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(12) Patent Application Publication (10) Pub. No.: US 2017/0135984 A1 Solomon (43) Pub US 20170135984A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0135984 A1 Solomon (43) Pub. Date: May 18, 2017 (54) INTRANASAL AND TRANSIDERMAL Publication Classification ADMINISTRATION OF (51) Int. Cl. KAPPA-OPOID-RECEPTORAGONSTS: A63L/366 (2006.01) SALVINORIN A FOR THE TREATMENT OF A636/537 (2006.01) NEUROPSYCHATRIC AND ADDICTIVE A63/37 (2006.01) DSORDERS A6IR 9/00 (2006.01) A636/85 (2006.01) (71) Applicant: Atlee Solomon, Vienna, VA (US) (52) U.S. Cl. CPC .......... A61 K3I/366 (2013.01); A61K 9/0014 (72) Inventor: Atlee Solomon, Vienna, VA (US) (2013.01); A61K 9/0043 (2013.01); A61 K 36/185 (2013.01); A61K 31/137 (2013.01); (21) Appl. No.: 15/354,078 A61K 36/537 (2013.01) (57) ABSTRACT Methods of treating neuropsychiatric disorders including (22) Filed: Nov. 17, 2016 affective disorders and addiction involve intranasal or trans dermal administration of a Substantially selective kappa opioid-receptor agonist that is also a partial D2 agonist, Such Related U.S. Application Data as the compound salvinorin A. Also disclosed are intranasal, (60) Provisional application No. 62/256,409, filed on Nov. transdermal and/or inhalation systems for delivering the 17, 2015. kappa-opioid-receptor agonist. US 2017/O 135984 A1 May 18, 2017 INTRANASAL AND TRANSIDERMAL ropsychiatric conditions (Dhuria, 2010; Djupesland, 2014). ADMINISTRATION OF In spite of this, the neuropsychiatric drug ketamine is KAPPA-OPOID-RECEPTORAGONSTS: currently under experimental investigation using the intra SALVINORIN A FOR THE TREATMENT OF nasal route of administration for treatment of acute and NEUROPSYCHATRIC AND ADDICTIVE chronic pain, autism, depression and other conditions (Af DISORDERS ridi, 2013: Yeaman, 2014: Clark, 2014, Lapidus, 2014: Graudins, 2015). Naltrexone can potentiate the effects of CROSS-REFERENCE TO RELATED ketamine (Krystal et al., 2006). APPLICATIONS 0008 Similar to the intranasal route of administration, transdermal administration presents challenges and only a 0001. This application claims the benefit of U.S. Provi few medications can be delivered through the transdermal sional Application No. 62/256,409, filed Nov. 17, 2015, and route in therapeutic amounts (Paudel, 2010; Ita, 2015). incorporated by reference herein in its entirety. 0009. As noted above, numerous studies have evaluated different routes of administration for salvinorin A. Never BACKGROUND OF THE INVENTION theless, none of the routes of administration that have been 0002 (1) Field of the Invention studied are particularly Suited for use in neuropsychiatry. 0003. The present invention is related to the treatment of neuropsychiatric conditions with kappa-opioid-receptor BRIEF SUMMARY OF THE INVENTION agonists and, in particular, to intranasal, transdermal and 0010. Accordingly, the applicant herein has invented an inhalation systems and methods of administration of kappa intranasal system and method and a transdermal system and opioid-receptor agonists for the treatment of neuropsychi method for administration of kappa-opioid-selective ago atric conditions. nists such as Salvinorin A, for the treatment of neuropsy 0004 (2) Description of the Related Art chiatric conditions. 0005 Salvinorin A is a naturally occurring psychoactive 0011 Thus in various embodiments, the present inven compound isolated from Salvia divinorum. Studies have tion involves a method of treating an affective disorder in a demonstrated that salvinorin A is a uniquely selective kappa patient in need thereof. The method may comprise admin opioid-receptor agonist with no significant effect on a bat istering intranasally to the patient, a therapeutically effective tery of 50 other receptors, transporters and ion channels amount of a Substantially selective kappa-opioid-receptor including mu- and delta-opioid receptors (Roth et al., 2004). agonist in a pharmaceutically acceptable preparation. In In addition to having kappa-opioid-agonist activity, Salvi various embodiments, the kappa-opioid-receptor agonist norin A has been found to be a D2 receptor partial agonist may be devoid of activity on 5HT receptors, in particular (Seeman et al., 2009). Notably, salvinorin Ahas been shown 5HT receptors, such that it produces Substantially no to have no significant effect on 5HTP receptors and as a manic effect. In various embodiments, the kappa-opioid result, administration of Salvinorin A to a subject would not receptor agonist also has D2 agonist activity and, in par be expected to produce mania (Yatham et al., 2010). Recent ticular, partial D2 agonist activity. In certain embodiments, studies have Suggested that salvinorin A may have anti the kappa-opioid-receptor agonist may be salvinorin A. depression and anti-addiction properties among other poten Administration may be with an intranasal delivery device. tially beneficial properties (Morani et al., 2009; Prevatt 0012. In various embodiments, the affective disorder may Smith et al., 2011; Harden et al., 2012: Orton et al., 2014). be depression, bipolar disorder or anxiety disorder. 