JP2007515415A6 - How to use Gaboxadol to treat insomnia - Google Patents

Abstract

  The present invention relates to a method of treating insomnia in a human patient in need thereof by administering to said patient an effective amount of gaboxadol per day for treating insomnia.

Description

  The present invention relates to a method of using gaboxadol in the manufacture of a medicament useful for the treatment of insomnia in human patients, a method of treating insomnia in human patients and a pharmaceutical composition comprising an amount of gaboxadol effective for the treatment of insomnia.

Gaboxadol (THIP or 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol) described in Patent Document 1 and Patent Document 2 is a major agent in the treatment of general sleep disorders. It shows the possibility.

  Several studies in animals have shown the usefulness of gaboxadol as an agent to increase the total amount of non-REM sleep and prolong the duration of non-REM sleep and REM sleep episodes. Studies in healthy humans have shown that gaboxadol can increase sleep persistence and promote deep sleep without affecting REM sleep.

  The inventors for the first time recognized the usefulness of gaboxadol as an oral treatment for insomnia in human patients. Accordingly, no treatment method has been proposed for the treatment of insomnia in human patients, the effects of treatment cessation in human patients have not been studied, and the abuse or dependence of treatment in human patients has not been investigated.

  We have now shown that gaboxadol is an effective treatment for insomnia in human patients, especially primary insomnia.

Furthermore, gaboxadol shows a significant improvement in human patients suffering from impaired day time functioning, especially in the early stage patients suffering from primary insomnia. Daytime dysfunction is a disorder of sleep, or any disease, disorder or condition that causes deprivation of sleep or obstruction of sleep, such as primary insomnia, secondary insomnia (secondary insomnia) insomnia), circadian rhythm sleep disorder, sleep disorder with occasional stress, sleep apnea, narcolepsy, sleep paralysis, snoring, night wonder, night sweats, late sleep syndrome, depression, chronic tension By suffering from sleep disorders due to headache, fibromyalgia, neuropathic pain, chronic pain, alcohol abuse, arthritis.
European Patent (EP-B1) No. 0000338 European Patent (EP-B1) No. 0840601

  The object of the present invention is the effective treatment of insomnia in human patients, especially primary insomnia, and other mental disorders, following common medical conditions or induced by drugs (secondary insomnia) Is to provide.

  It is a further object of the present invention to provide an effective treatment for insomnia in human patients that does not cause recoil insomnia after cessation of treatment, particularly long term treatment.

  It is a further object of the present invention to provide an effective treatment of insomnia in human patients that does not cause the abuse or dependence of treatment, particularly long-term treatment. In this regard, research has been conducted and it has been shown that it is particularly advantageous to administer gaboxadol at bedtime, such as from 1 hour before sleeping, for example 1/2 hour before sleeping.

  Further objects of the present invention will become apparent upon reading this specification.

Gaboxador is a general formula

;

;

  Throughout this specification, “gaboxadol” refers to a base (zwitterion), a pharmaceutically acceptable salt, such as a pharmaceutically acceptable acid addition salt, hydrate, or of the base or salt. The solvates, as well as any forms of the compounds, such as anhydrides and amorphous or crystalline forms are encompassed.

(Definition)
The phrase “insomnia” refers to a disease characterized by abnormalities in the amount, quality and timeliness of sleep, circadian rhythm sleep disorder, sleep disorder due to occasional stress, primary insomnia, and other mental disorders, Includes insomnia (referred to herein as secondary insomnia) following common medical conditions or induced by drugs.

Primary insomnia is not limited to those caused by other psychiatric disorders, substance physiological effects or general medical conditions, sleep that does not show any complications in the onset or persistence of sleep, or recovery of physical fitness (Nonrestorative sleep) related. Secondary insomnia is associated with other mental disorders, abnormalities in the onset or persistence of sleep due to the substance's physiological effects or general medical conditions, or sleep without recovery of physical fitness.
The substance is, for example, an acetylcholinesterase inhibitor or a beta blocker.

  The treatment is typically given for less than 1 week (short-term treatment), 1 to 4 weeks (intermediate treatment) or over 4 weeks (long-term treatment). A special type of long-term treatment is chronic treatment.

  The phrase “elderly” means a person over the age of 65.

  The phrase “adult” means a human who is 18 to 64 years old.

  The phrase “child” means a person who is 0 to 17 years old.

  The present invention provides a drug that is effective in treating insomnia in human patients and has no serious side effects.

