WO2000006163A1

WO2000006163A1 - Improved method for treatment of sleep-related respiratory disorders

Info

Publication number: WO2000006163A1
Application number: PCT/US1999/013427
Authority: WO
Inventors: Perry B. Molinoff; Geoffrey C. Dunbar
Original assignee: Bristol-Myers Squibb Company
Priority date: 1998-07-30
Filing date: 1999-06-15
Publication date: 2000-02-10
Also published as: AU4683499A

Abstract

An improved method of treatment for sleep-related respiratory disorders which provides a more robust respiratory stimulation activity with lessened side-effects to a patient suffering from a disorder such as sleep apnea. The method comprises the administration of effective doses of certain azapirones, such as buspirone, given in a manner that suppresses formation of the 1-(2-pyrimidinyl)piperazine metabolite.

Description

IMPROVED METHOD FOR TREATMENT OF SLEEP-RELATED RESPIRATORY DISORDERS

Cross Reference to Related Application

This application claims priority from provisional application U.S. serial number 60/095,007 filed July 30, 1998.

Background of the Invention

The present invention relates to an improved method for treating sleep-related respiratory disorder in adults and young children. Administration of certain azapirones in such a manner that formation of the 1- (2-pyrimidinyl)piperazine metabolite (1-PP) is minimized, provides a more robust therapeutic effect with reduced side-effect liability. The preferred embodiment also provides more reliably reproductible dose levels of the azapirone in the intended subjects.

Certain azapirone compounds and their pharmaceutically acceptable salts have been described as being useful in treating sleep apnea. These compounds have general structure (I) and are identified below.

(I)

Compound Reference

ipsapirone coxv EP 129,128

tandospirone U.S. 4.507,303

zalospirone 88,

These particular azapirones containing the pyrimidinylpiperazine moiety as an integral part of their molecular structure give rise to 1-(2- pyrimidinyl)piperazine (1-PP) as their major metabolite. This metabolite is seen in greatest abundance following oral administration. The most studied and well-known member of this compound class is buspirone, an important antianxiety agent first approved for use in anxious patients in 1986.

It has been reported that buspirone has a stimulating effect on respiration. Garner, et al. disclosed buspirone's stimulation of respiration in a study with cats reported in Am. Rev. Respir. Pis., 137:4 (1989), pp. 946-950. Rapaport, et al. reported similar findings in humans in Fed. Am. Soc. Exp. Biol., J2:5 Abstract 7030 (1988). These studies indicated the absence of compromised respiration usually observed with high doses of calmative medications.

Dement, et al. disclosed the use of certain azapirones to treat sleep apnea in EP 442.424A, and the specific use of buspirone for sleep apnea in EP 442.423A. Administration of the azapirone was by parenteral, oral or rectal routes with the oral route being preferred.

Sleep apneas comprise a spectrum of related disorders with varying severity and morbidity. Sleep apneas have been usually classified as being an obstructive, central, or mixed apnea, depending on the presence or absence of respiratory efforts during the periods in which airflow has ceased. Obstructive and mixed apneas occur with greatest frequency with the most familiar being obstructive sleep apnea syndrome in which sporadic recurring collapse of the patient's upper airway occurs during sleep. If the collapse is complete, there is no air exchange at the nose and mouth and breathing is interrupted. The usual result is a partial arousal from sleep and a return to normal breathing. The patient in most instances has no knowledge or memory of these apnea episodes but finds himself constantly suffering from fatigue and daytime sleepiness for no apparent reason. These recurrent apnea episodes with resultant hypoxemia and fragmented sleep can have serious neurologic and cardiac consequences. In recent years there has been a growing awareness of the seriousness of the sleep apnea problem due to its wide occurrence and the lack of a recognized effective treatment.

Surgical and mechanical interventions as well as oxygen administration have been employed as treatments. None of these are very suitable. Treatment of sleep apneas by pharmacological intervention has also had little success. Respiratory stimulants, theophylline, antidepressants and progestational agents have been used to treat sleep apneas but have not been found to be very effective.

