111111111111111111111111111f111
`11111
`4
`8
`
`I1111111111111111111111111111
`
`(12) United States Patent
`Mantelle
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,833,419 B2
`*Dec. 5, 2017
`
`TRANSDERMAL ESTROGEN DEVICE AND
`DELIVERY
`
`Applicant: NOVEN PHARMACEUTICALS,
`INC., Miami, FL (US)
`
`Inventor: Juan Mantelle, Miami, FL (US)
`
`Assignee: NOVEN PHARMACEUTICALS,
`INC., Miami, FL (US)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 14/870,574
`
`(22) Filed:
`
`Sep. 30, 2015
`
`(65)
`
`Prior Publication Data
`
`US 2016/0015655 Al
`
`Jan. 21, 2016
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 14/738,255, filed on
`Jun. 12, 2015, which is a continuation of application
`No. 14/024,985, filed on Sep. 12, 2013, now Pat. No.
`9,724,310, which is a continuation of application No.
`13/553,972, filed on Jul. 20, 2012, now Pat. No.
`9,730,900, which is a continuation of application No.
`12/216,811, filed on Jul. 10, 2008, now Pat. No.
`8,231,906.
`
`(51) Int. Cl.
`A61K 9/70
`A61K 31/565
`A61K 9/00
`A61K 47/10
`A61K 47/32
`(52) U.S. Cl.
`CPC
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2017.01)
`(2006.01)
`
` A61K 9/7069 (2013.01); A61K 9/0014
`(2013.01); A61K 9/7061 (2013.01); A61K
`31/565 (2013.01); A61K 47/10 (2013.01);
`A61K 47/32 (2013.01)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`4/1990 Miranda et al.
`4,915,950 A
`7/1990 Enscore et al.
`4,938,759 A
`1/1991 Chang et al.
`4,983,395 A
`2/1991 Sablotsky
`4,994,267 A
`2/1991 Sablotsky et al.
`4,994,278 A
`9/1992 Otsuka et al.
`5,151,271 A
`12/1993 Cleary et al.
`5,271,940 A
`4/1994 Sablotsky et al.
`5,300,291 A
`9/1994 Kochinke
`5,350,581 A
`8/1995 Mantelle
`5,446,070 A
`12/1995 Miranda et al.
`5,474,783 A
`12/1995 Gray et al.
`5,474,787 A
`4/1996 Kim et al.
`5,505,956 A
`10/1996 Allen et al.
`5,567,488 A
`12/1996 Burns
`5,584,355 A
`3/1997 Woodard et al.
`RE35,474 E
`8/1997 Miranda et al.
`5,656,286 A
`9/1997 Gonella
`5,665,377 A
`3/1998 Lehmann et al.
`5,730,999 A
`6/1998 Barnhart et al.
`5,762,952 A
`11/1998 Kenealy et al.
`5,837,280 A
`5/1999 Chen et al.
`5,902,603 A
`5/1999 Lipp et al.
`5,904,931 A
`5/1999 Farinas et al.
`5,906,830 A
`7/1999 Farinas et al.
`5,928,666 A
`9/1999 Miranda et al.
`5,958,446 A
`2/2000 Miranda et al.
`6,024,976 A
`12/2000 Rovati et al.
`6,156,335 A
`4/2001 Miranda et al.
`6,221,383 B1
`5/2001 Miranda et al.
`6,235,306 B1
`1/2002 Kanios et al.
`6,337,086 B1
`5/2003 Mantelle et al.
`6,562,363 B1
`6,638,528 B1 * 10/2003 Kanios
`
`6,808,739 B2
`
`10/2004 Sitz et al.
`(Continued)
`
` A61K 9/7069
`424/443
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`
`0 887 075 A2
`
`12/1998
`
`OTHER PUBLICATIONS
`
`Toole et al., "Evaluation of irritation and sensitisation of two 50
`gg/day oestrogen patches," Maturitas, vol. 43, pp. 257-263, Dec.
`2002.
