MXPA98007438A - Medications to treat the insom - Google Patents

Abstract

The invention provides a method for treating insomnia, which comprises administering an effective amount of olanzapine to a patient in need of the same.

Description

MEDICATIONS TO TREAT TNSOMNIUM FIELD OF THE INVENTION This invention provides a method for using 2-me i1-4- (4-me i1-1-piperazini1) -1 OH-thieno [2, 3-b] [1,5] benzodiazepine, (later referred to as "olanzapine" "), for the treatment of insomnia.

BACKGROUND OF THE INVENTION Insomnia is one of the most common diseases in general medical practice. There is an occurrence in a year as high as 40%. DSM-IV, p. 553 (American Psychiatric Association, Washington, D.C., 199I). A variety of pharmacological agents are used to treat insomnia; however, the "perfect" agent should allow < 3? E the dream occurs, with architecture of normal sleep, rather than producing a pharmacologically altered sleep or sleep configuration. The "perfect" agent will not cause effects in the day, either rebound anxiety or continuous sedation. Here the most desirable drugs continue to be a necessity that has at least several of the characteristics described by the "perfect" agent.

REF .: 28154 Benzodiazepine hypnotics have been prescribed in the past; However, benzodiazepines are generally not a drug of choice for the treatment of insomnia, due to side effects of bezodiazepine and difficulties with the treatment of the elderly patient with benzodiazepines. Insomnia not treated or treated inappropriately is associated with a four-fold increase in accidents. Goodman and Gillman, The Pharmacological Basis of Therapeutics, 385 (McGraw Hill, New York 9th ed.) 1996. Thus, there is a need for additional pharmacological treatments for the patient suffering from insomnia. Such pharmacological treatment should preferably provide a safety profile which is acceptable for prolonged use, if necessary or desired. It is known that olanzapine can provide antipsychotic activity and is commonly investigated for this purpose. Olanzapine is a known compound and is described in US Patent No. 5,229,382 as being useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, mild anxiety states, and psychosis. The North American Patent No. 5,229,382 is incorporated herein by reference in its entirety. However, olanzapine was not known to be useful for the treatment of insomnia. Applicants have discovered that olanzapine may be useful for the treatment of insomnia. Olanzapine could be aimed at widely covering the need for treatments that provide a favorable safety profile and effectively provide healing for the patient suffering from insomnia.

DESCRIPTION OF THE INVENTION The present claimed invention provides a method for treating insomnia, which comprises administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need of such treatment. A preferred embodiment of the present invention is to treat insomnia in a patient selected from the group consisting of an elderly patient, a patient suffering from prolonged periods of insomnia, and in a patient who has been taking a hypnotic agent for more than three consecutive weeks.

A further preferred embodiment is a method for treating insomnia without clinically significant alteration of the sleep architecture, which comprises administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need of such treatment. Olanzapine is of the formula or an acid addition salt thereof. When used herein the phrase "clinically significant alteration of the sleep architecture" means that the patient suffering from insomnia is able to sleep without a clinically significant pharmacological alteration of the sleep configuration. More preferably, the patient additionally does not suffer from the "rebound effect" of the treatment. The term "bounce effect" refers to to manifestations such as anxiety upon awakening. It is especially preferred that olanzapine be the polymorph olanzapine of Form II having a typical powder x-ray diffraction pattern, as represented by the following interplanar spacings: d 10.2689 8.577 7.4721 7.125 6.1459 6.071 t t 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 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, A typical example of an x-ray diffraction pattern for Form II is as follows where d represents the interplanar spacing and I / Ii represents the typical relative intensities: . 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 patterns described here were obtained using a Siemens D5000 x-ray powder diffractometer having a wavelength copper radiation source Ka,? = 1-541A. It is further preferred that the Form II polymorph olanzapine be administered as the substantially pure Form II polymorph olanzapine. As used herein, "substantially pure" refers to Form II associated with less than about 5% of Form I, preferably less than about 2% of Form I, and more preferably less than about 1% of Form I. Additionally, Form II "substantially pure" will contain less than about 0.5% of related substances, wherein "related substances" refers to undesirable chemical impurities or residual solvent or water. In particular, Form II "substantially pure" should contain less than about 0.05% acetonitrile content, more preferably, less than about 0.005% acetonitrile content. Additionally, polymorphic Form II preferably contains less than 0.5% associated water. The polymorphic substance obtained by the process taught in the patent ^ 382 will be designated as Form I and have a typical X-ray powder diffraction pattern, substantially as follows, obtained using a Siemens D5000 x-ray powder diffractometer, in where d represents the interplanar 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 t, 2.8172 2.7589 2.6597 2.6336 2.5956 A typical example of an x-ray diffraction pattern for Form I is as follows where d represents the interplanar spacing and I / Ii represents the typical relative intensities: 9. 9463 100.00 8. 5579 15.18 8. 2445 1.96 6. 8862 14.73 6. 3787 4.25 6. 2439 5.21 . 5895 1.10 . 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 The x-ray powder diffraction patterns here were obtained with a Ka wavelength copper? = 1.541A. The interplanar spacings in the column marked "d" are in Angstroms. The typical relative intensities are observed in the column marked "I / Ii". When used here, the term "mammal" will refer to the classes of large vertebrate mammals. The term "mammal" includes, but is not limited to, a human. The term "treatment" as used herein includes prophylaxis of the named condition or improvement or elimination of the condition once it has been established. As used herein, the term "insomnia" will refer to a condition characterized by inability of an individual to fall into a dream or to maintain sleep for the desired amount of time necessary to provide a rest, wakefulness sensation upon awakening. For additional clarity, the term insomnia will refer to the condition classified in the DSM-IV, p. 553 (American Psychiatric Association, Washington, D.C. 1994) as a category number 307.42. The diagnostic criteria include a predominant disease in the initiation or maintenance of difficult sleep, or non-restorative sleep, for at least one month; Sleep disturbance causes clinically significant distress or impairment of social, occupational, or other important areas of functioning; Sleep disturbance does not occur exclusively during the course of r Narcolepsy, sleep disorder related to Breathing, sleep disturbance due to heart rhythm, or a parasomna; Alteration does not occur exclusively during the course of a mental disorder; The alteration is not due to the psychological effects of a substance or a general medical condition. The results of pharmacological studies show that olanzapine has cholinergic muscarinic receptor activity. The compound is active at the dopamine D-1 and D-2 receptors as indicated by an IC50 of less than 1 uM in 3H-SCH233390 (Billard, et al., Life Sciences 35: 1885 (1984)) and spiperone 3H (Seeman et al. Nature 216: 717 (1976)) that bind assays respectively. Additionally, olanzapine is active at the 5-HT-2 receptor and the 5-HT 1C receptor. The pharmacological profile of the complex of the compound provides a medicament which may be useful for the treatment of insomnia. The utility of the compound for the treatment of insomnia can be supported by the following studies as described.

