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Title:  Stable pharmaceutical composition useful for treating gastrointestinal disorders
United States Patent: 
7,135,197
Issued: 
November 14, 2006

Inventors: 
Pena; Lorraine E. (Kalamazoo, MI), Huczek; Dennis L. (Portage, MI)
Assignee: 
Pharmacia Corporation (St. Louis, MO)
Appl. No.: 
10/356,915
Filed: 
February 3, 2003


 

George Washington University's Healthcare MBA


Abstract

The present invention provides a pharmaceutical composition comprising at least one pharmaceutically acceptable bismuth-containing compound, at least one pharmaceutically acceptable non-clay-derived suspending agent, and water. The suspension exhibits reduced upward pH drift by comparison with an otherwise similar suspension which comprises a clay-derived suspending agent. Such compositions are useful in the prevention and treatment of gastrointestinal diseases and/or disorders.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition, preferably an orally deliverable composition in the form of a suspension, comprising at least one pharmaceutically acceptable bismuth-containing compound, at least one pharmaceutically acceptable non-clay-derived suspending agent, and water. The suspension, during storage in a closed container maintained under ambient conditions for a period of at least about 5 months, exhibits reduced upward pH drift by comparison with an otherwise similar comparative suspension that comprises at least 0.1% of a clay-derived suspending agent. Such a suspension optionally further comprises at least one pharmaceutically acceptable anti-microbial preservative.

In another embodiment, the invention provides a pharmaceutical composition, preferably an orally deliverable composition in the form of a suspension, comprising at least one pharmaceutically acceptable bismuth-containing compound, at least one pharmaceutically acceptable non-clay-derived suspending agent, and water. A suspension of this embodiment comprises zero to not more than 0.08%, preferably not more than about 0.075%, more preferably not more than about 0.06%, still more preferably not more than about 0.05%, and yet more preferably not more than about 0.04%, by weight, of a clay-derived suspending agent. In a particularly preferred embodiment, the suspension comprises substantially no amount of a clay-derived suspending agent. The suspension optionally further comprises at least one pharmaceutically acceptable anti-microbial preservative.

The term "clay-derived suspending agent" herein means any suspending agent which occurs in and/or is extracted from clay, including such suspending agents in natural, purified, refined and/or synthetic form. Non-limiting illustrative examples of clay-derived suspending agents include magnesium aluminum silicate, bentonite, kaolin, etc. A "non-clay-derived suspending agent" herein includes, without limitation, all suspending agents which are not clay-derived suspending agents. The term "pharmaceutically acceptable" herein means suitable for oral administration to a human subject or non-human animal.

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutically Acceptable Bismuth-containing Compound

Compositions of the present invention comprise at least one pharmaceutically acceptable bismuth-containing compound, preferably in the form of a salt. Such bismuth-containing compounds illustratively include bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth nitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgallate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate and mixtures thereof. Bismuth subsalicylate is a particularly preferred bismuth-containing compound.

Compositions of the present invention typically comprise at least one pharmaceutically acceptable bismuth-containing compound in a total amount of about 0.01% to about 50%, preferably about 0.05% to about 25%, more preferably about 0.1% to about 10%, and still more preferably about 0.5% to about 5%, by weight.

Pharmaceutically Acceptable Non-clay-derived Suspending Agent

Compositions of the present invention comprise at least one pharmaceutically acceptable non-clay-derived suspending agent. Such non-clay-derived suspending agents can be inorganic or organic, cellulosic or non-cellulosic, and/or polymeric or non-polymeric. One illustrative class of non-clay-derived suspending agents includes polymers, for example cellulosic and non-cellulosic polymers. Cellulosic polymers are a particularly preferred group of non-clay-derived suspending agents. Non-limiting examples of suitable cellulosic polymers include methylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, hydroxyethylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, microcrystalline cellulose, a combination of carboxymethylcellulose sodium and microcrystalline cellulose (e.g. Avicel RC-591 of FMC Corp.), and mixtures thereof.

Particularly preferred suspending agents include carboxymethylcellulose sodium, microcrystalline cellulose, a combination of carboxymethylcellulose sodium and microcrystalline cellulose, xanthan gum, silicon dioxide, and mixtures thereof.

