CN1942185A - Treatment of impaired respiratory function with gaboxadol - Google Patents

Abstract

The present invention relates to a method for treating impaired respiratory function in a human patient suffering from sleep apnea, such as central sleep apnea or obstructive sleep apnea, comprising administering to said patient an effective amount of gaboxadol per day.

Description

Treatment of Respiratory Function Injury with Gaboxadol

field of invention

The present invention relates to the use of gaboxadol for the preparation of a medicament for the treatment of impaired respiratory function in human patients suffering from sleep apnea such as central sleep apnea or obstructive sleep apnea , and a method of treating impaired respiratory function in a human patient suffering from sleep apnea.

Background of the invention

A clear upper airway is essential for breathing, whether awake or asleep. Over the past two decades, numerous studies have demonstrated the existence of a complex syndrome characterized by abnormally low airway patency that occurs only during sleep and, consequently, abnormal breathing. If the patient has one or more of these symptoms, the breathing under the sleep state will show partial or complete apnea due to the collapse or obstruction of the upper airway.

Currently, treatment for sleep apnea typically includes upper airway surgery, intraoral mandibular correction devices, and long-term nasal continuous positive airway pressure (nCPAP). These methods are cumbersome, poorly tolerated and/or very expensive. Different drugs such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and progesterone have also been used in the treatment of these diseases, but they are not widely used in clinical practice due to their limited efficacy. The respiratory stimulants theophylline and azetazolamide, and carbonic anhydrase inhibitors have also been used in experimental studies for the treatment of central sleep apnea (CSA), but have not been used clinically.

In WO 00/51590 various mechanistic means for preventing or ameliorating sleep-related breathing disorders are disclosed. In addition GABA receptor agonists are said to be beneficial, examples mentioned are isomethylpinetine, muscimol, THIP, piperidine-4-sulfonic acid, flunitroazepam, zolpidem, arbeca baclofen, piracetam, and progamide. But some of these are not GABA receptor agonists.

Gaboxadol (4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol) in EP patent 0000338B1 and EP patent 0840601B1 has great potential for treating sleep-disordered breathing .

Description of the invention

The impaired respiratory function of human patients with sleep apnea urgently requires new and effective treatments. In particular, drug treatment of such diseases has advantages over existing invasive or non-invasive treatment methods, because many existing methods can only partially relieve symptoms and are too cumbersome for patients.

Human patients with sleep apnea often have concurrent depression, or patients with depression have a high incidence of sleep-disordered breathing. Therefore, there is reason to believe that there is an urgent need for simultaneous treatment of sleep-disordered breathing and depression in this category of patients.

Experts in the treatment of apnea generally agree that there are three different types of sleep apnea: obstructive, central, and mixed. Among the three, obstructive sleep apnea (OSA) is the most common; central sleep apnea (CSA) is relatively rare; and mixed type refers to the combination of the above two characteristics, and its treatment is the same as OSA.

Obstructive sleep apnea is characterized by repetitive pauses in breathing due to obstruction and/or collapse of the upper airway (larynx) during sleep, usually with decreased oxygen saturation followed by resumption of breathing. This is called an apneic event. Respiratory effort persisted in occasional apneic episodes. To use an analogy, OSA is like putting your hand on the suction port of a vacuum cleaner. Even though the vacuum is still trying to inhale (sustained breathing effort), your hands are still blocking all airflow (collapsed upper airway). Vacuum cleaners usually do their best in this situation, and the same goes for the human body.

Central sleep apnea is a neurological condition in which breathing effort stops during sleep, usually accompanied by a drop in blood oxygen saturation. Going back to the vacuum cleaner analogy: central apnea is like unplugging the vacuum cleaner. No power, no inhalation: If the brainstem center that controls breathing stops, there is no breathing effort and no breathing. Patients will be awakened from sleep due to the spontaneous breathing reflex, so these patients usually have little sleep.

