WO2025229492A1

WO2025229492A1 - Orexin type 2 receptor agonist microcapsules for sustained release dosing

Info

Publication number: WO2025229492A1
Application number: PCT/IB2025/054393
Authority: WO
Inventors: Tomoyuki MANOSHIRO; Ayako Baba; Hiromitsu KARUBE; Naoyuki Murata
Original assignee: Takeda Pharmaceutical Co Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 2024-04-29
Filing date: 2025-04-28
Publication date: 2025-11-06
Anticipated expiration: 2026-10-29

Abstract

The present disclosure provides a controlled release composition comprising an orexin type 2 receptor agonist or a salt or hydrate thereof and a lactic acid-glycolic acid polymer or salt thereof; wherein the composition is in the form of microcapsules. The present disclosure also provides methods of making such controlled release compositions and methods of using the controlled release compositions.

Description

OREXIN TYPE 2 RECEPTOR AGONIST MICROCAPSULES FOR SUSTAINED RELEASE DOSING

FIELD

[0001] The present disclosure provides a controlled release composition comprising an orexin type 2 receptor agonist or a salt or hydrate thereof and a lactic acid-glycolic acid polymer or salt thereof; wherein the composition is in the form of microcapsules. The present disclosure also provides methods of making such controlled release compositions and methods of using the controlled release compositions.

BACKGROUND OF THE INVENTION

[0002] Narcolepsy is a severe neurological sleep disorder characterized by excessive daytime sleepiness (EDS). In some cases, narcolepsy may be accompanied by a sudden loss of muscle tone and mobility (cataplexy). Narcolepsy accompanied by cataplexy is known as narcolepsy type 1 (NT1); narcolepsy in the absence of cataplexy is known as narcolepsy type 2 (NT2). In addition to EDS and cataplexy, other symptoms include hypnagogic/hypnopompic hallucinations, sleep paralysis and disturbed nighttime sleep (sleep fragmentation), which together comprise the narcolepsy symptom pentad. There are few effective treatments for narcolepsy and most only address one or two symptoms of the narcolepsy pentad. For example, stimulants (e.g. modafinil) may be used to treat EDS, antidepressants (e.g. clomipramine) may be used to treat cataplexy, and sodium oxybate and pitolisant may be used to treat both EDS and cataplexy. However, these drugs are known to have side effects such as insomnia, rebound symptom, and the potential for drug abuse (Trends in Pharmacol. Sci., Vol. 27, No. 7, 368-374, (2006)).

[0003] A number of orexin type 2 receptor agonists have been proposed in the art (J.

Med. Chem. No. 58, 7931-7937, (2015); Proc. Natl Acad. Sci. Vol. 119, No. 35, e2207531119, (2002); Ther. Adv. Neurol. Disord., Vol. 12, 1-12, (2019)). To date, studies evaluating OX2R agonists for treatment of narcolepsy have been designed to stimulate orexin type 2 receptors at dosage levels sufficient to promote arousal or wakefulness in a subject. Administration of OX2R agonists at wake-promoting dosages to subjects diagnosed with narcolepsy type 1 has shown improvement in daytime symptoms such as excessive sleepiness and cataplexy (J Sleep Res. 32(5):el3878. (2023), N Engl J Med. 389(4):309-321. (2023)). Administration of 0X2R agonists at dosage levels which are significantly less than arousal-promoting dosage levels (i.e., at “low dose”), as well as the therapeutic effect of such low dose administration, are heretofore not known.

[0004] Orexin type 2 receptor agonists have been investigated as therapeutic agents for treating narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome. See, for example, PCT Published Appl. No. WO 2017/135306. This publication discloses the OX2R agonist methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate and pharmaceutically acceptable salts and hydrates thereof (also referred to as Danavorexton herein).

[0005] Immediate release formulations of orexin type 2 receptor agonists may not provide the desired blood plasma concentration in subjects to account for different needs during waking periods and sleeping periods, especially for compounds having a relatively short half-life in the blood plasma.

[0006] Biodegradable polymers having a controlled releasing property are useful, for example, as base materials for microcapsules, and the like, for containing a physiologically active substance. It is known that biodegradable polymers such as polymers containing polylactic acid, a copolymer of lactic acid and glycolic acid, and the like are useful (for example, see JP Publ. No. 11269094).

[0007] Controlled release formulations attempt to solve the difficulties in providing the desired blood plasma concentration in subjects to account for different needs during waking periods and sleeping periods by releasing the drug in a predictable and rational programmed rate to achieve an optimal serum-drug concentration. However, controlled release formulations can exhibit a common drawback: an initial uncontrolled burst. In some controlled release formulations, immediately upon placement in the release medium, an initial large bolus of drug is released before the release rate reaches a stable profile.

[0008] There is a need to provide a controlled release formulation that reduces the initial release of a large bolus of orexin type 2 receptor agonist while providing a sustained release of the orexin type 2 receptor agonist over a period of weeks. SUMMARY OF THE INVENTION

[0009] The purpose and advantages of the disclosed subject matter will be set forth in and are apparent from the description that follows, as well as will be learned by practice of the disclosed subject matter. Additional advantages of the disclosed subject matter will be realized and attained by the compositions particularly pointed out in the detailed description and claims hereof, as well as from the appended drawings.

[0010] Administration of orexin type 2 receptor agonists at a dosage at or below a maximum non-awakening plasma concentration of the agonist is investigated in the present application. This dosage regimen relies upon a chronic dosing of the agonist at a dose sufficient to provide a blood plasma concentration at or below the maximum nonawakening concentration. This chronic dosing over a period of two weeks or more is expected to normalize compensatory neuroplastic changes in an NT1 subject’s wakefulness-regulating pathway associated with orexin loss. This present application provides a controlled release composition that allows for a sustained release of an 0X2R agonist at a dose sufficient to bring the plasma blood concentration of the 0X2R agonist at or below the non-awakening blood plasma concentration.

[0011] The present disclosure provides a controlled release composition comprising an orexin type 2 receptor agonist or a salt or hydrate thereof and a lactic acid-glycolic acid polymer or a salt thereof wherein:

[0012] the orexin type 2 receptor agonist or salt or hydrate thereof comprises about 10 % (w/w) to about 70 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer;

[0013] the lactic acid-glycolic acid polymer or salt thereof has a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol and comprises about 30 % (w/w) to about 90 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; and

[0014] wherein the orexin type 2 receptor agonist or salt thereof and the lactic acid- glycolic acid polymer or salt thereof are in the form of microcapsules that have a mean particle diameter of between about 20 microns and about 75 microns.

[0015] In some embodiments, the controlled release composition is in the form of microcapsules having a mean particle diameter of between about 40 microns and about 65 microns. [0016] In some embodiments, the orexin type 2 receptor agonist or salt or hydrate thereof comprises about 30 % (w/w) to about 40 % (w/w) of the controlled release composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; and the lactic acid-glycolic acid polymer or salt thereof comprises about 60 % (w/w) to about 70 % (w/w) of the controlled release composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer.

[0017] In some embodiments, the controlled release composition further comprises a dispersing agent, wherein the microcapsules and dispersing agent are in a mixture.

[0018] In some embodiments, the orexin type 2 receptor agonist in the controlled release composition is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt or hydrate thereof.

[0019] In some embodiments, the lactic acid-glycolic acid polymer or salt thereof in the controlled release composition has a weight-average molecular weight from about 9,000 g/mol to about 11,000 g/mol.

[0020] In some embodiments, the dispersing agent in the controlled release composition is mannitol.

[0021] In some embodiments, the controlled release composition is in the form of microcapsules, wherein the microcapsules are in a mixture with the dispersing agent, and the mixture is dispersed or dissolved in a liquid suitable for injection.

[0022] In some embodiments, the orexin type 2 receptor agonist or salt or hydrate thereof comprises about 30 % (w/w) to about 40 % (w/w) of the controlled release composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer, wherein the orexin type 2 receptor agonist is methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt or hydrate thereof; and the lactic acid- glycolic acid polymer or salt thereof has a weight-average molecular weight from about 9,000 g/mol to about 11,000 g/mol and comprises about 60 % (w/w) to about 70 % (w/w) of the controlled release composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; and

[0023] wherein the orexin type 2 receptor agonist or salt thereof and the lactic acid- glycolic acid polymer or salt thereof are in the form of microcapsules, and the microcapsules have a mean particle diameter of between about 40 microns and about 65 microns.

[0024] In some embodiments, the controlled release composition is in the form of microcapsules, wherein the microcapsules are in a mixture with mannitol, and the mixture is dispersed or dissolved in a liquid suitable for injection.

[0025] The present disclosure also provides a method of producing a controlled release composition, comprising:

[0026] mixing an orexin type 2 receptor agonist or a salt or hydrate thereof in an amount of about 10 % (w/w) to about 70 % (w/w) based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer into a solution containing lactic acid-glycolic acid polymer or salt thereof having a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol and an organic solvent to obtain an organic solution;

[0027] dispersing the organic solution in a solution of polyvinyl alcohol and water to form an oil-in-water emulsion;

[0028] removing the organic solvent to form a dispersion of microcapsules; and

[0029] sieving and washing the microcapsules.

[0030] In some embodiments, the method of producing a controlled release composition further comprises adding a dispersing agent after sieving and washing the microcapsules to form a mixture, and lyophilizing the mixture to form a powdered mixture of microcapsules and dispersing agent.

[0031] The present disclosure also provides a method of producing an injectable dosage form, further comprising reconstituting the powdered mixture of microcapsules and dispersing agent of the controlled release composition produced by:

[0032] mixing an orexin type 2 receptor agonist or a salt thereof in an amount of about 10 % (w/w) to about 70 % (w/w) based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer into a solution containing lactic acid- glycolic acid polymer or salt thereof having a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol and an organic solvent to prepare an organic solution,

[0033] dispersing the organic solution in a solution of polyvinyl alcohol and water to form an oil-in-water emulsion;

[0034] removing said organic solvent to form a dispersion of microcapsules;

[0035] sieving and washing the microcapsules; and

[0036] introducing the microcapsules into a vehicle suitable for injection into a mammal. [0037] The present disclosure also provides a method of treating narcolepsy type 1 in a human in need thereof, the method comprising: administering to the human a controlled release composition comprising an orexin type 2 receptor agonist or a salt or hydrate thereof and a lactic acid-glycolic acid polymer or salt thereof, wherein:

[0038] the orexin type 2 receptor agonist or salt or hydrate thereof comprises about 30 % (w/w) to about 40 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer, wherein the orexin type 2 receptor agonist is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt or hydrate thereof;

[0039] the lactic acid-glycolic acid polymer or salt thereof has a weight-average molecular weight from about 9,000 g/mol to about 11,000 g/mol and comprises about 60 % (w/w) to about 70 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; and

[0040] wherein the orexin type 2 receptor agonist or a salt thereof and the lactic acid- glycolic acid polymer or salt thereof are in the form of microcapsules, and the microcapsules have a mean particle diameter of between about 40 microns and about 65 microns; wherein the microcapsules are in a mixture with a dispersing agent, the mixture is dispersed or dissolved in a liquid suitable for injection, and wherein the composition provides a blood plasma concentration of the agonist after administration at or below a maximum non-awakening plasma concentration of the agonist over a dosing interval of about four weeks.

[0041] The present disclosure also provides a method of treating narcolepsy type 1 in a human in need thereof, the method comprising: administering to the human a controlled release composition comprising an orexin type 2 receptor agonist or salt or hydrate thereof and a lactic acid-glycolic acid polymer or salt thereof, wherein:

[0042] the orexin type 2 receptor agonist or salt or hydrate thereof comprises about 30 % (w/w) to about 40 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer, wherein the orexin type 2 receptor agonist is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt or hydrate thereof; [0043] the lactic acid-glycolic acid polymer or salt thereof has a weight-average molecular weight from about 9,000 g/mol to about 11,000 g/mol and comprises about 60 % (w/w) to about 70 % (w/w) based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; and

[0044] wherein the orexin type 2 receptor agonist or a salt thereof and the lactic acid- glycolic acid polymer or salt thereof are in the form of microcapsules, and the microcapsules have a mean particle diameter of between about 40 microns and about 65 microns; wherein the microcapsules are in a mixture with mannitol, and the mixture is dispersed or dissolved in a liquid suitable for injections, and wherein the composition provides a blood plasma concentration of the agonist after administration at or below a maximum non-awakening plasma concentration of the agonist over a dosing interval of about four weeks.

[0045] In some embodiments, the method of treating narcolepsy type 1 improves one or more nighttime symptoms selected from fragmented sleep, sleep paralysis, and hallucinations.

