KR20070010136A - Treatment of Impaired Respiratory Function Using Gadosadol - 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 centralized sleep apnea or obstructive sleep apnea, comprising administering to a patient an effective amount of agaboxol per day.

Description

TREATMENT OF IMPAIRED RESPIRATORY FUNCTION WITH GABOXADOL}

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

The basic requirement for breathing during waking and during sleep is the open upper respiratory tract. Many studies over the last two decades have enabled the identification of complex symptoms characterized by insufficiently low airway openness (and therefore breathing) that occur only during sleep. In patients suffering from one or more of many of these symptoms, breathing during sleep results in partial or complete disturbance following collapse or obstruction of the upper respiratory tract.

Basic treatment forms currently applied to sleep apnea include surgery of the upper respiratory tract, intraoral mandibular protrusions, and long-term treatment of nasal continuous positive airway pressure (nCPAP). These methods of treatment are cumbersome, unbearable and / or expensive. Various forms of pharmaceutical treatment have been used, such as tricyclic antidepressants, selective serotonin reuptake inhibitors and progesterone, but have not been widely used for clinical use because of limited efficacy. Respiratory stimulants, thiophylline, azetazolamide, and carbonic anhydrase inhibitors have been used experimentally in various forms of central sleep apnea (CSA), but have not been applied in conventional clinical practice.

WO 00/51590 discloses various mechanical approaches to prevent or ameliorate sleep related breathing disorders. Among others, GABA receptor agonists have also been found to be useful, for example, isogubacin, musimol, THIP, piperidine-4-sulfonic acid, flunitrazepam, zolpidem, abecarnyl, baclofen , Piracetam, and progabide. But many of these are not even GABA receptor agonists.

Gaboxosadols (4,5,6,7-tetrahydroisoxazolo (5,4- c ) pyridin-3-ol) described in EP Patent 0000338 B1 and EP Patent 0840601 B1 have shown significant efficacy in treating general sleep disorders. will be.

There is a need for new effective treatments for impaired respiratory function in human patients suffering from sleep apnea. In particular, the pharmaceutical treatment of such disorders will provide obvious advantages over the currently in use, many of which are only insufficient relief and some of which are cumbersome, disturbing or non-disruptive methods.

Human patients suffering from sleep apnea may suffer from depression at the same time, or a person suffering from depression may actually lead to sleep apnea. Therefore, there seems to be a special need for the treatment of these groups of patients who suffer simultaneously from sleep apnea and depression.

Apnea specialists generally agree that there are three different types of sleep apnea; Obturity, centrality and mixing. Of these three, obstructive sleep apnea (OSA) is the most common, central sleep apnea (CSA) is rare, and mixed sleep apnea is a combination of the two and the treatment is the same as OSA.

Obstructive sleep apnea is characterized by repeated resting of sleep during sleep by obstruction and / or collapse of the upper respiratory tract (throat), usually accompanied by a decrease in blood oxygen saturation and followed by waking for breathing. This is called apnea development. Efforts to breathe during the apnea episode continue. It may be helpful to give a parable; OSA is like clogging a vacuum inlet with your hand. Although the vacuum cleaner continues to inhale (continuous effort to breathe), the hand is blocking all the air through it (the upper airway collapse). Vacuum cleaners are usually a mess at this point, and the human body is the same.

Central sleep apnea is defined as a neurological condition that causes interruption of all breathing efforts during sleep, which is usually accompanied by a decrease in blood oxygen saturation. Let's take a vacuum cleaner again; Central sleep apnea is like unplugging a vacuum cleaner. No power, no inhalation: When the brainstem center that controls breathing stops, there is no breathing effort and no breathing. Such a person wakes up from sleep by automatic respiration, and consequently gets very little sleep.

Closure in the context of the present invention does not include closure by foreign substances or substances secreted by the body, such as mucus. In the simplest form, partial airway collapse or obstruction is manifested by severe and intense snoring. More pronounced airway collapse or obstruction results in so-called hypopopnea, a condition in which airflow is significantly reduced during respiration with or without hypoxia. The most serious form is obstructive apnea, which refers to the complete collapse of the upper respiratory tract. The more severe form of this symptom is accompanied by repeated episodes of closed airflow, during which the patient continues to breathe against the blocked airways. Reduced airflow eventually leads to hypoxia, changes in hemodynamics, and awakening from sleep. Cardiovascular side effects are also common in obstructive sleep apnea. Obstructive sleep apnea is accompanied by increased insulin resistance, diabetes, obesity, changes in fat metabolism and increased platelet aggregation. It is important that these aforementioned syndromes and side effects are not limited to severe cases. It can also be observed in partial sleep apnea cases, characterized by frequent respiratory depression or even severe snoring.