  In one embodiment, the invention relates to a pharmaceutical formulation comprising an amount of gaboxadol effective for the treatment of insomnia. Individual embodiments are primary insomnia and secondary insomnia. The treatment is typically given for a period of less than 1 week, 1 week to 4 weeks or more than 4 weeks. The pharmaceutical formulation is an oral dosage form such as a solid oral dosage form, typically a tablet or capsule, or a liquid oral dosage form such as a liquid. In certain embodiments, the pharmaceutical formulation is a solid oral dosage form, typically a tablet or capsule.

  In a further embodiment, gaboxadol is selected from zwitterions, typically hydrates thereof, but anhydrides are also suitable. A typical embodiment is zwitterionic monohydrate.

  In a further embodiment, gaboxadol is selected from acid addition salts, typically pharmaceutically acceptable acid addition salts. Typical embodiments include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethane-disulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid , Lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid or theophylline acetic acid addition salt Or an organic acid addition salt such as one. Another exemplary embodiment is an inorganic acid addition salt such as any one of hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid addition salt.

  Typically, gaboxadol is in the form of hydrochloride, hydrobromide or zwitterionic monohydrate.

  In a further embodiment, the gaboxadol is crystalline, such as crystalline hydrochloride, crystalline hydrobromide or crystalline zwitterionic monohydrate.

  In a further embodiment, the amount of gaboxadol in the formulation ranges from 2.5 mg to 20 mg, such as 5 mg to 15 mg. The amount of gaboxadol is calculated on the basis of the free base form. In an exemplary embodiment, the amount of gaboxadol in the formulation is 2.5 mg.

In a further exemplary embodiment, the amount of gaboxadol in the formulation is 5 mg.
In a further exemplary embodiment, the amount of gaboxadol in the formulation is 7.5 mg. In a further exemplary embodiment, the amount of gaboxadol in the formulation is 10 mg. In a further exemplary embodiment, the amount of gaboxadol in the formulation is 12.5 mg. In a further exemplary embodiment, the amount of gaboxadol in the formulation is 15 mg.

  In a further aspect, the present invention relates to a method of treating insomnia in a human patient in need thereof, comprising administering to the patient an amount of gaboxadol per day effective for treating insomnia.

Exemplary embodiments of gaboxadol are selected from acid addition salts such as pharmaceutically acceptable acid addition salts, for example
It is selected from hydrochloride or hydrobromide; zwitterionic hydrates such as zwitterionic monohydrate; or zwitterionic anhydrides.

A typical embodiment for an effective amount of gaboxadol is in the range of 2.5 mg to 20 mg, such as 5 mg to 15 mg gaboxadol per day.
Most conveniently, gaboxadol is in crystalline form.

  Exemplary embodiments of insomnia are selected from patients with primary insomnia or secondary insomnia.

  The patient may be any patient suffering from insomnia and is selected from children, adults or the elderly.

  Gaboxadol is administered as an oral dosage form, such as a solid oral dosage form, typically as a tablet or capsule, or as a liquid oral dosage form. Gaboxadol is most conveniently administered orally in unit dosage forms such as tablets or capsules containing the active ingredient in an amount of about 2.5 to about 20 mg, for example about 5 to about 15 mg. The

  Patients in need of short-term treatment are typically those suffering from circadian rhythm sleep disorders or sleep disorders due to occasional stress.

  Patients in need of medium-term, long-term or chronic treatment are typically patients with primary insomnia or secondary insomnia.

  In a further aspect, the present invention relates to a method of using gaboxadol for the manufacture of a medicament for the treatment of insomnia in human patients. In particular, the medicament comprises gaboxadol in an amount effective for the treatment of insomnia.

  In certain embodiments, the present invention relates to a method of using gaboxadol to manufacture a drug for the treatment of primary insomnia in adult or elderly human patients, the drug from about 1 hour prior to bedtime. Contains an oral dosage form comprising 5-15 mg of gaboxadol administered once a day by bedtime. Preferably, the gaboxador is from 0 to 45 minutes before bedtime, for example from about 1/2 hour to 45 minutes before bedtime, such as 0 to 30 minutes before bedtime, or 5 to 20 minutes before bedtime. It is administered by bedtime. Any one of the gaboxadol embodiments can be used. Further, the treatment may be a medium-term, long-term or chronic treatment.

  In one embodiment, gaboxadol is in the form of an acid addition salt, or zwitterionic hydrate or zwitterionic anhydride. In a further embodiment, gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from hydrochloride or hydrobromide, or in the form of zwitterionic monohydrate.

