USOO6787152B2 (12) United States Patent (10) Patent No.: US 6,787,152 B2 Kirby et al. (45) Date of Patent: Sep. 7, 2004 (54) COMPOSITIONS FOR RAPID AND NON- (58) Field of Search ................................. 424/449, 443, IRRITATING TRANSIDERMAL DELIVERY OF 424/448 PHARMACEUTICALLY ACTIVE AGENTS AND METHODS FOR FORMULATING SUCH (56) References Cited COMPOSITIONS AND DELIVERY THEREOF U.S. PATENT DOCUMENTS (75) Inventors: Kenneth B. Kirby, Lake Park, FL (US); 6,019.997 A * 2/2000 Scholz et al. ............... 424/449 Berno Pettersson, Perry, GA (US) * cited by examiner (73) Assignee: Transdermal Technologies, Inc., North Primary Examiner Thurman K. Page Palm Beach, FL (US) ASSistant Examiner-Isis Ghali (74) Attorney, Agent, or Firm McHale & Slavin, PA. (*) Notice: Subject to any disclaimer, the term of this (57) ABSTRACT patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. A transdermal delivery system (TDS) for use in treatment of living bodies may be applied as an open (liquid, gel) or (21) Appl. No.: 10/074,497 closed (patch) article. The TDS is composed of a particular active agent which dictates an associated Selection of certain (22) Filed: Feb. 11, 2002 Solvents, Solvent modifiers, Solute modifiers and skin Stabi 65 Prior PublicationO O Dat lizers with which the medicament forms a true Solution that (65) O CaO a rapidly crosses the skin barrier. The associated Selection of US 2003/0104040 A1 Jun. 5, 2003 the particular Solvents, Solvent modifiers, Solute modifiers O O and Skin Stabilizers is based on a balancing of the molecular Related U.S. Application Data properties of all the components against the molecular - - - properties of all the components plus the particular active (62) Rightgig Nipis. filed as application agent. The TDS may also include a Source of cellular energy (60) Provisional application No. 60,091.910, filed on Jul. 7, tO induce CAMP or cGMP. The TDS Improves delivery of 1998, now Pat. No. 6,444,234. active agents having a molecular weight greater than 340 7 Daltons and increases dosage above 0.25 mg/day for Such (51) Int. Cl." ......................... A61F 13/00; Act, active agents. (52) U.S. Cl. ........................ 424/449; 424/443; 424/448 4 Claims, 4 Drawing Sheets 4OO U th 3OO N. rts O) 2 OO OO i O O O 2O 3O Time (hr) U.S. Patent Sep. 7, 2004 Sheet 1 of 4 US 6,787,152 B2 G) On E - 3. s s & (uID/ 5n) pen eeula ad qun ouri U.S. Patent Sep. 7, 2004 Sheet 2 of 4 US 6,787,152 B2 O n O CN S (N C) th -H EH O r O s s (uo/frt) per eeuried quinouri Sep. 7, 2004 Sheet 3 of 4 US 6,787,152 B2 2 S e O O O O O S. CO ve y (uoy bri) pen eeur red aunourvi U.S. Patent Sep. 7, 2004 Sheet 4 of 4 US 6,787,152 B2 O n O N a. s sh G) to or E- re O O O O O S O O N CO St (uo/ bril) peae eulied quinouri US 6,787,152 B2 1 2 COMPOSITIONS FOR RAPID AND NON The inventors have also analyzed the chemistry and IRRITATING TRANSIDERMAL DELIVERY OF chemical Structures of active ingredients and carriers of PHARMACEUTICALLY ACTIVE AGENTS transdermal delivery Systems and have found other limiting AND METHODS FOR FORMULATING SUCH factors leading to the limited Success of transdermal drug COMPOSITIONS AND DELIVERY THEREOF 5 delivery. Most typically it has been observed that these Systems have not been widely acceptable because the drug RELATED APPLICATIONS carriers chemically bound with the medicament resulting in non-bioavailable compounds transmigrating the skin; or/and This application is a division of Ser. No. 09/381,095, filed the carrier, e.g., DMSO, reduces the medicament yielding a May 11, 2000, which is a sec. 371 application of PCT/US99/ non-bioavailable or non-bioeduivalent compound or creates 15297, filed Jul. 7, 1999, which claims priority to Provi toxic by-products of transmigration. sional Application No. 60/091,910, filed Jul. 7, 1998, now Only about 1% or less of known medicaments would not U.S. Pat. No. 6,444,234 issued Sep. 3, 2002. be excluded for administration by a TDD system based on the above limiting factors. Still further, TDD systems cur FILED OF THE INVENTION rently available are usually Subject to broadly varying results This invention relates to transdermal delivery of active 15 as a function of the circulation efficiency of the patient. Age, agents, including pharmaceuticals, cosmetics, nutrients, and Size and weight of the patient all impact how efficiently these the like, acroSS the skin barrier of humans or other animals systems perform. For most TDD systems there is virtually and to a method for developing new transdermal delivery no drug penetration for the first hour after application and Systems for any particular polar or non-polar active agent of often 24 to 48 hours are required to achieve a therapeutic Small or large molecular size, which delivery Systems are level. capable of rapidly delivering the active agent to a targeted The anatomy and physiology of the integument was location Systemically or locally. analyzed to understand the complex protective mechanism BACKGROUND OF THE INVENTION of physical, biochemical and bio-electrical gradients which work to minimize the penetration of foreign Substances and The pharmaceutical industry is actively Seeking to 25 Sensitize the organism to react more rapidly and aggres develop new and improved modes of drug delivery to Sively to future exposures. As a result of this analysis it is enhance the effectiveness of particular drugs, including, postulated that: targeting the drug to the intended site, reducing dosage, The primary pathway of transdermally delivered drugs is decreasing toxicity, and the like. Major efforts are underway paracellular, i.e., around the cells, then through the in molecule Stabilization for parenteral applications, elastin glue. extended release modalities for enteral drugs and photacti The glue-like compound, elastin, composed of collagen vated chemotherapeutic molecules, for example. Delivery of and hyaluronic acid and other lipids, which occupies medications via transdermal drug delivery (TDD) systems the interstices between the cells of the top-most layer of (patches) has also seen dramatic developments, see U.S. Pat. the skin (i.e., the epidermis, including, e.g., Stratum Nos. 4,879,275; 3,996,934; and 3,731,683. For example, it 35 corneum (SC), lucidum, granulosum, Spinosus) must be is now generally agreed that chemical modification of the dissolved (or otherwise disrupted) in order for a medi barrier properties of the Skin is a Safe and effective method cament or other active agent, dissolved in a Solvent, to to enhance penetration of medicaments (Ref. 1). However, transmigrate through viable skin (VS) to the subcuta to Some extent it seems that this mode of delivery has neous tissueS where the cutaneous plexi of the capillary reached its technological limits. 40 net can be reached and/or deeper penetration achieved The present inventors have analyzed the TDD Systems (Ref. 2). When the elastin is dissolved, other agents and have been able to identify certain limiting factors. These may then transmigrate the Outer layers, So the body include, for example, limitations to compounds which are immediately begins to attempt to repair the damage lipophilic medicaments, 45 caused by the dissolution. medicaments with an effective therapeutic dose of leSS Skin penetration enhances (SPE) which delipidize can than 1 mg per day; reduce the barrier capacity of the SC as a function of medicaments having a melting point below about 150 C.; Species of enhancer and its concentration. Permeability medicaments having molecular weight of from less than may often be adjusted by modifying the HLB of the about 300 to about 500 Daltons (the larger the 50 enhancer (Ref. 3). molecule, the leSS is the amount deliverable via the Capillary circulation acts as a sink for the medicament, Stratum corneum); thus maintaining a steep chemical potential gradient molecules which do not elicit a rapidly cascading immune across the skin (Ref. 4). response when transmigrating the skin. Diffusivity of a drug molecule is dependent on properties With regard to the molecular weight limitations, currently 55 of both the medicament and the medium (carrier). The commercially available TDD systems deliver molecules diffusivity in liquid media, in general, tends to decrease with molecular weights less than about 340D and in amounts with increased molecular volume (Ref. 5). generally less than about 1.0 mg per 24 hours. The rate of skin penetration is a function of (1) the Additionally, candidate medicaments should also, Diffusion Coefficient, (2) the barrier partitioning preferably, be Soluble in ethanol and/or isopropanol and/or 60 tendencies, (3) binding affinities, and (4) the rate of glycols or dimethyl sulfoxide (DMSO) and should not be metabolism of the medicament by the skin (Ref. 6). The chemically altered by solubilization. Another potentially Diffusion Coefficient of the medicament is influenced limiting factor is for compounds which can have efficacy at by (1) molecular weight, (2) molecular structure, (3) relatively Small doses introduced Systemically via the cap additives, (4) rate of metabolism of the medicament by illary net of the dermis. Main limiting factors thus include 65 the skin. Diffusion is also dependent on the carrier, with molecule size and irritation potential of the medicament plus diffusivity decreasing with increased molecular Vol Solvent(s) and other components. UC. US 6,787,152 B2 3 4 An optimum HLB is required for a medicament to pen elude or minimize this response to effectuate repeated etrate efficiently. The optimum HLB may be predicted challenge without anaphylaxis or ACD Sensitization.