`Marty, "New trends in transdermal technologies: Development of
`the skin patch, Menorest®," International Journal of Gynecology &
`Obstetrics, vol. 52, Suppl. 1, pp. S17-S20, Mar. 1996.
`Mantelle, "DOT Matrix® Technology," Modified-Release Drug
`Technology, Rathbone et al., eds., Chapter 30, pp. 405-415, May 28,
`2008.
`Novartis, "Estraderm®," Prescribing information, Jun. 2004.
`Novartis, "Vivelle®," Prescribing information, Jun. 2004.
`Novartis, "Vivelle-Dot®," Prescribing information, Jun. 2004.
`Bayer Healthcare, "Climara®," Prescribing information, 2007.
`3M Pharmaceuticals, "MenostarTM," Prescribing information, Jun.
`2004.
`Watson Pharma, Inc., "Alora®," Prescribing information, May
`2005.
`
`U.S. PATENT DOCUMENTS
`
`(Continued)
`
`6/1983 Nagai et al.
`4,390,520 A
`1/1985 Kroyer et al.
`4,494,278 A
`12/1985 Enscore et al.
`4,559,222 A
`4/1986 Homan et al.
`4,585,836 A
`5/1986 Blizzard et al.
`4,591,622 A
`4,624,665 A * 11/1986 Nuwayser
`
`4,655,767 A
`4,746,515 A
`4,769,028 A
`4,814,168 A
`4,911,707 A
`
`4/1987 Woodard et al.
`5/1988 Cheng et al.
`9/1988 Hoffmann et al.
`3/1989 Sablotsky et al.
`3/1990 Heiber et al.
`
` A61K 9/7084
`424/448
`
`Primary Examiner — Melissa Fisher
`(74) Attorney, Agent, or Firm — Foley & Lardner LLP
`
`ABSTRACT
`(57)
`Described are transdermal drug delivery systems for the
`transdermal administration of estrogen, comprising a poly-
`mer matrix and estrogen. Methods of making and using such
`systems also are described.
`
`15 Claims, 1 Drawing Sheet
`
`MYLAN - EXHIBIT 1001
`
`

`

`US 9,833,419 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`7,456,159 B2
`8,231,906 B2
`8,343,538 B2
`9,724,310 B2
`9,730,900 B2
`2002/0100185 Al
`2003/0099695 Al
`2003/0228354 Al
`2005/0129749 Al
`2005/0169977 Al
`2005/0202073 Al
`2006/0078602 Al
`2006/0233870 Al
`2006/0240087 Al
`2009/0041831 Al
`2013/0156815 Al
`2014/0200530 Al
`2015/0272905 Al
`
`11/2008 Houze et al.
`7/2012 Mantelle
`1/2013 Kanios et al.
`8/2017 Mantelle
`8/2017 Mantelle
`8/2002 Sitz et al.
`5/2003 Mueller
`12/2003 Muraoka et al.
`6/2005 Strauss
`8/2005 Kanios
`9/2005 Jackson et al.
`4/2006 Kanios
`10/2006 Houze et al.
`10/2006 Houze et al.
`2/2009 Miller et al.
`6/2013 Mantelle
`7/2014 Mantelle
`10/2015 Mantelle
`
`OTHER PUBLICATIONS
`
`Serono Laboratories, Inc., "Esclim®," Prescribing information,
`Aug. 1998.
`Office Action dated May 5, 2016 in U.S. Appl. No. 14/024,985 (US
`2014-0200530).
`Notice of Allowance dated Sep. 15, 2016 in U.S. Appl. No.
`14/024,985 (US 2014-0200530).
`Notice of Allowance dated Jan. 10, 2017 in U.S. Appl. No.
`14/024,985 (US 2014-0200530).
`Office Action dated May 5, 2016 in U.S. Appl. No. 13/553,972 (US
`2013-0156815).
`Notice of Allowance dated Aug. 26, 2016 in U.S. Appl. No.
`13/553,972 (US 2013-0156815).
`Notice of Allowance dated Dec. 9, 2016 in U.S. Appl. No.
`13/553,972 (US 2013-0156815).