  Preferably, an effective amount ranges from 2.5 mg to 20 mg gaboxadol, calculated as a base. Preferably, gaboxadol is in a crystalline form. Further embodiments of the medicament comprise a gaboxadol effective amount of 2.5 mg to 20 mg, such as 5 mg to 15 mg, such as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg or 15 mg. A typical embodiment is a crystalline gaboxadol such as 5 mg to 15 mg gaboxadol hydrochloride.

  An exemplary embodiment is a method of using gaboxadol as a hydrochloride salt to produce a medicament comprising an effective amount of gaboxadol from 5 mg to 15 mg for treating insomnia in a human patient.

  Human patients to be treated with gaboxadol can be virtually any subject, male or female of the human population, and they can be classified as children, adults or the elderly. Any of these patient groups relate to embodiments, and thus typical embodiments are like primary or secondary insomnia in elderly human patients, containing an effective amount of gaboxadol from 2.5 mg to 20 mg. The use of gaboxadol for the manufacture of a drug for the treatment of insomnia.

  In a further embodiment, the medicament is an oral dosage form. Typically, the drug is a solid oral dosage form such as a tablet or capsule, or a liquid oral dosage form. Exemplary embodiments comprise an effective amount of gaboxadol from 2.5 mg to 20 mg for treating insomnia such as primary or secondary insomnia in a human patient, such as an elderly human patient A method of using gaboxadol to manufacture a drug in an oral dosage form.

  In a further embodiment, the treatment is a short-term treatment. In a further embodiment, the treatment is an intermediate period of treatment. In a further embodiment, the treatment is a long-term treatment. In a further embodiment, the treatment is a chronic treatment. An exemplary embodiment provides an effective amount of gaboxadol from 2.5 mg to 20 mg for long-term treatment of insomnia, such as primary or secondary insomnia, in a human patient, such as an elderly human patient. A method of using gaboxadol, for example, to produce a medicament in an oral dosage form.

  In certain embodiments, the present invention comprises administering to a patient an oral dosage form comprising 5-15 mg gaboxadol per day, wherein gaboxadol is administered from about 1 hour before bedtime to bedtime. It relates to a method of treating primary insomnia in adult or elderly human patients in need thereof. Preferably, the gaboxador is from 0 to 45 minutes before bedtime, for example from about 1/2 hour to 45 minutes before bedtime, such as 0 to 30 minutes before bedtime, or 5 to 20 minutes before bedtime. It is administered by bedtime. Any embodiment of gaboxadol can be used. Further, the treatment may be a mid-term, long-term or chronic treatment.

In a further embodiment, the invention relates to a method for improving daytime function in a human patient in need thereof comprising administering to a patient an oral dosage form comprising 5-15 mg gaboxadol per day. In a further aspect, the invention relates to a method of treating daytime dysfunction in a human patient in need thereof comprising administering to a patient an oral dosage form comprising 5-15 mg gaboxadol per day. The human patient may have a sleep disorder, or any disease, disorder or condition that causes sleep deprivation or sleep disturbances, such as primary insomnia, secondary insomnia, circadian rhythm sleep disorder, sleep disorder due to occasional stress , Sleep apnea, narcolepsy, sleep paralysis, snoring, night wonder, night sweats, delayed sleep syndrome, depression, chronic tension headache, fibromyalgia, neuropathic pain, chronic pain, alcohol abuse or arthritis You may be affected. Each of these diseases, disorders or conditions can be the subject in one or more claims, for example, in one embodiment, the invention provides the patient with 5-15 mg gaboxadol per day. The present invention relates to a method for improving daytime dysfunction in human patients suffering from primary insomnia, comprising administering an oral dosage form comprising.
In the present invention, gaboxadol can be used as a base (ie zwitterion) or as a pharmaceutically acceptable acid addition salt thereof, or as an anhydride or hydrate or solvate of the salt or base. . The salts of the compounds used in the present invention are salts formed with non-toxic organic or inorganic acids. Examples of the organic salts include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethane-disulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid. Acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and theophylline acetic acid, and Examples include salts with 8-halotheophylline, such as 8-bromo-theophylline. Examples of the inorganic salt include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid. Gaboxadol can be used as a zwitterion, for example its monohydrate.

  The acid addition salts of the present invention may be treated with an acid in an inert solvent of gaboxadol followed by precipitation by a known method, isolation and optionally recrystallization, and if necessary wet or dry milling, or It can be obtained by micronization of the crystalline product by another conventional process or by the production of particles from a solvent-emulsification process. A suitable method is described in Patent Document 1.

