Compositions and methods for the treatment of obstructive sleep apnea (OSA)

Abstract

The present disclosure generally relates to compositions comprising delta-9-tetrahydrocannabinol (THC) and a carbonic anhydrase inhibitor, and methods of using these compositions for the treatment of obstructive sleep apnea (OSA). In specific embodiments, the method of treatment comprises administering dronabinol and acetazolamide, or combinations thereof, to a subject in need thereof.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE

[0001] The present disclosure relates generally to compositions and methods for the treatment of obstructive sleep apnea (OSA). Related Applications

[0002] This application claims priority to Australian Provisional Patent Application No. 2020902368, filed July 9, 2020, the entire contents of which are incorporated herein by reference. [Background technology]

[0002]

[0003] Obstructive sleep apnea (OSA) is characterized by narrowing or obstruction of the upper airway during sleep. This relatively common chronic disorder, often undiagnosed and untreated, can have a wide range of serious long-term consequences, including cardiovascular disease (Drager et al., 2017, Circulation, 136(19):1840-1850), cognitive impairment such as memory loss, impaired concentration, and impaired judgment (Olaithe et al., 2018, Sleep Medicine Reviews, 38:39-49), depression (Wheaton et al., 2012, Sleep, 35(4):461-467), and death or injury from traffic accidents (Stoohs et al., 1994, Sleep, 17(7):619-623). The costs associated with OSA are significant, including lost productivity and workplace and motor vehicle accidents (Sleep Health Foundation, 2017). It has recently been estimated that OSA affects approximately 936 million adults worldwide, and this is expected to increase due to the growing obesity epidemic and an aging global population (Benjafiled et al., 2018, Risk and Prevalence of Sleep Disordered Breathing: A3962-A3962; Grote, 2019, The Lancet Respiratory Medicine, 7(8):645-647).

[0003]

[0004] The current standard of care for treating OSA is continuous positive airway pressure (CPAP), but this therapy has several drawbacks. It can be cumbersome and expensive, and often leads to poor adherence, which significantly reduces its effectiveness. Thus, although CPAP has a high success rate, high levels of patient discomfort lead to low compliance, poor tolerability, and poor long-term adherence in patients. Furthermore, while medications and supplements have been used with varying success to treat insomnia and poor sleep quality, pharmacotherapy for OSA has had little success, and no effective drugs have yet been identified. Thus, there remains a pressing need for the development of pharmacological approaches for the treatment of OSA. Summary of the Invention

[0004]

[0005] In one aspect of the present disclosure, there is provided a method for the treatment of obstructive sleep apnea (OSA), comprising administering to a subject in need thereof delta-9-tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof.

[0005]

[0006] In another aspect of the present disclosure, there is provided the use of THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of OSA.

[0006]

[0007] In another embodiment of the present disclosure, a kit is provided comprising THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating OSA.

[0007]

[0008] In another embodiment of the present disclosure, there is provided a composition comprising THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof.

[0009] Various examples and embodiments of the present invention are herein described, by way of non-limiting example only, with reference to the following figures: [Brief explanation of the drawings]

[0008] [Figure 1]

[0010] 1 is a graphical representation of the dose response to acetazolamide (mg / day; x-axis) and reduction in apnea-hypopnea index (AHI) (%; y-axis) relative to baseline or placebo. [Figure 2]

[0011] 1 is a graphical representation of the dose response to dronabinol (mg / day; x-axis) and reduction in AHI (%; y-axis) relative to baseline or placebo. DETAILED DESCRIPTION OF THE INVENTION

[0009]

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Any materials and methods similar or equivalent to those described herein can be used to practice the present invention.

[0010]

[0013] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a specified element or integer or group of elements or integers, but not the exclusion of any other element or integer or group of elements or integers.

[0011]

[0014] The phrase "consisting of" means including and limited to whatever follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements must be present. The phrase "consisting essentially of" means including any elements listed after this phrase and limited to other elements that do not interfere with or contribute to the activity or function specified in this disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending on whether the other elements affect the activity or function of the listed elements.

[0012]

[0015] As used herein, the singular forms "a," "an," and "the" include plural embodiments unless the context clearly dictates otherwise. Thus, for example, reference to a "compound" includes a single compound as well as two or more compounds, reference to an "agent" includes one agent as well as two or more agents, etc.

[0013]

[0016] The term "about" is understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to persons of ordinary skill in the art, given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.

[0014]

[0017] The present disclosure is premised, at least in part, on the surprising discovery that delta-9-tetrahydrocannabinol (THC), or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof, can act synergistically to stabilize breathing patterns in patients with obstructive sleep apnea (OSA).

[0015]

[0018] Thus, in one aspect disclosed herein, there is provided a method for the treatment of OSA, comprising administering to a subject in need thereof THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof.

[0016] sleep apnea

[0019] The term "sleep apnea," as used herein, refers to a sleep disorder characterized by episodes of interrupted breathing during sleep, resulting in a decrease in oxygen saturation or arousal from sleep. This disruption results in fragmented, non-restorative sleep, usually accompanied by other symptoms, including loud, obstructive snoring, witnessed sleep apneas, and excessive daytime sleepiness.

[0017]

[0020] The term "apnea," as used herein, refers to a complete or near-complete cessation of airflow for at least 10 seconds followed by an arousal and / or an oxygen desaturation of greater than 4%.

[0018]

[0021] The term "hypopnea," as used herein, refers to a reduction in airflow of 30% or more and / or an oxygen desaturation of more than 4% for at least 10 seconds followed by arousal.

[0022] "Obstructive sleep apnea" or "OSA" is characterized by episodes of complete or partial collapse of the airway with associated desaturation of oxygen or arousals from sleep.

[0019]

[0023] OSA may be classified using, for example, the Apnea Hypopnea Index (AHI) or Respiratory Disorder Index (RDI), which are based on the average number of obstructive events per hour, as described by Iber et al. (2007, The AASM Manual for the Scoring of Sleep and Associated Events, 1st Edition). Methods for measuring obstructive events are known to those skilled in the art, an illustrative embodiment of which includes overnight polysomnography (PSG).

[0020]

[0024] The terms "overnight polysomnography," "overnight PSG," "nocturnal polysomnography," or "nocturnal PSG" may be used interchangeably herein to refer to tests used in the diagnosis of OSA. Overnight PSG consists of simultaneous recording of multiple physiological parameters related to sleep and wakefulness. Physiological parameters recorded during PSG are known to those skilled in the art, and illustrative examples include brain activity (e.g., electroencephalogram (EEG)), eye movement (e.g., electrooculogram (EOG)), jaw and leg muscle activity (e.g., electromyogram (EMG)), cardiac rhythm (electrocardiogram (ECG)), respiratory airflow (e.g., via nasal cannula and thermistor), respiratory effort (e.g., via abdominal and thoracic respiratory bands), and peripheral pulse oximetry (e.g., via infrared finger probe). From these parameters, OSA-related indices can be measured, including sleep onset latency, REM sleep onset latency, number of awakenings during sleep, total sleep time, percentage and time in each sleep stage, number of awakenings, AHI, and arterial oxygen saturation.

[0021]

[0025] According to the AHI, the severity of OSA can be classified as asymptomatic / minimal, mild, moderate, or severe (Table 1).

[0022] [Table 1]

[0023]

[0026] Classification of children with OSA can be performed using modified classification thresholds, where mild OSA is defined as an AHI >1 and <5, moderate OSA as an AHI ≥5 and <10, and severe OSA as an AHI ≥10, if one or more of the clinical symptoms of OSA are reported.

[0024]

[0027] In one embodiment, the OSA is mild to severe OSA due to AHI. In another embodiment, the OSA is moderate to severe OSA due to AHI.

[0028] Classification of OSA based on AHI may be made taking into account clinical symptoms such as excessive daytime sleepiness, sleep maintenance disorder, and cognitive dysfunction. For example, if one or more of the clinical symptoms of OSA are reported, an AHI of 5 to 14.9 is classified as mild OSA.

[0025] Tetrahydrocannabinol (THC)

[0029] Delta-9-tetrahydrocannabinolic acid (THCA) is synthesized in the cannabis plant by THCA synthase from the precursor cannabigerolic acid (CBGA) (Table 2). THCA decarboxylates to the neutral form, delta-9-tetrahydrocannabinol (THC), which is associated with cannabis's psychotropic effects, primarily mediated by activation of the CB1 G-protein-coupled receptor, resulting in a decrease in cyclic AMP (cAMP) levels via inhibition of adenylate cyclase. THC also exhibits partial agonist activity at the cannabinoid receptors CB1 and CB2. CB1 is primarily associated with the central nervous system, while CB2 is primarily expressed in cells of the immune system. Consequently, THC is also associated with pain relief, relaxation, fatigue, appetite stimulation, and changes in vision, hearing, and smell. Furthermore, more recent studies have shown that THC mediates anticholinesterase effects, which may suggest its use in the treatment of Alzheimer's disease and myasthenia gravis (Eubanks et al., 2006, Molecular Pharmaceuticals, 3(6):773-7).

[0026] [Table 2]

[0027]

[0030] THC can be extracted from any suitable plant part, including leaves, flowers or stems, and can be produced by any suitable means known to those skilled in the art.For example, THC extract can be produced by extraction using supercritical or subcritical CO2 or by volatilizing plant material with heated gas.Illustrative examples of the method of using THC and other cannabinoids extracted from plant material include the methods described in US Patent No. 10189762 and WO 2004 / 016277.

[0028]

[0031] In one embodiment, the THC described herein is synthetic THC. In a preferred embodiment, the THC is dronabinol.

[0032] Dronabinol is commercially available in capsule form under the trade name Marinol from AbbVie and one or more other manufacturers, distributors, and / or repackaged under a generic (i.e., non-proprietary) name. Dronabinol is also commercially available in liquid form under the trade name Syndros from Insys.

[0029]

[0033] Synthetic THC is particularly useful for pharmaceutical development because it can be prepared largely free of contaminants. Several methods for the synthesis of THC are known in the art, illustrative examples of which include the methods for the synthesis of dronabinol described in U.S. Patent Nos. 7,323,576 and 5,227,537, and U.S. Patent Application No. 11 / 840,585.

[0030]

[0034] The present disclosure further contemplates the use of pharmaceutically acceptable salts of THC. Suitable pharmaceutically acceptable salts of THC are known to those skilled in the art, and illustrative examples thereof include salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids known to those skilled in the art.

[0031] Carbonic anhydrase inhibitors

[0035] As used herein, the term "carbonic anhydrase inhibitor" refers to a class of drugs that inhibit the activity of carbonic anhydrase, an enzyme involved in catalyzing the reaction between carbon dioxide and water to carbonic acid and then bicarbonate ion. Suppression of carbonic anhydrase activity leads to metabolic acidosis, resulting in increased ventilation and oxygenation. Carbonic anhydrase inhibitors are used in the treatment or prevention of acute mountain sickness (i.e., high-altitude injury), as described by Swenson (2014, Carbonic Anhydrase Inhibitors and High Altitude Illness: In Frost and McKenna (eds.), Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry, Vol. 75, Springer, Dordrecht). Suitable carbonic anhydrase inhibitors are known to those skilled in the art, and illustrative examples thereof include acetazolamide, methazolamide, doloramide, and brinzolamide.

[0032]

[0036] In one embodiment, the carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide, methazolamide, doloramide, and brinzolamide. In another embodiment, the carbonic anhydrase inhibitor is a member of the thiadiazoles, sulfonamides, and monocarboxylic acid amides, or pharmaceutically acceptable salts thereof.

[0033]

[0037] In one preferred embodiment, the carbonic anhydrase inhibitor is acetazolamide.

[0038] The present disclosure further contemplates the use of pharmaceutically acceptable salts of the carbonic anhydrase inhibitors. Suitable pharmaceutically acceptable salts of the carbonic anhydrase inhibitors are known to those skilled in the art, and illustrative examples include salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids, well known to those skilled in the art.

