AU702710B2 - Transdermal therapeutic system (TTS) for the administration of testosterone - Google Patents

Transdermal therapeutic system (TTS) for the administration of testosterone Download PDF

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Publication number
AU702710B2
AU702710B2 AU58050/96A AU5805096A AU702710B2 AU 702710 B2 AU702710 B2 AU 702710B2 AU 58050/96 A AU58050/96 A AU 58050/96A AU 5805096 A AU5805096 A AU 5805096A AU 702710 B2 AU702710 B2 AU 702710B2
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Australia
Prior art keywords
testosterone
active ingredient
adhesive
acrylate
transdermal therapeutic
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Ceased
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AU58050/96A
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AU5805096A (en
Inventor
Daniel Bracher
Wilfried Fischer
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Hexal AG
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Hexal AG
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Publication of AU702710B2 publication Critical patent/AU702710B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Dermatology (AREA)
  • Reproductive Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nanotechnology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention concerns a transdermal therapeutic system for administering testosterone or a testosterone derivative as the active substance.

Description

testosterone. Of course, if testosterone is present in a less than saturated solution in a transdermal therapeutic system, the presence of permeation enhancers is indispensable to obtain satisfactory blood levels, see WO-A-9 210 231, page 11, line 33.
US-A-4 849 224 proposes a transdermal therapeutic system in which an active ingredient reservoir is formed by a carrier film (backing foil) and a porous membrane. The active ingredient may be testosterone or a testosterone ester.
Permeation enhancers may be provided in addition to the active ingredient. The useability of that known system is, of course, to be viewed critically insofar as the active ingredient reservoir, which is formed by the laminate of carrier film and membrane, is to adhere to the skin by means of a ring of adhesive. Since the adhesive is provided in annular form, in effect there is provided a window through which the active ingredient and the permeation enhancer can penetrate through to the skin via the membrane without the permeation enhancer coming into contact unnecessarily with the adhesive, there being provided additionally annular sealing elements to protect the adhesive. Since only limited adhesion can be obtained with an annular adhesive zone, the size of the known patch is restricted.
WO-A-9 210 231 EP-A-O 562 041 is based on the prior art of US-A-4 849 224, according to which a ring of adhesive is provided for the adhesion of a transdermal therapeutic system to the skin; see WO-A-9 210 231, page 13, lines 18/19.
Alternatively, a basal adhesive layer underlying the reservoir (separate basal adhesive layer underlaying the reservoir) and also an adhesive coating for the reservoir (adhesive overlay for the reservoir) are proposed. Since, in accordance with that prior art, the use of a permeation enhancer is, however, indispensable for the administration of testosterone, it is not clear how WO-A-9 210 231 seeks to prevent the undesirable penetration of the permeation enhancer into the adhesive if the adhesive is not provided in annular form.
WO-A-9 503 764, WO-A-9 423 707 and US-A-5 152 997 also describe transdermal therapeutic systems for the administration of testosterone, those systems being reservoir systems in which the active ingredient is present in less than saturated form and in which a permeation accelerator is provided. Those known teachings r thus correspond to the prior art as discussed by WO-A-9 210 231, page 11, line 33.
The problem underlying the invention is to provide a transdermal therapeutic system for the administration of testosterone or a testosterone derivative that does not require the use of permeation enhancers and guarantees satisfactory levels of the active ingredient in the blood.
For that purpose, there is proposed according to the invention a transdermal therapeutic system (TTS) for the administration of testosterone or a testosterone derivative as active ingredient, h-eing a carrier film (backing foil), a reservoir, an alcoholic carrier for the acti',e ingredient, an adhesive layer for contact ci :he system with the skin, and a removable cover film (release liner), in which the system does not comprise a permeation enhancer, the active ingredient is presenr n saturation in the carrier for the active ingredient, and there is provided between the reservoir and the adhesive layer a membrane which does not control the release of active ingredient, whilst the adhesive layer does control the release of active ingredient.
The invention is based on the sL-orising observation that a satisfactory level of active ingredient in the blood car be obtained also, or rather especially, when the active ingredient is present in sar.ration in the carrier for the active ingredient, whereas WO-A-9 210 231 requi:es undersaturation of the active ingredient.
According to the invention, there may be'used as testosterone derivative a testosterone ester, especially testosterone enanthate, testosterone cipionate, testosterone propionate or testosterone undecanoate, or a lower alkyl testosterone, especially methyl testosterone.
The active ingredient may be prssent in the form of a complex with cyclodextrin or cyclodextrin derivatives, especiaIly with (3-cyclodextrin.
The membrane may be a polyethylene or polypropylene membrane.
According to a preferred embodiment, the reservoir is formed by the carrier film and the membrane.
According to the invention, the alcoholic carrier for the active ingredient may be ethanol or a low molecular weight monohydric alcohol, such as isopropanol, or a low molecular weight polyhydric alcohol, for example propylene glycol, or mixtures thereof.
For the adhesive layer according to the invention there may be selected a pressuresensitive alcohol-resistant adhesive based, for example, on polyurethane, isobutylene, polyvinyl ether, silicone or acrylate.
The silicone-based adhesive may be a silicone adhesive that is based on two main components: a polymer or adhesive, especially polysiloxane, and a tackifying resin.