`Office Action dated Apr. 29, 2016 in U.S. Appl. No. 14/738,255 (US
`2015-0272905).
`Decision in European Opposition issued on Feb. 14, 2017 in
`application No. EP 09 790 211.8.
`Vaughan, "Using Solubility Parameters in Cosmetics Formulation,"
`J. Soc. Cosmet. Chem., vol. 36, pp. 319-333 (1985).
`Sobieski et al., "Silicone Pressure Sensitive Adhesives," Handbook
`of Pressure-Sensitive Adhesive Technology. 2"a ed., pp. 508-517 (D.
`Satas, ed.), Van Nostrand Reinhold, New York (1989).
`"Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive
`Technology, 2"a ed., pp. 396-456 (D. Satas, ed.), Van Nostrand
`Reinhold, N.Y. (1989).
`Nagai et al., "New Drug Delivery Systems," Kurashiki Printing Co.
`Ltd., Academic Document 2009-00984-005, published Jan. 31,
`2000.
`Sekine et al, "New Cosmetic Handbook," Nikko Chemical Co. Ltd.,
`et al., Academic Documents 2008-02180-001, published Oct. 30,
`2006.
`Novartis Pharmaceuticals Corporation, "Vivelle-Dot® (estradiol
`transdermal system)," prescription labeling, Aug. 2004.
`Benson, "Transdermal Drug Delivery: Penetration Enhancement
`Techniques," Current Drug Delivery, vol. 2, pp. 23-33, 2005.
`Feldmann et al, "Percutaneous Penetration of Steroids in Man," The
`Journal of Investigative Dermatology, vol. 52, No. 1, pp. 89-94,
`1969.
`Schaefer et al., "Contraception via Topical Application? A Review,"
`Contraception, vol. 20, No. pp. 225-236, Sep. 1979.
`International Preliminary Report on Patentability and Written Opin-
`ion dated Apr. 19, 2007.
`International Search Report dated Apr. 6, 2005 in application No.
`PCT/US2004/029789.
`International Search Report dated Feb. 24, 2011 in application No.
`PCT/US2009/050069.
`
`"Acrylic and Methaciylic Ester Polymers," Polymer Science and
`Engineering, vol. 1, 2"a ed., pp. 234-269, John Wiley & Sons
`(1984).
`Office Action dated Sep. 9, 2010 by the Examiner in U.S. Appl. No.
`12/216,811 (now U.S. Pat. No. 8,231,906).
`Office Action dated Jan. 20, 2011 by the Examiner in U.S. Appl. No.
`12/216,811 (now U.S. Pat. No. 8,231,906).
`Office Action dated Jun. 30, 2011 by the Examiner in U.S. Appl. No.
`12/216,811 (now U.S. Pat. No. 8,231,906).
`Office Action dated Sep. 13, 2011 by the Examiner in U.S. Appl. No.
`12/216,811 (now U.S. Pat. No. 8,231,906).
`Office Action dated Nov. 8, 2011 by the Examiner in U.S. Appl. No.
`12/216,811 (now U.S. Pat. No. 8,231,906).
`Office Action dated May 29, 2012 by the Examiner in U.S. Appl.
`No. 12/216,811 (now U.S. Pat. No. 8,231,906).
`Notice of Allowance dated Jun. 19, 2012 by the Examiner in U.S.
`Appl. No. 12/216,811 (now U.S. Pat. No. 8,231,906).
`Office Action dated Dec. 29, 2010 by the Examiner in U.S. Appl.
`No. 11/245,084 (now U.S. Pat. No. 8,343,538).
`Office Action dated Apr. 14, 2010 by the Examiner in U.S. Appl. No.
`11/245,084 (now U.S. Pat. No. 8,343,538).
`Office Action dated Jun. 10, 2009 by the Examiner in U.S. Appl. No.
`11/245,084 (now U.S. Pat. No. 8,343,538).
`Office Action dated Oct. 26, 2011 by the Examiner in U.S. Appl. No.
`11/245,084 (now U.S. Pat. No. 8,343,538).
`Office Action dated May 13, 2011 by the Examiner in U.S. Appl.
