Taste-masked pharmaceutical composition

Details Taste-masked pharmaceutical composition Taste-masked pharmaceutical composition

1999-03-02

2001-08-07

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S441000, C424S465000, C424S490000, C514S772300, C514S777000, C514S781000, C514S951000, C514S974000

Reexamination Certificate

active

06270807

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutical compositions for treating gastrointestinal distress, episodic heartburn, and the like, and more particularly to taste-masked, chewable pharmaceutical compositions containing a histamine H
2
-receptor antagonist.
BACKGROUND OF THE INVENTION
It is known that certain histamine H
2
-receptor antagonists are routinely administered orally to patients suffering from certain gastrointestinal conditions such as ulcers, dyspepsia, various reflux indications, and the like. Examples of commonly used histamine H
2
-receptor antagonist include cimetidine, ranitidine and famotidine. These compounds are usually administered orally in the form of tablets or capsules which are intended to be swallowed. Thus, for a substantial portion of patients being treated with a histamine H
2
-receptor antagonist, the taste of the histamine H
2
-receptor antagonist is unimportant. However, there are many segments of the patient population which have difficulty swallowing tablets, and would prefer a more easily ingested dosage form, such as a chewable tablet. Unfortunately, the histamine H
2
-receptor antagonists are known to have an unpalatably bitter taste which must be effectively masked to ensure good patient compliance with chewable tablets.
Attempts to produce palatably acceptable chewable pharmaceutical compositions comprising a histamine H
2
-receptor antagonist include efforts to mask the bitter taste of the histamine H
2
-receptor antagonist with a drug adsorbate, such as a synthetic cationic resin or a silicate taste-masking agent. Other attempts involve the use of an intense sweetener such as aspartame, or the like. Still other attempts have involved the use of a polymeric coating. For example, U.S. Pat. No. 5,260,072 to Roche et al. proposes a chewable tablet of a histamine H
2
-receptor antagonist comprising granules which are formed by rotogranulation of the medicament with a binder and a fine particulate carrier material, and are coated with a polymer blend of cellulose acetate, cellulose acetate butyrate or a combination of both along with polyvinylpyrrolidone.
These attempts at providing a palatably acceptable chewable pharmaceutical composition have not been entirely successful. Accordingly, there remains a need for effective methods of taste-masking histamine H
2
-receptor antagonists for the preparation of palatably acceptable chewable tablets.
SUMMARY OF THE INVENTION
The present invention provides a chewable pharmaceutical composition comprising a granulated histamine H
2
-receptor antagonist in which the individual granules are provided with a taste-masking coating comprising a water-insoluble, water-permeable methacrylate ester copolymer. The coating is applied to the granules in an amount which provides a taste-masking effect for a relatively short period during which the composition is being chewed by a patient, but which allows substantially immediate release of the histamine H
2
-receptor antagonist after the composition has been chewed and ingested.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Histamine H
2
-receptor antagonist are derivatives of histamine that bind to and exhibit inhibiting or blocking activity against H
2
-receptors. The histamine H
2
-receptor antagonists, or H
2
-blocking agents, are a discrete and limited group of medications readily recognized in the art, and are generally polar, hydrophilic molecules. Most pharmaceutical formulations which employ histamine H
2
-receptor antagonist, however, have an unpalatably bitter taste. Examples of histamine H
2
-receptor antagonist include, but are not limited to, ranitidine, cimetidine, nizatidine, famotidine, sufotidine, roxatidine, bisfentidine, tiotidine, lamtidine, niperotidine, mifentidine, zaltidine and loxtidine. Preferred histamine H
2
-receptor antagonist include cimetidine, ranitidine, and especially famotidine.
The pharmaceutically active agents useful in the present invention are preferably provided in the form or a pharmaceutically acceptable salt or a free base. Suitable salts are readily available and well known in the art. The preferred pharmaceutically acceptable salts are water-soluble. The histamine H
2
-receptor antagonist may be provided in a variety of water-soluble salt forms. Suitable water-soluble salt forms include hydrochloride salts, hydrobromide salts, sulfate salts, nitrate salts, citrate salts and tartrate salts.
The amount of histamine H
2
-receptor antagonist, either in salt form or free base, which is included in the composition of the present invention will be dependent upon the pharmaceutical activity of the particular compound. Generally, the amount of histamine H
2
-receptor antagonist is sufficient to deliver a therapeutically effective dose to a patient in need thereof. For example, the amount of histamine H
2
-receptor antagonist typically included in the composition is between about 1 to about 50% by weight. Preferably, the amount of histamine H
2
-receptor antagonist included in the composition is sufficient to provide an oral dosage form containing between about 2 to about 20% by weight of histamine H
2
-receptor antagonist.
The granules containing the histamine H
2
-receptor antagonist are preferably formed by blending the histamine H
2
-receptor antagonist, a pharmaceutically acceptable binder such as povidone (polyvinylpyrrolidone), and a carrier which adds bulk and smoothness to the body of the granules. Pharmaceutically acceptable binders, carriers, diluents, disintegrants, etc. are described in the “
Handbook of Pharmaceutical Excipients
,” 2nd Ed., 1994, which is incorporated here by reference.
Povidone or polyvinylpyrrolidone acts as a binder in the granulation process. Use of povidone as a binder imparts good mechanical strength to the granules. In this respect, povidone is superior to other binders such as cellulosic polymers, but other polymers may be used, e.g., hydroxypropyl methylcellulose or starch.
Lactose is a carrier which adds bulk and smoothness to the body of the granules and may increase the release rate and dissolution of the histamine H
2
-receptor antagonist, after the composition has been chewed and swallowed. Other useful carrier materials which may be substituted for lactose include other saccharides, e.g., fructose, sucrose, dextrose, confectioner's sugar and maltodextrins. The carrier material should be of a fine particle size, preferably in the range of 5 to 75 microns to fill in surface voids and provide a smooth surface to the granules.
Further, microcrystalline cellulose may be blended into the carrier materials and incorporated into the granules. Fine particle size microcrystalline cellulose may be added to such carrier materials in the range of about 5 to 20% of the weight of the granules, to provide increased strength to the granules.
The histamine H
2
-receptor antagonist may comprise from about 2 to about 85% of the weight of the granules, with the binder comprising from about 1 to about 10% of the weight of the granules, and with the carrier comprising from about 10 to about 90% of the weight of the granules.
The exact size of the coated granules is not critical. However, the granules are preferably sized in the range of from about 150 to about 2000 microns. The preferred range is 300-1250 &mgr;m. In general, particles of like size facilitate blending and provide regularity in dosage forms. The granules may be prepared using well known wet granulating techniques.
The granules containing the histamine H
2
-receptor antagonist are provided with a polymeric coating comprising a methacrylate ester copolymer. The polymeric coating is applied in an amount which is sufficient to mask the taste of the histamine H
2
-receptor antagonist so that the resulting chewable tablets containing the coated granules have an acceptable palatability as they are chewed and swallowed. At the same tine, the amount of coating is sufficiently low so that substantially immediate release of the histamine H
2
-receptor antagonist is achieved after the pharmaceutical composition is chewed and swallo

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