CA2591076A1 - Transdermal plaster with progesterone a-specific ligands (prasl) as an active ingredient - Google Patents
Transdermal plaster with progesterone a-specific ligands (prasl) as an active ingredient Download PDFInfo
- Publication number
- CA2591076A1 CA2591076A1 CA002591076A CA2591076A CA2591076A1 CA 2591076 A1 CA2591076 A1 CA 2591076A1 CA 002591076 A CA002591076 A CA 002591076A CA 2591076 A CA2591076 A CA 2591076A CA 2591076 A1 CA2591076 A1 CA 2591076A1
- Authority
- CA
- Canada
- Prior art keywords
- active ingredient
- transdermal patch
- matrix
- patch according
- adhesive
- 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.)
- Abandoned
Links
- 239000004480 active ingredient Substances 0.000 title claims abstract description 81
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 title claims abstract description 12
- 239000003446 ligand Substances 0.000 title claims abstract description 6
- 239000000186 progesterone Substances 0.000 title claims abstract description 6
- 229960003387 progesterone Drugs 0.000 title claims abstract description 6
- 239000011505 plaster Substances 0.000 title abstract description 4
- 229920000642 polymer Polymers 0.000 claims abstract description 16
- 229920002367 Polyisobutene Polymers 0.000 claims abstract description 11
- 239000012790 adhesive layer Substances 0.000 claims abstract description 11
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims abstract description 6
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000010410 layer Substances 0.000 claims abstract description 6
- 239000000262 estrogen Substances 0.000 claims abstract description 4
- 229920000058 polyacrylate Polymers 0.000 claims abstract description 4
- 230000001681 protective effect Effects 0.000 claims abstract description 3
- 229920006132 styrene block copolymer Polymers 0.000 claims abstract description 3
- 239000011159 matrix material Substances 0.000 claims description 55
- 239000000853 adhesive Substances 0.000 claims description 46
- 230000001070 adhesive effect Effects 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000011347 resin Substances 0.000 claims description 5
- 229920005989 resin Polymers 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 4
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 4
- 229920001531 copovidone Polymers 0.000 claims description 4
- 229920001519 homopolymer Polymers 0.000 claims description 4
- 239000002105 nanoparticle Substances 0.000 claims description 4
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229920001296 polysiloxane Polymers 0.000 claims description 3
- JWYVGKFDLWWQJX-UHFFFAOYSA-N 1-ethenylazepan-2-one Chemical compound C=CN1CCCCCC1=O JWYVGKFDLWWQJX-UHFFFAOYSA-N 0.000 claims description 2
- PBGPBHYPCGDFEZ-UHFFFAOYSA-N 1-ethenylpiperidin-2-one Chemical compound C=CN1CCCCC1=O PBGPBHYPCGDFEZ-UHFFFAOYSA-N 0.000 claims description 2
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 claims description 2
- UOACKFBJUYNSLK-XRKIENNPSA-N Estradiol Cypionate Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H](C4=CC=C(O)C=C4CC3)CC[C@@]21C)C(=O)CCC1CCCC1 UOACKFBJUYNSLK-XRKIENNPSA-N 0.000 claims description 2
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 claims description 2
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims description 2
- 229960005309 estradiol Drugs 0.000 claims description 2
- 229960005416 estradiol cypionate Drugs 0.000 claims description 2
- 229960004766 estradiol valerate Drugs 0.000 claims description 2
- 229960002568 ethinylestradiol Drugs 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- 239000011859 microparticle Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 229920005573 silicon-containing polymer Polymers 0.000 claims description 2
- UYIFTLBWAOGQBI-BZDYCCQFSA-N Benzhormovarine Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4O)C)CC2=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-BZDYCCQFSA-N 0.000 claims 1
- 229960003575 estradiol acetate Drugs 0.000 claims 1
- FHXBMXJMKMWVRG-SLHNCBLASA-N estradiol acetate Chemical compound C1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(OC(=O)C)=CC=C3[C@H]21 FHXBMXJMKMWVRG-SLHNCBLASA-N 0.000 claims 1
- 229950002007 estradiol benzoate Drugs 0.000 claims 1
- 230000035558 fertility Effects 0.000 abstract description 2
- 238000002657 hormone replacement therapy Methods 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 abstract 1
- 229940011871 estrogen Drugs 0.000 abstract 1
- 229910052710 silicon Inorganic materials 0.000 abstract 1
- 239000010703 silicon Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 11
