WO2013173317A1

WO2013173317A1 - TREATMENT OF OBSTRUCTIVE SLEEP APNEA WITH α2-ADRENERGIC RECEPTOR AGONISTS

Info

Publication number: WO2013173317A1
Application number: PCT/US2013/040922
Authority: WO
Inventors: Christopher C. Young
Original assignee: Prospire, Llc
Priority date: 2012-05-14
Filing date: 2013-05-14
Publication date: 2013-11-21

Abstract

This invention provides for methods, kits, and compositions for treating obstructive sleep apnea with one or more α₂-adrenergic agonist (e.g. dexmedetomidine). The invention is also directed to modulating receptors in a patient suffering from obstructive sleep apnea by administering dexmedetomidine. One embodiment of the invention is a method of a treating obstructive sleep apnea with dexmedetomidine. The dexmedetomidine may be provided in a timed-release patch or a two-component composition having a quick release component and a timed-release component.

Description

TREATMENT OF OBSTRUCTIVE SLEEP APNEA WITH a₂- ADRENERGIC RECEPTOR AGONISTS

FIELD OF THE INVENTION

[0001] This invention relates to the treatment of obstructive sleep apnea with

(X2-adrenergic receptor agonists.

BACKGROUND OF THE INVENTION

I. Sleep Apnea

[0002] Sleep apnea is a serious sleep disorder that occurs when a person's breathing is interrupted during sleep. It is a chronic condition that usually requires long-term

management.

[0003] People suffering from untreated sleep apnea stop breathing repeatedly during their sleep, sometimes hundreds of times. Untreated sleep apnea has been associated with an increased risk of high blood pressure, heart attack, stroke, obesity, and diabetes. It has also been associated with an increased risk of, or worsening of heart failure and an increased likelihood of arrhythmias or irregular heartbeat. In addition, patients suffering from sleep apnea are more likely to have work-related or driving accidents.

[0004] There are two mechanisms of sleep apnea, obstructive sleep apnea ("OSA") and central sleep apnea ("CSA"). OSA is a common syndrome characterized by pauses in breathing lasting seconds to minutes while asleep. OSA is caused by a blockage of the airway, usually when the soft tissue in the back of the throat collapses during sleep. In a patient suffering from CSA, the airway is not blocked but the brain fails to signal the muscles to breathe due to instability in the respiratory control center. Obstructive sleep events have been classified as central, obstructive, or mixed. The term "OSA" will be used to refer to all three subtypes of obstructive sleep events.

[0005] OSA is associated with poor sleep quality and excessive daytime sleepiness. OSA is linked to increased rates of hypertension, vascular disease, myocardial infarction, stroke, and diabetes. In addition, accident and death rates due to automobile collisions (presumably due to falling asleep at the steering wheel) and work-related accidents are higher in OSA patients than the general population. Ageing and obesity are independent risk factors for the development of OSA. While estimates of the incidence of OSA are difficult to make due to the low rate of diagnosis, it is predicted to be on the increase.

[0006] Not only does OSA increase the risk for a number of conditions including diabetes, hypertension, and peripheral vascular disease, but it also has a huge impact upon healthcare costs in the United States. It is estimated to occur in 9% of women and 24% of men (Young et al., N Engl J Med, 1993; 328: 1230-1235), with higher reported rates, in those older than 65 years of age (Young et al., Am J Respir Grit Care Med, 2002; 165: 1217-1239) and an incidence of over 70% in obese individuals presenting for bariatric surgery (Lopez et al., Am Surg, 2008; 74:834-838). In addition, a large number of individuals suffer from undiagnosed OSA. In the surgical setting, OSA more than doubles the risk for post-operative complications including arterial desaturation, respiratory depression, and need for intensive care unit (ICU) admission (Chung et al., Anesthesiology, 2008; 108:822-830).

[0007] Diagnosed OSA represents the "tip of the iceberg," since most individuals often do not know they have sleep apnea. When OSA is suspected, it can be diagnosed by an overnight sleep study using polysomnography (PSG); moderate to severe disease is diagnosed when there are more than 15 apneic or hypopneic episodes per hour.

[0008] While the pathogenesis of OSA is not clearly defined, all sub-types are subject to the same therapies. Currently several therapies are used to treat sleep apnea. Milder cases of chronic sleep apnea can be treated with lifestyle changes such as e.g. losing weight or quitting smoking. For moderate or severe sleep apnea, typically the treatment involves either the use of devices to help open up the blocked airways or surgical intervention.

[0009] The most common devices used for treatment of moderate or severe OSA are continuous positive airway pressure ("CPAP") devices, which are machines that deliver air pressure through a mask placed over patient's nose or face while sleeping. However, many patients refuse to use CPAP due to discomfort, excessive noise, drying of the mouth, or claustrophobia. Follow-up studies of patients prescribed this treatment indicate that fewer than half of patients continue to use CPAP one year following diagnosis, mainly because of patient discomfort (Kribbs et al., Am Rev Respir Disease, 1993; 147:887-895). Other devices used for the treatment of OSA include adjustable airway pressure devices or oral appliances designed to keep the patient's throat open.

[0010] Surgical therapies are even less accepted and generally represent "last ditch" treatment for severe OSA. Surgery to remove redundant tissue in the throat has been used to treat OSA, but results have been mixed, limiting the usefulness of this technique.

