JP2002512262A - R-Rave prazole compositions and methods - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for treating and preventing ulcer, a method for treating other conditions related to gastric hypersecretion, and a method for treating psoriasis. A method and composition utilizing optically pure (+) rabeprazole to treat human ulcers while simultaneously producing the deleterious effects associated with the racemic mixture of raiveprazole. Methods and compositions are provided that substantially reduce This optically pure (+) isomer is also useful for treating gastroesophageal reflux. (+) Reibprazole is an inhibitor of H ⁺ release and is therefore useful in treating other conditions associated with gastric hypersecretion, such as Zollinger-Ellison syndrome.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a composition of matter containing rabeprazole. The present invention also relates to methods of treating and preventing ulcers, other conditions related to gastric hypersecretion, and methods of treating psoriasis.

[0002] rave pantoprazole BACKGROUND racemic invention H ^+, is a potent irreversible inhibitors with oral activity of K ⁺ -ATP-ase. This compound is one of a class of compounds known as gastric "proton pump" inhibitors. These compounds are weak organic bases,
Passive diffusion from plasma into intracellular tubules containing the acid of gastric parietal cells. At the low pH found in these tubules, the protonated compounds rearrange to form pyridinium sulfenamides, which are localized on the ATPase localized to the membrane lining the intracellular tubules. Reacts with the sulfhydryl groups present in Alkylation of sulfhydryls inhibits the enzyme's ability to catalyze the secretion of H ⁺ into the cavity in exchange for K ⁺ ions. This inhibition results in an overall decrease in secretion of hydrochloric acid by the parietal cells into the gastric cavity. Thus, the pH in the stomach rises. As a result of the reduced acidity of the stomach, the activity of the protease pepsin is also significantly reduced. The proton pump is the final step in acid production, and this class of compounds covalently binds to the relevant H ⁺ , K ⁺ -ATPase, so that strong and long inhibition of gastric acid secretion can be achieved.

[0003] Proton pump inhibitors have also been reported to be effective in treating psoriasis (PC
See T application WO 95/18612).

The C _max of racemic leibprazole is about 4 to 5 hours in humans, and the serum half-life is about 50 minutes to 1.5 hours depending on the dose, which is the duration of the acid inhibitory effect, It does not reflect about 24 hours. Racemic Reibprazole is CY
Although comparable to omeprazole in its effects on liver drug metabolizing enzyme systems such as P.3A, it inhibits CYP.2C19 less than omeprazole and appears to be a more potent inducer of CYP.1A1 mRNA than pantoprazole.

[0005] Although no cardiovascular or apparent physical changes have been reported in humans upon administration of racemic leivprazole, clinical trials have only recently begun to appear. Most proton pump inhibitors significantly increase serum gastrin levels during fasting. Long-term elevated serum gastrin is associated with diffuse and focal enterochromatin-like cell hyperplasia and focal tumorigenesis (carcinoids) in rats
This is of concern because it appears to be related to (Larson et al., Gastroen
terology, vol. 90, 391-399 (1986)). Thus, despite its advantages, some deleterious effects of racemic leibprazole still exist.
Among them are long-term treatment of hepatocyte tumorigenesis and gastric carcinoid development,
And, but not limited to, headache, diarrhea, and skin changes in acute treatment. Accordingly, it is particularly desirable to find compounds that have the advantages of a racemic mixture of leveprazole and do not have the disadvantages described above.

[0006]Summary of the Invention The present invention relates to ulcers of the stomach, duodenum and esophagus, gastroesophageal reflux disease, Zollinger
-Including Ellison syndrome, as well as those that benefit from an inhibitory effect on gastric acid secretion
The use of optically pure R (+) leivprazole to treat other diseases
Related. R (+) leivprazole is an H⁺, K ⁺ -Inhibits ATPase and consequently secretes gastric acid by parietal cells
Inhibit and provide treatment for diseases associated with hyperacidity. The present invention provides an optically pure R
(+) Methods of treating psoriasis with leibprazole. Optically pure
Naive (+) rabuprazole provides this treatment while
Hepatocyte tumorigenesis, gastrin hypersecretion, gastric swelling associated with semi-mix administration
Includes ulceration or carcinoids, headache, diarrhea, and skin changes
Harmful effects are substantially reduced.

[0007] The present invention also relates to certain pharmaceutical compositions comprising the R (+) isomer of leivprazole.

[0008] DETAILED DESCRIPTION active compounds of these compositions and methods of the invention is an optical isomer of rave pantoprazole. The preparation of racemic leivprazole is described in U.S. Patent No. 5,045,552 and corresponding European Patent Application No. 268956. The active compound in the compositions and methods of the present invention is chemically 2-([[4- (3-methoxypropoxy)
-3-Methyl-2-pyridinyl] methyl] sulfinyl- [1H]-(+) isomer of benzimidazole (I), hereinafter referred to as (+)-reibprazole.

