Omeprazole form a, method thereof, pharmaceutical drug based on it and the method of treatment of gastrointestinal disorders

 

The invention relates to a form of omeprazole, which is effective as an inhibitor of the secretion of gastric acid and is useful as an antiulcer agent. Describes the form And omeprazole, and this form gives a clear picture of the x-ray powder diffraction. Also disclosed is a method of obtaining forms And omeprazole, a pharmaceutical preparation containing the form And omeprazole, and treatment of gastrointestinal disorders. 7 C. and 14 C.p. f-crystals, 2 ill., table 4.

Field of invention the Invention relates to a new crystalline form of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]--benzimidazole. 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] --benzimidazole known by the international nonproprietary name omeprazole, and his new crystalline form, hereinafter referred to as a form of omeprazole. In addition, the present invention also relates to the application form And omeprazole for the treatment of gastrointestinal disorders, pharmaceutical compositions containing the form And omeprazole, and how to obtain forms And omeprazole.

Background of the invention and 2D/img_data/61/612329.gif">-benzimidazole with international non-proprietary name omeprazole and its therapeutically acceptable salts described in EP 5129. X-ray single crystal data and the resulting molecular structure is only known up to the present crystalline form of omeprazole described Ohishi et al., Acta Cryst. (1989), C. 45, 1921-1923. This published crystalline form of omeprazole hereinafter referred to as form B of omeprazole.

Omeprazole is a proton pump inhibitor, i.e. effective in suppressing the secretion of gastric acid and is useful as an antiulcer agent. In a more General sense, omeprazole can be used to treat associated with gastric acid diseases in mammals and especially in humans.

A brief description of graphic materials Fig.1 is an x-ray powder diffraction pattern of form a of omeprazole.

Fig.2 is an x-ray powder diffraction pattern of form B of omeprazole.

Description of the invention it has been Unexpectedly discovered that the substance omeprazole can exist in more than one crystalline form. The present invention is to provide form And omeprazole, substantially free from other forms of omeprazole. X-ray powder diffraction (RPD) is used as the method of differences between the shape And omeprazole from other crystalline and non-crystalline form of omeprazole. Additionally, the present invention is to provide pharmaceutical preparations, including the form And omeprazole.

Form And omeprazole is a crystalline form exhibiting useful properties, such as the fact that she is well-defined, thermodynamically more stable and less hygroscopic than form B of omeprazole, especially at room temperature. Form And omeprazole also showed a more good chemical resistance such as heat resistance and light resistance than form B of omeprazole.

Form B of omeprazole may under certain conditions be completely or partially transformed into the form And omeprazole. Form And omeprazole, thus, differs in that it is thermodynamically more stable than form B of omeprazole.

Form And omeprazole also differs in that it is essentially non-hygroscopic.

Form And omeprazole different positions and intensities of peaks in rentgenovskaya based on accurate data Genie (Guinier). Data x-ray powder diffraction pattern, and the unit cell parameters for form B of omeprazole differ in comparison with the form And omeprazole. The form And omeprazole, thus, can be distinguished from form B of omeprazole using x-ray powder diffraction.

Form And omeprazole according to the present invention differs in that it gives a picture of the x-ray powder diffraction, such as in Fig.1, showing mainly the d-values and intensities are listed in table.A.

The peaks, identified by d-values calculated by the formula Bragg, and the intensities were derived from diffractogram hinge forms And omeprazole. Relative intensities are less reliable, and instead of numerical values using the following definitions: relative intensity, %* - Definition 25-100 - OS (very strong) 10-25 - with (strong) 3-10 - cf (medium) 1-3 - SL (weak)
* The relative intensities are derived from diffractograms measured with fixed slits.

Form And omeprazole the present invention also differs triclinic unit cell with parameters




Form And omeprazole may also be characterized using Raman spectroscopy, in which form And omeprazole has no stripes 1364 cm-1that observed for form B of omeprazole, and the relative intensities of the bands 842 and 836 cm-1. Ratio (the intensity of the band 842 cm-1/the intensity of the band 836 cm-1) <1 for the form And omeprazole, whereas form B of omeprazole is the ratio >1.

