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Enhancing Transdermal Delivery of Opioid Antagonists and Agonists Using Codrugs Linked to Bupropion Or Hydroxybupropion Audra L

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Enhancing Transdermal Delivery of Opioid Antagonists and Agonists Using Codrugs Linked to Bupropion Or Hydroxybupropion Audra L University of Kentucky UKnowledge Pharmaceutical Sciences Faculty Patents Pharmaceutical Sciences 2-18-2014 Enhancing Transdermal Delivery of Opioid Antagonists and Agonists Using Codrugs Linked To Bupropion or Hydroxybupropion Audra L. Stinchcomb University of Kentucky Peter A. Crooks University of Kentucky, [email protected] Mohamad O. Hamad University of Kentucky, [email protected] Paul K. Kiptoo University of Kentucky Click here to let us know how access to this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/ps_patents Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Stinchcomb, Audra L.; Crooks, Peter A.; Hamad, Mohamad O.; and Kiptoo, Paul K., "Enhancing Transdermal Delivery of Opioid Antagonists and Agonists Using Codrugs Linked To Bupropion or Hydroxybupropion" (2014). Pharmaceutical Sciences Faculty Patents. 27. https://uknowledge.uky.edu/ps_patents/27 This Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion in Pharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. US008653271B2 (12) United States Patent (10) Patent N0.: US 8,653,271 B2 Stinchcomb et a]. (45) Date of Patent: Feb. 18, 2014 (54) ENHANCING TRANSDERMAL DELIVERY (58) Field of Classi?cation Search OF OPIOID ANTAGONISTS AND AGONISTS USPC ............................... .. 546/45, 44, 46; 514/282 USING CODRUGS LINKED TO BUPROPION See application ?le for complete search history. OR HYDROXYBUPROPION (56) References Cited (75) Inventors: Audra L. Stinchcomb, Lexington, KY (US); Peter A. Crooks, Nicholasville, U.S. PATENT DOCUMENTS KY (US); Mohamed O. Hamad, Lexington, KY (US); Paul K. Kiptoo, 4,638,043 A * l/l987 Szycheret a1. ............... .. 528/75 Lexington, KY (US) OTHER PUBLICATIONS (73) Assignee: University of Kentucky Research Lau et. al. “Scope and Limitations of the Co-Drug Approach to Foundation, Lexington, KY (US) Topical Drug Delivery” Current Pharmaceutical Design, 2008, 14, 794-802.* Notice: Subject to any disclaimer, the term of this Hamad, P. Kiptoo, A. Stinchcomb, P. Crooks “Synthetic Strategies patent is extended or adjusted under 35 for the Preparation of “Gemini” Codrugs of Naltrexone, and U.S.C. 154(b) by 1255 days. Heterocodrugs of [5-Naltrexol With Hydroxybupropion for Transdermal Delivery” “http://WWWaapsj.org/abstracts/AMi2005/ (21) Appl. N0.: 11/907,954 AAPS2005-00l89l.pdi” online, accessed Feb. 9, 201 l.* “http://Web.archive.org/Web/2005 l0l307l834/aaps.org” online, Filed: Oct. 18, 2007 Oct. 13,2005, accessed Feb. 9, 201 l.* (22) “http://WWWaapsj .org/abstracts/AMfZOO5/” online, Thursday, May 5,2005 9:04 PM, accessed Feb. 9, 2011.* (65) Prior Publication Data US 2009/0017102 A1 Jan. 15, 2009 * cited by examiner Related US. Application Data Primary Examiner * David K O Dell (60) Provisional application No. 60/853,761, ?led on Oct. (74) Attorney, Agent, or Firm * CroWell & Moring LLP 24, 2006, provisional application No. 60/852,394, ?led on Oct. 18, 2006. (57) ABSTRACT The present invention is directed to novel codrugs comprising (51) Int. Cl. bupropion or hydroxybupropion and an opioid antagonist or C07D 489/00 (2006.01) an opioid agonist joined together by chemical bonding. The C07D 489/02 (2006.01) codrugs provide a signi?cant increase in the transderrnal ?ux C07D 489/12 (2006.01) across human skin, as compared to the basic opioid antagonist A61K 31/485 (2006.01) or opioid agonist. (52) US. Cl. USPC ................ .. 546/44; 546/45; 546/46; 514/282 13 Claims, 14 Drawing Sheets US. Patent Feb. 18, 2014 Sheet 1 0f 14 US 8,653,271 B2 FIGURE 1 1; Namexone (NTX) 2; G-B-Naltrexol (NTXOL) O HO O\>< HN>< {1 Cl CI 3; Bupropion (BUP) 4; Hydroxybupropion (BUPOH) US. Patent Feb. 18, 2014 Sheet 2 0f 14 US 8,653,271 B2 FIGURE 2 17 US. Patent Feb. 18, 2014 Sheet 3 0f 14 US 8,653,271 B2 Figure 3. Nor-5Q 7 3Reagents and conditions: (a) CHzClg or THF, Base = TEA or Pyridine, t = 0 °C, Argon. (b) CHgClg, TEA, t = 0 °C, Argon, Naltrexone. (c) CHgClg, TEA, t = 0 °C, Argon, Naltrexol. (d) -HC1 US. Patent Feb. 18, 2014 Sheet 4 0f 14 US 8,653,271 B2 Figure 4. N’w a N’% HO OH — HO OH O O O OH 1 2 b b o NwOH O W O Q40 O c|—4 %o|+ O O OH 10 12 b N {m N oX7 H Hoh. 90 o/lkoO o _ 0 o 0 6H OH 11; Naltrexone Duplex 13; Naltrexol Duplex a‘Reagents and conditions: (a) NaOH, formamidinesul?nic acid, 80-85°C, 1.5 h. (b) COC12, CHZCIZ, TEA, t = 0 °C, Argon. US. Patent Feb. 18, 2014 Sheet 5 0f 14 US 8,653,271 B2 Figure 5 (a) COC12, CHZCIZ, TEA, t I 0 oc, Argon. (b) NTX, CH2C12,TEA, t z 0 oc, Argon. (c) NTXOL, CHZCIZ, TEA, t = 0 cc, Argon. US. Patent Feb. 18, 2014 Sheet 6 of 14 US 8,653,271 B2 Figure 6 o>‘~~ Jko HO o , o 0 k1 R1 0 N\Q O K o rap|d,k2 Oi OH >~N )k 0 / O OH ~CO2 CI cl 23 27 ‘CO2 lkfs 94,, ‘<4 m <—-————-— OH I Cl rapld Cl 4 23 3 A schematic diagram showing stepwise hydrolytic cleavage of the carbonate codrug 25, into NTX and BUOH in isotonic phosphate buffer, pH 7.4 at 32°C. US. Patent Feb. 18, 2014 Sheet 7 0f 14 US 8,653,271 B2 FIGURE 7 2.5 q 0 codrug 25 I NTX, 1 A BUPOH, 4 2 0 Intermediate, 23 ofdrugDisappearanceorappearance (nmol) 100 Time, h US. Patent Feb. 18, 2014 Sheet 8 0f 14 US 8,653,271 B2 FIGURE 8 US. Patent Feb. 18, 2014 Sheet 9 0f 14 US 8,653,271 B2 FIGURE 9 Q N C] 6-B-NALTREXOL C02 lkl 0>—N & Cl 5 INTERMEDIATE US. Patent Feb. 18, 2014 Sheet 10 0f 14 US 8,653,271 B2 FIGURE 10 20 Naltrexol Hydroxybupropion CB-NTXOL-BUPOH Intermediate A OI (nmol)Amount 10 0 20 40 60 80 1 O0 US. Patent Feb. 18, 2014 Sheet 11 0114 US 8,653,271 B2 FIGURE 1 1 --O—- CB-NTXOL-BUPOH intact 30 —I— NTXOL from codrug + NTXOL (control) cumulativeofdrugamount permeated(nmol) + BUPOH from codrug 0 10 20 30 40 50 Time (h) US. Patent Feb. 18, 2014 Sheet 12 0f 14 US 8,653,271 B2 FIGURE 12 NTXOL (control) BUPOH from “CB-NTXOL E BUPOH o NTXOL from CB-NTXOL BUPOH CB-NTXOL BUPOH 0 0.5 1 1.5 2 2.5 pmol NTXOL equivalent/g of skin US. Patent Feb. 18, 2014 Sheet 14 0114 US 8,653,271 B2 FIGURE 14 1o'oo + G-beta-naltrexol from CB NTXOL-BUPOH —I— Hydroxybupropion from CB-NTXOL-BUPOH Plasma(nglml)conc. + 6-beta-naltrexol (control) 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 Time (h) US 8,653,271 B2 1 2 ENHANCING TRANSDERMAL DELIVERY chemical and pharmacokinetic properties of the codrug are OF OPIOID ANTAGONISTS AND AGONISTS superior to those of the individual parent drugs. Thus, careful USING CODRUGS LINKED TO BUPROPION design of the codrug entity can afford a unique product that OR HYDROXYBUPROPION may have superior physicochemical properties for drug deliv ery, compared to those of the individual drug entities them CROSS REFERENCE TO RELATED selves, leading to improved pharmaceutical properties. In APPLICATIONS addition, there are also other factors, such as the ability to control drug delivery by appropriate design of the biolabile This application claims priority under 35 USC §119 to linker(s) connecting the tWo drug entities, and the effect that US. Provisional Application No. 60/853,761 ?led Oct. 24, simultaneous delivery of the tWo drugs, as one chemical 2006 and US. Provisional Application No. 60/852,394 ?led entity, Will have on the pharrnacokinetics of each respective Oct. 18, 2006, the disclosures of Which are incorporated drug. Because the skin and plasma have an abundance of herein by reference. esterase enZymes, codrugs With esterase-susceptible linkages can be cleaved by these enZymes to release the active parent GOVERNMENT INTERESTS drugs in tissue and plasma. A codrug or a mutual prodrug consists of tWo drugs chemi A portion of this invention Was made With US. Govem cally linked together in order to improve the drug delivery ment support under a grant from the National Institutes of properties of one or both drugs. This unique concept of a Health under NIH Grant R0lAA0l3853. The Government codrug has been utiliZed to improve ocular delivery of an may have certain rights in this invention. 20 antiglaucoma agent, ethacrynic acid (CynkoWska et al., Bioorganic & Medicinal Chemistry Letters 15 (2005) 3524 FIELD OF THE INVENTION 3527). Other examples of codrugs include facilitated gas trointestinal absorption of loW molecular Weight heparin This invention relates to novel codrugs, and more particu (LMWH) via conjugation to deoxycholic acid (DOCA) to larly to novel codrugs comprising bupropion or hydroxybu 25 form LMWH-DOCA (Lee et al., J. Control. Release 111 propion and an opioid antagonist or an opioid agonist joined (2006) 290-298) and dual-acting thromboxane antagonist together by chemical bonding. The codrugs possess increased synthase inhibitors (BroWn et al., Bioorganic & Medicinal bioavailability as compared to the parent drugs. Chemistry Letters 6 (1996) 273-278). Opioid agonists are useful for treatment of a number of BACKGROUND OF THE INVENTION 30 conditions, including chronic pain, acute pain and depres sion. Opioid antagonists are useful for treatment of alcohol Transdermal delivery is desirable to reduce the side effects dependence, opioid addiction, and smoking.
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