Use of opioid for treatment of autism spectrum disorders

Abstract

Provided are a novel pharmaceutical composition and method for treating and / or preventing autism spectrum disorders, fragile X syndrome, and / or autism spectrum disorder-like symptoms. Specifically provided is a pharmaceutical composition for treating and / or preventing autism spectrum disorders, fragile X syndrome, and / or autism spectrum disorder-like symptoms, the composition containing: buprenorphine or a pharmaceutically acceptable salt thereof; and / or morphine or a pharmaceutically acceptable salt thereof.

Description

Opioid use for the treatment of autism spectrum disorders

[0001] The present invention relates to new pharmaceutical compositions and methods for the treatment and / or prevention of autism spectrum disorders, fragile X syndrome, autism spectrum disorder-like symptoms and / or disorders in social communication and / or social interaction, particularly preferably for the treatment of autism spectrum disorders.

[0002] Autism spectrum disorder (ASD) is characterized by persistent impairments in social communication and social interactions across multiple contexts, two or more restricted and repetitive patterns of behavior, interests, or activities (e.g., emotional and repetitive physical movements or speech, fixations and obsessions, very limited and persistent interests, and hyper- or hypo-sensitivity to sensory stimuli), and these symptoms are present from early developmental stage. There are 3.8 million patients worldwide (Non-Patent Document 1) and over 350,000 patients in Japan. The economic burden per patient is estimated to be more than 5 million yen per year (Non-Patent Document 2). Given that the disease often lasts a lifetime, the economic impact is significant. However, there are currently no effective treatments for the core symptoms of ASD. Behavioral therapy, such as applied behavior analysis, is the primary treatment for ASD. However, because behavioral therapy requires significant time and human resources and its effectiveness is known to decrease with age, only a very limited number of patients can benefit from it. Given these circumstances, there is a strong need for effective treatments for the core symptoms of ASD.

[0003] Currently, molecules known to be associated with social behavior, such as oxytocin and vasopressin, and their receptors, are attracting attention as target molecules for ASD therapeutics. Several studies have been published regarding opioid receptors and social behavior. In 1979, the theory that ASD symptoms are caused by excessive opioid signaling in the brain was proposed (Non-Patent Document 3). Clinical trials of the μ-opioid receptor antagonist naltrexone for ASD treatment were subsequently conducted, and its effectiveness in treating symptoms such as irritability was confirmed (Non-Patent Document 4). Conversely, analysis of μ-opioid receptor (MOR) knockout mice has shown that ASD-like symptoms can also be induced by reduced opioid signaling (Non-Patent Document 5). Furthermore, there have been reports that administration of MOR agonists to normal rats increases social behavior (Non-Patent Document 6). As described above, it has been suggested that opioid signaling may be involved in ASD symptoms and social behavior. However, as discussed in the review paper Non-Patent Document 5, the details are unclear, and it is also unclear whether it is better to reduce or increase opioid signaling in the treatment of ASD.

[0004] Patients with fragile X syndrome (FXS), a condition caused by an X chromosome abnormality, are known to often exhibit social impairment symptoms similar to those seen in ASD (Non-Patent Documents 7-9).

[0005] Buprenorphine is a μ-opioid receptor partial agonist and a κ-opioid receptor antagonist. Its dosage forms, including transdermal, transmucosal (buccal, sublingual, and suppositories), and injections (intravenous, intramuscular, and subcutaneous), have been approved as pain treatment drugs (Non-Patent Documents 10 to 16, the contents of which are incorporated herein by reference). Morphine is an opioid agonist, particularly a μ-opioid receptor agonist. Its dosage forms, including oral, transmucosal (suppositories), and injections (intravenous, subcutaneous, and the like), have been approved as pain treatment drugs (Non-Patent Documents 17 to 22, the contents of which are incorporated herein by reference). Patent Documents 1 and 2, and Non-Patent Documents 23 to 25, do not describe or suggest the use of morphine or buprenorphine in the treatment of ASD. Patent Document 3 describes data on the combined use of oxytocin and naloxone (a μ-opioid receptor antagonist). Non-Patent Document 26 describes the pharmacokinetics of buprenorphine when administered sublingually. Non-Patent Document 28 describes the results of evaluating the analgesic effect of buprenorphine using mice, etc.

[0006] International Publication WO2013 / 042054A1 U.S. Publication US2019 / 0298703A1 U.S. Publication US2019 / 0328830A1

[0007] JAMA Pediatr. 2014;168(8):721-728.Pediatrics 2014;133:e520-e529A neurochemical theory of autism. Trends Neurosci 2: 174-177.J Intellect Disabil Res. 2015 Apr;59(4):293-306.Br J Pharmacol. 2018 Jul; 175(14): 2750-2769.Vanderschuren LJ, Niesink RJ, Spruijt BM, Van Ree JM (1995b). Mu‐ and kappa‐opioid receptor‐mediated opioid effects on social play in juvenile rats. Eur J Pharmacol 276: 257-266.Howes et al., J Psychopharmacol (2018)RefBerry-Kravis et al., Nature Drug Dis (2018)Castagnola et al.,Fron Synaptic Neurosci (2017) Butrans® US Package Insert (Buprenorphine 5mcg / h, 10mcg / h, 20mcg / h transdermal formulations) Norspan® Tape 5mg, 10mg, 20mg Drug Interview Form (Japan) (Buprenorphine 5mg, 10mg, 20mg transdermal formulations) BELBUCA® US Package Insert (Buprenorphine Hydrochloride 75mcg, 15mcg, 300mcg, 450mcg, 600mcg, 750mcg, 900mcg buccal film) SUBTEX® US Package Insert (Buprenorphine 2mg, 8mg sublingual tablets) Temgesic 200μg, 400μg sublingual tablets Package insert (buprenorphine hydrochloride) Repetan® Suppositories 0.2 mg, 0.4 mg Drug Interview Form (Japan) (buprenorphine hydrochloride) Repetan® Injection 0.2 mg, 0.4 mg Drug Interview Form (Japan) (buprenorphine hydrochloride) INFUMORPH US Package Insert (morphine sulfate 200 mg / mL, 500 mg / mL injection) ARYMO® ER US Package Insert (morphine sulfate 15 mg, 30 mg, 60 mg extended-release tablets) Morphine Hydrochloride Injection 10 mg, 50 mg, 200 mg "Takeda" Drug Interview Form (Japan) Paseef® Capsules 30 mg, 60 mg, 120 mg Japanese Package Insert (morphine hydrochloride hydrate extended-release capsules) Opso® Oral Solution 5 mg, 10 mg Japanese package insert (morphine hydrochloride oral liquid) Ampec (registered trademark) suppositories 10 mg, 20 mg, 30 mg Japanese package insert (morphine hydrochloride suppositories) Social Cognitive and Affective Neuroscience, 2016, 1902-1909 Psychoneuroendocrinology (2016) 63, 43-49 Psychoneuroendocrinology (2015) 53,10-15AmJ Psychiatry 2016; 173:491-498; doi: 10.1176 / appi. ajp. 2015.15040535Br. J. clin. Pharmac. (1982), 13, 665-673Folia Pharmcol. Japon. 79, 147-162 (1982),

[0008] Provided are new pharmaceutical compositions and methods for treating and / or preventing autism spectrum disorders, fragile X syndrome, autism spectrum disorder-like symptoms, and / or disorders in social communication and / or social interaction, particularly preferably for treating autism spectrum disorders.

[0009] The present inventors have conducted extensive research into pharmaceutical compositions and methods for treating and / or preventing autism spectrum disorder, fragile X syndrome, autism spectrum disorder-like symptoms, and / or disorders in social communication and / or social interactions, particularly preferably for treating autism spectrum disorder, and have found suitable active ingredients and, further, preferred administration methods, dosages, etc. for the active ingredients.

[0010] The present invention relates to, for example, the following:

