Potassium salt of (s)-omeprazole, its preparation and pharmaceutical drug based on it

 

The present invention relates to a new form 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole, known by the international nonproprietary name omeprazole. More specifically, it relates to a new crystalline form of potassium salt of (S)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole. The present invention also relates to methods for obtaining this form of the potassium salt of (S)-omeprazole and containing pharmaceutical compositions. The specified connection ingibiruet secretion of gastric acid and may find application in medicine for the treatment of gastro-intestinal disturbance. 5 N. and 3 C.p. f-crystals, 2 Il.

The present invention relates to a new form 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole, known by the international nonproprietary name omeprazole. More specifically, it relates to a new crystalline form of potassium salt of (S)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole. The present invention also relates to methods for obtaining this form of the potassium salt of (S)-omeprazole and containing farmacevt-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole, with international non-proprietary name omeprazole, and its therapeutically acceptable salts described in EP 5129. Specific alkaline salt of omeprazole disclosed in EP 124495. Omeprazole is a proton pump inhibitor, is effective for suppressing secretion of gastric acid and is useful as an antiulcer agent. In a more General sense, omeprazole can be used for prevention and treatment associated with gastric acid diseases in mammals and especially in humans.

Omeprazole is a sulfoxide and is a chiral compound in which the sulfur atom is a stereogenic center. Thus, omeprazole is a racemic mixture of the two individual enantiomers, (R)- and (S)-enantiomer of omeprazole, referred to here as (R)-omeprazole and S-omeprazole. The absolute configuration of the enantiomers of omeprazole determined using x-ray study of N-alkylated derivative (+)-enantiomer in mesolevel form. It was found that (+)-enantiomer mesolevel form and (-)-enantiomer mesolevel forms are R and S configuration respectively. Conditions for measurement of optical rotation for each of these enantiomers is described in WO 94/27988.

Some of the salts of the kinetic and metabolic properties, that gives them improved therapeutic indices, such as a lower degree of variation between individual subjects.

In WO 96/02535 disclosed is a method of obtaining individual enantiomers of omeprazole and related structures of the compounds and their salts. In WO 96/01623 disclosed pharmaceutical dosage forms containing, for example, magnesium salt (R)- and (S)-omeprazole.

In WO 96/54171 disclosed is a method of obtaining the three-hydrate magnesium salt of (R)-omeprazole, where as intermediate compounds used potassium salt of (S)-omeprazole. Potassium salt of (S)-omeprazole according to the prior art crystallizes in the form of MES with methanol.

Some salt (S)-omeprazole, such as potassium salt, in the General case are suitable compounds for intravenous administration due to their inherent properties such as high stability and high solubility in water. The solvate with methanol, however, is not suitable for intravenous injection, as a concomitant introduction of methanol can be fatal to those who enter. There is therefore a need in the potassium salt of (S)-omeprazole, which is free from methanol.

The new form of the potassium salt of (S)-omeprazole according to the present invention uominiedonne, disclosed in WO 98/54171, referred to hereinafter as the Form of the potassium salt of (S)-omeprazole.

Brief description of drawings

Fig.1 is an x-ray powder diffraction pattern of the potassium salt of (S)-omeprazole, obtained according to the present invention, i.e. of the form b

Fig.2 is an x-ray powder diffraction pattern of the potassium salt of (S)-omeprazole, obtained according to example 2 in WO 98/54171, i.e. forms A.

Description of the invention

Unexpectedly it was found that the potassium salt of (S)-omeprazole exists in several structurally different forms. The present invention is to provide essentially pure form B of the potassium salt of (S)-omeprazole.

Form B of the potassium salt of (S)-omeprazole is preferred because it represents a hydrated form, while the previously known form And is a MES with methanol. Form B of the potassium salt of (S)-omeprazole is especially suitable for intravenous administration. Form B of the potassium salt of (S)-omeprazole additionally differs in that it is crystalline and preferably is vysokomaslichnoy.

Form B of the potassium salt of (S)-omeprazole, obtained according to the present invention, is essentially sugumar the prior art. Form B of the potassium salt of (S)-omeprazole, obtained according to the present invention, moreover, essentially free of potassium salts of (R)-omeprazole.

