US 2008 OO63698A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0063698 A1 Hartwig (43) Pub. Date: Mar. 13, 2008 (54) CRYSTALLIZATION INHIBITION OF DRUGS now abandoned, which is a continuation of applica IN TRANSIDERMAL DRUG DELIVERY tion No. 10/010,342, filed on Dec. 5, 2001, now SYSTEMIS AND METHODS OF USE abandoned. (75) Inventor: Rod Lawson Hartwig, Plantation, FL (60) Provisional application No. 60/251.294, filed on Dec. (US) 5, 2000. Correspondence Address: Publication Classification Noven Pharmaceuticals, Inc. Jay G. Kolman, Esq. (51) Int. Cl. 11960 S.W. 144 Street A6II 3/56 (2006.01) A6F 3/00 (2006.01) Miami, FL 33186 (US) A6IP 43/00 (2006.01) (73) Assignee: NOVEN PHARMACEUTICALS, A6F 3/02 (2006.01) INC. (52) U.S. Cl. ........................... 424/448; 424/449; 514/170 (57) ABSTRACT Appl. No.: 11/897,189 (21) The invention relates to compositions and methods for (22) Filed: Aug. 29, 2007 making a transdermal drug delivery system capable of achieving substantially zero-order kinetics for delivery of Related U.S. Application Data the active agent over a period of time in excess of 24 hours and at least 72 hours, comprising a pharmaceutically accept (63) Continuation of application No. 10/751,152, filed on able active agent carrier and a rosin ester which provides a Jan. 2, 2004, now abandoned, which is a continuation crystal inhibiting and drug stabilizing effect on the active of application No. 10/353,624, filed on Jan. 29, 2003, agents incorporated therein. 13 2 2 Patent Application Publication Mar. 13, 2008 Sheet 2 of 4 US 2008/0063698 A1 s 5 3 O (zuo/6n) uoneeued empernuno Patent Application Publication Mar. 13, 2008 Sheet 3 of 4 US 2008/0063698 A1 at O N N O vd X O - L t O cC - Hv E. O L 2 a X- cywd > y g ar. n n CO () (d an c. s. 5. r E E E cus ( cus X X X U o s 8 o (Zuo/6n) uola eeuied empaenung Patent Application Publication Mar. 13, 2008 Sheet 4 of 4 US 2008/0063698 A1 d Cl E X L s s US 2008/0063698 A1 Mar. 13, 2008 CRYSTALLIZATION INHIBITION OF DRUGS IN system can provide a continuous and controlled release of TRANSIDERMAL DRUG DELVERY SYSTEMS the active agent over a prolonged period of time so that the AND METHODS OF USE resulting blood levels remain constant. CROSS-REFERENCE TO RELATED 0008. It has been shown that the degree of saturation and APPLICATION solubility of the active agent in the carrier composition are determining factors in controlling delivery of the active 0001. This application is based on and claims the benefit agent from the transdermal system. Since only solubilized of Provisional Application 60/251.294 filed Dec. 5, 2000, active agent is available for delivery out of the transdermal which is incorporated in its entirety herein by reference. system, the carrier composition must not promote crystal growth or formation, especially during storage of the system BACKGROUND OF THE INVENTION prior to use. Generally, active agents have been found to be 0002 This invention relates generally to transdermal readily soluble in acrylic polymers. However, in order to drug delivery systems, and more particularly to pressure deliver a therapeutically effective amount to the systems sensitive adhesive compositions, that incorporate rosin user, and to also achieve the desired adhesive strength esters to inhibit crystal formation of the active agent in the required for topical application in a matrix-type system, composition during storage. additional polymers and ingredients are often added to the carrier composition (for example, incorporating a rubber, 0003. The use of transdermal drug delivery systems as a polysiloxane or polyvinylpyrrolidone polymer). Such addi means to topically administer an active agent is well known. tional polymers and ingredients can affect the recrystalliza Such systems incorporate the active agent into a carrier tion of the active agent in the carrier composition. The composition, such as a polymeric and/or pressure-sensitive tendency for crystal formation or growth is known, for adhesive composition, from which the active agent is deliv example, in the case of high melting point hydrophobic ered through the skin or mucosa of the user. drugs, such as hormones and steroidal active agents, which 0004. In general, transdermal drug delivery systems are tend to be poorly soluble or insoluble in pressure-sensitive either reservoir-type or matrix-type. Both types of systems adhesive carrier compositions because they form strong include a backing layer that forms the protective outer crystal bonds. surface of the finished transdermal device and which is 0009 Formulation of transdermal systems is further fre exposed to the environment during use, and a release liner quently hampered by poor solubility of certain active agents or protective layer that forms the inner surface and which in the carrier composition, which in turn also severely limits covers the adhesive means for affixing the device