppressants such as phenylpropanol-amine hydrochloride and stimulants such as caffeine c. Potassium, KC1, or another mineral supplement d. Vitamin C
e. Vitamin B-12 f. Antihypercholesterolemics, and especially Niacin - 27 - H-K 5/dlk ?~ ~3 JJ) 3 '1 ~ ~
9. Antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrochloride.
h. Antihistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyl-toloxamine citrate.
i. Decongestants, such as phenylephrine hydro-chloride, phenylpropanolamine hydrochloride, - pseudoephedrine hydrochloride, and ephedrine.
Preferred particular drugs, minerals, or vitamins for which the present delivery system is ideally suited include:
Niacin, Vitamin B-12, Potassium Chloride, Vitamin C, Aspirin, Caffeine, Phenylpropanolamine hydrochlor-ide, Ibuprofen, Pseudoephedrine, Nitroglycerin, and Gemfibro~il.
The active ingredient can be any type of medi-cation which acts systemically and which can be admini-: stered orally to transmit the active therapeutic agent into the gastrointestinal tract and into the blood-stream in therapeutically-effective levels without early excessive peak concentrations, without being inactivated by physiological fluids, and without passing unchanged through the body of the patient or subject by being excreted unabsorbed. Alternatively, the active ingredient can be any type of medication which acts through the buccal tissues of the mouth to transmit the active ingredient directly into the bloodstream, thus bypassing both any possible first pass liver metabolism and/or the gastric and intestinal fluids, which often have an adverse inactivating or destructive action on the active ingredient unless it is specially protected against such fluids as by means - 28 - . H-X S/dlk 2 ~
of an enteric coating or the like. The active ingredi-ent can also be a type of medication which can be transmitted into the blood circulation through the rectal tissues.
Representative active therapeutic agents include antacids, anti-inflammatory substances, coronary dilators, cerebral dilators, vasodilators, antibac-terials, psychotropics, antimanics, stimulants, anti-histamines, laxatives, decongestants, vitamins, and -the like. However, it is to be understood that the ! invention is also applicable to sublingual lozenges, suppositories, capsules and compressed tablets, the latter being intended to be swallowed in unit dosage form and which, upon ingestion according to a pre-scribed regimen, give slow and regular release of active therapeutic agent without an initial dumping of . a fixed percentage in the intestinal tract while being ; protected against normally-inactivating gastric fluids,whether administered for therapeutic, preventive, or dietary purposes, and whether employed in human or veterinary therapy.
It is therefore seen that the present invention provides a unique prolonged-release dosage formulation, especially a tablet, consisting of the following as essential ingredients: an effective dose of a bio-logically-absorbable drug or other therapeutic agent, a gel-forming dietary fiber, such as guar gum, a physiologically-acceptable acid, especially a food-grade organic acid or phosphoric acid, a mineral salt which releases a physiologically-acceptable gas upon ingestion, preferably a mineral carbonate or bicarbon-ate, and advantageously dextrose or another soluble sugar as a further disintegrant, and a method of prolonging the release of a drug or other active therapeutic agent upon administration to a living - 29 - H-K 5/dlk 2~3~
animal body, e.g., a human being or other animal, by employment of such a prolonged-release pharmaceutical, therapeutic, or dietary composition, all having the unpredictable and highly advantageous characteristics and effects as more fully set forth in the foregoing.
It is to be understood that the invention is not to be limited to the exact details of operation, or to the exact compositions, methods, procedures, or embodi-ments shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the full scope which can be legally accorded to the appended claims.
Example 8 A capsule example is:
Guar Gum 500 mg Magnesium Carbonate 80 mg Niacin 80 mg Citric Acid (fine powder) 10 mg Other fibers, drugs, mineral salts, and acids ~may obviously replace those employed in the foregoing Example.
Example 9 Minimum Ratio Example (600:1) (small amount of drug) Guar Gum 300 mg Vitamin B-12 500 mcg Calcium Carbonate 100 mg Citric Acid 50 mg Dextrose 100 mg MCC 25 mg Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 10 Maximum Ratio Example (1:2) (large amount of drug) Each tablet contains:
Guar Gum 350 mg Ibuprofen 700 mg Calcium Carbonate 50 mg Citric Acid 50 mg Dextrose 50 mg MCC 25 mg - 26 - H-K 5/dlk C(.)~,3 1, ~
Other fibers, drugs, mineral salts, acids, and soluble sugars may obviously replace those employed in the foregoing Example.