Form B of the potassium salt of (S)-omeprazole different positions and intensities of the main peaks in the x-ray powder diffraction pattern, but may also be different traditional FT-IR spectroscopy infrared spectroscopy with Fourier transform). Such characteristics do not have any other form of potassium salt of (S)-omeprazole and respectively form B of the potassium salt of (S)-omeprazole is easily distinguishable from any other crystalline forms of potassium salts of (S)-omeprazole, disclosed in the prior art technique. Under the expression "any form" refers to anhydrous form, hydrate, solvate, amorphous forms and polymorphs. So examples of any forms of potassium salt of (S)-omeprazole include, but are not limited to, anhydrous forms, monohydrate, dihydrate, half hydrate, trihydrate, alcoholate, such as motility and utility, amorphous forms and polymorphs.

Form B of the potassium salt of (S)-omeprazole may also differ in its unit cell.

In another aspect of the present invention, a method for obtaining the shape of B potassium salt of (S)-loola or dichloromethane by processing source of potassium, such as potassium hydroxide or potassium methylate, followed by separation of the resulting salt.

The crude (S)-omeprazole, is used in this way, it is possible to obtain, for example, by oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole to (S)-omeprazole oxidizing agent and a chiral titanium complex, possibly in the presence of a base in an organic solvent such as toluene or dichloromethane, as described in the prior art, see WO 98/54171.

Form B of the potassium salt of (S)-omeprazole, obtained according to the present invention, analyze, characterize and differentiate from previously known forms And by x-ray powder diffraction, a technique which is essentially known. Another suitable method for analysis, characterization and differentiation of form B of the potassium salt of (S)-omeprazole is of an appropriate form And is a traditional FT-IR.

The amount of water in the form B of the potassium salt of (S)-omeprazole determined by thermogravimetric analysis (TGA), a technique which is essentially known.

Form B of the potassium salt of (S)-omeprazole is effective in inhibiting the secretion of gastric acid and is useful as an antiulcer agent. In a more General sense, it can be the traveler, for example, reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Moreover, it can be used for treatment of other gastrointestinal disorders, in which the inhibitory effect on gastric acid is desirable, for example, in patients undergoing treatment nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with non-ulcer dyspepsia in patients with symptomatic gastroesophageal reflux, and in patients with ulcerogenic adenoma of the pancreas. Form B of the potassium salt of (S)-omeprazole can also be applied to patients in cases of intensive therapy in patients with acute bleeding from the upper section of the gastrointestinal tract, before and after surgery to prevent aspiration of gastric acid and to treat stress ulceration. In addition, the form B of the potassium salt of (S)-omeprazole may be useful in the treatment of psoriasis, as well as in the treatment of infections caused by Helicobacter, and related diseases. Form B of the potassium salt of (S)-omeprazole can also be used to treat inflammatory conditions in mammals, including humans.

Any suitable route of administration can be used to provide effective patient is e or parenteral preparations and the like. Dosage forms include capsules, tablets, disperse systems, suspensions and the like. Form B of the potassium salt of (S)-omeprazole, being easily soluble in water, especially suitable for parenteral drugs, such as intravenous.

According to this invention also proposed a pharmaceutical composition comprising form B of the potassium salt of (S)-omeprazole as the active ingredient, in combination with a pharmaceutically acceptable carrier, diluent or excipient and possibly other therapeutic ingredients. Compositions containing other therapeutic ingredients, particularly interesting in the treatment of infections caused by Helicobacter. The present invention also proposed the use of form B of the potassium salt of (S)-omeprazole in the manufacture of medicaments for use in the treatment associated with gastric acid status and treatment associated with gastric acid condition in which the subject is suffering from this condition, is administered a therapeutically effective amount of form B of the potassium salt of (S)-omeprazole.

The compositions of this invention include compositions suitable for oral or parenteral administration. These compositions for convenience, the, izvestnyh in pharmacy.

In the practical use of the present invention is most suitable route of administration, as well as the magnitude of a therapeutic dose form B of the potassium salt of (S)-omeprazole in each specific case will depend on the nature and severity of the disease that is being treated. Dose and frequency of dose may vary depending on age, weight and response of the individual patient. For patients with a syndrome of Zollinger-Ellison may require special conditions, such as the need for higher doses than for the average patient. For children and patients with liver disease, and patients undergoing long-term treatment, as a rule, will be useful dose, which is slightly lower than the average. Thus, in some conditions, it may be necessary to use dosages outside the range set below. Such higher and lower doses are within the scope of the present invention.