[0034] Methods for treating sleep apnea

[0039] The terms "treat," "treating," "treatment," and the like are used interchangeably herein to mean alleviating, reducing, mitigating, ameliorating, or otherwise inhibiting the severity of one or more symptoms of OSA in a subject. It should be understood that the terms "treat," "treating," "treatment," and the like, when used herein, do not imply that a subject is treated until OSA is eradicated or no longer evident. The treatment may reduce the severity of one or more symptoms of OSA.

[0035]

[0040] The term "subject," as used herein, refers to any mammal, including livestock and other farm animals (such as cows, goats, sheep, horses, pigs, and chickens), entertainment animals (such as racehorses), companion animals (such as cats and dogs), clinical trial animals, and humans. In one embodiment, the subject is a human.

[0036]

[0041] It should be understood that THC or its pharmaceutically acceptable salt and carbonic anhydrase inhibitor or its pharmaceutically acceptable salt are administered to the subject who needs it in therapeutically effective amount.As used herein, the term "therapeutically effective amount" generally refers to the amount of THC and the amount of carbonic anhydrase inhibitor that is sufficient to affect one or more beneficial or desired therapeutic outcomes (for example, reducing apnea episodes, reducing hypopnea episodes, reducing AHI, reducing excessive daytime sleepiness, reducing oxygen desaturation index (ODI), improving mood and well-being). The beneficial or desired therapeutic outcome may be quantified by measuring clinical parameters, illustrative examples of which include measurements of arterial oxygen saturation (SaO2) as described by Zamarron et al. (2003, Chest, 123(5):1567-1576), chest and abdominal movement measured by inductance plethysmography as described by Kogan et al. (2016, Respiratory Care, 61(8):1033-1037), nasal airflow as described by de Souse Michels et al. (2014, International Journal of Otolaryngology, 2014:717419), and heart rate spectroscopy as described by Roche et al. (2003, European Respiratory Journal, 22:937-942).Subjective measures of improvement in sleep quality may be developed using clinical methods known in the art, illustrative examples of which include the Epworth Sleepiness Scale (ESS) (Johns, 1991, Sleep, 14:540-545), the Leeds Sleep Evaluation Questionnaire (LSEQ) (Shahid et al., 2011, Leeds Sleep Evaluation Questionnaire (LSEQ), in Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer, New York), the Profile of Mood States (POMS) (McNair et al., 1971, POMS Manual for the Profile of Mood States, San Diego, CA: Educational and Industrial Testing Service), the Short Form 36 (SF-36) (Saris-Baglama et al., 2010, QualityMetric Health Outcomes Scoring Software 4.0, Lincoln, RI) and the Pittsburgh Sleep Quality Index (PSQI) (Buysse et al., 1989, Psychiatry Research, 28(2):193~213).

[0037]

[0042] Changes in OSA symptoms or severity, as measured by any of the quantitative or clinical methods described elsewhere herein, may be expressed using any appropriate statistical measure to demonstrate the extent of reduction in OSA symptoms or severity. In one embodiment, the methods disclosed herein reduce OSA symptoms or severity by at least 10%, preferably at least 20%, preferably at least 30%, preferably at least 40%, preferably at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, or more preferably at least 100%, compared to a subject with OSA who was not administered THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof.

[0038]

[0043] In one embodiment, the methods disclosed herein are useful for reducing AHI in a subject with OSA.

[0044] In one embodiment, the methods disclosed herein are useful for reducing AHI in a subject with OSA by more than 20% compared to a subject with OSA who was not administered THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof.

[0039]

[0045] An effective amount can be provided in one or more administrations. The exact amount required can vary depending on factors such as the nature and severity of the OSA being treated, the age and general health of the subject, and the form in which the active agent is administered.

[0040]

[0046] In one embodiment, the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose of about 1 mg to about 700 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67 mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92 mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114 mg, 115mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 131mg, 134mg, 13 5mg, 136mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 1 56mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 176mg,177mg、178mg、179mg、180mg、181mg、182mg、183mg、184mg、185mg、186mg、187mg、188mg、189mg、190mg、191mg、192mg、193mg、194mg、195mg、196mg、197mg、198mg、199mg、200mg、201mg、202mg、203mg、204mg、205mg、206mg、207mg、208mg、209mg、210mg、211mg、212mg、213mg、214mg、215mg、216mg、217mg、218mg、219mg、220mg、221mg、222mg、223mg、224mg、225mg、226mg、227mg、228mg、229mg、230mg、231mg、232mg、233mg、234mg、235mg、236mg、237mg、238mg、239mg、240mg、241mg、242mg、243mg、244mg、245mg、246mg、247mg、248mg、249mg、250mg、251mg、252mg、253mg、254mg、255mg、256mg、257mg、258mg、259mg、260mg、261mg、262mg、263mg、264mg、265mg、266mg、267mg、268mg、269mg、270mg、271mg、272mg、273mg、274mg、275mg、276mg、277mg、278mg、279mg、280mg、281mg、282mg、283mg、284mg、285mg、286mg、287mg、288mg、289mg、290mg、291mg、292mg、293mg、294mg、295mg、296mg、297mg、298mg、299mg、300mg、301mg、302mg、303mg、304mg、305mg、306mg、307mg、308mg、309mg、310mg、311mg、312mg、313mg、314mg、315mg、316mg、317mg、318mg、319mg、320mg、321mg、322mg、323mg、324mg、325mg、326mg、327mg、328mg、329mg、330mg、331mg、332mg、333mg、334mg、335mg、336mg、337mg、338mg、339mg、340mg、341mg、342mg、343mg、344mg、345mg、346mg、347mg、348mg、349mg、350mg、351mg、352mg、353mg、354mg、355mg、356mg、357mg、358mg、359mg、360mg、361mg、362mg、363mg、364mg、365mg、366mg、367mg、368mg、369mg、370mg、371mg、372mg、373mg、374mg、375mg、376mg、377mg、378mg、379mg、380mg、381mg、382mg、383mg、384mg、385mg、386mg、387mg、388mg、389mg、390mg、391mg、392mg、393mg、394mg、395mg、396mg、397mg、398mg、399mg、400mg、401mg、402mg、403mg、404mg、405mg、406mg、407mg、408mg、409mg、410mg、411mg、412mg、413mg、414mg、415mg、416mg、417mg、418mg、419mg、420mg、421mg、422mg、423mg、424mg、425mg、426mg、427mg、428mg、429mg、430mg、431mg、432mg、434mg、434mg、435mg、436mg、437mg、438mg、439mg、440mg、441mg、442mg、443mg、444mg、445mg、446mg、447mg、448mg、449mg、450mg、451mg、452mg、453mg、454mg、455mg、456mg、457mg、458mg、459mg、460mg、461mg、462mg、463mg、464mg、465mg、466mg、467mg、468mg、469mg、470mg、471mg、472mg、473mg、474mg、475mg、476mg、477mg、478mg、479mg、480mg、481mg、482mg、483mg、484mg、485mg、486mg、487mg、488mg、489mg、490mg、491mg、492mg、493mg、494mg、495mg、496mg、497mg、498mg、499mg、500mg、501mg、502mg、503mg、504mg、505mg、506mg、507mg、508mg、509mg、510mg、511mg、512mg、513mg、514mg、515mg、516mg、517mg、518mg、519mg、520mg、521mg、522mg、523mg、524mg、525mg、526mg、527mg、528mg、529mg、530mg、531mg、532mg、535mg、534mg、535mg、536mg、537mg、538mg、539mg、540mg、541mg、542mg、543mg、544mg、545mg、546mg、547mg、548mg、549mg、550mg、551mg、552mg、553mg、554mg、555mg、556mg、557mg、558mg、559mg、560mg、561mg、562mg、563mg、564mg、565mg、566mg、567mg、568mg、569mg、570mg、571mg、572mg、573mg、574mg、575mg、576mg、577mg、578mg、579mg、580mg、581mg、582mg、583mg、584mg、585mg、586mg、587mg、588mg、589mg、590mg、591mg、592mg、593mg、594mg、595mg、596mg、597mg、598mg、599mg、600mg、601mg、602mg、603mg、604mg、605mg、606mg、607mg、608mg、609mg、610mg、611mg、612mg、613mg、614mg、615mg、616mg、617mg、618mg、619mg、620mg、621mg、622mg、623mg、624mg、625mg、626mg、627mg、628mg、629mg、630mg、631mg、632mg、636mg、634mg、635mg、636mg、637mg、638mg、639mg、640mg、641mg、642mg、643mg、644mg、645mg、646mg、647mg、648mg、649mg、650mg、651mg、652mg、653mg、654mg、655mg、656mg、657mg、658mg、659mg、660mg、661mg、662mg、663mg、664mg、665mg、666mg、667mg、668mg、669mg、670mg、671mg、672mg、673mg、674mg、It is administered in doses of 675 mg, 676 mg, 677 mg, 678 mg, 679 mg, 680 mg, 681 mg, 682 mg, 683 mg, 684 mg, 685 mg, 686 mg, 687 mg, 688 mg, 689 mg, 690 mg, 691 mg, 692 mg, 693 mg, 694 mg, 695 mg, 696 mg, 697 mg, 698 mg, 699 mg, or 700 mg.

[0041]