`No. 11/245,084 (now U.S. Pat. No. 8,343,538).
`Office Action dated Jun. 13, 2012 by the Examiner in U.S. Appl. No.
`11/245,084 (now U.S. Pat. No. 8,343,538).
`Notice of Allowance dated Aug. 22, 2012 by the Examiner in U.S.
`Appl. No. 11/245,084 (now U.S. Pat. No. 8,343,538).
`Office Action dated Apr. 12, 2013 by the Examiner in U.S. Appl. No.
`13/553,972 (US 2013/0156815).
`Office Action dated Sep. 4, 2013 by the Examiner in U.S. Appl. No.
`13/553,972 (US 2013/0156815).
`Office Action dated Mar. 5, 2014 by the Examiner in U.S. Appl. No.
`13/553,972 (US 2013/0156815).
`Office Action dated May 5, 2015 by the Examiner in U.S. Appl. No.
`13/553,972 (US 2013/0156815).
`Notice of Allowance dated Oct. 2, 2015 by the Examiner in U.S.
`Appl. No. 13/553,972 (US 2013/0156815).
`Office Action dated May 20, 2015 by the Examiner in U.S. Appl.
`No. 14/024,985 (US 2014/0200530).
`Notice of Allowance dated Oct. 2, 2015 by the Examiner in U.S.
`Appl. No. 14/024,985 (US 2014/0200530).
`Office Action dated Aug. 12, 2015 by the Examiner in U.S. Appl.
`No. 14/738,255 (US 2015/0272905).
`Office Action dated Oct. 26, 2015 by the Examiner in U.S. Appl. No.
`14/738,255 (US 2015/0272905).
`Rietschel et al, "Effects of harvesting techniques on hydration
`dynamics: gravimetric studies of stratum corneum," J. Soc. Cosmet.
`Chem., vol. 29, pp. 777-782, Dec. 1978.
`Feldstein et al., "Modeling of percutaneous drug transport in vitro
`using skin-imitating Carbosil membrane," Journal of Controlled
`Release, vol. 52, pp. 25-40, 1998.
`Pfister, "Transdermal and Dermal Therapeutic Systems: Current
`Status," Transdermal and Topical Drug Delivery Systems, Ghosh et
`al., eds., Chapter 2, pp. 33-112, 1997.
`Dow Corning, :"Dow Corning® BIO-PSA Standard Silicone Adhe-
`sives," Product Information, Jul. 28, 2008.
`Janisch et al., Email correspondence, Mar. 10, 2016.
`Manngold, Apr. 28, 2004 letter to Angela Nwaneri re: Duro-Tak®
`87-4287 and 87-2287.
`Noven Pharmaceuticals, Inc., Response filed in European applica-
`tion No. 09790211.8 dated Dec. 19, 2014.
`Mantelle et al., "Effect of Silicone/Acrylic PSA Blends on Skin
`Permation," Proceed. Int'l. Symp. Control. Rel. Bioact. Mater., Jun.
`20-23, 1999.
`Notice of Allowance dated Mar. 23, 2017 in U.S. Appl. No.
`13/553,972 (US 2013/0156815).
`Notice of Allowance dated Apr. 26, 2017 in U.S. Appl. No.
`14/024,985 (US 2014/0200530).
`
`

`

`US 9,833,419 B2
`Page 3
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Notice of Allowance dated Jun. 27, 2017 in U.S. Appl. No.
`13/553,972 (US 2013/0156815).
`Notice of Allowance dated Jun. 27, 2017 in U.S. Appl. No.
`14/024,985 (US 2014/0200530).
`
`* cited by examiner
`
`

`

`U.S. Patent
`
`Dec. 5, 2017
`
`US 9,833,419 B2
`
`Vivollo- [kJ!
`Example 1
`—AD— Example 1 a
`
`1.2
`
`0.9
`
`0.0
`
`0
`
`12
`
`24
`
`
`
`36
`
`Time (Ire)
`
`48
`
`6o
`
`72
`
`84
`
`

`

`US 9,833,419 B2
`
`1
`TRANSDERMAL ESTROGEN DEVICE AND
`DELIVERY
`
`FIELD OF THE INVENTION
`
`Described herein are compositions and methods for the
`transdermal delivery of estrogen.