[0009]

[Outside 1]

The subject of the present invention, (+) leivprazole, is currently not commercially available.

The separation of racemic raibprazole into R (+) and S (−) leivprazole by chromatography has been described by Nochi et al. (Chem. Pharm).
. Bull. 44 , 1853-1857 (1996)), but its pharmacology and pharmacodynamics are not described for any of the enantiomers. In addition to the chromatographic separation of the racemates into enantiomers, the asymmetric oxidation of the thioether precursor and the bioreduction of the racemate to exclude the S (-) enantiomer are described in PCT application WO9602535 and The procedure can be carried out in a similar manner to that described for lansoprazole in US Pat. Both disclosures are incorporated herein by reference.

[0012] The optically pure (+) isomers of leibprazole, while providing effective treatment, include hepatocyte tumorigenesis, gastric carcinoids, headache, diarrhea, and skin alterations, although these Gastric, duodenal, and esophageal ulcers, gastroesophageal reflux disease, Zollinger-Ellison syndrome, psoriasis, and H ⁺ , K ⁺ − in that it substantially reduces the deleterious effects of racemic raibprazole). It has now been found to be an excellent drug for treating other diseases, including those that benefit from an inhibitory effect on ATPase. The R (+) isomer of leibprazole is also an excellent drug for treating ulcers and other diseases due to the increased predictability of dosage for patients, as discussed below.

The present invention is a method of treating an ulcer, comprising (+) leibprazole or a pharmaceutically acceptable substantially free of (-) stereoisomer in an amount sufficient to reduce the symptoms of the ulcer. Administering such a salt thereof to a human in need of such treatment. The method substantially reduces the concomitant occurrence of the harm associated with the administration of the racemate by administering an amount that is insufficient to cause the harm associated with the administration of the racemic mixture of leveprazole.

The present invention is directed to an oral anti-ulcer composition for the treatment of humans in need of an anti-ulcer treatment, comprising a pharmaceutically acceptable carrier for oral administration and a therapeutically effective amount of (+) Also encompassed are compositions that include leibprazole or a pharmaceutically acceptable salt thereof, but are substantially free of the (-) stereoisomer. Preferably, the composition is in the form of a tablet or capsule, and the amount of (+) leivprazole in the tablet or capsule is 10, 30, or 50 mg.

The invention further encompasses methods of treating gastroesophageal reflux disease, as well as methods of treating conditions resulting from or contributing to gastric hypersecretion. Conditions associated with human hypersecretion include, but are not limited to, Zollinger-Ellison syndrome.

Further, the invention encompasses a method of treating psoriasis while substantially reducing the harmful effects of racemic leivprazole.

Utilizing an optically pure or substantially optically pure (+) leivprazole isomer results in enhanced efficacy, reduced adverse effects and therefore improved therapeutic index Is done. In addition, the R (+) enantiomer has a desired half-life and exhibits less variation in the patient population between so-called metabolic and metabolic individuals than racemic leivprazole. Thus, the higher the predictability of an effective and safe dose for an individual patient, the higher the (+)
It is more desirable to use isomers.

The term “harmful effects” includes, but is not limited to, hepatocyte tumorigenesis, gastrin hypersecretion, gastric carcinoids, headache, diarrhea, and skin changes.

As used herein, the term “substantially free of its (−) stereoisomer” means that the composition has at least 90% by weight of (+) leibprazole and no more than 10% by weight of (−) ) Means to contain leivprazole. In a more preferred embodiment, the term "substantially free of the (-) isomer" means that the composition is at least 99%
It means that it contains less than 1% by weight of (+) leivprazole and less than 1% by weight of (-). These percentages are based on the total amount of leivprazole in the composition. "Substantially optically pure (+) isomer of raiveprazole" or "Substantially optically pure (+) raiveprazole" and "optically pure (+) isomer of raiveprazole" And the term "optically pure (+) leivprazole" are also included in the above amounts.

As used herein, the term “treating an ulcer” means treating, alleviating, or alleviating such a condition, and is therefore associated with nausea, heartburn, postprandial pain,
It means eliminating vomiting and diarrhea symptoms.

As used herein, the term “method of treating gastroesophageal reflux disease in a human” refers to treating, reducing, or alleviating a condition resulting from reflux of gastric contents into the esophagus. Means

As used herein, the term “treating a condition resulting from or contributing to hypersecretion of the human stomach” refers to treating, reducing or alleviating such disorders associated with hypersecretion. Means to eliminate the symptoms of the condition described above. Zollinger-Ellison syndrome is one of the conditions caused or contributed by hypersecretion.