Example 11 5Pharmacological Evaluation Dissolution Test The tablets from Example 2 are dissolved in a gastric simulator dissolution apparatus at 0.1 N HCl and are observed to take on the appearance of "cotton plugs" or balls of fiber-gel from which the Vitamin C
is slowly released. Samples are taken from each vessel --at 1, 4, and 6 hours and the Vitamin C content from each is analyzed. The results confirm that the Vitamin C is being slowly released over time from the fiber-gel matrix. Similar tests on other products of the invention likewise confirm the steady prolonged and efficient release of the drug or other therapeutic agent over a prolonged period but with ultimate release of substantially all of the active ingredient within the gastrointestinal tract.
Drugs or Therapeutic Agents Among drugs or therapeutic agents which may be incorporated according to this invention, but to which it should not be limited, are:
a. Antipyretics and analgesics such as acetamino-phen, aspirin and ibuprofen b~ Appetite suppressants such as phenylpropanol-amine hydrochloride and stimulants such as caffeine c. Potassium, KC1, or another mineral supplement d. Vitamin C
e. Vitamin B-12 f. Antihypercholesterolemics, and especially Niacin - 27 - H-K 5/dlk ?~ ~3 JJ) 3 '1 ~ ~
9. Antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrochloride.
h. Antihistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyl-toloxamine citrate.
i. Decongestants, such as phenylephrine hydro-chloride, phenylpropanolamine hydrochloride, - pseudoephedrine hydrochloride, and ephedrine.
Preferred particular drugs, minerals, or vitamins for which the present delivery system is ideally suited include:
Niacin, Vitamin B-12, Potassium Chloride, Vitamin C, Aspirin, Caffeine, Phenylpropanolamine hydrochlor-ide, Ibuprofen, Pseudoephedrine, Nitroglycerin, and Gemfibro~il.
The active ingredient can be any type of medi-cation which acts systemically and which can be admini-: stered orally to transmit the active therapeutic agent into the gastrointestinal tract and into the blood-stream in therapeutically-effective levels without early excessive peak concentrations, without being inactivated by physiological fluids, and without passing unchanged through the body of the patient or subject by being excreted unabsorbed. Alternatively, the active ingredient can be any type of medication which acts through the buccal tissues of the mouth to transmit the active ingredient directly into the bloodstream, thus bypassing both any possible first pass liver metabolism and/or the gastric and intestinal fluids, which often have an adverse inactivating or destructive action on the active ingredient unless it is specially protected against such fluids as by means - 28 - . H-X S/dlk 2 ~
of an enteric coating or the like. The active ingredi-ent can also be a type of medication which can be transmitted into the blood circulation through the rectal tissues.
Representative active therapeutic agents include antacids, anti-inflammatory substances, coronary dilators, cerebral dilators, vasodilators, antibac-terials, psychotropics, antimanics, stimulants, anti-histamines, laxatives, decongestants, vitamins, and -the like. However, it is to be understood that the ! invention is also applicable to sublingual lozenges, suppositories, capsules and compressed tablets, the latter being intended to be swallowed in unit dosage form and which, upon ingestion according to a pre-scribed regimen, give slow and regular release of active therapeutic agent without an initial dumping of . a fixed percentage in the intestinal tract while being ; protected against normally-inactivating gastric fluids,whether administered for therapeutic, preventive, or dietary purposes, and whether employed in human or veterinary therapy.
It is therefore seen that the present invention provides a unique prolonged-release dosage formulation, especially a tablet, consisting of the following as essential ingredients: an effective dose of a bio-logically-absorbable drug or other therapeutic agent, a gel-forming dietary fiber, such as guar gum, a physiologically-acceptable acid, especially a food-grade organic acid or phosphoric acid, a mineral salt which releases a physiologically-acceptable gas upon ingestion, preferably a mineral carbonate or bicarbon-ate, and advantageously dextrose or another soluble sugar as a further disintegrant, and a method of prolonging the release of a drug or other active therapeutic agent upon administration to a living - 29 - H-K 5/dlk 2~3~
animal body, e.g., a human being or other animal, by employment of such a prolonged-release pharmaceutical, therapeutic, or dietary composition, all having the unpredictable and highly advantageous characteristics and effects as more fully set forth in the foregoing.
