Formulation

Details Formulation Formulation

2001-04-06

2003-02-04

Dees, Jose' G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C424S489000, C514S819000, C514S925000, C514S926000, C514S937000

Reexamination Certificate

active

06515008

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to the formulation of H
2
-receptor antagonists in liquid formulations.
BACKGROUND OF THE INVENTION
Cimetidine is a histamine H
2
-antagonist which has been described in U.K. Patent Specification 1,397,436. Cimetidine has been shown to be useful in the treatment of duodenal, gastric, recurrent and stomal ulceration, and reflux oesophagitis and in the management of patients who are at high risk from haemorrhage of the upper gastrointestinal tract.
In the case of certain compounds which have bitterness problems and solubility characteristics, the provision of a dosage form which solves theses problems represents a considerable problem.
Many solutions to the problem of taste masking pharmaceutical compositions of cimetidine have been attempted. For example, cimetidine granules have been coated with various compositions such as ethylcellulose and polyvinyl and acrylic polymers. One such proposal is disclosed in U.S. Pat. No. 4,800,087 wherein a polymer mixture coating is employed. The mixture comprises a high temperature film forming copolymer of polymethyacrylic acid ester and acrylic acid ester and a low temperature film forming copolymers consisting of methacrylic acid ester and styrene acrylate. U.S. Pat. No. 4,892,740 discloses pharmaceutical preparations having improved flavouring characteristics obtained by the drug being coated by a polymeric substance which is soluble in gastric juice.
A non-aqueous, chewable composition for oral delivery of unpalatable drugs has also been attempted. In U.S. Pat. No. 5,597,844, Chauhan, Susil, the composition contains the drug intimately dispersed or dissolved in a pharmaceutically acceptable lipid that is solid at room temperatures. The composition also has a matrix that contains a granulating agent for the total composition and a rapid dispersal agent and optionally additives such as buffering agents, flavoring agents, surfactants and the like.
As noted, cimetidine has a pronounced bitter taste. This is not usually a problem when the dosage form employed is a capsule or a tablet designed to be swallowed, thereafter to disintegrate upon reaching the stomach. However, such dosage forms can be impractical when it is desired to administer a large amount of active ingredient, or to co-administer a relatively bulky second active ingredient such as an antacid or alginate. Moreover many individuals have difficulty in swallowing a solid dosage form. Consequently, a liquid dosage form is desirable but must be able to meet the taste and stability requirements necessary for formulation aspects.
It will be appreciated that a major requirement of such a dosage form is that they must be palatable, since an unpalatable formulation increases the risk of a patient neglecting to take a medicament. Such non-compliance with the dosing regimen will in turn delay or prevent the patient's recovery from the condition under treatment.
A further requirement of such a composition is that once the formulation reaches the stomach, the individual particles, in a liquid dosage form such as a suspension, should release the active ingredient rapidly and completely in order to ensure that substantially all of the active ingredient is absorbed; that is to say the formulation should be bioavailable.
As noted, in the case of cimetidine, because of its bitterness, the provision of such dosage forms represents a considerable problem
There are four crystalline forms (hereinafter referred to as polymorphs) of the anhydrous base, and three polymorphs of the monohydrate of the base have been characterized. The anhydrous forms have been designated as polymorphs A-D while the hydrated forms have been designated polymorphs M1-M3.
EP-A-257823 describes a stable aqueous suspension of cimetidine wherein at least 90% of the cimetidine is in the polymorphic B form. It is disclosed that the use of polymorph B overcomes the problem of polymorphic interconversion found in the case of polymorph A suspensions of relatively low viscosity which tend to result in lumpy and non homogeneous suspensions.
EPA 0 138 540-A describes suspensions containing cimetidine and the preferred examples are buffered solutions of high viscosity. Because of the high viscosity, such suspensions are not easily poured from a bottle and consequently are usually formulated in sachets.
U.S. Pat. No. 4,996,222, Pharmaceutical formulations, Carlin et al. discloses a stable pharmaceutical composition suitable for oral administration comprising a suspension of an effective histamine H2-antagonist amount of particulate cimetidine in an aqueous phase wherein substantially all of the cimetidine present is of the polymorphic B form. However, this formulation also failed to achieve a stable composition which masked the taste of cimetidine.
Lastly, U.S. Pat. No. 4,786,735 discloses a process for preparing cimetidine polymorph B Graboyes, et al., comprising precipitating cimetidine from an aqueous-alcoholic solution of an acid addition salt.
It is generally recognized that substantially all formulations of cimetidine currently marketed contain polymorph A. Polymorph A can be prepared by recrystallizing cimetidine from a non aqueous organic solvent, particularly isopropanol, as described in GB No. 1,543,238. This process has been shown to be highly reproducible and to result in cimetidine which is easy to filter and has good bulk handling and formulation properties. A method of preparing another polymorph, polymorph D (sometimes referred to as polymorph Z), has also been disclosed in GB No. 2,108,117A.
In contrast to polymorphs A and D, polymorphs B and C are disclosed by Hegedus as being difficult to handle, due at least in part to their thixotropic properties in aqueous suspension which make separation by conventional methods such as filtration and centrifugation very difficult. This has also been the experience of the applicants up until the time of making the present invention
There still exists a need in this field for a liquid formulation of cimetidine which is stable, and taste masks the bitter taste of the product for use in a commercial setting.
SUMMARY OF THE INVENTION
The present invention is directed to a stable pharmaceuctical composition comprising cimetidine polymorph B, microcrystalline cellulose, carboxymethylcellulose, propylene glycol, and xanthan gum.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to an unexpectently stable and good tasting liquid formulation of an H
2
receptor antagonist. While many teaching abound in the art on how to make a tastemasked, or concealed formulation of an H
2
receptor antagonist, the resulting liquid formulation have been commercially unacceptable. The formulations have failed on the basis of taste, and or on long-term stability.
For use herein the term histamine H
2
-antagonists shall mean cimetidine, ranitidine, famotidine, nizatidine, etinidine, lupitidine, nifentidine, niperotidine, roxatidine, sulfotidine, tuvatidine and zaltidine. Preferably the H
2
antagonist is cimetidine, famotidine and ranitidine. More preferably it is cimetidine.
It is well known that for stability purposes in a liquid suspension formulation, the polymorph B form of cimetidine is necessary as the Polymorph A form will precipitate out in the formulation. The present invention utilizes the preferred polymorph form, polymorph B.
This invention relates to new pharmaceutical compositions and methods for their preparation, and in particular it relates to suspensions comprising cimetidine.
It is clear that there has been a need for compositions of cimetidine which are liquid based and are palatable. Cimetidine is absorbed almost exclusively in the small intestine and liquid-based compositions offer the possibility that they could be absorbed more quickly and more efficiently than tablet compositions, particularly tablet compositions which have been coated to minimise unpleasant tastes. However, with solutions of cimetidine, the unpleasant bitter taste is a particular problem. Suspensions of cimetidine could in principle

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