[0011] Surgical intervention for OSA removes excess tissue from patient's noses or throats, which may be vibrating and causing snoring, or which may be blocking upper air passages thereby causing sleep apnea. One such intervention is uvulopalatopharyngoplasty ("UPPP") which removes tissue from the rear of the mouth and top of the throat often including the tonsils and adenoids. Another invention is maxillomandibular advancement, which involves surgically moving the jaw forward from the remainder of the face bones. Life-threatening sleep apnea is treated with a tracheostomy where the surgeon makes an opening in the patient's neck and inserts a metal or plastic tube through which the patient breathes while sleeping. Tracheostomy can relieve the obstruction of the airway, but many patients prefer to avoid this surgery. All of these surgical treatments are quite invasive requiring a general anesthetic.

[0012] The treatment of OSA remains difficult. CPAP is often not well accepted.

Surgery, such as uvulopalatopharyngoplasty, often only improves OSA when combined with CPAP therapy. However, even then it may not always be effective. Thus, there is a great need for a treatment of OSA that is effective and less invasive that the current surgical interventions.

[0013] Currently, there is no medication that has been shown to positively alter the symptoms of OSA.

II. a₂-adrenergic receptor agonists

[0014] a₂-adrenergic receptor agonists such as clonidine, dexmedetomidine, and xylazine are anesthetic agents used widely in clinical and veterinary settings because of their sedative, hypnotic, or analgesic effects. (Nelson et al., Anesthesiology , 2003; 98: 428-36). However, thus far they have not been used in the treatment of obstructive sleep apnea.

[0015] The highly selective a₂-adrenergic receptor agonist dexmedetomidine ("DEX") ((5)-4-[l-(2,3-dimethylphenyl)ethyl]-3H-imidazole), which is marketed as Precedex®, is used for short-term incubation of mechanically ventilated patients in intensive care units. (Cortinez et al. , Anesthesiology, 2004; 101 : 1077-83). DEX is relatively unique in its ability to provide sedation without causing respiratory depression.

[0016] DEX provides sedation and analgesia by acting through central a₂ mechanisms. It has been shown to exert these effects while sparing central respiratory drive. The analgesia provided by DEX is due to stimulation of alpha-receptors in the dorsal horn of the spinal cord. It does not act at central CNS opiate receptor as demonstrated by the reversal of its analgesic effects by alpha-blocking agents but not naloxone, an opioid antagonist (Sabbe et al., Anesthesiology, 1994; 80:1057-1072). Increasing targeted plasma concentrations of DEX in humans were shown to produce a statistically significant increase in respiratory rate, perhaps owing to a slight rise in PC0₂, with no significant change in arterial P0₂ or hemoglobin saturation (Ebert et al., Anesthesiology , 2000; 93:382-394). [0017] In another study, DEX was found to reduce the hypercapnic respiratory response and overall respiratory rate in humans, but in a fashion not significantly different from that seen during normal non-rapid eye movement sleep (Belleville et al., Anesthesiology , 1992; 77: 1125-1133). In studies performed in human volunteers, episodes of centrally mediated apnea were noted during remifentanil infusions and natural sleep phases, but not during dexmedetomidine infusions (Hsu et al., Anesthesiology, 2004; 101 : 1066-76). Pooled responses showed that Apnea/Hypopnea Index ("AHI") significantly increased during remifentanil infusion and significantly decreased during DEX infusion compared to baseline natural sleep. Interestingly, 3 of 8 subjects demonstrated AHI>15 during the natural sleep phase of the study, but 0 of 8 had AHI>15 during DEX infusion. An earlier study (Issa et al., Am Rev Resp Disease, 1992; 145:435-439) showed that oral clonidine, a less potent alpha- agonist than dexmedetomidine, administered to subjects with known OSA produced improvements in AHI during rapid eye movement ("REM") sleep. Hypoxemic events were reduced with the administration of clonidine.

[0018] Despite their widespread use, a₂-adrenergic receptor agonists have been found to have certain undesirable side effects. For example, heart rate and blood pressure is reduced, on average by 10-15%, during targeted sedation using this agent. The effects of use of dexmedetomidine as an anesthetic for patients suffering from obstructive sleep apnea have been investigated {see e.g. Patel et al, Anesth Analg., 2010; 111 : 1004-10) and found to reduce postoperative pain and the incidence of emergence delirium.

[0019] If a medical therapy were shown to be effective in limiting the incidence or severity of OSA, it would represent a significant advance in the treatment of this increasingly common medical diagnosis. Thus, there is a significant clinical need for a therapy that can reduce the incidence and severity of OSA-associated apnea and hypopnea that is easily administered, well tolerated, and does not require surgical intervention.

[0020] Dexmedetomidine infusion represents a significant advance in therapy for OSA as it reduces the severity of apnea and hypopnea and may eventually reduce the incidence of OSA related complications.

SUMMARY OF THE INVENTION

[0021] This invention is directed to methods, kits, and compositions for treating obstructive sleep apnea with one or more a₂-adrenergic agonists (such as e.g.

dexmedetomidine). The invention is also directed to modulating receptors in a patient suffering from obstructive sleep apnea by administering dexmedetomidine. [0022] One embodiment of the invention is a method of treating obstructive sleep apnea comprising administering a therapeutically effective amount of one or more a₂-adrenergic agonists to a patient suffering from obstructive sleep apnea. Preferably, the a₂-adrenergic agonist is dexmedetomidine. The agonist may be administered intravenously to e.g. a patient after surgery.