[0046] In some embodiments, the method of treating narcolepsy type 1 improves one or more daytime symptoms and one or more nighttime symptoms in patients with narcolepsy type 1.

[0047] In some embodiments, the method of treating narcolepsy type 1 improves one or more nighttime symptoms selected from fragmented sleep, sleep paralysis, and hallucinations; and improves one or more daytime symptoms selected from fragmented wakefulness and cataplexy symptom.

[0048] In some embodiments, the controlled release composition is provided in a dosage form for subcutaneous administration.

BRIEF DESCRIPTION OF THE DRAWINGS

[0049] The following figures are included to illustrate some aspects of the present disclosure and should not be viewed as exclusive embodiments. The subject matter disclosed is capable of considerable modifications, alterations, combinations, and equivalents in form and function, without departing from the scope of this disclosure.

[0050] FIG. l is a graph showing the plasma drug concentration (ng/mL) versus time (days) for a suspended form of the microcapsule powder of EXAMPLE 1 (“EXAMPLE 1”) and a suspended form of the microcapsule powder of EXAMPLE 2 (“EXAMPLE 2”) after separate administration to a respective monkey followed by measurement of the drug concentration in the blood plasma from EXAMPLE 10. As shown in FIG. 1, Cmax and AUC within 24 hours after administration of the suspended microcapsules of EXAMPLE 1 are lower than the measurements obtained for the suspended microcapsules of EXAMPLE 2, while keeping sustained release over 28 days.

[0051] FIG. 2 is a graph showing the plasma drug concentration (ng/mL) versus time (days) for a suspended form of the microcapsule powder of EXAMPLE 3 (“EXAMPLE 3”) and a suspended form of the microcapsule powder of EXAMPLE 4 (“EXAMPLE 4”) after separate administration to a respective monkey followed by measurement of the drug concentration in the blood plasma from EXAMPLE 11. As shown in FIG. 2, Cmax and AUC within 24 hours after administration of the suspended microcapsules of EXAMPLE 3 are lower than the measurements obtained for the suspended microcapsules of EXAMPLE 4, while keeping sustained release over 28 days.

[0052] FIG. 3 is a graph showing the plasma drug concentration (ng/mL) versus time (days) for a suspended form of the microcapsule powder of EXAMPLE 1 (“EXAMPLE 1”) and a suspended form of the microcapsule powder of EXAMPLE 3 (“EXAMPLE 3”) after separate administration to a respective monkey followed by measurement of the drug concentration in the blood plasma from EXAMPLE 12. As shown in FIG. 3, Cmax and AUC within 24 hours after administration of the suspended microcapsules of EXAMPLE 1 are lower than the measurements obtained for the suspended microcapsules of EXAMPLE 3, while keeping sustained release over 28 days.

[0053] FIG. 4 is a graph showing the plasma drug concentration (ng/mL) versus time (days) for a suspended form of the microcapsule powder of EXAMPLE 2 (“EXAMPLE 2”) and a suspended form of the microcapsule powder of EXAMPLE 4 (“EXAMPLE 4”) after separate administration to a respective monkey followed by measurement of the drug concentration in the blood plasma from EXAMPLE 13. As shown in FIG. 4, Cmax and AUC within 24 hours after administration of the suspended microcapsules of EXAMPLE 2 are lower than the measurements obtained for the suspended microcapsules of EXAMPLE 4, while keeping sustained release over 28 days.

[0054] FIG. 5 is a graph showing the plasma drug concentration (ng/mL) versus time (days) for a suspended form of the microcapsule powder of EXAMPLE 5 (“EXAMPLE 5”) after administration to a monkey followed by measurement of the drug concentration in the blood plasma from EXAMPLE 14. As shown in FIG. 5, it was confirmed that the microcapsule powder prepared in a 1 L scale achieved sustained release over 28 days.

DETAILED DESCRIPTION OF THE INVENTION

I. DEFINITIONS

[0055] As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0056] As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value.

[0057] As used herein, the term “administration” of an agent to a subject includes any route of introducing or delivering the agent to a subject to perform its intended function. Administration can be carried out by any suitable non-oral route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein. Administration includes self-administration and the administration by another. Administration of an orexin type 2 receptor agonist for treatment purpose in this invention is generally long-term, continuous, chronic, and/or repetitive. “After administration” of an orexin type 2 receptor agonist in the present invention means a certain time period elapses from the administration of the orexin type 2 receptor agonist to a subject. Generally, this means from about 24 to about 48 hours after the initial administration.

[0058] As used herein, the term “dosage form” or “pharmaceutical composition” means a composition containing a drug molecule. Examples of the dosage form include oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal tablet), capsule (including soft capsule, microcapsule), pill, granule, powder, troche, syrup, liquid, emulsion, suspension, aerosol, films (e.g., orally disintegrable films, oral mucosa-adhesive film) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparation (e.g., transdermal absorption type preparation, ointment, lotion, adhesive preparation), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like. The compound and medicament of the present invention can be respectively safely administered orally or parenterally (e.g., intrarectal, intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intravaginal, intraperitoneal, intratumoral, proximal tumor administrations, and administration to the lesion). These preparations can be a release control preparation (e.g., sustained-release microcapsule) such as an immediate-release preparation, a sustained-release preparation and the like.

[0059] The term “microcapsule” for purposes of the present disclosure refers to a particle with a diameter of 1-1000 pm, (when size is not further specified) irrespective of the precise interior or exterior structure. Within the broad category of microcapsules, “microspheres” specifically refers to spherical microcapsules. With respect to the present disclosure, microcapsule refers to a particle that is a microsphere comprised of a fairly homogeneous mixture of polymer and active agent,

[0060] As used herein, the term “effective amount” or “therapeutically effective amount” refers to a quantity of a compound sufficient to achieve a desired effect or a desired therapeutic effect. In the context of therapeutic applications, the amount of the compound administered to the subject can depend on the type and severity of the disease or symptom and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.

[0061] As used herein, the term “increase” refers to alter positively by at least about 5%, including, but not limited to, alter positively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.

[0062] As used herein, the term “reduce” refers to alter negatively by at least about 5% including, but not limited to, alter negatively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.

[0063] As used herein, the terms “orexin receptor 2 agonist,” “orexin type 2 receptor agonist,” or “0X2R agonist” refers to a drug or substance, such as a small molecule, that activates 0X2R. 0X2R is a G-protein coupled receptor (GPCR) which interacts with Gq class of heterotrimeric G proteins and P-arrestins. Orexin-A and Orexin-B peptides are known to increase calcium mobilization (Cell, Vol. 92, 573-585, (1998)) and promote recruitment of P-arrestins (J. Biol. Chem. Vol. 286, No. 19, 16726-16733, (2011)) in OX2R-expressed recombinant cells. OX2R agonists such as Danavorexton and YNT-185 have also been shown to increase calcium mobilization and promote recruitment of P- arrestins (Pharmacol. Biochem. Behav. 187 (2019), 172794; Proc. Natl Acad. Sci. USA., 114(22), 5731-5736, (2017)). Therefore, OX2R agonistic activity of drug candidates can be evaluated by calcium mobilization assays or P-arrestin recruitment assays using OX2R-expressed cells.

[0064] As used herein, the term “arousal” (including “arousal” in “arousal-promoting concentration”) means the status of a subject is near complete wakefulness which is examined by known measures such as Maintenance of Wakefulness Test (MWT) and EEG/EMG recordings.

[0065] As used herein, “blood plasma concentration” (sometimes simplified as “plasma concentration”) refers to a concentration of a pharmaceutical substance in blood plasma derived from a subject blood collected at certain time point. “Blood plasma concentration after administration” in the present invention means the blood plasma concentration of the pharmaceutical substance at the time point about 24 hours or later following to administration of the substance. “Average blood plasma concentration” means average of blood plasma concentrations of different time points 24 hours or later following the administration of a pharmaceutical substance in a subject.

[0066] As used herein, the terms “non-awakening plasma concentration” or “nonawakening concentration” refer to a plasma concentration of an orexin type 2 receptor agonist that will not induce arousal in a subject. Non-awakening plasma concentration can be identified by conducting a multiple-dose study. Such study can be conducted as part of preclinical and clinical PK/PD studies during drug development. Among nonawakening plasma concentrations, the “maximum non-awakening plasma concentration” is the highest concentration above which marginal arousal effect occurs. The phrase “at or below the maximum non-awakening plasma concentration” of an OX2R agonist means the plasma concentration of the OX2R agonist in a subject is larger than 0 (zero) and the same or less than the maximum non-awakening plasma concentration. In some embodiments, the plasma concentration of the OX2R agonist in a subject over a dosing interval is at or below the maximum non-awakening plasmatic concentration, but not less than about 1/20, about 1/12, about 1/10, about 1/8, about 1/5, or about 1/3 of the maximum non-awakening concentration of the agonist. The average plasma concentration of an 0X2R agonist can be about 1/20, about 1/10, about 1/8, about 1/5, about 1/4, about 1/3, about 1/2, or 1/1 of the maximum non-awakening concentration of the agonist, + 5%. In some embodiments, the average plasma concentration of the 0X2R agonist, at or below the maximum non-awakening plasma concentration, is about 1/60, 1/40 1/36, 1/30, 1/20/ or 1/10 of the arousal-promoting plasma concentration.

[0067] As used herein, the term “arousal-promoting concentration” of an 0X2R agonist refers to a threshold blood plasma concentration of the agonist which provides nearly complete wakefulness effect (i.e. maintenance of wakefulness for more than 75% in 10 min-bins.) in a subject. Certain 0X2R agonists have been shown to produce potent efficacy in wakefulness when the blood plasma concentration of the 0X2R agonist exceeded its arousal -promoting concentration in NT1 (narcolepsy type 1) subjects. The arousal-promoting concentration of an 0X2R agonist is significantly higher than the maximum non-awakening concentration of the 0X2R agonist.

[0068] The determination of blood plasma concentration can be performed with measures known to the skilled person in the art, including high-performance liquid chromatography-tandem mass spectrometry. The level is typically expressed as ng of analyte/mL. A maximum non-awakening concentration and an arousal-promoting concentration of an 0X2R agonist in a subject can be determined by combining timeseries measurement of blood plasma concentration with recording of nighttime and/or daytime sleep and awake patterns in the subject by known methods including EEG/EMG recording and actigraphy. When detecting the maximum non-awakening concentration or arousal-promoting concentration of an 0X2R agonist in a non-NTl subject, the measurement is performed during night time when autogenic orexin-A level of the subject is generally low.

[0069] As used herein, the term “treatment”, “treating”, or “treat” includes improvement, reduction, alleviation, or amelioration of one or more symptoms associated with a disease. In one embodiment of the methods and uses disclosed herein can improve one or more nighttime symptoms selected from fragmented sleep, sleep paralysis and hallucinations; and/or improves one or more daytime symptoms selected from fragmented wakefulness and cataplexy. Such improvements can be assessed using any one or more of MWT, MSLT (Multiple Sleep Latency test), EEG (electroencephalogram), or EMG (electromyogram), by comparing the conditions before and after administration of an 0X2R agonist to the subject, or by comparing the conditions between subjects administered placebo and administered an 0X2R agonist. In one embodiment, an 0X2R agonist of the present invention improves night time sleep fragmentation of NT1 patients as indicated by reducing the number of episodes of wakefulness during sleep phase (dark phase) by about 10% to about 20%, and/or increasing NREM (non-rapid eye-movement) sleep duration during the light phase by 10% to about 30%.

[0070] As used herein, the term “dosing interval” refers to the time between administrations of an 0X2R agonists to a subject. The dosing interval of an 0X2R agonist can depend on the pharmacokinetic profiles of the 0X2R agonist as well as the dosage form of the 0X2R agonist in a manner known to the person skilled in the art. When the dosage form is a sustained-release formulation for subcutaneous injection, the preferable dosing interval can be once a week, once every two weeks, once every four weeks, once every six weeks, or once every eight weeks, among others.

[0071] As used herein, the term “subject” refers to a mammal including human, bovine, horse, dog, cat, monkey, mouse, and rat, and preferably refers to a human.

[0072] As used herein, the term “pharmaceutically acceptable” substances refer to those substances which are suitable for administration to subjects.

II. CONTROLLED RELEASE COMPOSITIONS

[0073] A difficulty in determining an effective treatment for sleep disorders is that the desired drug release level can differ throughout the course of the day. Additionally, different sleep disorders can warrant a different drug release level at different times of the day. For example, a patient with narcolepsy experiences drowsiness during the day so the drug release level during the day should be higher than the drug release level during the night. Conversely, a patient with insomnia typically experiences difficulty falling and staying asleep at night so the drug release level during the night should be higher than the drug release level during the day.

