KR19990087713A - How to treat bipolar disorder - Google Patents

Abstract

The present invention provides a method of treating bipolar disorder, comprising administering an effective amount of olanzapine to a patient in need thereof. The present invention also provides a method of treating a depressive episode of bipolar disorder.

Description

How to treat bipolar disorder

Bipolar disorder is a mental illness that is prevalent across cultures and age groups. The lifetime prevalence of bipolar disorder can be as high as 1.6% [DSM-IV, p. 353 (American Psychiatric Association, Washington, DC 1994). Bipolar disorder is a recurrent disorder characterized by one or more episodes of episodes immediately before or after the major depressive episode. Or may be characterized as one or more major depressive episodes with at least one episode of high hypothyroidism, in addition, this symptom is no doubt clinically significant, social, occupational or other important. In some cases, high-grade episodes themselves do not cause damage, but injuries may occur due to interpersonal and occupational functions of unreliable chronic patterns that relieve depression or unpredictable mood episodes. Symptoms of bipolar disorder can include mental illness or medication, and other physical values for depression. , Substance abuse, or it must have been not due to the direct physiological effects of toxin exposure.

Bipolar disorder is highly associated with the risk of complete suicide. In addition, patients suffering from bipolar disorder are likely to suffer from truancy, academic negligence, job negligence or divorce.

Thus, bipolar disorder is a serious and fairly widespread psychological disorder that is clearly distinguished from mental disorders such as schizophrenia [DSM-IV, p. 353 (American Psychiatric Association, Washington, D.C. 1994)].

Olanzapine is known to provide antipsychotic activity and is currently being studied for this purpose. Olanzapine is a known compound and described in US Pat. No. 5,229,382 as useful for the treatment of schizophrenia, schizophrenia type disorders, acute mania, alleviated anxiety conditions and psychosis. The entirety of US Pat. No. 5,229,382 is incorporated herein by reference. However, olanzapine is not known to be useful in the treatment of bipolar disorder. Applicants have found that olanzapine may be useful in the treatment of bipolar disorder. Olanzapine can address the long and urgent need for treatment that provides a good safety profile and effectively alleviates patients suffering from bipolar disorder.

Olanzapine may also be useful for treating major depressive episodes of bipolar disorder. Thus, olanzapine may be a useful treatment for bipolar disorder not characterized by compositional episodes.

The present invention relates to 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (hereafter referred to as Bipolar Disorder) for the treatment of Bipolar Disorder. A method of using " olanzapine "

The present invention provides a method of treating bipolar disorder comprising administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

The present invention provides a method for treating depressive / depressive bipolar disorder comprising administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need of treatment for a depressive / depressive bipolar disorder.

The present invention also provides a method for treating a bipolar episode of bipolar disorder comprising administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

The use of olanzapine for the manufacture of a medicament for therapeutic administration to treat a bipolar disorder is provided.

Olanzapine is a compound of formula (I) or an acid addition salt thereof.

In general, bipolar disorder involves at least one episode of composition, but some patients suffering from bipolar disorder experience a major depression episode. The present invention provides a method of treating a patient suffering from or susceptible to bipolar disorder that does not experience a composition episode.

It is particularly preferred that the olanzapine is a type II olanzapine polymorph having a typical x-ray powder diffraction pattern as shown by the following interplanar spacing.

d 10.2689 8.577 7.4721 7.125 6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007

Typical examples of x-ray diffraction patterns for Form II are as follows, where d represents the surface spacing and I / I ₁ represents the typical relative intensity.

d I / I ₁ 10.2689 100.00 8.577 7.96 7.4721 1.41 7.125 6.50 6.1459 3.12 6.071 5.12 5.4849 0.52 5.2181 6.86 5.1251 2.47 4.9874 7.41 4.7665 4.03 4.7158 6.80 4.4787 14.72 4.3307 1.48 4.2294 23.19 4.141 11.28 3.9873 9.01 3.7206 14.04 3.5645 2.27 3.5366 4.85 3.3828 3.47 3.2516 1.25 3.134 0.81 3.0848 0.45 3.0638 1.34 3.0111 3.51 2.8739 0.79 2.8102 1.47 2.7217 0.20 2.6432 1.26 2.6007 0.77

The x-ray diffraction pattern described here was obtained using a Siemens D5000 x-ray powder diffractometer having a copper Kα radiation source having a wavelength λ = 1.541 GHz.