`
`BACKGROUND
`
`5
`
`10
`
`2
`surface may permit the use of less aggressive adhesives),
`there is a need for smaller transdermal drug delivery sys-
`tems.
`
`SUMMARY
`
`In accordance with one embodiment, there is provided a
`transdermal drug delivery system comprising a drug con-
`taining layer defining an active surface area and comprising
`a polymer matrix comprising estradiol, wherein the system
`includes greater than 0.156 mg/cm2 estradiol and achieves
`an estradiol flux that is greater than 0.01 mg/cm2/day, based
`on the active surface area. In some embodiments, the
`polymer matrix comprises a polymer blend comprising an
`acrylic adhesive, a silicone adhesive, and soluble PVP. In
`some embodiments, the polymer matrix comprises about
`2-25% by weight acrylic adhesive, about 45-70% by weight
`silicone adhesive, about 2-25% by weight soluble PVP,
`about 5-15% penetration enhancer, and about 0.1-10% by
`weight estradiol, all based on the total dry weight of the
`polymer matrix. 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 present in a ratio of from about 1:2
`to about 1:6, based on the total weight of the acrylic and
`silicone adhesives.
`In some embodiments, the penetration enhancer com-
`prises oleyl alcohol or dipropylene glycol, or both.
`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
`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.
`In some embodiments, the polymer matrix has a coat
`weight of greater than about 10 mg/cm2. In some embodi-
`ments, the polymer matrix has a coat weight selected from
`the group consisting of about 12.5 and about 15 mg/cm2.
`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 of about
`0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.
`In accordance with some embodiments, there is provided
`a method for administering estradiol, comprising applying to
`the skin or mucosa of a subject in need thereof 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/cm2 estradiol and achieves an estra-
`diol flux that is greater than 0.01 mg/cm2/day, based on the
`active surface area. In some embodiments, 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 of about
`0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.
`In accordance with some embodiments, there is provided
`a method of making a transdermal drug delivery system for
`administering estrogen, comprising forming a polymer
`
`15
`
`20
`
`30
`
`35
`
`40
`
`This invention relates generally to transdermal drug deliv-
`ery systems, and more particularly, to transdermal 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.
`Transdermal delivery systems (adhesive patches) as dos-
`age forms have been the subject of a vast number of patent
`applications over the last 25 years, yielding many patents but 25
`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 pharma-
`cokinetic parameters to satisfy physician and patient demand
`is more daunting. Parameters to be considered during com-
`mercial 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 anatomi-
`cal 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
`components) after removal. Size also may be important from
`a manufacturing and patient viewpoint, and appearance may 45
`be important from a patient viewpoint. The physical manu-
`facturing and production aspects of commercial product
`development (e.g., the identity and costs of materials, equip-
`ment, and labor) and supporting analytical methods required
`for regulatory compliance also can be significant.
`Of the physical parameters that are considered when
`developing a commercial transdermal drug delivery system,
`size, e.g., surface area at the site of application, is often
`dictated and limited by other physical and pharmacokinetic
`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 transder-
`mal drug delivery system that still exhibits acceptable phar-
`macokinetic properties. Still, because size directly impacts
`costs (e.g., costs of component materials, costs of packaging
`materials, costs for production and manufacturing equip-
`ment, 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
`
`50
`
`55
`
`60
`
`65
`
`

`

`US 9,833,419 B2
`
`3
`matrix comprising estrogen and a polymer blend comprising
`an acrylic adhesive, a silicone adhesive, and soluble PVP,
`and applying the polymer matrix to a support layer such that
`the system includes greater than 0.156 mg/cm2 estradiol. In
`some embodiments, the system has an active surface area 5
`that is about 60% of a size selected from the group consist-
`ing of 2.5, 3.75, 5.0, 7.5 and 10.0 cm2. In some embodi-
`ments, 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 10
`oleyl alcohol, about 8.0% by weight dipropylene glycol, and
`about 1.6% by weight estradiol. In some embodiments, the
`polymer matrix is applied to the support layer at a coat
`weight of greater than about 10 mg/cm2. In some embodi-
`ments, the polymer matrix coat weight is selected from the 15
`group consisting of about 12.5 and about 15 mg/cm2.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 illustrates the estradiol flux (m/cm2/hr) over time 20
`(0-81 hours) from transdermal delivery systems according to
`the invention (A & •), as compared to Vivelle-Dot® (•).