[0074] Controlled release formulations attempt to solve these difficulties by releasing the drug in a predictable and rational programmed rate to achieve an optimal serum-drug concentration. However, controlled release formulations can exhibit a common drawback: an initial uncontrolled burst of drug. In some controlled release formulations, immediately upon placement in the release medium, an initial large bolus of drug is released before the release rate reaches a stable profile. Accordingly, there is a need to provide a controlled release formulation that reduces the initial release of a large bolus of drug.

[0075] The present disclosure provides controlled release compositions that prevent excessive drug release (i.e., reduces the initial uncontrolled burst of drug) during the initial 24 hours after administration by increasing the drug loading amount and/or by increasing the mean particle diameter in the microcapsules.

[0076] The present disclosure provides a controlled release composition comprising: [0077] an orexin type 2 receptor agonist or salt or hydrate thereof in an amount of about 10 % (w/w) to about 70 % (w/w) based upon the total weight of the orexin type 2 receptor agonist and lactic acid-glycolic acid polymer;

[0078] lactic acid-glycolic acid polymer or salt thereof having a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol, in an amount of about 30 % (w/w) to about 90 % (w/w) based upon the total weight of the orexin type 2 receptor agonist and lactic acid-glycolic acid polymer;

[0079] wherein the orexin type 2 receptor agonist or a salt thereof and the lactic acid- glycolic acid copolymer or salt thereof are in the form of microcapsules that have a mean particle diameter of between about 20 microns and about 75 microns.

[0080] The present disclosure also provides a controlled release composition comprising:

[0081] methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l -carboxylate or salt or hydrate thereof in an amount of about 10 % (w/w) to about 70 % (w/w) based upon the total weight of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l- carboxylate or a salt thereof and lactic acid-glycolic acid polymer;

[0082] lactic acid-glycolic acid polymer or salt thereof having a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol, in an amount of about 30 % (w/w) to about 90 % (w/w) based upon the total weight of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l- carboxylate and lactic acid-glycolic acid polymer;

[0083] wherein methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy) methyl)piperidine-l -carboxylate or salt or hydrate thereof and the lactic acid-glycolic acid copolymer or salt thereof are in the form of microcapsules that have a mean particle diameter of between about 20 microns and about 75 microns. 1. Orexin Type 2 Receptor Agonist

[0084] A useful orexin type 2 receptor agonist for the methods, uses, or compositions of the present invention is a chemical molecule (compound) having orexin type 2 receptor agonist activity. Such compound can be selected from among known compounds or from newly designed/synthesized compounds. A compound having shorter half-life (i.e., less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, or less than 4 hours) is particularly useful when formulating it in a slow-release dosage form.

[0085] In some embodiments, the orexin type 2 receptor agonist is methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a salt or a hydrate thereof, which is described in Int’l. Publ. No. WO 2017/135306, incorporated herein by reference in its entirety.

[0086] The orexin type 2 receptor agonist can exist as a pharmaceutically acceptable salt. Examples of such salts include a salt with inorganic base, a salt with organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid and the like. Examples of the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salt, ammonium salt and the like. Examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like. Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. Examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

[0087] The orexin type 2 receptor agonist can exist as a hydrate or a non-hydrate, or a non-solvate (e.g., anhydride), or a solvate (e.g., hydrate). [0088] Furthermore, the orexin type 2 receptor agonist can exist as a pharmaceutically acceptable cocrystal or cocrystal salt. The cocrystal or cocrystal salt means a crystalline substance constituted with two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability). The cocrystal or cocrystal salt can be produced by known methods.

2. Lactic Acid-Glycolic Acid Polymer

[0089] In some embodiments, the lactic acid-glycolic acid polymer is a biodegradable polymer which decomposes in a living body over a period of at least about 6-8 weeks dependent upon the ratio of lactic acid to glycolic acid. In some embodiments, the lactic acid-glycolic acid polymer decomposes in a living body over a period of from about 3 weeks to about 12 weeks, from about 3 weeks to about 10 weeks, from about 3 weeks to about 8 weeks, from about 3 weeks to about 6 weeks, from about 3 weeks to about 4 weeks, from about 4 weeks to about 12 weeks, from about 4 weeks to about 10 weeks, from about 4 weeks to about 8 week, from about 4 weeks to about 6 weeks, from about 6 weeks to about 12 weeks, from about 6 weeks to about 10 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 8 weeks to about 10 weeks, or from about 10 weeks to about 12 weeks.

[0090] In some embodiments, the lactic acid-glycolic acid copolymer is prepared from the polymerization of lactic acid and glycolic acid. In some embodiments, the preparation of the lactic acid-glycolic acid is described in IntT Publ. No. WO 03/002092, incorporated herein by reference in its entirety.

[0091] The ratio of lactic acid to glycolic acid in the polymer is preferably about 100/0 to 50/50 (mole %) preferably about 50 to 95 mole % of lactic acid and about 50 to 5 mole % of glycolic acid, more preferably about 60 to 95 mole % of lactic acid and about 40 to 5 mole % of glycolic acid, still more preferably about 60 to 85 mole % of lactic acid and about 40 to 15 mole % of glycolic acid. The ratio is especially preferably about 75±2 mole % of lactic acid and about 25±2 mole % of glycolic acid.

[0092] The weight-average molecular weight of each polymer is a polystyrene-reduced weight-average molecular weight measured by gel permeation chromatography (GPC) using mono-dispersed polystyrene as a standard substance. Measurements were all conducted by a high performance GPC apparatus and tetrahydrofuran was used at a flow rate of 1.0 mL/min as the mobile phase. The detection method is based on differential refractive index.

[0093] In some embodiments, the lactic acid-glycolic acid polymer or salt thereof has a weight-average molecular weight from about 7,000 g/mol to about 15,000 g/mol. In some embodiments, the lactic acid-glycolic acid copolymer or salt thereof has a weightaverage molecular weight from about 9,000 g/mol to about 11,000 g/mol.

[0094] In some embodiments, the lactic acid-glycolic acid copolymer or salt thereof has a weight-average molecular weight from about 7,000 g/mol to about 15,000 g/mol, from about 7,000 g/mol to about 12,000 g/mol, from about 7,000 g/mol to about 11,000 g/mol, from about 7,000 g/mol to about 10,000 g/mol, from about 7,000 g/mol to about 9,000 g/mol, from about 9,000 g/mol to about 15,000 g/mol, from about 9,000 g/mol to about 12,000 g/mol, from about 9,000 g/mol to about 11,000 g/mol, from about 9,000 g/mol to about 10,000 g/mol, from about 10,000 g/mol to about 15,000 g/mol, from about 10,000 g/mol to about 12,000 g/mol, from about 10,000 g/mol to about 11,000 g/mol, from about 11,000 g/mol to about 15,000 g/mol, from about 11,000 g/mol to about 12,000 g/mol, or from about 12,000 g/mol to about 15,000 g/mol.

[0095] In some embodiments, the lactic acid-glycolic acid copolymer or salt thereof has a weight-average molecular weight of about 10,700 g/mol. In some embodiments, the lactic acid-glycolic acid copolymer or salt thereof has a weight-average molecular weight of about 10,676 g/mol. In some embodiments, the lactic acid-glycolic acid copolymer or salt thereof has a weight-average molecular weight of about 10,438 g/mol. In some embodiments, the lactic acid-glycolic acid copolymer or salt thereof has a weight-average molecular weight of about 10,000 g/mol. In some embodiments, the lactic acid-glycolic acid copolymer or salt thereof has a weight-average molecular weight of about 9,909 g/mol. In some embodiments, the lactic acid-glycolic acid copolymer or salt thereof has a weight-average molecular weight of about 9,900 g/mol.

3. Microcapsules

[0096] In some embodiments, the controlled release composition is in the form of microcapsules.

[0097] In some embodiments, the particle size distribution and mean particle size of the microcapsules can be measured using Coulter Counter-type particle counter (CDA-1000, Sysmex Corp., Kobe, Japan). Using an aperture tube with 100 microns opening, variations in conductivity caused by passing the microcapsule sample in the media through the aperture, are recorded as electrical pulses and analyzed to determine the particle size distribution and mean particle size.

[0098] In some embodiments, the microcapsules in the controlled release composition can have a mean particle diameter from about 40 microns to about 100 microns. In some embodiments, the microcapsules in the controlled release composition can have a mean particle diameter from about 40 microns to about 100 microns, from about 40 microns to about 90 microns, from about 40 microns to about 80 microns, from about 40 microns to about 70 microns, from about 40 microns to about 60 microns, from about 40 microns to about 50 microns, from about 50 microns to about 100 microns, from about 50 microns to about 90 microns, from about 50 microns to about 80 microns, from about 50 microns to about 70 microns, from about 50 microns to about 60 microns, from about 60 microns to about 100 microns, from about 60 microns to about 90 microns, from about 60 microns to about 80 microns, from about 60 microns to about 70 microns, from about 70 microns to about 100 microns, from about 70 microns to about 90 microns, from about 70 microns to about 80 microns, from about 80 microns to about 100 microns, from about 80 microns to about 90 microns, or from about 90 microns to about 100 microns. In some embodiments, the microcapsules in the controlled release composition can have a mean particle diameter of about 60 microns, about 65 microns, about 70 microns, about 75 microns, about 80 microns, about 85 microns, about 90 microns, about 95 microns, or about 100 microns. In some embodiments, the microcapsules in the controlled release composition can have a mean particle diameter of about 61 microns. In some embodiments, the microcapsules in the controlled release composition can have a mean particle diameter of about 63 microns. In some embodiments, the microcapsules in the controlled release composition can have a mean particle diameter of about 72 microns.

[0099] As used herein, the phrase “loading amount” refers to a calculated rate of the added amount of physiologically active substance (i.e., the orexin type 2 receptor agonist) to the total additive amount of each component comprising the microcapsule in the preparation. The physiologically active substance (i.e., the orexin type 2 receptor agonist) is to be added so that the physiologically active substance (i.e., the orexin type 2 receptor agonist) is contained with the amount of from about 10% to about 70% (weight/weight) to the whole microcapsule (content of the physiologically active substance in microcapsule). Therefore, the loading amount of physiologically active substance (i.e., orexin type 2 receptor agonist) is about 10% to about 70% by weight, about 20% to about 60%, or about 30% to about 50% by weight. In some embodiments, the loading amount is a calculated rate of the added orexin type 2 receptor agonist. In some embodiments, the loading amount is a calculated rate of the added methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1- carboxylate or a salt thereof.

[0100] In some embodiments, the loading amount (weight/weight) of the orexin type 2 receptor agonist in the microcapsule is from about 10% to about 70%. In some embodiments, the loading amount (weight/weight) of the orexin type 2 receptor agonist in the microcapsule is from about 20% to about 60%. In some embodiments, the loading amount (weight/weight) of the orexin type 2 receptor agonist in the microcapsule is from about 30% to about 50%. In some embodiments, the loading amount (weight/weight) of the orexin type 2 receptor agonist in the microcapsule is from about 10% to about 70%, from about 10% to about 60%, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30%, from about 10% to about 20%, from about 20% to about 70%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 40%, from about 20% to about 30%, from about 30% to about 70%, from about 30% to about 60%, from about 30% to about 50%, from about 30% to about 40%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 70%, from about 50% to about 60%, or from about 60% to about 70%. In some embodiments, the loading amount (weight/weight) of the orexin type 2 receptor agonist in the microcapsule is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70%. In some embodiments, the loading amount (weight/weight) of the orexin type 2 receptor agonist in the microcapsule is about 30%. In some embodiments, the loading amount (weight/weight) of the orexin type 2 receptor agonist in the microcapsule is about 40%.

[0101] In some embodiments, the loading amount (weight/weight) of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1- carboxylate or a salt thereof in the microcapsule is from about 10% to about 70%. In some embodiments, the loading amount (weight/weight) of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1- carboxylate or a salt thereof in the microcapsule is from about 20% to about 60%. In some embodiments, the loading amount (weight/weight) of methyl (2R,3S)-3- ((methyl sulfonyl )amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1- carboxylate or a salt thereof in the microcapsule is from about 30% to about 50%. In some embodiments, the loading amount (weight/weight) of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1- carboxylate or a salt thereof in the microcapsule is from about 10% to about 70%, from about 10% to about 60%, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30%, from about 10% to about 20%, from about 20% to about 70%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 40%, from about 20% to about 30%, from about 30% to about 70%, from about 30% to about 60%, from about 30% to about 50%, from about 30% to about 40%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 70%, from about 50% to about 60%, or from about 60% to about 70%. In some embodiments, the loading amount (weight/weight) of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate or a salt thereof in the microcapsule is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70%. In some embodiments, the loading amount (weight/weight) of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((ci s-4- phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate or a salt thereof in the microcapsule is about 30%. In some embodiments, the loading amount (weight/weight) of methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate or a salt thereof in the microcapsule is about 40%.