At least one pharmaceutically acceptable non-clay-derived suspending agent is present in a composition of the invention in a total amount of about 0.01% to about 15%, preferably about 0.05% to about 10%, and more preferably about 0.1% to about 5%, by weight. It will be understood that at least one pharmaceutically acceptable suspending agent will be selected, by type and amount, so as to create a suspension exhibiting acceptable flow properties and substantially no phase separation upon standing.

Pharmaceutically Acceptable Anti-microbial Preservative

In a preferred embodiment, a composition of the invention comprises at least one pharmaceutically acceptable anti-microbial preservative. Non-limiting examples of anti-microbial preservatives include butylparaben, editic acid, ethylparaben, glycerol, methylparaben, potassium sorbate, propionic acid, propylene glycol, propylparaben, salicylic acid, sorbic acid, sodium benzoate, sodium propionate, sodium salicylate, etc. Presently preferred anti-microbial preservatives include sorbic acid, benzoic acid, methylparaben, salicylic acid, and sodium salicylate, and salts thereof.

If desired, one or more pharmaceutically acceptable anti-microbial preservatives are present in a composition of the invention in a total amount, by weight, of about 0.01% to about 10%, preferably about 0.01% to about 5%, and more preferably about 0.01% to about 2.5%.

Initial pH and pH Stability

A presently contemplated advantage of compositions of the invention is that they exhibit little or no upward pH drift by comparison with currently marketed bismuth-containing suspensions. The term "upward pH drift" herein refers to an increase in pH, relative to pH measured immediately after preparation, of a suspension during storage in a closed container maintained under ambient conditions for a period of time. A composition of the invention preferably has a pH, measured immediately after preparation, which is acceptable for oral administration, for example to a human subject. In general, a suspension having a pH of about 2 to about 8 is considered acceptable for oral administration to a human subject. Preferably, a composition of the invention has a pH, measured immediately after preparation, of about 3 to about 7, and more preferably about 3.5 to about 6.

During storage of a composition of the invention in a closed container maintained under ambient conditions for a period of at least about 5 months, more preferably at least about 7 months, still more preferably at least about 10 months, yet more preferably at least about 12 months, and even more preferably at least about 24 months, the composition preferably exhibits an increase in pH of zero to not more than about 0.6, preferably not more than about 0.4, still more preferably not more than about 0.3, yet more preferably not more than about 0.2, and even more preferably not more than about 0.1.

In a particularly preferred embodiment, a composition of the invention, during storage in a closed container maintained under ambient conditions for a period of at least about 5 months, preferably at least about 7 months, more preferably at least about 10 months, still more preferably at least about 12 months, yet more preferably at least about 16 months, and even more preferably at least about 24 months, exhibits substantially no increase in pH.

In another embodiment, a composition of the invention, during storage in a closed container maintained under ambient conditions over a period of not less than about 5 months, preferably not less than about 7 months, more preferably not less than about 10 months, still more preferably not less than about 12 months, yet more preferably not less than about 16 months, and even more preferably not less than about 24 months, exhibits an average increase in pH during the storage period of zero to not more than 0.06/month, preferably not more than about 0.025/month, more preferably not more than about 0.008/month, and even more preferably not more than about 0.004/month.

In another embodiment, the invention provides an orally deliverable suspension comprising at least one pharmaceutically acceptable bismuth-containing compound, at least one pharmaceutically acceptable non-clay-derived suspending agent, and water. A suspension of this embodiment comprises zero to not more than about 0.08%, preferably not more than about 0.075%, more preferably not more than about 0.06%, still more preferably not more than about 0.05%, and yet more preferably not more than about 0.04%, by weight, of a clay-derived suspending agent and, during storage in a closed container maintained under ambient conditions for a period of at least about 5 months, preferably at least about 10 months, more preferably at least about 12 months, yet more preferably at least about 16 months and still more preferably at least about 24 months, the suspension exhibits reduced upward pH drift by comparison with an otherwise similar comparative composition wherein the at least one non-clay-derived suspending agent is replaced by a clay-derived suspending agent, for example magnesium aluminum silicate. Such a composition preferably further comprises at least one pharmaceutically acceptable anti-microbial preservative.

Water

Compositions of the invention preferably comprise about 50% to 99%, preferably about 60% to about 95%, and more preferably about 65% to about 92.5%, by weight, water.