Clinical observations A multicenter double-blind clinical trial was designed to assess the safety and efficacy * of olanzapine. Patients were randomly selected for olanzapine or placebo. The results of the study suggest that olanzapine may be useful for the treatment of insomnia. Olanzapine is effective over a wide range of dosage, the current dose administered is dependent on the condition being treated. For example, in the treatment of adult humans, dosages of about 5 to 25 mg per day can be used. One time one dosage per day is Normally enough. For the treatment of insomnia, a dosage range of 5 to 100 mg is adequate, while a dosage of 5 to 25 mg per day is preferred. Radiolabeled olanzapine can be detected in saliva and thus the compound can potentially be verified in patients to assess condescension or submission. A preferred formulation of the invention is a solid oral formulation comprising from about 5 to about 25 mg of olanzapine as an effective amount of the active ingredient. More preferably, the solid oral formulation is contained in packaging material which protects the formulation from moisture and light. For example, suitable packaging materials include amber colored high density polyethylene bottles, amber glass bottles, and other containers made of a material which inhibits the passage of light. More preferably, the package will include a desiccant pack. The container can be sealed with an aluminum foil blister to provide the desired protection and maintain the stability of the product.

The olan? Apina will normally be administered orally, for this purpose, it will usually be used in the form of a pharmaceutical composition. Accordingly, pharmaceutical compositions comprising olanzapine, as an active ingredient associated with a pharmaceutically acceptable carrier can be prepared. Making the compositions of the conventional techniques of the invention for the preparation of pharmaceutical compositions may be useful. For example, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container or container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. The active ingredient can be absorbed onto a solid granular container for example in a pouch. Examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxy-benzoate, talc, stearate magnesium or mineral oil. The Compositions of the invention, if desired, can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient. Depending on the method of administration, compositions for the treatment of central nervous system conditions can be formulated as tablets, capsules, injection solutions for parenteral use, gel or suspension for transdermal delivery, suspensions or elixirs for oral use or suppositories. Preferably, the compositions are formulated in a unit dosage form, each dosage usually containing from 5 to 25 mg of the active ingredient. The materials for the present invention can be purchased or prepared by a variety of methods well known to those skilled in the art. Olanzapine can be prepared as described by Chakrabarti in US Patent No. 5,229,382 (? 382), incorporated herein by reference in its entirety. Additionally, the following preparations illustrate a method for preparing the polymorphous olanzapine of the especially preferred Form II.

Compound characterization methods include, for example, x-ray powder configuration analysis, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), titrated water analysis, and H-NMR analysis by solvent content. The following examples are provided for purposes of illustration and are not construed as limiting the scope of the claimed invention.

