CZ290298A3 - Pharmaceutical preparation against bipolar disorder - Google Patents

Abstract

The invention provides a method for treating bipolar disorder comprising administering an effective amount of olanzapine to a patient in need thereof. Additionally, the present invention provides a method for treating Bipolar Disorder, Major Depressive Episode.

Description

Pharmaceutical composition against bipolar disorder

Technical field

This invention is directed to the use of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] -1,5-benzodiazepine (hereinafter referred to as "olanzapine) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of bipolar disorder, in particular a major depressive episode.

BACKGROUND OF THE INVENTION

Bipolar disorder is a psychiatric condition that is widespread across cultures and age groups. The prevalence of bipolar disorder may be greater than 1.6 7 (DSM-IV, p. 353 - American Phychiatric Association, Wasdhington, D. C., 1994). A bipolar disorder is a recurrent disorder characterized by at least one manic episode immediately before or after a major depressive episode or may be characterized by at least one major depressive episode accompanied by at least one hypomanic episode. In addition, the symptoms must cause clinically significant anxiety or aggravation in the social, professional or other important area of function. In some cases, hypomanic episodes themselves are not the cause of the deterioration, but this deterioration may be the result of a major depressive episode or chronic episode, and professional fluctuations may be better.

to evaluate the pattern of unpredictable moody unreliable interpersonal and symptoms of bipolar disorder may not be a psychological state or as a result of direct physiological effects of treatment, other somatic treatments for depression, drug withdrawal or exposure to toxin.

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Bipolar disorder is associated with a significant risk of completed suicide. In addition, a patient suffering from bipolar disorder is likely to go to school, neglect school or employment or divorce.

Therefore, bipolar disorder is a serious, fairly common psychological condition that clearly differs from psychological conditions such as schizophrenia (DSM-IV, p. 353 - American Phychiatric Association, Wasdhington, D. C., 1994).

It is known that olanzapine can provide an antipsychotic effect and is now under investigation for this purpose. Olanzapine is a known compound that is described in US Patent No. 5,229,382 as useful for the treatment of schizophrenia, schizophrenic disorder, acute mania, mild anxiety and psychosis. U.S. Patent No. 5,229,382 is hereby incorporated by reference in its entirety. However, olanzapine was not known to be useful in the treatment of bipolar disorder. The patentee has found that olanzapine may be useful for the treatment of bipolar disorder. Olanzapine could respond to a long felt need for treatment that provides a favorable safety profile and effective relief for a patient suffering from bipolar disorder.

SUMMARY OF THE INVENTION

The presently claimed invention provides the use of olanzapine or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of bipolar disorder.

The present invention advantageously provides the use of olanzapine or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of bipolar disorder, and the treatment of bipolar disorder. · Which is a depressive / depressive bipolar disorder

Furthermore, the present invention conveniently provides the use of olanzapine or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of bipolar disorder, which is a major depressive episode.

Olanzapine is used according to the invention for the manufacture of a medicament for therapeutic application in the treatment of bipolar disorder.

Olanzapine has the formula I

Generally, bipolar disorder comprises at least one manic episode, wherein patients suffering from bipolar disorder have experience of major depressive episodes. The present invention enables the treatment of a patient suffering from or susceptible to a bipolar disorder in which the patient flaccid to experience a manic episode.

In particular, the polymorphic form of diffraction, as by distances:

prefers that olanzapine in II with a typical X-ray powder pattern be represented by the following interplanar • · and ··

* · Λ · 19 · * 19 [d [nm]

1.02689 0.8577 0.74721 0.7125 0.61459 0.6071 0.54849 0.52181 0.51251 0.49874 0.47665 0.47158 0.44787 0.43307 0.42294 0.4141 0, 39873 0.37206 0.35645 0.35366 0.33828 0.32516 0.3134 0.30848 0.30638 0.30111 0.28739 0.28102 0.27217

0.26432 • * ·

O, 26007

In the following typical example, the powder X-ray diffraction pattern for Form II represents d interplanar distances and 1/1] represents typical relative intensities:

d [nm] I / II

1.02689 0.8577 0.74721 0.7125 0.61459 0.6071 0.54849 0.52181 0.51251 0.49874 0.47665 0.47158 0.44787 0.43307 0.42294 0.4141 0, 39873 0.37206 0.35645 0.35366 0.33828 0.32516