In the context of the present invention, obstructions mentioned in the description do not include obstructions caused by foreign bodies or human excretions such as mucus. The simplest form of a partially collapsed or blocked airway is heavy, powerful snoring. More airway collapse or obstruction manifests as a type of bradypnea, ie a marked decrease in respiratory airflow with or without a decrease in blood oxygen concentration. In the most severe form of obstructive apnea, a state in which the upper airway completely collapses, it is more common for patients to maintain respiratory effort despite repeated episodes of airway obstruction. The reduction in airflow eventually leads to hypoxemia, hemodynamic changes and arousal. Furthermore, cardiovascular complications are common in obstructive sleep apnea, which is associated with increased insulin resistance, diabetes, obesity, altered lipid metabolism, and increased platelet aggregation. It is worth noting that the above symptoms and complications do not only appear in critically ill patients. Similar symptoms have been observed in some sleep apnea patients with only recurrent hypoxemia and severe snoring.

Many factors have been identified as predisposing factors for airway collapse during sleep. These include obesity, hypertrophy of upper airway tissues (especially in children), and short jaws. However, most patients with mild, moderate, or severe sleep apnea do not have these factors and are therefore considered to have essential sleep apnea. Primary sleep apnea, on the other hand, appears to be due to a central nervous mechanism, resulting from decreased nerve activity in the muscles that keep the upper airway open during sleep. These mechanisms may also be an important reason for the above factors to cause and aggravate sleep-disordered breathing.

However, the absence of apparently abnormal anatomical factors does not exclude dynamic dysfunction of the tongue and upper airway dilator muscles. This functional deficit may originate in the central nervous system, at the level of signaling to peripheral muscles or neuromuscular junctions. This control deficit appears to be particularly pronounced only during sleep, suggesting that central, peripheral, and/or neuromuscular junctions that control the upper airway are particularly susceptible to disturbance in this state. Also, and importantly, healthy upper airway elasticity will ultimately resist airway collapsing forces caused by respiratory airflow in the airway. One condition is characterized by marked chemoreflex activation resulting in high ventilatory dynamics to optimize opportunities for high inspiratory airflow. If this potential collapsing force is counteracted by abnormally low airway elasticity, the airway tends to collapse. This underlying mechanism is of particular interest in certain forms of sleep-disordered breathing, such as central apnea, periodic breathing, and/or tidal breathing (all referred to here as central sleep apnea). This form of dyspnea is characterized by periodically driven oscillatory breathing activated by a multitude of chemical reflexes.

The stability of ventilatory control depends on a number of factors in the loop of events that maintain metabolic homeostasis. This loop of events includes central controller gain (including chemoreceptor responses, brainstem respiratory center responses and excitation) and a set of plant factors that determine the resulting mixed pulmonary capillary response to changes in ventilation. Degree of change in vascular gas tone. Finally there are factors which determine the change in chemoreceptor gas tension for a given change in mixed pulmonary capillary gas tension. These factors include pulmonary circulation delays and diffusional delays involved in chemoreflex feedback. This "loop gain" or degree of feedback control includes all factors that provide the basis for periodic breath sensitivity assessment. Consistent instability occurs when the loop gain is changed by a certain value, which can occur at any step in the loop. In this sense, it can be argued that different forms of sleep apnea, including central and obstructive, may have similar primary pathogenic backgrounds. In some cases, gains may vary substantially in the absence of sleep-disordered breathing, suggesting a highly stable respiratory control system. In other central apneas, a slight change in gain can trigger illness, suggesting a tendency for the control system to oscillate. This increased tendency is more common in patients such as heart failure and in patients whose upper airway caliber is highly dependent on upper airway dilator muscle activity to maintain ventilation. In addition, sleep itself, especially REM sleep, appears to be an important modulator of loop gain in some sleep-disordered breathing patients. Therefore, treatment based on the adjustment of one or several links in the circuit system will effectively change the characteristics of the circuit and reduce or eliminate sleep-disordered breathing.