IV. METHODS OF PRODUCING THE CONTROLLED RELEASE COMPOSITION

[0102] After the controlled release composition is administered into an organism, oligomers and monomers form due to the decomposition of a lactic acid polymer, however when the polymer is a lactic acid-glycolic acid polymer, the produced oligomer (lactic acid-glycolic acid oligomer) and monomer (lactic acid or glycolic acid) necessarily have one carboxyl group, which also can be counter ions of a physiologically active substance. Release of a physiologically active substance (i.e., an orexin type 2 receptor agonist) is not accompanied by movement of electric charge, namely, it is released in the form of a salt maintaining a counter ion, and as the movable counter ion species, lactic acid-glycolic acid oligomer (such molecular weight as to enable movement) and monomer (lactic acid or glycolic acid).

[0103] When a plurality of acids coexist, a strongly acidic salt is dominantly formed generally though differing depending on the composition ratio. Though the pKa of a carboxyl group of a lactic acid-glycolic acid oligomer is not known, it can be calculated based on the pKa of lactic acid or glycolic acid (= 3.86 or 3.83) according to the principle “change of free energy by introduction of a substituent can be approximated by additive law.” Contribution by a substituent to the dissociation constant has been found and can be utilized (Table 4.1 in “pKa Prediction for Organic Acid and Bases,” D. D. Perrin, B. Dempsey and E. P. Serjeant, 1981). Since pKas for a hydroxyl group and an ester bond are:

ApKa (OH) = -0. 90 and ApKa (ester bond) = -1.7 respectively, pKa of a carboxyl group of a lactic acid-glycolic acid oligomer is calculated, in view of contribution by an ester bond nearest to the dissociation group, as follow: pKa = pKa (lactic acid or glycolic acid) - ApKa (OH) + A pKa (ester bond) = 3. 06 or 3.03. As a result, since the lactic acid-glycolic acid oligomer is a stronger acid than lactic acid (pKa = 3.86) and glycolic acid (pKa = 3.83), it is supposed that in the above-mentioned composition, a salt of the lactic acid-glycolic acid oligomer and a physiologically active substance (i.e., an orexin type 2 receptor agonist) is formed dominantly, and that the property of this salt mainly determines the controlled releasing property of a physiologically active substance in the composition.

[0104] Here, a salt is formed of lactic acid-glycolic acid oligomer with a physiologically active substance (i.e., an orexin type 2 receptor agonist) which is slightly water-soluble but not fully water-soluble preferably exerts an influence on the controlled release mechanism. That is, as clarified in the consideration of the above-mentioned acid dissociation constant, the salt of the lactic acid-glycolic acid oligomer which is a stronger acid than the above-mentioned lactic acid monomer and the glycolic monomer exists dominantly at the initial period of releasing as the hydrolyzable salt of a physiologically active substance, and as a result, the solubility and distribution properties of the salt into body tissue become determining factors of the releasing speed of a physiologically active substance (i.e., an orexin type 2 receptor agonist), therefore, the initial releasing pattern of a drug can be controlled by the compounding amount of the lactic acid-glycolic acid oligomer. Then, with increase in oligomers and monomers generated by the hydrolysis of a lactic acid polymer, the releasing mechanism of a physiologically active substance having an oligomer and monomer as counter ions becomes dominant gradually, and release of a stable physiologically active substance (i.e., an orexin type 2 receptor agonist) is retained. Further, enhancement of incorporation efficiency of a physiologically active substance (i.e., an orexin type 2 receptor agonist) in producing a controlled release composition, and capability of suppression of the initial excess release after administration of a physiologically active substance (i.e., an orexin type 2 receptor agonist) incorporated can also be explained.

[0105] The term “water-insolubility” as used herein refers to a case in which when the physiologically active substance (i.e., an orexin type 2 receptor agonist)is stirred at a temperature of 40 °C or lower in distilled water for 4 hours, the weight of a substance dissolved in 1 L of this solution is 25 mg or less.

[0106] The term “slight water-solubility” as used herein refers to a case in which when the physiologically active substance (i.e., an orexin type 2 receptor agonist) is stirred at a temperature of 40 °C or lower in distilled water for 4 hours, the weight of a substance dissolved in 1 L of this solution is over 25 mg and 5 g or less. When the abovementioned substance is a salt of a physiologically active substance, the weight of a physiologically active substance dissolved in the above-mentioned operation is used for application of the above-mentioned definition.

[0107] Though the form of a controlled release composition in this specification is not particularly restricted, the form of a fine particle is preferable, and the form of a microsphere (also called microcapsule in the case of a controlled release composition containing a lactic acid-glycolic acid polymer) is particularly preferable. The term microsphere means an injectable fine particle in the form of sphere which can be dispersed in a solution. The verification of the form can be conducted, for example, by observation by a scanning electron microscopy (SEM).

[0108] The present disclosure provides a method of producing a controlled release composition comprising:

[0109] mixing an orexin type 2 receptor agonist or a salt thereof in an amount of about 10 % (w/w) to about 70 % (w/w) based upon the total weight of the orexin type 2 receptor agonist and lactic acid-glycolic acid polymer into a solution containing lactic acid- glycolic acid polymer or salt thereof having a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol, in an amount of about 30 % (w/w) to about 90 % (w/w) based upon the total weight of the orexin type 2 receptor agonist and lactic acid-glycolic acid polymer and an organic solvent to obtain an organic solution;

[0110] dispersing the organic solution in a solution of polyvinyl alcohol and water to form an oil-in-water emulsion;

[OHl] removing said organic solvent to form a dispersion of microcapsules; and

[0112] sieving and washing the microcapsules.

[0113] The present disclosure also provides a method of producing a controlled release composition comprising:

[0114] mixing methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((ci s-4- phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate or a salt thereof in an amount of about 10 % (w/w) to about 70 % (w/w) based upon the total weight of the orexin type 2 receptor agonist and lactic acid-glycolic acid polymer into a solution containing lactic acid-glycolic acid polymer or salt thereof having a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol, in an amount of about 30 % (w/w) to about 90 % (w/w) based upon the total weight of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate and lactic acid-glycolic acid polymer and an organic solvent to obtain an organic solution;

[0115] dispersing the organic solution in a solution of polyvinyl alcohol and water to form an oil-in-water emulsion;

[0116] removing said organic solvent to form a dispersion of microcapsules; and

[0117] sieving and washing the microcapsules.

[0118] In the following production process, drug holding agents (for example, gelatin, salicylic acid and the like) can be added, if necessary, by a method known per se.

1. In-water Drying Method (O/W Method)

[0119] In this method, an organic solvent solution of the lactic acid-glycolic acid polymer of the present invention (hereinafter, described as biodegradable polymer of the present invention in some cases) is first produced. The organic solvent used in producing the controlled release composition of the present invention has a boiling point preferably of 120 °C or lower.

[0120] In some embodiments, the organic solvent can be a halogenated hydrocarbon (for example, dichloromethane, chloroform, dichloroethane, tri chloroethane, carbon tetrachloride, and the like), an ether (for example, ethyl ether, isopropyl ether, and the like), a fatty ester (for example, ethyl acetate, butyl acetate, and the like), an aromatic hydrocarbon (for example, benzene, toluene, xylene, and the like), or an alcohol (for example, ethanol, methanol, and the like), or acetonitrile and the like. In some embodiments, the organic solvent is a halogenated hydrocarbons. These can be used in admixture of appropriate proportion. In some embodiments, the organic solvent is a mixed solution of a halogenated hydrocarbon and an alcohol. In some embodiments, the organic solvent is a mixed solution of dichloromethane and ethanol. In some embodiments, the organic solvent is di chloromethane.

[0121] The concentration of the biodegradable polymer of the present invention in an organic solvent solution varies depending on the molecular weight of the biodegradable polymer of the present invention and the kind of an organic solvent. In some embodiments, an organic solvent in an amount from about 40% to about 90% (w/w) based upon the total weight of the lactic acid-glycolic acid polymer and organic solvent is used. In some embodiments, an organic solvent in an amount (w/w) from about 40% to about 90%, from about 40% to about 80%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 90%, from about 50% to about 80%, from about 50% to about 70%, from about 50% to about 60%, from about 60% to about 90%, from about 60% to about 80%, from about 60% to about 70%, from about 70% to about 90%, from about 70% to about 80%, or from about 80% to about 90% based upon the total weight of the lactic acid-glycolic acid polymer and organic solvent is used.

[0122] In some embodiments, di chloromethane is used as the organic solvent. In some embodiments, dichloromethane in an amount (w/w) from about 40% to about 90%, from about 40% to about 80%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 90%, from about 50% to about 80%, from about 50% to about 70%, from about 50% to about 60%, from about 60% to about 90%, from about 60% to about 80%, from about 60% to about 70%, from about 70% to about 90%, from about 70% to about 80%, or from about 80% to about 90% based upon the total weight of the lactic acid-glycolic acid polymer and organic solvent can be used. Into the organic solvent solution of the biodegradable lactic acid-glycolic acid polymer of the present invention thus obtained, a physiologically active substance (i.e., an orexin type 2 receptor agent) is added and dissolved or dispersed. In this procedure, the addition amount of a physiologically active substance (i.e., an orexin type 2 receptor agent) is controlled so that the upper limit of the weight ratio of physiologically active substance (i.e., an orexin type 2 receptor agent) to biodegradable polymer (i.e., lactic acid-glycolic acid polymer) of the present invention is up to about 1 :3. In some embodiments, the weight ratio of the physiological active substance (i.e., an orexin type 2 receptor agonist) to biodegradable polymer (i.e., lactic acid-glycolic acid polymer) is about 1 : 1, about 1 :2, about 1 :3, or about 1 :4. In some embodiments, the weight ratio of the physiological active substance (i.e., an orexin type 2 receptor agonist) to biodegradable polymer (i.e., lactic acid-glycolic acid polymer) is about 1 :2. In some embodiments, the weight ratio of the physiological active substance (i.e., an orexin type 2 receptor agonist) to biodegradable polymer (i.e., lactic acid-glycolic acid polymer) is about 1 :3. In some embodiments, the weight ratio of the physiological active substance (i.e., an orexin type 2 receptor agonist) to biodegradable polymer (i.e., lactic acid-glycolic acid polymer) is about 1 :4.

[0123] Subsequently, the resulting organic solvent solution containing a composition composed of a physiologically active substance (i.e., an orexin type 2 receptor agonist) or salt thereof and the biodegradable polymer of the present invention are added into a water phase, to form an O (oil phase)/W (water phase) emulsion, then, the solvent in the oil phase is evaporated, to prepare a microcapsule. The volume of the water phase in this case is generally from about 1-fold to about 10000-fold of the oil phase volume. In some embodiments, the volume of the water phase in the O/W emulsion is from about 5-fold to about 50000-fold of the oil phase volume. In some embodiments, the volume of the water phase in the O/W emulsion is from about 10-fold to about 2000-fold of the oil phase volume.

[0124] An emulsifier can be added to the above-mentioned water phase. This emulsifier can be any compound providing it can form a generally stable O/W emulsion.

[0125] Specifically, for example, anionic surfactants (sodium oleate, sodium stearate, sodium laurylsulfate, and the like), nonionic surfactants (polyoxyethylene sorbitan fatty esters (TWEEN 80 and TWEEN 60 (manufactured by Atlas Powder), and the like), polyoxyethylene castor oil derivatives (HCO-60 and HCO-50 (manufactured by NIKKO Chemicals K. K), polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin, hyaluronic acid, and the like) are used. One of them or several of them in combination can be used. In some embodiments, the concentration of emulsifier used is from about 0.01% to about 10% by weight of the water in the O/W emulsion. In some embodiments, the concentration of emulsifier used is from about 0.05% to about 5% by weight of the water in the O/W emulsion.

[0126] In some embodiments, the emulsifier in the O/W emulsion can be polyvinyl alcohol. In some embodiments, the concentration of polyvinyl alcohol used is from about 0.01% to about 10% by weight of the water in the O/W emulsion. In some embodiments, the concentration of polyvinyl alcohol used is from about 0.05% to about 5% by weight of the water in the O/W emulsion. An osmotic pressure controlling agent can be added into the above-mentioned water phase. The osmotic pressure controlling agent can be advantageous providing it shows osmotic pressure when used in the O/W emulsion.