Anti-foaming Agent

Compositions of the invention optionally comprise at least one anti-foaming agent. Without being bound by theory, it is believed that an anti-foaming agent present in a composition of the invention can reduce intestinal gas experienced by a subject ingesting such a composition and/or limit foaming during preparation and/or processing of a composition of the invention. Silicone-based polymers are preferred antifoaming agents. Non-limiting examples of suitable anti-foaming agents include polydimethylsiloxane (e.g. simethicone USP), 7-9245 30% simethicone emulsion of Dow Corning, Sigma Antifoam A Concentrate, and dimethicone (e.g. FG-10 anti-foam emulsion of Dow Corning). If desired, at least one anti-foaming agent is present in a composition of the invention in a total amount, by weight, of about 0.0001% to about 5%, preferably about 0.0005% to about 4%, and more preferably about 0.001% to about 2.5%.

Additional Excipients

Compositions of the invention can comprise any additional pharmaceutically acceptable excipients. The term "excipient" herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling, storage, consistency, flow properties, appearance, disintegration, dispersion, dissolution, release or organoleptic properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule suitable for oral administration. Excipients can include, by way of illustration and not limitation, diluents, buffers, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, preservatives, fragrances, and substances added to improve appearance of the composition.

Dosage Forms

A composition of the invention is preferably in the form of liquid, preferably an orally deliverable liquid, and more preferably an imbibable suspension having a viscosity suitable for pouring and oral ingestion. Preferably, where the composition is in the form of an imbibable suspension, such a suspension has a Brookfield viscosity of about 100 to about 5000 cP, more preferably about 200 to about 4000 cP, and still more preferably about 300 to about 3000. Particularly preferably, such a suspension exhibits substantially no phase separation upon standing under ambient conditions for a period of at least about 5 days, preferably at least about 20 days, more preferably at least about 30 days, and still more preferably at least about 60 days.

In another embodiment, a composition of the invention is in the form of a discrete dosage unit, for example a suspension enclosed by a capsule. Compositions of the invention can be prepared by any suitable process, not limited to processes described herein.

Utility of Compositions of the Invention

Compositions of the invention are useful in the treatment of gastrointestinal disorders and/or disturbances. The term "gastrointestinal disorders and/or disturbances" herein includes any disease, disorder or disturbance of the gastrointestinal tract which is treatable or preventable by oral administration of a bismuth-containing compound. Such disturbances are well known and include, for example, diarrhea including travelers diarrhea, nausea, vomiting, heartburn, indigestion, upset stomach, and treatment and/or prevention of gastritis and ulcers, particularly when Campylobacter pylori or Helicobacter pylori infection is present.

In treatment of gastrointestinal disorders and/or disturbances, a subject will ingest a safe and effective amount of a composition of the invention. Such a safe and effective amount will depend on, inter alia, the condition being treated, the particular bismuth-containing compound(s) present in the composition, and the age, weight and general health of the subject being treated.

Typically, a composition of the invention will be administered in a therapeutically effective daily amount of about 10 mg to about 500 g. Such a composition can be administered one or more times per day. Preferably a composition of the invention is administered not more than about 15 times per day, and more preferably not more than about 10 times per day. Generally, an amount of a composition of the invention sufficient to provide a subject with a therapeutically effective daily dose is an amount which provides the subject with at least one bismuth-containing compound in a total amount of about 5 mg to about 10,000 mg, preferably about 50 mg to about 8,500 mg, more preferably about 100 mg to about 6,000 mg.
 

Claim 1 of 65 Claims

1. An orally deliverable liquid pharmaceutical suspension comprising: (a) at least one pharmaceutically acceptable bismuth-containing compound present in a total amount of about 0.1 % to about 10%, by weight; (b) an effective suspending amount of at least one pharmaceutically acceptable non-clay-derived suspending agent selected from the group consisting of cellulosic suspending agents, polymeric suspending agents, xanthan gum, silicon dioxide, and mixtures thereof; (c) at least one pharmaceutically acceptable anti-microbial preservative, wherein the preservative does not contain benzoic acid or salts thereof; and (d) water; wherein during storage in a closed container maintained under ambient conditions for a period of at least about 5 months, the suspension exhibits reduced upward pH drift by comparison with an otherwise similar comparative suspension that contains at least 0.1%, by weight, of magnesium aluminum silicate.
 

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