AU3870599A - R-rabeprazole compositions and methods - Google Patents

Description

WO 99/55157 PCT/US99/09205 R-RABEPRAZOLE COMPOSITIONS AND METHODS FIELD OF THE INVENTION This invention relates to compositions of matter containing rabeprazole. The invention also relates to 5 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, 10 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 15 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 20 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, 25 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 30 covalently with the associated H*,K'-ATPase, a profound -1- WO 99/55157 PCT/US99/09205 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 5 W095/18612] The Cmax 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, 10 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 15 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 20 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 25 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, 30 and headache, diarrhea and skin alterations on acute therapy. It would therefore be particularly desirable -2- WO 99/55157 PCT/US99/09205 to find a compound with the advantages of the racemic mixture of rabeprazole which would not have the aforementioned disadvantages. SUMMARY OF THE INVENTION 5 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 10 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 15 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 20 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 25 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 -3- WO 99/55157 PCT/US99/09205 preparation of racemic rabeprazole is described in United States Patent 5,045,552 and its equivalent European application 268956. Chemically, the active compound in the compositions and methods of the 5 invention is the (+) isomer of 2-[[[4-(3 methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl [lH]-benzimidazole(I), hereinafter referred to as rabeprazole. H O0 N NN

H

3 C 0

O-CH

3 10 1 (+) Rabeprazole, which is the subject of the present invention, is not presently commercially available. The separation of racemic rabeprazole into R(+) 15 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 20 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 25 applications WO 9602535 and 9617077; the disclosures of both are incorporated herein by reference. -4- WO 99/55157 PCTIUS99/09205 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 5 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 10 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 15 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 20 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 25 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 30 need of antiulcer therapy, which comprises a pharmaceutically acceptable carrier for oral administration and a therapeutically effective amount -5- WO 99/55157 PCT/US99/09205 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 (+) 5 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 10 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 15 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 index. Moreover, 20 the R(+) enantiomer provides a desirable half-life and shows less variation in the patient population between so-called extensive metabolizers and poor metabolizers than does racemic rabeprazole. It is therefore, more desirable to use the (+) isomer of rabeprazole than to 25 administer the racemic mixture because predictability of an effective and safe dose for an individual patient is greater. The term "adverse effects" includes, but is not limited to, hepatocellular neoplasia, gastrin -6- WO 99/55157 PCT/US99/09205 hypersecretion, gastric carcinoids, headache, diarrhea and skin alterations. The term "substantially free of its (-) stereoisomer" as used herein means that the 5 compositions contain at least 90% by weight of (+) rabeprazole and 10% by weight or less of (-) rabeprazole. In a more preferred embodiment the term "substantially free of the (-) isomer" means that the composition contains at least 99% by weight of (+) 10 rabeprazole, and 1% or less of (-) rabeprazole. These percentages are based upon the total amount of rabeprazole in the composition. The terms "substantially optically pure (+) isomer of rabeprazole" or "substantially optically pure (+) 15 rabeprazole" and "optically pure (+) isomer of rabeprazole" and "optically pure (+) rabeprazole" are also encompassed by the above-described amounts. The term "treating ulcers" as used herein means treating, alleviating or palliating such conditions, 20 and thus providing relief from the symptoms of nausea, heartburn, post-prandial pain, vomiting, and diarrhea. The term "a method for treating gastroesophageal reflux diseases in a human" as used herein means treating, alleviating or palliating the conditions that 25 result from the backward flow of the stomach contents into the esophagus. The term "treating a condition caused, or contributed to, by gastric hypersecretion in a human" as used herein means treating, alleviating or 30 palliating such disorders associated with -7- WO 99/55157 PCT/US99/09205 hypersecretion, thus providing relief from the symptoms of the aforementioned conditions. Zollinger-Ellison Syndrome is among the conditions caused by or contributed to by hypersecretion. 5 The term "treating psoriasis" as used herein means treating, alleviating or palliating the condition, and thus providing relief from the symptoms of pruritis, epidermal scaling, itching and burning. The magnitude of a prophylactic or therapeutic 10 dose of (+) rabeprazole in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration. The dose and perhaps the dose frequency will also vary according to the age, body 15 weight and response of the individual patient. In general, the total daily dose range for (+) rabeprazole for the conditions described herein is from about 5 mg to about 200 mg in single or divided doses. Preferably a daily dose range should be about 10 mg to about 50 mg 20 in single or divided doses. In managing the patient, the therapy should be initiated at a lower dose, perhaps at about 10 mg to about 15 mg and increased up to about 50 mg or higher depending on the patient's global response. It is further recommended that 25 children and patients over 65 years and those with impaired renal or hepatic function, initially receive low doses, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some 30 cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, -8- WO 99/55157 PCT/US99/09205 or terminate therapy in conjunction with individual patient response. The terms "an amount sufficient to alleviate or palliate ulcers but insufficient to cause said adverse effects," "an amount sufficient to 5 alleviate the symptoms of gastroesophageal reflux but insufficient to cause said adverse effects," "an amount sufficient to alleviate gastric hypersecretion but insufficient to cause said adverse effects" and "an amount sufficient to treat psoriasis" are encompassed 10 by the above-described dosage amounts and dose frequency schedule. The relative activity, potency and specificity of optically pure rabeprazole and racemic rabeprazole both as gastric antisecretory agents and