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(19) United States (12) Patent Application Publication (10) Pub US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist. Examples of central nervous system stimulants (60) Provisional application No. 61/233,686; ?led on Aug. (such as methylphenidate) and opioid receptor antagonists 13, 2009. (such as naltrexone) are provided. Patent Application Publication Oct. 31, 2013 Sheet 1 0f 12 US 2013/0289061 A1 E:“E E:“E @359:2 Pm:HE Amiga:“2:38 hm: 2:| 25| 8m| 2;| 8M| 2;| 2:| Patent Application Publication Oct. 31, 2013 Sheet 2 0f 12 US 2013/0289061 A1 33EgigsA???258:2 65wM: 2M| EN| =2I =2| 2:| EIEIUOS ddZF NVEIIN Patent Application Publication Oct. 31, 2013 Sheet 3 0f 12 US 2013/0289061 A1 :2522252328322 65w<N =________________g_____2=_____ 2:2_ I2: Patent Application Publication Oct. 31, 2013 Sheet 4 0f 12 US 2013/0289061 A1 Patent Application Publication Oct. 31, 2013 Sheet 6 0f 12 US 2013/0289061 A1 65wmm EN| =2I IQE 2:| EIHUOS ddi] INEIF NVEIIN Patent Application Publication Oct. 31, 2013 Sheet 7 0f 12 US 2013/0289061 A1 _I_ NALTREXUNE (10mg/kg)+ (7.5mg/kg)MPH NUCLEUSACCUMBENS MPH (75mg/kg) SALINE FIG.3C I NALTREXUNE (10mg/kg)+ MPH(75mg/kg) CAUDATE-PUTAMEN MPH (75mg/kg) SALINE | l l l l c c c c c Q Li? Q Li? Q Li? N N I- ' Patent Application Publication Oct. 31, 2013 Sheet 8 0f 12 US 2013/0289061 A1 Patent Application Publication Oct. 31, 2013 Sheet 9 0f 12 US 2013/0289061 A1 E2 “22392 65wmw H 232625:“; 8M| 8M| EN| =2I =2| 2:| (SUNUOEIS) 321038 dd!) Patent Application Publication Oct. 31, 2013 Sheet 11 0f 12 US 2013/0289061 A1 EINI'IEISVH % SEI ?'lVA INEIF NVEIIN Patent Application Publication Oct. 31, 2013 Sheet 12 0f 12 US 2013/0289061 A1 EINI'IEISVH % SEIII'IVA INEIF NVEIIN US 2013/0289061 A1 Oct. 31,2013 METHODS AND COMPOSITIONS TO administration. In one embodiment of the various pharma PREVENT ADDICTION ceutical compositions described herein, the pharmaceutical composition is formulated as a tablet or capsule. In one CROSS-REFERENCE TO RELATED embodiment of the various pharmaceutical compositions APPLICATIONS described herein, the opioid receptor antagonist is formulated such that When ingested, the opioid receptor antagonist [0001] This application is a continuation application of co remains intact. The various pharmaceutical compositions pending US. patent application Ser. No. 13/389,959 ?led on described herein are suitable for use in the methods described Apr. 27, 2012, Which is a 35 U.S.C. §371 National Phase Entry Application of International Application No. PCT/ herein. US2010/045486 ?led onAug. 13, 2010, Which designated the [0006] Another aspect of the invention relates to a method United States, and Which claims the bene?t under 35 U.S.C. of reducing or preventing the development of aversion to a §119(e) of US. Provisional Application No. 61/233,686, CNS stimulant in a subject comprising, administering a thera ?led Aug. 13, 2009, the contents of each of Which are incor peutic amount of the neurological stimulant and administer porated herein by reference in their entireties. ing an antagonist of the kappa opioid receptor, to thereby prevent the development of aversion to the CNS stimulant in GOVERNMENTAL SUPPORT the subject. In one embodiment of the methods described herein, the method further comprises selecting a subject at [0002] This invention Was made With Government support risk for the development of aversion to the CNS stimulant, under research grant R0 1 DA020796 aWarded by the National prior to the administering. In one embodiment of the methods Institutes of Health. The Government has certain rights in the described herein, the subject is diagnosed With attention de? invention. cit hyperactivity disorder (ADHD), narcolepsy, chronic fatigue syndrome, or depression. FIELD OF THE INVENTION [0007] Another aspect of the invention relates to a method [0003] The present invention relates to the ?eld of drug to decrease the dysphoria associated With the use of therapeu therapies and the prevention of addiction to drugs such as tic doses of a CNS stimulant comprising administering a those that activate the dopamine receptor. therapeutic amount of the CNS stimulant and administering a kappa opioid receptor antagonist, to thereby decrease the BACKGROUND OF THE INVENTION dysphoria. In one embodiment of the methods described herein, the method further comprises selecting a subject at [0004] Methylphenidate (MPH) is the most commonly pre risk for the development of dysphoria, prior to administering. scribed stimulant compound for treatment of attention de?cit hyperactivity disorder (ADHD)1’2. Although its therapeutic [0008] Another aspect of the invention relates to a method e?icacy and safety is Well documented in pediatric and adult to decrease the euphoria associated With the use of therapeu patients3 , serious concerns persist about its abuse potential tic doses of a CNS stimulant comprising administering a upon long-term usage4'9. Moreover, recreational or street-use therapeutic amount of the CNS stimulant and administering a of stimulants and analeptics is on the rise further adding to the mu opioid receptor antagonist, to thereby decrease the eupho concerns about stimulant abuses’lo’l 1. In fact, non-human ria. In one embodiment of the methods described herein, the primates can self-administer MPHl2’l3ia hallmark of addic method further comprises selecting a subject at risk for the tion. Prevailing notions of molecular mechanisms mediating development of euphoria, prior to administering. MPH addiction rely on the central actions of MPH on dopam [0009] Another aspect of the invention relates to a method ine and noradrenaline signaling mechanismsl4'l7. HoWever, of reducing or preventing the development of addiction to a these neurotransmitter mechanisms alone are inadequate for CNS stimulant in a subject, comprising, administering the fully explaining MPH addiction. CNS stimulant and administering a mu opioid receptor antagonist to thereby reduce or prevent the development of SUMMARY OF THE INVENTION addiction to the CNS stimulant in the subject. In one embodi ment of the methods described herein, the method further [0005] One aspect of the invention is a pharmaceutical comprises selecting a subject at risk for the development of composition comprising a central nervous system (CNS) addiction to the CNS stimulant, prior to the administering. stimulant and an opioid receptor antagonist. In one embodi ment of the pharmaceutical compositions described herein, [0010] Another aspect of the invention relates to a method the opioid receptor antagonist is selected from the group of treating a subject for ADHD, comprising administering a consisting of naltrexone, naloxone, diprenorphine, etorphine, therapeutically effective amount of methylphenidate and dihydroetorphine, and combinations thereof. In one embodi administering an opioid receptor antagonist to thereby treat ment of the various pharmaceutical compositions described the subject for ADHD. In one embodiment of the methods herein, the CNS stimulant is selected from the group consist described herein, the method further comprises selecting a ing of methylphenidate, amphetamine, moda?nil, and com subject at risk for the development of aversion or addiction to binations thereof. In one embodiment of the various pharma methylphenidate, prior to the administering. ceutical compositions described herein, the CNS stimulant is [0011] In one embodiment of the various methods present in a therapeutic amount and the opioid receptor described above, the CNS stimulant is selected from the antagonist is present in an amount for preferred inhibition of group consisting of methylphenidate, amphetamine, moda? the mu opioid receptor. In one embodiment of the various nil, and combinations thereof. In one embodiment of the pharmaceutical compositions described herein, the composi various methods described above, the CNS stimulant results tion is formulated for enteral administration. In one embodi in activation of a dopamine receptor. In one embodiment, the ment of the various pharmaceutical compositions described dopamine receptor is selected from the group consisting of herein, the pharmaceutical composition is formulated for oral D1, D2, D3, D4, D5, and combinations thereof. US 2013/0289061 A1 Oct. 31,2013 [0012] In one embodiment of the various methods dose (7.5 mg/kg) MPH and cocaine (10 mg/kg; positive con described above, the opioid receptor antagonist is selected trol) Was analyZed. In FIG. 1A, time spent in the drug-paired from the group consisting of naltrexone, naloxone, diprenor chamber during the pre-conditioning (PC) and test (Test) phine, etorphine, dihydroetorphine, and combinations sessions Was calculated and the difference betWeen the tWo thereof.
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