[0023] Another embodiment of the invention is a method of treating obstructive sleep apnea comprising administering: (a) a quick delivery composition comprising a

therapeutically effective amount of dexmedetomidine; and (b) a timed-release composition comprising a therapeutically effective amount of dexmedetomidine to a patient suffering from obstructive sleep apnea. The quick delivery composition is formulated so that a desired plasma level of dexmedetomidine is achieved quickly. The timed-release composition is formulated so as to release the drug for a specified amount of time and to maintain the desired plasma level. The quick delivery composition may be formulated for oral administration, transbuccal administration or nebulized for inhalation. In one embodiment, the quick delivery composition is a nasal spray. The timed-release composition may comprise a transdermal patch. The timed-release composition may be administered simultaneously with, before, or after the quick delivery composition. In one embodiment, the timed-release composition is formulated to release dexmedetomidine over a period of about 6 to about 8 hours.

[0024] Yet another embodiment of the invention is a method of treating obstructive sleep apnea comprising administering a patch comprising a therapeutically effective amount of dexmedetomidine to a patient suffering from obstructive sleep apnea. In one embodiment, the patch is a timed-release patch. In another embodiment, the patch comprises a quick delivery component and a timed-release component. The timed-release patch or

timed-release component may be formulated to release the dexmedetomidine over a period of about 6 to about 8 hours, alternatively over a period of about 4 to about 5 hours, alternatively over period of about 5 hours to about 7 hours. The quick delivery component may be formulated so that a desired plasma level of dexmedetomidine is achieved quickly. The timed-release component may be formulated to maintain the desired plasma level over a desired period of time.

[0025] Another aspect of the invention is a kit for treating obstructive sleep apnea comprising (1) a quick delivery composition comprising a therapeutically effective amount of dexmedetomidine; and (2) a timed-release composition comprising a therapeutically effective amount of dexmedetomidine. The quick delivery composition may be a nasal spray. Alternatively, the quick delivery is formulated for oral administration, transbuccal administration or nebulized for inhalation. In one embodiment, the timed-release

composition comprises a timed-release patch.

[0026] An alternate aspect of the invention is a timed-release patch for the treatment of obstructive sleep apnea comprising a quick delivery component comprising a therapeutically effective amount of dexmedetomidine and a timed-release component comprising a therapeutically effective amount of dexmedetomidine.

[0027] Another embodiment of the invention is a pharmaceutical composition for use in treating obstructive sleep apnea comprising a therapeutically effective amount of

dexmedetomidine. In one embodiment, the composition comprises a quick delivery component comprising a therapeutically effective amount of dexmedetomidine and a timed-aarelease component comprising a therapeutically effective amount of

dexmedetomidine. In another embodiment, the composition comprises a timed-release patch.

[0028] Yet another aspect of the invention is methods of modulating receptors in patients suffering from OSA. Accordingly, one embodiment of the invention is a method of modulating ventilatory control areas in the nervous system of a patient suffering from obstructive sleep apnea comprising administering an effective amount of dexmedetomidine. Another embodiment of the invention is a method of modulating rapid eye movement and/or non-rapid eye movement sleep in a patient suffering from obstructive sleep apnea comprising administering an effective amount of dexmedetomidine.

[0029] Other features and advantages of the invention will be apparent from the detailed description and examples that follow.

DETAILED DESCRIPTION

[0030] In the following detailed description of the illustrative embodiments, reference is made to the accompanying drawings that form a part hereof. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is understood that other embodiments may be utilized and that changes may be made without departing from the spirit or scope of the invention. To avoid detail not necessary to enable those skilled in the art to practice the embodiments described herein, the description may omit certain information known to those skilled in the art. The following detailed description is, therefore, not to be taken in a limiting sense.

[0031] Applicants have found that intravenous formulation of dexmedetomidine is efficacious in the treatment of sleep apneas. In particular, Applicants have found that intravenous formulations of dexmedetomidine are efficacious in the treatment of sleep apneas in post-operative patients with pre-existing sleep apnea. Furthermore, non-intravenous formulations of dexmedetomidine are an effective therapy for outpatient treatment of obstructive sleep apnea.

[0032] Exemplary suitable a₂ adrenergic agonists include but are not limited to apraclonidine, brimonidine, clonidine, detomidine, guanabenz, guanfacine, lofexidine, medetomidine, romifidine, tizanidine, tolonidine, xylazine, fadolmidine, xylometazoline and related derivatives of these agents.

I. Definitions

[0033] Various terms are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein.

[0034] As used herein, the term "obstructive sleep apnea" means any sleep disorder resulting in cessation of normal respiration during sleep, such as e.g. when the soft tissue in the back of the throat collapses during sleep. Obstructive sleep apnea is characterized by pauses in breathing lasting seconds to minutes while asleep resulting from central or peripheral {i.e. obstructive) reductions in respiratory functions. The term obstructive sleep apnea therefore encompasses obstructive sleep events classified as central, obstructive, or mixed.

[0035] The terms "effective period", "effective period of time", "effective conditions" or "desired period of time" refer generally to a period of time or other controllable conditions {e.g. , temperature, humidity for in vitro methods), necessary or preferred for an agent or pharmaceutical composition to achieve its intended result.

[0036] The terms "treating," "treatment," and "therapy" as used herein refer to curative therapy, prophylactic therapy, and preventative therapy.

[0037] As used herein, the term "about" when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ± 20% or ± 10%, more preferably ± 5%, even more preferably ± 1%, and still more preferably ± 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0038] As used herein, unless indicated otherwise, the terms "composition" and

"composition of the invention," are used interchangeably. Unless stated otherwise, the terms are meant to encompass, and are not limited to, pharmaceutical compositions and

nutraceutical compositions containing drug substance. The composition may also contain one or more "excipients" that are "inactive ingredients" or "compounds" devoid of pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body.

[0039] As used herein, the term "vehicle" includes but it is not limited to a diluent, adjuvant, excipient, carrier, or filler with which the compound or composition of the invention is stored, transported, and/or administered.