The polysiloxane adhesive is usually formulated with a cross-linker for the adhesive, typically a high molecular weight polydiorganosiloxane, and with the resin to yield a three-dimensional silicate structure using an appropriate organic solvent. The admixture of the resin with the polymer is the most important factor for changing the physical properties of the polysiloxane adhesives; see, for example, Sobieski et al., "Silicone Pressure Sensitive Adhesives", Handbook of Pressure Sensitive Adhesive Technology, 2nd ed., pp. 508-517 Satas, Van Nostrand Reinhold, New York (1989).
Suitable pressure-sensitive silicone adhesives are obtainable commercially under the trade mark BIO-PSA X7.
A further example of a silicone-based pressure-sensitive adhesive is trimethylated silicon dioxide that has been treated with polydimethylsiloxane having terminal trimethylsiloxy groups.
The acrylate-based adhesive may be any homopolymer, copolymer or terpolymer, consisting of various acrylic acid derivatives.
For example, the acrylate polymers may be polymers of one or more monomers of acrylic acids and other copolymerisable monomers. The acrylate polymers may also comprise copolymers of alkyl acrylates and/or methacrylates and/or copolymerisable secondary monomers or monomers having functional groups. The cohesive properties of the resulting acrylate polymers can be altered by altering the amount of each type that is added as monomer. Generally, the acrylate polymer consists of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate or alkyl methacrylate monomer, from 0 to 20% of a functional monomer, copolymerisable with acrylate, and from 0 to 40% of a different monomer.
Given hereinafter are acrylate monomers that can be used with acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate.
For example, there may be used functional monomers that are copolymerisable with the above-mentioned acrylates, methacrylates, alkyl acrylates or alkyl methacrylates, for example acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate.
Other details and examples of pressure-sensitive acrylates that are suitable for the invention are described in Satas Handbook of Pressure Sensitive Adhesive Technology "Acrylic Adhesives", 2nd ed., pp. 396-456 Satas, Van Nostrand Reinhold, New York (1989).
Suitable pressure-sensitive acrylates are obtainable commercially.
The transdermal therapeutic system according to the invention may additionally comprise a-tocopherol or an a-tocopherol derivative and/or a viscosity-increasing agent, such as hydroxypropyl cellulose.
The invention is illustrated hereinafter in greater detail by a Figure and an Example.
According to Figure 1, a transdermal therapeutic system according to the invention may comprise a carrier film (backing foil) which may be of slightly convex form, which together with a membrane forms a reservoir the membrane not controlling the release of active ingredient. Applied to the membrane according to Figure 1, is an adhesive layer which controls the release of active ingredient.
That adhesive layer is in turn covered by a cover film (release liner) which is to be removed before administration. According to the Figure, the carrier film (1) may be provided with an annular bead which lies on the circumferential edge region of the adhesive layer and is sealed to the membrane in the region of contact.
Example For the adhesive layer there is used a silicone-based pressure-sensitive adhesive (trimethylated silicon dioxide that has been treated with polydimethylsiloxane having terminal trimethylsiloxy groups; layer thickness when dry approximately from 35 to jIm; weight per unit surface area approximately from 50 to 60 g/m 2 A cover film of PET (thickness approximately 75 jim; weight per unit surface area approximately 100 g/m 2 is coated with the silicone adhesive by means of a coating apparatus. A microporous polyethylene membrane or a microporous polypropylene membrane (heat-sealable; thickness approximately 50 gm; weight per unit surface area approximately 10 g/m 2 is then laminated onto the coated cover film to produce a laminate of cover film, adhesive and membrane. The laminate is then welded onto a carrier film of polyester (aluminized with polyolefin sealing layer (heat-sealable); thickness approximately 70 [tm) by means of a sealing machine (having a welding ring) in such a manner that a gap remains for the introduction of an active ingredient solution. The fillable transdermal therapeutic system (empty TTS) is filled, for example using a Hamilton syringe or a tube pump equipped with a cannula, with the following active ingredient solution: Composition of the active ingredient solution per TTS: mg/TTS testosterone 96% ethanol propylene glycol oc-tocopherol hydroxypropyl cellulose Total 60.56 157.18 48.11 56.78 5.98 328.61 Filling volume of the reservoir: Density of the active ingredient solution: Filled amount in the reservoir: After filling, the filling gap is welded. Filled punched out by means of a punch.
360 RI 0.91285 g/cm 3 328.6 mg transdermal therapeutic systems are Patent Claims 1. Transdermal therapeutic system (TTS) for the administration of testosterone or a testosterone derivative as active ingredient, having a carrier film (backing foil), a reservoir, an alcoholic carrier for the active ingredient, an adhesive layer for contact of the system with the skin, and a removable cover film (release liner), in which the system does not comprise a permeation enhancer apart from the alcoholic carrier for the active ingredient, the active ingredient is present in saturation in the carrier for the active ingredient, and there is provided between the reservoir and the adhesive layer a membrane which does not control the release of active ingredient, whilst the adhesive layer does control the release of active ingredient.
2. System according to claim 1, characterised by a testosterone ester, especially testosterone enanthate, testosterone cipionate, testosterone propionate or testosterone undecanoate, or a lower alkyl testosterone, especially methyl testosterone, as testosterone derivative.
3. System according to claim 1 or claim 2, characterised in that the active ingredient is present in the form of a complex with cyclodextrin or a cyclodextrin derivative, especially -cyclodextrin.
4. System according to any one of the preceding claims, characterised in that the reservoir is formed by the carrier film and the membrane.
System according to any one of the preceding claims, characterised by ethanol or a low molecular weight monohydric or polyhydric alcohol, especially propylene glycol, or mixtures thereof, as alcoholic carrier for the active ingredient.