`
`DETAILED DESCRIPTION
`
`25
`
`The field of transdermal delivery systems suffers from the
`problem of needing to balance many different competing
`factors to develop a commercial product that exhibits, for
`example both clinical efficacy and satisfactory wear prop-
`erties while remaining acceptable to patients. For example, 30
`when selecting the size of a transdermal delivery system, it
`is necessary to balance factors that favor a smaller size (such
`as lower cost, better adhesive performance and improved
`aesthetics) against factors that favor a larger size (such as the
`target delivery rate (flux) and daily dose). The Vivelle-Dot® 35
`transdermal estradiol product (manufactured by Noven
`Pharmaceuticals Inc.) is available in five different active
`surface areas (2.5, 3.75, 5.0, 7.5 and 10.0 cm2) which each
`deliver different amounts of drug per day (0.025, 0.0375,
`0.05, 0.075 and 0.1 mg/day, respectively). Each of the 40
`Vivelle-Dot® products include 0.156 mg/cm2 estradiol.
`In accordance with some embodiments, the present inven-
`tion provides transdermal drug delivery systems for the
`transdermal delivery of estrogen that have a smaller active
`surface area than Vivelle-Dot® but achieve daily dosages 45
`that are about equal to or greater than the Vivelle-Dot®
`products. For example, the present invention includes trans-
`dermal drug delivery systems that achieve daily dosages that
`are about equal to a Vivelle-Dot® product, in a smaller sized
`system. The ability to provide a smaller system without 50
`sacrificing daily dosage represents a significant advance.
`Applicant surprisingly discovered that increasing the coat
`weight of the drug-containing adhesive layer resulted in an
`increased flux per unit area, and thus permitted the devel-
`opment of smaller transdermal drug delivery systems that 55
`achieve comparable daily dosages. This result was surpris-
`ing because coat weight is typically selected to control the
`duration of delivery, but is not generally understood to
`impact delivery rate. Thus, while it is known in the art to
`increase coat weight to provide delivery over a longer period 60
`of time, it was not known that increasing coat weight could
`increase delivery rate or flux, and thus permit the develop-
`ment of a smaller system while maintaining daily dosage.
`In accordance with some aspects, there are provided
`transdermal drug delivery systems and methods for the 65
`transdermal delivery of estrogen. In specific embodiments,
`the systems exhibit increased flux than other known estrogen
`
`4
`devices (such as Vivelle-Dot®, manufactured by Noven
`Pharmaceuticals Inc.) and, therefore, exhibit increased drug
`delivery per unit area. For example, in some embodiments,
`the systems exhibit a flux greater than the 0.01 mg/cm2/day
`exhibited by the Vivelle-Dot® products, such as a flux that
`is about 1.25, 1.33, 1.5, 1.67, 1.75, 2, 3, 4, or 5 times the flux
`of the Vivelle-Dot® products. In some embodiments, the
`systems have a greater coat weight than other known estro-
`gen devices. For example, in some embodiments, the sys-
`tems have a coat weight such that the amount of estradiol per
`unit area is greater than the 0.156 mg/cm2 estradiol of the
`Vivelle-Dot® products, such as a coat weight that is about
`1.25, 1.33, 1.5, 1.67, 1.75, 2, or 3 times the coat weight of
`the Vivelle-Dot® products, or greater. Thus, in accordance
`with some aspects, the invention permits the use of smaller
`devices to achieve comparable drug delivery.