It is an object of the present invention to provide an effective treatment for human patients with impaired respiratory function of sleep apnea, in particular central sleep apnea or obstructive sleep apnea or their mixture, which reduces and/or eliminates the Some or all of the disadvantages of methods known in the art.

Another object of the present invention is to provide effective treatment, especially long-term treatment, for human patients suffering from sleep apnea.

Another object of the present invention is to provide effective treatment, especially long-term treatment, to human patients who are not abusing or dependent on the treatment.

Another object of the present invention is to provide an effective treatment for human patients suffering from sleep apnea who also suffer from depression.

Other objects of the present invention will be apparent after reading the description of the present invention.

The general formula of gaboxadol is

And throughout the specification "gaboxadol" is meant to include any form of the compound, such as the base (zwitterion), a pharmaceutically acceptable salt, such as a pharmaceutically acceptable acid addition salt, base or salt hydrates or solvates, as well as dehydrates, and amorphous or crystalline forms.

The treatment of impaired respiratory function means that the symptoms of patients with impaired respiratory function suffering from sleep apnea are improved or alleviated during, for example, 10 minutes to 10 hours of sleep.

Typically, the treatment is for a period of less than one week (short term treatment), 1 to 4 weeks (intermediate treatment) or longer than four weeks (long term treatment). A specific type of long-term treatment is chronic treatment.

The term "elderly" refers to humans 65 years of age and older.

The term "adult" refers to a human being between the ages of 18 and 64.

According to the present invention, there is provided an effective drug without significant side effects for the treatment of impaired respiratory function in human patients suffering from sleep apnea, such as central sleep apnea or obstructive sleep apnea.

In a broad aspect, the invention relates to the use of gaboxadol for the manufacture of a medicament for the treatment of a human patient with sleep apnea.

In another aspect, the present invention relates to the use of gaboxadol for the preparation of a medicament for the treatment of impaired respiratory function in human patients with sleep apnea, such as central sleep apnea or obstructive sleep apnea .

In one embodiment, the sleep apnea is a mixture of central sleep apnea and obstructive sleep apnea.

In another embodiment, the patient suffers from both depression and sleep apnea.

In another embodiment, gaboxadol increases the patient's slow wave sleep and thus improves respiratory function.

In another embodiment, gaboxadol is an acid addition salt or a zwitterionic hydrate or zwitterionic dehydrate. 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 the zwitterionic monohydrate.

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. Therefore, a typical embodiment is the use of gaboxadol in the preparation of a medicament for the treatment of human respiratory function impairment, such as the respiratory function impairment of elderly human patients. Sand Duo. The effective amount of gaboxadol from 2.5 mg to 20 mg is calculated based on the base. Preferably, gaboxadol is in crystalline form. A further embodiment of the medicament comprises an effective amount of gaboxadol from 2.5 mg to 20 mg, such as 2.5 mg to 4 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg Or 18 mg to 20 mg, eg 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg or 15 mg. A typical embodiment is 5 mg to 15 mg of crystalline gaboxadol, eg gaboxadol hydrochloride.

Human patients treated with gaboxadol can be of virtually any human species, male or female, which can be classified as children, adults or the elderly. Embodiments relate to any patient among them. Typically, human patients are selected from adult or elderly patients.

In another embodiment the treatment is short term. In another embodiment the treatment is interim treatment. In another embodiment the treatment is chronic treatment. In another embodiment the treatment is chronic treatment.

A typical embodiment is the use of gaboxadol in the preparation of a drug for long-term treatment of impaired respiratory function in human patients suffering from sleep apnea, such as central sleep apnea or obstructive sleep apnea, such as elderly patients, such as It is an oral dosage form containing 2.5mg to 20mg effective dose of gaboxadol.