[0040] As used herein, the phrase "pharmaceutically acceptable salts" includes but it is not limited to the non-toxic alkali metal, alkaline earth metal, and ammonium salts commonly used in the pharmaceutical industry including the sodium, potassium, lithium, calcium, magnesium, barium, ammonium, and protamine zinc salts, which are prepared by methods well known in the art.

[0041] As used herein "pharmaceutically or therapeutically acceptable carrier" includes but is not limited to a carrier medium which does not interfere with the effectiveness of the biological activity of the active ingredients and which is not toxic to the host or patient.

[0042] As used herein, the term "pharmaceutically acceptable solvate" refers to an association of one or more solvent molecules and a compound of the invention. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to water, saline, water-salt mixtures, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, polyethylene glycol, and ethanolamine.

[0043] As used herein, the term "pharmaceutically acceptable" includes but is not limited to approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

II. Pharmaceutical compositions for the treatment of obstructive sleep apnea

[0044] One aspect of the invention is pharmaceutical compositions containing centrally acting a₂ adrenergic agonists formulated for the treatment of obstructive sleep apnea (OSA). One embodiment of the invention is a pharmaceutical composition comprising a

therapeutically effective amount of a₂ adrenergic agonists for use in the treatment of OSA. In one embodiment, the a₂ adrenergic agonist is dexmedetomidine.

[0045] These pharmaceutical compositions may be formulated for administration by oral, pulmonary, parental (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), inhalation, transdermal, or nasal routes of administration and can be formulated in dosage forms appropriate for each route of administration. [0046] The compositions of the invention may comprise pharmaceutically acceptable carrier or solvate. Suitable carriers and their formulations are described in Remington's Pharmaceutical Sciences, 2005, Mack Publishing Co. Typically, an appropriate amount of a pharmaceutically acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically acceptable carrier include liquids such as saline, Ringer's solution, and dextrose solution. In one embodiment, the pH of the solution is from about 5 to about 8, and more preferably from about 7 to about 7.5. The formulation may also comprise a lyophilized powder. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers, which matrices are in the form of shaped articles, e.g., films, liposomes, or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of the a₂-adrenergic agonist being administered.

[0047] Effective dosages and schedules for administering the composition may be determined empirically, and making such determinations is within the skill in the art. Those skilled in the art will understand that the dosage of any composition that must be

administered will vary depending on, for example, the patient which will receive the composition, the route of administration, the particular composition used including the coadministration of other drugs and other drugs being administered to the mammal. In addition, as used throughout, a therapeutically effective amount of a₂-adrenergic agonists for use in the treatment of OSA shall be the amount necessary to treat OSA without placing the patient under anesthesia.

[0048] Alternatively, the dosage administered can vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, and health of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.

[0049] It will furthermore be appreciated that a therapeutically effective amount of a particular composition can be determined by those of ordinary skill in the art with due consideration of the factors pertinent to the subject such as the subject's age, gender and weight.

[0050] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, with the elixirs containing inert diluents commonly used in the art, such as water or saline. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and

sweetening, flavoring, and perfuming agents. [0051] Preparations according to this invention for parental administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.

[0052] Suitable vehicles are well known to those skilled in the art of pharmacy, and non- limiting examples of suitable vehicles include glucose, sucrose, starch, lactose, gelatin, rice, silica gel, glycerol, talc, sodium chloride, dried skim milk, propylene glycol, water, sodium stearate, ethanol, and similar substances well known in the art. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles. Whether a particular vehicle is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient and the specific active ingredients in the dosage form. Pharmaceutical vehicles can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.

[0053] The invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decay or the composition will change in character. So called "stabilizers" or "preservatives" and may include, but are not limited to, amino acids, antioxidants, pH buffers, or salt buffers. Nonlimiting examples of antioxidants include butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, butylated hydroxy anisole and cysteine. Nonlimiting examples of preservatives include parabens, such as methyl or propyl p-hydroxybenzoate and benzalkonium chloride.

Additional nonlimiting examples of amino acids include glycine or proline.

[0054] A pharmaceutical composition of the invention (e.g. a pharmaceutical

composition comprising a a₂-adrenergic agonist (e.g. dexmedetomidine)) is formulated to be compatible with its intended route of administration.

[0055] One embodiment of the invention is a pharmaceutical composition comprising a a₂-adrenergic agonist (e.g. dexmedetomidine) which is formulated into a transdermal patch. In one embodiment, the transdermal patch is a timed-release patch. This timed-release patch slowly releases the drug and maintains plasma blood levels of the a₂-adrenergic agonist for a desired period of time. In one embodiment, the timed-release patch releases the

a₂-adrenergic agonist over a period of about 6 hours to about 8 hours, alternatively over a period of about 5 hours to about 7 hours, alternatively over a period of about 4 hours to about

6 hours, alternatively over a period of about 4 hours to about 8 hours.

[0056] In another embodiment, the patch comprises dexmedetomidine and contains two separate dosing components: a quick delivery component to achieve initial plasma levels rapidly; and a timed-release component. In one embodiment, the timed-release component maintains plasma levels of dexmedetomidine for a desired period of time. In another embodiment, the timed-release component maintains plasma levels of dexmedetomidine for a desired period of time such as e.g. from about 6 hours to about 8 hours. In an alternate embodiment of the invention, the timed-release component releases dexmedetomidine over a period of about 6 hours to about 8 hours, alternatively over a period of about 5 hours to about

7 hours, alternatively over a period of about 4 hours to about 6 hours, alternatively over a period of about 4 hours to about 8 hours.