[0011] (1) A pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms, comprising buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof. (1A) A pharmaceutical composition for the treatment and / or prevention of disorders in social communication and / or social interactions, comprising buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof. (1B) A pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms, comprising buprenorphine or a derivative thereof or a pharmaceutically acceptable salt thereof and / or morphine or a derivative thereof (e.g., codeine as a morphine derivative) or a pharmaceutically acceptable salt thereof. (1C) A pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms, comprising a μ-opioid agonist, buprenorphine or a pharmaceutically acceptable salt thereof, and / or morphine or a pharmaceutically acceptable salt thereof. (2) The pharmaceutical composition according to any one of (1) and (1A) to (1C) above, for the treatment and / or prevention of autism spectrum disorder. (2A) The pharmaceutical composition according to any one of (1) and (1A) to (1C) above, for the treatment and / or prevention of core symptoms of autism spectrum disorder. (3) The pharmaceutical composition according to any one of (1), (2), (1A) to (1C), and (2A) above, for administration to a patient diagnosed with autism spectrum disorder. (4) The pharmaceutical composition according to any one of (1) to (3), (1A) to (1C), and (2A) above, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose equal to or less than the amount effective for treating pain. (5) The pharmaceutical composition according to any one of (1) to (4), (1A) to (1C), and (2A) above, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose equal to or less than about half the amount effective for treating pain.(5A) The pharmaceutical composition according to any one of (1) to (5), (1A) to (1C), and (2A) above, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose about 1 / 10 or less of the amount effective for treating pain. (5B) The pharmaceutical composition according to any one of (1) to (5), (1A) to (1C), (2A), and (5A) above, which exhibits substantially no analgesic effect. (5C) The pharmaceutical composition according to any one of (1) to (5), (1A) to (1C), (2A), (5A), and (5B) above, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at an amount effective for treating autism spectrum disorder. (6) The pharmaceutical composition according to any one of (1) to (5), (1A) to (1C), (2A), and (5A) to (5C) above, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose equal to or less than the minimum effective dose for treating pain. (7) The pharmaceutical composition according to any one of (1) to (6), (1A) to (1C), (2A), and (5A) to (5C) above, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose of about 1 / 30 to about 3 times the minimum effective dose for treating pain. (7A) The pharmaceutical composition according to any one of (1) to (7), (1A) to (1C), (2A), and (5A) to (5C) above, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose of not more than about half the minimum effective dose for treating pain. (8) The pharmaceutical composition according to any one of (1) to (7), (1A) to (1C), (2A), (5A) to (5C), and (7A) above, wherein the buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is buprenorphine or a pharmaceutically acceptable salt thereof. (9) The pharmaceutical composition according to any one of (1) to (8), (1A) to (1C), (2A), (5A) to (5C), and (7A) above, wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of not more than about 1 ng / mL.(10) The pharmaceutical composition according to any one of (1) to (9), (1A) to (1C), (2A), (5A) to (5C), and (7A) above, wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 4 pg / mL to about 0.6 ng / mL. (10A) The pharmaceutical composition according to any one of (1) to (10), (1A) to (1C), (2A), (5A) to (5C), and (7A) above, wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of more than 3.3 pg / mL and not more than about 0.6 ng / mL. (10B) The pharmaceutical composition according to any one of (1) to (10), (1A) to (1C), (2A), (5A) to (5C), (7A), and (10A) above, wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 0.6 ng / mL or less. (10C) The pharmaceutical composition according to any one of (1) to (10), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A), and (10B) above, wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 1 pg / mL to about 1 ng / mL. (10D) The pharmaceutical composition according to any one of (1) to (10), (1A) to (1C), (2A), (5A) to (5C), (7A), and (10A) to (10C) above, wherein the pharmaceutical composition provides a plasma concentration of buprenorphine within the range of about 4 pg / mL to about 1 ng / mL (e.g., about 4 pg / mL to about 0.6 ng / mL) (e.g., for about 30 minutes or more continuously). (10E) The pharmaceutical composition according to any one of (1) to (10), (1A) to (1C), (2A), (5A) to (5C), (7A), and (10A) to (10D) above, wherein the pharmaceutical composition provides a plasma concentration of buprenorphine within the range of about 4 pg / mL to about 1 ng / mL (e.g., about 3 pg / mL to about 0.6 ng / mL). (11) The pharmaceutical composition according to any one of (1) to (10), (1A) to (1C), (2A), (5A) to (5C), (7A), and (10A) to (10E), wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 0.2 ng / mL or less.(12) The pharmaceutical composition according to any one of (1) to (11), (1A) to (1C), (2A), (5A) to (5C), (7A), and (10A) to (10E) above, wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 8 pg / mL to about 0.2 ng / mL. (12A) The pharmaceutical composition according to any one of (1) to (12), (1A) to (1C), (2A), (5A) to (5C), (7A), and (10A) to (10E) above, wherein the maximum plasma concentration is a maximum plasma concentration at steady state. (13) The pharmaceutical composition according to any one of the above (1) to (12), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), and (12A), which is any one of the following a) to c): a) a pharmaceutical composition for transdermal administration containing about 0.01 mg to about 10 mg of buprenorphine or a pharmaceutically acceptable salt thereof, b) a pharmaceutical composition for transdermal administration that releases buprenorphine or a pharmaceutically acceptable salt thereof at a rate of about 0.01 μg / h to about 10 μg / h, and c) a pharmaceutical composition for transmucosal administration containing about 0.0001 mg to 0.1 mg of buprenorphine or a pharmaceutically acceptable salt thereof. (13A) The pharmaceutical composition according to any one of the above (1) to (13), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), and (12A), which is any one of the following a) to c): a) a pharmaceutical composition for transdermal administration containing about 0.01 mg to about 5 mg of buprenorphine or a pharmaceutically acceptable salt thereof, b) a pharmaceutical composition for transdermal administration that releases buprenorphine or a pharmaceutically acceptable salt thereof at a rate of about 0.1 μg / h to about 5 μg / h, and c) a pharmaceutical composition for transmucosal administration containing 0.001 mg to 0.075 mg of buprenorphine or a pharmaceutically acceptable salt thereof.(13B) The pharmaceutical composition according to any one of (1) to (13), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A), and (13A) above, which is either one of: (a) a pharmaceutical composition for transdermal administration containing about 0.56 mg to about 1.7 mg of buprenorphine or a pharmaceutically acceptable salt thereof; or (b) a pharmaceutical composition for transdermal administration that releases buprenorphine or a pharmaceutically acceptable salt thereof at a rate of about 0.56 μg / h to about 1.7 μg / h. (13C) The pharmaceutical composition according to any one of the above (1) to (13), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A), (13A) and (13B), which is either: (13C) a) a pharmaceutical composition for transdermal administration containing about 0.56 mg or about 1.7 mg of buprenorphine or a pharmaceutically acceptable salt thereof, or (13D) a pharmaceutical composition for transdermal administration which releases buprenorphine or a pharmaceutically acceptable salt thereof at about 0.56 μg / h or about 1.7 μg / h. (14) The pharmaceutical composition according to any one of the above (1) to (13), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A) and (13A) to (13C), which is for administration at an administration interval of 12 hours or more. (14A) The pharmaceutical composition according to any one of (1) to (14), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A), and (13A) to (13C) above, which is administered twice a day or less. (15) The pharmaceutical composition according to any one of (1) to (14), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A), (13A) to (13C), and (14A) above, which has a sustained efficacy of 12 hours or more after administration. (16) The pharmaceutical composition according to any one of (1) to (15), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A), (13A) to (13C), and (14A) above, for administering buprenorphine or a pharmaceutically acceptable salt thereof without concomitant use with other drugs.(16A) The pharmaceutical composition according to any one of (1) to (16), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A), (13A) to (13C), and (14A) above, which is a pharmaceutical composition for transdermal administration or a pharmaceutical composition for transmucosal administration. (16B) The pharmaceutical composition according to any one of (1) to (16), (1A) to (1C), (2A), (5A) to (5C), (10A) to (10E), (12A), (13A) to (13C), and (14A) above, which is a pharmaceutical composition for transdermal administration. (16C) The pharmaceutical composition according to any one of (1) to (16), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A), (13A) to (13C), and (14A) above, which is a pharmaceutical composition for transmucosal administration. (17) The pharmaceutical composition according to any one of (1) to (7), (1A) to (1C), (2A), (5A) to (5C), and (7A) above, wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is morphine or a pharmaceutically acceptable salt thereof. (18) The pharmaceutical composition according to (17) above, which provides a maximum plasma concentration of morphine or a pharmaceutically acceptable salt thereof of about 200 ng / mL or less. (19) The pharmaceutical composition according to (17) or (18) above, which provides a maximum plasma concentration of morphine or a pharmaceutically acceptable salt thereof of about 1 ng / mL to about 200 ng / mL. (19A) The pharmaceutical composition according to any one of (1) to (19), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A), (13A) to (13C), (14A), and (16A) to (16C) above, which activates the nucleus accumbens and the medial prefrontal cortex but does not activate the dorsomedial periaqueductal gray matter.

