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AU762589B2 - Estradiol-containing patch for transdermal administration of hormones - Google Patents
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AU762589B2 - Estradiol-containing patch for transdermal administration of hormones - Google Patents

Estradiol-containing patch for transdermal administration of hormones Download PDF

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Publication number
AU762589B2
AU762589B2 AU52842/99A AU5284299A AU762589B2 AU 762589 B2 AU762589 B2 AU 762589B2 AU 52842/99 A AU52842/99 A AU 52842/99A AU 5284299 A AU5284299 A AU 5284299A AU 762589 B2 AU762589 B2 AU 762589B2
Authority
AU
Australia
Prior art keywords
active substance
containing patch
pressure
patch according
reservoir
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
AU52842/99A
Other versions
AU5284299A (en
Inventor
Elvira Kirstgen
Reinhold Meconi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LTS Lohmann Therapie Systeme AG
Original Assignee
LTS Lohmann Therapie Systeme AG
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 LTS Lohmann Therapie Systeme AG filed Critical LTS Lohmann Therapie Systeme AG
Publication of AU5284299A publication Critical patent/AU5284299A/en
Application granted granted Critical
Publication of AU762589B2 publication Critical patent/AU762589B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal 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
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053Transdermal 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
    • A61K9/7061Polyacrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565Compounds 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/20Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing organic materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/58Adhesives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/24Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34Gestagens

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hematology (AREA)
  • Materials Engineering (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)