[0127] In some embodiments, the osmotic pressure controlling agent can be a polyhydric alcohol, a monohydric alcohol, a monosaccharide, a disaccharide, an oligosaccharide, an amino acid, a derivative thereof, or the like.

[0128] In some embodiments, the osmotic pressure controlling agent can be a polyhydric alcohol. In some embodiments, the polyhydric alcohol can be a trihydric alcohol such as glycerin and the like, a pentahydric alcohol such as arabitol, xylitol, adonitol, and the like, a hexahydric alcohol such as mannitol, sorbitol, dulcitol, and the like, or another alcohol. In some embodiments, the polyhydric alcohol can be a hexahydric alcohol. In some embodiments, the osmotic pressure controlling agent can be mannitol.

[0129] In some embodiments, the osmotic pressure controlling agent can be a monohydric alcohol. In some embodiments, the monohydric alcohols can be methanol, ethanol, isopropyl alcohol, and the like. In some embodiments, the monohydric alcohol can be ethanol.

[0130] In some embodiments, the osmotic pressure controlling agent can be a monosaccharide. In some embodiments, the monosaccharide can be a pentose such as arabinose, xylose, ribose, 2-deoxyribose, and the like, or a hexose such as glucose, fructose, galactose, mannose, sorbose, rhamnose, fucose, and the like. In some embodiments, the monosaccharide can be a hexose.

[0131] In some embodiments, the osmotic pressure controlling agent can be an oligosaccharide. In some embodiments, the oligosaccharide can be a trios such as maltotriose, raffinose, and the like or a tetros such as stachyose and the like. In some embodiments, the oligosaccharide can be a trios. [0132] In some embodiments, the osmotic pressure controlling agent is a derivative of a monosaccharide, a disaccharide, or an oligosaccharide. In some embodiments, the derivative of a monosaccharide, a disaccharide, or an oligosaccharide is glucosamine, galactosamine, glucuronic acid, galacturonic acid, and the like.

[0133] In some embodiments, the osmotic pressure controlling agent can be an amino acid. In some embodiments, the amino acid can be an L-amino acids. In some embodiments, the L-amino acid can be glycine, leucine, arginine, and the like. In some embodiments, the osmotic pressure controlling agent can be L-arginine.

[0134] These osmotic pressure controlling agents can be used alone or in admixture.

[0135] These osmotic pressure controlling agents are used in concentrations so that the osmotic pressure of the water phase of the O/W emulsion is from about 1/50-fold to about 5-fold of the osmotic pressure of physiological saline. In some embodiments, the osmotic pressure of the water phase of the O/W emulsion is from about 1/25 to about 3-fold of the osmotic pressure of physiological saline. When mannitol is used as an osmotic pressure controlling agent, its concentration is preferably 0.5% to 1.5%.

[0136] As the method of removing an organic solvent, a method known to those of skill in the art can be used. In some embodiments, a method in which an organic solvent is evaporated while stirring by a propeller type stirrer or magnetic stirrer and the like at normal pressure or reduced pressure where the amount of organic solvent is gradually reduced can be used. In some embodiments, a method in which an organic solvent is evaporated while controlling the degree of vacuum using a rotary evaporator and the like can be used.

[0137] The obtained microcapsule can be separated by sieving or centrifugation or filtration, then, free physiologically active substances, emulsifier, and the like adhered to the surface of a microcapsule can be washed several times repeatedly with distilled water, dispersed again into distilled water and the like, and freeze-dried.

[0138] To the O/W emulsion, a coagulation preventing agent (i.e., dispersing agent) can be added for preventing mutual coagulation of particles. In some embodiments, the coagulation preventing agent (i.e., dispersing agent) can be a water-soluble polysaccharide such as mannitol, lactose, glucose, starches (for example, com starch and the like) and the like, an amino acid such as glycine and the like, or a protein such as fibrin, collagen and the like, are used. In some embodiments, the coagulation preventing agent (i.e., dispersing agent) is mannitol. [0139] In some embodiments, the amount of the coagulation preventing agent (i.e., dispersing agent) can be from 0 to about 24% by weight based on the microcapsule total weight. In some embodiments, amount of mannitol can be from about 1% to about 24% by weight based on the microcapsule total weight.

[0140] In some embodiments, the obtained microcapsules can be freeze dried (lyophilized).

[0141] After freeze drying, if necessary, any remaining water and organic solvent in the dispersion of microcapsules can be removed by heating under conditions causing no mutual fusion of microcapsules and under reduced pressure. In some embodiments, the dispersion of microcapsules are heated at a temperature around or slightly higher than the intermediate point glass transition temperature of an biodegradable polymer (i.e., lactic acid-glycolic acid polymer) measured by a differential scanning calorimeter under conditions of a temperature increasing speed of 10 °C to 20 °C per minute. In some embodiments, heating is conducted at temperatures around the intermediate point glass transition temperature of a biodegradable polymer or within the range from the intermediate point glass transition temperature thereof to a temperature higher by about 30 °C than the intermediate point glass transition temperature. Particularly, when a lactic acid-glycolic acid polymer is used as an biodegradable polymer, heating is conducted preferably at temperatures lying within the range from around the intermediate point glass transition temperature to a temperature higher than the intermediate point glass transition temperature by 10 °C, further preferably at temperatures lying within the range from around the intermediate point glass transition temperature to a temperature higher than the intermediate point glass transition temperature by 5 °C.

[0142] Though the heating time varies depending on the amount of microcapsules and the like, the heating time can be from about 12 hours to about 168 hours. In some embodiments, the heating time to remove any remaining water or organic solvent from the dispersion of microcapsules can be from about 24 hours to about 120 hours or from about 48 hours to about 96 hours, after the microcapsule itself reaches a given temperature.

[0143] The heating method is not particularly restricted provided that a set of microcapsules can be uniformly heated.

[0144] As the heat drying method, for example, a method of heat drying in a constant temperature chamber, fluidized chamber, moving chamber or kiln, in a microwave, and the like can be used. Among them, a method of heat drying in a constant temperature chamber is preferable.

[0145] In some embodiments, the microcapsules can be sieved through a sieve to obtain microcapsules having a desired mean particle diameter. In some embodiments, the microcapsules can be sieved through a sieve having an opening diameter from 10 pm to about 100 pm. In some embodiments, the microcapsules can be sieved through a sieve having an opening diameter from about 10 pm to about 100 pm, from about 10 pm to about 80 pm, from about 10 pm to about 60 pm, from about 10 pm to about 40 pm, from about 10 pm to about 20 pm, from about 20 pm to about 100 pm, from about 20 pm to about 80 pm, from about 20 pm to about 60 pm, from about 20 pm to about 40 pm, from about 40 pm to about 100 pm, from about 40 pm to about 80 pm, from about 40 pm to about 60 pm, from about 60 pm to about 100 pm, from about 60 pm to about 80 pm, or from about 80 pm to about 100 pm.

[0146] In some embodiments, the microcapsules can be sieved through one sieve. In some embodiments, the microcapsules can be sieve through two sieves. In some embodiments, the microcapsules can be sieved through three sieves. In some embodiments, the sieves are in series. In some embodiments, the microcapsules can be sieved through a sieve having an opening diameter of about 75 pm. In some embodiments, the microcapsules can be sieved through a sieve having an opening diameter of about 20 pm. In some embodiments, the microcapsules can be sieved through a series of two sieves the first having an opening diameter of about 75 pm and the second having an opening diameter of about 20 pm.

2. Two-step Method

[0147] A physiologically active substance (i.e., an orexin type 2 receptor agonist) or salt thereof can be added to an organic solvent solution to make an organic solvent solution containing a physiologically active substance.

[0148] The organic solvent used in the two-step method can be the same as described herein in the in-water drying method of section (IV)(1). When a mixed organic solvent is used, the ratio of the two solvents is the same as described herein in the drying method of section (IV)(1).

[0149] Methods of removing an organic solvent for precipitating a composition containing a physiologically active substance (i.e., an orexin type 2 receptor agonist) are known to those skilled in the art. In some embodiments, a method in which an organic solvent is evaporated while controlling the degree of vacuum using a rotary evaporator and the like can be used.

[0150] The organic solvent solution of a composition containing a physiologically active substance (i.e., an orexin type 2 receptor agonist) thus obtained is produced again, and a controlled release composition (microsphere of fine particle (i.e., microcapsules)) can be produced.

[0151] In some embodiments, the organic solvent can be a halogenated hydrocarbon (for example, dichloromethane, chloroform, dichloroethane, tri chloroethane, carbon tetrachloride, and the like), an ether (for example, ethyl ether, isopropyl ether, and the like), a fatty ester (for example, ethyl acetate, butyl acetate, and the like), an aromatic hydrocarbon (for example, benzene, toluene, xylene, and the like), or an alcohol (for example, ethanol, methanol, and the like), or acetonitrile and the like. In some embodiments, the organic solvent is a halogenated hydrocarbons. These can be used in admixture of appropriate proportion. In some embodiments, the organic solvent is a mixed solution of a halogenated hydrocarbon and an alcohol. In some embodiments, the organic solvent is a mixed solution of dichloromethane and ethanol. In some embodiments, the organic solvent is di chloromethane.

[0152] Next, the resultant organic solvent solution containing a physiologically active substance (i.e., an orexin type 2 receptor agonist) is added into a water phase, to form an O (oil phase)/W (water phase) emulsion, then, the solvent in the oil phase is evaporated, to prepare a microcapsule. The volume of the water phase in this case is generally from about 1-fold to about 10000-fold, more preferably from about 5-fold to about 5000-fold, particularly preferably from about 10-fold to about 2000-fold of the oil phase volume.

[0153] An emulsifier and/or an osmotic pressure controlling agent described herein in section (IV)(1) can be added into the water phase followed by the preparation method described herein in section (IV)(1).

[0154] As the method of removing an organic solvent, a method known to those of skill in the art can be used. In some embodiments, a method in which an organic solvent is evaporated while stirring by a propeller type stirrer or magnetic stirrer and the like at normal pressure or reduced pressure where the amount of organic solvent is gradually reduced can be used. In some embodiments, a method in which an organic solvent is evaporated while controlling the degree of vacuum using a rotary evaporator and the like can be used.

[0155] The obtained microcapsule can be separated by sieving or centrifugation or filtration, then, free physiologically active substances, emulsifier, and the like adhered to the surface of a microcapsule can be washed several times repeatedly with distilled water, dispersed again into distilled water and the like, and freeze-dried.

[0156] To the two step method, a coagulation preventing agent can be added for preventing mutual coagulation of particles. In some embodiments, the coagulation preventing agent can be a water-soluble polysaccharide such as mannitol, lactose, glucose, starches (for example, corn starch and the like) and the like, an amino acid such as glycine and the like, or a protein such as fibrin, collagen and the like, are used. In some embodiments, the coagulation preventing agent is mannitol.

[0157] Further, after freeze drying, if necessary, water and organic solvent in the dispersion of microcapsules can be removed by heating under conditions causing no mutual fusion of microcapsules under reduced pressure.

[0158] Though the heating time varies depending on the amount of microcapsules and the like, the heating time is from about 12 hours to about 168 hours. In some embodiments, the heating time to remove any remaining water or organic solvent from the dispersion of microcapsules is from about 24 hours to about 120 hours or from about 48 hours to about 96 hours, after the microcapsule itself reaches a given temperature.

[0159] The heating method is not particularly restricted provided that a set of microcapsules can be uniformly heated.

[0160] As the heat drying method, for example, a method of heat drying in a constant temperature chamber, fluidized chamber, moving chamber or kiln, or in a microwave, and the like can be used. Among them, a method of heat drying in a constant temperature chamber is preferable.

[0161] The resultant microcapsules are in the form of relatively uniform spheres, which cause little resistance in injection administration, and do not cause needle clogging easily.

[0162] Since a slim injection needle can be used, injection into a patient can be less painful. 3. One-step Method

[0163] A physiologically active substance (i.e., an orexin type 2 receptor agonist) or salt thereof is added to an organic solvent solution to make an organic solvent solution of a physiologically active substance.

[0164] The organic solvent can be the same as described herein in the in-water drying method of section (IV)(1). When a mixed organic solvent is used, the ratio of the two solvents is the same as described herein in the in-water drying method of section (IV)(1).

[0165] Next, the organic solvent solution containing the physiologically active substance (i.e., an orexin type 2 receptor agonist) is added into a water phase, to form an O (oil phase)/W (water phase) emulsion, then, the solvent in the oil phase is evaporated, to prepare a microcapsule. The volume of the water phase is generally from about 1-fold to about 10000-fold, more preferably from about 5-fold to about 5000-fold, particularly preferably from about 10-fold to about 2000-fold of the oil phase volume.

