USOO8445002B2 (12) United States Patent (10) Patent No.: US 8.445,002 B2 Mansouri (45) Date of Patent: May 21, 2013 (54) DERMAL DELIVERY COMPOSITIONS (56) References Cited COMPRISING ACTIVE AGENT-CALCUM PHOSPHATE PARTICLE COMPLEXES AND U.S. PATENT DOCUMENTS METHODS OF USING THE SAME 4,948,575 A * 8/1990 Cole et al. ....................... 424/44 5,158,756 A * 10/1992 Ogawa et al. ...... ... 423.309 (75) Inventor: Zahra Mansouri, Tahoe City, CA (US) 5,604.200 A * 2/1997 Taylor-McCord ............. 514/9.3 6,096,324 A 8, 2000 Mansouri 6,120,782 A 9, 2000 Mansouri (73) Assignee: Laboratory Skin Care, Inc., Tahoe 6,262,020 B1* T/2001 Lezdey et al. .................. 514/5.9 City, CA (US) 6,395,311 B2* 5/2002 Jia .................. ... 424/744 6,573.249 B2 * 6/2003 Lezdey et al. ................... 514/54 (*) Notice: Subject to any disclaimer, the term of this 2002fOO18797 A1 2/2002 Cui et al. patent is extended or adjusted under 35 2005/00 13874 A1 1/2005 Ito et al. ........................ 424,602 2005/02341 14 A1 10, 2005 Lee U.S.C. 154(b) by 0 days. 2006/0257658 A1* 11/2006 Tanaka et al. ................. 428/402 2007, OOO3487 A1* 1/2007 Ek ............... ... 424/46 (21) Appl. No.: 12/742,235 2008/005.1335 A1 2/2008 Kleiner et al. .................. 514/12 2008, 0220233 A1 9/2008 Kjellin et al. (22) PCT Filed: May 6, 2010 2010/0086606 A1* 4/2010 Ogawa .......................... 424/489 2012/0130435 A1* 5, 2012 Hart et al. ...... ... 606,301 (86). PCT No.: PCT/US2O10/033942 2012/0134919 A1* 5/2012 Engqvist et al. ... 424,129 2012/0207803 A1* 8, 2012 Bell .............................. 424/401 S371 (c)(1), (2), (4) Date: Apr. 12, 2011 OTHER PUBLICATIONS Meisel M., "About Face, Anti-aging, natural products lead the thriv (87) PCT Pub. No.: WO2010/1298.19 ing skin care category Happi Household and Personal Products Industry. (May 7, 2008) web article: http://www.happi.com/articles/ PCT Pub. Date: Nov. 11, 2010 2008/05/about-face; 15 pp. (65) Prior Publication Data * cited by examiner US 2011 FO189239 A1 Aug. 4, 2011 Primary Examiner — Robert A Wax Assistant Examiner — Olga V Tcherkasskaya Related U.S. Application Data (74) Attorney, Agent, or Firm — Bozicevic, Field & Francis LLP: Bret E. Field (60) Provisional application No. 61/176,057, filed on May 6, 2009. (57) ABSTRACT Dermal delivery compositions are provided. Aspects of the (51) Int. Cl. dermal delivery compositions include the presence of active A6 IK9/00 (2006.01) agent-calcium phosphate particle complexes, where these A6 IK 9/14 (2006.01) complexes include uniform, rigid, spherical nanoporous cal (52) U.S. Cl. cium phosphate particles associated with one or more active USPC ........................................... 424/400; 424/489 agents. Also provided are methods of using the compositions (58) Field of Classification Search in active agent delivery applications. None See application file for complete search history. 18 Claims, 11 Drawing Sheets U.S. Patent May 21, 2013 Sheet 1 of 11 US 8.445,002 B2 FG 1A FG B U.S. Patent May 21, 2013 Sheet 2 of 11 US 8.445,002 B2 FIG. 2A FIG. 2B U.S. Patent May 21, 2013 Sheet 3 of 11 US 8.445,002 B2 FIG 3 :::::::::: U.S. Patent May 21, 2013 Sheet 4 of 11 US 8.445,002 B2 FG, 4A FIG 4B U.S. Patent May 21, 2013 Sheet 5 of 11 US 8.445,002 B2 FG 5A FG U.S. Patent May 21, 2013 Sheet 6 of 11 US 8.445,002 B2 FG 6 S. U.S. Patent May 21, 2013 Sheet 7 of 11 US 8.445,002 B2 FIG 7B FIG. 7A U.S. Patent May 21, 2013 Sheet 8 of 11 US 8.445,002 B2 F.G. 8 U.S. Patent May 21, 2013 Sheet 9 of 11 US 8.445,002 B2 FG. 9 6. ..). O . 5 U.S. Patent May 21, 2013 Sheet 10 of 11 US 8.445,002 B2 F.G. 10 Skin Delivered Lysozyme (ug) Skin Delivered Lysozyme (%) Tape With Without With Without layer Hydroxysomes" | Hydroxysomes" | Hydroxysomes' | Hydroxysomes' 1. 7.210 Lig 48.35 ug O60.0/ 4. O39/o 2 0.979 ug 0.56 ug O.O896 O.O470/6. 3 0.284 ig 0.03 ug O.O2/o O. O.02% 4 0.100 Ig 0.00 ug O. O.19 OOO 5 0.029 ug 0.00 ug OOO29. O.OO 6 0.024 ug 0.00 ug OOO29 O. OO U.S. Patent May 21, 2013 Sheet 11 of 11 US 8.445,002 B2 F.G. 1 US 8,445,002 B2 1. 2 DERMAL DELVERY COMPOSITIONS forearm. FIG. 5A shows calcium phosphate particle penetra COMPRISING ACTIVE AGENT-CALCUM tion to the first layer of the stratum corneum. FIG. 5B shows PHOSPHATE PARTICLE COMPLEXES AND calcium phosphate particle penetration to the third layer of METHODS OF USING THE SAME the stratum corneum. FIG. 6 is an image of mouse skin prior to application of CROSS-REFERENCE TO RELATED calcium phosphate particles. No Ca" is evident in the upper APPLICATIONS Statum COrneum. FIG. 7A shows calcium particles in the upper stratum cor Pursuant to 35 U.S.C. S 119 (e), this application claims neum as well as Smaller particles in the lower stratum cor priority to the filing date of U.S. Provisional Patent Applica 10 neum. FIG. 7B shows the loss of integrity of the spherical tion Ser. No. 61/176,057 filed May 6, 2009; the disclosure of calcium particles which application is herein incorporated by reference. FIG. 8 is a picture showing penetration of CTC fluorescent throughout the Stratum corneum following topical applica INTRODUCTION tion. 15 FIG. 9 shows the results of STAY-C50 with and without A variety of different active agents have been and continue calcium phosphate particle tape Stripping. to be developed for use in the treatment of a variety of differ FIG. 10 is a table showing amount and percentage of ent conditions, including both disease and non-disease con lysozyme with and without calcium phosphate particles as ditions. For Such applications, an effective amount of the measured by tape stripping. active agent must be delivered to the subject in need thereof. FIG. 11 shows Franz cell transdermal delivery of a ribo A variety of different delivery formulations and routes have flavin monophosphate active agent with and without calcium been developed, where such routes may vary depending on phosphate particles. the nature of the active agent. Typically, less invasive delivery routes are better tolerated and therefore are more desirable. DETAILED DESCRIPTION One type of delivery route that is of great interest because 25 of its minimally invasive nature is dermal delivery. In dermal Dermal delivery compositions are provided. Aspects of the delivery, an active agent composition is applied to a skin site dermal delivery compositions include the presence of active to deliver the active agent to the subject. Many dermal deliv agent-calcium phosphate particle complexes, where these ery technologies currently in use or under evaluation are not complexes include uniform, rigid, spherical nanoporous cal entirely satisfactory. For example, certain dermal delivery 30 cium phosphate particles associated with one or more active technologies may disrupt the integrity of the stratum corneum agents. Also provided are methods of using the compositions (Sc) and/or rely on the presence of permeation enhancers, in active agent delivery applications. which can cause unwanted damage and/or irritation. In addi Before the present invention is further described, it is to be tion, certain dermal delivery technologies may be polymer understood that this invention is not limited to particular and/or liposome based technologies, neither of which tech 35 embodiments described, as Such may vary. It is also to be nologies truly delivers through the Sc. Furthermore these understood that the terminology used herein is for the purpose technologies cannot be applied to large molecular weight of describing particular embodiments only, and is not bio-actives, etc. intended to be limiting, since the scope of the present inven As such, there continues to be a need for the development tion will be limited only by the appended claims. of new dermal delivery technologies which overcome one or 40 Where a range of values is provided, it is understood that more of the disadvantages experienced with current dermal each intervening value, to the tenth of the unit of the lower delivery approaches. limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or SUMMARY intervening value in that stated range, is encompassed within 45 the invention. The upper and lower limits of these smaller Dermal delivery compositions are provided. Aspects of the ranges may independently be included in the Smaller ranges dermal delivery compositions include the presence of active and are also encompassed within the invention, Subject to any agent-calcium phosphate particle complexes, where these specifically excluded limit in the stated range. Where the complexes include uniform, rigid, spherical nanoporous cal stated range includes one or both of the limits, ranges exclud cium phosphate particles associated with one or more active 50 ing either or both of those included limits are also included in agents. Also provided are methods of using the compositions the invention. in active agent delivery applications. Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about is used BRIEF DESCRIPTION OF THE FIGURES herein to provide literal support for the exact number that it 55 precedes, as well as a number that is near to or approximately FIGS.