Sleep apneic conditions are also implicated in other disorders involving vulnerability to cardiorespiratory collapse during sleep. It is hypothesized that recurrent apnea might be the cause of sudden infant death syndrome (SIDS) and apparent life-threatening events (ALTE) in infants. (See: Pediatric Therapy 3rd Edition. Eichenwald and Stroder Eds., osby, 1993. pp. 1136-1139.) These serious disorders appear to involve abnormal cardiorespiratory control in which CNS activity and the state of consciousness play modulating roles. While the precise role of apneic episodes or respiratory pauses in the pathogenesis of SIDS is not clear, prolonged apnea and cyanosis during sleep have been observed in infants whose subsequent deaths were presumed due to SIDSr

Although the usefulness of azapirones. particularly buspirone, in treating patients with sleep apnea has been previously disclosed, the present improved method for using azapirones to treat sleep apneas, SIDS and related conditions is novel and is not suggested by the prior art. Summary of the Invention

The method of the present invention is intended for the treatment of patients suffering from sleep-related respiratory disorders such as sleep apnea, SIDS and ALTE. The method essentially involves administration of an azapirone; buspirone is preferred, or a pharmacologically acceptable acid addition salt thereof; to a patient in need of such treatment. For use in the instant method the azapirone is administered in a manner that achieves high blood levels of the azapirone and suppresses formation of the major metabolite, 1-(2-pyrimidinyl)piperazine (1-PP).

Detailed Description of the Invention

The invention improves upon the discovery that buspirone administration is an effective treatment in preventing or reducing the incidence of sleep apneas. In the context of this invention, sleep apneas comprise all the sub-categories such as those caused by upper airway obstruction; those who origins arise in the central nervous system; and those of a mixed type with contribution from both components, This invention is also intended for use in other disorders involving vulnerability to cardiorespiratory collapse during sleep. In particular, the method is directed at infants at risk of ALTE and/or SIDS. It should be appreciated that no established therapy for these disorders exists. As an example, treatment modalities for sleep apnea's most common subtype, chronic obstructive sleep apnea, have included weight loss, surgical removal of tissue that may cause obstruction, avoidance of all sedatives, mechanical interventions and oxygen masks. None of these measures has been effective in any consistent manner. In this, as well as other sleep apneas, pharmacologic intervention has been used but effectiveness has not been established. Respiratory stimulants, antidepressants, theophylline and various progestational agents have been tried but not found to be very effective.

A review (Guilleminault, "Obstructive Sleep Apnea Syndrome," in Psychiatric Clinics of North America, Vol. 10, No.4, pp. 607-618 (1987)) reveals a widespread occurrence as well as a range of serious medical sequelae. Also in the context of this invention is the use of other azapirones in addition to buspirone, in treating sleep apneas and other sleep-related respiratory disorders.

The method of the present invention then is intended to encompass the use of related azapirone compounds of general structure (I) identified below.

(I)

These particular azapirones containing the pyrimidinylpiperazine moiety as an integral part of their molecular structure give rise to 1-(2- pyrimidinyl)piperazine (1-PP) as their major metabolite. This metabolite is seen in greatest abundance following oral administration. The most studied and well-known member of this compound class is buspirone.

An objective of this invention is to provide an improved method for treating sleep-related respiratory disorders such as sleep apnea, ALTE, and SIDS with azapirones. The preferred azapirone for use in this improved method of treatment is buspirone, Clinical pharmacologic studies with buspirone have shown that it is extensively metabolized, particularly following oral administration of standard formulations of buspirone.

Pharmacologic studies have indicated that 1-PP, the major metabolite of the selected pyrimidinylpiperazinyl azapirones of this improved method of treatment invention, can antagonize other therapeutic effects, e.g. anxiolytic and antidepressant activities, seen for these compounds. In addition, the incidence of undesired side-effects occurring in azapirone treated subjects appears to correlate with blood levels of 1-PP. In effect, a method of azapirone administration that would significantly increase the unchanged drug-to-metabolite ratio would represent a useful improvement for treatment of sleep-related respiratory disorders.

The improved method of this invention utilizes methods of administration for the azapirone component of the treatment therapy that will minimize production of the 1-PP metabolite thereby increasing the blood levels of the parent drug. The ratio of unchanged azapirone to 1-PP is significantly higher when the azapirone is administered either orally in an extended release formulation (Nickiasson, U.S. 5,431,922); transdermally; or transmucosally. Transmucosal administration involves drug delivery via the oral mucosa (buccal, sublingual absorption), nasal mucosa (transnasal absorption), vaginal and rectal mucosa.