Typically, a suitable dosage form may cover a range of doses from 5 mg to 120 mg total daily dose, administered as a single dose or equally divided doses. The preferred dose range is from 5 mg to 100 mg and more preferably is I oral administration.

The connection according to this invention can be combined as the active component in a homogeneous mixture with a pharmaceutical carrier according to conventional methods. Especially suitable oral drugs are disclosed in WO 96/01623 and EP 247983, descriptions of which are fully incorporated herein by reference.

You can also apply a combination of treatments, including the form B of the potassium salt of (S)-omeprazole and other active ingredients in separate dosage forms. Examples of such active ingredients include antibacterial compounds, nonsteroidal anti-inflammatory agents, anti-acid agents, alginates and prokinetics agents.

The following additional examples illustrate the connection of the present invention, that is, form B of the potassium salt of (S)-omeprazole, but it is not expected that they limit the scope of the present invention as defined above or as stated below.

Examples

Form B of the potassium salt of (S)-omeprazole

A solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (67 mmol) in toluene (4 ml/g 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole) filled with water (0.9 mmol) and D-(-)-diethyltartrate (14 mmol) at 50With and added N,N-diisopropylethylamine (10 mmol). Then to the solution was added Gidropress cumene (74 mmol), maintaining the temperature at approximately 35C.

After 3 hours the reaction mixture was diluted with toluene (2 ml/g 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole) was added potassium methylate (26 mmol) as a suspension in toluene (8 ml/g Coma). The obtained crystals were filtered and dried (36C, vacuum) during the night. Output: 0,72 g (1.9 mmol; 7% compared to Coma).

The content of solvent received by titration according to Karl Fischer and GC (gas chromatography), respectively (% wt./wt.):

Water 3,4

Methanol 0,01

TGA (thermogravimetric analysis)

Approximately 2% (wt./wt.) the water content included in the crystal lattice (i.e. ~0.5 N2O on one molecule of the form B of the potassium salt of (S)-omeprazole)

XRD (x-ray powder diffraction)

X-ray powder diffraction pattern of product, measured from 1 to 40With angle 2, CuK1radiation, shows the following characteristic list of peaks:

whether included for clarity.

The peaks, identified by the values of d calculated by the formula Bragg, and the intensities were obtained from the diffraction pattern for form B of the potassium salt of (S)-omeprazole. Relative intensities are less reliable, and instead of numeric values, use the following definition:

The relative intensity,% Definition of

25-100 OS (very strong)

10-25 s (strong)

3-10 cf (average)

1-3 SL (weak)

Claims

1. Form B of the potassium salt of (S)-omeprazole, characterized in that it is the hydrated form.

2. Form B of the potassium salt of (S)-omeprazole under item 1, characterized in that it is crystalline.

3. Form B of the potassium salt of (S)-omeprazole under item 1 or 2, characterized in that it gives a picture of the x-ray powder diffraction, showing essentially the following d values:

4. The way to obtain form B of the potassium salt of (S)-omeprazole as defined in any of paragraphs.1-3 that includes a stage on which transform (S)-omeprazole in the corresponding potassium salt in toluene or dichloromethane by processing source of potassium, such as potassium hydroxide or potassium methylate, followed by separation of obrazovky-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole oxidizing agent and a chiral titanium complex, it is possible in the presence of a base in an organic solvent such as toluene or dichloromethane, to obtain (S)-omeprazole.

6. Pharmaceutical drug that will inhibit the secretion of gastric acid and containing the potassium salt form B (S)-omeprazole as defined in any of paragraphs.1-3, in a mixture with a pharmaceutically acceptable excipient.

7. Pharmaceutical drug under item 6, characterized in that it is suitable for intravenous injection and contains the potassium salt form B (S)-omeprazole in a mixture with suitable pharmaceutically acceptable excipients for intravenous administration.

8. The method of treatment of gastrointestinal disorders in which the patient is suffering from gastrointestinal disorders, is administered a therapeutically effective amount of form B of the potassium salt of (S)-omeprazole as defined in any of paragraphs.1-3.

 

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