In accordance with this invention is also a method for obtaining forms And omeprazole.

The form And omeprazole obtained by slow crystallization and form B of omeprazole produced by rapid solidification. The form And omeprazole can be obtained by reaction crystallization or recrystallization any form of omeprazole or mixtures of any form in a suitable solvent, such as, for example, methanol, at about room temperature and for an extended period of time. Examples of extended periods of time include, but are not limited to several hours, such as from 2 hours to several weeks. Suitable solvents are alkalemia alcohols and, in particular, a lower alcohol, including CE the La or mixtures of any form in a suitable solvent at about room temperature and for an extended period of time. Examples of suitable solvents include, but are not limited to methanol, ethanol, acetone, ethyl acetate, methyl tert-butyl ether, toluene, or any mixture. Examples of extended periods of time include, but are not limited to several hours, such as from 2 hours to several weeks.

Form And omeprazole obtained according to the present invention, substantially free from other crystalline and non-crystalline forms of omeprazole, such as form B of omeprazole. It should be understood that essentially free from other forms of means the shape And omeprazole contains less than 10%, preferably less than 5% of any other form of omeprazole, such as form B of omeprazole.

Form And omeprazole in a mixture with other solid form/forms of omeprazole, such as form B of omeprazole, also exhibits useful properties, such as the fact that it is chemically more stable than the pure form B of omeprazole. The mixture, which includes a number of forms And omeprazole by weight, are chemically more stable than other mixtures, including fewer forms And omeprazole weight. Such mixtures, which includes the form of omeprazole that can be applied in Jimi forms of omeprazole, such as form B obtained in accordance with the previous state of the art.

The present invention also relates to mixtures containing a form And omeprazole in a mixture with other solid forms of omeprazole. Such mixtures preferably contain more than 50% by weight of form a of omeprazole. Other embodiments include, for example, mixtures containing detective number of forms And omeprazole, 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% (by weight) forms And omeprazole.

Examples of other solid forms of omeprazole include, but are not limited to the form B of omeprazole, amorphous forms and other polymorphs.

Detective number of forms And omeprazole is a quantity that can be detected using conventional methods such as infrared spectroscopy with Fourier transform Raman spectroscopy, RPD, etc.,

The expression chemical resistance includes, but is not limited heat resistance and light fastness.

The connection according to this invention, i.e. the form And omeprazole obtained according to the present invention, analyze, describe, and distinguish from form B of omeprazole by using x-ray powder diffraction, the manner in which the we B omeprazole is Raman spectroscopy.

Form And omeprazole was effective in inhibiting the secretion of gastric acid and is useful as an antiulcer agent. In a more General sense, it can be used to treat conditions associated with gastric acid, including, for example, reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer, in mammals and in particular humans. In addition, it can be used for treatment of other gastrointestinal disorders where it is desirable inhibitory effect on gastric acid, for example, in patients undergoing treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients suffering from non-ulcer dyspepsia in patients suffering from symptomatic gastroesophageal reflux disease, and in patients suffering from ulcerogenic adenoma of the pancreas. The connection according to this invention may also be used by patients in cases of intensive treatment, patients suffering from acute bleeding of the upper section of the gastrointestinal tract, pre - and post-operative to prevent aspiration of gastric acid and to treat stress ulceration. In addition, cter, and related diseases. The connection according to this invention can also be used for treating inflammatory conditions in mammals, including humans.

In order to enter the patient an effective dose of omeprazole form a according to this invention, it is possible to use any suitable route of administration. For example, you can use drugs for oral or parenteral administration, and the like. Dosage forms include capsules, tablets, colloidal solutions, suspensions and the like, for example covered intersolubility shell capsules and/or tablets, capsules and/or tablets containing coated intersolubility shell pellets of omeprazole. All dosage forms form And omeprazole can be mixed with other suitable components.

