Title:  Taste-masked pharmaceutical composition

United States Patent:  6,270,807

Assignee:  L. Perrigo Company (Allegan, MI)

Filed:  March 2, 1999

A chewable dosage form containing a histamine H₂ -receptor antagonist in an amount which is effective to treat a gastrointestinal disorder is provided in a palatably acceptable form. The dosage form comprises granules containing the histamine H₂ -receptor antagonist, which are provided with a taste-masking coating comprising a water-insoluble, water-permeable methacrylate ester copolymer in which 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 H₂ -receptor antagonist after the composition has been chewed and ingested.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Histamine H₂ -receptor antagonist are derivatives of histamine that bind to and exhibit inhibiting or blocking activity against H₂ -receptors. The histamine H₂ -receptor antagonists, or H₂ -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 H₂ -receptor antagonist, however, have an unpalatably bitter taste. Examples of histamine H₂ -receptor antagonist include, but are not limited to, ranitidine, cimetidine, nizatidine, famotidine, sufotidine, roxatidine, bisfentidine, tiotidine, lamtidine, niperotidine, mifentidine, zaltidine and loxtidine. Preferred histamine H₂ -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 H₂ -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 H₂ -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 H₂ -receptor antagonist is sufficient to deliver a therapeutically effective dose to a patient in need thereof. For example, the amount of histamine H₂ -receptor antagonist typically included in the composition is between about 1 to about 50% by weight. Preferably, the amount of histamine H₂ -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 H₂ -receptor antagonist.

The granules containing the histamine H₂ -receptor antagonist are preferably formed by blending the histamine H₂ -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 H₂ -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 H₂ -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 .mu.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 H₂ -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 H₂ -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 H₂ -receptor antagonist is achieved after the pharmaceutical composition is chewed and swallowed, e.g., immediate release in the stomach.

The methacrylate ester copolymer is a water-insoluble, water-permeable, and slightly water-swellable polymer. The polymeric coating is not soluble in the gastrointestinal fluids and is not sensitive to the pH thereof, i.e., the water-permeability of the coating is not a function of pH, or is only very slightly dependent on pH.  Particularly preferred are copolymers of ethylacrylate and methylmethacrylate, although other copolymers such as terpolymers and other copolymers comprising three or more different monomeric units having properties similar to ethylacrylate-methylmethacrylate copolymers are also preferred. The preferred ethylacrylate-methylmethacrylate copolymer has a molecular weight of approximately 800,000. A particularly preferred ethylacrylate-methylmethacrylate copolymer is Eudragrit.RTM. NE30D which is commercially available from Rohm Pharmaceuticals.

The polymer coating can be applied to the particles containing an H₂ -receptor antagonist in any suitable manner. Preferably, the polymeric film is applied as a uniform coating having a smooth surface structure and a relatively constant thickness. For example, the polymer coating may be applied to the granules by utilizing pneumatic spray guns. The pneumatic spray guns may have a nozzle diameter of from about 0.8 millimeters to about 2 millimeters and may be operated at a coating solution atomization air pressure of from about 0.5 to about 3 bar. The spraying rate of the spray guns may be easily regulated using peristaltic pumps or pressure vessels. Ideally, spraying should be continuous with simultaneous drying so that the granules do not become too moist (overly wet). The freshly sprayed polymer coating should dry as quickly as possible to avoid agglomeration of the particles. Other suitable methods include the use of fluidized-bed processes. Modified coating drums (usually cylindrical horizontally rotating units with a perforated wall) are also suitable for coating the granules.

The polymer coating composition is preferably an aqueous solution containing a methacrylate ester copolymer of the type described above. The coating composition may include minor amounts of emulsifiers, wetting agents, drying agents, curing accelerators and stabilizers. For example, glyceryl monostearate may be added to the coating solution as a tackiness reducing agent which prevents granule growth through agglomeration. Minor amounts of talc can also be incorporated into the coating composition or subsequently applied to improve or enhance flow properties of the coated granules.

The thickness of the polymer coating can range from about 2 microns to about 20 microns, and the weight of the coating is generally from about 2 to about 20% of the weight of the coated granule. Because the coating is relatively thin, the coated granules are substantial in the same size range as the uncoated granules, i.e., from about 150 to about 2000 microns.

The polymer coated granules can be further manufactured into chewable tablets by compressing the polymer coated granules, either alone or in combination with extra-granular excipients, adjuvants, fillers, and/or other active ingredients. For example, fillers, lubricants, binders, compression aids, disintigrants, flavoring agents, sweeteners and wetting agents may be employed. The chewable tablets can also contain solid diluents, such as sugars and sugar alcohols such as lactose, xylitol, sorbitol and mannitol. Where desired, intense sweeteners can be added, for example ammonium glycyrrhizinate, sodium cyclamate, sodium saccharinate and aspartame. Useful binders include acacia, tragacanth, gelatin, sucrose, pre-gelatinized starch, starch, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, and polyacrylamide. Examples of disintegrants include crosslinked polyvinylpyrrolidone, starch derivatives such as sodium carboxymethyl starch and cellulose derivatives. Lubricants, guildants and anti-adhesive agents include metallic stearates such as magnesium stearate, talc, and high melting point waxes. Typical compression aids include microcrystalline cellulose, dicalcium phosphate and compressible sugar. To further assist patient compliance, the tablets can also contain flavorants such as fruit flavors, mint flavors, and the like. Other ingredients which may be added and are described in the "Handbook of Pharmaceutical Excipients", 2nd Ed, 1994 and "Food Chemicals Index", 3rd Ed.

The polymer coated granules containing a histamine H₂ -receptor antagonist may be thoroughly mixed with any desired excipients, adjuvants, fillers and the like, and directly compressed into chewable tablets employing the appropriate punches and dies.

Claim 1 of 20 Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A chewable dosage form comprising:

a histamine H₂ -receptor antagonist in an amount which is effective to treat a gastrointestinal disorder, the histamine H₂ -receptor antagonist selected from the group consisting of ranitidine, nizatidine, famotidine, sufotidine, roxatidine, bisfentidine, tiotidine, lamtidine, niperotidine, mifentidine, zaltidine and loxtidine, the histamine H₂ -receptor antagonist being present in the form of granules which are provided with a polymeric coating, the polymeric coating being present in an amount which is sufficient to mask the taste of the histamine H₂ -receptor antagonist, but which allows substantially immediate release of the histamine H₂ -receptor antagonist after the dosage form is chewed and swallowed, the polymeric coating consisting essentially of a methacrylate ester copolymer which is water-insoluble and water-permeable, and optionally a minor amount of one or more ingredients selected from emulsifiers, wetting agents, drying agents, curing accelerators and stabilizers.

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