It is to be understood that the invention is not to be limited to the exact details of operation, or to the exact compositions, methods, procedures, or embodi-ments shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the full scope which can be legally accorded to the appended claims.
- 30 - H-R 5/dlk
Claims (2)
1,000:0.5 and 1:1.5.
The composition of claim 1, wherein the gel-forming dietary fiber comprises about 25% to about 85%
- 32 - HK 5/dlk by weight, the physiologically-acceptable acid com-prises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
The composition of claim 14, wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5%
by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
The composition of claim 1, wherein a soluble sugar is also present in an amount between about 1% and about 30% by weight of the composition.
The composition of claim 16, wherein a soluble sugar is present in an amount between about 3% and about 12% by weight of the composition.
The composition of claim 1, wherein the gel-forming dietary fiber comprises about 25% to about 85%
by weight, the physiologically-acceptable acid com prises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of soluble sugar.
The composition of claim 1, wherein the gel-forming dietary fiber comprises about 25% to about 85%
- 33 - HK 5/dlk by weight, the physiologically-acceptable acid com-prises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and also containing between about 3% and about 12% by weight of a soluble sugar.
The composition of claim 1, wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5%
by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of a soluble sugar.
The composition of claim 1, wherein the drug or therapeutic agent is niacin.
The composition of claim 21, wherein niacin is present in granular form, with a cellulose coating about the granules thereof.
The composition of claim 21, wherein the niacin is present in amount between about 100 and about 200 mg/per unit dosage form.
The composition of claim 23, in tablet form.
A prolonged-release unit dosage formulation or composition consisting essentially of an effective dose of niacin, a gel-forming dietary fiber in an amount between about 25% to about 85% by weight of the compo-- 34 - HK 5/dlk sition, a physiologically-acceptable edible acid in an amount of about 2% to about 50% by weight, and a mineral salt which releases a physiologically-accept-able gas upon ingestion in an amount of between about 5% and about 75% by weight.
The composition of claim 25, in tablet form.
The composition of claim 25, wherein the amount of the niacin is between about 100 mg and about 200 mg per tablet.
The composition of claim 25, wherein the niacin is present in granular form, the granules being coated with a cellulose coating.
The composition of claim 28, wherein the coating is a combination of a carboxymethylcellulose coating and an ethylcellulose coating.
The composition of claim 25, wherein the gel-forming fiber is psyllium husk powder or guar gum.
The composition of claim 25, wherein the acid is a food-grade organic acid or phosphoric acid.
The composition of claim 31, wherein the acid is citric acid.
The composition of claim 25, wherein the mineral salt is a carbonate or bicarbonate.
The composition of claim 33, wherein the mineral salt is calcium calbonate.
- 35 - , HK 5/dlk A method for prolonging the release of a drug or other active therapeutic agent, comprising the step of preparing a prolonged-release unit dosage formulation or composition which consists essentially of an effec-tive dose of a biologically-absorbable drug or other therapeutic agent, a gel-forming dietary fiber, a physiologically-acceptable acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion, the combination of the fiber, acid, and salt providing prolonged release of the drug or therapeutic agent upon exposure of the composition to biological fluids.
The method of claim 35, wherein the gas released is carbon dioxide.
The method of claim 36, wherein the mineral salt is a mineral carbonate or bicarbonate.
The method of claim 37, wherein the mineral salt is calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicar-bonate.
The method of claim 35, wherein the acid is a food-grade organic acid or phosphoric acid.
The method of claim 35, wherein, in addition to the previously-recited ingredients, the composition contains a soluble sugar.
The method of claim 35, wherein the gel-form-- 36 - H-K 5/dlk ing dietary fiber comprises about 25% to about 85% by weight of the composition.
The method of claim 41, wherein the gel-form-ing dietary fiber comprises about 50% by weight of the composition.
The method of claim 35, wherein the physiolo-gically-acceptable acid comprises about 2% to about 50%
by weight of the composition.
The method of claim 43, wherein the physiolo-gically-acceptable acid comprises about 596 by weight of the composition.
The method of claim 35, wherein the mineral salt comprises about 5% to about 7596 by weight of the composition.
