(19) TZZ ¥_ZZZ__T (11) EP 2 310 001 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/70 (2006.01) A61K 31/565 (2006.01) 01.07.2015 Bulletin 2015/27 (86) International application number: (21) Application number: 09790211.8 PCT/US2009/050069 (22) Date of filing: 09.07.2009 (87) International publication number: WO 2010/006143 (14.01.2010 Gazette 2010/02) (54) TRANSDERMAL ESTRADIOL DEVICE AND DELIVERY TRANSDERMALE ÖSTRADIOLVORRICHTUNG UND FREISETZUNG DISPOSITIF D’ADMINISTRATION TRANSDERMIQUE D’ESTRADIOL (84) Designated Contracting States: (74) Representative: Zacco Denmark A/S AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Arne Jacobsens Allé 15 HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL 2300 Copenhagen S (DK) PT RO SE SI SK SM TR Designated Extension States: (56) References cited: AL BA RS US-A1- 2003 099 695 US-A1- 2005 202 073 US-A1- 2006 078 602 (30) Priority: 10.07.2008 US 216811 • Vivelle-Dot (estradiol transdermal system). (43) Date of publication of application: Continuousdelivery for twice weekly application. 20.04.2011 Bulletin 2011/16 Anonymous. Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936. Printed in (73) Proprietor: Noven Pharmaceuticals, INC. the USA. Pages 1-4. Miami, FL 33186 (US) Remarks: (72) Inventor: MANTELLE, Juan Thefile contains technical information submitted after Miami the application was filed and not included in this FL 33176 (US) specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 310 001 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 310 001 B1 Description FIELD OF THE INVENTION 5 [0001] Described herein are compositions and methods for the transdermal delivery of estrogen. BACKGROUND [0002] This invention relates generally to transdermal drug delivery systems, and more particularly, to transdermal 10 drug delivery systems for the delivery of estrogen. The use of a transdermal system, for example, a patch comprising a pressure-sensitive adhesive containing a drug, as a means of delivering drug through the skin is well known. However, there remains a need for transdermal drug delivery systems designed for the delivery of specific drugs, such as estrogen, and there remains a particular need for smaller transdermal drug delivery systems that exhibit desired pharmacokinetic properties. 15 [0003] Transdermal delivery systems (adhesive patches) as dosage forms have been the subject of a vast number of patent applications over the last 25 years, yielding many patents but few commercial products in comparison. To those working in the field, the relatively small number of commercial products is not surprising. Although regulatory, economic, and market hurdles play a role in limiting the number of products on the market, the task of developing a transdermal delivery system that achieves desired physical and pharmacokinetic parameters to satisfy physician and patient demand 20 is more daunting. Parameters to be considered during commercial product development may include drug solubility, drug stability (e.g., as may arise from interaction with other component materials and/or the environment), delivery of a therapeutic amount of drug at a desired delivery rate over the intended duration of use, adequate adhesion at the anatomical site of application, integrity (e.g., minimal curling, wrinkling, delaminating and slippage) with minimal discom- fort, irritation and sensitization both during use and during and after removal, and minimal residual adhesive (or other 25 components) after removal. Size also may be important from a manufacturing and patient viewpoint, and appearance may be important from a patient viewpoint. The physical manufacturing and production aspects of commercial product development (e.g., the identity and costs of materials, equipment, and labor) and supporting analytical methods required for regulatory compliance also can be significant. [0004] Of the physical parameters that are considered when developing a commercial transdermal drug delivery 30 system,size, e.g.,surface area atthe siteof application, is often dictated andlimited by other physicaland pharmacokineti c requirements, such as desired drug delivery rates and daily dosages. In general, it is easier to develop a relatively "large" transdermal drug delivery system that will achieve drug delivery at target therapeutic levels over an intended duration of therapy, than it is to develop a smaller transdermal drug delivery system that still exhibits acceptable pharmacokinetic properties. Still, because size directly impacts costs (e.g., costs of component materials, costs of packaging materials, 35 costs for production and manufacturing equipment, labor costs relative to product yield per run time, etc.) and patients generally prefer smaller systems to larger ones (both for aesthetic reasons and comfort, since a smaller surface may permit the use of less aggressive adhesives), there is a need for smaller transdermal drug delivery systems. [0005] US 2005/202073 A1 relates to a transdermal matrix patch comprising 0.175 mg/cm 2 estradiol. The patch is not monolithic and does not include a penetration enhancer. 