Hydroxyomeprazole compositions

Details Hydroxyomeprazole compositions Hydroxyomeprazole compositions

2001-08-10

2002-12-24

Rose, Shep K. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S926000, C514S927000

Reexamination Certificate

active

06498171

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to compositions of matter containing hydroxyomeprazole. 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
Omeprazole I is an orally active, potent,
irreversible inhibitor of H
+
,K
+
-ATPase. It is commercially available in the form of Prilosec® delayed release capsules from Astra Merck Inc. 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 omeprazole is at about 0.5 to 3.5 hours in humans, and the serum half-life is about 30 to 60 minutes, although this is highly variable, as discussed below. The major metabolites in human serum are 5-hydroxyomeprazole II (referred to as hydroxyomeprazole herein) and omeprazole sulfone III.
The two major primary metabolites, omeprazole sulfone and 5-hydroxyomeprazole, are formed by cytochromes P450 3A (CYP3A) and 2C19 (CYP2C19), respectively. Both metabolites undergo further metabolism to the common metabolite 5-hydroxyomeprazole sulfone via CYP2C19 and CYP3A, respectively. Thus, both CYP enzymes are sequentially—but alternatively—involved in omeprazole metabolism. CYP2C19, the S-mephenytoin hydroxylase, is polymorphically expressed in the human population. The mutant allele constitutes the recessive trait. Homozygous carriers of the mutation completely lack CYP2C19 and are referred to as poor metabolizers (PM's); persons homozygous and heterozygous for the “normal” allele are extensive metabolizers (EM's). A hereditary deficiency of the alternative enzyme, CYP3A, has not been demonstrated in the human population.
The individual enantiomers of racemic omeprazole are differentially metabolized by CYP 2C19. (+) Omeprazole is rapidly hydroxylated; (−) is not. The individual enantiomers of racemic omeprazole do not appear to be differentially metabolized by CYP 3A4; both are oxidized to the achiral sulfone at comparable rates. This results in a divergence in serum metabolite concentration profiles between poor metabolizers and extensive metabolizers. The mean 8-hour AUC ratio of (+)-omeprazole/(+)-hydroxyomeprazole is 30 times higher and the 8-hour AUC of omeprazole sulfone is more than 10 times higher in poor metabolizers than are the corresponding parameters in extensive metabolizers.
It would be desirable to find a compound with the advantages of omeprazole which would provide a more predictable dosage regimen in the patient population and that would decrease the chances for drug-drug interactions.
SUMMARY OF THE INVENTION
This invention relates to the use of hydroxyomeprazole 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. Hydroxyomeprazole 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 hydroxyomeprazole. Hydroxyomeprazole provides a more predictable dosage regimen in the patient population and decreases the chances for drug-drug interactions by avoiding oxidative metabolism for which the cytochrome P450 2C19 enzyme system is required.
The invention also relates to certain pharmaceutical compositions containing hydroxyomeprazole.
DETAILED DESCRIPTION OF THE INVENTION
The active compound of these compositions and methods is hydroxyomeprazole. The preparation of racemic hydroxyomeprazole has been described by Renberg et al. [
Drug Metabolism and Disposition,
17:1, 69-76 (1989)], the disclosure of which is incorporated herein by reference. Chemically, the compound of the invention is 2-[[(5-hydroxymethyl-4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl-[1H]-benzimidazole (II), hereinafter referred to as hydroxyomeprazole. Hydroxyomeprazole is not presently commercially available.
Hydroxyomeprazole possesses a center of asymmetry at the sulfoxide sulfur, giving rise to two enantiomers. Throughout the instant disclosure, when the term is not otherwise modified, hydroxyomeprazole includes the (+) enantiomer, the (−) enantiomer and any mixture of the two. The preparation of the individual enantiomers of the parent, omeprazole, has been described in the literature, but the enantiomers of hydroxyomeprazole have been previously disclosed only as identities assigned to peaks on a chromatogram. The individual enantiomers of hydroxyomeprazole can be obtained by asymmetric oxidation of the thioether precursor and bioreduction of the racemate to eliminate one or the other enantiomer 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. The thioether precursor is available by the method of Renberg (op. cit.).
The literature does not appear to provide any reports of testing in vivo or of the administration of racemic hydroxyomeprazole or either of its enantiomers to human subjects. The inhibitory effects of omeprazole and rac-hydroxyomeprazole on aminopyrine uptake in isolated gastric glands have been reported; the IC
50
of racemic omeprazole was 0.48 &mgr;M and the IC
50
of racemic hydroxyomeprazole was 33 &mgr;M. Renberg et al. [
Drug Metabolism and Disposition,
17:1, 69-76 (1989)] concluded that the contribution of race-hydroxy-omeprazole to the pharmacological response to treatment with omeprazole in humans was probably insignificant.
It has now been discovered that hydroxyomeprazole 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 exhibiting fewer or less severe adverse effects than omeprazole, less potential for drug-drug interactions than omeprazole and a more predictable dosing regimen than omeprazole. Adverse effects of omeprazole include hepatocellular neoplasia, gastric carcinoids, headache, diarrhea and skin alterations.
The present invention encompasses a method of treating ulcers, which comprises administering to a human in need of such therapy, an amount of hydroxyomeprazole, or a pharmaceutically acceptable salt thereof, said amount being sufficient to alleviate the symptoms of ulcers.
The present invention also encompasses an oral antiulcer composition for the treatment of a human in need of antiulcer therapy, which comprises a pharmaceutica

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