  Salt precipitation is typically performed in an inert solvent, such as an inert polar solvent such as an alcohol (eg, ethanol, 2-propanol and n-propanol), but with water or water and an inert solvent. Mixtures can also be used.

  In the present invention, gaboxadol is administered orally and can be present in a form suitable for the administration, for example, in the form of a tablet, capsule, powder, syrup or solution. Preferably, for the purposes of the present invention, gaboxadol is administered in the form of a solid pharmaceutical formulation, suitably as a tablet or capsule.

Methods for producing solid pharmaceutical formulations are known in the art.
Tablets are produced by mixing the active ingredient with the usual adjuvants and / or diluents and then compressing the mixture on a conventional tablet press. Examples of adjuvants or diluents include: corn starch, lactose, talc, magnesium stearate, gelatin, lactose, thickeners (gums) and the like. Other adjuvants or additives such as colorants, aromas, preservatives and the like can be used provided that they are compatible with the active ingredients.

  Suitable formulations of gaboxadol are described in WO 02/094225 filed on May 17, 2002. Any of the aspects or embodiments of this patent application are suitable embodiments of the medicaments or pharmaceutical formulations herein and are not intended to limit the invention in any way.

  The dose is 2.5-20 mg per day as described above. The dose does not vary between patient diagnosis or treatment periods.

  In a study using acute treatment in healthy subjects exposed to a phase advance model, effects on short-term treatment were confirmed. Evaluation of the effect on insomnia during the intermediate treatment period was performed using a treatment period of 4 weeks or more in patients with primary insomnia. Long-term or chronic treatment was evaluated in a 12-month safety study. The patient population includes primary insomnia patients with an age range of 18 to 65 years (adult) and 65 years and older (elderly).

Abuse and dependence were assessed using a clinical abuse liability study and patient monitoring during the gaboxadol post-drug holiday.
<Result>
Two trials in adult patients with primary insomnia and in healthy volunteers using a phase advance model showed that gaboxadol improves sleep duration when measured by polysomnograph (PSG) . Sleep duration is measured by any parameter, wakefulness after sleep onset, number of wakefulness after sleep start or total sleep time. Data from clinical trials involving a phase advance model in healthy subjects also showed that subjects felt this effect as a reduction in arousal. The effect was observed at doses as low as 5 mg per day. Furthermore, gaboxadol promoted sleep onset in studies conducted with patients with primary insomnia and subjects in a phase advance model. In these studies, the effect was also confirmed by the patient feeling onset of sleep by himself. Based on both PSG and subjective diary records, a dose of 5-15 mg of gaboxadol is necessary to achieve an effect in adults and the elderly (gaboxadol is 1/2 hour before bedtime and just before bedtime). Administered).

In addition, gaboxadol is stage 3 and 4 and induces a dose-dependent increase during slow wave sleep (SWS), which is considered the deepest stage of sleep. The effect ranged from +15 to 46% compared to placebo.
The enhancement of SWS observed in EEG was identified in spectral analysis as an increase in slow wave activity with a similar effect area as described for slow wave sleep.

<Improvement of daytime functions>
Daytime performance (used synonymously with daytime function) in adult (18-65 years) primary insomnia patients ("Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, DSM IV-TR"), 3 Weekly placebo subject parallel group, evaluated in outpatient study.
Performance was measured using a 100-point visual analogue scale (VAS) with standardized questions. Questions were asked about daytime functional ability, fatigue, activity and relaxation. Patient responses were recorded in the diary the night after each treatment night (gaboxadol was given approximately 1/2 hour before bedtime). In addition, daytime function was recorded once a week using the Sheehan disability scale (see Sheehan et al 1996, The measurement of disability. International Clinical Psychopharamcology; 11 (suppl 3), 89-95). .

  Based on the weekly averages of the questions and measures, it can be concluded that gaboxadol doses of 5, 10, and 15 mg significantly improve daytime performance. The effect is most pronounced between 2 and 3 weeks.