[0012] (101) A method for treating and / or preventing autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms, comprising administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof to a patient in need thereof. (101A) A method for treating and / or preventing disorders in social communication and / or social interaction, comprising administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof. (101B) A method for treating and / or preventing autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms, comprising administering buprenorphine or a derivative thereof or a pharmaceutically acceptable salt thereof and / or morphine or a derivative thereof (e.g., codeine as a morphine derivative) or a pharmaceutically acceptable salt thereof. (101C) A method for treating and / or preventing autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms, comprising administering a μ-opioid agonist, buprenorphine or a pharmaceutically acceptable salt thereof, and / or morphine or a pharmaceutically acceptable salt thereof. (102) The method according to any one of (101) and (101A) to (101C) above for treating and / or preventing autism spectrum disorder. (102A) The method according to any one of (101) and (101A) to (101C) above for treating and / or preventing core symptoms of autism spectrum disorder. (103) The method according to any one of (101), (102), (101A) to (101C), and (102A) above for administration to a patient diagnosed with autism spectrum disorder. (104) The method according to any one of the above (101) to (103), (101A) to (101C), and (102A), which comprises administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof in a dose not exceeding the pain therapeutically effective amount.(105) The method according to any one of the above (101) to (104), (101A) to (101C), and (102A), which comprises administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose of not more than about 1 / 2 the amount effective for treating pain. (105A) The method according to any one of the above (101) to (105), (101A) to (101C), and (102A), which comprises administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose of not more than about 1 / 10 the amount effective for treating pain. (105B) The method according to any one of the above (101) to (105), (101A) to (101C), (102A), and (105A), which does not substantially exhibit an analgesic effect. (105C) The method according to any one of the above (101) to (105), (101A) to (101C), (102A), (105A), and (105B), wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is administered in an amount effective for treating autism spectrum disorder. (106) The method according to any one of the above (101) to (105), (101A) to (101C), (102A), and (105A) to (105C), wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is administered in an amount equal to or less than the minimum effective amount for treating pain. (107) The method according to any one of the above (101) to (106), (101A) to (101C), (102A), and (105A) to (105C), wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 / 30 to about 3 times the minimum effective dose for treating pain. (107A) The method according to any one of the above (101) to (107), (101A) to (101C), (102A), and (105A) to (105C), wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 / 2 or less of the minimum effective dose for treating pain.(108) The method according to any one of the above (101) to (107), (101A) to (101C), (102A), (105A) to (105C), and (107A), wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is buprenorphine or a pharmaceutically acceptable salt thereof. (109) The method according to any one of the above (101) to (108), (101A) to (101C), (102A), (105A) to (105C), and (107A), wherein the maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof in a patient receiving the method is about 1 ng / mL or less. (110) The method according to any one of the above (101) to (109), (101A) to (101C), (102A), (105A) to (105C), and (107A), wherein the maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof in a patient to which the method is administered is from about 4 pg / mL to about 0.6 ng / mL. (110A) The method according to any one of the above (101) to (110), (101A) to (101C), (102A), (105A) to (105C), and (107A), wherein the maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof in a patient to which the method is administered is more than 3.3 pg / mL and not more than about 0.6 ng / mL. (110B) The method according to any one of the above (101) to (110), (101A) to (101C), (102A), (105A) to (105C), (107A), and (110A), wherein the maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof in a patient receiving the method is about 0.6 ng / mL or less. (110C) The method according to any one of the above (101) to (110), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A), and (110B), wherein the maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof in a patient receiving the method is about 1 pg / mL to about 1 ng / mL.(110D) The method according to any one of the above (101) to (110), (101A) to (101C), (102A), (105A) to (105C), (107A) and (110A) to (110C), wherein the peak plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof in a patient receiving the administration is within the range of about 4 pg / mL to about 1 ng / mL (e.g., about 4 pg / mL to about 0.6 ng / mL) (e.g., for about 30 minutes or more continuously). (110E) The method according to any one of the above (101) to (110), (101A) to (101C), (102A), (105A) to (105C), (107A) and (110A) to (110D), wherein the maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof in a patient receiving the method is within the range of about 4 pg / mL to about 1 ng / mL (e.g., about 3 pg / mL to about 0.6 ng / mL). (111) The method according to any one of the above (101) to (110), (101A) to (101C), (102A), (105A) to (105C), (107A) and (110A) to (110E), wherein the maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof in a patient receiving the method is about 0.2 ng / mL or less. (112) The method according to any one of the above (101) to (111), (101A) to (101C), (102A), (105A) to (105C), (107A), and (110A) to (110E), wherein the maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof in a patient administered the method is from about 8 pg / mL to about 0.2 ng / mL. (112A) The method according to any one of the above (101) to (112), (101A) to (101C), (102A), (105A) to (105C), (107A), and (110A) to (110E), wherein the maximum plasma concentration or plasma concentration is the maximum plasma concentration or plasma concentration at steady state.(113) The method according to any one of the above (101) to (112), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), and (112A), comprising any one of the following a) to c): a) transdermally administering about 0.01 mg to about 10 mg of buprenorphine or a pharmaceutically acceptable salt thereof, b) transdermally administering about 0.01 μg / h to about 10 μg / h of buprenorphine or a pharmaceutically acceptable salt thereof, and c) transmucosally administering about 0.0001 mg to 0.1 mg of buprenorphine or a pharmaceutically acceptable salt thereof. (113A) The method according to any one of the following a) to c): a) transdermally administering about 0.01 mg to about 5 mg of buprenorphine or a pharmaceutically acceptable salt thereof, b) transdermally administering about 0.1 μg / h to about 5 μg / h of buprenorphine or a pharmaceutically acceptable salt thereof, and c) transmucosally administering 0.001 mg to 0.075 mg of buprenorphine or a pharmaceutically acceptable salt thereof. (113B) The method according to any one of the above (101) to (113), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), and (113A), which is either of: a) transdermally administering about 0.56 mg to about 1.7 mg of buprenorphine or a pharmaceutically acceptable salt thereof; or b) transdermally administering about 0.56 μg / h to about 1.7 μg / h of buprenorphine or a pharmaceutically acceptable salt thereof. (113C) The method according to any one of the above (101) to (113), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), (113A) and (113B), wherein the method is any one of: a) transdermally administering about 0.56 mg or about 1.7 mg of buprenorphine or a pharmaceutically acceptable salt thereof; or b) transdermally administering about 0.56 μg / h or about 1.7 μg / h of buprenorphine or a pharmaceutically acceptable salt thereof.(114) The method according to any one of the above (101) to (113), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), and (113A) to (113C), wherein buprenorphine or a pharmaceutically acceptable salt thereof is administered at an administration interval of 12 hours or more. (114A) The method according to any one of the above (101) to (114), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), and (113A) to (113C), wherein the administration frequency is twice a day or less. (115) The method according to any one of the above (101) to (114), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), (113A) to (113C), and (114A), wherein the efficacy lasts for 12 hours or more after administration. (116) The method according to any one of the above (101) to (115), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), (113A) to (113C), and (114A), wherein buprenorphine or a pharmaceutically acceptable salt thereof is administered without concomitant use with other drugs. (116A) The method according to any one of the above (101) to (116), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), (113A) to (113C), and (114A), wherein buprenorphine or a pharmaceutically acceptable salt thereof is administered transdermally or transmucosally. (116B) The method according to any one of the above (101) to (116), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), (113A) to (113C), and (114A), wherein buprenorphine or a pharmaceutically acceptable salt thereof is administered transdermally.(116C) The method according to any one of the above (101) to (116), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), (113A) to (113C), and (114A), wherein buprenorphine or a pharmaceutically acceptable salt thereof is administered transmucosally. (117) The method according to any one of the above (101) to (107), (101A) to (101C), (102A), (105A) to (105C), and (107A), wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is morphine or a pharmaceutically acceptable salt thereof. (118) The method according to the above (117), wherein the peak plasma concentration of morphine or a pharmaceutically acceptable salt thereof is about 200 ng / mL or less. (119) The method according to the above (117) or (118), wherein the peak plasma concentration of morphine or a pharmaceutically acceptable salt thereof is about 1 ng / mL to about 200 ng / mL. (119A) The method according to any one of the above (101) to (119), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), (113A) to (113C), (114A), and (116A) to (116C), wherein the nucleus accumbens and the medial prefrontal cortex are activated, but the dorsomedial periaqueductal gray matter is not activated.

[0013] (201) Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. (201A) Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of disorders in social communication and / or social interactions. (201B) Buprenorphine or a derivative thereof or a pharmaceutically acceptable salt thereof and / or morphine or a derivative thereof (e.g., codeine as a morphine derivative) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. (201C) Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof, which are μ-opioid agonists, for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. (202) Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof according to any of the above (201) and (201A) to (201C) for the treatment and / or prevention of autism spectrum disorder. (202A) Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof according to any of the above (201) and (201A) to (201C) for the treatment and / or prevention of core symptoms of autism spectrum disorder. (203) Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof according to any one of (201), (202), (201A) to (201C), and (202A) above, for administration to a patient diagnosed with autism spectrum disorder.(1) to (19), (1A) to (1C), (2A), (5A) to (5C), (7A), (10A) to (10E), (12A), (13A) to (13C), (14A), (16A) to ( 16C), (101) to (119), (101A) to (101C), (102A), (105A) to (105C), (107A), (110A) to (110E), (112A), (113A ) to (113C), (114A), and (116A) to (116C) (hereinafter referred to as the above group). Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof according to any one of (201) to (203), (201A) to (201C), and (202A), comprising one or more features according to any one or more of (201) to (203), (201A) to (201C), and (202A).

[0014] (301) Use of buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. (301A) Use of buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment and / or prevention of disorders in social communication and / or social interactions. (301B) Use of buprenorphine or a derivative thereof or a pharmaceutically acceptable salt thereof and / or morphine or a derivative thereof (e.g., codeine as a morphine derivative) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. (301C) Use of buprenorphine or a pharmaceutically acceptable salt thereof, and / or morphine or a pharmaceutically acceptable salt thereof, which are μ-opioid agonists, for the manufacture of a pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. (302) The use according to any one of the above (301) and (301A) to (301C) for the manufacture of a pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder. (302A) The use according to any one of the above (301) and (301A) to (301C) for the manufacture of a pharmaceutical composition for the treatment and / or prevention of core symptoms of autism spectrum disorder. (303) The use according to any one of the above (301), (302), (301A) to (301C), and (302A) for the manufacture of a pharmaceutical composition for administration to patients diagnosed with autism spectrum disorder. (304) The use according to any one of the above (301) to (303), (301A) to (301C), and (302A) for the manufacture of a pharmaceutical composition containing buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof in an amount not greater than an effective amount for treating pain.(305) The use according to any one of the above (301) to (304), (301A) to (301C), and (302A) for the manufacture of a pharmaceutical composition in which the content of buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is about 1 / 2 or less of the effective amount for treating pain. (305A) The use according to any one of the above (301) to (305), (301A) to (301C), and (302A) for the manufacture of a pharmaceutical composition in which the content of buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is about 1 / 10 or less of the effective amount for treating pain. (305B) The use according to any one of the above (301) to (305), (301A) to (301C), (302A), and (305A), wherein the pharmaceutical composition does not substantially exhibit an analgesic effect. (305C) The use according to any one of the above (301) to (305), (301A) to (301C), (302A), (305A), and (305B) for the manufacture of a pharmaceutical composition in which the content of buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is an amount effective for treating autism spectrum disorder. (306) The use according to any one of the above (301) to (305), (301A) to (301C), (302A), and (305A) to (305C) for the manufacture of a pharmaceutical composition in which the content of buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is not more than the minimum effective amount for treating pain. (307) The use according to any one of the above (301) to (306), (301A) to (301C), (302A), and (305A) to (305C) for the manufacture of a pharmaceutical composition in which the content of buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is about 1 / 30 to about 3 times the minimum effective amount for the treatment of pain. (307A) The use according to any one of the above (301) to (307), (301A) to (301C), (302A), and (305A) to (305C) for the manufacture of a pharmaceutical composition in which the content of buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is about 1 / 2 or less the minimum effective amount for the treatment of pain.(308) The use according to any one of the above (301) to (307), (301A) to (301C), (302A), (305A) to (305C), and (307A), wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is buprenorphine or a pharmaceutically acceptable salt thereof. (309) The use according to any one of the above (301) to (308), (301A) to (301C), (302A), (305A) to (305C), and (307A), wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 1 ng / mL or less. (310) The use according to any one of the above (301) to (309), (301A) to (301C), (302A), (305A) to (305C), and (307A), wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 4 pg / mL to about 0.6 ng / mL. (310A) The use according to any one of the above (301) to (310), (301A) to (301C), (302A), (305A) to (305C), and (307A), wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of more than 3.3 pg / mL and not more than about 0.6 ng / mL. (310B) The use according to any one of the above (301) to (310), (301A) to (301C), (302A), (305A) to (305C), (307A), and (310A), wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 0.6 ng / mL or less. (310C) The use according to any one of the above (301) to (310), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A), and (310B), wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 1 pg / mL to about 1 ng / mL.(310D) The use according to any one of the above (301) to (310), (301A) to (301C), (302A), (305A) to (305C), and (310A) to (310C), wherein the pharmaceutical composition provides a plasma concentration of buprenorphine within the range of about 4 pg / mL to about 1 ng / mL (e.g., about 4 pg / mL to about 0.6 ng / mL) (e.g., for about 30 minutes or more continuously). (310E) The use according to any one of the above (301) to (310), (301A) to (301C), (302A), (305A) to (305C), (307A), and (310A) to (310D), wherein the pharmaceutical composition provides a plasma concentration of buprenorphine within the range of about 4 pg / mL to about 1 ng / mL (e.g., about 3 pg / mL to about 0.6 ng / mL). (311) The use according to any one of the above (301) to (310), (301A) to (301C), (302A), (305A) to (305C), (307A), and (310A) to (310E), wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 0.2 ng / mL or less. (312) The use according to any one of the above (301) to (311), (301A) to (301C), (302A), (305A) to (305C), (307A), and (310A) to (310E), wherein the pharmaceutical composition provides a maximum plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 8 pg / mL to about 0.2 ng / mL. (312A) The use according to any one of the above (301) to (312), (301A) to (301C), (302A), (305A) to (305C), (307A), and (310A) to (310E), wherein the maximum plasma concentration or plasma concentration is a maximum plasma concentration or plasma concentration at steady state.(313) The use according to any one of the above (301) to (312), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), and (312A), wherein the pharmaceutical composition is any one of the following a) to c): a) a pharmaceutical composition for transdermal administration containing about 0.01 mg to about 10 mg of buprenorphine or a pharmaceutically acceptable salt thereof, b) a pharmaceutical composition for transdermal administration that releases buprenorphine or a pharmaceutically acceptable salt thereof at about 0.01 μg / h to about 10 μg / h, and c) a pharmaceutical composition for transmucosal administration containing about 0.0001 mg to 0.1 mg of buprenorphine or a pharmaceutically acceptable salt thereof. (313A) The use according to any one of the above (301) to (313), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), and (312A), wherein the pharmaceutical composition is any one of the following a) to c): a) a pharmaceutical composition for transdermal administration containing about 0.01 mg to about 5 mg of buprenorphine or a pharmaceutically acceptable salt thereof, b) a pharmaceutical composition for transdermal administration that releases buprenorphine or a pharmaceutically acceptable salt thereof at a rate of about 0.1 μg / h to about 5 μg / h, and c) a pharmaceutical composition for transmucosal administration containing 0.001 mg to 0.075 mg of buprenorphine or a pharmaceutically acceptable salt thereof. (313B) The use according to any one of the above (301) to (313), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), and (313A), wherein the pharmaceutical composition is either of: a) a pharmaceutical composition for transdermal administration containing about 0.56 mg to about 1.7 mg of buprenorphine or a pharmaceutically acceptable salt thereof; or b) a pharmaceutical composition for transdermal administration that releases buprenorphine or a pharmaceutically acceptable salt thereof at a rate of about 0.56 μg / h to about 1.7 μg / h.(313C) The use according to any one of the above (301) to (313), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), (313A) and (313B), wherein the pharmaceutical composition is either of: a) a pharmaceutical composition for transdermal administration containing about 0.56 mg or about 1.7 mg of buprenorphine or a pharmaceutically acceptable salt thereof; or b) a pharmaceutical composition for transdermal administration that releases buprenorphine or a pharmaceutically acceptable salt thereof at about 0.56 μg / h or about 1.7 μg / h. (314) The use according to any one of the above (301) to (313), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), and (313A) to (313C), wherein the pharmaceutical composition is for administration at an administration interval of 12 hours or more. (314A) The use according to any one of the above (301) to (314), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), and (313A) to (313C), wherein the pharmaceutical composition is for administration twice a day or less. (315) The pharmaceutical composition according to any one of the above (301) to (314), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), (313A) to (313C), and (314A), wherein the pharmaceutical composition is a pharmaceutical composition whose efficacy lasts for 12 hours or more after administration. (316) The use according to any one of the above (301) to (315), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), (313A) to (313C), and (314A), wherein the pharmaceutical composition is a pharmaceutical composition containing only buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient.(316A) The use according to any one of the above (301) to (316), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), (313A) to (313C), and (314A), wherein the pharmaceutical composition is a pharmaceutical composition for transdermal administration or a pharmaceutical composition for transmucosal administration. (316B) The use according to any one of the above (301) to (316), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), (313A) to (313C), and (314A), wherein the pharmaceutical composition is a pharmaceutical composition for transdermal administration. (316C) The use according to any one of the above (301) to (316), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), (313A) to (313C), and (314A), wherein the pharmaceutical composition is a pharmaceutical composition for transmucosal administration. (317) The use according to any one of the above (301) to (307), (301A) to (301C), (302A), (305A) to (305C), and (307A), wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is morphine or a pharmaceutically acceptable salt thereof. (318) The use according to the above (317), wherein the pharmaceutical composition provides a maximum plasma concentration of morphine or a pharmaceutically acceptable salt thereof of about 200 ng / mL or less. (319) The use according to the above (317) or (318), wherein the pharmaceutical composition provides a maximum plasma concentration of morphine or a pharmaceutically acceptable salt thereof of about 1 ng / mL to about 200 ng / mL. (319A) The use according to any one of (301) to (319), (301A) to (301C), (302A), (305A) to (305C), (307A), (310A) to (310E), (312A), (313A) to (313C), (314A), and (316A) to (316C), wherein the pharmaceutical composition is for activating the nucleus accumbens and the medial prefrontal cortex and not activating the dorsomedial periaqueductal gray matter.

