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(12) United States Patent (10) Patent No.: US 9,642,912 B2 Kisak Et Al

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USOO9642912B2 (12) United States Patent (10) Patent No.: US 9,642,912 B2 Kisak et al. (45) Date of Patent: *May 9, 2017 (54) TOPICAL FORMULATIONS FOR TREATING (58) Field of Classification Search SKIN CONDITIONS CPC ...................................................... A61K 31f S7 (71) Applicant: Crescita Therapeutics Inc., USPC .......................................................... 514/171 Mississauga (CA) See application file for complete search history. (72) Inventors: Edward T. Kisak, San Diego, CA (56) References Cited (US); John M. Newsam, La Jolla, CA (US); Dominic King-Smith, San Diego, U.S. PATENT DOCUMENTS CA (US); Pankaj Karande, Troy, NY (US); Samir Mitragotri, Santa Barbara, 5,602,183 A 2f1997 Martin et al. CA (US); Wade A. Hull, Kaysville, UT 5,648,380 A 7, 1997 Martin 5,874.479 A 2, 1999 Martin (US); Ngoc Truc-ChiVo, Longueuil 6,328,979 B1 12/2001 Yamashita et al. (CA) 7,001,592 B1 2/2006 Traynor et al. 7,795,309 B2 9/2010 Kisak et al. (73) Assignee: Crescita Therapeutics Inc., 8,343,962 B2 1/2013 Kisak et al. Mississauga (CA) 8,513,304 B2 8, 2013 Kisak et al. 8,535,692 B2 9/2013 Pongpeerapat et al. (*) Notice: Subject to any disclaimer, the term of this 9,308,181 B2* 4/2016 Kisak ..................... A61K 47/12 patent is extended or adjusted under 35 2002fOOO6435 A1 1/2002 Samuels et al. 2002fOO64524 A1 5, 2002 Cevc U.S.C. 154(b) by 204 days. 2005, OO 14823 A1 1/2005 Soderlund et al. This patent is Subject to a terminal dis 2005.00754O7 A1 4/2005 Tamarkin et al. claimer. 2005, 0196354 A1 9/2005 Soshinsky 2006/0229.364 A1 10/2006 Hobbs et al. (21) Appl. No.: 14/578,812 2008.0075793 A1 3/2008 Dunshee et al. 2011 0028460 A1 2/2011 Kisak et al. (22) Filed: Dec. 22, 2014 2013, OO79371 A1 3/2013 Sundberg et al. 2013,00794.04 A1 3/2013 Kisak et al. (65) Prior Publication Data 2013/O165504 A1 6/2013 Bancel et al. 2013/02599.24 A1 10/2013 Bancel et al. US 2015/0297723 A1 Oct. 22, 2015 FOREIGN PATENT DOCUMENTS Related U.S. Application Data GB 2008.946 6, 1979 (63) Continuation-in-part of application No. 13/791,460, WO WO 96/33706 10, 1996 filed on Mar. 8, 2013, now Pat. No. 9,308,181, which WO WO 2005/OO951O 2, 2005 is a continuation-in-part of application No. (Continued) 13/680,623, filed on Nov. 19, 2012, now Pat. No. 8,513.304, which is a continuation of application No. OTHER PUBLICATIONS 12/848,792, filed on Aug. 2, 2010, now Pat. No. 8.343.962, which is a continuation-in-part of PCT Application No. PCT/CA2014/051049: Filing date Oct. 31, application No. 12/281.561, filed as application No. 2014: Nuvo Research Inc.; International Search Report mailed Feb. PCT/IB2007/001983 on Mar. 6, 2007, now Pat. No. 10, 2015. 7,795,309. (Continued) (60) Provisional application No. 60/778,847, filed on Mar. 6, 2006. Primary Examiner — Raymond Henley, III (51) Int. Cl. (74) Attorney, Agent, or Firm — Thorpe North & A6 IK3I/56 (2006.01) Western, LLP A6 IK 47/8 (2017.01) A 6LX 3/573 (2006.01) A6 IK 47/4 (2017.01) (57) ABSTRACT A6 IK 47/12 (2006.01) A6 IK 9/00 (2006.01) The present disclosure is drawn to topical formulations and A6 IK 47/20 (2006.01) related methods. In one embodiment, a topical formulation A6 IK 9/06 (2006.01) is provided that includes at least one corticosteroid, a first A6DF 7/03 (2006.01) compound, and a second compound. The first compound and A6.1 F 7/O2 (2006.01) second compound are different and each is selected from the (52) U.S. Cl. group consisting of N-lauroyl sarcosine, sodium octyl Sul CPC .............. A61K 47/183 (2013.01); A61F 7/03 fate, methyl laurate, isopropyl myristate, oleic acid, glyceryl (2013.01); A61K 9/0014 (2013.01); A61K 9/06 oleate, and Sodium lauryl Sulfoacetate. (2013.01); A61 K3I/573 (2013.01); A61 K 47/12 (2013.01); A61K 47/14 (2013.01); A61 K 47/20 (2013.01); A61F 2007/0261 (2013.01) 46 Claims, 4 Drawing Sheets US 9,642.912 B2 Page 2 (56) References Cited FOREIGN PATENT DOCUMENTS WO WO 2005/O18530 3, 2005 WO WO 2013,106496 T 2013 OTHER PUBLICATIONS Teixeira, et al., “Local anesthetic-induced microscopic and mesoscopic effects in micelles. A fluorescence, spin label and SAXS”; 2001 Biochimica et Biophysica; ACTA 1510 (2001) pp. 93-105. * cited by examiner U.S. Patent May 9, 2017 Sheet 1 of 4 US 9,642,912 B2 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - OControl iF1 AF2 i)CF3 & seF4 F5 & iOF6 4.7O AF8 4.60 i. sEF10 to F11 U.S. Patent May 9, 2017 Sheet 2 of 4 US 9,642,912 B2 F1-F9 Viscosity 7.00 to Control HF1 CF3 e iF4 8 OF5 s OF6 AF8 tF10 IOF11 O.OO iososo. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - G Time Zero Month 1 Month 2 Month 3 U.S. Patent May 9, 2017 Sheet 3 of 4 US 9,642,912 B2 O Control F1 sF2 F3 a 64 i OF5 CF6 F7 iAF8 U.S. Patent May 9, 2017 Sheet 4 of 4 US 9,642,912 B2 F1-F9 Permeation Durapore Membrane 7000 sex 6OOO i s O Control 5 O O O . F1 F2 toe F3 sep F4 D F5 HF7 sF10 OF11 US 9,642,912 B2 1. 2 TOPCAL FORMULATIONS FOR TREATING molecules across the skin by, for example, disrupting the SKIN CONDITIONS lipid bilayers of the stratum corneum. Over 300 Substances have been identified as MPETMs but This application is a continuation-in-part of U.S. patent surprisingly few have been successfully developed into application Ser. No. 13/791,460 filed on Mar. 8, 2013 and commercial formulations. Many potent MPETMs are irritat issued as U.S. Patent No. 9.308,181, which is a continua ing to the cells of the epidermis which can limit both the tion-in-part of U.S. patent application Ser. No. 13/680,623. choice and concentration of MPETMs suitable for topical filed Nov. 19, 2012 and issued as U.S. Pat. No. 8,513,304, formulations. Discovery of new MPETMs to increase skin which was a continuation of U.S. patent application Ser. No. permeability is a highly desirable area and has had high 12/848,792, filed Aug. 2, 2010 and issued as U.S. Pat. No. 10 activity over the last 30 years. However, the number of 8.343.962, which was a continuation-in-part of U.S. patent substances identified to be penetration enhancers is still application Ser. No. 12/281.561, filed on Jan. 12, 2009 and relatively small when considering the more than 25,000,000 issued as U.S. Pat. No. 7,795,309, which was a national substances identified in the CAS registry (Chemical stage of PCT/IB2007/001983 filed on Mar. 6, 2007, which 15 Abstracts Service, Columbus, Ohio, www.cas.org). The claimed priority to U.S. Provisional Application Ser. No. number of candidate drugs suitable for topical and transder 60/788,847, each of which is incorporated herein by refer mal administration could be significantly increased with CCC. improved penetration enhancers. BACKGROUND SUMMARY Topical formulations for application to the skin can be With this background in mind, the present disclosure is useful in cosmetic applications, for treating conditions of the drawn to topical formulationstransdermal systems, and upper skin layers, and for transdermal administration of methods for treating skin conditions. In one embodiment, a active agents to the local tissue underlying the skin or into 25 topical formulation is provided that comprises (i) at least one the blood for systemic distribution. For example, using a corticosteroid, (ii) a first compound, and (iii) a second topical formulation of a pharmaceutical agent is advanta compound. The first compound and second compound are geous because it can avoid first-pass metabolism, circum different and each is selected from the group consisting of vent gastrointestinal (“GI) absorption, allow delivery of an N-lauroyl sarcosine, Sodium octyl sulfate, methyl laurate, active ingredient with a relatively short biological half-life 30 isopropyl myristate, oleic acid, glyceryl oleate, and sodium and/or a narrow therapeutic window, and facilitate uniform lauryl Sulfoacetate. plasma dosing of the active ingredient, and/or can improve In another embodiment, a method of treating a skin user compliance. condition Such as psoriasis or dermatitis can comprise In spite of the advantages, transdermal administration is topical or transdermal administration of a corticosteroid to a usually limited to about a dozen Small lipophilic drugs, 35 Subject. The formulation can comprise at least one corticos available in transdermal patch format (including scopol teroid, a first compound, and a second compound. The first amine, fentanyl, estradiol, nitroglycerine, nicotine, and tes compound and second compound are different and each is tosterone). Skin has evolved to impede the flux of exogenous selected from the group consisting of N-lauroyl sarcosine, molecules so as to provide a strong barrier to molecular Sodium octyl sulfate, methyl laurate, isopropyl myristate, delivery, particularly agents such as pharmaceutical agents. 40 oleic acid, glyceryl oleate, and sodium lauryl Sulfoacetate. In Transdermal drug administration is difficult because skin is one embodiment, the first and second compound can an excellent diffusion barrier. improve the flux and/or stability of the topical formulation Structurally, the skin consists of two principal parts: (i) a when compared to a comparative formulation devoid of the relatively thin outermost layer (the “epidermis'), and (ii) a first compound and the second compound and replaced with thicker inner region (the “dermis).
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  • Review Article