40 [0006] US 2003/099695 A1 relates to a monolithic transdermal system comprising 0.175 mg/cm2 estradiol, silicone and polyacrylate adhesives and a penetration enhancer. [0007] US 2006/078602 A1 relates to a transdermal patch comprising 2 % estradiol. acrylic based and silicone based polymers and a penetration enhancer. [0008] Vivelle-Dot (estradiol transdermal system). Continuous delivery for twice weekly application. Novartis Pharma- 45 ceuticals Corporation, East Hanover, NJ 07936 relates to a monolithic transdermal patch comprising 0.156 mg/cm2 estradiol, acrylic and silicone adhesives and a penetration enhancer. SUMMARY 50 [0009] In accordance with one embodiment, there is provided a monolithic transdermal drug delivery system comprising a drug containing layer comprising a polymer matrix comprising estradiol as the only drug, wherein the monolithic system comprises a single polymer matrix layer comprising 2-25% by weight acrylic adhesive, 45-70% by weight silicone ad- hesive, 2-25% by weight soluble PVP, 5-15% penetration enhancer, and 0.1-10% by weight estradiol, all based on the total dry weight of the polymer matrix, and the system includes greater than 0.156 mg/cm2 estradiol and achieves an 55 estradiol flux that is greater than 0.01 mg/cm2/day, based on the active surface area of said drug containing layer, when measured using a skin permeation study using split thickness, cryo-preserved cadaver skin on modified Franz diffusion cells with the receptor filled with 7.5 mL of 0.9% NaCl and 0.01% NaN3 in deionized water maintained at a constant 32oC and magnetically stirred at approximately 300 rpm, with samples, at specified time points, or the receptor phase 2 EP 2 310 001 B1 (with complete replacement of the receptor phase) and quantified by high- performance liquid chromatography. In some embodiments, the polymer matrix comprises about 20% by weight acrylic adhesive, about 56.9% by weight silicone adhesive, about 7.5% by weight soluble PVP, about 6.0% by weight oleyl alcohol, about 8.0% by weight dipropylene glycol, and about 1.6 % by weight estradiol. In some embodiments, the acrylic adhesive and silicone adhesive are 5 present in a ratio of from about 1:2 to about 1:6, based on the total weight of the acrylic and s ilicone adhesives. [0010] In some embodiments, the penetration enhancer comprises oleyl alchol or dipropylene glycol, or both. [0011] In some embodiments, the polymer matrix comprises an amount of estradiol effective to deliver a therapeutically effective amount of estradiol over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days. In some embodiments, the polymer 10 matrix comprises an amount of estradiol effective to deliver an amount of estradiol selected from the group consisting of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day. [0012] In some embodiments, the polymer matrix has a coat weight of greater than about 10 mg/cm2. In some em- bodiments, the polymer matrix has a coat weight selected from the group consisting of about 12.5 and about 15 mg/ cm 2. [0013] In some embodiments, the system has an active surface area that is about 60% of a size selected from the 15 group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm2 and is effective to deliver an amount of estradiol per day of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively. [0014] In accordance with some embodiments, there is provided a transdermal drug delivery system comprising a polymer matrix comprising estradiol, wherein the system has an active surface area that is about 60% of a size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm2 and is effective to deliver an amount of estradiol per day 20 of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively. [0015] The delivery system of the invention may by used in a method for administering estradiol, comprising applying to the skin or mucosa of a subject in need thereof a transdermal drug delivery system as described herein, such as a transdermal drug delivery system comprising a drug-containing layer defining an active surface area and comprising a polymer matrix comprising estradiol, wherein the system includes greater than 0.156 mg/cm 2 estradiol and achieves an 25 estradiol flux that is greater than 0.01 mg/cm2/day, based on the active surface area.