[0047] Thus, in one embodiment, the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg to about 700 mg, preferably about 1 mg, preferably about 2 mg, preferably about 3 mg, preferably about 4 mg, preferably about 5 mg, preferably about 6 mg, preferably about 7 mg, preferably about 8 mg, preferably about 9 mg, preferably about 10 mg, preferably about 11 mg, preferably about 12 mg, preferably about 13 mg, preferably about 14 mg, preferably about 15 mg, preferably about 16 mg, preferably about 17 mg, preferably about 18 mg, preferably about 19 mg. g, preferably about 20 mg, preferably about 21 mg, preferably about 22 mg, preferably about 23 mg, preferably about 24 mg, preferably about 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, preferably about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36 mg, preferably about 37 mg, preferably about 38 mg, preferably about 39 mg, preferably about 40 mg, preferably about 41 mg, preferably about 42 mg, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, preferably about 63 mg, preferably about 64 mg, or about 65 mg, preferably about 66 mg, preferably about 67 mg, preferably about 68 mg, preferably about 69 mg, preferably about 70 mg, preferably about 71 mg, preferably about 72 mg, preferably about 73 mg, preferably about 74 mg, preferably about 75 mg, preferably about 76 mg, preferably about 77 mg, preferably about 78 mg, preferably about 79 mg, preferably about 80 mg, preferably about 81 mg, preferably about 82 mg, preferably about 83 mg, preferably about 84 mg, preferably about 85 mg, preferably about 86 mg, preferably about 87 mg,Preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg, preferably about 98 mg, preferably about 99 mg, preferably about 100 mg, preferably about 101 mg, preferably about 102 mg, preferably about 103 mg, preferably about 104 mg, preferably about 105 mg, preferably about 106 mg, preferably about 107 mg, preferably about 108 mg, preferably about 109 mg, preferably about 110 mg, preferably about 111 mg, preferably about 112 mg, preferably about 113 mg, preferably about 114 mg, preferably about 115 mg, preferably about 116 mg, preferably about 117 mg, preferably about 118 mg, preferably about 119 mg, preferably about 120 mg, preferably about 121 mg, preferably about 122 mg, preferably about 123 mg, preferably about 124 mg, preferably about 125 mg, preferably about 126 mg, preferably about 127 mg, preferably about 128 mg, preferably about 129 mg, preferably about 130 mg, preferably about 131 mg, preferably about 132 mg, preferably about 131 mg, preferably about 134 mg, preferably about 135 mg, preferably about 136 mg, preferably about 137 mg, preferably about 138 mg, preferably about 139 mg, preferably about 140 mg, preferably about 141 mg, preferably about 142 mg, preferably about 143 mg, preferably about 144 mg, preferably about 145 mg, preferably about 146 mg, preferably about 147 mg, preferably about 148 mg, preferably about 149 mg, preferably about 150 mg, or about 151 mg, preferably about 152 mg, preferably about 153 mg, preferably about 154 mg, preferably about 155 mg, preferably about 156 mg, preferably about 157 mg, preferably about 158 ​​mg, preferably about 159 mg, preferably about 160 mg, preferably about 161 mg, preferably about 162 mg, preferably about 163 mg, preferably about 164 mg, preferably about 165 mg, preferably about 166 mg, preferably about 167 mg, preferably about 168 mg, preferably about 169 mg, preferably about 170 mg, preferably about 171 mg,Preferably about 172 mg, preferably about 173 mg, preferably about 174 mg, preferably about 175 mg, preferably about 176 mg, preferably about 177 mg, preferably about 178 mg, preferably about 179 mg, preferably about 180 mg, preferably about 181 mg, preferably about 182 mg, preferably about 183 mg, preferably about 184 mg, preferably about 185 mg, preferably about 186 mg, preferably about 187 mg, preferably about 188 mg, preferably about 189 mg, preferably about 190 mg, preferably about 191 mg, preferably about 192 mg mg, preferably about 193 mg, preferably about 194 mg, preferably about 195 mg, preferably about 196 mg, preferably about 197 mg, preferably about 198 mg, preferably about 199 mg, preferably about 200 mg, preferably about 201 mg, preferably about 202 mg, preferably about 203 mg, preferably about 204 mg, preferably about 205 mg, preferably about 206 mg, preferably about 207 mg, preferably about 208 mg, preferably about 209 mg, preferably about 210 mg, preferably about 211 mg, preferably about 212 mg, 213 mg, preferably about 214 mg, preferably about 215 mg, preferably about 216 mg, preferably about 217 mg, preferably about 218 mg, preferably about 219 mg, preferably about 220 mg, preferably about 221 mg, preferably about 222 mg, preferably about 223 mg, preferably about 224 mg, preferably about 225 mg, preferably about 226 mg, preferably about 227 mg, preferably about 228 mg, preferably about 229 mg, preferably about 230 mg, preferably about 231 mg, preferably about 232 mg, preferably about 233 mg, or about 234 mg, preferably about 235 mg, preferably about 236 mg, preferably about 237 mg, preferably about 238 mg, preferably about 239 mg, preferably about 240 mg, preferably about 241 mg, preferably about 242 mg, preferably about 243 mg, preferably about 244 mg, preferably about 245 mg, preferably about 246 mg, preferably about 247 mg, preferably about 248 mg, preferably about 249 mg, preferably about 250 mg, preferably about 251 mg, preferably about 252 mg, preferably about 253 mg, preferably about 254 mg,Preferably about 255 mg, preferably about 256 mg, preferably about 257 mg, preferably about 258 mg, preferably about 259 mg, preferably about 260 mg, preferably about 261 mg, preferably about 262 mg, preferably about 263 mg, preferably about 264 mg, preferably about 265 mg, preferably about 266 mg, preferably about 267 mg, preferably about 268 mg, preferably about 269 mg, preferably about 270 mg, preferably about 271 mg, preferably about 272 mg, preferably about 273 mg, preferably about 274 mg, preferably about 275 mg, preferably about 276 mg, preferably about 277 mg, preferably about 278 mg, preferably about 279 mg, preferably about 280 mg, preferably about 281 mg, preferably about 282 mg, preferably about 283 mg, preferably about 284 mg, preferably about 285 mg, preferably about 286 mg, preferably about 287 mg, preferably about 288 mg, preferably about 289 mg, preferably about 290 mg, preferably about 291 mg, preferably about 292 mg, preferably about 293 mg, preferably about 294 mg, preferably about 295 mg, preferably about 296 mg, preferably about 297 mg, preferably about 298 mg, preferably about 299 mg, preferably about 300 mg, preferably about 301 mg, preferably about 302 mg, preferably about 303 mg, preferably about 304 mg, preferably about 305 mg, preferably about 306 mg, preferably about 307 mg, preferably about 308 mg, preferably about 309 mg, preferably about 310 mg, preferably about 311 mg, preferably about 312 mg, preferably about 313 mg, preferably about 314 mg, preferably about 315 mg, preferably about 316 mg, or about 317 mg, preferably about 318 mg, preferably about 319 mg, preferably about 320 mg, preferably about 321 mg, preferably about 322 mg, preferably about 323 mg, preferably about 324 mg, preferably about 325 mg, preferably about 326 mg, preferably about 327 mg, preferably about 328 mg, preferably about 329 mg, preferably about 330 mg, preferably about 331 mg, preferably about 332 mg, preferably about 333 mg, preferably about 334 mg, preferably about 335 mg, preferably about 336 mg, preferably about 337 mg,Preferably about 338 mg, preferably about 339 mg, preferably about 340 mg, preferably about 341 mg, preferably about 342 mg, preferably about 343 mg, preferably about 344 mg, preferably about 345 mg, preferably about 346 mg, preferably about 347 mg, preferably about 348 mg, preferably about 349 mg, preferably about 350 mg, preferably about 351 mg, preferably about 352 mg, preferably about 353 mg, preferably about 354 mg, preferably about 355 mg, preferably about 356 mg, preferably about 357 mg, preferably about 358 mg, preferably about 359 mg, preferably about 360 mg, preferably about 361 mg, preferably about 362 mg, preferably about 363 mg, preferably about 364 mg, preferably about 365 mg, preferably about 366 mg, preferably about 367 mg, preferably about 368 mg, preferably about 369 mg, preferably about 370 mg, preferably about 371 mg, preferably about 372 mg, preferably about 373 mg, preferably about 374 mg, preferably about 375 mg, preferably about 376 mg, preferably about 377 mg, preferably about 378 mg, preferably about 379 mg, preferably about 380 mg, preferably about 381 mg, preferably about 382 mg, preferably about 383 mg, preferably about 384 mg, preferably about 385 mg, preferably about 386 mg, preferably about 387 mg, preferably about 388 mg, preferably about 389 mg, preferably about 390 mg, preferably about 391 mg, preferably about 392 mg, preferably about 393 mg, preferably about 394 mg, preferably about 395 mg, preferably about 396 mg, preferably about 397 mg, preferably about 398 mg, preferably about 399 mg, or about 400 mg, preferably about 401 mg, preferably about 402 mg, preferably about 403 mg, preferably about 404 mg, preferably about 405 mg, preferably about 406 mg, preferably about 407 mg, preferably about 408 mg, preferably about 409 mg, preferably about 410 mg, preferably about 411 mg, preferably about 412 mg, preferably about 413 mg, preferably about 414 mg, preferably about 415 mg, preferably about 416 mg, preferably about 417 mg, preferably about 418 mg, preferably about 419 mg, preferably about 420 mg,Preferably about 421 mg, preferably about 422 mg, preferably about 423 mg, preferably about 424 mg, preferably about 425 mg, preferably about 426 mg, preferably about 427 mg, preferably about 428 mg, preferably about 429 mg, preferably about 430 mg, preferably about 431 mg, preferably Preferably about 432 mg, preferably about 434 mg, preferably about 434 mg, preferably about 435 mg, preferably about 436 mg, preferably about 437 mg, preferably about 438 mg, preferably about 439 mg, preferably about 440 mg, preferably about 441 mg, preferably about 442 mg, preferably about 443 mg, preferably about 444 mg, preferably about 445 mg, preferably about 446 mg, preferably about 447 mg, preferably about 448 mg, preferably about 449 mg, preferably about 450 mg, preferably about 451 mg, preferably about 452 mg mg, preferably about 453 mg, preferably about 454 mg, preferably about 455 mg, preferably about 456 mg, preferably about 457 mg, preferably about 458 mg, preferably about 459 mg, preferably about 460 mg, preferably about 461 mg, preferably about 462 mg, preferably about 463 mg, preferably about 464 mg, preferably about 465 mg, preferably about 466 mg, preferably about 467 mg, preferably about 468 mg, preferably about 469 mg, preferably about 470 mg, preferably about 471 mg, preferably about 472 mg, 473 mg, preferably about 474 mg, preferably about 475 mg, preferably about 476 mg, preferably about 477 mg, preferably about 478 mg, preferably about 479 mg, preferably about 480 mg, preferably about 481 mg, preferably about 482 mg, preferably about 483 mg, preferably about 484 mg, preferably about 485 mg, preferably about 486 mg, preferably about 487 mg, preferably about 488 mg, preferably about 489 mg, preferably about 490 mg, preferably about 491 mg, preferably about 492 mg, preferably about 493 mg, or about 494 mg, preferably about 495 mg, preferably about 496 mg, preferably about 497 mg, preferably about 498 mg, preferably about 499 mg, preferably about 500 mg, preferably about 501 mg, preferably about 502 mg, preferably about 503 mg, preferably about 504 mg, preferably about 505 mg, preferably about 506 mg, preferably about 507 mg, preferably about 508 mg, preferably about 509 mg, preferably about 510 mg, preferably about 511 mg, preferably about 512 mg, preferably about 513 mg, preferably about 514 mg,Preferably about 515 mg, preferably about 516 mg, preferably about 517 mg, preferably about 518 mg, preferably about 519 mg, preferably about 520 mg, preferably about 521 mg, preferably about 522 mg, preferably about 523 mg, preferably about 524 mg, preferably about 525 mg, preferably about 526 mg, preferably about 527 mg, preferably about 528 mg, preferably about 529 mg, preferably about 530 mg, preferably about 531 mg, preferably about 532 mg, preferably about 535 mg, preferably about 534 mg, preferably about 535 mg, preferably about 536 mg, preferably about 537 mg, preferably about 538 mg, preferably about 539 mg, preferably about 540 mg, preferably about 541 mg, preferably about 542 mg, preferably about 543 mg, preferably about 544 mg, preferably about 545 mg, preferably about 546 mg, preferably about 547 mg, preferably about 548 mg, preferably about 549 mg, preferably about 550 mg, preferably about 551 mg, preferably about 552 mg, preferably about 553 mg, preferably about 554 mg, preferably about 555 mg, 556 mg, preferably about 557 mg, preferably about 558 mg, preferably about 559 mg, preferably about 560 mg, preferably about 561 mg, preferably about 562 mg, preferably about 563 mg, preferably about 564 mg, preferably about 565 mg, preferably about 566 mg, preferably about 567 mg, preferably about 568 mg, preferably about 569 mg, preferably about 570 mg, preferably about 571 mg, preferably about 572 mg, preferably about 573 mg, preferably about 574 mg, preferably about 575 mg, preferably about 576 mg, or about 577 mg, preferably about 578 mg, preferably about 579 mg, preferably about 580 mg, preferably about 581 mg, preferably about 582 mg, preferably about 583 mg, preferably about 584 mg, preferably about 585 mg, preferably about 586 mg, preferably about 587 mg, preferably about 588 mg, preferably about 589 mg, preferably about 590 mg, preferably about 591 mg, preferably about 592 mg, preferably about 593 mg, preferably about 594 mg, preferably about 595 mg, preferably about 596 mg, preferably about 597 mg,Preferably about 598 mg, preferably about 599 mg, preferably about 600 mg, preferably about 601 mg, preferably about 602 mg, preferably about 603 mg, preferably about 604 mg, preferably about 605 mg, preferably about 606 mg, preferably about 607 mg, preferably about 608 mg, preferably about 609 mg, preferably about 610 mg, preferably about 611 mg, preferably about 612 mg, preferably about 613 mg, preferably about 614 mg, preferably about 615 mg, preferably about 616 mg, preferably about 617 mg, preferably about 618 mg mg, preferably about 619 mg, preferably about 620 mg, preferably about 621 mg, preferably about 622 mg, preferably about 623 mg, preferably about 624 mg, preferably about 625 mg, preferably about 626 mg, preferably about 627 mg, preferably about 628 mg, preferably about 629 mg, preferably about 630 mg, preferably about 631 mg, preferably about 632 mg, preferably about 636 mg, preferably about 634 mg, preferably about 635 mg, preferably about 636 mg, preferably about 637 mg, preferably about 638 mg, 639 mg, preferably about 640 mg, preferably about 641 mg, preferably about 642 mg, preferably about 643 mg, preferably about 644 mg, preferably about 645 mg, preferably about 646 mg, preferably about 647 mg, preferably about 648 mg, preferably about 649 mg, preferably about 650 mg, preferably about 651 mg, preferably about 652 mg, preferably about 653 mg, preferably about 654 mg, preferably about 655 mg, preferably about 656 mg, preferably about 657 mg, preferably about 658 mg, preferably about 659 mg, or about 660 mg, preferably about 661 mg, preferably about 662 mg, preferably about 663 mg, preferably about 664 mg, preferably about 665 mg, preferably about 666 mg, preferably about 667 mg, preferably about 668 mg, preferably about 669 mg, preferably about 670 mg, preferably about 671 mg, preferably about 672 mg, preferably about 673 mg, preferably about 674 mg, preferably about 675 mg, preferably about 676 mg, preferably about 677 mg, preferably about 678 mg, preferably about 679 mg, preferably about 680 mg,Preferably administered at a dose of about 681 mg, preferably about 682 mg, preferably about 683 mg, preferably about 684 mg, preferably about 685 mg, preferably about 686 mg, preferably about 687 mg, preferably about 688 mg, preferably about 689 mg, preferably about 690 mg, preferably about 691 mg, preferably about 692 mg, preferably about 693 mg, preferably about 694 mg, preferably about 695 mg, preferably about 696 mg, preferably about 697 mg, preferably about 698 mg, preferably about 699 mg or more preferably about 700 mg.