Drug delivery formulations comprise the selected azapirones formulated into extended release oral formulations such -as those described in U.S. 5,431,922; transdermal drug delivery devices such as skin patches, creams, ointments, and the like; oral mucosal formulations such as buccal and sublingual dosage forms (e.g. lozenges, patches, fast-dissolving tablets, chewing gum, and the like); transnasal formulations such as aerosol sprays, nose drops and nasal ointments; vaginal and rectal formulations such as suppositories, creams, ointments and the like.

Preferred routes of administration for the azapirone are transdermal and transmucosal. The most preferred route is transdermal. Transdermal drug delivery devices suitable for delivery of the azapirone are described in U.S. 5,633,009 to Kenealy, et al. and comprise devices in liquid form with a fill and seal laminate structure, peripheral adhesion laminate structures and solid state adhesive laminate structures or with the drug in the adhesive.

The delivery of an azapirone, such as buspirone, by a transdermal drug delivery device as disclosed in U.S. 5,633,009; provides maximum amounts of unchanged drug and minimal amounts of the 1-PP metabolite. In addition, the transdermal delivery system provides other advantages in azapirone treatment of sleep-related respiratory disorders. The transdermal device, e.g. an adhesive patch, delivers the azapirone reproducibly and without the high variability resulting from various causes such as changes in gastrointestinal transit time, gastric emptying, genetically determined variations in rates of metabolism and, for infants, emesis or spitting up. A transdermal device provides a visible means of confirming drug administration, particularly in the elderly where forgetfulness or memory lapse can result in missed oral dosing of the drug or, on occasion, in inappropriate duplication of oral dosing.

For dosing with infants, a transdermal patch offers greater ease in matching the dose to the infant's body weight merely by employing patches of varying size. Oral dosing of infants, particularly in infants prone to spitting up, makes dosing the proper amount of drug unreliable. Should cessation of dosing be desired, the patch can simply be removed from the skin. Reduction of azapirone levels following oral administration is less amenable to control due to the bolus-dosing of oral formulations.

The advantage of a transdermal patch for treating sleep-related respiratory disorders are:

• ease of administration, particularly to infants;

• visible marker of dosing, e.g. a reminder in the elderly; • ease of removal to interrupt drug delivery; and

• maximizes unchanged drug to metabolite ratio.

The dosage of azapirone administered will, of course, vary depending on the age, health, and weight of the recipient; nature and extent of symptoms/disorder; concurrent treatments; frequency of treatment; and effect desired. For the most preferred method of delivery, a transdermal delivery system, the amount of azapirone will vary depending on the desired dosage amount, permeability and thickness of the pressure-sensitive adhesive component, the skin contact time and other factors known to those skilled in the art. For buspirone, the transdermal flux should range between about 0.5 and 2.5 mg per hour. Over a full 24-hour period, approximately 12 to 60 mg of buspirone would be delivered.

Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art and having the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Claims

1. An improved method for treating sleep-related respiratory disorders comprising sleep apnea and risk of sudden infant death syndrome and apparent life-threatening events wherein the improvement comprises administration to a patient afflicted with a sleep-related respiratory disorder of an azapirone or its pharmaceutically acceptable salt selected from the group consisting of buspirone, gepirone, ipsapirone, tandospirone and zalospirone; with the azapirone being administered in such a manner as to suppress formation of the 1-pyrimidinylpiperazine metabolite, the route of administration selected from transmucosal, transdermal, or oral with an extended release oral formulation.

2. The method of claim 1 wherein the disorder is sleep apnea.

3. The method of claim 1 wherein the disorder is risk of sudden infant death syndrome.

4. The method of claim 1 wherein the disorder is risk of apparent life- threatening events.

5. The method of claim 1 wherein the azapirone is buspirone.

6. The method of claim 1 wherein the azapirone is administered transdermally.

7. The method of claim 6 wherein the azapirone is buspirone.

8. The method of claim 2 wherein buspirone is administered transdermally.

9. The method of claim 3 wherein buspirone is administered transdermally.

10. The method of claim 4 wherein buspirone is administered transdermally.