WO1996040087A2 - Composition acrylique adhesive sensible a la pression reticulee avec de l'acetylacetonate d'aluminium et contenant un medicament qui renferme un groupe hydroxy aromatique reactif - Google Patents

Composition acrylique adhesive sensible a la pression reticulee avec de l'acetylacetonate d'aluminium et contenant un medicament qui renferme un groupe hydroxy aromatique reactif Download PDF

Info

Publication number
WO1996040087A2
WO1996040087A2 PCT/US1996/008492 US9608492W WO9640087A2 WO 1996040087 A2 WO1996040087 A2 WO 1996040087A2 US 9608492 W US9608492 W US 9608492W WO 9640087 A2 WO9640087 A2 WO 9640087A2
Authority
WO
WIPO (PCT)
Prior art keywords
drug
composition
patch
aluminum acetylacetonate
estradiol
Prior art date
Application number
PCT/US1996/008492
Other languages
English (en)
Other versions
WO1996040087A3 (fr
Inventor
Chunhua Li
Edward Schonfeld
Tara Chu
Chia-Ming Chiang
Original Assignee
Cygnus, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cygnus, Inc. filed Critical Cygnus, Inc.
Priority to AU60326/96A priority Critical patent/AU6032696A/en
Publication of WO1996040087A2 publication Critical patent/WO1996040087A2/fr
Publication of WO1996040087A3 publication Critical patent/WO1996040087A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates

Definitions

  • the present invention relates to transdermal drug delivery patches. More particularly it concerns a matrix type transdermal drug delivery patch whose matrix comprises a mixture of a pressure sensitive acrylate adhesive crosslinked with aluminum acetylacetonate and a drug, such as estradiol, which has a reactive aromatic hydroxyl group.
  • Transdermal drug delivery patches normally include a backing layer that forms the outer face of the patch, a drug reservoir underlying the backing layer, and means to affix the patch to the skin.
  • the drug reservoir may be a liquid solution or suspension of the drug or a solid matrix of a drug-carrier mixture.
  • the carrier of the solid matrix may be an adhesive or have nonadhesive properties. If it is adhesive, the matrix may serve as the means for affixing the patch to the skin. If it is not adhesive, an in-line adhesive layer may underlie the matrix for affixing the patch to the skin.
  • the reservoir is a liquid, the patch will often include a drug-permeable membrane that underlies the reservoir and an in-line adhesive layer that underlies the membrane.
  • Pressure sensitive adhesives are often used as the adhesive in the above- described patches. Pressure sensitive adhesives are used either as the carrier of the drug-containing matrix or as a separate in-line adhesive layer. In either instance the pressure sensitive adhesive will be admixed with drug.
  • Solution polyacrylate adhesives are one type of pressure sensitive adhesive that are used in transdermal drug delivery patches. Solution polyacrylates are made by copolymerizing one or more acrylate monomers, a modifying monomer and a monomer containing functional groups in a solution of an organic solvent. 2-Ethylhexylacrylate, butylacrylate and isooctylacrylate are commonly used as the acrylate monomer. The polyacrylate may be crosslinked on uncrosslinked.
  • Crosslinked acrylate adhesives generally have better cohesive strength and resistance to cold flow than uncrosslinked acrylate adhesives. Increased cohesive strength is desirable in transdermal uses of acrylates to reduce the mass transfer of adhesive to the skin when the patch is removed. Resistance to cold flow is desirable to prevent the adhesive from oozing from the patch during storage or wear. Accordingly, crosslinked solution polyacrylates are preferred.
  • U.S. 5,393,529 describes an adhesive matrix type transdermal patch for delivering estradiol or estradiol esters.
  • the adhesive of the matrix may be a crosslinked or uncrosslinked solution polyacrylate containing a water-swellable polymer.
  • Aluminum acetylacetonate is included in a list of possible agents for crosslinking the polyacrylate.
  • U.S. 5,292,951 describes estrogen-containing gels for topical application.
  • the gels are comprised of estrogen, crosslinked acrylate polymers and relatively large amounts of a fat or oil that serves as an estrogen solubilizer.
  • the present invention provides an adhesive composition comprising a crosslinked pressure sensitive acrylate adhesive mixed with an aromatic hydroxy-containing drug that does not develop objectionable color and has good cohesive strength and cold flow properties. Disclosure of the Invention
  • One aspect of the invention is a pressure sensitive adhesive composition useful in a transdermal drug delivery patch comprising a mixture of: a) a drug having a reactive aromatic hydroxyl group; and b) an aluminum acetylacetonate crosslinked solution polyacrylate pressure sensitive adhesive.
  • transdermal drug delivery patch in the form of a laminated composite comprising:
  • a backing layer that forms the top surface of the patch (a) a backing layer that forms the top surface of the patch; and (b) a matrix layer underlying the backing layer that comprises:
  • the pressure sensitive adhesive component of the invention compositions and patches is a solution polyacrylate.
  • Such polyacrylates are made by copolymerizing one or more main acrylate monomers ("acrylate” is intended to include both acrylates and methacrylates), one or more modifying monomers, and one or more functional group-containing monomers in an organic solvent solution.
  • the acrylate monomers used to make these polymers are normally alkyl acrylates of 4-17 carbon atoms, with 2-ethylhexylacrylate, butylacrylate and isooctylacrylate being preferred.
  • Modifying monomers are typically included to alter the Tg of the polymer.
  • modifying monomers are acrylates such as ethyl acrylate, vinyl acetate, and methyl methacrylate.
  • the functional group-containing monomer provides sites for crosslinking.
  • the functional group(s) will normally be carboxyl, hydroxyl, or combinations thereof.
  • Monomers that provide such groups are acids, e.g. acrylic acid, and hydroxy-containing monomers such as hydroxyethyl acrylate. Examples of such solution polyacrylates are disclosed in the art. See, for instance, U.S. 5,393,529, the disclosure of which with respect to such copolymers is incorporated herein.
  • Preferred copolymers are those of 2-ethylhexylacrylate, vinyl acetate, hydroxyethylacrylate, and glycidyl methacrylate.
  • the drug component of the invention composition is a drug that has a reactive aromatic hydroxyl group.
  • aromatic hydroxyl group intends a hydroxyl or hydroxyimino group that is attached directly to an annular carbon atom of a mono- or polycyclic aromatic moiety.
  • Examples of such drugs are 17 ⁇ -estradiol, 17 ⁇ - estradiol, 17 ⁇ -estradiol cypionate, ethinyl estradiol, 3,17 ⁇ -estradiol dienanthate, 17 ⁇ - estradiolvalerate, 17-deacetyl norgestimate, and norgestimate.
  • Other drugs may be included in the composition.
  • the aromatic hydroxy-containing drug is estradiol
  • progestogens and/or androgens may be included.
  • the aromatic hydroxy- containing drug will usually constitute between about 0.5% and 10% by weight of the adhesive composition.
  • the acrylate adhesive is crosslinked with sufficient aluminum acetylacetonate to significantly improve the cohesive strength and cold flow properties of the adhesive relative to those of the uncrosslinked adhesive.
  • the crosslinking density should be low since high degrees of crosslinking may adversely affect the tack and pull adhesion or yield a nontacky product.
  • the amount of aluminum acetylacetonate used is in the range of 0.1 to 1% by weight.
  • the adhesive composition is crosslinked by mixing a solution of the polyacrylate, aluminum acetylacetonate, and drug in the desired proportions, causing the mixture to effect crosslinking, and then removing the solvent.
  • the adhesive compositions of the invention may be used to form the matrix (drug reservoir) component of a transdermal patch or be used as a separate in-line adhesive layer. In either application, the composition defines the basal surface (i.e. the surface that contacts the skin) of the patch when the patch is in use. As indicated, when the composition is used to form the matrix, the drug is incorporated into the adhesive before crosslinking.
  • compositions of this invention are unexpectedly substantially free of objectionable yellowing or other coloring.
  • the use of other metallic acetylacetonates as crosslinking agents were found to produce colored compositions, or unacceptably high or low levels of crosslinking.
  • the composition possesses acceptable cohesive strength and cold flow properties. Cohesive strength may be determined by a dynamic viscosity test. Cold flow may be observed visually. Normally the cold flow is observed after storage of the patch at elevated temperatures (e.g. 450C) for several months.
  • Example 1 Preparation of Adhesive of Duro-Tak 2287. Aluminum Acetylacetonate and 17 J-estradiol. Duro-Tak 87-2287 is a solution polyacrylate available from National
  • the cold flow properties of the assembly were tested by storing the assembly at 450C for 3 mos. No cold flow of the adhesive layer was observed. The adhesive layer of the patch remains uncolored after storage at 450C for 3 mos.
  • patch assemblies were made from Duro-Tak 87-2287 and 3% estradiol without crosslinking agent. These assemblies exhibited poor dynamic viscosity (1.79E + 07). The adhesive remains clear after storage but cold flow was observed.
  • Example 2 Comparison Preparations of Polyacrylate Crosslinked With Other Metallic Acetylacetonates and 17 ⁇ -estradiol.
  • Duro-Tak 87-2516 is a solution polyacrylate available from National
  • Example 1 Mixtures of Duro-Tak 87-2516 and 3% estradiol were prepared and cured as in Example 1. The mixture was cast into a release liner as in Example 1 and dried. The cured mixture and assembly were tested as in Example 1. The results were: dynamic viscosity, 5.00E + 07; E2 flux, 0.5 ⁇ 0.04 ⁇ g/cm 2 /hr; no cold flow; distinct yellow color.