[0057] In one embodiment, the compositions (including transdermal patches) are formulated to provide a plasma dosage of about 0.1 to about 0.8 ng/mL, alternatively from about 0.4 to about 0.6 ng/mL, alternatively from about 0.1 to about 0.3 ng/mL, alternatively from about 0.6 to about 0.8 ng/mL, alternatively from about 0.3 to about 0.5 ng/mL of dexmedetomidine .

III. Kits for the treatment of obstructive sleep apnea

[0058] The invention also provides for kits containing centrally acting a₂-adrenergic agonists formulated for the treatment of obstructive sleep apnea (OSA). In one embodiment, these kits comprise dexmedetomidine. The kits may further include instructions for use.

[0059] One embodiment of the invention is a kit comprising dexmedetomidine formulated in a transdermal patch containing quick delivery component and a timed-release component to maintain plasma levels for a desired period of time. The quick delivery component allows the drug to achieve initial plasma levels rapidly; and a timed-release component maintains the desired plasma levels of dexmedetomidine for a desired period of time, such as e.g. from about 6 to about 8 hours. In one embodiment, the kit may comprise two separate patches with one patch comprising the quick delivery component and the other patch comprising the timed-release component. In another embodiment, the timed-release component releases dexmedetomidme over a period of about 6 hours to about 8 hours, alternatively over a period of about 5 hours to about 7 hours, alternatively over a period of about 4 hours to about 6 hours, alternatively over a period of about 5 hours to about 8 hours.

[0060] Another embodiment of the invention is a kit for treating obstructive sleep apnea (OSA) comprising a nasal spray containing dexmedetomidme and a timed-release transdermal patch containing dexmedetomidme. The nasal spray allows dexmedetomidme to achieve initial plasma levels quickly while the transdermal patch (the timed-release component) maintains the desired plasma levels of dexmedetomidme for a desired period of time. In one embodiment, the timed-release component maintains plasma levels for from about 6 to about 8 hours. Optimally, the transdermal patch is formulated so to release dexmedetomidme over a period of about 6 hours to about 8 hours, alternatively over a period of about 5 hours to about 7 hours, alternatively over a period of about 4 hours to about 6 hours, alternatively over a period of about 5 hours to about 8 hours.

[0061] In one embodiment, the timed-release transdermal patch maintains plasma levels of dexmedetomidme for a period of about 6 to about 8 hours.

[0062] Yet another embodiment of the invention is a kit for treating obstructive sleep apnea (OSA) comprising dexmedetomidme formulated in a quick release formulation and a timed- release formulation which maintains the desired plasma levels of the drug. The quick release formulation provide for rapid onset of the effects (e.g. sleep). The quick release formulation may comprise dexmedetomidme formulated for oral or transbuccal

administration or nebulized for inhalation. In one embodiment, the timed-release formulation releases dexmedetomidme over a period of about 6 hours to about 8 hours, alternatively over a period of about 5 hours to about 7 hours, alternatively over a period of about 4 hours to about 6 hours, alternatively over a period of about 5 hours to about 8 hours.

IV. Methods of treatment of obstructive sleep apnea

[0063] Another aspect of the invention is methods of treating obstructive sleep apnea by administering centrally acting a₂-adrenergic agonists (such as e.g. dexmedetomidme) to a subject in need thereof. The a₂-adrenergic agonist (e.g. dexmedetomidme) may be provided as part of a pharmaceutical composition or kit.

[0064] Applicants found that intravenous administration of dexmedetomidme is efficacious in treatment of post-operative patients with pre-existing sleep apnea. Applicants also found non-intravenous formulations are an effective therapy for outpatient treatment of sleep apnea. To mimic the bolus/infusion model of intravenous dosing, dexmedetomidme can be administered outside the hospital in a number of ways, including but not limited to: (1) transdermal patch containing two separate dosing components of dexmedetomidine: a quick delivery component to achieve initial plasma levels rapidly; and a timed-release component to maintain desired plasma levels for a desired period; (2) a nasal spray for rapid onset of effects and a timed-release transdermal patch to maintain plasma levels for a desired period as well as some other means (oral, transbuccal, nebulized for inhalation) for rapid onset of effects and a timed-release transdermal patch to maintain plasma levels for a desired period.

[0065] Thus, in one embodiment of the invention, the method of treating obstructive sleep apnea comprises intravenous administration of the a₂-adrenergic agonist (e.g.

dexmedetomidine) to a patient suffering from obstructive sleep apnea. This method is particularly useful in the treatment of post-operative patients suffering from obstructive sleep apnea. Accordingly, in another embodiment, the method of treating obstructive sleep apnea comprises intravenous administration after surgery of the a₂-adrenergic agonist (e.g.

dexmedetomidine) to a patient suffering from obstructive sleep apnea. In one embodiment of this method, the a₂-adrenergic agonist (e.g. dexmedetomidine) is supplied with an initial loading dose followed by continual administration of the agonist for the desired period of time. In another embodiment, the a₂-adrenergic agonist is dexmedetomidine which may optionally be supplied with a loading dose of about 0.5 mcg/kg followed by infusion at a rate of 0.6 mcg/kg/hour.