`Definitions
`Technical and scientific terms used herein have the mean-
`ings commonly understood by one of ordinary skill in the art
`to which the present invention pertains, unless otherwise
`defined. Reference is made herein to various methodologies
`known to those of ordinary skill in the art. Publications and
`other materials setting forth such known methodologies to
`which reference is made are incorporated herein by refer-
`ence in their entireties as though set forth in full. Any
`suitable materials and/or methods known to those of ordi-
`nary skill in the art can be utilized in carrying out the present
`invention. However, specific materials and methods are
`described. Materials, reagents and the like to which refer-
`ence is made in the following description and examples are
`obtainable from commercial sources, unless otherwise
`noted.
`As used herein, the singular forms "a," "an," and "the"
`designate both the singular and the plural, unless expressly
`stated to designate the singular only.
`The term "about" and the use of ranges in general,
`whether or not qualified by the term about, means that the
`number comprehended is not limited to the exact number set
`forth herein, and is intended to refer to ranges substantially
`within the quoted range while not departing from the scope
`of the invention. As used herein, "about" will be understood
`by persons of ordinary skill in the art and will vary to some
`extent on the context in which it is used. If there are uses of
`the term which are not clear to persons of ordinary skill in
`the art given the context in which it is used, "about" will
`mean up to plus or minus 10% of the particular term.
`The phrase "substantially free" as used herein generally
`means that the described composition (e.g., transdermal
`drug delivery system, polymer matrix, etc.) comprises less
`than about 5%, less than about 3%, or less than about 1% by
`weight, based on the total weight of the composition at issue,
`of the excluded component.
`As used herein "subject" denotes any animal in need of
`drug therapy, including humans. For example, a subject may
`be suffering from or at risk of developing a condition that
`can be treated or prevented with estrogen, or may be taking
`estrogen for health maintenance purposes.
`As used herein, the phrases "therapeutically effective
`amount" and "therapeutic level" mean that drug dosage or
`plasma concentration in a subject, respectively, that provides
`the specific pharmacological response for which the drug is
`administered in a subject in need of such treatment. It is
`emphasized that a therapeutically effective amount or thera-
`peutic level of a drug will not always be effective in treating
`the conditions/diseases described herein, even though such
`dosage is deemed to be a therapeutically effective amount by
`those of skill in the art. For convenience only, exemplary
`
`

`

`US 9,833,419 B2
`
`5
`dosages, drug delivery amounts, therapeutically effective
`amounts and therapeutic levels are provided below with
`reference to adult human subjects. Those skilled in the art
`can adjust such amounts in accordance with standard prac-
`tices as needed to treat a specific subject and/or condition/
`disease.
`As used herein, "active surface area" means the surface
`area of the drug-containing layer of the transdermal drug
`delivery system.
`As used herein, "coat weight" refers to the weight of the
`drug-containing layer per unit area of the active surface area
`of the transdermal drug delivery system.
`As used herein, "estrogen" includes estrogenic steroids
`such as estradiol (17-(3-estradiol), estradiol benzoate, estra-
`diol 1713-cypionate, estropipate, equilenin, equilin, estriol,
`estrone, ethinyl estradiol, conjugated estrogens, esterified
`estrogens, and mixtures thereof.
`As used herein, "flux" (also called "permeation rate") is
`defined as the absorption of a drug through skin or mucosal
`tissue, and is described by Fick's first law of diffusion:
`
`J=-D(dCm/dx)
`
`where J is the flux in g/cm2/sec, D is the diffusion coefficient
`of the drug through the skin or mucosa in cm2/sec and
`dCm/dx is the concentration gradient of the drug across the
`skin or mucosa.
`As used herein, the term "transdermal" refers to delivery,
`administration or application of a drug by means of direct
`contact with skin or mucosa. Such delivery, administration
`or application is also known as dermal, percutaneous, trans-
`mucosal and buccal. As used herein, "dermal" includes skin
`and mucosa, which includes oral, buccal, nasal, rectal and
`vaginal mucosa.