The method of claim 45, wherein the mineral salt comprises about 15% by weight of the composition.
The method of claim 35, wherein the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
The method of claim 35, wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physiologically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
- 37 - ' HK 5/dlk The method of claim 48, wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
The method of claim 35, wherein a soluble sugar is also present in an amount between about 1% and about 30% by weight of the composition.
The method of claim 50, wherein a soluble sugar is present in an amount between about 3% and about 12% by weight of the composition.
The method of claim 35, wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physiologically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of soluble sugar.
The method of claim 35, wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physiologically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 3% and about 12% by weight of soluble sugar.
- 38 - H-K 5/dlk The method of claim 35, wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of a soluble sugar.
The method of claim 35, wherein the drug or therapeutic agent is niacin.
The method of claim 55, wherein niacin is present in granular form, with a cellulose coating about the granules thereof.
The method of claim 55, wherein the niacin is present in amount between about 100 and about 200 mg/per unit dosage form.
The method of claim 57, wherein the dosage unit is a tablet.
A prolonged-release unit dosage formulation con-sisting essentially of an effective dose of niacin, a gel-forming dietary fiber in an amount of about 25% to about 85% by weight of the composition, a physiologi-cally-acceptable edible acid in an amount between about
The composition of claim 1, wherein the gel-forming dietary fiber comprises about 25% to about 85%
- 32 - HK 5/dlk by weight, the physiologically-acceptable acid com-prises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
The composition of claim 14, wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5%
by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
The composition of claim 1, wherein a soluble sugar is also present in an amount between about 1% and about 30% by weight of the composition.
The composition of claim 16, wherein a soluble sugar is present in an amount between about 3% and about 12% by weight of the composition.
The composition of claim 1, wherein the gel-forming dietary fiber comprises about 25% to about 85%
by weight, the physiologically-acceptable acid com prises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of soluble sugar.
The composition of claim 1, wherein the gel-forming dietary fiber comprises about 25% to about 85%
- 33 - HK 5/dlk by weight, the physiologically-acceptable acid com-prises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and also containing between about 3% and about 12% by weight of a soluble sugar.
The composition of claim 1, wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5%
by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of a soluble sugar.
The composition of claim 1, wherein the drug or therapeutic agent is niacin.
The composition of claim 21, wherein niacin is present in granular form, with a cellulose coating about the granules thereof.
The composition of claim 21, wherein the niacin is present in amount between about 100 and about 200 mg/per unit dosage form.
The composition of claim 23, in tablet form.
A prolonged-release unit dosage formulation or composition consisting essentially of an effective dose of niacin, a gel-forming dietary fiber in an amount between about 25% to about 85% by weight of the compo-- 34 - HK 5/dlk sition, a physiologically-acceptable edible acid in an amount of about 2% to about 50% by weight, and a mineral salt which releases a physiologically-accept-able gas upon ingestion in an amount of between about 5% and about 75% by weight.
The composition of claim 25, in tablet form.
The composition of claim 25, wherein the amount of the niacin is between about 100 mg and about 200 mg per tablet.
The composition of claim 25, wherein the niacin is present in granular form, the granules being coated with a cellulose coating.
The composition of claim 28, wherein the coating is a combination of a carboxymethylcellulose coating and an ethylcellulose coating.
The composition of claim 25, wherein the gel-forming fiber is psyllium husk powder or guar gum.
The composition of claim 25, wherein the acid is a food-grade organic acid or phosphoric acid.
The composition of claim 31, wherein the acid is citric acid.
The composition of claim 25, wherein the mineral salt is a carbonate or bicarbonate.
The composition of claim 33, wherein the mineral salt is calcium calbonate.
- 35 - , HK 5/dlk A method for prolonging the release of a drug or other active therapeutic agent, comprising the step of preparing a prolonged-release unit dosage formulation or composition which consists essentially of an effec-tive dose of a biologically-absorbable drug or other therapeutic agent, a gel-forming dietary fiber, a physiologically-acceptable acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion, the combination of the fiber, acid, and salt providing prolonged release of the drug or therapeutic agent upon exposure of the composition to biological fluids.
The method of claim 35, wherein the gas released is carbon dioxide.
The method of claim 36, wherein the mineral salt is a mineral carbonate or bicarbonate.