In accordance with this invention also proposed a pharmaceutical composition comprising form a of omeprazole as the active ingredient in combination with pharmaceutically acceptable carrier, diluent or excipient and possibly other therapeutic ingredients. Compositions that include other therapeutic ingredients, particularly interesting in the treatment of infections, viszla use in the treatment condition, associated with gastric acid, and a method of treatment of a condition associated with gastric acid, in which the subject is suffering from this condition, is administered a therapeutically effective amount of form a of omeprazole.

The compositions of this invention include compositions suitable for oral or parenteral administration. These compositions are for convenience can be presented in a standard dosage form and prepared by any methods known from the field of 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 And omeprazole in any given case will depend on the nature and severity of the disease that is being treated. Dose and frequency of dose may also vary in accordance with age, weight and response of the individual patient. For patients suffering from the syndrome of Zollinger-Ellison may require special conditions, such as the need for higher doses than for the average patient. For children and patients suffering from liver disease, and patients undergoing long-term treatment, usually useful is be necessary to use doses beyond the range set below. Such higher and lower doses are within the scope of the present invention.

Typically, a suitable dosage form for oral administration can cover a range of doses from 5 mg to 250 mg total daily dose, administered as a single dose or equally divided doses. The preferred dose range is from 10 mg to 80 mg

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, such as preparations for oral administration, are described in WO 96/01623 and EP 247983.

Can also be used combined methods of treatment, including the form And omeprazole and other active ingredients in separate dosage forms or in a constant dosage form. Examples of such active ingredients include antibacterial compounds, nonsteroidal anti-inflammatory drugs, antacids, alginates and prokinetics agents.

The following additional examples illustrate the connection according to this invention, i.e. the form And omeprazole, but you don't want /> The form And omeprazole
Omeprazole (55.8 g) is added at room temperature to methanol (348 ml) containing ammonia (1.3 ml; 25%). This suspension is then stirred in the dark for approximately 45 hours and then filtered. The filtrate is dried for 18 hours at 30oWith under reduced pressure (<5 mbar (0.5 kPa)). Output: 43,9,

Example 2
Receipt of form B of omeprazole
Omeprazole (50 g) are added to a methanol (750 ml) containing ammonia (0.7 ml; 25%), 50oC. the Solution is then filtered and cooled for approximately 20 minutes to approximately 0oC. the Resulting crystals filtered and washed with chilled on ice with methanol and then dried. The filtrate is dried for 24 hours at 40oWith under reduced pressure (<5 mbar (0.5 kPa)). Output: 39,

Example 3
Description of omeprazole form a and form B of omeprazole using x-ray powder diffraction
X-ray diffraction analysis was carried out in accordance with standard methods, which can be found, for example, Bunn, S. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York. The unit cell parameters for forms a and B of omeprazole were calculated from x-ray powder DEFRA what I all the peaks in the diffraction pattern for form a and form B of omeprazole can be calculated, using the corresponding unit cell parameters, proves that the unit cell are accurate and that the diffraction pattern indicate pure forms. The diffraction pattern of form a of omeprazole, obtained in accordance with Example 1 in this application, is shown in Fig.1, and the diffraction pattern of form B of omeprazole, obtained in accordance with Example 2 in this application, is shown in Fig.2.

The peaks, identified by the values of d calculated by the formula Bragg, and the intensities were obtained from the diffraction pattern for form a and form B of omeprazole given in table 1. This table also shows the unit cell parameters for forms a and B of omeprazole. Relative intensities are less reliable, and instead of numeric values using the following definitions:
The relative intensity, %* - Define
25-100 - OS (very strong)
10-25 - with (strong)
3-10 - cf (average)
1-3 - SL (weak)
Some additional weak or very weak peaks detected in the diffractograms were omitted in table 1.

Table 1: Data x-ray powder diffraction for form a and form B of omeprazole is shown in Fig. 1 and 2. All peaks listed for form a and form B ome the cell are:
Unit cell of the form a



=111,51(3)o
=116,78(3)o
=at 90.77(3)o
Unit cell of the form B



=112,14(7)o
=115,56(5)o
=91,76(7)o
Thermodynamic stability of form And omeprazole were studied in experiments on suspensions. It was found that this form is thermodynamically stable at room temperature. Using differential scanning calorimetry were defined melting point and enthalpy of fusion for forms a and B of omeprazole (see tab. 2).