`As used herein, "transdermal drug delivery system" refers
`to a system (e.g., a device) comprising a composition that
`releases estrogen upon application to the skin (or any other
`surface noted above). A transdermal drug delivery system
`may comprise a backing layer, a drug-containing layer, and
`a release liner layer. In some embodiments, the transdermal
`drug delivery system is a substantially non-aqueous, solid
`form, capable of conforming to the surface with which it
`comes into contact, and capable of maintaining such contact
`so as to facilitate topical application without adverse physi-
`ological response, and without being appreciably decom-
`posed by aqueous contact during topical application to a
`subject. Many such systems are known in the art and
`commercially available, such as transdermal drug delivery
`patches. As described below, in one embodiment, the trans-
`dermal drug delivery system comprises a drug-containing
`polymer matrix that comprises a pressure-sensitive adhesive
`or bioadhesive, and is adopted for direct application to a
`user's (e.g., a subject's) skin. In other embodiments, the
`polymer matrix is non-adhesive and may be provided with
`separate adhesion means (such as a separate adhesive layer)
`for application and adherence to the user's skin.
`As used herein, "polymer matrix" refers to a polymer
`composition which contains one or more drugs. In some
`embodiments, the matrix comprises a pressure-sensitive
`adhesive polymer or a bioadhesive polymer. In other
`embodiments, the matrix does not comprise a pressure-
`sensitive adhesive or bioadhesive. As used herein, a polymer
`is an "adhesive" if it has the properties of an adhesive per se,
`or if it functions as an adhesive by the addition of tackifiers,
`plasticizers, crosslinking agents or other additives. Thus, in
`some embodiments, the polymer matrix comprises a pres-
`sure-sensitive adhesive polymer or a bioadhesive polymer,
`with estrogen dissolved or dispersed therein. The polymer
`
`15
`
`6
`matrix also may comprise tackifiers, plasticizers, crosslink-
`ing agents or other additives described herein. U.S. Pat. No.
`6,024,976 describes polymer blends that are useful in accor-
`dance with the transdermal systems described herein. The
`5 entire contents of U.S. Pat. No. 6,024,976 is incorporated
`herein by reference.
`As used herein, the term "pressure-sensitive adhesive"
`refers to a viscoelastic material which adheres instanta-
`neously to most substrates with the application of very slight
`10 pressure and remains permanently tacky. A polymer is a
`pressure-sensitive adhesive within the meaning of the term
`as used herein if it has the properties of a pressure-sensitive
`adhesive per se or functions as a pressure-sensitive adhesive
`by admixture with tackifiers, plasticizers or other additives.
`The term pressure-sensitive adhesive also includes mix-
`tures of different polymers and mixtures of polymers, such
`as polyisobutylenes (PIB), of different molecular weights,
`wherein each resultant mixture is a pressure-sensitive adhe-
`sive. In the last case, the polymers of lower molecular
`20 weight in the mixture are not considered to be "tackifiers,"
`said term being reserved for additives which differ other than
`in molecular weight from the polymers to which they are
`added.
`In some embodiments, the polymer matrix is a pressure-
`25 sensitive adhesive at room temperature and has other desir-
`able characteristics for adhesives used in the transdermal
`drug delivery art. Such characteristics include good adher-
`ence to skin, ability to be peeled or otherwise removed
`without substantial trauma to the skin, retention of tack with
`30 aging, etc. In some embodiments, the polymer matrix has a
`glass transition temperature (Tg), measured using a differ-
`ential scanning calorimeter, of between about —70° C. and 0°
`C.
`As used herein, the term "rubber-based pressure-sensitive
`35 adhesive" refers to a viscoelastic material which has the
`properties of a pressure-sensitive adhesive and which con-
`tains at least one natural or synthetic elastomeric polymer.
`In some embodiments, the transdermal drug delivery
`system includes one or more additional layers, such as one
`40 or more additional polymer matrix layers, or one or more
`adhesive layers that adhere the transdermal drug delivery
`system to the user's skin. In other embodiments, the trans-
`dermal drug delivery system is monolithic, meaning that it
`comprises a single polymer matrix layer comprising a pres-
`45 sure-sensitive adhesive or bioadhesive with drug dissolved
`or dispersed therein, an