Claims (3)

  1. 6. System according to any one of the preceding claims, characterised by an adhesive layer of a pressure-sensitive, alcohol-resistant adhesive based on poly- urethane, isobutylene, polyvinyl ether, silicone or acrylate.
  2. 7. System according to any one of the preceding claims, characterised in that the carrier for the active ingredient additionally comprises a-tocopherol or an a- tocopherol derivative.
  3. 8. System according to any one of the preceding claims, characterised in that the carrier for the active ingredient additionally comprises a viscosity-increasing agent, such as hydroxypropyl cellulose. Abstract The invention relates to a transdermal therapeutic system for the administration of testosterone or a testosterone derivative as active ingredient.
AU58050/96A 1995-05-10 1996-05-10 Transdermal therapeutic system (TTS) for the administration of testosterone Ceased AU702710B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19517145 1995-05-10
DE19517145A DE19517145C2 (en) 1995-05-10 1995-05-10 Transdermal therapeutic system (TTS) for administration of testosterone
PCT/EP1996/002013 WO1996035427A1 (en) 1995-05-10 1996-05-10 Transdermal therapeutic system for administering testosterone

Publications (2)

Publication Number Publication Date
AU5805096A AU5805096A (en) 1996-11-29
AU702710B2 true AU702710B2 (en) 1999-03-04

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AU58050/96A Ceased AU702710B2 (en) 1995-05-10 1996-05-10 Transdermal therapeutic system (TTS) for the administration of testosterone

Country Status (17)

Country Link
EP (1) EP0825865B1 (en)
JP (1) JPH11504643A (en)
CN (1) CN1183723A (en)
AT (1) ATE208200T1 (en)
AU (1) AU702710B2 (en)
BR (1) BR9608255A (en)
CA (1) CA2220358A1 (en)
CZ (1) CZ287678B6 (en)
DE (2) DE19517145C2 (en)
DK (1) DK0825865T3 (en)
HU (1) HUP9801130A3 (en)
NO (1) NO975140L (en)
NZ (1) NZ308516A (en)
PL (1) PL323145A1 (en)
SK (1) SK149797A3 (en)
WO (1) WO1996035427A1 (en)
ZA (1) ZA963743B (en)