The method of claim 37, wherein the mineral salt is calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicar-bonate.
The method of claim 35, wherein the acid is a food-grade organic acid or phosphoric acid.
The method of claim 35, wherein, in addition to the previously-recited ingredients, the composition contains a soluble sugar.
The method of claim 35, wherein the gel-form-- 36 - H-K 5/dlk ing dietary fiber comprises about 25% to about 85% by weight of the composition.
The method of claim 41, wherein the gel-form-ing dietary fiber comprises about 50% by weight of the composition.
The method of claim 35, wherein the physiolo-gically-acceptable acid comprises about 2% to about 50%
by weight of the composition.
The method of claim 43, wherein the physiolo-gically-acceptable acid comprises about 596 by weight of the composition.
The method of claim 35, wherein the mineral salt comprises about 5% to about 7596 by weight of the composition.
The method of claim 45, wherein the mineral salt comprises about 15% by weight of the composition.
The method of claim 35, wherein the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
The method of claim 35, wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physiologically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
- 37 - ' HK 5/dlk The method of claim 48, wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5.
The method of claim 35, wherein a soluble sugar is also present in an amount between about 1% and about 30% by weight of the composition.
The method of claim 50, wherein a soluble sugar is present in an amount between about 3% and about 12% by weight of the composition.
The method of claim 35, wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physiologically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of soluble sugar.
The method of claim 35, wherein the gel-forming dietary fiber comprises about 25% to about 85% by weight, the physiologically-acceptable acid comprises about 2% to about 50% by weight, the mineral salt comprises about 5% to about 75% by weight, and the ratio of the weight of the gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 3% and about 12% by weight of soluble sugar.
- 38 - H-K 5/dlk The method of claim 35, wherein the gel-forming dietary fiber comprises about 50% by weight, the physiologically-acceptable acid comprises about 5% by weight, the mineral salt comprises about 15% by weight, and the ratio of the weight of gel-forming fiber to the weight of the drug or therapeutic agent is between about 1,000:0.5 and 1:1.5, and containing also between about 1% and about 30% by weight of a soluble sugar.
The method of claim 35, wherein the drug or therapeutic agent is niacin.
The method of claim 55, wherein niacin is present in granular form, with a cellulose coating about the granules thereof.
The method of claim 55, wherein the niacin is present in amount between about 100 and about 200 mg/per unit dosage form.
The method of claim 57, wherein the dosage unit is a tablet.
A prolonged-release unit dosage formulation con-sisting essentially of an effective dose of niacin, a gel-forming dietary fiber in an amount of about 25% to about 85% by weight of the composition, a physiologi-cally-acceptable edible acid in an amount between about
2% and about 50% by weight, and a mineral salt which releases a physiologically-acceptable gas upon inges-tion in an amount of between about 5% and about 75% by weight.
- 39 - HK 5/dlk The formulation of claim 59, wherein the dosage unit is a tablet.
The formulation of claim 60, wherein the amount of the niacin is between about 100 mg and about 200 mg per tablet.
The formulation of claim 59, wherein the niacin is present in granular form, the granules being coated with a cellulose coating.
The formulation of claim 62, wherein the coating is a combination of a carboxymethylcellulose coating and an ethylcellulose coating.
The formulation of claim 59, wherein the gel-forming fiber is psyllium husk powder or guar gum.
The formulation of claim 59, wherein the acid is a food-grade organic acid or phosphoric acid.
The formulation of claim 65, wherein the acid is citric acid.
The formulation of claim 59, wherein the mineral salt is a carbonate or bicarbonate.
The formulation of claim 67, wherein the mineral salt is calcium carbonate.
The composition of claim 1, wherein the drug or therapeutic agent is an analgesic, an antihypercho-lesterolemic, a vitamin, a stimulant, an appetite suppressant, or a mineral supplement.
- 40 - HK 5/dlk The method of claim 35, wherein the drug or therapeutic agent is an analgesic, an antihypercho-lesterolemic, a vitamin, a stimulant, an appetite suppressant, or a mineral supplement.
- 41 - HK 5/dlk
- 39 - HK 5/dlk The formulation of claim 59, wherein the dosage unit is a tablet.
The formulation of claim 60, wherein the amount of the niacin is between about 100 mg and about 200 mg per tablet.