[0042]

[0048] In one embodiment, the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose selected from the group consisting of about 25 mg, about 125 mg, about 250 mg, and about 250 mg.

[0043]

[0049] In one embodiment, THC or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 0.25 mg to about 20 mg (e.g., 0.25 mg, 0.50 mg, 0.75 mg, 1 mg, 1.25 mg, 1.50 mg, 1.75 mg, 2 mg, 2.25 mg, 2.50 mg, 2.75 mg, 3 mg, 3.25 mg, 3.50 mg, 3.75 mg, 4 mg, 4.25 mg, 4.50 mg, 4.75 mg, 5 mg, 5.25 mg, 5.50 mg, 5.75 mg, 6 mg, 6.25 mg, 6.50 mg, 6.75 mg, 7 mg, 7.25 mg, 7.50 mg, 7.75 mg, 8 mg, 8.25 mg, 8.50 mg, 8.75 mg, 9 mg, 9.25 mg, 9.50 mg, 9.75 mg, 10 mg, 10 .25mg, 10.50mg, 10.75mg, 11mg, 11.25mg, 11.50mg, 11.75mg, 12mg, 12.25mg, 12.50mg, 12. 75mg, 13mg, 13.25mg, 13.50mg, 13.75mg, 14mg, 14.25mg, 14.50mg, 14.75mg, 15mg, 15.25mg , 15.50mg, 15.75mg, 16mg, 16.25mg, 16.50mg, 16.75mg, 17mg, 17.25mg, 17.50mg, 17.75mg, 18mg, 18.25mg, 18.50mg, 18.75mg, 19mg, 19.25mg, 19.50mg, 19.75mg, or 20mg).

[0044]

[0050] Thus, in one embodiment, THC or a pharmaceutically acceptable salt thereof is present in an amount of from about 0.25 mg to about 20 mg, preferably about 0.25 mg, preferably about 0.50 mg, preferably about 0.75 mg, preferably about 1 mg, preferably about 1.25 mg, preferably about 1.50 mg, preferably about 1.75 mg, preferably about 2 mg, preferably about 2.25 mg, preferably about 2.50 mg, preferably about 2.75 mg, preferably about 3 mg, preferably about 3.25 mg, preferably about 3.50 mg, preferably about 3.75 mg, preferably about 4 mg, preferably about 4.25 mg, preferably about 4.50 mg, preferably about 4.75 mg, preferably about 5 mg, preferably about 5.25 mg, preferably about 5.50 mg, preferably about 5.75 mg, preferably about 6 mg, preferably about 6.25 mg, preferably about 6.50 mg, preferably about 6.75 mg, preferably about 7 mg, preferably about 7.25 mg, preferably about 7.50 mg, preferably about 7.75 mg, preferably about 8 mg, preferably about 8.25 mg, preferably about 8.50 mg, preferably about 8.75 mg, preferably about 9 mg, preferably about 9.25 mg g, preferably about 9.50 mg, preferably about 9.75 mg, preferably about 10 mg, preferably about 10.25 mg, preferably about 10.50 mg, preferably about 10.75 mg, preferably about 11 mg, preferably about 11.25 mg, preferably about 11.50 mg, preferably about 11.75 mg, preferably about 12 mg, preferably about 12.25 mg, preferably about 12.50 mg, preferably about 12.75 mg, preferably about 13 mg, preferably about 13.25 mg, preferably about 13.50 mg, preferably about 13.75 mg, preferably about 14 mg , preferably about 14.25 mg, preferably about 14.50 mg, preferably about 14.75 mg, preferably about 15 mg, preferably about 15.25 mg, preferably about 15.50 mg, preferably about 15.75 mg, preferably about 16 mg, preferably about 16.25 mg, preferably about 16.50 mg, preferably about 16.75 mg, preferably about 17 mg, preferably about 17.25 mg, preferably about 17.50 mg, preferably about 17.75 mg, preferably about 18 mg, preferably about 18.25 mg, preferably about 18.50 mg, preferably about 18.It is administered in a dose of about 75 mg, preferably about 19 mg, preferably about 19.25 mg, preferably about 19.50 mg, preferably about 19.75 mg, or more preferably about 20 mg.

[0045]

[0051] In one embodiment, the THC or a pharmaceutically acceptable salt thereof is administered at a dose selected from the group consisting of about 0.5 mg, about 2.5 mg, about 5 mg, and about 10 mg.

[0046]

[0052] In one embodiment, the THC or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.5 mg and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose of about 25 mg.

[0047]

[0053] In one embodiment, the THC or a pharmaceutically acceptable salt thereof is administered in a dose of about 2.5 mg and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose of about 125 mg.

[0048]

[0054] In one embodiment, the THC or a pharmaceutically acceptable salt thereof is administered in a dose of about 5 mg and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose of about 250 mg.

[0049]

[0055] In one embodiment, the THC or a pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose of about 500 mg.

[0050]

[0056] THC or its pharmaceutically acceptable salt and carbonic anhydrase inhibitor or its pharmaceutically acceptable salt may be administered orally, topically, parenterally, transdermally, by inhalation, intranasally, by irrigation, by a deposit, by insufflation, topically to the eye, or through the ear. THC or its pharmaceutically acceptable salt and carbonic anhydrase inhibitor or its pharmaceutically acceptable salt may be administered in dosage units as a formulation containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and solvents. Formulations include liposomes, nanoparticles, microparticles, polymer-based formulations, dispersions, suspensions, device coatings, powders, microspheres, carrier-mediated formulations, deposits, and encapsulations.

[0051]

[0057] The term "parenteral" as used herein includes subcutaneous injections, aerosol for administration to the lungs or nasal cavity, intravenous, intramuscular, intrathecal, intracranial, injection or infusion techniques.

[0058] Oral administration of THC has been demonstrated to be an effective route of administration (Goodwin et al., 2006, Therapeutic Drug Monitoring, 28(4):545-551). Similarly, oral administration of carbonic anhydrase inhibitors such as acetazolamide has been demonstrated to be effective in terms of absorption and bioavailability (Wallace et al., 1977, Journal of Pharmaceutical Sciences, 66(4):527-530).

[0052]

[0059] Thus, in a preferred embodiment, THC or a pharmaceutically acceptable salt thereof and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are orally administered to a subject.

[0053]

[0060] Suitable dosage forms for oral administration are known to those skilled in the art, illustrative examples of which include tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, solutions, syrups, or elixirs.

[0054]

[0061] In one embodiment, the THC or a pharmaceutically acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are in liquid, oil, tablet, or capsule form.

[0055]

[0062] Dosage forms for oral administration may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to produce pharmaceutically elegant and palatable preparations. Suitable sweeteners include sucrose, lactose, glucose, aspartame, or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid, or agar. Suitable flavoring agents include peppermint oil, wintergreen oil, cherry, orange, or raspberry flavoring. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methylparaben, propylparaben, or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride, or talc. Suitable time-delay agents include glyceryl monostearate or glyceryl distearate.

[0056]

[0063] Dosage forms for oral administration may also contain suitable pharmaceutically acceptable carriers, diluents, or excipients known to those skilled in the art, illustrative examples of which include inert diluents (e.g., calcium carbonate, lactose, calcium phosphate, or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binders (e.g., starch, gelatin, or acacia gum), lubricants (e.g., magnesium stearate, stearic acid, or talc), medium-chain triglyceride oils (e.g., sesame oil), and materials that delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period (e.g., glyceryl monostearate or glyceryl distearate, microcrystalline cellulose). Coatings may also be carried out to form osmotic therapeutic tablets for controlled release, using techniques described in U.S. Patent Nos. 4,256,108, 4,160,452, and 4,265,874.

[0057]

[0064] It is further contemplated herein that THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof, may be co-administered with one or more other suitable therapeutic agents, illustrative examples of which include anti-inflammatory agents, bronchodilators, and nasal decongestants.

[0058]

[0065] In one aspect disclosed herein, there is provided the use of THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of OSA.

[0059]

[0066] In another embodiment disclosed herein, there is provided THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of OSA.

[0060]

[0067] In accordance with the methods disclosed herein, THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof, may be co-administered as separate compositions.

[0061]

[0068] In one embodiment, the THC or a pharmaceutically acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are administered sequentially.

[0069] By "sequential" administration, it is intended that there is an interval between the administration of THC or a pharmaceutically acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof. The interval between sequential administrations may be a few seconds, minutes, hours, or days. In a preferred embodiment, the interval between sequential administrations of THC or a pharmaceutically acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof is less than 1 hour, preferably less than 30 minutes, and most preferably less than 1 minute. The sequential administrations may be in any order (i.e., administration of THC or a pharmaceutically acceptable salt thereof before administration of the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof, or administration of the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof before administration of THC or a pharmaceutically acceptable salt thereof).

[0062]

[0070] In another embodiment, the THC, or a pharmaceutically acceptable salt thereof, and the carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof, are administered simultaneously.

[0071] By "concurrent" administration, it is intended that the THC or a pharmaceutically acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are administered at the same time. In accordance with the methods disclosed herein, the THC or a pharmaceutically acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof may be administered simultaneously as two separate compositions or dosage forms. Alternatively, the THC or an acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are administered simultaneously as a single composition or dosage form.

[0063]

[0072] Thus, in one embodiment, there is provided a composition comprising delta-9-tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof.

[0064]

[0073] In another embodiment, there is provided a composition comprising delta-9-tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof, for use in the treatment of OSA.

[0065]

[0074] In a preferred embodiment, the composition comprising THC or a pharmaceutically acceptable salt thereof and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof is formulated for oral administration.

[0066]

[0075] In one embodiment, the composition provides from about 0.25 mg to about 20 mg (e.g., 0.25 mg, 0.50 mg, 0.75 mg, 1 mg, 1.25 mg, 1.50 mg, 1.75 mg, 2 mg, 2.25 mg, 2.50 mg, 2.75 mg, 3 mg, 3.25 mg, 3.50 mg, 3.75 mg, 4 mg, 4.25 mg, 4.50 mg, 4.75 mg, 5 mg, 5.25 mg, 5.50 mg, 5.75 mg, 6 mg, 6.25 mg, 6.50 mg, 6.75 mg, 7 mg, 7.25 mg, 7.50 mg, 7.75 mg, 8 mg, 8.25 mg, 8.50 mg, 8.75 mg, 9 mg, 9.25 mg, 9.50 mg, 9.75 mg) of THC or a pharmaceutically acceptable salt thereof per dose. g, 10mg, 10.25mg, 10.50mg, 10.75mg, 11mg, 11.25mg, 11.50mg, 11.75mg, 12mg, 12.25mg, 12. 50mg, 12.75mg, 13mg, 13.25mg, 13.50mg, 13.75mg, 14mg, 14.25mg, 14.50mg, 14.75mg, 15mg, 15.25mg, 15.50mg, 15.75mg, 16mg, 16.25mg, 16.50mg, 16.75mg, 17mg, 17.25mg, 17.50mg, 17.75mg, 18mg, 18.25mg, 18.50mg, 18.75mg, 19mg, 19.25mg, 19.50mg, 19.75mg, or 20mg).