More preferably, the type II olanzapine isoform is administered as substantially pure type II olanzapine isoform.

The term “substantially pure” herein refers to Form II combined with less than about 5%, preferably less than about 2%, more preferably less than about 1%. In addition, “substantially pure” Form II will contain less than about 0.5% of related material, where “related material” means unwanted chemical impurities or residual solvents or water.

The isotopes obtainable by the method taught in the '382 patent are designated Form I and have substantially the following typical x-ray powder diffraction pattern, obtained using a Siemens D5000 x-ray powder diffractometer (here Where d represents the surface spacing).

d 9.9463 8.5579 8.2445 6.8862 6.3787 6.2439 5.5895 5.3055 4.9815 4.8333 4.7255 4.6286 4.533 4.4624 4.2915 4.2346 4.0855 3.8254 3.7489 3.6983 3.5817 3.5064 3.3392 3.2806 3.2138 3.1118 3.0507 2.948 2.8172 2.7589 2.6597 2.6336 2.5956

Typical examples of x-ray diffraction patterns for Form I are as follows, where d represents the surface spacing and I / I ₁ represents the typical relative intensity.

d I / I ₁ 9.9463 100.00 8.5579 15.18 8.2445 1.96 6.8862 14.73 6.3787 4.25 6.2439 5.21 5.5895 1.10 5.3055 0.95 4.9815 6.14 4.8333 68.37 4.7255 21.88 4.6286 3.82 4.533 17.83 4.4624 5.02 4.2915 9.19 4.2346 18.88 4.0855 17.29 3.8254 6.49 3.7489 10.64 3.6983 14.65 3.5817 3.04 3.5064 9.23 3.3392 4.67 3.2806 1.96 3.2138 2.52 3.1118 4.81 3.0507 1.96 2.948 2.40 2.8172 2.89 2.7589 2.27 2.6597 1.86 2.6336 1.10 2.5956 1.73

Here, the x-ray powder diffraction pattern was obtained using copper Kα having a wavelength λ = 1.541 GHz. The spacing indicated by "d" in the column is in angstroms. Typical relative intensities are indicated as "I / I ₁ " in the column.

As used herein, the term "mammal" refers to the mammalian class of higher vertebrates. The term "mammal" includes but is not limited to humans. The term “treating” herein includes the prevention of a named disease or the amelioration or removal of a disease once established.

The term “bipolar disorder” herein refers to a disease characterized as bipolar disorder as category 296.xx in DSM-IV-R [Diagnostic and Statistical Manual of Mental Disorders, Revised, 3rd Edition (1994)]. For greater clarity, we consider the treatment of both Bipolar Disorder I and Bipolar Disorder II as described in DSM-IV-R. DSM-IV-R was created by the Task Force on Nomenclature and Statistics, and clearly describes the diagnostic categories. Those skilled in the art will understand that there are other nomenclature, disease taxonomy and classification systems for pathological psychological disorders, and that these systems evolve with the development of medicine.

The results of the drug study show that olanzapine has muscarinic cholinergic receptor activity. This compound was less than 1 uM each in the 3H-SCH233390 binding assay (Billard et al., Life Sciences 35: 1885 (1984)) and the 3H spheron binding assay (Seeman et al., Nature 216: 717 (1976)). It is active against dopamine D-1 and D-2 receptors as indicated by its IC50. In addition, olanzapine is active against the 5-HT-2 receptor and the 5-HT1C receptor. The complex drug profile of this compound provides a medicament that may be useful in the treatment of bipolar disorder.

The effectiveness of the compounds in treating bipolar disorder can be supported by studies as described below.