Various factors of airway collapse predisposition have been identified. Among these are obesity, high nutritional upper respiratory tract tissue (particularly in children) and short jaws. However, many of the mild, moderate or severe sleep apnea patients do not exhibit any of these factors and may therefore be called intrinsic sleep apnea cases. Essential sleep apnea appears to be caused by central nervous mechanisms associated with a decrease in nerve activity for the upper airway muscles responsible for maintaining the upper airway opening during sleep. Such mechanisms may also be important for causing or worsening sleep disturbed breathing in cases with predisposition factors as described above.

However, the absence of distinct anatomical factors in question does not exclude the dynamic operating error of the tongue and upper airway dilatation muscle tissue. Such functional defects may originate from the central nervous system, either at the signal transduction to peripheral muscles, or at the level of neuromuscular junctions. These regulatory defects appear to be particularly pronounced only during sleep, indicating that central, peripheral and / or neuromuscular regulation of the upper airways is particularly susceptible to this condition. More importantly, the upper airway tension will ultimately counteract the airway collapse caused by the suction flow of air into the airways. Characterized by enhanced chemical reflex activation and thus high ventilation impulses to optimize high suction flow opportunities. If this potential deprivation meets the opposition caused by inappropriately low airway tension, the prayer will be deprived. This interim mechanism is particularly plausible in certain forms of sleep disorder breathing called central apnea, periodic breathing and / or Cheyne-Stokes breathing, all of which are referred to herein as central sleep apnea. This type of respiratory disorder is characterized by a pattern of breathing vibrations that occurs periodically by significant chemical reflex activity.

Ventilatory control stability depends on various factors related to the chain of events responsible for maintaining metabolic homeostasis. This ring is a set of plant factors that determine how much the gas tension of the mixed lung capillaries will change for a given change in central control acquisition (including chemoreceptor reactivity, brain stem respiratory central reactivity and excitability) and ventilation. It includes. Finally, there are factors that determine the change in gas tension at the chemoreceptor for a given change in lung capillary gas tension. These factors include pulmonary circulation delay and diffusion delay associated with the chemical reflection feedback process. The degree of feedback control or 'loop gain', which includes all these factors, provides an object for periodic breathability assessment. If the ring gain changes by a single value, instability can occur and this change can occur at any stage involved in the ring. In this sense, it can be seen that different forms of sleep apnea, including central and obstructive forms, may have a similar underlying pathological background. In some cases, the benefit may vary substantially without the occurrence of sleep disturbance breathing, meaning a very stable breath control system. In other cases, central apnea can occur after a slightly changed gain, suggesting a control system that is prone to vibration. Such increased ease may be more pronounced in patients with, for example, incomplete upper airway openings that are highly dependent on heart failure and in particular, upper airway dilatation muscle activity for maintaining ventilation. In addition, sleep itself, especially REM sleep, appears to be a particularly important transducer of loop benefit in certain patients with sleep disturbed breathing. According to this reasoning, treatment that transforms one or many of the elements contained within the ring system may effectively modify the properties of the ring and reduce or eliminate sleep disturbed breathing.

It is an object of the present invention to provide an effective effect of impaired respiratory function in human patients suffering from sleep apnea, in particular central sleep apnea or obstructive sleep apnea, or combinations thereof, which reduce and / or eliminate some or all of the problems of methods known in the art. Provide treatment.

It is a further object of the present invention to provide an effective treatment, in particular long term treatment, of a human patient without causing abuse or dependence of the treatment.

It is a further object of the present invention to provide an effective treatment, in particular long term treatment, of human patients suffering from sleep apnea.

It is a further object of the present invention to provide an effective treatment for human patients suffering from sleep apnea and depression simultaneously.

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

Gaboxadol has the following general formula, and throughout the specification, 'gaboxadol' refers to a base (zwitterion), a pharmaceutically acceptable salt (eg, a pharmaceutically acceptable acid addition salt), a hydrate or solvate of a base or salt And also any form of compounds such as anhydrides and also amorphous or crystalline forms.

Treatment of impaired respiratory function is intended to improve or alleviate the respiratory function of patients suffering from sleep apnea during sleep periods such as 10 minutes to 10 hours.

Treatment is generally carried out for less than 1 week (short term treatment), 1 to 4 weeks (medium term treatment) or for more than 4 weeks (long term treatment). A special form of long-term treatment is chronic treatment.

The term 'elderly' means a human 65 years of age or older.

The term 'adult' means a human being between 18 and 64 years old.

In the present invention, there is provided an effective medicament for treating impaired respiratory function of a human patient suffering from sleep apnea, such as central sleep apnea or obstructive sleep apnea, with no serious side effects.

In a broad aspect, the present invention relates to the use of gaboxador for the manufacture of a medicament for the treatment of sleep apnea in human patients.

