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Zzzzzzzzzzzzz Vv Myyyyyyyyy US 20110245783A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0245783 A1 Stinchcomb et al. (43) Pub. Date: Oct. 6, 2011 (54) ABUSE DETERRENT TRANSDERMAL (22) Filed: Apr. 4, 2011 FORMULATIONS OF OPIATEAGONSTS Related U.S. Application Data AND AGONSTANTAGONSTS (60) Provisional application No. 61/320,526, filed on Apr. 2, 2010. (75) Inventors: Audra Lynn Stinchcomb, Publication Classification Lexington, KY (US); Guohua Li, (51) Int. Cl. Lexington, KY (US); Stan Lee A6M 35/00 (2006.01) Banks, Frankfort, KY (US); Jeffery B32B 37/02 (2006.01) Lynn Howard, Richmond, KY B32B 37/2 (2006.01) (US); Miroslaw Jerzy Golinski, Lexington, KY (US) (52) U.S. Cl. ............................ 604/290; 604/307; 156/60 (57) ABSTRACT Described herein are abuse-resistant multi-layer transdermal (73) Assignee: AllTranz Inc., Lexington, KY (US) patches comprising opioids and opioid prodrugs having a barrier layer located between the layer containing opioid or opioid prodrug and a layer containing an opioid antagonist or (21) Appl. No.: 13/079,758 opioid antagonist prodrug. ZZZZZZZZZZZZZ 10 F 25 3O 40 VV MYYYYYYYYY - SO Patent Application Publication Oct. 6, 2011 Sheet 1 of 4 US 2011/0245783 A1 WYYYYYYY.MMYY <4N2. 2, 222-30 NNNNNN: FIG. 3 ZZZZZZZZZZZ\ YYYYYYYYYYYYY Patent Application Publication Oct. 6, 2011 Sheet 2 of 4 US 2011/0245783 A1 -mm -------------- O. 7 | O. 6 0. 4. -- Naltrexone O. 3. -- Total buprenorphine O 2 O. O 5 O 15 20 25 30 35 Time (min.) Figure 5. Release of NTX and total buprenorphine from buprenorphine prodrugnaltrexone patch (13% NTX-EC/HPC film, 5% BUPPD) in ethanol. 0.3. s --Naitrexone --Total buprenorphine O O S - Time (min.) Figure 6. Release of NTX and total buprenorphine from buprenorphine prodrug:naltrexone patch (13% NTX-EC/HPC film, 5% BUPPD) in water. Patent Application Publication Oct. 6, 2011 Sheet 3 of 4 US 2011/0245783 A1 -- Naloxote trial 1 was Naloxone tria2 rise-Total buprenorphinet trial 1 --Total buprenorphine trial 2 1. 2 O. 8 O 5 O. al O. 2 O ------------------------------~~~~~----------------------------- O 2O 40 6 8O 10) 2O O Time (min.) Figure 7. Release of NLX and total buprenorphine from buprenorphine prodrug:naloxone patch (10% NLX-EC/HPC film, 7% BUPPD) in ethanol. --- re-Naloxore triai 1. el-Naxohe trial 2 O.O.P. Poirot Total buprenorphine trial 1 -- Total buprenorphine trial 2 v. a 0.06 E S 0.05 - f 0.04 ; g 0.03 - 3: s OO2 aw 0.01 OOO : ' S- -g ------ ------------------------- O 2O 40 60 8O 100 AO Time (min.) Figure 8. Release of NLX and total buprenorphine from buprenorphine prodrug:naloxone patch (10% NLX-EC/HPC film, 7% BUPPD) in water. Patent Application Publication Oct. 6, 2011 Sheet 4 of 4 US 2011/0245783 A1 accine NTX (EVA film) trial ram NTX (EVA film) trial 2 O.2 - “ gro. NTX (HPC film) trial 1 ne-NTX (HPC film) trial 2 S. O ----------------------------------------------------...-aa------ O 2O 40 60 30 1OO 12) 1.O Time (min.) Figure 9. Release kinetics in ethanol from a 5% NTX ethylcellulose film using an ethylene vinyl acetate (EVA) membrane (3MTM CotranTM 9728) or a prepared hydroxypropylcellulose membrane to separate the bi-layer system. US 2011/0245783 A1 Oct. 6, 2011 ABUSE DETERRENT TRANSIDERMAL 0006 Further, patients undergoing withdrawal from nar FORMULATIONS OF OPIATE AGONSTS cotic or alcohol abuse and those Suffering from chronic, AND AGONSTANTAGONSTS under-treated or intractable pain often also suffer from a lack of appetite, nausea and/or frequent emesis. As such, oral and CROSS REFERENCES TO RELATED Sublingual therapies for these patients are often either poorly APPLICATIONS tolerated or fail to provide an effective therapeutic dose. 0001. This application claims the benefit of U.S. Provi 0007 For these patients, transdermal administration can sional Application Ser. No. 61/320,526, filed Apr. 2, 2010, provide a favorable route of administration. Transdermal dos which is incorporated herein by reference in its entirety. ing provides the patient with a desirable systemic delivery profile which can minimize or eliminate any “highs' (dizzi FIELD ness and drowsiness) associated with more rapid absorption and can reduce the side effects associated with oral adminis 0002. Described herein are opioid agonists, opioid ago tration of a drug, Such as abdominal pain, nausea and vomit nist-antagonist or prodrugs of the foregoing in an abuse ing. Additionally, transdermal administration avoids first resistant formulation and dosage form for transdermal deliv pass metabolism which can allow for higher therapeutic ery of the opioid agonist, opioid agonist-antagonist or concentrations to be achieved, and also offers a patient free prodrugs of the foregoing. dom from injections and Surgical implantations. Transdermal delivery can also improve patient compliance by reducing the BACKGROUND dose frequency. A transdermal patch can offer Sustained release of a drug for an extended period (e.g., one week). 