Abstract

L'invention se rapporte à une composition acrylique adhésive sensible à la pression, à base de solvant organique et sans effet de jaunissement, et qui présente de bonnes propriétés en matière de force de cohésion et d'écoulement à froid. Cette composition est utile dans la fabrication de timbres transdermiques pour l'administration des médicaments. Il s'agit d'une composition acrylique adhésive sensible à la pression à base de solvant organique, réticulée avec de l'acétylacétonate d'aluminium et combiné avec un médicament (par exemple estradiol) qui renferme un groupe hydroxyle aromatique réactif.
PCT/US1996/008492 1995-06-07 1996-06-03 Composition acrylique adhesive sensible a la pression reticulee avec de l'acetylacetonate d'aluminium et contenant un medicament qui renferme un groupe hydroxy aromatique reactif WO1996040087A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60326/96A AU6032696A (en) 1995-06-07 1996-06-03 Pressure sensitive acrylate adhesive composition cross-linke d with aluminum acetylacetonate and containing a drug having a reactive aromatic hydroxyl group

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US48429495A 1995-06-07 1995-06-07
US08/484,294 1995-06-07

Publications (2)

Publication Number Publication Date
WO1996040087A2 true WO1996040087A2 (fr) 1996-12-19
WO1996040087A3 WO1996040087A3 (fr) 1997-01-30

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/008492 WO1996040087A2 (fr) 1995-06-07 1996-06-03 Composition acrylique adhesive sensible a la pression reticulee avec de l'acetylacetonate d'aluminium et contenant un medicament qui renferme un groupe hydroxy aromatique reactif

Country Status (2)