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AU1429697A (en) * 1995-12-29 1997-07-28 Cygnus, Inc. Systems and methods for the transdermal administration of androgenic agents
US6007837A (en) * 1996-07-03 1999-12-28 Alza Corporation Drug delivery devices and process of manufacture
AU721267B2 (en) * 1996-07-03 2000-06-29 Alza Corporation Drug delivery devices and process of manufacture
DE19646050A1 (en) * 1996-11-08 1998-05-14 Labtec Gmbh Transdermal therapeutic system e.g. containing testosterone, melatonin
US6174545B1 (en) 1997-07-01 2001-01-16 Alza Corporation Drug delivery devices and process of manufacture
ES2226394T3 (en) * 1998-05-22 2005-03-16 Novosis Ag TRANSDERMAL SYSTEMS CONTAINING ACTIVE SUBSTANCE THAT IS RELEASED CONTROLLED IN TIME.
FR2793689B1 (en) * 1999-05-19 2001-08-24 Pf Medicament TRANSDERMAL DEVICE FOR THE ADMINISTRATION OF TESTOSTERONE OR A DERIVATIVE THEREOF
US6503894B1 (en) 2000-08-30 2003-01-07 Unimed Pharmaceuticals, Inc. Pharmaceutical composition and method for treating hypogonadism
EP1611882B1 (en) 2004-06-01 2010-04-07 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch
GEP20125432B (en) 2005-10-12 2012-03-26 Unimed Pharmaceuticals Llc Improved testosterone gel and use thereof
FR2895679B1 (en) * 2005-12-29 2012-06-08 Pf Medicament STABILIZATION OF TESTOSTERONE IN TRANSDERMAL DEVICES
CN101480399B (en) * 2008-09-25 2011-10-05 宋博 Application of andrusol in preparing medicament for treating asthenospermia
DE102011012712A1 (en) 2011-03-01 2012-09-06 Frank Lehmann-Horn Use of aldosterone receptor antagonists for the treatment of female sexual dysfunction

Citations (3)

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US4704282A (en) * 1984-06-29 1987-11-03 Alza Corporation Transdermal therapeutic system having improved delivery characteristics
US4849224A (en) * 1987-11-12 1989-07-18 Theratech Inc. Device for administering an active agent to the skin or mucosa
WO1992010231A1 (en) * 1990-12-11 1992-06-25 Theratech, Inc. Subsaturated transdermal drug delivery device exhibiting enhanced drug flux

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US4286592A (en) * 1980-02-04 1981-09-01 Alza Corporation Therapeutic system for administering drugs to the skin
US4725439A (en) * 1984-06-29 1988-02-16 Alza Corporation Transdermal drug delivery device
GB8804164D0 (en) * 1988-02-23 1988-03-23 Tucker J M Bandage for administering physiologically active compound
US5474783A (en) * 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
PT100502A (en) * 1991-05-20 1993-08-31 Alza Corp PHARMACEUTICAL COMPOSITIONS FOR INCREASING THE CAPACITY OF PERMEACAO IN THE SKIN USING GLYCEROL MONOLINOLEATE
CA2075517C (en) * 1992-04-01 1997-03-11 John Wick Transdermal patch incorporating a polymer film incorporated with an active agent
CA2135925C (en) * 1992-06-11 2001-04-10 Werner E. Heiber Use of glycerin in moderating transdermal drug delivery
DE59405277D1 (en) * 1993-04-20 1998-03-26 Hexal Ag ACTIVE SUBSTANCE PLASTER
DE4313402A1 (en) * 1993-04-23 1994-10-27 Hexal Pharma Gmbh Transdermal preparation of active compound
US5460820B1 (en) * 1993-08-03 1999-08-03 Theratech Inc Method for providing testosterone and optionally estrogen replacement therapy to women

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Publication number Priority date Publication date Assignee Title
US4704282A (en) * 1984-06-29 1987-11-03 Alza Corporation Transdermal therapeutic system having improved delivery characteristics
US4849224A (en) * 1987-11-12 1989-07-18 Theratech Inc. Device for administering an active agent to the skin or mucosa
WO1992010231A1 (en) * 1990-12-11 1992-06-25 Theratech, Inc. Subsaturated transdermal drug delivery device exhibiting enhanced drug flux

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Publication number Publication date
EP0825865A1 (en) 1998-03-04
BR9608255A (en) 1999-02-02
PL323145A1 (en) 1998-03-16
ATE208200T1 (en) 2001-11-15
CN1183723A (en) 1998-06-03
DE19517145C2 (en) 2000-02-24
EP0825865B1 (en) 2001-11-07
DE59608150D1 (en) 2001-12-13
WO1996035427A1 (en) 1996-11-14
NZ308516A (en) 1999-05-28
NO975140D0 (en) 1997-11-07
ZA963743B (en) 1996-11-18
DK0825865T3 (en) 2002-02-18
HUP9801130A3 (en) 2001-03-28
HUP9801130A2 (en) 1998-08-28
DE19517145C1 (en) 1996-11-28
JPH11504643A (en) 1999-04-27
CZ287678B6 (en) 2001-01-17
NO975140L (en) 1997-11-10
CZ351297A3 (en) 1998-03-18
SK149797A3 (en) 1998-05-06
AU5805096A (en) 1996-11-29
CA2220358A1 (en) 1996-11-14

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