[0015] Use of buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof, comprising one or more of the features described in any one or more of the preceding items.

[0016] The pharmaceutical compositions and methods of the present invention are useful for the treatment and / or prevention of various psychiatric disorders, in particular autism spectrum disorders, fragile X syndrome, autism spectrum disorder-like symptoms, and / or disorders in social communication and / or social interaction.

[0017] 1 shows the results of evaluating the social behavior-improving effect of morphine using valproic acid model mice, which are ASD model mice. 2 shows the results of evaluating the social behavior-improving effect of buprenorphine using valproic acid model mice, which are ASD model mice. 3 shows the results of evaluating the social behavior-improving effect of tramadol using valproic acid model mice, which are ASD model mice. 4 shows the relationship between the plasma concentration of unchanged morphine, improvement in social impairment, and analgesic efficacy. 5 shows the relationship between the plasma concentration of unchanged buprenorphine, improvement in social impairment, and analgesic efficacy. 6 shows the results of evaluating the sustained social behavior-improving effect of buprenorphine using valproic acid model mice. 7 shows the results of evaluating the social behavior-improving effect of buprenorphine using FMR-1 knockout mice. 8 shows the results of evaluating the effect of concomitant use of naloxone on the social behavior-improving effect of buprenorphine using valproic acid model mice. 9 shows the results of quantifying activation of the nucleus accumbens (NAc) by buprenorphine using valproic acid model mice.

[0033] Figure 1 shows the results of quantifying activation of the medial prefrontal cortex by buprenorphine using valproic acid model mice.

[0034] Figure 1 shows the results of quantifying activation of the dorsomedial periaqueductal gray (dmPAG) by buprenorphine using valproic acid model mice.

[0018] The term "consisting of" means having only the elements. The term "including" means being open-ended and not excluding unrecited elements.

[0019] The present invention will be described below with reference to embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the above-mentioned field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0020] "Autistic Spectrum Disorder (ASD)" is a type of neurodevelopmental disorder, including autistic disorder, Asperger's syndrome, and pervasive developmental disorder not otherwise specified. The term (definition), characteristics, and diagnostic criteria for ASD can be found in the International Classification of Diseases (ICD) 11th Edition by the World Health Organization (WHO) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-5®) by the American Psychiatric Association. Criteria for accurate diagnosis of ASD are not limited to the ICD-11 and DSM-5. Core symptoms of ASD include persistent impairments in social communication and / or social interaction and symptoms related to restricted and repetitive patterns of behavior, interests, or activities in patients with ASD, such as persistent impairments in social communication and / or social interaction. "Autism spectrum disorder-like symptoms" include cases where a person does not meet the diagnostic criteria for autism spectrum disorder but exhibits autism spectrum disorder-like symptoms. "Autism spectrum disorder-like symptoms" also include autism spectrum disorder-like symptoms associated with other diseases (e.g., Fragile X syndrome, Rett syndrome, tuberous sclerosis complex (TSC) etc.). "Autism spectrum disorder-like symptoms" include, for example, "impairment (including persistent impairment) of social communication and / or social interaction" and "symptoms related to restricted and repetitive patterns of behavior, interests, or activities," preferably impairment (including persistent impairment) of social communication and / or social interaction.

[0021] The terms (definitions), characteristics of the disorders, and diagnostic criteria for "Fragile X syndrome" and "Rett syndrome" can be found in, for example, the 11th edition of the International Classification of Diseases (ICD) compiled by the World Health Organization (WHO).

[0022] As used herein, prevention includes avoiding the occurrence of symptoms. Treatment includes alleviating, mitigating, or ameliorating symptoms. A "pain therapeutically effective amount" is a dose effective for treating pain. For example, buprenorphine transdermal formulations containing 5 mg, 10 mg, and 20 mg have been approved, and the buprenorphine release rates in these formulations are 5 μg / h, 10 μg / h, and 20 μg / h, respectively (Non-Patent Documents 10 and 11). For example, buprenorphine transmucosally administered formulations, such as buccal films, have been approved at 0.075 mg, 0.15 mg, 0.3 mg, 0.6 mg, 0.75 mg, and 0.9 mg. Furthermore, sublingual tablets, such as 200 μg, 400 μg, 2 mg, and 8 mg, have been approved (Non-Patent Documents 12-14). For example, 0.2 mg and 0.4 mg suppositories have been approved (Non-Patent Document 15), and 0.2 mg and 0.4 mg buprenorphine injections have been approved (Non-Patent Document 16). For example, 5 mg, 10 mg, 15 mg, 30 mg, and 60 mg morphine oral formulations have been approved as "pain therapeutically effective amounts" (Non-Patent Documents 18 and 21). For example, 10 mg, 50 mg, and 200 mg morphine injections have been approved (Non-Patent Document 19). For example, 10 mg, 20 mg, and 30 mg morphine transmucosally administered formulations (suppositories) have been approved (Non-Patent Document 22). The "minimum effective pain therapeutic amount" refers to the minimum dose used in pain treatment. For example, it refers to the minimum dose approved as a pain treatment drug. In one embodiment, when buprenorphine is administered transdermally, a formulation containing approximately 5 mg of buprenorphine is used as the minimum effective pain therapeutic amount. Here, since the transdermal buprenorphine formulations described in Non-Patent Documents 7 and 8 are formulations administered once every seven days, in one embodiment, when buprenorphine is administered transdermally, the minimum dose (per day) used for pain treatment is a formulation containing about 0.7 mg. In one embodiment, when buprenorphine is administered transdermally, the minimum effective dose for pain treatment is, for example, about 5 μg / h. An example of the minimum dose (per day) used for pain treatment is the dose when administered at about 5 μg / h for 24 hours, i.e., about 0.12 mg.In one embodiment, when buprenorphine is administered transmucosally (e.g., orally), the minimum effective amount for treating pain is about 0.075 mg. In one embodiment, about 0.075 mg is the daily dose. In one embodiment, when morphine is administered orally, the minimum effective amount for treating pain is about 5 mg. In one embodiment, when morphine is administered transmucosally or as an injection, the minimum effective amount for treating pain is about 10 mg. An "effective amount for treating autism spectrum disorder" is an amount effective for treating and / or preventing autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. Preferably, it is an amount effective for treating and / or preventing autism spectrum disorder.

