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(12) Patent Application Publication (10) Pub. No.: US 2002/0004065 A1 Kanios (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2002/0004065 A1 Kanios (43) Pub US 2002000.4065A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0004065 A1 Kanios (43) Pub. Date: Jan. 10, 2002 (54) COMPOSITIONS AND METHODS TO Related U.S. Application Data EFFECT THE RELEASE PROFILE IN THE TRANSIDERMALADMINISTRATION OF (63) Non-provisional of provisional application No. ACTIVE AGENTS 60/177,103, filed on Jan. 20, 2000. (76) Inventor: David Kanios, Miami, FL (US) Publication Classification (51) Int. Cl. ................................................... A61K 9/70 (52) U.S. Cl. .............................................................. 424/449 Correspondence Address: Noven Pharmaceuticals, Inc. (57) ABSTRACT 11960 S.W. 144th Street Compositions and methods for the transdermal delivery of Miami, FL 33186 (US) active agents up to a period of Seven days or more at Substantially a Zero-order release rate comprising a pharma (21) Appl. No.: 09/765,932 ceutically acceptable adhesive matrix and a polymeric plas tic material that provides a release rate regulating effect on (22) Filed: Jan. 19, 2001 the active agents. Patent Application Pu blication Jan. 10, 2002 Sheet 1 of 6 US 2002/0004065 A1 ZWZ. % 33 2 Patent Application Publication US 2002/0004065 A1 89|| Patent Application Publication Jan. 10, 2002 Sheet 3 of 6 US 2002/0004065 A1 É c a N m CO a. O) to o C c) we E f (N O N r co g d cC. wr E E w cN -S Ss at- c. C i) C lo ce O c CN r-r me -d (uillio"b S15Tl) xn Patent Application Publication Jan. 10, 2002 Sheet 4 of 6 US 2002/0004065A1 c - r wir ww. co v w 9 a. r O) S ) g CE E es Shc - d ri to s 2 S. 32 C. C. C. S. S. S. : $; ; sh cy d Ys C d d c co (If ui 3"bs fill) xr Patent Application Publication Jan. 10, 2002 Sheet 5 of 6 US 2002/0004.065 A1 ssi s s N (u full 3 b Sf 61i) Xn US 2002/0004065A1 (Suq)HWIL US 2002/0004O65 A1 Jan. 10, 2002 COMPOSITIONS AND METHODS TO EFFECT user, employ a drug permeable adhesive layer (often referred THE RELEASE PROFILE IN THE TRANSIDERMAL to as an “in-line adhesive' Since the drug must pass ADMINISTRATION OF ACTIVE AGENTS through), applied over the drug matrix carrier layer. In an attempt to better control the release rate of the drug, Such FIELD OF INVENTION devices often employ one or more additional drug permeable 0001. This invention relates generally to transdermal layerS Such as rate controlling membranes, or containing drug delivery Systems, and more particularly to pharmaceu excipients, Such as drug delivery enhancers. Hence, Such tically acceptable adhesive matrix compositions, that use devices are also commonly referred to as multilayer or polymeric plastic materials, in particular insoluble cellulose multilaminate. derivatives Such as ethyl celluloses, to regulate the drug 0008. In a “monolithic or monolayer” matrix-type device, release profile. The invention additionally relates to trans the active agent is typically Solubilized or homogenously dermal drug delivery Systems providing Substantially Zero blended in an adhesive carrier composition, typically a order drug release profiles for an extended period of time of preSSure-Sensitive adhesive or bioadhesive, which functions up to Seven days or longer. as both the drug carrier and the means of affixing the System to the skin or mucosa. Such devices, commonly referred to BACKGROUND OF THE INVENTION as drug-in-adhesive devices, are described, for example, in U.S. Pat. Nos. 4,994,267, 5,446,070, 5,474,783 and 5,656, 0002 The use of transdermal drug delivery systems as a 286, all of which are assigned to Noven Pharmaceuticals, means to topically administer an active agent is well known. Inc., Miami, Fla. Such Systems incorporate the active agent into a carrier composition, Such as a polymeric and/or pressure-Sensitive 0009 While matrix-type devices, especially drug-in-ad adhesive composition, from which the active agent is deliv hesive devices, have achieved more uniform and controlled ered through the Skin or mucosa of the user. drug deliver rates, and for longer periods of time, most transdermal Systems remain Subject to a higher initial drug 0003. In general, transdermal drug delivery systems are release than is required to achieve therapeutic efficacy. For either reservoir-type or matrix-type devices. Both types of many drugs and/or therapeutic Situations, it would be advan devices employ a backing layer that forms the protective tageous to eliminate or Suppress this higher initial release outer Surface of the finished transdermal System and which and achieve a "steady state” (Zero order) release profile is exposed to the environment during use, and a release liner which uniformly delivers a therapeutically effective amount or protective layer that forms the inner Surface and which of drug over the extended duration of