Clinical observation

A double blind multicenter clinical trial was planned to assess the safety and efficacy of olanzapine. Patients were randomized to olanzapine or placebo. The results of this study suggest that olanzapine may be useful for the treatment of bipolar disorder.

Olanzapine is effective over a wide dosage range and the actual dosage administered depends on the disease to be treated. For example, dosages of about 0.25-50 mg / day, preferably 1-30 mg / day, most preferably 1-20 mg / day, can be used in the treatment of adults. A single daily dose is usually sufficient, but divided doses may also be administered. For the treatment of bipolar disorder, a dosage range of 1 to 30 mg / day, preferably 1 to 20 mg / day, is suitable. Since radiolabeled olanzapine can be detected in saliva, this compound can be potentially monitored in patients to assess compliance.

Preferred formulations of the present invention are solid oral formulations containing about 1 to about 20 mg or 1 to 10 mg of olanzapine as an effective amount of the active ingredient.

Most preferably, the solid oral formulation is contained in a packaging that protects the formulation from moisture and light. For example, suitable packaging includes amber high density polyethylene bottles, amber glass bottles and other containers made of light blocking materials. Most preferably, the package will include a desiccant pack. The container can be sealed with an aluminum foil blowing agent to provide the desired protection and to maintain the stability of the product.

Olanzapine will usually be administered orally or by injection, and is generally used in the form of pharmaceutical compositions for this purpose.

Thus, pharmaceutical compositions can be prepared which contain olanzapine as an active ingredient in admixture with a pharmaceutically acceptable carrier. In preparing the compositions of the present invention, conventional techniques for preparing pharmaceutical compositions can be used. For example, the active ingredient will generally be mixed with the carrier, diluted with the carrier, or contained in a carrier, which may be in the form of a capsule, sachet, paper, or other container. If the carrier serves as a diluent, the carrier may be a solid, semisolid or liquid substance that serves as a vehicle, excipient or medium for the active ingredient. The active ingredient can be absorbed into granular solid containers, for example sachets. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxy-benzoate , Talc, magnesium stearate or mineral oil. The compositions of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient, if desired.

Depending on the method of administration, the composition for the treatment of central nervous system diseases may be formulated as tablets, capsules, injections for parenteral administration, gels or suspensions for transdermal delivery, suspensions or elixirs for oral administration, or suppositories. Preferably, the compositions may be formulated in unit dosage forms containing 0.25 to 25 mg, more generally 1 to 20 mg of active ingredient, respectively. Another preferred composition is a unit dosage form containing 1 to 30 mg of active ingredient.

Materials for the present invention can be purchased or prepared by a number of procedures known to those skilled in the art. Olanzapine can be prepared as described in Chakrarabarti, US Pat. No. 5,229,382 ('382), which is incorporated herein by reference in its entirety. In addition, the following preparation examples illustrate the preparation of particularly preferred type II olanzapine isomers.

Methods of characterizing compounds include, for example, x-ray powder pattern analysis, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), titration analysis on water and H ¹ -NMR analysis on solvent content.

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

Preparation Example 1

Technical grade olanzapine

To a suitable three-necked flask was added the following material:

Dimethylsulfoxide (for analysis): 6 vol Intermediate 1: 75 g N-methylpiperazine (reagent): 6 equivalents

Intermediate 1 can be prepared using methods known to those skilled in the art. For example, a method for preparing intermediate 1 is taught in the '382 patent.

Subsurface nitrogen sparge lines were added to remove ammonia formed during the reaction. The reaction was heated to 120 ° C. and maintained at this temperature for the entire reaction. The reaction was followed by HPLC until <5% of Intermediate 1 remained unreacted. After the reaction was completed, the mixture was slowly cooled to 20 ° C. (about 2 hours). The reaction mixture was then transferred to appropriate three-neck round bottom flasks and water baths. To this solution 10 volumes of reagent grade methanol were added with stirring and the reaction stirred at 20 ° C. for 30 minutes. Three volumes of water were added slowly over about 30 minutes. The reaction slurry was cooled to 0-5 ° C. and stirred for 30 minutes. The product was filtered off and the wet cake was washed with cold methanol. The wet cake was dried overnight at 45 ° C. in vacuo. The product was identified as technical grade olanzapine. Yield: 76.7%, efficacy: 98.1%.