In another aspect, the present invention relates to a method of treating a human patient with sleep apnea comprising daily administering to said patient an effective amount of gaboxadol. In a further aspect of the present invention, it relates to a method of treating impaired respiratory function in a human patient suffering from sleep apnea, such as central sleep apnea or obstructive sleep apnea, comprising daily administering to said patient an effective amount of gaboxadol. Typically, effective amounts in oral dosage forms include 2.5 mg to 20 mg per day.

The timing of administration of gaboxadol according to the invention depends on the formulation and/or route of administration. Typically, gaboxadol is administered as a long-term treatment regimen in most cases, thereby achieving pharmacokinetic steady-state conditions. It can be administered orally or parenterally immediately according to a specific sleep time, for example, 10 minutes to 3 hours before the onset of sleep. Therefore, when using gaboxadol to prepare a drug, or when administering gaboxadol, the typical embodiment is oral dosage administration or oral administration, wherein a specific sleep time of 5 minutes to 5 hours before the onset of sleep, for example, at Gaboxadol was administered immediately 10 minutes to 3 hours before sleep onset.

In another aspect, the present invention relates to the use of gaboxadol for the preparation of a medicament for the treatment of human patients with sleep apnea, the medicament comprising gaboxadol in an effective amount of 2.5 mg to 20 mg, said dose being given in a single sleep cycle The substantial portion of is valid.

In another aspect, the present invention relates to the use of gaboxadol for the preparation of a medicament for the treatment of human patients suffering from sleep apnea, such as central sleep apnea or obstructive sleep apnea, the medicament comprising 2.5 mg to 20 mg of For gaboxadol, the amount is effective during the main part of a single sleep cycle.

In yet another aspect, the present invention relates to a method for treating impaired respiratory function in a human patient suffering from sleep apnea, such as central sleep apnea or obstructive sleep apnea, comprising administering to said patient an effective amount of 2.5 mg to 20 mg daily Gaboxadol, said amount is effective for the major part of a single sleep cycle.

In further embodiments, the major portion is 40% or more, 50% or more, 60% or more, 70% or more, such as 80% or more.

In further embodiments, a single sleep cycle is one to eight hours. Typically, a single sleep cycle is from one to four hours, or one to six hours, such as 1, 2, 3, 4, 5, 6, 7 or 8 hours.

In a further embodiment, the amount of gaboxadol is released from a composition for controlled release, such as an extended release composition.

In a further embodiment, 50% to 100% of the amount of gaboxadol is released within three hours of administration.

In a further embodiment, 80% to 100% of the amount of gaboxadol is released within five hours of administration.

According to the present invention, gaboxadol may be used in the form of a base (zwitterion) or a pharmaceutically acceptable acid addition salt thereof or an anhydrate or a hydrate and a solvate of such a salt or base. The salts of the compounds used in the present invention are salts formed with nontoxic organic or inorganic acids. Examples of such organic salts are salts with the following acids: maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, Acetic acid, propionic acid, tartaric acid, salicylic acid, citric 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 acids, and 8-halophyllines such as 8-bromophylline. Examples of such inorganic salts are: hydrochlorides, hydrobromides, sulfates, sulfamates, phosphates and nitrates. Gaboxadol is also available in zwitterionic form, for example in the form of its monohydrate.

The preparation of the acid addition salts of the present invention may comprise treatment of gaboxadol with an acid in an inert solvent, subsequent precipitation, isolation and optionally recrystallization by known methods and, if desired, by wet or dry grinding methods or other convenient Methods The crystalline product was micronized, or granules were prepared by solvent emulsification process. Suitable methods are described in EP patent 0000338.

Precipitation of salts is typically performed in an inert solvent such as an inert polar solvent such as an alcohol (eg, ethanol, 2-propanol and n-propanol), although water or a mixture of water and an inert solvent may also be used.

According to the invention, gaboxadol is administered orally, and it may be prepared in any suitable form for such administration. For example in the form of tablets, capsules, powders, syrups or solutions. Typically, gaboxadol is administered in the form of solid pharmaceutical entities, preferably tablets or capsules, according to the purposes of the present invention.