[0023] In this specification, unless the context dictates otherwise, the use of "about" before a numerical value X includes a range of + / - 10% of the numerical value X and includes a value rounded to the nearest significant figure, taking into account the significant digits of the numerical value X. For example, about 1 ng / mL includes 0.9 ng / mL and 1.4 ng / mL.

[0024] Buprenorphine is 21-cyclopropyl-7-α-[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6,14-endo-ethano-6,7,8,14 tetrahydrooripavine. Buprenorphine has the following formula: The buprenorphine or a pharmaceutically acceptable salt thereof used in the present invention may be administered as a possible isomer of buprenorphine (e.g., keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotamer, racemate or a mixture thereof), a prodrug or a pharmaceutically acceptable salt thereof.

[0025] One or more hydrogen, carbon, and / or other atoms of the buprenorphine of the present invention may be substituted with isotopes of the hydrogen, carbon, and / or other atoms, respectively. Examples of such isotopes include, but are not limited to, ２ H. ３ H. １１ C.１３ C. １４ C. １５ N. １８ O. １７ The isotopes of buprenorphine of the present invention include hydrogen, carbon, nitrogen, and oxygen, such as O. The buprenorphine of the present invention also includes buprenorphine substituted with such isotopes. The isotope-substituted buprenorphine is also useful as a pharmaceutical and includes all radiolabeled forms of buprenorphine. Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled form," which is useful as a research and / or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

[0026] The radiolabeled buprenorphine of the present invention can be prepared by methods well known in the art. For example, tritium-labeled buprenorphine compounds can be prepared by introducing tritium into buprenorphine via catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted buprenorphine precursor with tritium gas in the presence of a suitable catalyst, such as Pd / C, with or without a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0027] Morphine has the following formula: The morphine or a pharmaceutically acceptable salt thereof used in the present invention may be administered as a possible isomer of morphine (e.g., keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotamer, racemate or a mixture thereof), a prodrug or a pharmaceutically acceptable salt thereof.

[0028] One or more hydrogen, carbon and / or other atoms of the morphine of the present invention may be replaced by an isotope of the hydrogen, carbon and / or other atom, respectively. Examples of such isotopes include ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ The isotope-substituted morphine of the present invention includes hydrogen, carbon, nitrogen, and oxygen, such as O. The morphine of the present invention also includes morphine substituted with such isotopes. The isotope-substituted morphine is also useful as a pharmaceutical, and includes all radiolabeled forms of morphine. Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled form," and the "radiolabeled form" is useful as a research and / or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

[0029] The radiolabeled morphine of the present invention can be prepared by methods well known in the art. For example, tritium-labeled morphine compounds can be prepared by introducing tritium into morphine through catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted precursor of morphine with tritium gas in the presence of a suitable catalyst, such as Pd / C, with or without a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0030] As used herein, examples of "pharmaceutically acceptable salts" include basic salts, for example, alkali metal salts such as lithium salts, sodium salts, potassium salts, etc.; alkaline earth metal salts such as calcium salts, barium salts, etc.; transition metal salts such as zinc salts, iron salts, etc.; magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, ethylenediamine salts, meglumine salts, procaine salts, etc.; aralkylamine salts such as N,N-dibenzylethylenediamine, etc.; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts, etc.; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, tetrabutylammonium salts, etc.; Examples of acid salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, hydrobromide, hydroiodide, and perchlorate; organic acid salts such as formate, acetate, propionate, trifluoroacetate, citrate, lactate, tartrate, oxalate, maleate, fumarate, succinate, mandelate, glutarate, malate, benzoate, phthalate, and ascorbate; sulfonate salts such as methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate; and acidic amino acid salts such as aspartate and glutamate. These salts can be formed by conventional methods. As a "pharmaceutically acceptable salt," acid salts are preferred, more preferably hydrochloride or sulfate, and particularly preferably hydrochloride.

[0031] Buprenorphine or a pharmaceutically acceptable salt thereof, and morphine or a pharmaceutically acceptable salt thereof used in the present invention may be in the form of a solvate, co-crystal, and / or crystalline polymorph. Solvates include organic solvates in which any number of organic solvent molecules are coordinated, and hydrates in which any number of water molecules are coordinated. As used herein, the term "solvate" refers to a solvate of the compound or a pharmaceutically acceptable salt thereof, and includes, for example, a monosolvate, a disolvate, a monohydrate, a dihydrate, and the like. Examples of solvates include hydrates, ethanol solvates, methyl acetate solvates, ethyl acetate and 2-propanol solvates, n-propyl acetate and 2-propanol solvates, acetonitrile solvates, 1,2-dimethoxyethane solvates, and methyl isobutyl ketone solvates. Preferably, hydrates, such as monohydrates and trihydrates, are used. One embodiment of buprenorphine or a pharmaceutically acceptable salt thereof is buprenorphine hydrochloride. An embodiment of morphine or a pharmaceutically acceptable salt thereof includes morphine hydrochloride (for example, morphine hydrochloride hydrate) and morphine sulfate.

[0032] A pharmaceutical composition can be prepared by mixing an effective amount of the compound used in the present invention with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, disintegrants, lubricants, etc., as needed. Furthermore, by appropriately changing the effective amount of the compound, dosage form, and / or various pharmaceutical additives, the pharmaceutical composition can also be made into a pharmaceutical composition for children, the elderly, critically ill patients, or surgical patients.

[0033] The administration route of the pharmaceutical composition of the present invention is not particularly limited, and it can be administered either orally or parenterally. Parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration. In one embodiment, the administration route of the pharmaceutical composition of the present invention is transdermal or transmucosal administration (e.g., oral mucosal, sublingual, or suppository, preferably oral mucosal or sublingual), for example, transdermal administration.

[0034] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0035] In the case of parenteral administration, any of the commonly used dosage forms such as injections, infusions, topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.) can be suitably administered. Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types. Pharmaceutical compositions for transdermal administration include, but are not limited to, solid preparations for topical use (e.g., powders for topical use), liquid preparations for topical use (e.g., liniments, lotions), sprays (aerosols for topical use, pump sprays), ointments, creams, gels, patches (e.g., tapes (e.g., plasters, plasters), poultices), etc. For example, patches.

[0036] The embodiments of the method, agent, and pharmaceutical composition of the present invention are not particularly limited and can be appropriately determined depending on the severity of symptoms, the patient's weight and age, the dosage form of the drug, and the like. Examples of embodiments of the present invention are given below. Examples of embodiments of the method, medicament, and pharmaceutical composition of the present invention include all possible combinations and ranges of the above-mentioned items and the items exemplified below. Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is administered at a dose equal to or less than the pain-therapeutically effective amount (e.g., a dose of about 1 / 2 or less, about 1 / 10 or less of the pain-therapeutically effective amount). Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is administered at a dose equal to or less than about 3 times (e.g., less than about 3 times), or about 2 times (e.g., about 1 time or less, about 1 / 2 time or less, about 1 / 3 time or less, about 1 / 4 time or less) of the minimum pain-therapeutically effective amount. Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is administered at about 1 / 33 times or more of the minimum effective dose for treating pain (e.g., a dosage greater than about 1 / 33 times), or about 1 / 30 times or more of the minimum effective dose for treating pain (e.g., about 1 / 25 times or more, about 1 / 20 times or more, about 1 / 10 times or more). Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is administered at about 1 / 33 to about 3 times the minimum effective dose for treating pain (e.g., more than about 1 / 33 and less than about 3 times), about 1 / 30 to about 3 times (e.g., about 1 / 30 to about 3 times), about 1 / 30 to about 2 times, about 1 / 30 to about 1 time, about 1 / 30 to about 1 / 2 times, about 1 / 20 to about 3 times (e.g., about 1 / 20 to about 3 times), about 1 / 20 to about 2 times, about 1 / 20 to about 1 time, about 1 / 30 to about 1 / 2 times, about 1 / 10 to about 3 times (e.g., about 1 / 10 to about 3 times), about 1 / 10 to about 2 times, about 1 / 10 to about 1 time, or about 1 / 10 to about 1 / 2 times the minimum effective dose for treating pain.