[0166] An emulsifier and/or osmotic pressure controlling agent described in section (IV)(1) can be added into the water phase followed by the preparation method described in section (IV)(1).

V. DOSAGE FORMS AND MODES OF ADMINISTRATION

[0167] The controlled release composition of the present invention can be any form such as microsphere, microcapsule, fine particle (micro particle) and the like. In some embodiments, the controlled release composition is in the form of a microcapsule.

[0168] The controlled release composition of the present invention can be administered itself or can be used as a raw material substance and made into various drug forms before administration, as an injection or implantable agent into muscle, subcutaneous, organs and the like, as a permucosal agent into nose, rectum, uterus and the like, as oral agents (for example, capsules (hard capsule, soft capsule and the like), solid drugs such as granules, powder and the like, or liquid drugs such as syrup, emulsion, suspension and the like) and the like.

[0169] The methods and uses disclosed herein comprise administering an OX2R agonist to a subject in need thereof. In some embodiments, the OX2R agonist is administered non-orally. In some embodiments, the non-oral administration is intravenous administration, subcutaneous administration, transdermal administration, intradermal administration, or transmucosal administration. In some embodiments, the non-oral administration is intravenous administration. In some embodiments, the non-oral administration is subcutaneous administration. In some embodiments, the controlled release composition comprising an orexin type 2 receptor agonist is administered by subcutaneous injection. In some embodiments, the controlled release composition comprising methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate is administered by subcutaneous injection.

[0170] In some embodiments, the controlled release composition is provided in a dosage form for subcutaneous administration. In some embodiments, the controlled release compositions of the present disclosure can be administered as an injection. In some embodiments, the controlled release compositions for injection can be made into an aqueous suspension together with a dispersing agent (for example, surfactants such as TWEEN 80, HCO-60 and the like and/or polysaccharides such as sodium hyaluronate, carboxymethylcellulose, sodium alginate, and the like), a preservative (for example, methylparaben, propylparaben, and the like), an isotonization agent (for example, sodium chloride, mannitol, sorbitol, glucose, proline, and the like), or dispersed together with a vegetable oil such as sesame oil, corn oil, and the like to give an oily suspension, which can be used as a controlled release injection.

[0171] The mean particle diameter of the controlled release composition of the present disclosure, can advantageously be in the range satisfying the degree of dispersion and needle passing property when used as a suspended injection.

[0172] In some embodiments, the controlled release composition is sterilized prior to administration. In some embodiments, the controlled release composition of the present disclosure is sterilized by x-ray, by addition of a preservative, and the like.

[0173] In some embodiments, the controlled release composition of the present disclosure can be used for mammals (for example, human, cattle, pig, dog, cat, mouse, rat, rabbit, and the like) since it has low toxicity.

[0174] The dosage of the controlled release composition of the present invention depends on the kind and content of the physiologically active substance (i.e., the orexin type 2 receptor agonist) which is the main drug, drug form, duration time of release of a physiologically active substance, disease to be treated, animal to be treated, and the like, and can advantageously be the therapeutically effective amount of a physiologically active substance (i.e., the orexin type 2 receptor agonist).

[0175] Although varying depending on the kind and content of a physiologically active substance (i.e., the orexin type 2 receptor agonist), duration of a physiologically active substance release, subject species, and purpose of administration, the dose of a controlled release composition can be set at any level, as long as the active ingredient is effective. When a controlled release composition of the present disclosure is administered to humans, the dose of the composition per administration can be chosen as appropriate over the range from about 1 mg to about 10 g, preferably from about 10 mg to about 2 g per adult (weight 50 kg). When the controlled release composition is an injectable preparation, the volume of a suspension can be chosen as appropriate over the range from about 0.1 mL to about 5 mL, preferably from about 0.5 mL to about 3 mL.

[0176] The dose frequency can be appropriately selected depending on the kind and content of a physiologically active substance (i.e., the orexin type 2 receptor agonist) which is the main drug, drug form, duration time of release of a physiologically active substance (i.e., the orexin type 2 receptor agonist), disease to be treated, animals to be treated, and the like, such as once per several weeks, once per month, once per several months (for example, 3, 4, or 6 months, and the like) and the like. In some embodiments, the controlled release composition is administered one time every 2 months. In some embodiments, the controlled release composition is administered one time every 6 weeks. In some embodiments, the controlled release composition is administered one time every 4 weeks. In some embodiments, the controlled release composition is administered one time every 3 weeks. In some embodiments, the controlled release composition is administered one time every 2 weeks.

VI. METHODS AND USES

[0177] The methods and uses disclosed herein can treat narcolepsy type 1 in a subject in need thereof. The methods and uses disclosed herein can also treat symptoms such as excessive daytime sleepiness (EDS), cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis and disturbed nighttime sleep (sleep fragmentation). In some embodiments, treating narcolepsy type 1 can comprise reducing or alleviating one or more symptoms of narcolepsy type 1. The one or more symptoms of narcolepsy type 1 can be selected from excessive daytime sleepiness (EDS), cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis and disturbed nighttime sleep (sleep fragmentation). In some embodiments, the one or more symptoms of narcolepsy type 1 can be selected from excessive daytime sleepiness (EDS), cataplexy (including cataplexy-like symptom) in active phase, and sleep fragmentation during sleep phase. The methods and uses disclosed herein can also treat comorbidities of narcolepsy type 1, such as obesity, type 2 diabetes, cardiovascular diseases, apnea during sleep, mood disorders, anxiety, attention-deficit hyperactivity disorder (ADHD), restless leg syndrome, sleep parasomnias and the like. Narcolepsy can be diagnosed by diagnostic criteria generally used in the field, e.g., the third edition of the International Classification of Sleep Disorders (ICSD-3) and the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (Current Medical Research and Opinion 32(10): 1611-1622 (2016)). Additionally, nighttime sleep can be improved, for example, by reducing the number of waking incidents during the sleep cycle.

[0178] The methods and uses disclosed herein can increase wakefulness, and/or decrease and/or treat excessive sleepiness, and/or decrease occurrence of cataplexy episodes in a subject in need thereof during active phase. In some embodiments, excessive sleepiness as used herein is also known as excessive daytime sleepiness (EDS) or excessive need for sleep (ENS). The methods and uses disclosed herein can also decrease sleep fragmentation, and/or decrease occurrence of sleep paralysis/ hallucinations during the sleep phase. In some embodiments, wakefulness, excessive sleepiness, cataplexy symptom, sleep fragmentation, and/or sleep paralysis/hallucinations can be determined by known methods such as using any one or more of electroencephalogram (EEG), electromyogram (EMG), Maintenance Wakefulness Test (MWT), polysomnography, and the like (Sleep 45(8):zsac091 (2022)). MWT is a validated objective measure of the time taken for a subject to fall asleep under soporific conditions (Electroencephalogr. Clin. Neurophysiol. 53(6): 658-661 (1982)). MWT is quantified by EEG optionally combined with EMG. An electroencephalogram (EEG) is a test that detects electrical activity in the brain using small, metal discs or electrodes attached to the scalp. In some embodiments, wakefulness and/or decrease of sleepiness can be determined by using the multiple sleep latency test (MSLT) or the Oxford Sleep Resistance (OSLER) test. In some embodiments, the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), or the Stanford Sleepiness Scale. MSLT and polysomnography have been used to assess the sleep in patients with potential narcolepsy, and some electrophysiological features appears in NTl patients were reported previously (Nat. Rev. Dis. Primers 3: 16100 (2017)). In some embodiments, treating excessive sleepiness can comprise reducing or alleviating one or more symptoms of excessive sleepiness. The one or more symptoms of excessive daytime sleepiness can be selected from the group consisting of drowsiness, languor, inertness, fatigue, and sluggishness.

[0179] In some embodiments, the subject suffers from diseases or disorders or symptoms associated with excessive sleepiness. In some embodiments, the subject is a sleep- deprived subject, a subject with excessive sleepiness, a subject with disruptive regular sleep cycle, or a subject with a need to decrease sleepiness.

[0180] In some embodiments, actigraphy can be employed to study the effects of an OX2R agonist on sleep and wake patterns. The term actigraphy refers to methods using miniaturized computerized wristwatch-like devices to monitor and collect data generated by movements. Most actigraphs contain an analogue system to detect movements. In some devices, a piezo-electric beam detects movement. See, Sadeh et al., Sleep Medicine Reviews 6(2): 113-124 (2002).

[0181] The methods and uses disclosed herein can decrease excessive sleepiness or improve Karolinska Sleepiness Scale (KSS) rating in a subject in need thereof. In some embodiments, the KSS rating is improved 1, 2, 3, 4, or 5 or more ratings. In some embodiments, the subject has a KSS rating of 1, 2, 3, 4, or 5 after treatment.

[0182] The methods and uses disclosed herein can comprise performing one or more tests to quantify a subject’s sleepiness. In some embodiments, the test is selected from the multiple sleep latency test (MSLT), maintenance of wakefulness test (MWT), and the Oxford Sleep Resistance (OSLER) test. In some embodiments, the test is MWT. In some embodiments, the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale, Ullanlinna Narcolepsy Scale (UNS), Work Limitations Questionnaire (WLQ), SF-8 (subset of SF-36 questionnaire) or a combination of these tests.

[0183] The present disclosure provides a method of treating narcolepsy type 1 in a human in need thereof, the method comprising:

[0184] an orexin type 2 receptor agonist or a salt thereof in an amount of about 10 % (w/w) to about 70 % (w/w) based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; [0185] lactic acid-glycolic acid polymer or salt thereof having a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol, in an amount of about 30 % (w/w) to about 90 % (w/w) based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer;

[0186] wherein the orexin type 2 receptor agonist or a salt thereof and the lactic acid- glycolic acid polymer or salt thereof are in the form of microcapsules that have a mean particle diameter of between about 20 microns and about 75 microns; and

[0187] wherein the composition provides a blood plasma concentration of the agonist after administration at or below a maximum non-awakening plasma concentration of the agonist over a dosing interval of about four weeks.

[0188] The present disclosure also provides a method of treating narcolepsy type 1 in a human in need thereof, the method comprising:

[0189] methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l -carboxylate or a salt thereof in an amount of about 10 % (w/w) to about 70 % (w/w) based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer;

[0190] lactic acid-glycolic acid polymer or salt thereof having a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol, in an amount of about 30 % (w/w) to about 90 % (w/w) based upon the total weight of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l- carboxylate and lactic acid-glycolic acid polymer;

[0191] wherein methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy) methyl)piperidine-l -carboxylate or a salt thereof and the lactic acid-glycolic acid polymer or salt thereof are in the form of microcapsules that have a mean particle diameter of between about 20 microns and about 75 microns; and

[0192] wherein the composition provides a blood plasma concentration of the agonist after administration at or below a maximum non-awakening plasma concentration of the agonist over a dosing interval of about four weeks.

[0193] In some embodiments, the method of treating narcolepsy type 1 improves one or more nighttime symptoms selected from fragmented sleep, sleep paralysis and hallucinations. [0194] In some embodiments, the method of treating narcolepsy type 1 improves one or more daytime symptoms and one or more nighttime symptoms in patients with narcolepsy type 1.

[0195] In some embodiments, the method of treating narcolepsy type 1 improves one or more nighttime symptoms selected from fragmented sleep, sleep paralysis and hallucinations; and improves one or more daytime symptoms selected from fragmented wakefulness and cataplexy symptom.

[0196] The determination of blood plasma concentration can be performed using methods known to the skilled person in the art, including high-performance liquid chromatography-tandem mass spectrometry. The level is typically expressed as ng of analyte/mL. A maximum non-awakening concentration and an arousal-promoting concentration of an OX2R agonist in a subject can be determined by combining timeseries measurement of blood plasma concentration with recording of nighttime and/or daytime sleep and awake patterns in the subject by known methods including EEGZEMG recording and actigraphy. When detecting the maximum non-awakening concentration or arousal-promoting concentration of an OX2R agonist in a non-NTl subject, the measurement is performed during night time when autogenic orexin-A level of the subject is generally low.