[0067]

[0076] Thus, in one embodiment, the composition contains about 0.25 mg to about 20 mg, preferably about 0.25 mg, preferably about 0.50 mg, preferably about 0.75 mg, preferably about 1 mg, preferably about 1.25 mg, preferably about 1.50 mg, preferably about 1.75 mg, preferably about 2 mg, preferably about 2.25 mg, preferably about 2.50 mg, preferably about 2.75 mg, preferably about 3 mg, preferably about 3.25 mg, preferably about 3.50 mg, preferably about 3.75 mg, preferably about is about 4 mg, preferably about 4.25 mg, preferably about 4.50 mg, preferably about 4.75 mg, preferably about 5 mg, preferably about 5.25 mg, preferably about 5.50 mg, preferably about 5.75 mg, preferably about 6 mg, preferably about 6.25 mg, preferably about 6.50 mg, preferably about 6.75 mg, preferably about 7 mg, preferably about 7.25 mg, preferably about 7.50 mg, preferably about 7.75 mg, preferably about 8 mg, preferably about 8.25 mg, preferably about 8.50 mg, preferably about 8.75 mg, preferably about 9 mg g, preferably about 9.25 mg, preferably about 9.50 mg, preferably about 9.75 mg, preferably about 10 mg, preferably about 10.25 mg, preferably about 10.50 mg, preferably about 10.75 mg, preferably about 11 mg, preferably about 11.25 mg, preferably about 11.50 mg, preferably about 11.75 mg, preferably about 12 mg, preferably about 12.25 mg, preferably about 12.50 mg, preferably about 12.75 mg, preferably about 13 mg, preferably about 13.25 mg, preferably about 13.50 mg, preferably about 13.7 5 mg, preferably about 14 mg, preferably about 14.25 mg, preferably about 14.50 mg, preferably about 14.75 mg, preferably about 15 mg, preferably about 15.25 mg, preferably about 15.50 mg, preferably about 15.75 mg, preferably about 16 mg, preferably about 16.25 mg, preferably about 16.50 mg, preferably about 16.75 mg, preferably about 17 mg, preferably about 17.25 mg, preferably about 17.50 mg, preferably about 17.75 mg, preferably about 18 mg, preferably about 18.25 mg, preferably about 18.50 mg, preferably about 18.75 mg, preferably about 19 mg, preferably about 19.25 mg, preferably about 19.50 mg, preferably about 19.75 mg, or more preferably about 20 mg.

[0068]

[0077] In one embodiment, the composition provides a single dose of about 1 mg to about 700 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112 mg, 113mg, 114mg, 115mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 13 1mg, 134mg, 135mg, 136mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 1 54mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg,175mg、176mg、177mg、178mg、179mg、180mg、181mg、182mg、183mg、184mg、185mg、186mg、187mg、188mg、189mg、190mg、191mg、192mg、193mg、194mg、195mg、196mg、197mg、198mg、199mg、200mg、201mg、202mg、203mg、204mg、205mg、206mg、207mg、208mg、209mg、210mg、211mg、212mg、213mg、214mg、215mg、216mg、217mg、218mg、219mg、220mg、221mg、222mg、223mg、224mg、225mg、226mg、227mg、228mg、229mg、230mg、231mg、232mg、233mg、234mg、235mg、236mg、237mg、238mg、239mg、240mg、241mg、242mg、243mg、244mg、245mg、246mg、247mg、248mg、249mg、250mg、251mg、252mg、253mg、254mg、255mg、256mg、257mg、258mg、259mg、260mg、261mg、262mg、263mg、264mg、265mg、266mg、267mg、268mg、269mg、270mg、271mg、272mg、273mg、274mg、275mg、276mg、277mg、278mg、279mg、280mg、281mg、282mg、283mg、284mg、285mg、286mg、287mg、288mg、289mg、290mg、291mg、292mg、293mg、294mg、295mg、296mg、297mg、298mg、299mg、300mg、301mg、302mg、303mg、304mg、305mg、306mg、307mg、308mg、309mg、310mg、311mg、312mg、313mg、314mg、315mg、316mg、317mg、318mg、319mg、320mg、321mg、322mg、323mg、324mg、325mg、326mg、327mg、328mg、329mg、330mg、331mg、332mg、333mg、334mg、335mg、336mg、337mg、338mg、339mg、340mg、341mg、342mg、343mg、344mg、345mg、346mg、347mg、348mg、349mg、350mg、351mg、352mg、353mg、354mg、355mg、356mg、357mg、358mg、359mg、360mg、361mg、362mg、363mg、364mg、365mg、366mg、367mg、368mg、369mg、370mg、371mg、372mg、373mg、374mg、375mg、376mg、377mg、378mg、379mg、380mg、381mg、382mg、383mg、384mg、385mg、386mg、387mg、388mg、389mg、390mg、391mg、392mg、393mg、394mg、395mg、396mg、397mg、398mg、399mg、400mg、401mg、402mg、403mg、404mg、405mg、406mg、407mg、408mg、409mg、410mg、411mg、412mg、413mg、414mg、415mg、416mg、417mg、418mg、419mg、420mg、421mg、422mg、423mg、424mg、425mg、426mg、427mg、428mg、429mg、430mg、431mg、432mg、434mg、434mg、435mg、436mg、437mg、438mg、439mg、440mg、441mg、442mg、443mg、444mg、445mg、446mg、447mg、448mg、449mg、450mg、451mg、452mg、453mg、454mg、455mg、456mg、457mg、458mg、459mg、460mg、461mg、462mg、463mg、464mg、465mg、466mg、467mg、468mg、469mg、470mg、471mg、472mg、473mg、474mg、475mg、476mg、477mg、478mg、479mg、480mg、481mg、482mg、483mg、484mg、485mg、486mg、487mg、488mg、489mg、490mg、491mg、492mg、493mg、494mg、495mg、496mg、497mg、498mg、499mg、500mg、501mg、502mg、503mg、504mg、505mg、506mg、507mg、508mg、509mg、510mg、511mg、512mg、513mg、514mg、515mg、516mg、517mg、518mg、519mg、520mg、521mg、522mg、523mg、524mg、525mg、526mg、527mg、528mg、529mg、530mg、531mg、532mg、535mg、534mg、535mg、536mg、537mg、538mg、539mg、540mg、541mg、542mg、543mg、544mg、545mg、546mg、547mg、548mg、549mg、550mg、551mg、552mg、553mg、554mg、555mg、556mg、557mg、558mg、559mg、560mg、561mg、562mg、563mg、564mg、565mg、566mg、567mg、568mg、569mg、570mg、571mg、572mg、573mg、574mg、575mg、576mg、577mg、578mg、579mg、580mg、581mg、582mg、583mg、584mg、585mg、586mg、587mg、588mg、589mg、590mg、591mg、592mg、593mg、594mg、595mg、596mg、597mg、598mg、599mg、600mg、601mg、602mg、603mg、604mg、605mg、606mg、607mg、608mg、609mg、610mg、611mg、612mg、613mg、614mg、615mg、616mg、617mg、618mg、619mg、620mg、621mg、622mg、623mg、624mg、625mg、626mg、627mg、628mg、629mg、630mg、631mg、632mg、636mg、634mg、635mg、636mg、637mg、638mg、639mg、640mg、641mg、642mg、643mg、644mg、645mg、646mg、647mg、648mg、649mg、650mg、651mg、652mg、653mg、654mg、655mg、656mg、657mg、658mg、659mg、660mg、661mg、662mg、663mg、664mg、665mg、666mg、667mg、668mg、669mg、670mg、671mg、672mg、673mg, 674mg, 675mg, 676mg, 677mg, 678mg, 679mg, 680mg, 681mg, 682mg, 683mg, 684mg, 685mg, 686mg, 687mg, 688mg, 689mg, 690mg, 691mg, 692mg, 693mg, 694mg, 695mg, 696mg, 697mg, 698mg, 699mg or 700mg).

[0069]