0006. Several routes of administration have been used for 0013. In various aspects of this embodiment, the kappa Salvia divinorum and for Salvinorin A with varying degrees opioid-receptor agonist may be administered with either or of Success. In traditional practice among the Mazatec people both of a cannabinoid compound and ketamine in a phar of Mexico, Salvia divinorum was ingested by chewing the maceutically acceptable preparation. The pharmaceutically fresh leaves as a quid or by smoking (Valdes, 1994; Siebert, acceptable preparation for the cannabinoid compound and/ 1994). Absorption upon chewing is apparently by the buccal or ketamine may include the same carrier system in which route in as much as encapsulated Salvinorin A is inactive the kappa-opioid-receptor agonist is administered and the when administered orally (Siebert, 1994; Ott, 1995). Sub Substances may be administered together or separately in lingual administration has generally yielded inconsistent any combination thereof. Alternatively, the carrier system results or no absorption at all (Siebert, 1994; Mendelson et for the cannabinoid compound and/or ketamine may be al., 2011). The most common route of administration of different from that of the kappa-opioid-receptor agonist and Salvia divinorum has been inhalation by Smoking the leaves the Substances may be administered separately. In some (Giroud et al., 2000). More recently, the inhalation route of embodiments, naltrexone is included. administration has been used for the active component, 0014. In various embodiments, the present invention may salvinorin A, in human Subjects (Johnson et al., 2011; involve a method of treating addiction in a Subject in need Maqueda et al., 2015). thereof. The method may comprise administering intrana 0007 Although infrequently used, the intranasal route of Sally to the patient, a therapeutically effective amount of a administration has been proposed for use in pharmacologic Substantially selective kappa-opioid-receptor agonist in a treatment of neuropsychiatric conditions. Potential advan pharmaceutically acceptable preparation. In various tages of intranasal administration are rapid onset of action, embodiments, the kappa-opioid-receptor agonist may be the ability to bypass the blood-brain barrier, improvement in devoid of activity on 5HT, receptors, in particular 5HT, bioavailability and avoidance of parenteral administration receptors, such that it produces Substantially no manic effect. (Andrade, 2015). Nevertheless, there are numerous chal In various embodiments, the kappa-opioid-receptor agonist lenges and potential problems that have limited the use of also has D2 agonist activity and, in particular, partial D2 intranasal administration of drugs for the treatment of neu agonist activity. In certain embodiments, the kappa-opioid US 2017/O 135984 A1 May 18, 2017 receptor agonist may be salvinorin A. Administration may which the kappa-opioid-receptor agonist is administered and be with an intranasal delivery device. the Substances may be administered together or separately in 0015. In various embodiments, the addiction may be an any combination thereof. Alternatively, the carrier system addiction to nicotine, cocaine, opioids, amphetamine, meth for the cannabinoid compound and/or ketamine may be amphetamine, ethanol, heroin, morphine, phencyclidine, different from that of the kappa-opioid-receptor agonist and 3.4-methylenedioxy-methamphetamine, as well as other the Substances may be administered separately. In some addictive substances and addictive behaviors. embodiments, naltrexone is included. 0016. In various aspects of this embodiment, the kappa 0021. In various other embodiments, the present inven opioid-receptor agonist may be administered with either or tion involves a method of treating an affective disorder in a both of a cannabinoid compound and ketamine in a phar patient in need thereof. The method may comprise admin maceutically acceptable preparation. The pharmaceutically istering transdermally to the patient, a therapeutically effec acceptable preparation for the cannabinoid compound and/ tive amount of a Substantially selective kappa-opioid-recep or ketamine may include the same carrier system in which tor agonist in a pharmaceutically acceptable preparation. In the kappa-opioid-receptor agonist is administered and the various embodiments, the kappa-opioid-receptor agonist Substances may be administered together or separately in may be devoid of activity on 5HT receptors,
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