[0037] The plasma concentration (preferably the maximum plasma concentration) of buprenorphine or a pharmaceutically acceptable salt thereof is, for example, about 2 ng / mL or less, about 1.5 ng / mL or less, about 1 ng / mL or less, about 0.9 ng / mL or less, about 0.8 ng / mL or less, or about 0.7 ng / mL or less, preferably about 0.6 ng / mL or less, about 0.62 ng / mL or less, less than about 0.6 ng / mL, less than about 0.62 ng / mL, about 0.5 ng / mL or less, about 0.4 ng / mL or less, or about 0.3 ng / mL or less. More preferably, the concentration is about 0.2 ng / mL or less, for example, about 0.18 ng / mL or less, about 0.17 ng / mL or less, about 0.15 ng / mL or less, about 0.1 ng / mL or less, about 90 pg / mL or less, about 80 pg / mL or less, about 70 pg / mL or less, about 60 pg / mL or less, or about 50 pg / mL or less (note that the plasma concentration is expressed as a buprenorphine-equivalent concentration ignoring the salt portion; the same applies hereinafter). The plasma concentration (preferably the maximum plasma concentration) of buprenorphine or a pharmaceutically acceptable salt thereof is, for example, about 0.1 pg / mL or more, about 0.5 pg / mL or more, about 1 pg / mL or more, about 2 pg / mL or more, about 3 pg / mL or more, greater than about 3 pg / mL, or greater than about 3.3 pg / mL. Preferably, the concentration is, for example, about 4 pg / mL or more, more than about 4 pg / mL, about 5 pg / mL or more, about 6 pg / mL or more, about 7 pg / mL or more, about 8 pg / mL or more, about 9 pg / mL or more, about 10 pg / mL or more, about 11 pg / mL or more, about 12 pg / mL or more, about 13 pg / mL or more, about 14 pg / mL or more, about 15 pg / mL or more, about 16 pg / mL or more, about 17 pg / mL or more, or about 18 pg / mL or more.The concentration is, for example, about 0.9 ng / mL or less, about 0.8 ng / mL or less, or about 0.7 ng / mL or less. Preferably, the concentration is, for example, about 0.6 ng / mL or less, about 0.62 ng / mL or less, less than about 0.6 ng / mL, less than about 0.62 ng / mL, about 0.5 ng / mL or less, about 0.4 ng / mL or less, or about 0.3 ng / mL or less. More preferably, the concentration is, for example, about 0.2 ng / mL or less, about 0.18 ng / mL or less, about 0.17 ng / mL or less, about 0.15 ng / mL or less, about 0.1 ng / mL or less, about 90 pg / mL or less, about 80 pg / mL or less, about 70 pg / mL or less, about 60 pg / mL or less, about 50 pg / mL or less, or about 40 pg / mL or less. The plasma concentration (preferably the maximum plasma concentration) of buprenorphine or a pharmaceutically acceptable salt thereof may be, for example, about 1 pg / mL to about 2 ng / mL or less, about 1 pg / mL to about 1 ng / mL or less, about 1 pg / mL to about 0.6 ng / mL, about 1 pg / mL to about 0.2 ng / mL, about 1 pg / mL to about 0.1 ng / mL, about 1 pg / mL to about 50 pg / mL, about 3 pg / mL to about 2 ng / mL or less, about 3 pg / mL to about 1 ng / mL or less, about 3 pg / mL to about 0.6 ng / mL, about 3 pg / mL to about 0.3 ng / mL, about 3 pg / mL to about 0.2 ng / mL, about 3 pg / mL to about 0.1 ng / mL, about 3 pg / mL to about 50 pg / mL, About 4 pg / mL to about 2 ng / mL or less, about 4 pg / mL to about 1 ng / mL or less, about 4 pg / mL to about 0.6 ng / mL, about 4 pg / mL to about 0.2 ng / mL, about 4 pg / mL to about 0.1 ng / mL, about 4 pg / mL to about 50 pg / mL, about 5 pg / mL to about 2 ng / mL or less, about 5 pg / mL to about 1 ng / mL or less, about 5 pg / mL to about 0.6 ng / mL, about 5 pg / mL to about 0.2 ng / mL, about 5 pg / mL to about 0.1 ng / mL, about 5 pg / mL to about 50 pg / mL, About 6 pg / mL to about 2 ng / mL or less, about 6 pg / mL to about 1 ng / mL or less, about 6 pg / mL to about 0.6 ng / mL, about 6 pg / mL to about 0.2 ng / mL, about 6 pg / mL to about 0.1 ng / mL, about 5 pg / mL to about 50 pg / mL,About 8 pg / mL to about 2 ng / mL or less, about 8 pg / mL to about 1 ng / mL or less, about 8 pg / mL to about 0.6 ng / mL, about 8 pg / mL to about 0.2 ng / mL, about 8 pg / mL to about 0.1 ng / mL, about 8 pg / mL to about 80 pg / mL, about 8 pg / mL to about 50 pg / mL, about 10 pg / mL to about 2 ng / mL or less, about 10 pg / mL to about 1 ng / mL or less, about 10 pg / mL to about 0.6 ng / mL, about 10 pg / mL to about 0.2 ng / mL, about 10 pg / mL to about 0.1 ng / mL, about 10 pg / mL to about 50 pg / mL, about 15 pg / mL to about 2 ng / mL or less, about 15 pg / mL to about 1 ng / mL or less, about 15 pg / mL to about 0.6 ng / mL, about 15 pg / mL to about 0.2 ng / mL, about 15 pg / mL to about 0.1 ng / mL, about 15 pg / mL to about 50 pg / mL, About 18 pg / mL to about 2 ng / mL or less, about 18 pg / mL to about 1 ng / mL or less, about 18 pg / mL to about 0.6 ng / mL, about 18 pg / mL to about 0.2 ng / mL, about 18 pg / mL to about 0.17 ng / mL, about 18 pg / mL to about 0.1 ng / mL, about 18 pg / mL to about 50 pg / mL, Examples of the plasma concentration range include about 20 pg / mL to about 2 ng / mL or less, about 20 pg / mL to about 1 ng / mL or less, about 20 pg / mL to about 0.6 ng / mL, about 20 pg / mL to about 0.2 ng / mL, about 20 pg / mL to about 0.1 ng / mL, and about 20 pg / mL to about 50 pg / mL. In a further embodiment, for any of the above plasma concentration ranges, a range excluding both endpoints (e.g., for about 3 pg / mL to about 0.6 ng / mL, greater than about 3 pg / mL and less than about 0.6 ng / mL) is exemplified. In one embodiment, the plasma concentration is a peak plasma concentration at steady state. In one embodiment, the plasma concentration is a plasma concentration at steady state. In one embodiment, the plasma concentration is maintained for 30 consecutive minutes or more, for example, 1 hour or more, for example, 2 hours or more.

[0038] The content or dosage of buprenorphine or a pharmaceutically acceptable salt thereof (e.g., the content or dosage in a pharmaceutical composition for transdermal administration) is, for example, about 20 mg or less, about 10 mg or less, about 7 mg or less, about 5 mg or less, about 4 mg or less, about 2.5 mg or less, about 2 mg or less, about 1 mg or less, about 0.7 mg or less, about 0.5 mg or less, about 0.4 mg or less, about 0.3 mg or less, about 0.2 mg or less, or about 0.1 mg or less (note that the content or dosage is expressed as the buprenorphine equivalent amount without taking into account the salt portion; the same applies hereinafter). The content or dosage of buprenorphine or a pharmaceutically acceptable salt thereof (e.g., the content or dosage in a pharmaceutical composition for transdermal administration) is, for example, about 0.001 mg or more, about 0.003 mg or more, about 0.005 mg or more, about 0.01 mg or more, about 0.03 mg or more, about 0.05 mg or more, about 0.1 mg or more, about 0.3 mg or more, or about 0.5 mg or more. The content of buprenorphine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition for transdermal administration of the present invention may be about 0.56 mg to about 1.7 mg, or may be about 0.56 mg or about 1.7 mg. The content or dosage of buprenorphine or a pharmaceutically acceptable salt thereof (e.g., dosage or release rate in a pharmaceutical composition for transdermal administration) is, for example, about 20 μg / h or less, about 10 μg / h or less, about 5 μg / h or less, about 2.5 μg / h or less, about 3 μg / h or less, about 2 μg / h or less, about 1 μg / h or less, or about 0.1 μg / h or less (note that the release rate is expressed in buprenorphine equivalent amounts not taking into account the salt portion; the same applies hereinafter). The content or dosage of buprenorphine or a pharmaceutically acceptable salt thereof (e.g., dosage or release rate in a pharmaceutical composition for transdermal administration) is, for example, about 0.01 μg / h or more, about 0.05 μg / h or more, about 0.1 μg / h or more, about 0.5 μg / h or more, or about 1 μg / h or more. The release rate of the pharmaceutical composition for transdermal administration of buprenorphine or a pharmaceutically acceptable salt thereof of the present invention may be from about 0.56 μg / h to about 1.7 μg / h, and may be about 0.56 μg / h or about 1.7 μg / h.The content or dosage of buprenorphine or a pharmaceutically acceptable salt thereof (e.g., the content or dosage in a pharmaceutical composition for transmucosal administration) is, for example, about 1 mg or less, about 0.5 mg or less, about 0.2 mg or less, about 0.1 mg or less, about 0.075 mg or less, about 0.05 mg or less, or about 0.01 mg or less. The content or dosage of buprenorphine or a pharmaceutically acceptable salt thereof (e.g., the content or dosage in a pharmaceutical composition for transmucosal administration) is, for example, about 0.00001 mg or more, about 0.0001 mg or more, about 0.001 mg or more, or about 0.01 mg or more. The content or dosage of buprenorphine or a pharmaceutically acceptable salt thereof is, for example, about 0.3 μg / kg to about 30 μg / kg (e.g., more than about 0.3 μg / kg and less than about 30 μg / kg), about 0.5 μg / kg to about 20 μg / kg, or about 1 μg / kg to about 10 μg / kg. For example, when administered to a 60 kg patient, the content or dosage is, for example, about 18 μg to about 1.8 mg (e.g., more than about 18 μg and less than about 1.8 mg), about 30 μg to about 1.2 mg, or about 60 μg to about 0.6 mg. For example, when administered to a 40 kg patient, the content or dosage is, for example, about 12 μg to about 1.2 mg (e.g., more than about 12 μg and less than about 1.2 mg), about 20 μg to about 0.8 mg, or about 40 μg to about 0.4 mg. For example, when administered to a 20 kg patient, the dosage may be, for example, about 6 μg to about 0.6 mg (eg, greater than about 6 μg and less than about 0.6 mg), about 10 μg to about 0.4 mg, or about 20 μg to about 0.2 mg.

[0039] The plasma concentration (preferably the maximum plasma concentration) of morphine or a pharmaceutically acceptable salt thereof is, for example, about 500 ng / mL or less, about 350 ng / mL or less, about 300 ng / mL or less, about 200 ng / mL or less, about 100 ng / mL or less, about 10 ng / mL or less, or about 7 ng / mL or less. The plasma concentration (preferably the maximum plasma concentration) of morphine or a pharmaceutically acceptable salt thereof is, for example, about 0.1 ng / mL or more, about 0.5 ng / mL or more, about 1 ng / mL or more, about 2 ng / mL or more, about 5 ng / mL or more, or about 10 ng / mL or more. In one embodiment, the plasma concentration is the maximum plasma concentration at steady state. In another embodiment, the plasma concentration is the plasma concentration at steady state. In one embodiment, the plasma concentration is maintained for 30 consecutive minutes or more (e.g., 1 hour or more, 2 hours or more). The content or dosage of morphine or a pharmaceutically acceptable salt thereof is, for example, 10 mg or less, 5 mg or less, 3 mg or less, 1 mg or less, or 0.1 mg or less. The content or dosage of morphine or a pharmaceutically acceptable salt thereof is, for example, 0.01 mg or more, 0.05 mg or more, 0.1 mg or more, 0.5 mg or more, or 1 mg or more. The content or dosage of morphine or a pharmaceutically acceptable salt thereof is, for example, about 0.03 mg / kg to about 0.3 mg / kg (e.g., more than about 0.03 mg / kg and less than about 0.3 mg / kg), or about 0.03 mg / kg to about 0.1 mg / kg. For example, when administered to a 60 kg patient, the content or dosage is, for example, about 1.8 mg to about 18 mg (e.g., more than about 1.8 mg and less than about 18 mg), or about 1.8 mg to about 6 mg. For example, when administered to a 40 kg patient, the dosage may be, for example, about 1.2 mg to about 12 mg (e.g., greater than about 1.2 mg and less than about 12 mg), or about 1.2 mg to about 4 mg. For example, when administered to a 20 kg patient, the dosage may be, for example, about 0.6 mg to about 6 mg (e.g., greater than about 0.6 mg and less than about 6 mg), or about 0.6 mg to about 2 mg.

