Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-28
2001-01-16
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06174902
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions of matter containing rabeprazole. The invention also relates to methods of treating and preventing ulcers, treating other conditions related to gastric hypersecretion, and treating psoriasis.
BACKGROUND OF THE INVENTION
Racemic rabeprazole is an orally active, potent, irreversible inhibitor of H
+
, K
+
-ATPase. The compound is one of the class of compounds known as gastric “proton pump” inhibitors. These compounds are weak organic bases which diffuse passively from the plasma into the acid-containing intracellular canaliculi of gastric parietal cells. At the low pH found in the lumen of these canaliculi, the protonated compounds rearrange to form pyridinium sulfenamides, which react with sulfhydryl groups present on the ATPase localized in the membranes lining the intracellular canaliculi. The alkylation of the sulfhydryl inhibits the ability of the enzyme to catalyze the secretion of H
+
into the lumen in exchange for K
+
ions. This inhibition results in an overall reduction in hydrochloric acid secretion by the parietal cells into the cavity of the stomach, thus increasing intragastric pH. As a consequence of reduced acidity in the stomach, the activity of the proteolytic enzyme pepsin is also markedly decreased. Because the proton pump is the final step in acid production and the compounds of this class combine covalently with the associated H
+
, K
+
-ATPase, a profound and prolonged inhibition of gastric acid secretion can be achieved.
Proton pump inhibitors have also been reported as useful in treating psoriasis. [See PCT application WO95/18612]
The C
max
of racemic rabeprazole is at about 4 to 5 hours in humans and the serum half-life is about 50 minutes to 1.5 hours depending on dose, but this does not reflect the duration of the acid inhibitory effect, which is about 24 hours. Racemic rabeprazole is comparable to omeprazole in its effects on hepatic drug metabolizing enzyme systems such as CYP 3A, although it appears to be less inhibitory of CYP 2C19 than is omeprazole and a more potent inducer of CYP 1A1 mRNA than is pantoprazole.
No cardiovascular or obvious physical changes have been so far reported in humans on administration of racemic rabeprazole, but reports of clinical trials are only recently beginning to appear. Most proton pump inhibitors produce significantly elevated fasting serum gastrin levels. This is cause for concern because prolonged elevated serum gastrin appears to be associated with diffuse and focal enterochromaffin-like cell hyperplasia and focal neoplasia (carcinoids) in rats. [Larsson et al.
Gastroenterology
90, 391-399 (1986)]. Thus, despite its advantages, some adverse effects of racemic rabeprazole may remain, including, but not limited to, some incidence of hepatocellular neoplasia and gastric carcinoids on long-term therapy, and headache, diarrhea and skin alterations on acute therapy. It would therefore be particularly desirable to find a compound with the advantages of the racemic mixture of rabeprazole which would not have the aforementioned disadvantages.
SUMMARY OF THE INVENTION
This invention relates to the use of optically pure R(+)rabeprazole for treating ulcers of the stomach, duodenum and esophagus, gastroesophageal reflux diseases, Zollinger-Ellison Syndrome, and other disorders including those that would benefit from an inhibitory action on gastric acid secretion. R(+)Rabeprazole inhibits the H
+
, K
+
-ATPase associated with the gastric proton pump and the resulting secretion of gastric acid by parietal cells providing therapy in diseases associated with gastric hyperacidity. The invention also relates to a method of treating psoriasis using optically pure R(+) rabeprazole. Optically pure (+) rabeprazole provides this treatment while substantially reducing adverse effects, including, but not limited to, hepatocellular neoplasia, gastrin hypersecretion, gastric neoplasms or carcinoids, headache, diarrhea and skin alterations which are associated with the administration of the racemic mixture of rabeprazole.
The invention also relates to certain pharmaceutical compositions containing the R(+) isomer of rabeprazole.
DETAILED DESCRIPTION OF THE INVENTION
The active compound of these compositions and methods is an optical isomer of rabeprazole. The preparation of racemic rabeprazole is described in U.S. Pat. No. 5,045,552 and its equivalent European application 268956. Chemically, the active compound in the compositions and methods of the invention is the (+) isomer of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl-[1H]-benzimidazole(I), hereinafter referred to as (+)-rabeprazole.
(+) Rabeprazole, which is the subject of the present invention, is not presently commercially available.
The separation of racemic rabeprazole into R(+) rabeprazole and S(−) rabeprazole by chromatography has been described by Nochi et al [
Chem. Pharm. Bull
. 44, 1853-1857 (1996)], but the pharmacology and pharmacodynamics have not been described for either enantiomer. In addition to the chromatographic separation of the racemate into its enantiomers, asymmetric oxidation of the thioether precursor and bioreduction of the racemate to eliminate the S(−) enantiomer can be carried out in analogous fashion to the procedure described for lansoprazole in PCT applications WO 9602535 and 9617077; the disclosures of both are incorporated herein by reference.
It has now been discovered that the optically pure (+) isomer of rabeprazole is a superior agent for treating ulcers of the stomach, duodenum and esophagus, gastroesophageal reflux diseases, Zollinger-Ellison Syndrome, psoriasis and other disorders, including those that would benefit from an inhibitory action on H
+
, K
+
-ATPase in that it provides this effective treatment while substantially reducing the adverse effects of racemic rabeprazole including, but not limited to, hepatocellular neoplasia, gastric carcinoids, headache, diarrhea and skin alterations. The R(+) isomer of rabeprazole is also a superior agent for treating ulcers and other disorders by virtue of the greater predictability of dosage among patients, as discussed below.
The present invention encompasses a method of treating ulcers, which comprises administering to a human in need of such therapy, an amount of (+) rabeprazole, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer, said amount being sufficient to alleviate the symptoms of ulcers. The method substantially reduces the concomitant liability of adverse effects associated with the administration of the racemic compound by providing an amount which is insufficient to cause the adverse effects associated with the racemic mixture of rabeprazole.
The present invention also encompasses an oral antiulcer composition for the treatment of a human in need of antiulcer therapy, which comprises a pharmaceutically acceptable carrier for oral administration and a therapeutically effective amount of (+) rabeprazole, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer. Preferably the composition is in the form of a tablet or capsule and the amount of (+) rabeprazole in the tablet or capsule is 10, 30 or 50 mg.
The present invention further encompasses a method of treating gastroesophageal reflux disease and of treating conditions caused by or contributed to by gastric hypersecretion. Conditions associated with hypersecretion in humans may include, but are not limited to, Zollinger-Ellison syndrome.
The present invention further encompasses a method of treating psoriasis while substantially reducing the adverse effects of racemic rabeprazole.
Utilizing the optically pure or substantially optically pure isomer of (+) rabeprazole results in enhanced efficacy, diminished adverse effects, and accordingly, an improved therapeutic ind
Koch Patrick
Rubin Paul D.
Yelle William E.
Heslin & Rothenberg, P.C.
Reamer James H.
Sepracor Inc.
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