device's desired use. covers whatever adhesive means is employed for affixing the System to the Skin or mucosa of a user. The release liner or 0010 For example, the high initial release of certain protective layer is removed prior to application, eXposing drugs may cause adverse or undesired effects, or create the adhesive means, which is typically a pressure-Sensitive toxicity concerns, thereby foreclosing the use of transdermal administration. In other instances, the higher initial release adhesive. may reduce the amount of drug required for treatment to the 0004. In the “classic' reservoir-type device, the active point of risking underdosing, or may make it impractical to agent is usually dissolved or dispersed in a carrier that try and increase the duration of the device's application typically yields a non-finite carrier form, like a fluid or gel, while retaining therapeutic effectiveness. The ability to and which is kept Separate from the adhesive means used to reduce the frequency of replacing the transdermal drug affix the device to the user. The device has a pocket or delivery System would concomitantly increase user compli “reservoir” which physically serves to hold the active agent ance, reduce any lag or drop off in efficacious blood levels, and carrier, and which is formed in or by the backing layer and reduce the amount of drug required for treatment (also itself. A peripheral adhesive layer is then used to affix the provided by reducing the higher initial blood level associ device to the user. The early reservoir-type devices incor ated with the higher release rate). porated drugs which were readily absorbed through the skin 0011. Therefore, despite the existence of many different like nitroglycerin and nicotine. types of transdermal delivery Systems in the art, there 0005 Such devices have a number of disadvantages remains a continuing need for improving the release profile including a non-uniform drug release profile wherein a high of drugs to achieve Substantially Zero order, as well as dose of drug is released initially upon application to the user, extending the duration of use of each transdermal System. often described as a “burst effect.” This burst or high initial 0012 U.S. patent Ser. No. 07/897.269 discloses the use release of drug then drops off after a period of time to a rate of glycerin to counteract the burst effect of drugs in trans that is less than is able to achieve a therapeutically effective dermal formulations. amount. Drug delivery according to this profile is described as first order release. 0013. It has now been found that the addition of certain polymeric plastic polymers, in particular insoluble cellulose 0006 While such classic devices are still in use today, the derivatives Such as ethyl celluloses, into a pressure-Sensitive term reservoir is being used interchangeably with matrix adhesive matrix composition, eliminates or Suppresses the type devices which Still rely upon a Separate adhesive means initial high release rate of a drug Subject to a first order used to affix the device to the user. release rate profile Such that the System achieves Substan 0007. In a matrix-type device, the active agent is dis tially Zero order release, and is able to maintain a Substan Solved or dispersed in a carrier that typically yields a finite tially Zero order release profile for an extended period of carrier form, which can be Self-adhesive or non-adhesive. time up to Seven days or longer. Non-adhesive matrix-type devices, that is, those which still 0014. Although not wishing to be bound by theory, rely upon a separate adhesive means to affix the device to the particularly in this case where the Structure of the compo US 2002/0004O65 A1 Jan. 10, 2002 Sition has not been analyzed, it is postulated that the 0021. It is another object of the invention to provide an insoluble polymeric plastic material affects the uptake/ab adhesive matrix-type transdermal drug delivery System Sorption of water or moisture from the application Site into which achieves a Substantially Zero-order release profile of the matrix composition which would otherwise create Some the active agent by incorporating a polymeric plastic mate of the kinetic driving force for release of the drug. This rial into an adhesive drug matrix. appears especially significant in the presence of hydrophobic 0022. It is still another object of the invention to achieve drugs and/or in conjunction with the use of hydrophilic a Substantially Zero-order release profile of the active agent crystallization inhibitors, Such as polyvinylpyrrolidones. for an extended period of time of up to Seven days or longer, 0.015 Ethyl celluloses have been extensively used in and effectively continue to deliver the active agent in a industrial applications since their commercial introduction therapeutically effective amount. in the mid-1930s.
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