[0040] In one embodiment, the method, agent, medicament, or pharmaceutical composition of the present invention may contain a single active ingredient and be administered alone. In one embodiment, the administration interval is about 12 hours or more (e.g., about 24 hours, more than about 24 hours). In one embodiment, the administration frequency is two or less times per day (e.g., once per day).

[0041] The methods, agents, medicaments, pharmaceutical compositions, etc. of the present invention may include package inserts or labels written to identify the patient or subject targeted by the present invention as a treatment target and to provide instructions to medical professionals, such as physicians, involved in the prevention or treatment of the disease, regarding guidelines for treatment and / or prevention, such as dosage and administration, precautions, etc. However, these official documents are not limited to paper media and can be provided via the Internet. Furthermore, guidelines for prevention or treatment can be provided to physicians and others based on various other information sources in addition to official documents. Therefore, it is understood that the present invention also encompasses embodiments in which the drug is used based on information other than package inserts or labels. The methods, agents, medicaments, and pharmaceutical compositions of the present invention may be used in combination with, or without, other psychiatric medications (including digital medications) and / or other therapies (including various non-drug therapies).

[0042] The pharmaceutical composition or method of the present invention preferably has one or more excellent features selected from the following: a) It is useful for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, autism spectrum disorder-like symptoms, and / or disorders in social communication and / or social interaction. Preferably, it is useful for the treatment and / or prevention of autism spectrum disorder. Particularly preferably, it is useful for the treatment and / or prevention of core symptoms of autism spectrum disorder. b) It has a low effective pharmacological dose and concentration. Therefore, it can be a pharmaceutical product with a high safety margin. It can also be a pharmaceutical product with a low risk of side effects. c) It exhibits efficacy at doses (or plasma concentrations) equivalent to or preferably lower than those approved for pain treatment. Therefore, it is highly safe as a pharmaceutical product. In addition, for example, it may be subject to fewer restrictions as a controlled substance. For example, it does not require a special program (e.g., REMS) for administration. d) It has a long duration of efficacy. This enables treatment with fewer administrations, which is expected to increase patient compliance, for example. Furthermore, for example, when the patient is a child, it is expected to reduce the burden on caregivers.

[0043] Buprenorphine and its pharmaceutically acceptable salts, and morphine and its pharmaceutically acceptable salts can be synthesized according to known methods.

[0044] The present invention will be described below based on examples, but the present invention is not limited to these examples in any way.

[0045] (Example 1: Evaluation of drug efficacy using a valproic acid model mouse) The valproic acid model mouse (VPA model) is an ASD model mouse based on clinical evidence that administration of valproic acid during human pregnancy significantly increases the probability that newborns will suffer from ASD. Because ASD-like symptoms such as social impairment and cognitive impairment are observed in this mouse, it is one of the most commonly used ASD model mice. As described in a previous study (Hara Y, Ago Y, Higuchi M, Hasebe S, Nakazawa T, Hashimoto H, Matsuda T, Takuma K. Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism. Horm Behav. 2017 Nov;96:130-136. doi: 10.1016 / j.yhbeh.2017.09.013. Epub 2017 Sep 28. PMID: 28942000.), a VPA model was established by administering valproic acid to ICR mice during the fetal period. A single dose of the MOR agonist analgesic morphine, buprenorphine, or tramadol was administered to the VPA model to examine its effects on social interaction deficits. To evaluate sociality, a method called the Social Interaction Test was used. In the Social Interaction Test, two mice were placed in a cage, and the number of seconds that a subject mouse (test mouse) sniffed the other mouse (intruder mouse), a social behavior, was quantified. Saline, morphine hydrochloride, buprenorphine hydrochloride, or tramadol hydrochloride was administered subcutaneously, and the amount of social behavior was quantified for 20 minutes starting from 1 hour after administration. Doses were calculated as hydrochlorides for morphine and tramadol, and as free form for buprenorphine. The results are shown in Figures 1 to 3.Morphine and buprenorphine showed significant improvement in social impairment at low doses less than 1 / 10 of the doses at which their analgesic effects were maximized (8 mg / kg, 1 mg / kg, Non-Patent Document 28). On the other hand, both compounds showed a characteristic dose-dependence, in which the improvement in social impairment decreased at high doses close to the analgesic dose. Furthermore, tramadol, which is used as an analgesic drug like morphine and buprenorphine and has MOR agonist activity in vivo, showed no improvement in social impairment. Based on these results, morphine and buprenorphine are considered to have an effect of improving social impairment in ASD and to be useful as therapeutic agents for ASD. Furthermore, while morphine and buprenorphine show enhanced analgesic effects at high doses, surprisingly, they tend to show high efficacy in improving social impairment, especially at low doses. Buprenorphine in particular improved social impairment at even lower doses than morphine, and is therefore expected to be a safe therapeutic agent for ASD with a low risk of side effects.

[0046] (Example 2: Pharmacokinetics) Morphine hydrochloride or buprenorphine was diluted with saline to various doses and administered subcutaneously to ICR mice. Blood samples were collected and brain samples were removed at various time points after administration, and drug concentrations in plasma and brain were measured by LC-MS. The doses were calculated as the hydrochloride salt for morphine and as the free form for buprenorphine. The results are shown in Tables 1 and 2. Figures 4 and 5 show the relationship between the plasma concentrations of unchanged morphine and buprenorphine and the improvement in social impairment and analgesic efficacy. The left axis of Figures 4 and 5 shows the improvement in social impairment measured in the same manner as in Example 1, and the right axis shows the analgesic effect. The relationship between the plasma concentrations of unchanged morphine and buprenorphine and the improvement in social impairment and analgesic efficacy was plotted using data from Non-Patent Document 28, Fig. 4. The horizontal axis shows the concentration of unchanged drug in plasma calculated from the administered dose at the time of efficacy evaluation. For both morphine and buprenorphine, the plasma drug concentration at which a social impairment-improving effect is observed is lower than the concentration at which an analgesic effect is observed, and the concentration at which the maximum pharmacological effect is observed is more than 10 times different. Table 1 shows the time course of the plasma concentrations of unchanged morphine and its M6G metabolite.

[0047] *60 minutes after administration of 0.1 mg / kg, data from N=3 (morphine: 23.8 ng / mL, M6G: 321 ng / mL) were excluded as outliers due to apparent measurement errors. Table 2 shows the time course of plasma concentrations of unchanged buprenorphine.

[0048] BLQ: LLOQ (Lower limit of quantification: 2 pg / mL) or less *: Sample was diluted 10 times before quantification.

[0049] (Example 3: Confirmation of sustained effect) As in Example 1, saline or buprenorphine was subcutaneously administered to a VPA model, and the amount of social behavior was quantified for 20 minutes starting 3 hours after administration or 20 minutes starting 12 hours after administration. The results are shown in Figure 6. The effect of buprenorphine at 0.003 mg / kg on improving social impairment was observed even 3 and 12 hours after administration. On the other hand, oxytocin, which is currently being developed as a treatment for autism spectrum disorder, has been shown to improve social impairment in a model similar to this experiment, but its efficacy has been reported to disappear 3 hours after administration (Horm Behav. 2017 Nov; 96: 130-136.). Therefore, it was suggested that buprenorphine has a longer-lasting effect on improving social impairment compared to oxytocin, making it a potentially useful therapeutic agent. As shown in Table 2, the buprenorphine plasma concentration at 12 hours after administration was lower than that at 3 hours after administration at both 0.003 mg / kg and 0.03 mg / kg doses, but no clear difference was observed in the tendency for the sociability-improving effect at 3 hours and 12 hours after administration in Figure 6. This suggests that the maximum plasma concentration (Cmax) in particular influences the sociability-improving effect.

[0050] (Example 4: Estimation of a preferred buprenorphine dosage in humans) As shown in Figures 2 and 3, buprenorphine showed a significant effect of improving sociality at doses of 1 μg / kg to 10 μg / kg in VPA model mice. As shown in Example 2, the Cmax of buprenorphine at doses of 0.3 μg / kg and 30 μg / kg was 26.6 pg / mL and 2360 pg / mL, respectively. Therefore, a preferred maximum plasma concentration for ASD use in mice is within the range of about 26.6 pg / mL to about 2360 pg / mL (preferably, greater than about 26.6 pg / mL and less than about 2360 pg / mL). Here, the Cmax of buprenorphine at doses of 1 μg / kg and 10 μg / kg, which showed significant social improvement effects, was 67 pg / mL (estimated) and 670 pg / mL, respectively. Therefore, a particularly preferred range of maximum plasma concentrations in mice includes approximately 67 pg / mL to 670 pg / mL. In mice, a latency response was observed at doses of 10 μg / kg or higher subcutaneously in analgesic evaluation (Non-Patent Document 28), so 10 μg / kg is the minimum dose at which an analgesic effect is observed. According to the Butrans™ package insert, a transdermal formulation, the Cmax at the approved minimum dose (5 mg formulation, release rate 5 μg / h) is 176 pg / mL. According to the BELBUCA® package insert, a transmucosal formulation, the Cmax at the minimum approved dose (75 μg) is 0.17±0.30 ng / mL. According to the package insert for Norspan Tape®, a transdermal formulation, the Cmax at the minimum approved dose (5 mg formulation, release rate 5 μg / h) is 84 pg±19 / mL. Therefore, a 10 μg / kg dose of buprenorphine in mice (Cmax: 670 pg / mL) is considered to be equivalent to a Cmax of approximately 84 pg / mL to 176 pg / mL in humans. As discussed above, the preferred maximum plasma concentration for ASD use in mice is within the range of 26.6 pg / mL (at a dose of 0.3 μg / kg) to 2360 pg / mL (at a dose of 30 μg / kg) (preferably, greater than about 26.6 pg / mL and less than about 2360 pg / mL).By proportional calculation, the preferred maximum plasma concentration in humans for ASD use was estimated to be within the range of about 3.3 pg / mL to about 620 pg / mL (preferably greater than about 3.3 pg / mL and less than about 620 pg / mL). Furthermore, the particularly preferred maximum plasma concentration in humans, corresponding to the particularly preferred range of maximum plasma concentrations in mice (67 pg / mL to 670 pg / mL), was estimated to be about 8.4 pg / mL to about 176 pg / mL. Furthermore, in mice, significant social improvement effects were observed at 10 μg / kg, the minimum dose at which an analgesic effect was observed, and at 1 μg / kg, which is 1 / 10 of that dose. Therefore, in other words, particularly preferred doses of buprenorphine include doses that are about 1 / 10 to about 1 times the minimum dose approved for use as a pain treatment drug (e.g., a 5 mg-containing transdermal formulation (a 7-day administration formulation with a daily dose of about 0.7 mg), a transdermal formulation with a release rate of 5 μg / h, a 75 μg oral transmucosal formulation, etc.). Furthermore, the doses corresponding to a 0.3 μg / kg administration and a 30 μg / kg administration in mice are about 1 / 33 and about 3 times, respectively, the minimum dose approved for use as a pain treatment drug.