[0078] Thus, in one embodiment, the composition contains about 1 mg to about 700 mg, preferably about 1 mg, preferably about 2 mg, preferably about 3 mg, preferably about 4 mg, preferably about 5 mg, preferably about 6 mg, preferably about 7 mg, preferably about 8 mg, preferably about 9 mg, preferably about 10 mg, preferably about 11 mg, preferably about 12 mg, preferably about 13 mg, preferably about 14 mg, preferably about 15 mg, preferably about 16 mg, preferably about 17 mg, preferably about 18 mg, of a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof per dose. g, preferably about 19 mg, preferably about 20 mg, preferably about 21 mg, preferably about 22 mg, preferably about 23 mg, preferably about 24 mg, preferably about 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, preferably about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36 mg, preferably about 37 mg, preferably about 38 mg, preferably about 39 mg, preferably about 40 mg, preferably about 41 mg, preferably about 42 mg, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, preferably about 63 mg, or about 64 mg, preferably about 65 mg, preferably about 66 mg, preferably about 67 mg, preferably about 68 mg, preferably about 69 mg, preferably about 70 mg, preferably about 71 mg, preferably about 72 mg, preferably about 73 mg, preferably about 74 mg, preferably about 75 mg, preferably about 76 mg, preferably about 77 mg, preferably about 78 mg, preferably about 79 mg, preferably about 80 mg, preferably about 81 mg, preferably about 82 mg, preferably about 83 mg, preferably about 84 mg, preferably about 85 mg, preferably about 86 mg,Preferably about 87 mg, preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg, preferably about 98 mg, preferably about 99 mg, preferably about 100 mg, preferably about 101 mg, preferably about 102 mg, preferably about 103 mg, preferably about 104 mg, preferably about 105 mg, preferably about 106 mg, preferably about 107 mg, preferably about 108 mg, preferably about 109 mg, preferably about 110 mg, preferably about 111 mg, preferably about 112 mg, preferably about 113 mg, preferably about 114 mg, preferably about 115 mg, preferably about 116 mg, preferably about 117 mg, preferably about 118 mg, preferably about 119 mg, preferably about 120 mg, preferably about 121 mg, preferably about 122 mg, preferably about 123 mg, preferably about 124 mg, preferably about 125 mg, preferably about 126 mg, preferably about 127 mg, preferably about 128 mg, preferably about 129 mg, preferably about 130 mg, preferably about 131 mg, preferably about 132 mg, preferably about 131 mg, preferably about 134 mg, preferably about 135 mg, preferably about 136 mg, preferably about 137 mg, preferably about 138 mg, preferably about 139 mg, preferably about 140 mg, preferably about 141 mg, preferably about 142 mg, preferably about 143 mg, preferably about 144 mg, preferably about 145 mg, preferably about 146 mg, preferably about 147 mg, preferably about 148 mg, preferably about 149 mg, or about 150 mg, preferably about 151 mg, preferably about 152 mg, preferably about 153 mg, preferably about 154 mg, preferably about 155 mg, preferably about 156 mg, preferably about 157 mg, preferably about 158 ​​mg, preferably about 159 mg, preferably about 160 mg, preferably about 161 mg, preferably about 162 mg, preferably about 163 mg, preferably about 164 mg, preferably about 165 mg, preferably about 166 mg, preferably about 167 mg, preferably about 168 mg, preferably about 169 mg, preferably about 170 mg,Preferably about 171 mg, preferably about 172 mg, preferably about 173 mg, preferably about 174 mg, preferably about 175 mg, preferably about 176 mg, preferably about 177 mg, preferably about 178 mg, preferably about 179 mg, preferably about 180 mg, preferably about 181 mg, preferably about 182 mg, preferably about 183 mg, preferably about 184 mg, preferably about 185 mg, preferably about 186 mg, preferably about 187 mg, preferably about 188 mg, preferably about 189 mg, preferably about 190 mg, preferably about 191 mg, preferably about 192 mg, preferably about 193 mg, preferably about 194 mg, preferably about 195 mg, preferably about 196 mg, preferably about 197 mg, preferably about 198 mg, preferably about 199 mg, preferably about 200 mg, preferably about 201 mg, preferably about 202 mg, preferably about 203 mg, preferably about 204 mg, preferably about 205 mg, preferably about 206 mg, preferably about 207 mg, preferably about 208 mg, preferably about 209 mg, preferably about 210 mg, preferably about 211 mg, preferably about 212 mg, preferably about 213 mg, preferably about 214 mg, preferably about 215 mg, preferably about 216 mg, preferably about 217 mg, preferably about 218 mg, preferably about 219 mg, preferably about 220 mg, preferably about 221 mg, preferably about 222 mg, preferably about 223 mg, preferably about 224 mg, preferably about 225 mg, preferably about 226 mg, preferably about 227 mg, preferably about 228 mg, preferably about 229 mg, preferably about 230 mg, preferably about 231 mg, preferably about 232 mg, or about 233 mg, preferably about 234 mg, preferably about 235 mg, preferably about 236 mg, preferably about 237 mg, preferably about 238 mg, preferably about 239 mg, preferably about 240 mg, preferably about 241 mg, preferably about 242 mg, preferably about 243 mg, preferably about 244 mg, preferably about 245 mg, preferably about 246 mg, preferably about 247 mg, preferably about 248 mg, preferably about 249 mg, preferably about 250 mg, preferably about 251 mg, preferably about 252 mg, preferably about 253 mg,Preferably about 254 mg, preferably about 255 mg, preferably about 256 mg, preferably about 257 mg, preferably about 258 mg, preferably about 259 mg, preferably about 260 mg, preferably about 261 mg, preferably about 262 mg, preferably about 263 mg, preferably about 264 mg, preferably about 265 mg, preferably about 266 mg, preferably about 267 mg, preferably about 268 mg, preferably about 269 mg, preferably about 270 mg, preferably about 271 mg, preferably about 272 mg, preferably about 273 mg, preferably about 274 mg, preferably about 275 mg, preferably about 276 mg, preferably about 277 mg, preferably about 278 mg, preferably about 279 mg, preferably about 280 mg, preferably about 281 mg, preferably about 282 mg, preferably about 283 mg, preferably about 284 mg, preferably about 285 mg, preferably about 286 mg, preferably about 287 mg, preferably about 288 mg, preferably about 289 mg, preferably about 290 mg, preferably about 291 mg, preferably about 292 mg, preferably about 293 mg, preferably about 294 mg, preferably about 295 mg, preferably about 296 mg, preferably about 297 mg, preferably about 298 mg, preferably about 299 mg, preferably about 300 mg, preferably about 301 mg, preferably about 302 mg, preferably about 303 mg, preferably about 304 mg, preferably about 305 mg, preferably about 306 mg, preferably about 307 mg, preferably about 308 mg, preferably about 309 mg, preferably about 310 mg, preferably about 311 mg, preferably about 312 mg, preferably about 313 mg, preferably about 314 mg, preferably about 315 mg, or about 316 mg, preferably about 317 mg, preferably about 318 mg, preferably about 319 mg, preferably about 320 mg, preferably about 321 mg, preferably about 322 mg, preferably about 323 mg, preferably about 324 mg, preferably about 325 mg, preferably about 326 mg, preferably about 327 mg, preferably about 328 mg, preferably about 329 mg, preferably about 330 mg, preferably about 331 mg, preferably about 332 mg, preferably about 333 mg, preferably about 334 mg, preferably about 335 mg, preferably about 336 mg,Preferably about 337 mg, preferably about 338 mg, preferably about 339 mg, preferably about 340 mg, preferably about 341 mg, preferably about 342 mg, preferably about 343 mg, preferably about 344 mg, preferably about 345 mg, preferably about 346 mg, preferably about 347 mg, preferably about 348 mg, preferably about 349 mg, preferably about 350 mg, preferably about 351 mg, preferably about 352 mg, preferably about 353 mg, preferably about 354 mg, preferably about 355 mg, preferably about 356 mg, preferably about 357 mg mg, preferably about 358 mg, preferably about 359 mg, preferably about 360 mg, preferably about 361 mg, preferably about 362 mg, preferably about 363 mg, preferably about 364 mg, preferably about 365 mg, preferably about 366 mg, preferably about 367 mg, preferably about 368 mg, preferably about 369 mg, preferably about 370 mg, preferably about 371 mg, preferably about 372 mg, preferably about 373 mg, preferably about 374 mg, preferably about 375 mg, preferably about 376 mg, preferably about 377 mg, preferably about 378 mg, preferably about 379 mg, preferably about 380 mg, preferably about 381 mg, preferably about 382 mg, preferably about 383 mg, preferably about 384 mg, preferably about 385 mg, preferably about 386 mg, preferably about 387 mg, preferably about 388 mg, preferably about 389 mg, preferably about 390 mg, preferably about 391 mg, preferably about 392 mg, preferably about 393 mg, preferably about 394 mg, preferably about 395 mg, preferably about 396 mg, preferably about 397 mg, preferably about 398 mg, or about 399 mg, preferably about 400 mg, preferably about 401 mg, preferably about 402 mg, preferably about 403 mg, preferably about 404 mg, preferably about 405 mg, preferably about 406 mg, preferably about 407 mg, preferably about 408 mg, preferably about 409 mg, preferably about 410 mg, preferably about 411 mg, preferably about 412 mg, preferably about 413 mg, preferably about 414 mg, preferably about 415 mg, preferably about 416 mg, preferably about 417 mg, preferably about 418 mg, preferably about 419 mg,Preferably about 420 mg, preferably about 421 mg, preferably about 422 mg, preferably about 423 mg, preferably about 424 mg, preferably about 425 mg, preferably about 426 mg, preferably about 427 mg, preferably about 428 mg, preferably about 429 mg, preferably about 430 mg, or about 431 mg, preferably about 432 mg, preferably about 434 mg, preferably about 434 mg, preferably about 435 mg, preferably about 436 mg, preferably about 437 mg, preferably about 438 mg, preferably about 439 mg, preferably about 440 mg, preferably about 441 mg, preferably about 442 mg, preferably about 443 mg, preferably about 444 mg, preferably about 445 mg, preferably about 446 mg, preferably about 447 mg, preferably about 448 mg, preferably about 449 mg, preferably about 450 mg, preferably about 451 mg g, preferably about 452 mg, preferably about 453 mg, preferably about 454 mg, preferably about 455 mg, preferably about 456 mg, preferably about 457 mg, preferably about 458 mg, preferably about 459 mg, preferably about 460 mg, preferably about 461 mg, preferably about 462 mg, preferably about 463 mg, preferably about 464 mg, preferably about 465 mg, preferably about 466 mg, preferably about 467 mg, preferably about 468 mg, preferably about 469 mg, preferably about 470 mg, preferably about 471 mg, 72 mg, preferably about 473 mg, preferably about 474 mg, preferably about 475 mg, preferably about 476 mg, preferably about 477 mg, preferably about 478 mg, preferably about 479 mg, preferably about 480 mg, preferably about 481 mg, preferably about 482 mg, preferably about 483 mg, preferably about 484 mg, preferably about 485 mg, preferably about 486 mg, preferably about 487 mg, preferably about 488 mg, preferably about 489 mg, preferably about 490 mg, preferably about 491 mg, preferably about 492 mg, or about 493 mg, preferably about 494 mg, preferably about 495 mg, preferably about 496 mg, preferably about 497 mg, preferably about 498 mg, preferably about 499 mg, preferably about 500 mg, preferably about 501 mg, preferably about 502 mg, preferably about 503 mg, preferably about 504 mg, preferably about 505 mg, preferably about 506 mg, preferably about 507 mg, preferably about 508 mg, preferably about 509 mg, preferably about 510 mg, preferably about 511 mg, preferably about 512 mg, preferably about 513 mg,Preferably about 514 mg, preferably about 515 mg, preferably about 516 mg, preferably about 517 mg, preferably about 518 mg, preferably about 519 mg, preferably about 520 mg, preferably about 521 mg, preferably about 522 mg, preferably about 523 mg, preferably about 524 mg, preferably about 525 mg, preferably about 526 mg, preferably about 527 mg, preferably about 528 mg, preferably about 529 mg, preferably about 530 mg, preferably about 531 mg, preferably about 532 mg, preferably about 535 mg, preferably about 534 mg mg, preferably about 535 mg, preferably about 536 mg, preferably about 537 mg, preferably about 538 mg, preferably about 539 mg, preferably about 540 mg, preferably about 541 mg, preferably about 542 mg, preferably about 543 mg, preferably about 544 mg, preferably about 545 mg, preferably about 546 mg, preferably about 547 mg, preferably about 548 mg, preferably about 549 mg, preferably about 550 mg, preferably about 551 mg, preferably about 552 mg, preferably about 553 mg, preferably about 554 mg, 555 mg, preferably about 556 mg, preferably about 557 mg, preferably about 558 mg, preferably about 559 mg, preferably about 560 mg, preferably about 561 mg, preferably about 562 mg, preferably about 563 mg, preferably about 564 mg, preferably about 565 mg, preferably about 566 mg, preferably about 567 mg, preferably about 568 mg, preferably about 569 mg, preferably about 570 mg, preferably about 571 mg, preferably about 572 mg, preferably about 573 mg, preferably about 574 mg, preferably about 575 mg, or about 576 mg, preferably about 577 mg, preferably about 578 mg, preferably about 579 mg, preferably about 580 mg, preferably about 581 mg, preferably about 582 mg, preferably about 583 mg, preferably about 584 mg, preferably about 585 mg, preferably about 586 mg, preferably about 587 mg, preferably about 588 mg, preferably about 589 mg, preferably about 590 mg, preferably about 591 mg, preferably about 592 mg, preferably about 593 mg, preferably about 594 mg, preferably about 595 mg, preferably about 596 mg,Preferably about 597 mg, preferably about 598 mg, preferably about 599 mg, preferably about 600 mg, preferably about 601 mg, preferably about 602 mg, preferably about 603 mg, preferably about 604 mg, preferably about 605 mg, preferably about 606 mg, preferably about 607 mg, preferably about 608 mg, preferably about 609 mg, preferably about 610 mg, preferably about 611 mg, preferably about 612 mg, preferably about 613 mg, preferably about 614 mg, preferably about 615 mg, preferably about 616 mg, preferably about 617 mg mg, preferably about 618 mg, preferably about 619 mg, preferably about 620 mg, preferably about 621 mg, preferably about 622 mg, preferably about 623 mg, preferably about 624 mg, preferably about 625 mg, preferably about 626 mg, preferably about 627 mg, preferably about 628 mg, preferably about 629 mg, preferably about 630 mg, preferably about 631 mg, preferably about 632 mg, preferably about 636 mg, preferably about 634 mg, preferably about 635 mg, preferably about 636 mg, preferably about 637 mg, 638 mg, preferably about 639 mg, preferably about 640 mg, preferably about 641 mg, preferably about 642 mg, preferably about 643 mg, preferably about 644 mg, preferably about 645 mg, preferably about 646 mg, preferably about 647 mg, preferably about 648 mg, preferably about 649 mg, preferably about 650 mg, preferably about 651 mg, preferably about 652 mg, preferably about 653 mg, preferably about 654 mg, preferably about 655 mg, preferably about 656 mg, preferably about 657 mg, preferably about 658 mg, or about 659 mg, preferably about 660 mg, preferably about 661 mg, preferably about 662 mg, preferably about 663 mg, preferably about 664 mg, preferably about 665 mg, preferably about 666 mg, preferably about 667 mg, preferably about 668 mg, preferably about 669 mg, preferably about 670 mg, preferably about 671 mg, preferably about 672 mg, preferably about 673 mg, preferably about 674 mg, preferably about 675 mg, preferably about 676 mg, preferably about 677 mg, preferably about 678 mg, preferably about 679 mg,Preferably about 680 mg, preferably about 681 mg, preferably about 682 mg, preferably about 683 mg, preferably about 684 mg, preferably about 685 mg, preferably about 686 mg, preferably about 687 mg, preferably about 688 mg, preferably about 689 mg, preferably about 690 mg, preferably about 691 mg, preferably about 692 mg, preferably about 693 mg, preferably about 694 mg, preferably about 695 mg, preferably about 696 mg, preferably about 697 mg, preferably about 698 mg, preferably about 699 mg, or more preferably about 700 mg.