0003 Pain is the most frequently reported symptom and is 0008 Because of the inherent potential for abuse, it is a common clinical problem confronting the clinician. Mil important that any pharmaceutical composition containing an lions of people in the United States suffer from severe pain opioid agonist or opioid agonist-antagonist or prodrugs of that, according to numerous recent reports, is chronically either be made as abuse-resistant or abuse-deterrent as pos under-treated or inappropriately managed. sible. This is particularly true with extended release opioid 0004 Opioids have long been recognized as one of the products, including transdermal applications. Illicit users most effective treatments of pain. However, they also have a often will attempt to circumvent the extended release prop high potential of abuse. In fact, opioid and narcotic abuse are erties of these dosage forms by injecting, chewing or other major worldwide problems connected with tremendous wise misusing or abusing the product in order to achieve an social and personal strife. As of 1992, the estimated United immediate release of the opioid agonist, opioid agonist-an States economic cost of drug and alcohol abuse was $246 tagonist or prodrugs of the foregoing. billion. A recent National Household Survey on Drug Abuse 0009. The Food and Drug Administration (“FDA) has survey conducted by the Substance Abuse and Mental Health recently emphasized the importance of reducing the risk of Services Administration reported in July 2007 that nearly one opioid abuse. In a Feb. 9, 2009 press release, the FDA publicly in twelve full-time workers in the United States have serious announced a program in which it would meet with the manu enough drug/alcohol problems to require medical treatment. facturers of extended release and transdermal opioids regard Providing recovery assistance for drug addicts and alcoholics ing opioid misuse and abuse. Under the terms of the with pharmacological interventions has proven helpful. announced program, the manufactures will be required to 0005 Certain opioids, such as buprenorphine (BUP), develop Risk Evaluation and Mitigations Strategies to ensure butorphanol, dezocine, meptazinol, nalbuphine and pentazo proper opioid use. cine, have both agonistandantagonist qualities. For example, the main agonist-antagonist effect of buprenorphine is 0010 Thus, it would be desirable to transdermally admin through its binding to u-opioid and K-opioid receptors, acting ister an opioid agonist or agonist-antagonist, Such as clinically as an agonist at lower doses and as an antagonist at buprenorphine, where the formulation or dosage form used to higher doses. The dual agonist-antagonist activity of these deliver the opioid agonist or agonist-antagonist is resistant to opioids make them effective at not only treating pain, but also possible abuse or other illicit diversion. at reducing the severity of the withdrawal symptoms experi enced when a former abuser begins to eliminate opioid and/or SUMMARY alcohol. Buprenorphine is currently available as a Sublingual dosage form, both alone (Subutex (R) and in combination with 0011. Some embodiments described herein, include an naloxone (Suboxone(R) for the treatment of pain and opioid opioid agonist, agonist-antagonist or prodrugs of the forego dependence. The Sublingual administration of these formula ing, in an abuse resistant composition, formulation and dos tions results in clinically relevant drawbacks. For example, age form (e.g., a patch) for transdermal delivery of the opioid. the necessity of taking multiple daily doses, or even once 0012. Other embodiments, objects, features and advan daily dosing, decreases patient compliance. In addition, the tages will be set forth in the detailed description of the daily and multiple daily dosing necessary with Sublingual embodiments that follows, and in part will be apparent from dosage forms may cause more frequent and more extreme the description, or may be learned by practice, of the claimed peaks and troughs in the blood-plasma concentration of the invention. These objects and advantages will be realized and active medications. These peaks and troughs increase the attained by the processes and compositions particularly potential for a patient to experience both the adverse effects pointed out in the written description and claims hereof. The associated with Supra-therapeutic concentrations and ineffec foregoing Summary has been made with the understanding tive relief associated with below therapeutic concentrations. that it is to be considered as a brief and general synopsis of Additionally, many Sublingual tablets have a bitter taste, some of the embodiments disclosed herein, is provided solely which reduces patient compliance. for the benefit and convenience of the reader, and is not US 2011/0245783 A1 Oct. 6, 2011 intended to limit in any manner the scope, or range of equiva citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspar lents, to which the appended claims are lawfully entitled. tic, glutamic, benzoic, anthranilic, mesylic, Stearic, tosylic, pamoic, napsylic, hydrobromic, Valeric, oleic, lauric, Sali BRIEF DESCRIPTION OF THE DRAWINGS cylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, 0013 FIG.
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