[0051] Example 5: Evaluation of Drug Efficacy Using FMR-1 Knockout Mice. Patients with human fragile X syndrome (FXS), a disorder caused by an X chromosome abnormality, are known to often exhibit social impairment symptoms similar to those seen in ASD (Non-Patent Documents 7-9). Fmr1 knockout mice (Cell, 1994, 15; 78(1):23-33) are mouse models mimicking human fragile X syndrome (FXS) and are also widely used as models of ASD. Buprenorphine hydrochloride, a partial agonist of the MOR used as an analgesic, and physiological saline as a vehicle were administered in single doses to examine the effects on social dysfunction in Fmr1 knockout mice. Buprenorphine was calculated as the free form. To evaluate social function, a 3-chamber test (Nature Medicine, 2017, 23; p. 674-677) was used. In the 3-chamber test, two types of mice (unfamiliar and familiar) were placed in cups on the left and right ends of three compartments. The ratio of the time spent exploring the high-novelty and low-novelty mice was calculated and quantified as social function (preference for the high-novelty mice). The results are shown in Figure 7. Fmr1 knockout mice exhibited social impairment compared to wild-type normal B6 mice, and subcutaneous administration of buprenorphine significantly improved social impairment. This efficacy was observed at a low dose less than 1 / 10 of the dose (1 mg / kg) at which buprenorphine's analgesic effect is maximized, indicating a characteristic effect in the low-dose range.

[0052] (Example 6: Antagonist test) As in Example 1, saline or the MOR-selective antagonist naloxone hydrochloride was subcutaneously administered to the VPA model at 1 mg / kg as the hydrochloride, followed by subcutaneous administration of 0.003 mg / kg of buprenorphine 15 minutes later. The amount of social behavior was quantified for 20 minutes starting from 1 hour after buprenorphine administration. The results are shown in Figure 8. The effect of administering 0.003 mg / kg of buprenorphine on improving social impairment was antagonized by concomitant administration of naloxone. This indicates that buprenorphine improves social impairment by activating MOR.

[0053] Example 7 Analysis of Activated Brain Regions Saline or 0.0003, 0.003, or 0.03 mg / kg of buprenorphine was administered to a VPA model. One hour later, the brain was removed and immunostained with an anti-c-Fos antibody. The number of c-Fos-positive cells was quantified as the number of activated neurons in the nucleus accumbens (NAc) and medial prefrontal cortex, which are brain regions known to promote social behavior, and the dorsomedial periaqueductal gray (dmPAG), which is a brain region known to reduce social behavior and be involved in the expression of analgesic effects. The results are shown in Figures 9 to 11. As shown in Figures 9 and 10, previous research (Coley AA, Padilla-Coreano N, Patel R, Tye KM. Valence processing in the PFC: Reconciling circuit-level and systems-level views. Int Rev Neurobiol. 2021;158:171-212. doi: 10.1016 / bs.irn.2020.12.002. Epub 2021 Feb 4. PMID: 33785145.) showed that the number of activated neurons in the nucleus accumbens and medial prefrontal cortex, brain regions that are thought to be responsible for promoting social behavior, increased significantly at 0.003 mg / kg, a dose that improved social impairment.Furthermore, as shown in Figure 10, in previous studies (Franklin TB, Silva BA, Perova Z, Marrone L, Masferrer ME, Zhan Y, Kaplan A, Greetham L, Verrechia V, Halman A, Pagella S, Vyssotski AL, Illarionova A, Grinevich V, Branco T, Gross CT. Prefrontal cortical control of a brainstem social behavior circuit. Nat Neurosci. 2017 Feb;20(2):260-270. doi:10.1038 / nn.4470. Epub 2017 Jan 9. PMID: 28067904; PMCID: PMC5580810.), there was no change in the number of activated neurons at 0.003 mg / kg. On the other hand, at a dose of 0.03 mg / kg, which showed an analgesic effect but reduced the effect on improving social impairment, the number of activated neurons significantly increased not only in the nucleus accumbens and medial prefrontal cortex but also in the dorsal medial periaqueductal gray matter. Based on these findings, it is believed that a dose that activates the nucleus accumbens and medial prefrontal cortex but not the dorsal medial periaqueductal gray matter is preferable for improving social impairment using buprenorphine.Previous research (de Freitas RL, Medeiros P, Khan AU, Coimbra NC. μ1-Opioid receptors in the dorsomedial and ventrolateral columns of the periaqueductal grey matter are critical for the enhancement of post-ictal antinociception. Synapse. 2016 Dec;70(12):519-530. doi:10.1002 / syn.21926. Epub 2016 Sep 6. PMID:27503688.) has shown that activation of the dorsomedial periaqueductal grey matter is important for the analgesic effect of opioids. Therefore, a lower dose of buprenorphine than that used for analgesia may be preferable for improving social impairment.

[0054] Example 8: Study to Investigate the Effect of Low-Dose Buprenorphine Administration on ASD Symptoms The following study will be conducted to investigate the effect of low-dose buprenorphine administration on ASD in children with autism spectrum disorder. Several dozen children diagnosed with autism spectrum disorder according to DSM-5 criteria will be studied, and the effects of buprenorphine administration will be examined while undergoing clinical and biological monitoring. Buprenorphine will be administered to the subjects via a transdermal patch at a patch dose of 0.56 mg or 1.7 mg and a release rate of approximately 0.56 μg / h or approximately 1.7 μg / h. For example, a buprenorphine patch (patched dose 5 mg, release rate 5 μg / h) may be administered at 1 / 9 or 1 / 3 the amount. Standard ASD symptom assessment scales, such as the Social Responsiveness Scale-Second Edition (SRS-2), the Childhood Autism Rating Scale-Second Edition (CARS-2), and the Repetitive Behavior Scale-Revised (RBS-R), will be used to assess whether medication has had any effect on symptom change. Regarding changes in gaze patterns in ASD patients, which have been suggested as a potential objective symptom assessment index, a gaze measurement device will be used to assess whether medication has had any effect.

[0055] (Formulation Examples) The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.

[0056] Buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof can be administered as a pharmaceutical composition by any conventional route, for example, orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of an injectable solution or suspension, topically, e.g., in the form of a lotion, gel, ointment, or cream, or intranasally or in the form of a suppository. Pharmaceutical compositions containing buprenorphine or a pharmaceutically acceptable salt thereof in free form or in the form of a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0057] The pharmaceutical composition containing buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof, and the method of administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof of the present invention are useful for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. Furthermore, the pharmaceutical composition or method of the present invention is a medicine or treatment method with a low effective concentration and high safety.

Claims

1. A pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms, comprising buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1 for the treatment and / or prevention of autism spectrum disorder.

3. The pharmaceutical composition according to claim 1, for administration to a patient diagnosed with an autism spectrum disorder.

4. The pharmaceutical composition according to claim 1, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose not greater than an amount effective for treating pain.

5. The pharmaceutical composition according to claim 1, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose of about half or less of the effective amount for treating pain.

6. The pharmaceutical composition according to claim 1, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose equal to or less than the minimum effective dose for treating pain.

7. The pharmaceutical composition according to claim 1, for administering buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof at a dose that is about 1 / 30 to about 3 times the minimum effective dose for treating pain.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is buprenorphine or a pharmaceutically acceptable salt thereof.

9. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition provides a peak plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 1 ng / mL or less.

10. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition provides a peak plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 4 pg / mL to about 0.6 ng / mL.

11. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition provides a peak plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 0.2 ng / mL or less.

12. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition provides a peak plasma concentration of buprenorphine or a pharmaceutically acceptable salt thereof of about 8 pg / mL to about 0.2 ng / mL.

13. Below a) to c): a) a pharmaceutical composition for transdermal administration containing about 0.01 mg to about 10 mg of buprenorphine or a pharmaceutically acceptable salt thereof; b) a pharmaceutical composition for transdermal administration that releases buprenorphine or a pharmaceutically acceptable salt thereof at a rate of about 0.01 μg / h to about 10 μg / h; and c) a pharmaceutical composition for transmucosal administration containing about 0.0001 mg to 0.1 mg of buprenorphine or a pharmaceutically acceptable salt thereof; The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is any one of the following:

14. a) a pharmaceutical composition for transdermal administration containing about 0.56 mg to about 1.7 mg of buprenorphine or a pharmaceutically acceptable salt thereof; or b) a pharmaceutical composition for transdermal administration, which releases buprenorphine or a pharmaceutically acceptable salt thereof at a rate of about 0.56 μg / h to about 1.7 μg / h; The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is any one of the following:

15. a) a pharmaceutical composition for transdermal administration containing about 0.56 mg or about 1.7 mg of buprenorphine or a pharmaceutically acceptable salt thereof; or b) a pharmaceutical composition for transdermal administration that releases buprenorphine or a pharmaceutically acceptable salt thereof at a rate of about 0.56 μg / h or about 1.7 μg / h; The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is any one of the following:

16. 9. The pharmaceutical composition according to claim 8, for administration at intervals of 12 hours or more.

17. 9. The pharmaceutical composition according to claim 8, wherein the efficacy lasts for 12 hours or more after administration.

18. 9. The pharmaceutical composition according to claim 8, for administering buprenorphine or a pharmaceutically acceptable salt thereof without concomitant use with other drugs.

19. The pharmaceutical composition according to any one of claims 1 to 7, wherein buprenorphine or a pharmaceutically acceptable salt thereof and / or morphine or a pharmaceutically acceptable salt thereof is morphine or a pharmaceutically acceptable salt thereof.

20. 20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition provides a peak plasma concentration of morphine or a pharmaceutically acceptable salt thereof of about 200 ng / mL or less.

21. 20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition provides a peak plasma concentration of morphine or a pharmaceutically acceptable salt thereof of about 1 ng / mL to about 200 ng / mL.