Claims (40)

  A method of treating insomnia in a human patient in need thereof, comprising administering to the patient an amount of gaboxadol per day effective for treating insomnia.   2. The method of claim 1, wherein gaboxadol is administered in an oral dose form.   3. A process according to any one of claims 1 or 2, wherein the gaboxadol is in the form of an acid addition salt or a zwitterionic hydrate or zwitterionic anhydride.   The gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from hydrochloride or hydrobromide, or is in the form of zwitterionic monohydrate. The method described in one.   5. The method according to any one of claims 1-4, wherein the effective amount ranges from 2.5 mg to 20 mg gaboxadol, such as 5 mg to 15 mg per day.   6. The method according to any one of claims 1 to 5, wherein the insomnia is selected from circadian rhythm sleep disorder or sleep disorder due to occasional stress.   The method according to any one of claims 1 to 6, wherein the insomnia is selected from primary or secondary insomnia.   The method according to any one of claims 1 to 7, wherein the patient is selected from the elderly or adults.   The method according to any one of claims 1 to 7, wherein the patient is selected from children.   Including administering to a patient an oral dosage form containing 5-15 mg of gaboxadol per day, with gaboxadol being administered approximately 1 hour before bedtime, for example, 1/2 hour before bedtime to bedtime Of treating primary insomnia in an adult or elderly human patient in need thereof   11. The method according to any one of claims 1 to 10, wherein the gaboxadol is a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form.   A method of improving day time functioning in a human patient in need thereof comprising administering to a patient an oral dosage form comprising 5-15 mg gaboxadol per day.   13. A method according to any one of claims 1 to 12, wherein the treatment is selected from short-term treatment or intermediate duration treatment.   13. A method according to any one of claims 1 to 12, wherein the treatment is a long term treatment.   15. The method according to any one of claims 1 to 14, wherein the gaboxadol is crystalline.   A method of using gaboxadol for the manufacture of a medicament for the treatment of insomnia in human patients, wherein the medicament is an oral dosage form.   A method of using gaboxadol to manufacture a drug that is an oral dosage form for improving daytime function in human patients.   18. The method of use according to any one of claims 16 or 17, wherein gaboxadol is in the form of an acid addition salt or a zwitterionic hydrate or a zwitterionic anhydride.   19. Any one of claims 16-18, wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from hydrochloride or hydrobromide, or in the form of zwitterionic monohydrate. Usage as described in one.   20. Use according to any one of claims 16 to 19, wherein the effective amount ranges from 2.5 mg to 20 mg gaboxadol, such as 5 mg to 15 mg per day.   The medicament comprises an effective amount of gaboxadol, and said amount is 2.5 mg to 20 mg, such as 5 mg to 15 mg, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg or 15 mg. Item 20. The method according to any one of Items 16 to 19.   The method according to any one of claims 16 to 21, wherein the insomnia is selected from circadian rhythm sleep disorder or sleep disorder due to occasional stress.   23. The method of use according to any one of claims 16 to 22, wherein the insomnia is selected from primary insomnia.   23. The method of use according to any one of claims 16 to 22, wherein insomnia is selected from secondary insomnia.   25. The method of use according to any one of claims 16 to 24, wherein the patient is selected from the elderly or adults.   25. The method of use according to any one of claims 16 to 24, wherein the patient is selected from children.   27. The method of use according to any one of claims 16 to 26, wherein the medicament is a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form.   A method of using gaboxadol to produce a drug for the treatment of primary insomnia in adult or elderly human patients, wherein the drug is about 1 hour before bedtime, e.g., about 1/2 of bedtime. The method of use, which is an oral dosage form comprising 5-15 mg of gaboxadol administered from before time to bedtime.   29. The method of use according to any one of claims 16 to 28, wherein the treatment is a short-term treatment.   29. The method of use according to any one of claims 16 to 28, wherein the treatment is an intermediate period of treatment.   29. The method of use according to any one of claims 16 to 28, wherein the treatment is a long-term treatment.   A pharmaceutical formulation comprising an amount of gaboxadol effective in treating insomnia.   33. A pharmaceutical formulation according to claim 32, wherein gaboxadol is in the form of an acid addition salt or a zwitterionic hydrate or zwitterionic anhydride.   34. Any one of claims 32-33, wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from hydrochloride or hydrobromide, or in the form of a zwitterionic monohydrate. A pharmaceutical formulation according to 1.   35. According to any one of claims 32 to 34, wherein the amount of gaboxadol is 2.5 mg to 20 mg, such as 5 mg to 15 mg, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg or 15 mg. The pharmaceutical formulation as described.   36. The pharmaceutical composition according to any one of claims 32-35, wherein the insomnia is selected from circadian rhythm sleep disorder or sleep disorder due to occasional stress.   37. A pharmaceutical formulation according to any one of claims 32-36, wherein the insomnia is selected from primary or secondary insomnia.   38. A pharmaceutical formulation according to any one of claims 32-37, wherein the formulation is in an oral dosage form.   39. A pharmaceutical formulation according to any one of claims 32-38, wherein the formulation is a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form.   40. A pharmaceutical formulation according to any one of claims 32-39, wherein the gaboxadol is in crystalline form.