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(12) United States Patent (10) Patent No.: US 8,354,116 B2 Carter Et Al

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(12) United States Patent (10) Patent No.: US 8,354,116 B2 Carter Et Al USOO8354116B2 (12) United States Patent (10) Patent No.: US 8,354,116 B2 Carter et al. (45) Date of Patent: Jan. 15, 2013 (54) BIFUNCTIONAL SYNTHETIC MOLECULES Chinese Office Action, with English translation, dated Apr. 20, 2011 in corresponding foreign patent application No. CN 200880 103516. 1. (75) Inventors: Stephen G. Carter, Andover, MA (US); Wang, Xiu Q., et al., “Erythropoietin Depresses Nitric Oxide Kanu Patel, Londonderry, NH (US); Synthase Expression by Human Endothelial Cells'. Hypertension. Zhen Zhu, Tewksbury, MA (US); Lixin 1999, 33:894-899. Qiao, Tewksbury, MA (US) Krapf, Reto, et al., “Arterial Hypertension Induced by Erythropoietin and Erythropoiesis-Stimulating Agents (ESA). Clinical Journal of the American Society of Nephrology, Feb. 2009, vol. 4 No. 2, pp. (73) Assignee: BioChemics, Inc., Danvers, MA (US) 470-480 + refs. Canadian Communication dated Mar. 8, 2012 in corresponding (*) Notice: Subject to any disclaimer, the term of this Canadian patent application No. CA 2690357. patent is extended or adjusted under 35 Canadian Communication dated Jul. 25, 2011 in corresponding U.S.C. 154(b) by 1247 days. Canadian patent application No. CA 2690357. Chinese Communication, with English translation, dated Mar. 28. (21) Appl. No.: 11/820,172 2012 in corresponding Chinese Patent Application No. 200880 1035161, 11 pages. (22) Filed: Jun. 18, 2007 * cited by examiner (65) Prior Publication Data Primary Examiner — Robert A Wax US 2008/0312296A1 Dec. 18, 2008 Assistant Examiner — Melissa Mercier (51) Int. Cl. (74) Attorney, Agent, or Firm — Nields, Lemack & Frame, A6 IK9/00 (2006.01) LLC A6 IK 8/02 (2006.01) (52) U.S. Cl. ........................................ 424/400; 424/401 (57) ABSTRACT (58) Field of Classification Search ........................ None The synthesis and use of bifunctional molecules to improve See application file for complete search history. the topical and transdermal delivery efficiency of various types of therapeutic agents or agents designed to promote the (56) References Cited transdermal delivery of those therapeutic agents either into the skin tissue or into the systemic circulation. Three major U.S. PATENT DOCUMENTS classes of molecules are covalently joined as bifunctional 4,555,398 A * 1 1/1985 Oda .............................. 514,307 Substances; chemical vasodilators, passive dermal penetra 5,460,821 A 10, 1995 Masiz ........................... 424/449 tion enhancers and therapeutic or diagnostic drugs. Chemical 5,645,854 A 7, 1997 Masiz ........................... 424/449 vasodilators may be delivered into the skin to increasing the 5,853,751 A 12/1998 MasiZ ........................... 424/449 blood flow in a tissue that has compromised circulation or 6,019,997 A * 2/2000 Scholz et al. ................. 424/449 6,372,712 B1 * 4/2002 Briesewitz et al. .......... 514, 20.9 they may be used as part of a delivery vehicle to promote the 6,635,274 B1 10/2003 Masiz ........................... 424/449 delivery of the drug. Passive dermal penetration enhancers are those chemicals that promote the passive penetration of FOREIGN PATENT DOCUMENTS drugs and other chemicals through the stratum corneum and CA 2360590 A1 4/2002 epidermis of the skin tissue. Drugs and diagnostic agents are OTHER PUBLICATIONS the third group of chemicals that are candidates for the link age of molecules. Laietal. Structural Characteristics of Human Erythropoietin, Mar. 5, 1986. The Journal of Biological Chemistry, 3116-3121.* 4 Claims, No Drawings US 8,354,116 B2 1. 2 BFUNCTIONAL SYNTHETIC MOLECULES tional molecule with Superior dermal penetrating character istics combined with an active vasodilation function or com BACKGROUND OF THE INVENTION bined with the drug. By covalently binding these agents together as they are formulated and maintaining this bond as The current invention describes the preparation of a novel they pass through the stratum corneum and epidermis, both series of chemically bifunctional function molecules with the functional groups are co-migrating in the same physical space design purpose of improving the pharmacologic characteris and also at the same time. The coordination of function and tics of either the vasodilator or the drug/diagnostic moiety. location in the skin tissue amplifies uptake of the drug or the There are published reports suggesting that in many medical delivery promoter, making the delivery vehicle more efficient conditions related to peripheral vascular disease and neuropa 10 and more substantial in effect. thy, including diabetic neuropathy, there is a compromised The combinations of individual molecules, as defined by microcirculatory environment around the nerves, which may classes according to function, include but are not limited to have an influence on the normal functions of the nerves, chemical vasodilators, passive dermal penetration enhancing leading to the abnormal sensations or lack of sensations noted agents and drugs or diagnostic agents. The identification of a with these medical conditions. Improving the metabolic State 15 reaction chemical functional group available to serve as a in the tissue around the nerve cells in the skin through an linkage point to bond with a different functional class of improved blood flow, increasing the oxygenation and nutrient molecule is critical to the selection of the specific molecules. delivery to the tissue as well as improving the removal of Examples of the chemicals available for selection for the cellular and tissue waste products, improves the health and chemical vasodilator class of molecules that are candidates to functioning of the nerve cells, which in turn creates an envi serve as one component of the bifunctional molecule, ronment for the reversal of a deteriorating medical condition include, by example only but are not limited to: amrinone, or slows the rate of deterioration. The use of bifunctional arginine, bamethan Sulphate, bencyclane fumarate, benfu function molecules, including the use of vasodilators linked rodil hemisuccinate, benzyl nicotinate, buflomedil hydro to a penetration enhancer molecule would improve the deliv chloride, buphenine hydrochloride, butalamine hydrochlo ery of these agents to the compromised tissue. 25 ride, cetiedil citrate, ciclonicate, cinepazide maleate, The preparation of the stable and covalently linked bifunc cyclandelate, di-isopropylammonium dichloroacetate, ethyl tional molecules from components such as a vasodilator (e.g., nicotinate, hepronicate, hexyl nicotinate, ifenprodil tartrate, nicotinic acid ortolaZoline) linked to a penetration enhancing inositol nicotinate, isoxSuprine hydrochloride, kallidinoge moiety (e.g., menthol or linoleic acid), allows for the more nase, methyl nicotinate, naftidrofuryl oxalate, nicametate cit efficient and coordinated delivery of the active agents (i.e., 30 rate, niceritrol, nicoboxil, nicofuranose, nicotinyl alcohol, drugs or vasodilators). The improved delivery of a functional nicotinyl alcohol tartrate, nitric oxide, nonivamide, oXpenti drug agent or vasodilator improves the treatment of a medical fylline, papaverine, papaveroline, pentifylline, peroxynitrite, condition in a manner that can be more accurately measured pinacidil, pipratecol, propentofyltine, raubasine, Suloctidil, and predicted since the physicochemical characteristics and teasuprine, thymoxamine hydrochloride, tocopherol nicoti the temporal positioning of the molecule in the skin are better 35 nate, tolaZoline, Xanthinol nicotinate, diazoxide, hydralazine, understood and defined as opposed to those associated with minoxidil, and Sodium nitroprusside. Centrally acting agents an unlinked or un-bonded formulation containing the same include clonidine, quanaberZ, and methyl dopa. Alpha two Substances. adrenoceptor blocking agents include indoramin, phenoxy The efficiency and the focused application of use with the benzamine, phentolamine, and praZosin. Adrenergic neuron present invention includes the use of a broad class of novel 40 blocking agents include bedmidine, debrisoquine, and molecules, containing at least two types of functional char guanethidine. ACE inhibitors include benazepril, captopril, acteristics, including linking a vasodilator or a drug molecule cilaZapril, enalapril, fosinopril, lisinopril, perindopril, to a molecule designed to promote penetration through the quinapril, and ramipril. Ganglion-blocking agents include skin or to another type of vasodilator. The three classes of pentolinium and trimetaphan. Calcium channel blockers molecules: Vasodilators, penetration enhancers and drugs 45 include amlodipine, diltiazem, felodipine, isradipine, nicar may be linked as combinations of vasodilator to drug; vasodi dipine, nifedipine, nimodipine, and Verapamil. Prostaglan lator to penetration enhancer and penetration enhancer to dins including: prostacyclin, thrombuxane A2, leukotrienes, drug. PGA, PGA1, PGA2, PGE1, PGE2, PGD, PGG, and PGH. Angiotensin II analogs include Saralasin. Other Suitable DETAILED DESCRIPTION OF THE INVENTION 50 vasodilators include nitroglycerin, labetalol, thrazide, isosor bide dinitrate, pentaerythritol tetranitrate, digitalis, hydrala The invention describes the preparation of novel bifunc Zine, diaZOxide, and sodium nitroprusside. Typically the tional function molecules, created from chemical agents vasodilator linked to the penetration enhancer molecule, is known to participate in the promotion of transdermal drug present in the topical vehicle at concentration between delivery. In addition, the preparation of these
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