[0197] The methods, compositions, and uses in this invention are characterized in that the blood plasma concentration of an orexin type 2 receptor (OX2R) agonist in a subject is at or below the maximum non-awakening plasma concentration of the agonist. In one embodiment, when an OX2R agonist is administered to a subject in need thereof, the blood plasma concentration of the OX2R agonist in the subject is at or below the maximum non-awakening plasma concentration of the agonist when measured at 24 hours or later after administration. By using certain formulations, such as infusion and sustained-release formulations, an initial release of the OX2R agonist can continue for about 24 hours to about 48 hours following administration, and the plasma concentration of the OX2R agonist can rise above the maximum non-awakening concentration, but does not reach the arousal-promoting concentration. When the blood plasma concentration of the OX2R agonist is at or below the maximum non-awakening concentration, it is larger than 0 (zero) and is the same as, or less than, the maximum non-awakening plasma concentration. In some embodiments, the plasma concentration of the OX2R agonist in a subject is about 1/20 to 1/1, about 1/12 to 1/1, about 1/10 to 1/1, about 1/8 to 1/1, about 1/5 to 1/1, or about 1/3 to 1/1 of the maximum non-awakening concentration of the agonist.

[0198] The dose of an 0X2R agonist can be determined by i) identifying the maximum non-awakening concentration of the 0X2R agonist in a subject (e.g. by using EEG), and then ii) identifying the dose of the 0X2R agonist that achieves the maximum nonawakening concentration after administration. The person skilled in the art in the pharmaceutical industry can select a dose that is lower than the dose determined in the step ii). In some embodiments, the blood plasma concentration of an 0X2R agonist that is at or below the maximum non-awakening plasma concentration of the agonist in a human is about 0.01 ng/mL to about 1 mg/mL, about 0.03 ng/mL to about 300 ng/mL, about 0.05 ng/mL to about 100 ng/mL, about 0.08 ng/mL to about 50 ng/mL, or about 1 ng/mL to about 30 ng/mL. In some embodiments, the dose of an 0X2R agonist that provides a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the agonist in a human is about 0.1 mg to about 50 mg, about 0.5 mg to about 30 mg, or about 1 mg to about 20 mg.

VII. COMBINATION THERAPY

[0199] The methods of treating NT1 of the present invention can further comprise combining the administration of an 0X2R agonist at or below the maximum nonawakening plasma concentration with administration of an additional 0X2R agonist at a dose to induce arousal plasma concentration. The additional 0X2R agonist and the 0X2R agonist can be different or the same. In this treatment method, the additional 0X2R agonist can be administered to a subject in need to provide acute treatment of NT1 symptom, followed by administration of the 0X2R agonist to provide maintenance treatment. Between the administrations of the two 0X2R agonists, there can be a dosing interval of 1 to 5 days depending on the clearance profile of the additional 0X2R agonist. In some embodiments, the 0X2R agonist administered at or below the maximum nonawakening plasma concentration is a controlled release composition.

VIII. PHARMACEUTICAL COMPOSITIONS, DOSAGE FORMS AND DELIVERY DEVICES

[0200] The pharmaceutical composition comprises pharmaceutically acceptable carriers. As pharmaceutically acceptable carriers, various organic or inorganic carrier substances conventionally used as preparation materials can be used. These are incorporated as solvent, solubilizing agent, suspending agent, isotonicity agent, buffer, and soothing agent for liquid preparations; and preparation additives such as preservative, antioxidant, colorant, sweetening agent and the like can be added as necessary.

EXAMPLES

[0201] The following non-limiting examples provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the compositions, and assay, screening, and therapeutic methods of the invention, and are not intended to limit the scope of what the inventors regard as their invention.

[0202] The weight-average molecular weight of each polymer is a polystyrene-reduced weight-average molecular weight measured by gel permeation chromatography (GPC) using mono-dispersed polystyrene as a standard substance. Measurements were all conducted by a high performance GPC apparatus and tetrahydrofuran was used at a flow rate of 1.0 mL/min as the mobile phase. The detection method is based on differential refractive index.

EXAMPLE 1

[0203] A solution of 1.736 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 10,676) and 1.152 g of compound A (drug) in 4.34 g of dichloromethane were combined to prepare an oil phase (O phase). At this point, the loading amount of the drug was 40%. The O phase solution was poured into 0.3 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation) pre-adjusted to about 18 °C, and was emulsified with a HOMOGENIZING MIXER (PRIMIX Corporation) to prepare O/W emulsion (turbine rotation frequency: about 4,000 rpm). This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 75 pm and 20 pm in series, then the microcapsules were collected from the top of the second sieve of 20 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.305 g of mannitol were mixed with a small amount of distilled water on a stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drug-containing microcapsules and mannitol (hereinafter referred to as "microcapsule powder"). [0204] The mean particle diameter of the microcapsules in the microcapsule powder was about 44.8 pm. The content of drug in the obtained microcapsule powder was 32.3% and the yield was about 49.5%. The content of drug in the microcapsule was measured as 39.3%.

[0205] The term "the content of drug in the microcapsule" as referred herein means a calculated rate in which the value calculated by multiplying the total of the charged weight of each raw material (drug, lactic acid-glycolic acid polymer, and mannitol) by the yield (hereinafter referred to as "obtained amount"), followed by multiplying by "the content of drug in the microcapsule powder" is divided by the value calculated by subtracting the amount of mannitol from the obtained amount, that is, it means the value calculated by the following formula:

[0206] Content (%) of drug in the microcapsule = [Total (g) of the charged weight of each raw material]x[Yield (%)]x[Content (%) of drug in the microcapsule powder]/[[ Total (g) of the charged weight of each raw material]x[Yield (%)]-[Amount (g) of mannitol]]

[0207] wherein, [Total (g) of the charged weight of each raw material]x[Yield (%)]= [Obtained amount (g)], and corresponds to the content of drug as the physiologically active substance to the whole microcapsule (the same is applied hereinafter).

EXAMPLE 2

[0208] A solution of 2.025 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 10,676) and 0.864 g of compound A (drug) in 5.09 g of dichloromethane were combined to prepare an oil phase (O phase) At this point, the loading amount of the drug was 30%. The O phase solution was poured into 0.3 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation) pre-adjusted to about 18 °C, and was emulsified with a HOMOGENIZING MIXER (PRIMIX Corporation) to prepare O/W emulsion (turbine rotation frequency: about 4,000 rpm). This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 75 pm and 20 pm in series, then the microcapsules were collected from the top of the second sieve of 20 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.305 g of mannitol were mixed with a small amount of distilled water on a stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drug-containing microcapsules and mannitol (the "microcapsule powder").

[0209] The mean particle diameter of the microcapsules in the microcapsule powder was about 47.6 pm. The content of drug in the obtained microcapsule powder was 24.4% and the yield was about 52.2%. The content of drug in the microcapsule was calculated as 29.4%.

EXAMPLE 3

[0210] A solution of 1.729 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 10,676) and 1.152 g of compound A (drug) in 4.38 g of dichloromethane were combined to prepare an oil phase (O phase) At this point, the loading amount of the drug was 40%. The O phase solution was poured into 0.3 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation) pre-adjusted to about 18 °C, and was emulsified with a HOMOGENIZING MIXER (PRIMIX Corporation) to prepare O/W emulsion (turbine rotation frequency: about 4,000 rpm). This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 100 pm and 45 pm in series, then the microcapsules were collected from the top of the second sieve of 45 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.305 g of mannitol were mixed with small amount of distilled water on a stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drug-containing microcapsules and mannitol (the "microcapsule powder").

[0211] The mean particle diameter of the microcapsules in the microcapsule powder was about 63.4 pm. The content of drug in the obtained microcapsule powder was 30.6% and the yield was about 39.5%. The content of drug in the microcapsule was calculated as 39.1%.

EXAMPLE 4

[0212] A solution of 2.026 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 10,676) and 0.864 g of compound A (drug) in 5.08 g of dichloromethane were combined to prepare an oil phase (O phase) At this point, the loading amount of the drug was 30%. The O phase solution was poured into 0.3 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation) pre-adjusted to about 18 °C, and was emulsified with a HOMOGENIZING MIXER (PRIMIX Corporation) to prepare O/W emulsion (turbine rotation frequency: about 4,000 rpm). This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 100 pm and 45 pm in series, then the microcapsules were collected from the top of the second sieve of 45 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.3052 g of mannitol were mixed with small amount of distilled water on a stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drug-containing microcapsules and mannitol (the "microcapsule powder").

[0213] The mean particle diameter of the microcapsules in the microcapsule powder was about 61.5 pm. The content of drug in the obtained microcapsule powder was 24.6% and the yield was about 50.6%. The content of drug in the microcapsule was calculated as 29.7%.

EXAMPLE 5

[0214] A solution of 5.868 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 10.438) and 3.842 g of compound A (drug) in 14.7 g of dichloromethane were combined to prepare an oil phase (O phase) At this point, the loading amount of the drug was 40%. The O phase solution was poured into 1 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation) pre-adjusted to about 18 °C, and was emulsified with a HOMOGENIZING MIXER (PRIMIX Corporation) to prepare O/W emulsion (turbine rotation frequency: about 4,000 rpm). This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 100 pm and 45 pm in series, then the microcapsules were collected from the top of the second sieve of 45 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.6997 g of mannitol were mixed with a small amount of distilled water on the stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drugcontaining microcapsules and mannitol (the "microcapsule powder").

[0215] The mean particle diameter of the microcapsules in the microcapsule powder was about 72.2 pm. The content of drug in the obtained microcapsule powder was 31.8% and the yield was about 44.0%. The content of drug in the microcapsule was calculated as 37.0%. EXAMPLE 6

[0216] A solution of 1.451 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 10,676) and 1.44 g of compound A (drug) in 3.63 g of dichloromethane were combined to prepare an oil phase (O phase) At this point, the loading amount of the drug was 50%. The O phase solution was poured into 0.3 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation) pre-adjusted to about 18 °C, and was emulsified with a HOMOGENIZING MIXER (PRIMIX Corporation) to prepare O/W emulsion (turbine rotation frequency: about 4,000 rpm). This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 75 pm and 20 pm in series, then the microcapsules were collected from the top of the second sieve of 20 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.4061 g of mannitol were mixed with a small amount of distilled water on a stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drugcontaining microcapsules and mannitol (the "microcapsule powder").

[0217] The mean particle diameter of the microcapsules in the microcapsule powder was about 47.5 pm. The content of drug in the obtained microcapsule powder was 35.9% and the yield was about 43.8%. The content of drug in the microcapsule was calculated as 47.4%.

EXAMPLE 7

[0218] A solution of 0.668 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 9,909) and 0.7493 g of compound A (drug) in 1.45 g of dichloromethane were combined to prepare an oil phase (O phase) At this point, the loading amount of the drug was 60%. The O phase solution was poured into 0.3 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation) pre-adjusted to about 18 °C, and was emulsified with a HOMOGENIZING MIXER (PRIMIX Corporation) to prepare O/W emulsion (turbine rotation frequency: about 4,000 rpm). This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 75 pm and 20 pm in series, then the microcapsules were collected from the top of the second sieve of 20 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.203 g of mannitol were mixed with small amount of distilled water on a stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drug-containing microcapsules and mannitol (the "microcapsule powder").

[0219] The mean particle diameter of the microcapsules in the microcapsule powder was about 43.4 pm. The content of drug in the obtained microcapsule powder was 46.1% and the yield was about 48.3%. The content of drug in the microcapsule was calculated as 59.8%.

EXAMPLE 8

[0220] A solution of 0.648 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 9,909) and 0.5619 g of compound A (drug) in 0.91 g of dichloromethane were combined to prepare an oil phase (O phase) At this point, the loading amount of the drug was 70%. The O phase solution was poured into 0.3 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation) pre-adjusted to about 18 °C, and was emulsified with a HOMOGENIZING MIXER (PRIMIX Corporation) to prepare O/W emulsion (turbine rotation frequency: about 4,000 rpm). This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 75 pm and 20 pm in series, then the microcapsules were collected from the top of the second sieve of 20 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.2037 g of mannitol were mixed with a small amount of distilled water on a stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drugcontaining microcapsules and mannitol (the "microcapsule powder").

[0221] The mean particle diameter of the microcapsules in the microcapsule powder was about 43.9 pm. The content of drug in the obtained microcapsule powder was 48.7% and the yield was about 35.6%. The content of drug in the microcapsule was calculated as 71.4%.

EXAMPLE 9

[0222] A solution of 2.132 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 10.438) and 0.2501 g of compound A (drug) in 5.33 g of dichloromethane were combined to prepare the oil phase (O phase) At this point, the loading amount of the drug was 10%. The O phase solution was poured into 0.3 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation) pre-adjusted to about 18 °C, and was emulsified with a HOMOGENIZING MIXER (PRIMIX Corporation) to prepare O/W emulsion (turbine rotation frequency: about 4,000 rpm). This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 75 pm and 20 pm in series, then the microcapsules were collected from the top of the second sieve of 20 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.275 g of mannitol were mixed with a small amount of distilled water on a stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drug-containing microcapsules and mannitol (the "microcapsule powder").