Country Link
AU (1) AU6032696A (fr)
WO (1) WO1996040087A2 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0836506A1 (fr) * 1995-06-07 1998-04-22 Cygnus, Inc. Timbre transdermique et procede d'administration de 17-deacetyl norgestimate, seul ou en combinaison avec un strogene
WO2001049273A2 (fr) * 2000-01-07 2001-07-12 Lts Lohmann Therapie-Systeme Ag Composition pharmaceutique pour administration transdermique d'hormones avec un additif ameliorant la permeation
WO2001092344A2 (fr) * 2000-06-01 2001-12-06 Kraton Polymers Research, B.V. Compositions comprenant un copolymere bloc fonctionnalise reticule avec de l'acetylacetonate d'aluminium
US6436433B1 (en) * 1997-02-21 2002-08-20 Lts Lohmann Therapie-Systeme Ag Transdermal or topical plaster system with a polyacrylate matrix with improved physical properties
DE10157745A1 (de) * 2001-11-24 2003-06-26 Hf Arzneimittelforsch Gmbh Transdermales therapeutisches System zur Verabreichung von 17alpha-Estradiol
US6653408B1 (en) 2002-11-21 2003-11-25 Kraton Polymers U.S. Llc Compositions comprising a functionalized block copolymer crosslinked with aluminum acetylacetonate
JP2006528144A (ja) * 2003-07-23 2006-12-14 エルテーエス ローマン テラピー−ジステーメ アーゲー プラミペキソール活性剤を含む経皮治療システム
US7576226B2 (en) 2003-06-30 2009-08-18 Richter Gedeon Vegyeszeti Gyar Rt. Process of making isomers of norelgestromin and methods using the same
WO2018022818A1 (fr) 2016-07-27 2018-02-01 Corium International, Inc. Systèmes d'administration transdermique de mémantine
US9993466B2 (en) 2016-07-27 2018-06-12 Corium International, Inc. Donepezil transdermal delivery system
US10016372B2 (en) 2016-07-27 2018-07-10 Corium International, Inc. Transdermal delivery systems with pharmacokinetics bioequivalent to oral delivery
US10251844B2 (en) 1998-03-30 2019-04-09 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system and method of use thereof for treating parkinsonism
US10759076B2 (en) 2014-07-04 2020-09-01 Luye Pharma Ag Device for the manufacture of pharmaceutical patches
US11173132B2 (en) 2017-12-20 2021-11-16 Corium, Inc. Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point
US11541018B2 (en) 2016-06-23 2023-01-03 Corium, Llc Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10234673B4 (de) 2002-07-30 2007-08-16 Schwarz Pharma Ag Heißschmelz-TTS zur Verabreichung von Rotigotin und Verfahren zu seiner Herstellung sowie Verwendung von Rotigotin bei der Herstellung eines TTS im Heißschmelzverfahren

Citations (5)

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EP0435200A2 (fr) * 1989-12-28 1991-07-03 Nitto Denko Corporation Composition de gel contenant des oestrogènes
US5204109A (en) * 1989-12-28 1993-04-20 Nitto Denko Corporation Percutaneous gel preparation
US5240711A (en) * 1989-11-29 1993-08-31 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Transdermal therapeutic system comprising as active component buprenorphine
US5298258A (en) * 1989-12-28 1994-03-29 Nitto Denko Corporation Acrylic oily gel bioadhesive material and acrylic oily gel preparation
US5306503A (en) * 1990-06-25 1994-04-26 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Patch with a high content of softening ingredients

Patent Citations (5)

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US5240711A (en) * 1989-11-29 1993-08-31 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Transdermal therapeutic system comprising as active component buprenorphine
EP0435200A2 (fr) * 1989-12-28 1991-07-03 Nitto Denko Corporation Composition de gel contenant des oestrogènes
US5204109A (en) * 1989-12-28 1993-04-20 Nitto Denko Corporation Percutaneous gel preparation
US5298258A (en) * 1989-12-28 1994-03-29 Nitto Denko Corporation Acrylic oily gel bioadhesive material and acrylic oily gel preparation
US5306503A (en) * 1990-06-25 1994-04-26 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Patch with a high content of softening ingredients