    Review Article

    Free Radical Biology & Medicine, Vol. 33, No. 6, pp. 774–797, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0891-5849/02/$–see front matter PII S0891-5849(02)00956-5 Review Article STRUCTURE AND FUNCTION OF XANTHINE OXIDOREDUCTASE: WHERE ARE WE NOW? ROGER HARRISON Department of Biology and Biochemistry, University of Bath, Bath, UK (Received 11 February 2002; Accepted 16 May 2002) Abstract—Xanthine oxidoreductase (XOR) is a complex molybdoflavoenzyme, present in milk and many other tissues, which has been studied for over 100 years. While it is generally recognized as a key enzyme in purine catabolism, its structural complexity and specialized tissue distribution suggest other functions that have never been fully identified. The publication, just over 20 years ago, of a hypothesis implicating XOR in ischemia-reperfusion injury focused research attention on the enzyme and its ability to generate reactive oxygen species (ROS). Since that time a great deal more information has been obtained concerning the tissue distribution, structure, and enzymology of XOR, particularly the human enzyme. XOR is subject to both pre- and post-translational control by a range of mechanisms in response to hormones, cytokines, and oxygen tension. Of special interest has been the finding that XOR can catalyze the reduction of nitrates and nitrites to nitric oxide (NO), acting as a source of both NO and peroxynitrite. The concept of a widely distributed and highly regulated enzyme capable of generating both ROS and NO is intriguing in both physiological and pathological contexts. The details of these recent findings, their pathophysiological implications, and the requirements for future research are addressed in this review.
  • Download (PDF 277.63

    Download (PDF 277.63

    PROJECT REVIEW “Characterization of the main metabolites of 17-methylstenblone and 17 methylmethenolone produced by human hepatocytes and liver fractions” Prof C. Ayotte, (INRS-Institut Armand-Frappier, Canada) New steroids openly appear on the market in products labelled with a rather confusing nomenclature. Once characterized, pharmaceutical grade products not being available, knowledge of the biotransformation pathways essential to an efficient detection of utilization by athletes is difficult to gain since administration to human volunteers should be restricted to the minimum. The alternative is a reliable in vitro model. Human hepatocytes, fresh or cryopreserved are now available commercially. We have successfully produced and identified phase I metabolites from incubations of human hepatocytes with different steroids, such as 17-methyldrostanolone and desoxymethyltestosterone (DMT). The aim of this project is to produce in vitro from human hepatocytes and liver fractions the metabolites of two steroids, the 17-methylated derivatives of stenbolone and its isomer methenolone. The principal metabolites will be synthesized and characterized by NMR and mass spectrometry. The characterization of metabolites will enable the identification of markers of utilization to be incorporated in routine testing methods. The approach for the chemical synthesis of metabolites will be shared with NMI insuring the distribution to other doping control laboratories. Improving the knowledge of steroid biotransformation is a further benefit from these studies. Characterization of 17-Methylstenbolone and 17-Methylmethenolone and Identification of Metabolites Produced by Human Hepatocytes and Liver Fractions WADA Project no. 11A16CA Christiane Ayotte, Philippe Räss, Alexandre Sylvestre, INRS-Institut Armand-Frappier Summary We have synthesized and characterized two designer steroids, 17α-methylmethenolone and 17α- methylstenbolone; the latter is proposed on the internet and two groups have reported different and contradictory results.