100.00 7, 96

1.41 6, 50

3, 12

5, 12 0, 52

6, 86

2.47

7.41 4.03 6, 80 14.72

1.48 23, 19 11.28 9, 01 14.04 2.27

4, 85 3, 47 1.25 ·

• ·

- 6 - • · * »» »» · · • · · · · · · · • v · · · · · · · · · · · · 0.3134 0, 81 0.30848 0, 45 0.30638 1.34 0.30111 3, 51 0.28739 0.79 0.28102 1.47 0.27217 0.20 0.26432 1.26 0.26007 0, 77 Submitted here roentgenograms Powder diffraction is use X-ray powder diffractometer

Siemens D5000 with Cu K radiation _and radiation wavelength λ == 0, 1541 nm.

It is further preferred that polymorphic olanzapine Form II will be administered in substantially pure polymorphic olanzapine Form II.

As used herein, the term "substantially pure" refers to Form II associated with less than about 5% Form I, preferably less than about 2% Form I, and more preferably less than about 1% Form I. Further, "substantially Pure Form II will contain less than about 0.5% of the associated substances, wherein the term "associated substances" refers to undesirable chemical impurities or the remainder of the solvent or water.

The polymorphic form obtainable by the method mentioned in US Patent No. 5,229,382 will be designated Form I and has essentially the following typical powder diffraction pattern, obtained using an X-ray powder diffractometer. 'laziness i:

* · · D d [d [nm]

0.99463 0.85579 0.82445 0.68862 0.63787 0.62439 0.55895 0.53055 0.49815 0.48333 0.47255 0.46286 0.4533 0.44624 0.42915 0.42346 0, 40855 0.38254 0.37489 0.36983 0.35817 0.35064 0.33392 0.32806 0.32138 0.31118 0.30507 0.2948

0.28172 ····· · »· • · · *« «« «« «

, 27589

, 26597

, 26336

259, 25956

In the following typical X-ray example for Form I, d represents the interplanar distances and I / Ii represents typical relative intensities:

d [nm]

0.99463 0.85579 0.82445 0.68862 0.63787 0.62439 0.55895 0.53055 0.49815 0.48333 0.47255 0.46286 0.4533 0.44624 0.42915 0.42346 0, 40855 0.38254 0.37489 0.36983 0.35817 0.35064

I / Ii

100.00 15, 18 1.96 14.73 4.25

5, 21 1.10 0, 95

6, 14 68.37 21.88 3.82 17.83

5, 02

9, 19 18, 88 17.29

6, 49

10, 64 14.65 3.04 9, 23 · · · * * fl fl fl fl fl fl · · · · · · · · · · · · · · A * A · · · · · · · · · · · A A A ·

0.33392 4, 67 0.32806 1.96 0.32138 2.52 0.31118 4, 81 0.30507 1.96 0.2948 2.40 0.28172 2, 89 0.27589 2, 27 0.26597 1, 86 0.26336 1, 10 0.25956 1.73

Here, said x-ray powder diffraction obtained using Cu K a radiation source _and having a wavelength λ = 0.1541 nm. The inter-plane distances in the column labeled "d" are in nanometers (nm). Typical relative intensities are in the column labeled "I / 11."

As used herein, the term vertebrate, mammal class, is not limited to, optionally, "treating a condition or improvement, or" a mammal will refer to the higher. The term "mammal includes, but is not human." As used herein, the term "treatment" includes prophylaxis named elimination of the established condition.

As used herein, the term "bipolar disorder should refer to the condition characterized as bipolar disorder in DSM-IV-R, Diagnostic and Statistical Manual of Mental Disorders, Revised, 3, eds., (1994), as category 296.xx. For further clarification, the patentee contemplates the treatment of both bipolar I disorder and bipolar II disorder as described in DSM-IV-R. The DSM-IV-R has been prepared by the Nomenclature and Statistics Committee of the American Psychiatric Association and provides a clear description

- «« kategorií kategorií V V V V V V V V V V V V V V V V V V V V V V V One of skill in the art will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathological psychological conditions and that these systems evolve with the development of medical science.