plasma gastrin 15 elevating agents can be determined by a pharmacological study in animals according to the method of Decktor et al. [J. Pharmacol. Exp. Ther. 249, 1-5 (1989)]. The test provides an estimate of relative activity, potency and, through a measure of specificity, an estimate of 20 therapeutic index. Fasted rats, implanted with a gastric cannula, receive single oral or parenteral doses of (+) rabeprazole, (-) rabeprazole or racemate, 1 hour before collection of gastric juice over a four hour period. Acid output and pH are then determined on 25 each sample. Dose response evaluations are performed with each compound to determine the lowest dose which inhibits acid output by at least 95% and maintains gastric pH above 7.0. Plasma gastrin levels are then determined in a second group of rats treated with the 30 doses selected in the first series of tests. Blood samples are taken for analyses over the five hour period after dosing, and both peak level as well as area-under-the-curve analyses of the gastrin responses -9- WO 99/55157 PCT/US99/09205 are made. These responses are then analyzed statistically using Student's "t" test to assess whether equivalent antisecretory doses show differences in gastrin responses. 5 Any suitable route of administration may be employed for providing the patient with an effective dosage of (+) rabeprazole. Rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, and like forms of administration are 10 possible, but oral administration is preferred. Oral dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, and the like. The pharmaceutical compositions of the present invention comprise (+) rabeprazole as the active 15 ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients. The terms "pharmaceutically acceptable salts" or 20 "a pharmaceutically acceptable salt thereof" refer to salts prepared from pharmaceutically acceptable non toxic bases. Since the compound of the present invention is a weak acid and is unstable at low pH, salts may be prepared from pharmaceutically acceptable 25 non-toxic bases including inorganic and organic bases. Suitable pharmaceutically acceptable base addition salts for the compound of the present invention include metallic salts of aluminum, calcium, lithium, magnesium, potassium, sodium, titanium and zinc or 30 organic salts made from lysine, N,N' dibenzylethylenediamine, chloroprocaine, choline, -10- WO 99/55157 PCTIUS99/09205 diethanolamine, ethylenediamine, meglumine (N methylglucamine) and procaine. Sodium salts are preferred. The compositions of the present invention include 5 suspensions, solutions, elixirs or solid dosage forms. Carriers such as starches, sugars, and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like are suitable in the case of oral solid preparations (such 10 as powders, capsules, and tablets), and oral solid preparations are preferred over the oral liquid preparations. It has been found that the inclusion of mannitol and of basic salts of calcium and magnesium in the compositions allows the preparation of tablets and 15 capsules that retain good stability. If desired, tablets and granules may be coated by standard aqueous or nonaqueous techniques. Oral dosage forms suitable for rabeprazole are described in US patent 5,035,899 and in PCT applications W096/01624, W097/12580 and 20 W097/25030, the disclosures of which are incorporated herein by reference. In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release formulations, 25 which are well known in the art. Compositions suitable for rectal administration are described in European Application 645140, the disclosure of which is incorporated herein by reference. Pharmaceutical compositions of the present 30 invention suitable for oral administration may be presented as discrete units such as capsules, cachets, -11- WO 99/55157 PCT/US99/09205 or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non aqueous liquid, an oil-in-water emulsion, or a water 5 in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In 10 general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. 15 For example, a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder 20 or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, 25 each tablet contains from about 10 mg to about 100 mg of the active ingredient, and each cachet or capsule contains from about 10 mg to about 100 mg of the active ingredient. Most preferably, the tablet, cachet or capsule contains either one of three dosages, about 10 30 mg, about 30 mg or about 50 mg of (+) rabeprazole for oral administration. -12- WO 99/55157 PCTIUS99/09205 The invention is further defined by reference to the following examples describing in detail the preparation of the compositions of the present invention, as well as their utility. It will be 5 apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention. EXAMPLES 10 Example 1 - Tablets Composition per tablet: R(+) rabeprazole 30 mg Precipitated calcium carbonate 50 mg Corn Starch 40 mg 15 Lactose 73.4 mg Hydroxypropylcellulose 6 mg Magnesium stearate (0.05 ml) Total 200.0 mg EXAMPLE 1 20 R(+) Rabeprazole, precipitated calcium carbonate, corn starch, lactose and hydroxypropylcellulose are mixed together, water is added, and the mixture is kneaded, then dried in vacuum at 400 C. for 16 hours, ground in a mortar and passed through a 16-mesh sieve 25 to give granules. To this is added magnesium stearate and the resultant mixture is made up into tablets each weighing 200 mg on a rotary tableting machine. -13- WO 99/55157 PCTIUS99/09205 Example 2 - Granules Composition per tablet: R(+) rabeprazole 30 mg Magnesium carbonate 20 mg 5 Corn Starch 80 mg Microcrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg Pluronic F68 4 mg 10 Lactose 26 mg Water (0.05 ml) Total 200 mg EXAMPLE 2 15 The ingredients above are mixed well in the proportions shown, water is added, and the mixture is kneaded and granulated in an extruder granulator (screen size 1.0 mm $). The granules are immediately converted to spherical form in a spheronizer. The 20 spherical granules are then dried under vacuum at 400 C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules. -14- WO 99/55157 PCT/US99/09205 Example 3 - Capsules Enteric coating composition: Eudragit L-30D 138 mg (solids 41.4 mg) 5 Talc 4.1 mg Polyethylene glycol 5000 12.4 mg Tween 80 2.1 mg Water 276 ptl 10 Composition of enteric granules: Granules of Example 5 200 mg Enteric coat 60 mg Total 260 mg Composition per capsule: 15 Enteric granules 260 mg No. 1 hard capsule 76 mg Total 336 mg EXAMPLE 3 20 Enteric granules are produced by coating the granules obtained in Example 2 with the enteric coating composition shown using a fluidized bed granulator under conditions such that the inlet air temperature is 500 C. and the granule temperature is about 400 C. 25 Number 1 hard capsules are filled with the enteric granules thus obtained in an amount of 260 mg per capsule using a capsule filling machine. An enteric coating, such as the polyacrylate Eudragit L® and Eudragit S® series, is applied by spray 30 coating the tablets, preferably with an aqueous dispersion of the coating polymer. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the excipients or to the final weight of the tablet. -15-