- 239000006185 dispersion Substances 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 11
- 239000004615 ingredient Substances 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000007792 addition Methods 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- UAXPVEKEMXWFNV-HXUWFJFHSA-N (2r)-3,3,3-trifluoro-2-[[1-[2-fluoro-5-(trifluoromethyl)phenyl]cyclopropyl]methyl]-2-hydroxy-n-(1-oxo-3h-2-benzofuran-5-yl)propanamide Chemical compound C([C@@](O)(C(=O)NC=1C=C2COC(=O)C2=CC=1)C(F)(F)F)C1(C=2C(=CC=C(C=2)C(F)(F)F)F)CC1 UAXPVEKEMXWFNV-HXUWFJFHSA-N 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000012907 medicinal substance Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- 229920002402 Oppanol® B 100 Polymers 0.000 description 2
- 229920002422 Oppanol® B 12 SFN Polymers 0.000 description 2
- 206010040914 Skin reaction Diseases 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000000622 irritating effect Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000011241 protective layer Substances 0.000 description 2
- 231100000430 skin reaction Toxicity 0.000 description 2
- 230000035483 skin reaction Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 101100465509 Arabidopsis thaliana PSAO gene Proteins 0.000 description 1
- RRDBGKFTNJDTBK-WAJSLEGFSA-N OC(=O)C1=CC=CC=C1.OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)O)[C@@H]4[C@@H]3CCC2=C1 Chemical class OC(=O)C1=CC=CC=C1.OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)O)[C@@H]4[C@@H]3CCC2=C1 RRDBGKFTNJDTBK-WAJSLEGFSA-N 0.000 description 1
- HNGBPDWKPSIRGP-WAJSLEGFSA-N acetic acid (8R,9S,13S,14S)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol Chemical class CC(O)=O.OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)O)[C@@H]4[C@@H]3CCC2=C1 HNGBPDWKPSIRGP-WAJSLEGFSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 102220047090 rs6152 Human genes 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000013464 silicone adhesive Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
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
-
- 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
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
-
- 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
-
- 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
- A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
-
- 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
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- 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
- A61P15/18—Feminine contraceptives
-
- 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
-
- 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
- A61P5/30—Oestrogens
-
- 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
- A61P5/34—Gestagens
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to a transdermal plaster with progesterone A-specific ligands (PRASL) as an active ingredient, consisting of a rear layer, at least one adhesive layer which adheres thereto and which contains an active ingredient and which is based on a silicon polymer, polyisobutylene polymer (PIB), a polyacrylate polymer or a styrene block copolymer with butadiene or isoprene (SBS or SIS), in addition to a removable protective film. The inventive transdermal therapeutical plaster containing PRASL, optionally combined with estrogens, is suitable for hormone replacement therapy and fertility control.
Description
Transdermal plaster with progesterone A-specific ligands (PRASL) as an active ingredient (Description) Technical field The invention relates to a transdermal patch with progesterone A-specific ligands (PRASL) as active ingredient.
The transdermal therapeutic patch according to the invention, comprising PRASL where appropriate also in combination with oestrogens, is suitable for hormone replacement therapy and for fertility control.
Prior art Transdermal administration of PRASL is disclosed in the patent literature WO 03/075915 Al. In this case, this represents - a generally known transdermal patch which optionally comprises a penetration enhancer, or - an emulsion, an ointment, a cream or a gel.
The majority of known transdermal patches are passive matrix systems consisting of a backing layer which is substantially impermeable by water vapour and impermeable by the active ingredient, of an active ingredient-containing adhesive layer and of a removable protective layer. In the passive matrix systems disclosed to date, the active ingredient is moreover present completely dissolved in the adhesive layer.
This form of preparation may, however, also be disadvantageous.