[0223] The mean particle diameter of the microcapsules in the microcapsule powder was about 49.8 pm. The content of drug in the obtained microcapsule powder was 8.53 % and the yield was about 67.5%. The content of drug in the microcapsule was calculated as 10.0%.

EXAMPLE 10

[0224] 619.20 mg of the microcapsule powder prepared in EXAMPLE 1 and 819.67 mg of the microcapsule powder prepared in EXAMPLE 2 were each separately suspended in about 2.0 mL of dispersal vehicle, and each suspension was subcutaneously administered to a monkey (10 mg/kg dose calculated as drug) followed by measurement of the drug concentration in the blood plasma. The plasma drug concentration after 24 hours and up to 4 weeks after the administration of the suspended microcapsules of EXAMPLE 1 (“EXAMPLE 1”) and EXAMPLE 2 (“EXAMPLE 2”) is shown in FIG. 1. The calculated results of the maximum concentration (Cmax) and area under the blood concentrationtime curve (AUC) within 24 hours after the administration and AUC (of onset part) from 24 hours to 28 days after the administration are shown in TABLE 1. As shown in FIG. 1 and TABLE 1, Cmax and AUC within 24 hours after the administration of the suspended microcapsules of EXAMPLE 1 are lower than the measurements obtained for the suspended microcapsules of EXAMPLE 2, while keeping sustained release over 28 days. That is, the suspension of a microcapsule powder having a loading amount of drug of 40% (compared to a drug loading of 30%) provides increased suppression of excessive drug release within 24 hours after administration. Table 1

EXAMPLE 11

[0225] 653.59 mg of the microcapsule powder prepared in EXAMPLE 3 and 836.82 mg of the microcapsule powder prepared in EXAMPLE 4 were each separately suspended in about 2.0 mL of dispersal vehicle, and each suspension was subcutaneously administered to a monkey (10 mg/kg dose calculated as drug), then the drug concentration in the blood plasma was measured. The plasma drug concentration within 24 hours and up to 4 weeks after the administration of the suspended microcapsules of EXAMPLE 3 and EXAMPLE 4 is shown in FIG. 2. The calculated results of the maximum concentration (Cmax) and area under the blood concentration-time curve (AUC) within 24 hours after the administration and AUC (of onset part) from 24 hours to 28 days after the administration are shown in TABLE 2. As shown in FIG. 2 and TABLE 2, Cmax and AUC within 24 hours after the administration of the suspended microcapsules of EXAMPLE 3 are lower than the measurements obtained for the suspended microcapsules of EXAMPLE 4, while keeping sustained release over 28 days. That is, the suspension of a microcapsule powder having a loading amount of drug is 40% (compared to a drug loading of 30%) provides increased suppression of excessive drug release within 24 hours after administration.

Table 2 EXAMPLE 12

[0226] 619.20 mg of the microcapsule powder prepared in EXAMPLE 1 and 653.59 mg of the microcapsule powder prepared in EXAMPLE 3 were each separately suspended in about 2.0 mL of dispersal vehicle, and each suspension was subcutaneously administered to a monkey (10 mg/kg dose calculated as drug), then the drug concentration in the blood plasma was measured. The plasma blood concentration within 24 hours and up to 4 weeks after the administration of the suspended microcapsules of EXAMPLE 1 (“EXAMPLE 1”) and EXAMPLE 3 (“EXAMPLE 3”) is shown in FIG. 3. The calculated results of the maximum concentration (Cmax) and area under the blood concentration-time curve (AUC) within 24 hours after the administration and AUC (of onset part) from 24 hours to 28 days after the administration are shown in TABLE 3. As shown in FIG. 3 and TABLE 3, Cmax and AUC within 24 hours after the administration of the suspended microcapsules of EXAMPLE 1 are lower than the measurements obtained for the suspended microcapsules of EXAMPLE 3, while keeping sustained release over 28 days. That is, the suspension of a microcapsule powder containing microcapsules with a larger mean particle diameter (44.8 pm for EXAMPLE 1 versus 63.4 pm for EXAMPLE 3) can provide increased suppression of excessive drug release within 24 hours after the administration.

Table 3

EXAMPLE 13

[0227] 819.67 mg of the microcapsule powder prepared in EXAMPLE 2 or 836.82 mg of the microcapsule powder prepared in EXAMPLE 4 were each separately suspended in about 2.0 mL of dispersal vehicle, and each suspension was subcutaneously administered to a monkey (10 mg/kg dose calculated as drug), then the drug concentration in the blood plasma was measured. The plasma drug concentration within 24 hours and up to 4 weeks after the administration of the suspended microcapsules of EXAMPLE 2 (“EXAMPLE 2”) and EXAMPLE 4 (“EXAMPLE 4”) is shown in FIG. 4. The calculated results of the maximum concentration (Cmax) and area under the blood concentration-time curve (AUC) within 24 hours after the administration and AUC (of onset part) from 24 hours to 28 days after the administration are shown in TABLE 4. As shown in FIG. 4 and TABLE 4, Cmax and AUC within 24 hours after the administration of the suspended microcapsules of EXAMPLE 2 are lower than the measurements obtained for the suspended microcapsules of EXAMPLE 4, while keeping sustained release over 28 days. That is, the suspension of a microcapsule powder containing microcapsules with a larger mean particle diameter (47.6 pm for EXAMPLE 2 versus 61.5 pm for EXAMPLE 4) can provide increased suppression of excessive drug release within 24 hours after the administration.

Table 4

EXAMPLE 14

[0228] 188.1 mg of the microcapsule powder prepared in EXAMPLE 5 was suspended in about 2.0 mL of dispersal vehicle, and subcutaneously administered to a monkey (2 mg/kg dose calculated as drug), then the drug concentration in the blood plasma was measured. The plasma blood concentration within 24 hours and up to 4 weeks after the administration of the suspended microcapsules of EXAMPLE 5 (“EXAMPLE 5”) is shown in FIG. 5. The calculated results of the maximum concentration (Cmax) and area under the blood concentration-time curve (AUC) within 24 hours after the administration and AUC (of onset part) from 24 hours to 28 days after the administration are shown in TABLE 5. As shown in FIG. 5 and TABLE 5, similar to EXAMPLE 10 to EXAMPLE 14, it was confirmed the microcapsule powders prepared in 1 L scale achieved sustained release of drug over 28 days. Table 5

EXAMPLE 15

[0229] A solution of 0.614 g of lactic acid-glycolic acid polymer (weight-average molecular weight: 10,438) and 0.406 g of compound A (drug) in 1.533 g of dichloromethane were combined to prepare an oil phase (O phase). At this point, the loading amount of the drug was 40%. The O phase solution was poured into 0.3 L of an aqueous solution of 0.1% (w/w) polyvinyl alcohol (EG-40P, Mitsubishi Chemical Corporation), and was emulsified with a membrane-based crossflow equipment (Micropore Technologies) to prepare an O/W emulsion. This O/W emulsion was in-water dried for about 3 hours and sieved through a sieve having an opening of 100 pm and 45 pm in series, then the microcapsules were collected from the top of the second sieve of 45 pm while rinsing the microcapsules with the distilled water. The collected microcapsules and 0.193 g of mannitol were mixed with a small amount of distilled water on a stainless steel tray, then freeze-dried with a freeze drier (FDU-2110, EYELA) to obtain the mixed powder of the drug-containing microcapsules and mannitol (the "microcapsule powder").

[0230] The mean particle diameter of the microcapsules in the microcapsule powder was about 67.4 pm. The content of drug in the obtained microcapsule powder was 30.8% and the yield was about 77.3%. The content of drug in the microcapsule was calculated as 38.4%.

[0231] All the publications, patents, and the patent applications cited herein are incorporated herein by reference in their entireties.

[0232] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the disclosure. All the various embodiments of the present disclosure will not be described herein. Any modifications and variations of the disclosure can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.

[0233] It is to be understood that the present disclosure is not limited to particular uses, methods, reagents, compounds, compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0234] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0235] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1 to 3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1 to 5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.

Claims

WHAT IS CLAIMED IS:

1. A controlled release composition, comprising an orexin type 2 receptor or a salt or hydrate thereof and a lactic acid-glycolic acid polymer or salt thereof wherein: the orexin type 2 receptor agonist or salt or hydrate thereof comprises about 10 % (w/w) to about 70 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; the lactic acid-glycolic acid polymer or salt thereof has a weight-average molecular weight of 7,000 g/mol to 15,000 g/mol and comprises about 30 % (w/w) to about 90 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; and wherein the orexin type 2 receptor agonist or salt or hydrate thereof and the lactic acid-glycolic acid polymer or salt thereof are in the form of microcapsules that have a mean particle diameter of between about 20 microns and about 75 microns.

2. The controlled release composition according to Claim 1, wherein the microcapsules have a mean particle diameter of between about 40 microns and about 65 microns.

3. The controlled release composition according to Claim 1, wherein: the orexin type 2 receptor agonist of salt or a hydrate thereof comprises about 30 % (w/w) to about 40 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; and the lactic acid-glycolic acid polymer comprises about 60 % (w/w) to about 70 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer.

4. The controlled release composition according to any one of Claims 1 through 3, further comprising a dispersing agent, and wherein the microcapsules and dispersing agent are in a mixture.

5. The controlled release composition according to Claim 1, wherein the orexin type 2 receptor agonist is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt or hydrate thereof.

6. The controlled release composition according to any one of Claims 1 through 5, wherein the lactic acid-glycolic acid polymer or salt thereof has a weight-average molecular weight from about 9,000 g/mol to about 11,000 g/mol.

7. The controlled release composition according to any one of Claims 4 through 6, wherein the dispersing agent is mannitol.

8. The controlled release composition according to any one of Claims 4 through 7, wherein the microcapsules are in a mixture with the dispersing agent, and the mixture is dispersed or dissolved in a liquid suitable for injection.

9. The controlled release composition according to Claim 1, wherein: the orexin type 2 receptor agonist or salt or hydrate thereof comprises about 30 % (w/w) to about 40 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer, wherein the orexin type 2 receptor agonist is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt or hydrate thereof; the lactic acid-glycolic acid polymer or salt thereof has a weight-average molecular weight from about 9,000 g/mol to about 11,000 g/mol and comprises about 60 % (w/w) to about 70 % (w/w) of the composition based upon the total weight of orexin type 2 receptor agonist and lactic acid-glycolic acid polymer; and wherein the orexin type 2 receptor agonist or salt or hydrate thereof and the lactic acid-glycolic acid polymer or salt thereof are in the form of microcapsules, and the microcapsules have a mean particle diameter of between about 40 microns and about 65 microns.

10. The controlled release composition according to Claim 9, wherein the microcapsules are in a mixture with mannitol, and the mixture is dispersed or dissolved in a liquid suitable for injection.

11. A method of producing the controlled release composition according to Claim 1, comprising: mixing the orexin type 2 receptor agonist or a salt or hydrate thereof solution containing lactic acid-glycolic acid polymer or salt thereof and an organic solvent to obtain an organic solution, dispersing the organic solution in a solution of polyvinyl alcohol and water to form an oil-in-water emulsion; removing the organic solvent to form a dispersion of microcapsules; and sieving and washing the microcapsules.

12. The method of producing a controlled release composition according to Claim 11, further comprising adding a dispersing agent after sieving and washing the microcapsules to form a mixture, and lyophilizing the mixture to form a powdered mixture of microcapsules and dispersing agent.

13. A method of producing an injectable dosage form, further comprising reconstituting the powdered mixture of microcapsules and dispersing agent produced in Claim 12 into a vehicle suitable for injection into a mammal.

14. A method of treating narcolepsy type 1 in a human in need of treatment, the method comprising: administering to the human a controlled release composition of Claim 1 or Claim 9, wherein the composition provides a blood plasma concentration of the agonist after administration at or below a maximum non-awakening plasma concentration of the agonist over a dosing interval of about four weeks.

15. The method of Claim 14, wherein the method improves one or more nighttime symptoms selected from fragmented sleep, sleep paralysis and hallucinations.

16. The method of Claim 14, wherein the method improves one or more daytime symptoms and one or more nighttime symptoms in patients with narcolepsy type 1.

17. The method of Claim 14, wherein the method improves one or more nighttime symptoms selected from fragmented sleep, sleep paralysis and hallucinations; and improves one or more daytime symptoms selected from fragmented wakefulness and cataplexy symptom.

18. The method of Claim 14, wherein the controlled release composition is provided in a dosage form for subcutaneous administration.