Preparation 1 Technical Grade Olanzapine Intermediary 1 In a suitable three-necked bottle the following is added: Dimethyl sulfoxide (analytical): 6 volumes Intermediate 1: 75 g N-methylpiperazine (reactive): 6 equivalents Intermediate 1 can be prepared using methods known to the person skilled in the art. For example, the preparation of intermediate 1 is taught in the '382 patent. A nitrogen spray line in the subsurface is added to remove the ammonia formed during the reaction. The reaction was heated to 120 ° C and maintained at this temperature throughout the duration of the reaction. Reactions were followed by CLAR until < 5% of intermediate 1 was left unreacted. After the reaction was complete, the mixture was allowed to cool slowly to 20 ° C (about 2 hours). The reaction mixture was then transferred to an appropriate three-necked round bottom flask and washed with water. To this solution with stirring were added 10 volumes of reactive grade methanol and the reaction was stirred at 20 ° C for 30 minutes. Three volumes of water were added slowly in about 30 minutes. The reaction water suspension was cooled to zero to 5 ° C and stirred for 30 minutes. The product was filtered and the Wet cake was washed with cooled methanol. The wet cake was dried in vacuo at 45 ° C overnight. The product was identified as olanzapine technique. Yield: 76.7%; Power: 98.1%.

Preparation 2 Polymorph Olanzapine Form II A sample of 270 g of 2-methyl-4- (4-methyl-1-piperazinyl) -lOH-thieno [2, 3-b] [1,5] benzodiazepine of technical grade was suspended in anhydrous ethyl acetate (2.7 L). The mixture was heated to 76 ° C and maintained at 76 ° C for 30 minutes. 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 process described above for preparing Form II provides a pharmaceutically refined product having potency > 97%, total related substances < 0.5% and an isolated performance of > 73%.

EXAMPLE 1 A portion of the hydroxypropyl cellulose was dissolved in purified water to form a solution by granulation. The remaining hydroxypropyl cellulose (total of 4.0% w / w of the weight of the final tablet), which was of an extra fine grade, was combined with olanzapine (1.18% w / w), lactose (79.32% w / w) and a portion of crospovidone (5% w / w) in a high shear granulator or direct. All the ingredients were screened safely prior to addition and dry mixing in the granulator. This mixture was then granulated with hydroxypropyl cellulose solution in the high or straight cutting granulator. The granulation was wet sieved using methods? standards The wet granulation was then dried in a fluid bed dryer and sieved. The material was then added to a spinning drawer mixer. The administration powders consist of microcrystalline cellulose (granular) (10% w / w), magnesium stearate (0.5% w / w), and the residue or remnant of the crospovidone was added to the sifted granulation. The mixture was mixed and compressed with the appropriate tool in the tablet compression equipment.

Sub-coating: The hydroxypropyl methylcellulose (10% w / w) was mixed with purified water to form a solution. The core tablets were divided into approximately equal sections and spray coated with the hydroxypropyl methylcellulose solution. The operation was carried out in a perforated mortar or pestle.

Coating of Core Tablets The Color Mixture Blank (hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80, and titanium dioxide) was mixed with purified water to form the coating suspension. The coated tablets were divided into approximately equal sections and spray coated with the coating suspension described above. The operation was carried out in a perforated coating crucible.

The coated tablets were lightly bathed with carnauba wax and printed with appropriate identification.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (13)

1. The use of olanzapine or a pharmaceutically acceptable salt thereof for the proportion of a medicament for the treatment of insomnia in a mammal.

2. A use according to claim 1, characterized in that the olanzapine is olanzapine of Form II having a typical x-ray diffraction pattern as follows, wherein d represents the interplanar spacing: t d t 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 t 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007

3. A use according to claim 1, characterized in that the patient in need of treatment is of advanced age.

4. A use according to claim 1, characterized in that the patient is who suffers from insomnia for prolonged periods which has occurred for more than three consecutive weeks.

5. A use according to claim 1, characterized in that the patient has been previously treated with a hypnotic agent.

6. A use, according to claim 1, characterized in that the effective amount is from about 1 mg to about 25 mg per day.

7. A use according to claim 6, characterized in that the effective amount is from about 5 mg to about 20 mg per day.

8. The use of olanzapine or a salt thereof pharmaceutically acceptable for the preparation of a medicine for the treatment of insomnia where the Treatment does not provide clinically significant alteration of the sleep architecture.

9. A use according to claim 8, characterized in that the effective amount is an amount of about 5 mg a in about 25 mg per day.

10. A use according to claim 9, characterized in that the patient is of advanced age.

11. A use according to claim 9, characterized in that the olanzapine is olanzapine of Form II which tempts a typical x-ray diffraction pattern as follows, wherein 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 10 4,141 3,973 3,7206 3.5645 3.5366 15 3.3828 3.2516 3.134 3.0848 3.0638 20 3-.0111 2.8739 2.8102 2.7217 2.6432 25 2.6007

12. Olanzapine or a pharmaceutically acceptable salt thereof, for use in the treatment of insomnia, characterized in that the treatment does not provide clinically significant alteration of the sleep architecture in the mammal in need of such treatment.

13. Olanzapine or a pharmaceutically acceptable salt thereof, for use in the treatment of insomnia.