[0066] In yet another embodiment of the invention, the method of treating obstructive sleep apnea comprises administering a quick delivery composition comprising one or more a₂-adrenergic agonists (e.g. dexmedetomidine) and a timed-release composition comprising one or more a₂-adrenergic agonists (e.g. dexmedetomidine) to a patient suffering from obstructive sleep apnea. The quick delivery composition is formulated so that the

a₂-adrenergic agonists (e.g. dexmedetomidine) can achieve the desired plasma levels rapidly. The timed-release composition is formulated so that the one or more a₂-adrenergic agonists (e.g. dexmedetomidine) maintains plasma levels for a desired prior of time such as e.g. about 6 hours to about 8 hours. Optimally, the timed-release composition is formulated so to release dexmedetomidine over a period of about 6 hours to about 8 hours, alternatively over a period of about 5 hours to about 7 hours, alternatively over a period of about 4 hours to about 6 hours, alternatively over a period of about 5 hours to about 8 hours. The timed-release composition may be administered before, after or simultaneously with the quick delivery composition. [0067] In one embodiment, dexmedetomidme is provided in the form of a transdermal patch. Thus, the method involves placing the transdermal patch containing dexmedetomidme in contact with the patient's skin. The transdermal patch may comprise a quick delivery component and a timed-release component. The quick delivery component allows dexmedetomidme to achieve initial plasma levels quickly while the timed-release component maintains the plasma levels for a desired period of time. In another embodiment, the timedrelease component maintains plasma levels for approximately 6 hours to 8 hours. In an alternate embodiment, the timed-release component of the transdermal patch may be formulated so to release dexmedetomidme over a period of about 6 hours to about 8 hours, alternatively over a period of about 5 hours to about 7 hours, alternatively over a period of about 4 hours to about 6 hours, alternatively over a period of about 5 hours to about 8 hours.

[0068] In yet another embodiment, dexmedetomidme is provided in the form of (1) a nasal spray and (2) a transdermal patch. Thus, the method comprises intranasal

administration of dexmedetomidme and placing the patch on the patient's skin. The nasal spray allows the drug to achieve initial plasma levels quickly while the transdermal patch maintains the desired plasma levels for a desired period of time such as e.g. about 6 hours to about 8 hours. In one embodiment, the transdermal patch releases dexmedetomidme over a period of about 6 hours to about 8 hours, alternatively over a period of about 5 hours to about 7 hours, alternatively over a period of about 4 hours to about 6 hours, alternatively over a period of about 5 hours to about 8 hours.

[0069] In an alternate embodiment, dexmedetomidme is provided in the form of (1) a quick release composition and (2) a transdermal patch. Thus, the method comprises administration of the quick release composition and placing the patch on the patient's skin. The quick release allows the drug to achieve initial plasma levels quickly while the transdermal patch maintains the plasma levels for a desired period of time such as e.g. about 6 hours to about 8 hours. The quick release composition may be formulated for oral or transbuccal or nebulized for inhalation. In one embodiment, the transdermal patch may be formulated to release dexmedetomidme over a period of about 6 hours to about 8 hours, alternatively over a period of about 5 hours to about 7 hours, alternatively over a period of about 4 hours to about 6 hours, alternatively over a period of about 5 hours to about 8 hours.

[0070] Those of skill in the art would recognize that this desired plasma dosage of the one or more a₂-adrenergic agonists {e.g. dexmedetomidme) used in the methods and compositions of the invention will vary depending on the subject and can be determined consideration of the factors pertinent to the subject such as e.g. the subject's age, gender, and weight. Accordingly, in one embodiment, the methods comprise the step of determining the optimal dose of the one or more a₂-adrenergic agonists (e.g. dexmedetomidine). In one embodiment, the methods provide for maintaining a desired plasma dosage of about 0.4 to about 0.6 ng/mL of dexmedetomidine.

[0071] Furthermore, those of skill in the art would also recognize that the desired period of time for the desired plasma dosages will vary depending on the subject and can be determined consideration of the factors pertinent to the subject such as e.g. the subject's age, gender, and weight as well as the desired or required amount of sleep.

[0072] Another embodiment of the invention is a method of modulating ventilatory control areas in the nervous system of a patient suffering from obstructive sleep apnea comprising administering an effective amount of dexmedetomidine. Yet another

embodiment is a method of modulating rapid eye movement and/or non-rapid eye movement sleep in a patient suffering from obstructive sleep apnea comprising administering an effective amount of dexmedetomidine. These methods may utilize pharmaceutical compositions, kits, and patches described herein for the treatment of OSA.

[0073] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

Examples

Example 1: Dexmedetomidine Effects in Obstructive Sleep Apnea Patients

[0074] As discussed in the background of the invention, there is a significant clinical need for a therapy that can reduce the incidence and severity of OSA-associated apnea and hypopnea that is easily administered, well tolerated, and does not require surgical intervention. One approach is the use of dexmedetomidine ("DEX") infusion in patients with OSA. DEX mediates its effects via a₂-adrenergic stimulation of the brain and spinal cord, resulting in sedation and analgesia with sparing of respiratory drive. For this study, individuals with known OSA will be recruited to participate in a voluntary study examining the impact of dexmedetomidine infusion on PSG measures of apnea and hypopnea during an overnight sleep study. [0075] This study is designed to demonstrate the reduction of Apnea/Hypopnea Index in patients with known obstructive sleep apnea by the infusion of dexmedetomidine. While a number of mechanisms for the pathogenesis of OSA have been postulated; (Dempsey et ah, Physiol Rev, 2010; 90: 47-112) upper airways collapse during forceful inspiration is a common occurrence in patients with OSA.