[0070]

[0079] In some embodiments, periodic re-administration (sequential or simultaneous) of the active agents may be necessary to achieve the desired therapeutic effect. The exact dosage and rate of THC or its pharmaceutically acceptable salt and carbonic anhydrase inhibitor or its pharmaceutically acceptable salt will depend on several factors, including the age, weight, general health, sex, and nutritional needs of the subject, as well as any drugs or medications used in combination with or simultaneously with the administration of the composition, as described elsewhere herein. If multiple divided doses are required, they may be administered hourly, daily, weekly, monthly, or at other suitable time intervals, and the dose may be reduced proportionally if the needs of the situation dictate.

[0071]

[0080] In one embodiment, THC or a pharmaceutically acceptable salt thereof and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are administered daily.

[0081] In one embodiment, the THC or a pharmaceutically acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are administered once or twice per day.

[0072]

[0082] In one embodiment, the THC or a pharmaceutically acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are administered twice per day.

[0083] In one embodiment, THC or a pharmaceutically acceptable salt thereof and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are administered from about 10 minutes to about 120 minutes before sleep (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 minutes before sleep). , 60 minutes, 61 minutes, 62 minutes, 63 minutes, 64 minutes, 65 minutes, 66 minutes, 67 minutes, 68 minutes, 69 minutes, 70 minutes, 71 minutes, 72 minutes, 73 minutes, 74 minutes, 75 minutes, 76 minutes, 77 minutes, 78 minutes, 79 minutes, 80 minutes, 81 minutes, 82 minutes, 83 minutes, 84 minutes, 85 minutes, 86 minutes, 87 minutes, 88 minutes, 89 minutes, 90 minutes, 91 minutes, 92 minutes, 93 minutes, 94 minutes , 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 minutes before the administration of the steroid hormone.

[0073]

[0084] Thus, in one embodiment, THC or a pharmaceutically acceptable salt thereof and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are administered about 10 minutes to about 120 minutes before sleep, preferably about 10 minutes, preferably about 11 minutes, preferably about 12 minutes, preferably about 13 minutes, preferably about 14 minutes, preferably about 15 minutes, preferably about 16 minutes, preferably about 17 minutes, preferably about 18 minutes, preferably about 19 minutes, preferably about 20 minutes, preferably about 21 minutes, preferably about 22 minutes, preferably about 23 minutes, preferably about 24 minutes, preferably about 25 minutes, preferably about 26 minutes, preferably about 27 minutes, preferably about 28 minutes, preferably about 29 minutes, preferably about 30 minutes, preferably about 31 minutes, preferably about 32 minutes, preferably about 33 minutes, preferably about 34 minutes, preferably about 35 minutes, preferably about 36 minutes, preferably about 37 minutes, preferably about 38 minutes, preferably about 39 minutes, preferably about 40 minutes, preferably about 41 minutes, preferably about 42 minutes, preferably about 43 minutes, preferably about 44 minutes, preferably about 45 minutes, preferably about 46 minutes, preferably about 47 minutes, preferably about 48 minutes, preferably about 49 minutes, preferably about 50 minutes, preferably about 51 minutes, preferably about 52 minutes, preferably about 53 minutes, preferably about 54 minutes, preferably about 55 minutes, preferably about 56 minutes, preferably about 57 minutes, preferably about 58 minutes, preferably about 59 minutes, preferably about 60 minutes, preferably about 61 minutes, preferably about 62 minutes, preferably about 63 minutes, preferably about 64 minutes, preferably about 65 minutes, preferably about 66 minutes, preferably about 67 minutes, preferably about 68 minutes, preferably about 69 minutes, preferably about 70 minutes, preferably about 71 minutes, preferably about 72 minutes, preferably about 73 minutes, preferably about 74 minutes, preferably about 75 minutes, preferably about 6 minutes, preferably about 27 minutes, preferably about 28 minutes, preferably about 29 minutes, preferably about 30 minutes, preferably about 31 minutes, preferably about 32 minutes, preferably about 33 minutes, preferably about 34 minutes, preferably about 35 minutes, preferably about 36 minutes, preferably about 37 minutes, preferably about 38 minutes, preferably about 39 minutes, preferably about 40 minutes, preferably about 41 minutes, preferably about 42 minutes, preferably about 43 minutes, preferably about 44 minutes, preferably about 45 minutes, preferably about 46 minutes, preferably about 47 minutes, preferably about 48 minutes, preferably about 49 minutes, preferably about 50 minutes, preferably About 51 minutes, preferably about 52 minutes, preferably about 53 minutes, preferably about 54 minutes, preferably about 55 minutes, preferably about 56 minutes, preferably about 57 minutes, preferably about 58 minutes, preferably about 59 minutes, preferably about 60 minutes, preferably about 61 minutes, preferably about 62 minutes, preferably about 63 minutes, preferably about 64 minutes, preferably about 65 minutes, preferably about 66 minutes, preferably about 67 minutes, preferably about 68 minutes, preferably about 69 minutes, preferably about 70 minutes, preferably about 71 minutes, preferably about 72 minutes, preferably about 73 minutes, preferably about 74 minutes, preferably about 75 minutes, or about 76 minutes, preferably about 77 minutes, preferably about 78 minutes, preferably about 79 minutes, preferably about 80 minutes, preferably about 81 minutes, preferably about 82 minutes, preferably about 83 minutes, preferably about 84 minutes, preferably about 85 minutes, preferably about 86 minutes, preferably about 87 minutes, preferably about 88 minutes, preferably about 89 minutes, preferably about 90 minutes, preferably about 91 minutes, preferably about 92 minutes, preferably about 93 minutes, preferably about 94 minutes, preferably about 95 minutes, preferably about 96 minutes, preferably about 97 minutes, preferably about 98 minutes, preferably about 99 minutes, preferably about 100 minutes,Preferably, the subject is administered about 101 minutes, preferably about 102 minutes, preferably about 103 minutes, preferably about 104 minutes, preferably about 105 minutes, preferably about 106 minutes, preferably about 107 minutes, preferably about 108 minutes, preferably about 109 minutes, preferably about 110 minutes, preferably about 111 minutes, preferably about 112 minutes, preferably about 113 minutes, preferably about 114 minutes, preferably about 115 minutes, preferably about 116 minutes, preferably about 117 minutes, preferably about 118 minutes, preferably about 119 minutes, or more preferably about 120 minutes before administration.

[0074]

[0085] In another embodiment, THC or a pharmaceutically acceptable salt thereof and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof are administered to a subject about 30 minutes to about 60 minutes prior to sleep.

[0075]

[0086] In other embodiments disclosed herein, THC or its pharmaceutically acceptable salt and a carbonic anhydrase inhibitor or its pharmaceutically acceptable salt are formulated as separate unit dosage forms for administration.The unit dosage form may be suitable for oral administration, for example, in the form of a liquid, capsule, or tablet.Those skilled in the art will understand that the unit dosage forms containing THC or its pharmaceutically acceptable salt and / or a carbonic anhydrase inhibitor or its pharmaceutically acceptable salt do not have to be of the same type.Thus, the method of the present disclosure contemplates the administration of, for example, THC by oil and the carbonic anhydrase inhibitor by capsule or tablet.

[0076]

[0087] The inventors demonstrate that intervention by administration of active agents (i.e., THC or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof) can treat OSA (e.g., by reducing or alleviating the symptoms or severity of OSA, particularly sleep-related respiratory events, including apneas, hypopneas, and respiratory event-related arousals). Oral administration is expected to enable the active agents to cross the blood-brain barrier and affect the therapeutic outcomes described herein.

[0077] kit

[0088] The present disclosure further contemplates a kit comprising THC, or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating OSA.

[0078]

[0089] All the necessary materials and reagents for treating OSA in a subject can be assembled into a kit.In one embodiment, the kit includes two separate pharmaceutical compositions: one contains THC or a pharmaceutically acceptable salt thereof, and the second contains a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof.In another embodiment, the kit includes a container containing the separate compositions, such as a divided bottle or a divided foil packet.Further examples of suitable containers include syringes (e.g., pre-filled syringes), boxes, and bags.Usually, the kit further includes instructions for using the components.

[0079]

[0090] In one embodiment, the kit includes THC or a pharmaceutically acceptable salt thereof and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof in a blister pack. The term "blister pack," as used herein, refers to commonly used packaging for pharmaceutical unit dosage forms (e.g., tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil, preferably a transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. The tablets or capsules are placed in the recesses, and the sheet of relatively stiff material is sealed against the plastic foil on the side of the foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed within the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure against the recesses, thereby forming openings in the sheet at the locations of the recesses. The tablet or capsule can then be removed through said opening.

[0080]

[0091] In one embodiment, the kit further comprises a memory aid, for example in the form of numbers or codes next to the tablets or capsules, whereby the numbers correspond to the days of the regimen in which the tablets or capsules so designated should be taken. Another example of such a memory aid is a calendar printed on a card, for example, as follows: "Week 1, Monday, Tuesday, ... etc. ... Week 2, Monday, Tuesday, ..." etc. Other variations of memory aids will be readily apparent to those skilled in the art.

[0081]

[0092] The kit may optionally include a suitable therapeutic agent to be administered in combination with the THC or a pharmaceutically acceptable salt thereof and the carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof, illustrative examples of which include anti-inflammatory agents, bronchodilators, and nasal decongestants.

[0082]

[0093] The present disclosure also contemplates a commercial package, also referred to as a "treatment pack," containing THC or a pharmaceutically acceptable salt thereof, and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt thereof, along with instructions for use in treating OSA.

[0083]

[0094] Those skilled in the art will understand that the invention described herein is susceptible to variations and modifications other than those specifically described. It should be understood that the invention includes all such variations and modifications that fall within its spirit and scope. The invention also includes all of the steps, properties, compositions, and compounds referred to or shown in this specification, individually or collectively, in any and all combinations of any two or more of said steps or properties.

[0084]

[0095] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0096] All patents, patent applications and publications mentioned herein are incorporated by reference in their entirety.

[0085]

[0097] The various embodiments enabled herein are further described by the following non-limiting examples. [Example]

[0086] Example 1 - Exemplary Combinations for the Treatment of Obstructive Sleep Apnea (OSA)

[0098] An exemplary combination according to the present disclosure has the following components:

[0087] [Table 3]

[0088] Example 2 - Exemplary Methods for Treating Respiratory Symptoms of OSA

[0099] An exemplary method for treating OSA according to the present disclosure is as follows. Example 1 Combination: Oral administration or co-administration of the active agents to a subject at night (i.e., 10-60 minutes before sleep).

[0089] Example 3 - Clinical Trial Design and Plan

[0100] Twelve subjects with known or suspected OSA (i.e., an apnea-hypopnea index (AHI) of 15 or greater) will be enrolled in a randomized, three-way crossover design with a placebo run-in to study the effects of three different dose levels of a combination of delta-9-tetrahydrocannabinol (THC) or its pharmaceutically acceptable salt (i.e., dronabinol) and a carbonic anhydrase inhibitor or its pharmaceutically acceptable salt (i.e., acetazolamide) on AHI, oxygen desaturation index (ODI), daytime somnolence, and subject satisfaction. The total treatment period for subjects will be 56 days, including 28 treatment days and 28 washout days.