As used herein, the term “treating psoriasis” means treating, alleviating, or alleviating the condition, thus reducing the symptoms of pruritus, epidermal shedding, itching, and burns. Means to remove.

[0024] The magnitude of a prophylactic or therapeutic dose of (+) leivprazole in the treatment of acute or chronic diseases will vary depending on the severity of the condition being treated and the route of administration.
The dose, and possibly the frequency of dosing, will also vary with age, weight, and individual patient response. Generally, the total daily dose range of (+) leivprazole for the conditions described herein is from about 5 mg to about 200 mg in single or divided doses. Preferably, a daily dose range is about 10 mg in a single dose or in divided doses.
To about 50 mg. In treating a patient, treatment should begin with a low dose, perhaps about 10 mg to about 15 mg, and increase to about 50 mg or more, depending on the patient's systemic response. Furthermore, it is recommended that children and patients aged 65 and older and those with impaired kidney or liver function receive low doses first and titrate based on individual response (s) and blood level (s). . As will be apparent to those skilled in the art, it may be necessary to use doses outside these ranges. Further, it should be noted that the clinician or treating physician knows when and how to interrupt, adjust, or terminate treatment in conjunction with individual patient response. "Sufficient to reduce or alleviate ulcers but not sufficient to cause the above-mentioned adverse effects", "sufficient to reduce symptoms of gastroesophageal reflux but causing the above-mentioned adverse effects" Insufficient amount "," sufficient to reduce gastric hypersecretion but not sufficient to cause the harmful effects ", and" sufficient amount to treat psoriasis " The terms are encompassed by the dosage and dosing schedules described above.

The relative activity, potency, and specificity of both optically pure and racemic leibprazole as gastric antisecretory agents and plasma gastrin-elevating agents were determined by the method of Deckter et al. (J. Pharmacol. Exp. Ther., 249, 1
-5 (1989)). This test provides an assessment of relative activity, efficacy, as well as an assessment of therapeutic index through measurement of specificity. One hour before gastric juice collection for up to 4 hours, fasted rats implanted with a gastric cannula are given a single oral dose or parenteral volume of (+) reibprazole, (-) reibprazole, or a racemic mixture. The acid production and pH are then measured for each sample. A dose response assessment of each compound is performed to determine the lowest dose that inhibits acid production by at least 95% and maintains gastric pH above 7.0. Next, plasma gastrin levels are measured in a second group of rats treated with the doses selected in the first series of studies. Blood samples are taken for analysis over the 5 hour post-dose period and both peak level analysis and area under the curve for gastrin response are performed. Subsequently, these responses are analyzed statistically using the Student's "t" test to assess whether equivalent antisecretory doses show a difference in gastrin response.

Any suitable route of administration may be employed for providing a patient with an effective dose of (+) leivprazole. Rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, and similar dosage forms are possible, but oral administration is preferred. Oral dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules and the like.

[0027] The pharmaceutical composition of the present invention comprises (+) leivprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. Is also included.

The term “pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof”
Refers to salts prepared from pharmaceutically acceptable non-toxic bases. Because the compounds of the present invention are weak acids and unstable at low pH, salts can be prepared from pharmaceutically acceptable non-toxic bases, including inorganic or organic salts. Suitable pharmaceutically acceptable base addition salts for compounds of the present invention include metal salts of aluminum, calcium, lithium, magnesium, potassium, sodium, titanium, and zinc, or lysine, N, N '.
-Organic salts made from dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Sodium salts are preferred.

The compositions of the present invention include suspensions, solutions, elixirs, or solid dosage forms. In the case of oral solid preparations (such as powders, capsules and tablets), carriers such as starch, saccharides and microcrystalline cellulose, diluents, granules, lubricants, binders, disintegrants, etc. are suitable. Are preferred over oral liquid preparations. It has been found that the incorporation of mannitol and basic salts of calcium and magnesium into the composition allows the preparation of tablets and capsules which retain good stability. If necessary, tablets and granules can be coated by standard aqueous or non-aqueous techniques. Suitable oral dosage forms for leibprazole are described in US Pat. No. 5,035,899 and PCT application WO
96/01624, WO 97/12580, and WO 97/25030. These disclosures are incorporated herein by reference.

In addition to the usual dosage forms described above, the compounds of the present invention may also be administered by controlled release formulations well known in the art. Compositions suitable for rectal administration are described in European Application 6451
40. The disclosure of which is incorporated herein by reference.