In another aspect, the present invention relates to the use of a medicinal medicated saga for the treatment of impaired respiratory function in human patients suffering from sleep apnea, such as central sleep apnea or obstructive sleep apnea.

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

In a further embodiment, the human patient is suffering from depression and sleep apnea at the same time.

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

In a further embodiment, the pseudoboxdol is in the form of an acid addition salt or zwitter ion hydrate, or zwitter ion anhydride. In a further embodiment, the pseudoboxdol is in the form of a pharmaceutically acceptable acid addition salt selected from hydrochloric acid, or hydrobromide, or in the form of zwitter ion monohydrate.

In further embodiments, the medicament is in oral dosage form. Usually a medicament is a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form. Thus, a common embodiment is the use of gaxadol for the manufacture of a medicament in oral dosage form containing an effective amount of 2.5 mg to 20 mg agaxador for the treatment of impaired respiratory function in human patients such as elderly human patients. Effective amounts of gadosadol in the range of 2.5 mg to 20 mg are calculated based on the base. Preferably, the temporary copystone is in crystalline form. Further embodiments of the medicament may be 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. effective doses of gavoxadol of mg, 16-18 mg, or 18 mg to 20 mg, ie 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg. Typical embodiments are from 5 mg to 15 mg of crystalline gavoxadol, such as gavoxadol hydrochloric acid.

Human patients treated with agaxolide are, in fact, any subject of the human population, male or female, which can be divided into children, adults, or the elderly. All of these patient groups are involved in the implementation. Usually, human patients are selected from adult or elderly patients.

In further embodiments, the treatment is a short term treatment. In further embodiments, the treatment is intermediate treatment. In further embodiments, the treatment is long term treatment. In further embodiments, the treatment is chronic treatment.

Ordinary embodiments include oral administration containing an effective amount of 2.5 mg to 20 mg agaxador for long-term treatment of impaired respiratory function in human patients, such as elderly human patients suffering from sleep apnea, such as centralized sleep apnea or obstructive sleep apnea. It is the use of the provisional medicinal adolescents for the manufacture of a pharmaceutical.

In a further aspect, the present invention relates to a method of treating sleep apnea in a human patient comprising administering to the human patient an effective amount of gavoxadol per day. In a further 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 a human patient an effective amount of agaxador per day. do. Usually, an effective amount in an oral dosage form contains 2.5 mg to 20 mg agaxadorol per day.

The timing of the administration of gaboxador according to the invention will depend on the formulation used and / or the route of administration. Usually, in most cases, the administration of agaxdol is given according to a long-term treatment plan, thus reaching pharmacokinetic steady state conditions. Medicines for oral or parenteral administration may also be supplied in a state closely related to a particular sleep period, such as, for example, 10 minutes to 3 hours before the onset of sleep. Thus, when using gaxadol for the manufacture of a medicament or when administering gaboxosa, a common embodiment is oral medicine or oral administration, where gaboxosa is 5 minutes to the onset of sleep, such as 10 minutes to 3 hours before the onset of sleep. Supplied closely related to specific sleep periods before 5 hours.

In a further aspect, the present invention relates to the use of gabxadol for the manufacture of a medicament comprising an amount of 2.5 mg to 20 mg of gabxadol for the treatment of sleep apnea of a human patient, wherein the amount is effective for a significant portion of a single sleep period. will be.

In a further aspect, the present invention relates to a medicament for the manufacture of a medicament containing a dose of 2.5 mg to 20 mg agaxador for the treatment of impaired respiratory function in human patients suffering from sleep apnea, such as central sleep apnea or obstructive sleep apnea It relates to stone use, wherein the amount is effective for a substantial part of a single sleep period.

In a further aspect, the present invention also 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, which provides an effective amount of 2.5 mg to 20 mg avaloxol per day. Administering to said patient, wherein said amount is effective for a substantial portion of a single sleep period.

In further embodiments, a substantial portion is such as at least 40%, at least 50%, at least 60%, at least 70%, at least 80%.

In further embodiments, the single sleep period is 1 to 8 hours. Usually, a single sleep period is such as 1 to 4 hours, or 1 to 6 hours, ie 1, 2, 3, 4, 5, 6, 7, or 8 hours.

In further embodiments the amount of provisional xanthol is released from the composition for controlled release, such as a sustained release composition.

In a further embodiment, 50-100% of the amount of avaloxadol is released within a period of 3 hours from administration.

In a further embodiment, an amount of 80-100% of the pseudoboxdol is released within a period of 5 hours from administration.

In the present invention, the temporary copydol can be used as a base (ie, zwitterion), or a pharmaceutically acceptable acid addition salt thereof, or an anhydride or hydrate or solvate of such base or salt. Salts of the compounds used in the present invention are salts formed from nontoxic organic or inorganic acids. Examples of such organic salts are maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, manic acid Delic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-amino-benzoic acid, glutamic acid, benzene sulfonic acid and theophylline acetic acid, as well as 8-halophylline, for example 8 Salts formed with bromo-theophylline. Examples of such inorganic salts are salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid. The temporary copy stone can be used as a zwitter ion, for example, its monohydrate.