The formulation of claim 59, wherein the niacin is present in granular form, the granules being coated with a cellulose coating.
The formulation of claim 62, wherein the coating is a combination of a carboxymethylcellulose coating and an ethylcellulose coating.
The formulation of claim 59, wherein the gel-forming fiber is psyllium husk powder or guar gum.
The formulation of claim 59, wherein the acid is a food-grade organic acid or phosphoric acid.
The formulation of claim 65, wherein the acid is citric acid.
The formulation of claim 59, wherein the mineral salt is a carbonate or bicarbonate.
The formulation of claim 67, wherein the mineral salt is calcium carbonate.
The composition of claim 1, wherein the drug or therapeutic agent is an analgesic, an antihypercho-lesterolemic, a vitamin, a stimulant, an appetite suppressant, or a mineral supplement.
- 40 - HK 5/dlk The method of claim 35, wherein the drug or therapeutic agent is an analgesic, an antihypercho-lesterolemic, a vitamin, a stimulant, an appetite suppressant, or a mineral supplement.
- 41 - HK 5/dlk
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/440,730 US5096714A (en) | 1988-06-28 | 1989-11-22 | Prolonged release drug tablet formulations |
| US07/440,730 | 1989-11-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2030449A1 true CA2030449A1 (en) | 1991-05-23 |
Family
ID=23749942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2030449 Abandoned CA2030449A1 (en) | 1989-11-22 | 1990-11-21 | Prolonged release drug tablet formulations |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2030449A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090010906A1 (en) * | 2004-08-31 | 2009-01-08 | Henning Blume | Peroral dosage forms to achieve a sustained-release effect after medicament dosage with a meal |
-
1990
- 1990-11-21 CA CA 2030449 patent/CA2030449A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090010906A1 (en) * | 2004-08-31 | 2009-01-08 | Henning Blume | Peroral dosage forms to achieve a sustained-release effect after medicament dosage with a meal |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5096714A (en) | Prolonged release drug tablet formulations | |
| US5445826A (en) | Delivery system containing a gel-forming dietary fiber and a drug | |
| US5023245A (en) | Improved niacin formulation | |
| AU676556B2 (en) | Controlled release oxybutynin formulations | |
| EP0730444B1 (en) | Sustained release formulations for 24 hour release of metoprolol | |
| AU628754B2 (en) | Therapeutic agents | |
| US5399362A (en) | Once-a-day metoprolol oral dosage form | |
| US5118510A (en) | Niacin drink mix formulation | |
| JP3250737B2 (en) | Controlled release formulation (Albuterol) | |
| SE453797B (en) | THERAPEUTIC, SOLID UNIT DOSAGE FORM WITH EXTENDED DISPOSAL SAMPLES WHERE BERARM MATERIALS INCLUDE HYDROXYPROPYLMETHYL CELLULOSA WITH HIGH MOLECULES WEIGHT | |
| KR20000011247A (en) | Composition and pharmaceutical dosage form for colonic drug delivery using polysaccharides | |
| PL186696B1 (en) | Preparation of controllable drug release within a patient's body in particular for slightly soluble nasic drugs | |
| CA2124353A1 (en) | Sustained release composition and method utilizing xanthan gum and an active ingredient | |
| US5466469A (en) | Granular drug delivery system | |
| JPH10511407A (en) | Sustained release matrix for high dose poorly soluble drugs | |
| JPH03200724A (en) | Tablet having double action | |
| NZ516959A (en) | An oral controlled drug delivery system in the form of a multiparticulate or monolithic system that is buoyant in gastric fluid | |
| AU745697B2 (en) | Lipstatin derivative-soluble fiber tablets | |
| CA2030449A1 (en) | Prolonged release drug tablet formulations | |
| AU709413B2 (en) | Sustained-release drug delivery employing a powdered hydrocolloid gum obtainable from higher plants | |
| CA2205442C (en) | Nsaid delivery employing a powdered hydrocolloid gum obtainable from higher plants | |
| CA2030448A1 (en) | Niacin drink mix formulation | |
| EP0200252A1 (en) | Tablets comprising trimethoprim and a sulfonamide | |
| WO2002100438A1 (en) | Oral controlled release drug delivery system with husk powder from lepidium sativum seeds | |
| EP1414417A1 (en) | Pharmaceutical formulation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |