US 2004O2O2709A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0202709 A1 Kirby et al. (43) Pub. Date: Oct. 14, 2004 (54) COMPOSITIONS FOR RAPID AND (60) Provisional application No. 60/091,910, filed on Jul. NON-IRRITATING TRANSIDERMAL 7, 1998. DELIVERY OF PHARMACEUTICALLY ACTIVE AGENTS AND METHODS FOR Publication Classification FORMULATING SUCH COMPOSITIONS AND DELIVERY THEROF (51) Int. Cl. ................................................... A61K 9/70 (52) U.S. Cl. .............................................................. 424/449 (76) Inventors: Kenneth B. Kirby, Lake Park, FL (US); Berno Pettersson, Perry, GA (57) ABSTRACT (US) A transdermal delivery system (TDS)for use in treatment of Correspondence Address: living bodies may be applied as an open (liquid, gel) or MCHALE & SLAVIN, PA. closed (patch) article. The TDS is composed of a particular 2855 PGA BLVD active agent which dictates an associated Selection of certain PALM BEACH GARDENS, FL 33410 (US) Solvents, Solvent modifiers, Solute modifiers and skin Stabi lizers with which the medicament forms a true Solution that (21) Appl. No.: 10/831,416 rapidly crosses the skin barrier. The associated Selection of (22) Filed: Apr. 23, 2004 the particular Solvents, Solvent modifiers, Solute modifiers 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) Division of application No. 10/074,497, filed on Feb. agent. The TDS may also include a Source of cellular energy 11, 2002, which is a division of application No. to induce CAMP or cGMP. The TDS improves delivery of 09/381,095, filed on May 11, 2000, now Pat. No. active agents having a molecular weight greater than 340 6,444,234, filed as 371 of international application Daltons and increases dosage above 0.25 mg/day for Such No. PCT/US99/15297, filed on Jul. 7, 1999. active agents. Patent Application Publication Oct. 14, 2004 Sheet 1 of 4 US 2004/0202709 A1 .H O) E 4 O O O O O O O O e n CN r (uo/bri) pea eeulled aunouri Patent Application Publication Oct. 14, 2004 Sheet 2 of 4 US 2004/0202709 A1 s 3. s (uo/frt) peae euated quinouri Patent Application Publication Oct. 14, 2004 Sheet 3 of 4 US 2004/0202709 A1 i O O O S 3 usO (uo/bri) peae euced unouri Patent Application Publication Oct. 14, 2004 Sheet 4 of 4 US 2004/0202709 A1 s O O N s (uo/frt) pea eeuded runouri US 2004/0202709 A1 Oct. 14, 2004 COMPOSITIONS FOR RAPID AND 0010 With regard to the molecular weight limitations, NON-IRRITATING TRANSIDERMAL DELIVERY OF currently commercially available TDD systems deliver mol PHARMACEUTICALLY ACTIVE AGENTS AND ecules with molecular weights less than about 340 D and in METHODS FOR FORMULATING SUCH amounts generally less than about 1.0 mg per 24 hours. COMPOSITIONS AND DELIVERY THEROF 0011 Additionally, candidate medicaments should also, RELATED APPLICATIONS preferably, be Soluble in ethanol and/or isopropanol and/or glycols or dimethyl sulfoxide (DMSO) and should not be 0001) This application is a division of Ser. No. 10/074, chemically altered by solubilization. Another potentially 497, filed Feb. 11, 2002 and now U.S. Pat. No. s limiting factor is for compounds which can have efficacy at which is a division of Ser. No. 09/381,095, filed May 11, relatively Small doses introduced Systemically via the cap 2000, now U.S. Pat. No. 6,444,234 issued Sep. 3, 2002 which is a sec. 371 application of PCT/US/99/15297, filed illary net of the dermis. Main limiting factors thus include Jul. 7, 1999 which claims priority to Provisional Application molecule size and irritation potential of the medicament plus 60/091,910, filed Jul. 7, 1998. Solvent(s) and other components. 0012. The inventors have also analyzed the chemistry and FILED OF THE INVENTION chemical Structures of active ingredients and carriers of 0002 This invention relates to transdermal delivery of transdermal delivery Systems and have found other limiting active agents, including pharmaceuticals, cosmetics, nutri factors leading to the limited Success of transdermal drug ents, and the like, across the skin barrier of humans or other delivery. Most typically it has been observed that these animals and to a method for developing new transdermal Systems have not been widely acceptable because the drug delivery Systems for any particular polar or non-polar active carriers chemically bound with the medicament resulting in agent of Small or large molecular Size, which delivery non-bioavailable compounds transmigrating the skin; or/and Systems are capable of rapidly delivering the active agent to the carrier, e.g., DMSO, reduces the medicament yielding a a targeted location Systemically or locally. non-bioavailable or non-bio-equivalent compound or creates toxic by-products of transmigration. BACKGROUND OF THE INVENTION 0013 Only about 1% or less of known medicaments 0003. The pharmaceutical industry is actively seeking to would not be excluded for administration by a TDD System develop new and improved modes of drug delivery to based on the above limiting factors. Still further, TDD enhance the effectiveness of particular drugs, including, Systems currently available are usually Subject to broadly targeting the drug to the intended site, reducing dosage, varying results as a function of the circulation efficiency of decreasing toxicity, and the like. Major efforts are underway the patient. Age, size and weight of the patient all impact in molecule Stabilization for parenteral applications, how efficiently these systems perform. For most TDD sys extended release modalities for enteral drugs and photacti tems there is virtually no drug penetration for the first hour Vated chemotherapeutic molecules, for example. Delivery of after application and often 24 to 48 hours are required to medications via transdermal drug delivery (TDD) systems achieve a therapeutic level. (patches) has also seen dramatic developments, see U.S. Pat. Nos. 4,879,275; 3,996,934; and 3,731,683. For example, it 0014. The anatomy and physiology of the integument is now generally agreed that chemical modification of the was analyzed to understand the complex protective mecha barrier properties of the Skin is a Safe and effective method nism of physical, biochemical and bio-electrical gradients to enhance penetration of medicaments (Ref. 1). However, which work to minimize the penetration of foreign Sub to Some extent it seems that this mode of delivery has stances and Sensitize the organism to react more rapidly and reached its technological limits. aggressively to future exposures. As a result of this analysis it is postulated that: 0004) The present inventors have analyzed the TDD Systems and have been able to identify certain limiting 0015 The primary pathway of transdermally deliv factors. These include, for example, limitations to com ered drugs is paracellular, i.e., around the cells, then pounds which are through the elastin glue. 0005) lipophilic medicaments, 0016. The glue-like compound, elastin, composed of collagen and hyaluronic acid and other lipids, which 0006 medicaments with an effective therapeutic occupies the interstices between the cells of the dose of less than 1 mg per day; top-most layer of the skin (i.e., the epidermis, includ ing, e.g., Stratum corneum (SC), lucidum, granulo 0007 medicaments having a melting point below Sum, Spinosus) must be dissolved (or otherwise about 150° C.; disrupted) in order for a medicament or other active 0008 medicaments having molecular weight of agent, dissolved in a Solvent, to transmigrate through from less than about 300 to about 500 Daltons (the viable skin (VS) to the subcutaneous tissues where larger the molecule, the leSS is the amount deliver the cutaneous plexi of the capillary net can be able via the stratum corneum); reached and/or deeper penetration achieved (Ref. 2). When the elastin is dissolved, other agents may then 0009 molecules which do not elicit a rapidly cas transmigrate the Outer layers, So the body immedi cading immune response when transmigrating the ately begins to attempt to repair the damage caused skin. by the dissolution. US 2004/0202709 A1 Oct. 14, 2004 0017 Skin penetration enhances (SPE) which deli 0026. Transient increases in cutaneous blood flows pidize can reduce the barrier capacity of the SC as a may result in increased Systemic absorption of the function of Species of enhancer and its concentration. drug from the depot of the TDD (Ref. 5). Permeability may often be adjusted by modifying the 0027) Furthermore, cellular biological issues were HLB of the enhancer (Ref. 3). reviewed in order to identify and categorize membrane and 0018 Capilary circulation acts as a sink for the organelle functions, both in the integument and in other medicament, thus maintaining a steep chemical tissues, which might be Subject to variations which might potential gradient across the skin (Ref. 4). help or hinder tissue transmigration of a medicament and Solvent. In particular, it is proposed that, 0019. Diffusivity of a drug molecule is dependent on 0028 SPE's and solvent modification systems can properties of both the medicament and the medium cause irritation apart from the medicament they are (carrier). The diffusivity in liquid media, in general, delivering. Chronic exposure to irritants has the tends to decrease with increased molecular volume potential to become carcinogenic and, therefore, care (Ref. 5). must be taken in the design and testing of TDD 0020. The rate of skin penetration is a function of (1) Systems. the Diffusion Coefficient, (2) the barrier partitioning 0029 Efferent tactile corpuscles of nerves form an tendencies, (3) binding affinities, and (4) the rate of “early warning detection System.” The cellular and metabolism of the medicament by the skin (Ref.