Description

Estradiol-containing patch for transdermal application of hormones The invention relates to an active substance-containing patch for controlled release of estradiol or its pharmaceutically acceptable derivatives, alone or in combination with gestagens, to the human or animal skin.
Estrogen- and/or gestagen-containing patches are already known. They do, however, have disadvantages in that they either contain ethanol or involve the potential danger of the active substance recrystallizing in the course of time.
From DE-OS 32 05 258 and EP 0 285 563 it is known to simultaneously administer estradiol and ethanol in a patch formulation. The production of this patch is, however, very complicated, and the patches have little wearing comfort after they have been applied, since they lack flexibility.
EP 0 285 563 describes a transdermal therapeutic system for the combined application of estrogens and gestagens. The reservoir contains the active substance formulation and optionally a membrane, as well as ethanol as percutaneous, absorption-enhancing agent. Since the release of active substance is mainly controlled by the membrane, this transdermal therapeutic system is fundamentally different from the active substance patch according to the present invention. In the patch described by this document, the adhesive merely has the function of fixing the patch on the skin. The fact that it is capable of contributing to the control of the active substance release does not constitute its main task, but is merely a possibly even unwanted side effect. The patch is a so-called "pouch patch", since the active substance formulation is present within a pouch, consisting of an impermeable backing layer and a membrane with adhesive layer. As a consequence of its complicated structure, the production of this patch requires great expenditure since the individual components must be prepared separately and then, in a further process step, combined to form a patch.
EP 0 275 716 describes a transdermal two-layer system in contrast to the mono-layer system of the present invention for simultaneous administration of one or more estrogens, which are dissolved or microdispersed in the polymer layer.
Here, the pressure-sensitive layer contains, apart from the active compounds, substances which enhance transdermal absorption. Polymer and pressure-sensitive layers may consist of polyacrylates, silicones or polyisobutylenes.
EP 0 328 806 describes a membrane-free transdermal therapeutic system the matrix of which consists of a polyacrylate adhesive, a solvent, a penetration enhancer and estrogens, its derivatives and combinations thereof.
WO 87/07138 describes an estradiol patch comprising a backing layer, a matrix containing the active substance, and a pressure-sensitive adhesive, which adhesive is covered by a removable protective layer. The production of the matrix and pressure-sensitive adhesive is carried out in process steps requiring a great expenditure in terms of the technology to be applied, by homogenizing, degasifying, coating, drying and separating into individual pieces. In one embodiment, the backing layer must even be coated with a pressure-sensitive adhesive, which means a further process step. The combining of the individual parts takes place in a separate process step. The overall production of the patch thus involves great expenditure and is complicated.
From US 4 624 665, systems are known which contain the active substance in microencapsuled form in the reservoir. The reservoir is embedded between a backing layer and a membrane.
The outer margin of the system is provided with a pressuresensitive adhesive. The structure and production of this system is very complicated since the active substance must be microencapsulated and distributed in a homogenous phase, which then, in further process steps, must be embedded between backing layer and membrane. In addition, the system must then be provided with an adhesive margin and covered with a protective layer.
Further, from EP 0 186 019 active substance patches are known wherein to a rubber/adhesive resin mass are added waterswellable polymers, and from which patches estradiol can be released. It has, however, emerged that the release of estradiol from these active substance patches is too low by far and does not meet therapeutic requirements.
In DE-OS 20 06 969 a patch or an adhesive bandage is described which has systemic action and wherein contraceptive substances are incorporated in the adhesive component or the adhesive film. The adhesive film may be an acrylate.
Thus the present invention seeks to avoid the abovementioned disadvantages and to provide a stable, i.e.
recrystallization-free estrogen- and/or gestagen-containing patch having sufficient active substance release, whose release is not subject to change by storage.
Surprisingly, it has emerged that this may be achieved by an estrogen- and/or gestagen-containing pressure-sensitive adhesive which contains cholesterol or corn starch.
According to one aspect, the present invention provides an active substance-containing patch according to the main claim. The oo subclaims relate to especially preferred embodiments of the subject matter of the invention.
As now claimed, according to one aspect, the present invention provides active substance-containing patch for controlled release of estradiol or its pharmaceutically acceptable derivatives in combination with gestagens to the human or animal skin, consisting of a backing layer, an active substance-containing reservoir connected thereto which is suitable for combined active substance release and has been produced using pressure-sensitive adhesives and comprises a crystallization inhibitor, and of a detachable protective layer, characterized in that the hormonecontaining pressure-sensitive adhesive of the active substance-containing reservoir contains 1-20%-wt. of corn starch as crystallization inhibitor.
Cholesterol is known as a pharmaceutical raw material and is described as such by the pharmacopoeias. Cholesterol acts as a swelling-regulating substance and as protective substance.
It is used by reason of its being well tolerated by the skin since it makes the epidermis soft and smooth. In addition, it increases the water absorption capability.
Corn starch is also described in the pharmacopoeias. Corn starch is used because of its adhesive power and absorption capacity, and because of its swelling capacity.
The active substance patch according to the invention can be used for cosmetic as well as therapeutic purposes in human and veterinary medicine.
S The recrystallization-free estrogen- and/or gestagencontaining patch having sufficient active substance release contains in its reservoir estradiol and its pharmaceutically acceptable derivatives, alone or in combination with gestagens, in a concentration of a total of 1 relative to the totality of the reservoir components, in fact in a molar ratio of 1:1 to 1:10.
The estradiol-containing reservoir may contain at least one component belonging to the- group comprising age-protecting agents, plasticizers, antioxidants and absorption enhancers.
Suitable plasticizers are known to those skilled in the art, and are described, for example, in DE 37 43 946. The estradiol-containing reservoir usually contains plasticizers in a portion of up to Furthermore, the reservoir contains age-protecting agents in a concentration of up to l%-wt. These are known to those *e
C
.e 0 skilled in the art and are described, for example, in DE 37 43 946.
The materials for the impermeable backing layer and the detachable protective layer are also known to those skilled in the art.
The estradiol-containing reservoir may be made from the solution, dispersion and from the melt.
In case the reservoir has no sufficient inherent tack on the skin, it can be provided with an additional active substancefree pressure-sensitive adhesive or with a circumferential pressure-sensitive adhesive margin. In this way it is ensured that the transdermal patch adheres on the skin over the entire period of application.
A particularly preferred structure of the transdermal estradiol-containing patch is a matrix system, wherein, as is known, the matrix takes over the control of the active substance release and is subject to the 4t-law according to Higuchi. This does not mean, however, that a membrane system is not of advantage in special cases. In membrane systems, an active substance release-controlling membrane is located between reservoir and pressure-sensitive adhesive layer.
The thickness of the transdermal patch is dependent on the therapeutic requirements and can be adjusted accordingly.
Usually, it ranges from 0.03 0.6 mm.
In the following, the invention will be illustrated by way of embodiment examples.
EXAMPLE 1: 131.91 g 3.2 55.89 of Durotak 387-2287 solution (67.8 g of solid matter) of cholesterol of ethanol/acetic acid ethyl ester (2:1 g/g) are homogenized by stirring at room temperature.
Subsequently, of estradiol hemihydrate and norethindrone acetate are added and this is stirred for about 2 hours.
The resultant active substance-containing adhesive mass is coated on the detachable protective layer (Hostaphan RN 100, coated on one side with silicone by Hoechst Diafoil) such that an active substance-containing reservoir having a weight per unit area of approximately 80 g/m 2 results. On this reservoir is laminated the impermeable backing layer (polyester film, 19 upm-thick). Subsequently, active substance patches of 16 cm 2 are punched out.
EXAMPLE 2: 131.91 3.2 55.89 of Durotak 387-2287 solution (67.8 g of solids) of corn starch of ethanol/acetic acid ethyl ester (2:1 g/g) are homogenized by stirring at room temperature.
Subsequently, of estradiol hemihydrate and norethindrone acetate are added and this is stirred for about 2 hours.
The resultant active substance-containing adhesive mass is coated on the detachable protective layer (Hostaphan RN 100, coated on one side with silicone by Hoechst Diafoil) such that an active substance-containing reservoir having a weight per unit area of approximately 80 g/m 2 results. On this reservoir is laminated the impermeable backing layer (polyester film, 19 mn-thick). Subsequently, active substance patches of 16 cm 2 are punched out.
For measuring the human skin penetration, the skin is clamped into the Franz cell. An estrogen- and/or gestagen-containing patch having a surface of 1.539 cm 2 is stuck on this skin and the active substance release is measured at 37 oC (acceptor medium: 0.9% sodium chloride solution 0.1% NaN 3 The examination on recrystallization phenomena is carried through in counterlight.
The results are listed in Table 1.
TABLE 1: Analysis results Active substance Human skin Example content penetration Recrystalug/16 cm 2 pg/16 cm 2 lisation (24-48 Std.) Es NeA Es NeA 1 3.200 11.200 97 131 none 2 3.200 11.200 173 163 none Comparison product 3.200 11.200 33 46 consider- Evorel able Conti Es: Estradiol hemihydrate NeA: Norethindrone acetate 8 As is shown by the Table, with the patch according to the invention one obtains a clearly increased penetration through the human skin as compared to the comparison product. At the same time it can be ascertained that in the examples according to the invention no recrystallization occurs.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that the prior art forms part of the common general knowledge in Australia.
oo **e oo* *oo