Study Design

[0076] Twenty volunteers with OSA will be recruited from patients presenting to the Duke Sleep Laboratory. This study will be carried out in patients who have previously undergone polysomnography which documented significant OSA, and who have not undergone any changes that are likely to alter the severity of their condition since the time of their diagnostic sleep study (loss of weight; surgical therapy for OSA; removal of tonsils; discontinuation of medications likely to affect arousal or respiratory function, etc.). After obtaining informed consent, patients will be screened by history and physical examination, 12-lead EKG, and comprehensive metabolic profile. Exclusion criteria will include a history of illicit drug or alcohol dependence, impaired hepatic (AST/ ALT > 2x upper limit of normal range) or renal function (receiving dialysis or serum creatinine > 1.5 mg/dL), high-grade (> 1^st degree) heart block, or known allergy to dexmedetomidine.

[0077] Participants will be instructed to adhere to their habitual sleep period, intake of caffeine and alcohol, and nap behavior on the day of the sleep study. They will be instructed to arrive at the sleep laboratory approximately 1.5 hours before their usual bedtime. They will have an intravenous catheter inserted 30 minutes before lights out. Subjects will receive an IV infusion throughout the study. Subjects will be randomized in a 2X2 crossover design to receive DEX or placebo for either the initial or final 4-hour phase. DEX infusions will last for two (2) hours, followed by a 2-hour washout period; placebo infusions will be

administered over four (4) hours at rates mimicking the DEX infusion rates in order to maintain subject and investigator blinding {see Table 1).

[0078] For the infusion study protocol shown in Table 1 , the placebo is a 50 mL bag of NS. Dexmedetomidine = 2 mL Precedex® (100 mcg/mL) in 48 mL. NS = 50 mL at 4 mcg/mL. Placebo and Dex infusions will be piggy backed on IV NS infusion at 75 ml/hour. Table 1: Study Infusion Protocol

Weight Loading infusion over 20 minutes Loading volume Maintenance infusion (kg) (mL/hr) (mL) (mL/hr)

50.0 37.5 12.5 7.5

55.0 41.3 13.8 8.2

60.0 45.0 15.0 9.0

65.0 48.8 16.3 9.7

70.0 52.5 17.5 10.5

75.0 56.3 18.8 11.2

80.0 60.0 20.0 12.0

85.0 63.8 21.3 12.7

90.0 67.5 22.5 13.5

95.0 71.3 23.8 14.2

100.0 75.0 25.0 15.0

105.0 78.8 26.3 15.7

110.0 82.5 27.5 16.5

115.0 86.3 28.8 17.2

120.0 90.0 30.0 18.0

125.0 93.8 31.3 18.7

130.0 97.5 32.5 19.5

135.0 101.3 33.8 20.2

140.0 105.0 35.0 21.0

145.0 108.8 36.3 21.7

150.0 112.5 37.5 22.5

155.0 116.3 38.8 23.2

160.0 120.0 40.0 24.0

165.0 123.8 41.3 24.7

170.0 127.5 42.5 25.5

175.0 131.3 43.8 26.2

180.0 135.0 45.0 27.0

185.0 138.8 46.3 27.7

[0079] Eligible subjects will undergo an overnight sleep study using polysomnography ("PSG") as previously described by Krystal et al, Sleep, 2010; 33:669-677. The PSG will include: five EEG leads (C3/A2, C4/A1, Fz/Al+A2, 01/A2, 02/A1), two EOG leads, a submentalis (surface) EMG, one ECG lead, bilateral anterior tibialis EMG, oral/nasal airflow (thermocouple), nasal pressure (nasal cannula linked to pressure transducer), respiratory effort (inductance plethysmography), finger pulse oximeter, snoring (microphone) and a position sensor. EEG, ECG, and EMG signals will be recorded with a sampling rate of 200 Hz; all other signals will be digitized at 100 Hz. Appropriate bandpass filters will be used. Signals will be collected using Grass-Telefactor Aurora Digital PSG systems. The PSGs will be scored blind to treatment condition under the direction of experienced, board-certified Sleep Medicine physicians, using standard scoring criteria (Iber et al., The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specification, 1st ed. Weschester, III: American Academy of Sleep Medicine; 2007).

[0080] The primary outcome is frequency of apnea or hypopnea as measured by AHI; secondary outcomes include severity and duration of arterial desaturations, measures of sleep architecture (sleep onset latency, duration of time spent in REM and NREM sleep, sleep efficiency), and arousals. The primary outcome for the second aim will be PSG

measurements of respiratory rates and thoracic and abdominal excursions.

[0081] The dose chosen in this study adheres to FDA-approved package insert recommendations for conscious sedation. The lower end of the dosing range (0.5 mcg/kg loading dose administered over 20 minutes, followed by 0.6 mcg/kg/hr infusion for 1 hour and 40 minutes) will be investigated as recommended for "less invasive procedures." This should result in plasma steady state concentrations of DEX of approximately 0.4 - 0.6 ng/mL.

[0082] Bolus /infusion weight based dosing. The dose of dexmedetomidine selected will be the same (based on subject body weight) for all subjects. This dose may not be the optimal dose to produce the desired endpoints. Only a dose titration study using step increases in dosing will show the optimal dosing range.

[0083] While the invention has been described and illustrated herein by references to various specific materials, procedures and examples, it is understood that the invention is not restricted to the particular combinations of material and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary, only, with the true scope and spirit of the invention being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition for treating obstructive sleep apnea comprising a therapeutically effective amount of one or more a₂-adrenergic agonists.

2. The pharmaceutical composition of claim 1, wherein the one or more a₂-adrenergic agonists is dexmedetomidme.

3. The pharmaceutical composition of claims 1 or 2, wherein the pharmaceutical composition is formulated for intravenous administration.