[0031] Pharmaceutical compositions of the present invention suitable for oral administration may be in individual units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as powders or granules, or as a solution, Or it may be provided as a suspension in an aqueous, non-aqueous, water-in-oil emulsion, or oil-in-water emulsion. Such compositions may be prepared by any of the methods of pharmacy, each method involving the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and if necessary, shaping the product into the desired form. .

For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed with an optional binder, lubricant, inert diluent, surfactant, or dispersant in a suitable machine. Can be prepared. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Preferably, each tablet will contain from about 10 mg to about 100 mg of the active ingredient, and each cachet or capsule will contain from about 10 mg to about 100 mg of the active ingredient. Most preferably, the tablet, cachet, or capsule contains any one of three doses of about 10 mg, about 30 mg, or about 50 mg of (+) leivprazole for oral administration.

The present invention is further defined by reference to the following examples which describe in detail the preparation of the compositions of the present invention as well as their utility. It will be apparent to those skilled in the art that many modifications can be made to both materials and methods without departing from the objects and advantages of the invention.

Embodiment

[0035]

[Table 1]

Example 1 R (+) leivprazole, precipitated calcium carbonate, corn starch, lactose, and hydroxypropylcellulose were mixed together, water was added, and the mixture was kneaded, then vacuumed at 40 ° C. for 16 hours. Dry, crush in a mortar and pass through a 16 mesh screen to obtain granules. Magnesium stearate is added thereto, and the resulting mixture is made into tablets each weighing 200 mg on a rotary tableting machine.

[0037]

[Table 2]

Example 2 The above ingredients are mixed well in the proportions indicated, water is added and the mixture is kneaded and granulated with an extruder granulator (screen size diameter 1.0 mm). The granules are immediately transformed into spheres with a spheronizer. The spherical granules are then dried under vacuum at 40 ° C. for 16 hours and passed through a circular sieve to obtain granules of 12 to 42 mesh.

[0039]

[Table 3]

Example 3 Enteric coated granules were obtained by using a fluidized bed granulator under conditions such that the intake air temperature was 50 ° C. and the granule temperature was about 40 ° C. Prepared by coating with an enteric coating composition. The enteric granules thus obtained were numbered 1 using a capsule filling machine in an amount of 260 mg per capsule.
Fill into hard capsules.

Enteric coatings such as the polyacrylate Eudragit L® and Eudragit S® series are preferably applied by spray coating tablets using an aqueous dispersion of this coating polymer. I do. Tablets of other potency may be prepared by varying the ratio of active ingredient to excipients or to the final weight of the tablet.

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] November 24, 1999 (1999.11.24)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) // C07D 401/12 C07D 401/12 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV , MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Patrick Koch 19, Ft. DD08 DD25 DD28 DD41 DD67 EE11J EE12J EE23 EE31 EE32 EE38 EE48J FF25 4C086 AA01 AA02 BC39 GA07 GA08 GA16 MA01 MA04 MA35 MA37 MA52 ZA68 ZA89 ZC41

Claims (12)

[Claims] 1. A method for treating ulcer, comprising the steps of:
ole) or an optically pure R (+) isomer, or a pharmaceutically acceptable salt thereof, to a human. 2. A method of treating gastroesophageal reflux disease, comprising administering to a human a therapeutically effective amount of an optically pure R (+) isomer of leibprazole or a pharmaceutically acceptable salt thereof. A method comprising the steps of: 3. A method for treating a condition resulting from or contributing to gastric hypersecretion, comprising the optically pure R (+) isomer of leibprazole or a pharmaceutically acceptable salt thereof. Administering a therapeutically effective amount to a human. 4. The method of claim 3, wherein said condition is Zollinger-Ellison syndrome. 5. A method of treating psoriasis, comprising the step of administering to a human a therapeutically effective amount of an optically pure R (+) isomer of leibprazole or a pharmaceutically acceptable salt thereof. Including methods. 6. The method according to claim 1, wherein (+) leivprazole is administered orally. 7. The method of claim 6, wherein the amount of (+) leivprazole 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 according to any one of claims 1 to 5, wherein the amount of (+) leivprazole or a pharmaceutically acceptable salt thereof is greater than about 90% by weight of the total weight of leibprazole. 10. The method of any one of claims 1 to 5, wherein the amount of (+) leivprazole or a pharmaceutically acceptable salt thereof is greater than about 99% by weight of the total weight of leibprazole. 11. A pharmaceutically acceptable carrier for oral therapy, comprising a therapeutically effective amount of (+) leivprazole or a pharmaceutically acceptable salt thereof, wherein the (-)
A pharmaceutical composition that is substantially free of stereoisomers. 12. The pharmaceutical composition according to claim 11, which has a tablet or capsule dosage form.