The results of pharmacological studies indicate that olanzapine has activity on cholinergic muscarinic receptors. The compound is active at dopamine receptors D1 and D-2 as determined by the IC dose _; , less than 1 µm at 3H-SCH233390 (Billard et al., Life Sciences, 35, 1855 (1984)) and Hspiperone ³ binding assays (Seeman et al., Nature, 216, 717 (1976)). Furthermore, olanzapine is active at the 5-HT-2 receptor and at the 5-HT1C receptor. The complex pharmacological profile of the compound provides a drug that may be useful for the treatment of bipolar disorder.

The utility of the compound in the treatment of bipolar disorder may be substantiated by the studies described herein.

Cine observations

Double-blind multicenter clinical trials were designed to determine the safety and efficacy of olanzapine. Patients were randomized to olanzapine or placebo. The results of the study suggest that olanzapine may be useful for the treatment or treatment of bipolar disorder.

Olanzapine is effective over a wide dose range, the actual dose being administered depends on the condition being treated. For example, in the treatment of adult humans, daily dosages of from about 0.25 to 50 mg, preferably from 1 to 30 mg, and most preferably from 1 to 20 mg, may be used. Once-daily dosing is normally sufficient, although divided doses may be administered.

· · V v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v · ♦ · · ··

For the treatment of bipolar disorder, a dosage range of 1 to 30 mg per day is suitable, although a dosage of 1 to 20 mg per liner is preferred. Radiolabelled olanzapine can be detected in the saliva, thereby monitoring patient compliance.

A preferred composition of the invention is a solid formulation. an oral preparation comprising, as an effective amount of the active ingredient, about 1 to about 20 mg or about 1 to 10 mg of olanzapine.

Most preferably, the solid oral formulation is contained in packaging materials that protect the formulation from moisture and light. Suitable packaging materials include, for example, amber-colored high density polyethylene bottles, amber-colored glass bottles, and other containers made of materials that prevent light transmission. Most preferably, the package will comprise a drying bag. The packaging may be sealed with an aluminum foil blister to provide the desired protection and maintain product stability.

Olanzapine will normally be administered orally or by injection, and is usually formulated for this purpose in the form of a pharmaceutical composition.

Thus, pharmaceutical compositions containing olanzapine as an active ingredient in association with a pharmaceutically acceptable carrier can be prepared. In preparing the compositions of the present invention, conventional methods for preparing pharmaceutical compositions can be used. Usually, the active ingredient is, for example, mixed with a carrier or diluted with a carrier or enclosed within a carrier, which may be in the form of a capsule, sachet, paper or other container. If the carrier serves «« »» »»

9 as a diluent, it may be a solid, semi-solid or liquid substance that has the function of vehicle, excipient or carrier for the active ingredient. The active ingredient can be adsorbed on a solid granular carrier, for example in a sachet. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methylcellulose, methyl propylhydroxybenzoate, talc, magnesium stearate or mineral oil. If desired, the compositions of the invention may be formulated so as to provide rapid, controlled or prolonged release of the active ingredient after administration to the patient.

Depending on the route of administration, formulations for treating central nervous system conditions may be prepared as tablets, capsules, injectable solutions for parenteral use, a gel or suspension for transdermal administration, a suspension or elixir for oral use, or a suppository. Preferably, the compositions are prepared in unit dosage form, each dosage containing usually from 0.25 to 25 mg, more preferably from 1 to 20 mg, of the active ingredient. Alternatively, preferred unit dosage forms contain from 1 to 30 mg of active ingredient.

The materials for the present invention can be obtained or prepared by various methods known to one of ordinary skill in the art. Olanzapine can be prepared as described by Chakrabarti in U.S. Patent No. 5,229,382 ('382), which is incorporated by reference in its entirety. The following examples further illustrate a process for preparing a particularly preferred Form II polymorphic olanzapine.

Methods of characterizing the compound include, for example, structural powder X-ray analysis, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), volumetric analysis for water and ^J HNMR analysis for solvent content.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are provided for the purpose of illustration and are not to be construed as limiting the scope of the claimed invention.

PREPARATION 1

01anzapine of technical quality

NH?