[0090]

[0101] Subjects will complete five sleep studies (V1-V5) in a sleep clinic, involving overnight monitoring of the subject using an overnight polysomnogram (PSG). At each sleep clinic visit, subjects will complete a series of questionnaires, including the Epworth Sleepiness Scale, SF-36, and POMS, to assess daytime somnolence, mood, and quality of life. Blood samples will also be collected to assess blood counts, electrolytes, urea, liver enzymes, and levels of THC and its two major metabolites, OH-THC and COOH-THC.

[0091]

[0102] The first sleep study (V1) is used to confirm OSA in the subject and establish a baseline AHI. Subjects are then provided with treatment packs for the subsequent treatment periods, with each treatment pack containing doses numbered by treatment week (i.e., 1-4) and treatment night (i.e., 1-7). All treatment packs contain a placebo during week 1. Subjects are randomized to one of six treatment groups, with the order of low, medium, and high dose treatment periods varying within each of the six treatment groups (Table 4).

[0092] [Table 4]

[0093]

[0103] All treatment periods are followed by a 7-night washout period. Thus, the second sleep study (V2) is conducted on night 7 of treatment period 1 (i.e., placebo), the third sleep study (V3) is conducted on night 7 of treatment period 2, the fourth sleep study (V4) is conducted on night 7 of treatment period 3, and the fifth sleep study (V5) is conducted on night 7 of treatment period 4 (Table 5). Approximately 10 days after the fifth sleep study (V5), subjects return to the sleep clinic for an end-of-study visit (V6), where adverse events are reported, the ESS, POMS, and SF-36 questionnaires are completed, and a final blood sample is collected.

[0094] [Table 5]

[0095]

[0104] The efficacy of each study arm will be assessed from measures of sleep quality / length / satisfaction based on the results of the overnight PGS and compared using a mixed design analysis of covariance (MANCOVA) with treatment (placebo, low, medium, high dose) as the between-subject variable, time as the within-subject variable, and baseline score as the covariate.

[0096]

[0105] Dronabinol is highly lipid-soluble and typically achieves significant plasma / blood concentrations within 30-60 minutes of ingestion, with peak effects occurring within 2-4 hours. Acetazolamide is absorbed fairly rapidly from the gastrointestinal tract, typically achieving average peak plasma concentrations within approximately 2 hours of ingestion.

[0097]

[0106] OSA can negatively impact physical and psychological functioning, as well as quality of life. Sleep disruption and blood gas abnormalities disrupt sleep-related restorative processes and further induce chemical and organic central nervous system cell injury. This leads to dysfunction in the prefrontal cortex, which manifests behaviorally in what neuropsychologists call "executive dysfunction." Executive dysfunction has been proposed to significantly affect the functional application of cognitive abilities, resulting in maladaptive daytime behaviors. Reduced attention, slowed reaction times, and impaired concentration are linked to an increased risk of accidents involving motor vehicles and machinery operation.

[0098]

[0107] It is expected that nighttime administration of THC and a carbonic anhydrase inhibitor will stabilize the breathing patterns of patients with OSA, effectively controlling sleep-related respiratory events, normalizing AHI and oxyhemoglobin saturation levels, and improving neurocognitive deficits and associated symptoms. Without being bound by theory or a particular application mode, it is possible that the changes in vagal balance associated with THC (e.g., dronabinol) may synergize with the metabolic acidosis induced by carbonic anhydrase inhibitors (e.g., acetazolamide), thereby increasing the difference between prevailing CO2 partial pressure and the apnea threshold CO2 partial pressure to treat OSA. Coadministration of THC and a carbonic anhydrase inhibitor should reduce the effective concentrations of both drugs to safe, non-toxic levels while achieving clinical efficacy.

[0099] Example 4 - Clinical Trial Results

[0108] As detailed in Table 4 above, Subject 1 completed Treatment Period 7 and Subject 2 completed Treatment Period 8. On the seventh night of each treatment period, subjects underwent overnight polysomnography to determine their AHI, as described elsewhere herein. The AHI data and reduction relative to baseline for each subject are shown in Table 6.

[0100] [Table 6]

[0101]

[0109] These data demonstrate that the combination of dronabinol and acetazolamide is highly effective in treating OSA, especially since the AHI measured for each patient indicates a reduction in the OSA staging from severe / moderate to asymptomatic or mild (Table 1).

[0102]

[0110] Given the unexpectedly effective combination of dronabinol and acetazolamide for the treatment of OSA, we used published results on the efficacy of dronabinol and acetazolamide as single agents for the treatment of OSA to determine whether the combination of dronabinol and acetazolamide is synergistic. Thirteen published studies on the efficacy of acetazolamide as a single agent for the treatment of OSA were included. These studies tested a wide range of doses in diverse patient cohorts. The observed AHI reductions ranged from 19.8% to 60.2%. Relevant to the present study, we assessed published study designs for consistency with the inclusion / exclusion criteria applied in this study to determine the dose-response relationship between acetazolamide and AHI reduction. Studies that included subjects with congestive heart failure, high altitude, variable dosing, or a low baseline AHI (<15) were excluded from further analysis, resulting in seven studies being included in the analysis described herein (Table 7). Acetazolamide dose and reduction in AHI relative to baseline or placebo were represented graphically, and linear trend lines were plotted to estimate the relationship between AHI reduction and acetazolamide dose (Figure 1). There was a strong correlation between acetazolamide dose and AHI reduction (R 2 =0.9276). A linear trend line was used to predict the reduction in AHI for the acetazolamide doses used in this study (Table 8).

[0103] [Table 7]

[0104] [Table 8]

[0105]

[0111] A similar analysis was undertaken for dronabinol using data from Carley et al. (2018, Sleep, 41(1):zsx184). Using methods previously described for acetazolamide, the dose-response relationship was determined for two doses of dronabinol (i.e., 2.5 mg and 10 mg) (Table 9; Figure 2). The resulting trend line was used to determine the predicted reduction in AHI at the doses used in this study (Table 10).

[0106] [Table 9]

[0107] [Table 10]

[0108]

[0112] Formula E pred A+B =(E A +E B )-(E A E B The Bliss independence method using ) was used to calculate the predicted combined effect of the combination of dronabinol and acetazolamide at the doses used in this study. The results are shown in Table 11. Synergy between the two drugs occurs when the difference between the observed activities of the combined drugs exceeds the predicted activity. Based on these measures, the combination of dronabinol and acetazolamide exhibits synergy to reduce AHI in patients with OSA (Table 12).

[0113]

[0109] [Table 11]

[0110] [Table 12]

[0111] conclusion

[0114] The data presented herein demonstrate that the combination of THC and a carbonic anhydrase inhibitor, such as acetazolamide, exhibits unexpected synergistic effects to treat OSA.The co-administration of two different doses of THC and a carbonic anhydrase inhibitor is sufficient to reduce AHI, which is a clinically recognized measure for the treatment and / or improvement of symptoms associated with OSA.Together, these data enable methods for the treatment of OSA, and compositions for the simultaneous administration of THC and a carbonic anhydrase inhibitor, whether in a single composition or dosage form, or the co-administration of two separate compositions or dosage forms. List of References · Benjafiled et al., 2018, Risk and Prevalence of Sleep Disordered Breathing: A3962-A3962 · Buysse et al., 1989, Psychiatry Research, 28(2): 193-213 · Carley et al., 2018, Sleep, 41(1): zsx184 · Chin et al., 1992, Japanese Journal of Thoracic Disease, 30:270-277 · de Souse Michels et al., 2014, International Journal of Otolaryngology, 2014: 717419 · Drager et al., 2017, Circulation, 136(19): 1840-1850 · Edwards et al., 2012, The Journal of Physiology, 590:1199-1211 · Eubanks et al., 2006, Molecular Pharmaceuticals, 3(6): 773-7 · Eskandari et al., 2018, Journal of Clinical Sleep Medicine, 14:309-317. · Goodwin et al., 2006, Therapeutic Drug Monitoring, 28(4): 545-551 · Grote, 2019, The Lancet Respiratory Medicine, 7(8): 645-647 · Iber et al.,2007, The AASM Manual for the Scoring of Sleep and Associated Events, 1 st edition · Inoue, 1987, Japanese Journal of Neuropsychopharmacology, 9:493-513 · Inoue et al., 1999, Psychiatry and Clinical Neurosciences, 53:321-322. · Johns, 1991, Sleep, 14: 540-545 · Kogan et al., 2016, Respiratory Care, 61(8): 1033-1037 · McNair et al., 1971, POMS Manual for the Profile of Mood States, San Diego, CA: Educational and Industrial Testing Service · Olaithe et al., 2018, Sleep Medicine Reviews, 38: 39-49 · Roche et al., 2003, European Respiratory Journal, 22: 937-942 · Saris-Baglama et al., 2010, QualityMetric Health Outcomes Scoring Software 4.0, Lincoln, RI · Shahid et al., 2011, Leeds Sleep Evaluation Questionnaire (LSEQ), in Shahid et al. (eds), STOP, THAT and One Hundred Other Sleep Scales, Springer, New York · Stoohs et al., 1994, Sleep, 17(7): 619-623 · Swenson, 2014, Carbonic Anhydrase Inhibitors and High Altitude Illness, in: Frost and McKenna (eds), Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry, vol. 75, Springer, Dordrecht · Tojima et al., 1988, Thorax, 43:113-119 · Wallace et al., 1977, Journal of Pharmaceutical Sciences, 66(4): 527-530 · Wheaton et al., 2012, Sleep, 35(4): 461-467 · Whyte et al., 1988, Sleep, 11:463-472 · Zamarron et al., 2003, Chest, 123(5): 1567-1576 · US Patent Application No. 11 / 840,585 · US Patent No. 4,160,452 · US Patent No. 4,256,108 · US Patent No. 4,265,874 · US Patent No. 5,227,537 · US Patent No. 7,323,576 · US Patent No. 10,189,762 · WO 2004 / 016277

Claims

1. A composition comprising delta-9-tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt thereof, and acetazolamide or a pharmaceutically acceptable salt thereof, for use in treating obstructive sleep apnea (OSA).

2. The composition described in claim 1, wherein acetazolamide is administered at a dose of 1 mg to 700 mg.

3. The composition described in claim 2, wherein acetazolamide is administered at a dose selected from the group consisting of 25 mg, 125 mg, 250 mg, and 500 mg.

4. 4. The composition of claim 1, wherein the THC is synthetic THC.

5. 5. The composition of any one of claims 1 to 4, wherein the THC is administered in a dose of 0.25 mg to 20 mg.

6. 6. The composition of claim 5, wherein the THC is administered in a dose selected from the group consisting of 0.5 mg, 2.5 mg, 5 mg, and 10 mg.

7. 7. The composition of any one of claims 1 to 6, wherein the THC and acetazolamide are administered orally to the subject.

8. 8. The composition of any one of claims 1 to 7, wherein the OSA is mild to severe OSA according to the apnea-hypopnea index (AHI).

9. The composition of any one of claims 1 to 8, wherein the OSA is moderate to severe OSA caused by AHI.

10. 10. The composition of any one of claims 1 to 9, wherein the THC and acetazolamide are administered to the subject 10 to 60 minutes before sleep.

11. 11. The composition of claim 10, wherein the THC and acetazolamide are administered to the subject 30 to 60 minutes before sleep.

12. 1. Use of THC, or a pharmaceutically acceptable salt thereof, and acetazolamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of OSA.

13. 1. A kit for use in the treatment of OSA, comprising delta-9-tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt thereof, and acetazolamide or a pharmaceutically acceptable salt thereof.

14. 14. The kit of claim 13, wherein the THC and acetazolamide are administered sequentially.

15. 15. The kit of claim 13 or 14, wherein THC and acetazolamide are administered simultaneously.

16. A composition comprising delta-9-tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt thereof, and acetazolamide or a pharmaceutically acceptable salt thereof.

17. 17. The composition of claim 16 for use in the treatment of OSA.

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