Claims (12)

1. A method of treating ulcers which comprises administering to a human a therapeutically effective amount of optically pure R(+)isomer of rabeprazole, or 5 a pharmaceutically acceptable salt thereof.

2. A method of treating gastroesophageal reflux disease which comprises administering to a human a therapeutically effective amount of optically pure R(+)isomer of rabeprazole, or a pharmaceutically 5 acceptable salt thereof.

3. A method of treating a condition caused by or contributed to by gastric hypersecretion which comprises administering to a human a therapeutically effective amount of optically pure R(+)isomer of 5 rabeprazole, or a pharmaceutically acceptable salt thereof.

4. The method according to claim 3 wherein said condition is Zollinger-Ellison Syndrome.

5. A method of treating psoriasis which comprises administering to a human a therapeutically effective amount of optically pure R(+)isomer of rabeprazole, or a pharmaceutically acceptable salt 5 thereof.

6. The method of any of claims 1-5 wherein (+) rabeprazole is administered orally. -16- WO 99/55157 PCT/US99/09205

7. The method of claim 6 wherein the amount of (+) rabeprazole or a pharmaceutically acceptable salt thereof administered is from about 5 mg to about 200 mg per day.

8. The method of claim 7 wherein the amount administered is from about 10 mg to about 50 mg per day.

9. The method of any of claims 1-5 wherein the amount of (+) rabeprazole or a pharmaceutically acceptable salt thereof is greater than approximately 90% by weight of the total weight of rabeprazole.

10. The method of any of claims 1-5 wherein the amount of (+) rabeprazole or a pharmaceutically acceptable salt thereof is greater than approximately 99% by weight of the total weight of rabeprazole.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier for oral therapy and a therapeutically effective amount of (+) rabeprazole or a pharmaceutically acceptable salt 5 thereof, substantially free of its (-) stereoisomer.

12. A pharmaceutical composition according to claim 11 in the form of a tablet or capsule. -17-