Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-12-06
2001-07-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S465000, C424S489000
Reexamination Certificate
active
06264984
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to effervescent compositions containing histamine H
2
antagonists incompatible with acidulants and more particularly, it relates to effervescent histamine H2 antagonists containing compositions containing certain acidulants found to be compatible with such antagonists.
BACKGROUND OF THE INVENTION
Effervescent compositions usually comprise excipients, active ingredients, and a source of carbon dioxide typically referred to as an effeverscent couple. Effervescent couples are usually composed of an alkaline bicarbonate or carbonate and an acid. In the presence of water, the alkaline bicarbonate or carbonate and the acid generate carbon dioxide. Thus, effeverscent compositions are extremely sensitive to moisture. This necessitates special steps to protect the raw materials and the finished formulation from exposure to moisture, throughout the manufacturing process and thereafter. Anhydrous citric acid is the most commonly employed acidulant in the manufacture of effeverscent compositions. Anhydrous citric acid is however, extremely hygroscopic. So also are the most commonly employed sources of carbon dioxide, i.e, alkali bicarbonates and carbonates.
The aforementioned problems are compounded when an effervescent composition is to contain, as the active, a histamine H
2
antagonist. Histamine H
2
antagonists are incompatible with acids, particularly the acids employed in effervescent compositions. Published EP Patent specification No. 233853 discloses that use of citric acid in effervescent compositions containing a histamine H
2
antagonist evidences incompatibility of the H
2
antagonist with the acids contained in the effervescent composition. In an effort to resolve this, citric acid was replaced by a mixture of mono- and di- alkaline citrates.
U.S. Pat. No. 4,824,664 teaches that histamine H
2
antagonists are not stable with the acids contained in effervescent products. They endeavor to overcome this instability by granulating the effervescent mixture and generating during such granulation a mixture of mono- and di- alkali citrate in a specified ratio.
U.S. Pat. No. 5,102,665 teaches preparation of a stable effervescent ranitidine using mono-alkali citrate as the sole acidulant. The effervescent system disclosed therein is granulated in alcohol prior to manufacturing the composition.
SUMMARY OF THE INVENTION
In light of the above teaching of the prior art, one skilled in the art would, in view of the known incompatibility of histamine H
2
antagonists, and in particular, ranitidine, with acids employed in effervescent products would refrain from making such a combination. Surprisingly and unexpectedly, the present inventors have discovered that certain acids (i.e., non-hydroxy group containing acidulants) can be incorporated in effervescent compositions containing histamine H
2
antagonists and that the resultant compositions are stable. In other words, surprisingly and unexpectedly, the histamine H
2
antagonists are stable in effervescent compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The acidulants that can be utilized in preparing the effervescent histamine H
2
antagonist compositions of the present invention are non-hydroxy group containing acidulants. For example, adipic acid, succinic acid, fumaric acid or a derivative thereof that hydrolyzes to form a non-hydroxy group containing acidulants, for example, succinic anhydride.
Although small amounts of a hydroxy containing acidulant may be incorporated in the effervescent composition of the present invention, the composition of the present invention most desirably employs as substantially all of the acidulant, a non-hydroxy group containing acidulant. Most preferably the composition of the present invention is devoid of hydroxy group containing acidulant. In some instances a very small amount of hydroxy group containing acidulant can be tolerated in the composition.
As noted earlier, the present inventors discovered that citric acid, a hydroxy group containing acidulant typically employed in effervescent compositions is incompatible with histamine H
2
antagonists when they are incorporated in effervescent compositions. Moreover, malic acid and other hydroxy group containing acidulants present even more of a problem than citric acid. Tartaric acid also presents a compatibility problem, but less than citric acid.
Surprisingly and unexpectedly, the present inventors discovered that when the hydroxy group containing acidulant (such as citric acid and tartaric acid) employed in a histamine H
2
antagonist containing effervescent formulation, as part of the effervescent couple, is replaced by a non-hydroxy group containing acidulant (such as adipic acid or succinic acid), in an amount equivalent to the hydroxy group containing acidulant, the resultant effervescent product has acceptable taste, stability and effervescence. Thus, the present invention enables the preparation of histamine H
2
antagonist containing effervescent products, by simple dry mixing of ingredients without the need for alkaline metal mono- or di- citrates, (whether added as such, or generated in the effervescent system by wet granulation) and without the need for an effervescent couple containing citric acid.
The compositions of the present invention contain, as an active, a histamine H
2
antagonist. The histamine H
2
antagonist is preferably selected from the group consisting of ranitidine, cimetidine, famotidine and nizatidine, and pharmaceutically acceptable salts thereof. Ranitidine and cimetidine are more preferred. Ranitidine and its pharmaceutically acceptable salts are most preferred.
The amount of ranitidine, in the form of its salt, may be from 40 to 300 mg, preferably in the range of 50 to 150 mg and most preferably from 50 to 75 mg per dosage unit.
The histamine H
2
antagonist is generally present in the composition in an amount such that a dose of the composition will contain such amount of the histamine H
2
antagonist as has been approved by the applicable governmental health authority for prescriptive (“R
x
”) or over-the-counter (“O.T.C.”) use. In the United States such amounts are as follows:
OTC Dose
R
x
Dose
Ranitidine
75 mg
150-300
mg
Cimetidine
200 mg
300-800
mg
Famotidine
10 mg
20-40
mg
Nizatidine
75 mg
150-300
mg
The effervescent couple employed in the compositions of the present invention is comprised of an alkaline component and an acidulant. The alkaline component and the acidulant react in the presence of water to produce carbon dioxide (i.e., effervescence). As noted earlier, the acidulant should be substantially comprised of one or more non-hydroxy group containing acidulant. Adipic acid, succinic acid, fumaric acid and succinic anhydride are preferred. Succinic anhydride will hydrolyze to form succinic acid.
As the alkaline component of the effervescent couple, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, sodium glycine carbonate and mixtures thereof may be employed.
The amounts of acid and alkaline bicarbonate or carbonate may each separately constitute 25 to 60% (w/w), more preferably 30 to 50% (w/w), of the effervescent composition. The equivalent or stoichiometric ratio of acid to alkaline carbonate or bicarbonate may be within the range of 1:2 to 2: 1.
The composition of the present invention can include sweetening agents such as sucrose, aspartame, cyclamic acid salts, acesulfame-K, saccharin acid or its salts, and mixtures thereof. Filler and flow promoting materials can also be employed, for example, silicon dioxide.
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patent: 5102665 (1992-04-01), Schaeffer
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patent: 5759575 (1998-06-01), Gergely et al.
patent: 5762951 (1998-06-01), Maasz
patent: 5792473 (1998-08-01), Gergely et al.
patent: 0 233 853 B1 (1990-09-01), None
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patent: 0 7
Hussein Ma'moun M.
Migton John
Bristol--Myers Squibb Company
Di Nola-Baron Liliana
Furman, Jr. Theodore R.
Page Thurman K.
Zeller Charles J.
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