Intermediate 1

A suitable triple neck flask was charged with:

Dimethylsulfoxide (analytical reagent) Intermediate 1

N-methylpiperazine (reagent) of 75 g equivalents

Intermediate 1 can be prepared using methods known to those skilled in the art. For example, the preparation of an intermediate

It · a a a a a a a a a a a a a * * * * * * * * * * * * * * * * U.S. Pat. No. 5,229,382:

A subsurface layer of nitrogen was added to remove the ammonia formed during the reaction. The reaction mixture was heated to 120 ° C and maintained at this temperature for the duration of the reaction. The reaction was monitored by HPLC, to a content equal to or less than 5, unreacted intermediate 1. After completion of the reaction, the mixture was allowed to cool slowly to 20 ° C (approximately

h). The reaction mixture was then transferred to an appropriate three-neck round bottom flask for water bath. To this solution was added 10 volumes of reaction-grade methanol under stirring, and the reaction mixture was stirred at 20 ° C for 30 minutes. 3 volumes of water were slowly added over approximately 30 minutes. The reaction suspension was cooled to 0 áž5.5% ^. C and mixed for 30 minutes. The product was filtered and the wet filter cake was washed with chilled methanol. The wet filter cake was dried under vacuum at 45 ° C overnight. The product was identified as technical olanzapine.

Yield: 76.7 7; content: 98.1%.

PREPARATION

Form II of polymorphic olanzapine

A 270 g sample of technical grade 2-methyl-4- (4-methyl-1-piperazinyl) -10Hthieno [2,3-b] [1,5] benzodiazepine was suspended in 2.7 L of anhydrous ethyl acetate. The mixture was heated for 7 6 C and held for 30 minutes at 7 6 ^c 'C. The mixture was allowed to cool to 25 ° C. The resulting product was isolated using vacuum filtration. The product was identified as Form II using X-ray powder analysis.

Yield: 197 g.

The method described above for the preparation of Form II yielded a pharmaceutically superior product with a content equal to or greater than 97 with a total content of < 0.5% associated substances and > 73% isolated yield.

Example 1

A portion of the hydroxypropylcellulose was dissolved in purified water to form a solution for granulation. The remaining residual hydroxypropylcellulose (4.0% by weight of the final tablet weight), which was of extremely pure quality, was mixed with 1.18% by weight of olanzapine, 79.32% by weight of lactose and a proportion of 5% by weight of crospovidone in a high shear granulator. . All ingredients were guaranteed to be cross-linked prior to addition and dry blended in the granulator. This mixture was then granulated with a solution of hydroxypropylmethylcellulose in a high shear granulator. The granulation was performed in wet conditions using standard methods. The wet granulate was then dried in a fluid bed dryer and adjusted to a uniform particle size. The material was then added to a rotary drum mixer.

Loose powders composed of 10% by weight of granulated microcrystalline cellulose, 0.5% by weight of magnesium stearate and the remainder of Crospovidone were added to the uniform particle size granulate. The mixture was mixed and compressed on an appropriately equipped tablet press.

The coating of the hydroxypropyl methylcellulose was mixed with purified water to form a solution. The tablet cores were divided into approximately equal parts and spray coated with a hydroxypropylmethylcellulose solution. The operation was performed in a perforated coating drum.

Coating of tablet cores

The white dye mixture (hydroxypropylmethylcellulose, polyethylene glycol, polysorbate 80, and titanium dioxide) was mixed with purified water to form a coating suspension. The coated tablets were divided into approximately equal portions and spray coated with the coating suspension described above. The operation was performed in a perforated coating drum.

The film-coated tablets were lightly dusted with carnauba wax and imprinted with an appropriate label.

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Claims (1)

PATENT CLAIMS Use of olanzapine or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of bipolar disorder. 2. Use olanzapine or j eho pharmaceutically acceptable salts according to claim 1, for production pharmaceutical means for treatment of bipolar disorders, which is bipolar disorder I. 3. Use olanzapine or j eho pharmaceutically acceptable salts according to claim 2, for production pharmaceutical means for treatment of bipolar disorders, which is bipolar disorder II. Use of olanzapine according to claim 1, for the manufacture of a pharmaceutical composition for the treatment of bipolar disorder, wherein olanzapine is in Form II with the following typical X-ray powder diffraction pattern, wherein d represents the interplanar distances: d [nm] 1.02689 0.8577 0.74721 0.7125 0.61459 0.6071 0.54849 • 9 • · 9 9 ·· ··· « 4 9 9 · · · ·