The acid addition salts according to the invention are subjected to treatment of gaboxanes with an acid in an inert solvent, followed by precipitation, isolation and optionally recrystallization by known methods and, if necessary, by wet or dry milling or other convenient processes. By micronization of the crystalline product, or by particle preparation from a solvent-emulsification process. Suitable methods are described in EP patent 0000338.

Precipitation of the salt is usually carried out in an inert solvent, for example an inert polar solvent such as alcohol (eg ethanol, 2-propanol and n-propanol), but water or a mixture of water and an inert solvent can also be used. .

According to the present invention, gaboxosa must be administered orally, which can be in any suitable form for such administration, for example in the form of tablets, capsules, powders, syrups or solutions. Preferably and in accordance with the purpose of the present invention, gabxadol is administered in the form of a solid pharmaceutical object, suitably as a tablet or capsule.

Methods of preparing solid pharmaceutical formulations are well known in the art. Thus, tablets can be prepared by mixing the active ingredient with a common adjuvant and / or diluent and then compressing the mixture with a conventional tablet press. Examples of adjuvants or diluents include: corn starch, lactose, talc, magnesium stearate, gelatin, lactose, rubber, and the like. Any other adjuvant or additives, such as colorants, fragrances, preservatives, etc., may also be used, provided they are miscible with the active ingredient.

Suitable formulations of gabxadol are described in WO 02/094225 (filed 2002.5.17). Without limiting the invention in any way, it is intended that any of the aspects or embodiments of the patent application is a suitable embodiment of the pharmaceutical or pharmaceutical composition herein.

Experiment method

Gaboxosadol at a dose of 2.5 mg to 20 mg in human patients suffering from sleep apnea. Administered before going to bed.

Claims (24)

Use of Gaboxadol for the manufacture of a medicament for the treatment of sleep apnea in human patients. Use of Gaboxadol for the manufacture 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. Use according to claim 1 or 2, wherein the sleep apnea is central sleep apnea. Use according to claim 1 or 2, wherein the sleep apnea is a blend of obstructive sleep apnea. Use according to claim 1 or 2, wherein the sleep apnea is a mixture of central sleep apnea and obstructive sleep apnea. The use according to any one of claims 1 to 5, wherein the avaloxide increases the slow wave sleep of the patient and thus improves respiratory function. The use according to any one of claims 1 to 6, wherein the human patient suffers from sleep apnea and depression simultaneously. 8. Use according to any one of the preceding claims, wherein the carboxylatedol is in the form of an acid addition salt such as hydrochloric acid or hydrobromide, or a zwitter ion hydrate or zwitter ion anhydride such as zwitter ion monohydrate. The use according to any one of claims 1 to 8, wherein the medicament is in an oral dosage form. Use according to claim 9, wherein the medicament is a solid oral dosage form such as a tablet or capsule or a liquid oral dosage form. The method according to claim 9 or 10, wherein the medicament is 2.5 mg to 20 mg, for example 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, Use comprising 12 mg to 14 mg, 14 mg to 16 mg, 16 to 18 mg, or 18 mg to 20 mg, generally 5 mg to 15 mg of gaboxosadol. Use according to any of the preceding claims, wherein the human patient is selected from elderly or adults. Use according to any one of claims 1 to 12, wherein the treatment is a short term treatment. Use according to any one of claims 1 to 12, wherein said treatment is an intermediate treatment. Use according to any one of claims 1 to 12, wherein the treatment is a long term treatment. The use according to any one of claims 1 to 15, wherein the provisional doldol is crystalline. 17. The use according to any one of claims 1 to 16, wherein the medicament contains an amount of 2.5 mg to 20 mg agaxador, such as 5 mg to 15 mg, said amount being effective for a substantial part of a single sleep period. Use according to claim 17, wherein said substantial portion is at least 50%, for example at least 80%. Use according to claim 17 or 18, wherein said single sleep period is 1 to 8 hours. 20. The use according to any one of claims 17 to 19, wherein the amount of provisional axdol is released from the composition for controlled release, such as sustained release. 21. The use according to claim 20, wherein the amount 50 to 100% of the temporary axitol is released within a period of 3 hours from administration. 21. The use according to claim 20, wherein an amount of 80 to 100% of the pseudoboxol is released within a period of 5 hours from administration. 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 administering to a patient an effective amount of agaboxol per day. A method of treating sleep apnea, such as centralized sleep apnea or obstructive sleep apnea in a human patient, comprising administering an effective amount of agaboxol per day to the following patient.