Methods of preparing solid pharmaceutical formulations are well known in the art. Tablets may thus be prepared by mixing the active ingredient with customary adjuvants and/or diluents and subsequently compressing the mixture in a suitable tablet machine. Examples of adjuvants or diluents include: corn starch, lactose, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives compatible with the active ingredients, such as colorants, fragrances, preservatives, etc., can be used.

Suitable formulations of gaboxadol are described in WO 02/094225, filed 17 May 2002. No aspect or specific embodiment in this patent application is intended to limit the invention in any way, it is a suitable embodiment of the medicament or pharmaceutical composition herein.

Experimental procedure

Gaboxadol was administered orally at a dose of 2.5 mg to 20 mg to human patients with sleep apnea at bedtime.

Claims (24)

1. gaboxadol is used for the treatment of the purposes aspect the human patients medicine of sleep apnea in preparation.

2. gaboxadol is used for the treatment of for example purposes aspect the respiratory function damage medicine of the human patients of centric sleep apnea or obstructive sleep apnea of sleep apnea in preparation.

3. claim 1 or 2 purposes, wherein sleep apnea is a centric sleep apnea.

4. claim 1 or 2 purposes, wherein sleep apnea is an obstructive sleep apnea.

5. claim 1 or 2 purposes, wherein sleep apnea is the mixing of centric sleep apnea and obstructive sleep apnea.

6. each purposes among the claim 1-5, wherein gaboxadol has increased patient's S sleep and has therefore improved respiratory function.

7. each purposes among the claim 1-6, wherein the patient suffers from sleep apnea and depression simultaneously.

8. each purposes among the claim 1-7, wherein gaboxadol is the form of acid-addition salts, for example hydrochlorate or hydrobromate, or amphion hydrate, for example amphion monohydrate or amphion dehydrate.

9. each purposes among the claim 1-8, wherein this medicine is a peroral dosage form.

10. the purposes of claim 9, wherein this medicine is for example tablet or a capsule of solid oral dosage form, or liquid oral dosage form.

11. each purposes among the claim 9-10, wherein this medicine contains the gaboxadol of 2.5mg to 20mg, for example 2.5mg to 4mg, 4mg to 6mg, 6mg to 8mg, 8mg to 10mg, 10mg to 12mg, 12mg to 14mg, 14mg to 16mg, 16mg to 18mg or 18mg to 20mg typically are 5mg to 15mg.

12. each purposes among the claim 1-11, wherein human patients is selected from old people or adult.

13. each purposes among the claim 1-12, wherein said treatment is a short term therapy.

14. each purposes among the claim 1-12, wherein said treatment is an intermediate period treatment.

15. each purposes among the claim 1-12, wherein said treatment is long-term treatment.

16. each purposes among the claim 1-15, wherein said gaboxadol is crystalline.

17. each purposes among the claim 1-16, wherein this medicine contains the gaboxadol of 2.5mg to 20mg, for example contains 5mg to 15mg gaboxadol, and described amount is effective in the major part of single sleep period.

18. the purposes of claim 17, wherein said major part are 50% or more, for example 80% or more.

19. each purposes among the claim 17-18, wherein said single sleep period is one to eight hours.

20. each purposes among the claim 17-19, wherein the amount of gaboxadol discharges from the compositions that is used for sustained release and for example prolongs release.

21. the purposes of claim 20, wherein the gaboxadol of 50% to 100% amount discharged in the three hour time of administration.

22. the purposes of claim 20, wherein the gaboxadol of 80% to 100% amount discharged in the five hour time of administration.

23. treatment suffers from for example method of the respiratory function damage of the human patients of centric sleep apnea or obstructive sleep apnea of sleep apnea, comprises the gaboxadol that gives described patient's effective dose every day.

24. treatment suffers from for example method of the human patients of centric sleep apnea or obstructive sleep apnea of sleep apnea, comprises the gaboxadol that gives described patient's effective dose every day.