Preparation Example 2

Type II olanzapine isoform

Technical grade 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine 270 g sample was suspended in anhydrous ethyl acetate (2.7 L). . The mixture was heated to 76 ° C and held at 76 ° C for 30 minutes. The mixture was cooled to 25 ° C. The 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 preparing Form II provides a pharmaceutically good product having an efficacy of ≧ 97%, a total related substance of <0.5% and an isolation yield of> 73%.

Example 1

Some hydroxypropyl cellulose was dissolved in purified water to form a granulation solution. The remaining ultrafine grade hydroxypropyl cellulose (total 4.0% w / w final tablet weight) was transferred to olanzapine (1.18% w / w), lactose (79.32% w / w) and some crospovidone (5) in a high shear granulator. % w / w). All ingredients were protected, sieved and blended dry in a granulator prior to addition. This mixture was then granulated using a hydroxypropyl cellulose solution in a high shear granulator. Granules were wet sized using standard methods. The wet granules were then dried in a fluid bed dryer and sorted by size. This material was then added to a tumble bin mixer.

A developing powder consisting of microcrystalline cellulose (granules) (10% w / w), magnesium stearate (0.5% w / w) and the remaining crospovidone was added to the sized granules. The mixture was blended and compressed into a suitable instrument on a tablet compression device.

Sub-coating:

Hydroxypropyl methylcellulose (10% w / w) was mixed with purified water to form a solution. The core tablets were divided into approximately equal parts and spray coated with hydroxypropyl methylcellulose solution. This operation was performed in a perforated coating pan.

Coating of Core Tablets:

The coloring mixture white (hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80 and titanium dioxide) was mixed with purified water to form a coating suspension. The subcoated tablets were divided into approximately equal parts and spray coated with the coating suspension described above. This operation was performed in a perforated coating pan.

Carnauba wax was lightly sprayed onto the coated tablets and the appropriate identification was engraved.

Claims (16)

A method of treating bipolar disorder comprising administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a mammal in need of treatment for Bipolar Disorder. 2. The method of claim 1, wherein said bipolar disorder is bipolar disorder I. The method of claim 2, wherein the bipolar disorder is bipolar disorder II. 2. The method of claim 1, wherein said olanzapine is a type II olanzapine isoform having the following typical x-ray diffraction pattern, where d represents an interplanar spacing. d 10.2689 8.577 7.4721 7.125 6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 3. The method of claim 2, wherein said olanzapine is a type II olanzapine isoform having the following typical x-ray diffraction pattern, where d represents the interplanar spacing. d 10.2689 8.577 7.4721 7.125 6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 4. The method of claim 3, wherein said olanzapine is a type II olanzapine isoform having the following typical x-ray diffraction pattern, where d represents the interplanar spacing. d 10.2689 8.577 7.4721 7.125 6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 The method of claim 1 wherein said effective amount is about 1 mg to about 25 mg / day. The method of claim 4, wherein said effective amount is about 1 mg to about 20 mg / day. A method of treating bipolar disorder comprising administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient suffering from bipolar disorder or requiring susceptible treatment for bipolar disorder without experiencing mania. 10. The method of claim 9, wherein said olanzapine is type II. The method of claim 9, wherein the effective amount is about 2.5 mg to about 30 mg / day. A method of treating a bipolar disorder of a bipolar disorder comprising administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need of treatment of a Bipolar Disorder, Major Depressive Episode. 13. The method of claim 12, wherein said effective amount is about 2.5 mg to about 30 mg / day. Use of olanzapine in the manufacture of a medicament for the treatment of bipolar disorder. Use according to claim 14, wherein the bipolar disorder is a major depressive episode of bipolar disorder. Use according to claim 14, wherein the patient is a patient who does not experience a composition episode.