A higher value of enthalpy of melting and high melting point form And omeprazole indicate that this form is more thermodynamically stable than form B of omeprazole, and the order of these values indicates monotropy.

Experimentally it was found that the shape And omeprazole has lower hygroscopicity in whom the relative humidity (RH) of 90%.

Lower hygroscopicity is a positive quality that characterizes the active pharmaceutical ingredient.

Also compared the stability of forms a and B of omeprazole during storage. Studies were performed within 1 and 3 months, respectively, at a temperature of 40oC and a relative humidity of 75%. It was found that the shape And has a much better stability than form B.

Thus, when comparing forms a and B of omeprazole has been shown that the form is thermodynamically more stable, less hygroscopic, and has better storage stability.

Regarding data on the biological activity of the claimed form of omeprazole, the applicant informs the following. Forms a and B of omeprazole are different crystal forms of omeprazole and differ only in their properties in relation to the preparation and storage of pharmaceuticals. Omeprazole regardless of their form, has the same biological activity, and it is a proton pump inhibitor that is well known from the prior art. Therefore, the shape And omeprazole can be used in the treatment of the same diseases as other forms of omeprazole.

2. Form And omeprazole under item 1, characterized in that it is thermodynamically stable at room temperature.

3. Form And omeprazole under item 1, characterized in that it is essentially non-hygroscopic.

4. Form And omeprazole according to any one of paragraphs.1-3, characterized in that it has a triclinic unit cell with parametria=111,51(3)o,=116,78(3)o,=at 90.77(3)o.

5. Form And omeprazole according to any one of paragraphs.1-4, characterized in that there is no band 1364 cm-1that observed in Raman spectroscopy for the form b

6. Form And omeprazole according to any one of paragraphs.1-5, characterized in that the ratio of the intensity of the bands 842 cm-1to the intensity of the bands 836 cm-1observed with Raman spectroscopy, is less than 1.

7. Omeprazole, characterized in that it contains more than 80% by weight of form a of omeprazole as defined in any of paragraphs.1-6.

8. Omeprazole under item 7, characterized in that it contains 90% by mass in RMI And omeprazole.

10. Omeprazole under item 7, characterized in that it contains 98% by weight of the specified form And omeprazole.

11. Omeprazole under item 7, characterized in that it contains 99% by weight of the specified form And omeprazole.

12. The method of obtaining forms And omeprazole according to any one of paragraphs.1-6, including the stage at which: a) is dissolved or suspended omeprazole in any form or mixture of any form in a suitable solvent; b) crystallized solution, and in) are obtained in this way form And omeprazole.

13. The method according to p. 12, characterized in that the solvent used in stage (a) selected from the group consisting of methanol, ethanol, acetone, ethyl acetate, methyl tert-butyl ether, toluene, or any mixture thereof.

14. The method according to p. 12 or 13, characterized in that stage (a) is carried out at 15-25oC.

15. The method according to any of paragraphs.12-14, characterized in that stage (b) is carried out for an extended period of time.

16. The method according to any of paragraphs.12-15, characterized in that stage (b) is carried out for at least 2 hours

17. The method according to any of paragraphs.12-16, characterized in that to induce crystallization may use the form As omeprazole.

18. Form And omeprazole, obtained by the method according to any of p is with the omeprazole, as defined in any of paragraphs.1-6, in a mixture with a pharmaceutically acceptable excipient.

20. Omeprazole according to any one of paragraphs.1-6 as the active ingredient in the manufacture of medicaments for the treatment of gastrointestinal disorders.

21. The method of treatment of gastrointestinal disorders in which the patient is suffering from gastrointestinal disorders, is administered a therapeutically effective amount of omeprazole as defined in any of paragraphs.1-6.

 

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