Claims (12)

1. Active substance-containing patch for controlled release of estradiol or its pharmaceutically acceptable derivatives in combination with gestagens to the human or animal skin, consisting of a backing layer, an active substance-containing reservoir connected thereto which is suitable for combined active substance release and has been produced using pressure-sensitive adhesives and comprises a crystallization inhibitor, and of a detachable protective layer, characterized in that the hormone-containing pressure- sensitive adhesive of the active substance-containing reservoir contains 1-20%-wt. of corn starch as crystal- lization inhibitor.
2. Active substance-containing patch according to Claim 1, characterized in that the reservoir contains estradiol or its pharmaceutically acceptable derivatives, alone or in combination with gestagens, in a portion of 1 preferably 1.5
3. Active substance-containing patch according to Claim 1 or 2, characterized in that the reservoir contains estradiol or its pharmaceutically acceptable derivatives, alone or in combination with gestagens, in a molar ratio of 1:1 to 1:10.
4. Active substance-containing patch according to any one of Claims 1 to 3, characterized in that the pressure- sensitive adhesive contains tackifying resins in a concentration of 1 Active substance-containing patch according to one or more of Claims 1 to 4, characterized in that the reservoir contains at least one component belonging to the group of age-protecting agents, antioxidants and absorption enhancers. *o.
6. Active substance-containing patch according to one or more of Claims 1 to 5, characterized in that the pressure- sensitive adhesive is a pressure-sensitive solution adhesive, a pressure-sensitive dispersion adhesive or a pressure- sensitive hot-melt adhesive.
7. Active substance-containing patch according to one or more of Claims 1 to 6, characterized in that the backing layer is impermeable to the components of the reservoir.
8. Active substance-containing patch according to one or more of Claims 1 to 7, characterized in that the reservoir consists of several layers and is provided with an additional active substance-containing pressure-sensitive adhesive layer.
9. Active substance-containing patch according to one or more of Claims 1 to 8, characterized in that an active substance release-controlling membrane is provided between the reservoir and the pressure-sensitive adhesive layer. Active substance-containing patch according to one or more of Claims 1 to 9, characterized in that the reservoir is provided with a circumferential, pressure-sensitive adhesive margin.
11. Active substance-containing patch according to one or more of Claims 1 to 10, characterized in that the thickness of the active substance-containing patch is in the range of 0.03 0.6 mm.
12. Use of the active substance-containing patch according to Claims 1 to 11 for cosmetic purposes.
13. Use of the active substance-containing patch according to one of Claims 1 to 11 as a preparation for therapeutic purposes in human or veterinary medicine. 11
14. Active substance-containing patch and use thereof substantially as hereinbefore described with reference to examples 1 and 2. DATED THIS 30th day of April, 2003. LTS LOHMANN THERAPIE-SYSTEME AG By Its Patent Attorneys DAVIES COLLISON CAVE 99* *9 9** *9
AU52842/99A 1998-07-29 1999-07-16 Estradiol-containing patch for transdermal administration of hormones Ceased AU762589B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19834006 1998-07-29
DE19834006A DE19834006A1 (en) 1998-07-29 1998-07-29 Estradiol-containing patch for the transdermal application of hormones
PCT/EP1999/005084 WO2000006130A1 (en) 1998-07-29 1999-07-16 Estradiol-containing patch for transdermal administration of hormones