to the skin its therapeutic application. This formulating aspect is par or mucosa of a user. The release liner or protective layer is ticularly difficult in matrix-type systems because the carrier removed prior to application, exposing the adhesive means, composition has to be optimized not only to incorporate and which is typically a pressure-sensitive adhesive. The active administer the desired active agents, but also to obtain agent is located between the release liner and backing layer, Sufficient wear properties (means of attachment to the user) usually solubilized or dispersed in a solvent or carrier for the adhesive carrier. While using low concentrations in composition. order to incorporate the active agent into the carrier may not 0005. In a reservoir-type device, the active agent, typi deleteriously affect the carrier's adhesive properties, low cally in fluid or gel form, is isolated from the adhesive means active agent concentration can result in difficulties in achiev used to affix the device to the user. Traditionally, a reservoir ing an acceptable delivery rate. Poor or inadequate solubility system referred to a device having a pocket or “reservoir of the active agent further gives rise to crystal formation or which served to hold the active agent and which was formed growth. in or by the backing layer itself. A peripheral adhesive layer 0010 Generally, concentrations of the active agent sub was then used to affix the device to the user. While such stantially at or near the Saturation solubility, and even devices are still in use today, the term reservoir has become Supersaturated (i.e., an amount of active agent at a concen known as a device which employs one or more permeable tration greater than the solubility of the active agent in the layers, such as rate controlling membranes and drug perme carrier composition at room temperature) are sought in order able adhesives layers, laminated over the reservoir (which is to increase or maximize delivery rates. Such systems are typically nothing more than another layer containing the also desirable because they provide the ability to potentially drug in a carrier composition), in order to more effectively achieve continuous administration of the active drug in control the delivery rate of the active agent and attachment therapeutically effective amounts for prolonged periods of of the device to the user. time, such as greater than 24 hours, and even up to 7 days 0006. A matrix-type device generally comprises the or more. In these systems, however, the active agent can active agent solubilized or dispersed in an adhesive carrier more easily recrystallize, especially during storage. Crystal composition, typically a pressure-sensitive adhesive or bio lization may occur after a few weeks or months of storage. adhesive, which functions as both the drug carrier and the This gives rise to stability problems. adhesive means of applying the system to the skin or 0011 Active agent that is present in crystalline form mucosa. Such devices are described, for example, in U.S. cannot be delivered through skin or mucosa. Inadequate Pat. Nos. 4,994,267, 5,446,070, 5,474,783 and 5,656,286, all delivery of the active agent in turn leads to blood levels of which are assigned to Noven Pharmaceuticals, Inc., falling below that which are therapeutically effective. Some Miami, Fla. transdermal systems rely upon both solubilized and crystal 0007. A particular advantage over other forms of drug line forms of active agent to achieve the desired drug loading delivery, Such as oral administration, is that the transdermal in the carrier composition. Although the drug crystals in US 2008/0063698 A1 Mar. 13, 2008 Such systems are intended to dissolve later, for example after recrystallization of the active agent after a few weeks or application, such a process is unpredictable and interferes months of storage, and deliver the same at a controlled and with achieving a controlled delivery rate, especially a Zero predictable release rate. order kinetic delivery rate. 0019. It is still another object of this invention to provide 0012 Failure to control crystal formation and growth can a method for increasing the solubilizing and stabilizing of further interfere with the physical properties of the trans active agents in transdermal delivery systems. dermal system. The presence of crystals, particularly in large amounts, can interfere with the carrier composition’s adhe 0020. It is additionally an object of this invention to sive properties in matrix-type transdermal systems. Further provide a method for making a transdermal drug delivery more, Surface crystals can come into direct contact with the system that achieves a Substantially Zero-order kinetic rate skin or mucosa and promote irritation. The presence of drug of drug delivery for a prolonged period of time without crystals is therefore generally undesirable.