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0836506A4 (fr) * 1995-06-07 1999-05-26 Cygnus Therapeutic Systems Timbre transdermique et procede d'administration de 17-deacetyl norgestimate, seul ou en combinaison avec un strogene
US5972377A (en) * 1995-06-07 1999-10-26 Cygnus, Inc. Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen
US6071531A (en) * 1995-06-07 2000-06-06 Ortho-Mcneil Pharmaceutical, Inc. Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen
EP0836506A1 (fr) * 1995-06-07 1998-04-22 Cygnus, Inc. Timbre transdermique et procede d'administration de 17-deacetyl norgestimate, seul ou en combinaison avec un strogene
US6436433B1 (en) * 1997-02-21 2002-08-20 Lts Lohmann Therapie-Systeme Ag Transdermal or topical plaster system with a polyacrylate matrix with improved physical properties
US10322093B2 (en) 1998-03-30 2019-06-18 Ucb Biopharma Sprl Method for producing a transdermal therapeutic system which contains a D2 agonist
US10251844B2 (en) 1998-03-30 2019-04-09 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system and method of use thereof for treating parkinsonism
WO2001049273A3 (fr) * 2000-01-07 2002-05-23 Lohmann Therapie Syst Lts Composition pharmaceutique pour administration transdermique d'hormones avec un additif ameliorant la permeation
WO2001049273A2 (fr) * 2000-01-07 2001-07-12 Lts Lohmann Therapie-Systeme Ag Composition pharmaceutique pour administration transdermique d'hormones avec un additif ameliorant la permeation
WO2001092344A3 (fr) * 2000-06-01 2002-06-20 Kraton Polymers Res Bv Compositions comprenant un copolymere bloc fonctionnalise reticule avec de l'acetylacetonate d'aluminium
WO2001092344A2 (fr) * 2000-06-01 2001-12-06 Kraton Polymers Research, B.V. Compositions comprenant un copolymere bloc fonctionnalise reticule avec de l'acetylacetonate d'aluminium
DE10157745A1 (de) * 2001-11-24 2003-06-26 Hf Arzneimittelforsch Gmbh Transdermales therapeutisches System zur Verabreichung von 17alpha-Estradiol
US6653408B1 (en) 2002-11-21 2003-11-25 Kraton Polymers U.S. Llc Compositions comprising a functionalized block copolymer crosslinked with aluminum acetylacetonate
US7576226B2 (en) 2003-06-30 2009-08-18 Richter Gedeon Vegyeszeti Gyar Rt. Process of making isomers of norelgestromin and methods using the same
US7816546B2 (en) 2003-06-30 2010-10-19 Richter Gedeon Vegyeszeti Gyar Rt. Process for the synthesis of high purity d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime
JP2006528144A (ja) * 2003-07-23 2006-12-14 エルテーエス ローマン テラピー−ジステーメ アーゲー プラミペキソール活性剤を含む経皮治療システム
JP4925823B2 (ja) * 2003-07-23 2012-05-09 エルテーエス ローマン テラピー−ジステーメ アーゲー プラミペキソール活性剤を含む経皮治療システム
US10759076B2 (en) 2014-07-04 2020-09-01 Luye Pharma Ag Device for the manufacture of pharmaceutical patches
US11541018B2 (en) 2016-06-23 2023-01-03 Corium, Llc Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent
US9993466B2 (en) 2016-07-27 2018-06-12 Corium International, Inc. Donepezil transdermal delivery system
US10307379B2 (en) 2016-07-27 2019-06-04 Corium, Inc. Donepezil transdermal delivery system
US10300025B2 (en) 2016-07-27 2019-05-28 Corium, Inc. Donepezil transdermal delivery system
US10016372B2 (en) 2016-07-27 2018-07-10 Corium International, Inc. Transdermal delivery systems with pharmacokinetics bioequivalent to oral delivery
US10945968B2 (en) 2016-07-27 2021-03-16 Corium, Inc. Memantine transdermal delivery systems
US11103463B2 (en) 2016-07-27 2021-08-31 Corium, Inc. Methods for treating alzheimer's disease with donepezil transdermal system
WO2018022818A1 (fr) 2016-07-27 2018-02-01 Corium International, Inc. Systèmes d'administration transdermique de mémantine
US11173132B2 (en) 2017-12-20 2021-11-16 Corium, Inc. Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point

Also Published As

Publication number Publication date
AU6032696A (en) 1996-12-30
WO1996040087A3 (fr) 1997-01-30

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