4. The pharmaceutical composition of claims 1 or 2, wherein the pharmaceutical composition is formulated as a patch.

5. The pharmaceutical composition of claim 4, wherein the patch is a transdermal patch.

6. The pharmaceutical composition of claim 5, wherein the patch is a timed-release patch.

7. The pharmaceutical composition of claim 6, wherein the timed-release patch is formulated to release the dexmedetomidme over a period of about 6 hours to about 8 hours.

8. The pharmaceutical composition of claim 4, wherein the patch comprises a quick delivery component and a timed-release component.

9. The pharmaceutical composition of claim 8, wherein the quick delivery component is formulated so that a desired plasma level of dexmedetomidme is achieved quickly.

10. The pharmaceutical composition of claim 8, wherein the timed-release component is formulated to maintain the desired plasma level.

11. The pharmaceutical composition of claim 8, wherein the timed-release component is formulated to release the dexmedetomidme over a period of about 6 hours to about 8 hours.

12. A method of treating obstructive sleep apnea comprising administering a

therapeutically effective amount of one or more a₂-adrenergic agonists to a patient suffering from obstructive sleep apnea.

13. The method of claim 6, wherein the one or more a₂-adrenergic agonists is dexmedetomidine .

14. The method of claim 6, wherein the one or more a₂-adrenergic agonists is

administered intravenously.

15. A pharmaceutical composition for treating obstructive sleep apnea comprising a quick delivery composition comprising a therapeutically effective amount of dexmedetomidine and a timed-release composition comprising a therapeutically effective amount of

dexmedetomidine .

16. The pharmaceutical composition of claim 15, wherein the quick delivery composition is formulated so that a desired plasma level of dexmedetomidine is achieved quickly.

17. The pharmaceutical composition of claim 15 or 16, wherein the timed-release composition is formulated to maintain the desired plasma level.

18. The pharmaceutical composition of claim 15, wherein the timed-release composition is formulated to release dexmedetomidine over a period of about 6 hours to about 8 hours.

19. The pharmaceutical composition of claim 15, wherein the quick delivery composition is formulated for oral administration, transbuccal administration or nebulized for inhalation.

20. The pharmaceutical composition of claim 15, wherein the quick delivery composition is a nasal spray.

21. The pharmaceutical composition of claim 15, wherein the timed-release composition comprises a transdermal patch.

22. A method of treating obstructive sleep apnea comprising administering a quick delivery composition comprising a therapeutically effective amount of dexmedetomidine; and a timed-release composition comprising a therapeutically effective amount of

dexmedetomidine to a patient suffering from obstructive sleep apnea.

23. The method of claim 22, wherein the quick delivery composition is formulated so that a desired plasma level of dexmedetomidine is achieved quickly.

24. The method of claim 22, wherein the timed-release composition is formulated to maintain the desired plasma level.

25. The method of claim 22, wherein the timed-release composition is formulated to release dexmedetomidine over a period of about 6 hours to about 8 hours.

26. The method of claim 22, wherein the quick delivery composition is formulated for oral administration, transbuccal administration or nebulized for inhalation.

27. The method of claim 22, wherein the quick delivery composition is a nasal spray.

28. The method of claim 22, wherein the timed-release composition comprises a transdermal patch.

29. The method of claim 22, wherein the timed-release composition is administered simultaneously with, before, or after the quick delivery composition.

30. A method of treating obstructive sleep apnea comprising administering a patch comprising a therapeutically effective amount of dexmedetomidine to a patient suffering from obstructive sleep apnea.

31. The method of claim 30, wherein the patch is a timed-release patch.

32. The method of claim 31 , wherein the timed-release patch is formulated to release the dexmedetomidine over a period of about 6 hours to about 8 hours.

33. The method of claim 31 , wherein the patch comprises a quick delivery component and a timed-release component.

34. The method of claim 33, wherein the quick delivery component is formulated so that a desired plasma level of dexmedetomidine is achieved quickly.

35. The method of claim 33, wherein the timed-release component is formulated to maintain the desired plasma level.

36. The method of claim 33, wherein the timed-release component is formulated to release the dexmedetomidine over a period of about 6 hours to about 8 hours.

37. A kit for treating obstructive sleep apnea comprising (1) a quick delivery composition comprising a therapeutically effective amount of dexmedetomidine; and (2) a timed-release composition comprising a therapeutically effective amount of dexmedetomidine.

38. The kit of claim 37, wherein the quick delivery composition comprises a nasal spray.

39. The kit of claim 37, wherein the quick delivery is formulated for oral administration, transbuccal administration or nebulized for inhalation.

40. The kit of claim 37, wherein the timed-release patch is formulated to release the dexmedetomidine over a period of about 6 hours to about 8 hours

41. The kit of claim 37, wherein the timed-release composition comprises a timed-release patch.

42. A timed-release patch for the treatment of obstructive sleep apnea comprising a quick delivery component comprising a therapeutically effective amount of dexmedetomidine and a timed-release component comprising a therapeutically effective amount of dexmedetomidine.

43. A pharmaceutical composition for use in modulating ventilatory control areas in the nervous system of a patient suffering from obstructive sleep apnea comprising an effective amount of dexmedetomidine

44. A method of modulating ventilatory control areas in the nervous system of a patient suffering from obstructive sleep apnea comprising administering an effective amount of dexmedetomidine .

45. A pharmaceutical composition use in rapid eye movement and/or non-rapid eye movement sleep in a patient suffering from obstructive sleep apnea comprising an effective amount of dexmedetomidine.

46. A method of modulating rapid eye movement and/or non-rapid eye movement sleep in a patient suffering from obstructive sleep apnea comprising administering an effective amount of dexmedetomidine.