Publications (2)

Publication Number Publication Date
AU5284299A AU5284299A (en) 2000-02-21
AU762589B2 true AU762589B2 (en) 2003-06-26

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Family Applications (1)

Application Number Title Priority Date Filing Date
AU52842/99A Ceased AU762589B2 (en) 1998-07-29 1999-07-16 Estradiol-containing patch for transdermal administration of hormones

Country Status (14)

Country Link
EP (1) EP1100478A1 (en)
JP (1) JP2002521426A (en)
KR (1) KR20010072071A (en)
CN (1) CN1310615A (en)
AR (1) AR019948A1 (en)
AU (1) AU762589B2 (en)
BR (1) BR9912688A (en)
CA (1) CA2338861A1 (en)
DE (1) DE19834006A1 (en)
IL (1) IL141032A0 (en)
PL (1) PL345696A1 (en)
TR (1) TR200100290T2 (en)
WO (1) WO2000006130A1 (en)
ZA (1) ZA200100721B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005047906A (en) * 2003-07-16 2005-02-24 Taisho Pharmaceut Co Ltd Anti-inflammatory analgesic composition for external use
KR100689534B1 (en) * 2005-05-18 2007-03-02 삼성전자주식회사 Handheld terminal

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008795A1 (en) * 1991-10-31 1993-05-13 Schering Aktiengesellschaft Transdermal therapeutic systems containing crystallization inhibitors
EP0737477A1 (en) * 1993-12-27 1996-10-16 Akzo Nobel N.V. Percutaneously absorbable preparation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH674618A5 (en) * 1987-04-02 1990-06-29 Ciba Geigy Ag
US5676968A (en) * 1991-10-31 1997-10-14 Schering Aktiengesellschaft Transdermal therapeutic systems with crystallization inhibitors
DE4229820C2 (en) * 1992-09-07 1998-12-03 Jenapharm Gmbh Progestogen-based pharmaceutical preparation
DE4416927C1 (en) * 1994-05-13 1995-08-31 Lohmann Therapie Syst Lts Device for release of active agents from melt-type adhesive

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008795A1 (en) * 1991-10-31 1993-05-13 Schering Aktiengesellschaft Transdermal therapeutic systems containing crystallization inhibitors
EP0737477A1 (en) * 1993-12-27 1996-10-16 Akzo Nobel N.V. Percutaneously absorbable preparation

Also Published As

Publication number Publication date
KR20010072071A (en) 2001-07-31
IL141032A0 (en) 2002-02-10
ZA200100721B (en) 2002-05-27
BR9912688A (en) 2001-11-27
PL345696A1 (en) 2002-01-02
EP1100478A1 (en) 2001-05-23
JP2002521426A (en) 2002-07-16
AR019948A1 (en) 2002-03-27
AU5284299A (en) 2000-02-21
WO2000006130A1 (en) 2000-02-10
DE19834006A1 (en) 2000-02-24
TR200100290T2 (en) 2001-07-23
CA2338861A1 (en) 2000-02-10
CN1310615A (en) 2001-08-29

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