The release of dissolved active ingredients from the patch matrix proceeds non-linearly and approaches, in CONFIRMATION COPY
_ 2 _ accordance =with Fick's second law, asymptotically a maximum value. This maximum value is limited inter alia by the saturation concentration of the active ingredient in the matrix. This means that the amount of active ingredient released from the patch to the skin per unit time decreases as the application time progresses. However, linear release of the active ingredient over the entire period of application would be very desirable especially for a hormone-containing pharmaceutical form which is to be used over a prolonged period of several days, because this corresponds much more to the physiological secretion of hormones. Such kinetics of release cannot be achieved with transdermal patches disclosed to date.
The Patent WO 03/075915 Al further proposes the use of an emulsion, of an ointment, of a cream or of a gel.
The use of an emulsion, of an ointment, of a cream or of a gel as administration form for a PRASL-containing pharmaceutical form does not, however, appear very suitable for various reasons. Thus, open use of a very potent medicinal substance (PRASL induces pharmacological effects in daily doses of as little as pg upwards) must be regarded as problematic.
Transdermal gels are normally applied to large areas of 25 skin (100-200 cm2). It is known that most of the medicinal substance remains on the surface of the skin for a lengthy time and penetrates completely into lower layers of skin, and is then partly absorbed, only over a period of several hours. However, this is associated 30 with a not inconsiderable risk of contamination of a partner. Relatively large amounts of the active ingredient can be transferred by skin contact and thus lead to uncontrolled treatment of an uninvolved person.
In addition, some of the active ingredient applied openly to the surface of the skin may, for example during showering, enter the drains and thus cause environmental pollution.
_ 3 _ It is furthermore known that the molecular weight of a medicinal substance represents a limiting quantity for its transdermal availability. Active ingredients such as PRASL having a molecular weight of MW ? 500 Da are regarded as having low skin penetration.
It must therefore be assumed that in the case of conventional patches with PRASL a large amount of the active ingredient must be employed in order to attain an effective plasma level.
Description of the invention The present invention is thus based on the object of providing a transdermal patch which achieves a pharmacologically effective plasma level of PRASL
(corresponding to a transdermal administration of about 30-50 ug/d).
In order to avoid the risk of the occurrence of active ingredient-excipient incompatibilities and of irritative skin reactions, these patches should where possible comprise no penetration-enhancing additions of excipients. It was further intended to provide a transdermal patch with the PRASL active ingredient, which releases a maximal proportion of the assimilated active ingredient and accordingly achieves a patch having a low percentage content of the active ingredient in the pharmaceutical form. In order to achieve an increase in the patients' acceptance by reducing the dosage interval, it is further intended to find a transdermal patch with PRASL which enables linear transport of active ingredient over a period of several days.
The object is achieved according to the invention by a transdermal patch comprising the active ingredient of the general formula Ri HO R3 H
Ar R
The transdermal therapeutic patch according to the invention, comprising PRASL where appropriate also in combination with oestrogens, is suitable for hormone replacement therapy and for fertility control.
Prior art Transdermal administration of PRASL is disclosed in the patent literature WO 03/075915 Al. In this case, this represents - a generally known transdermal patch which optionally comprises a penetration enhancer, or - an emulsion, an ointment, a cream or a gel.
The majority of known transdermal patches are passive matrix systems consisting of a backing layer which is substantially impermeable by water vapour and impermeable by the active ingredient, of an active ingredient-containing adhesive layer and of a removable protective layer. In the passive matrix systems disclosed to date, the active ingredient is moreover present completely dissolved in the adhesive layer.
This form of preparation may, however, also be disadvantageous.
The release of dissolved active ingredients from the patch matrix proceeds non-linearly and approaches, in CONFIRMATION COPY
_ 2 _ accordance =with Fick's second law, asymptotically a maximum value. This maximum value is limited inter alia by the saturation concentration of the active ingredient in the matrix. This means that the amount of active ingredient released from the patch to the skin per unit time decreases as the application time progresses. However, linear release of the active ingredient over the entire period of application would be very desirable especially for a hormone-containing pharmaceutical form which is to be used over a prolonged period of several days, because this corresponds much more to the physiological secretion of hormones. Such kinetics of release cannot be achieved with transdermal patches disclosed to date.
The Patent WO 03/075915 Al further proposes the use of an emulsion, of an ointment, of a cream or of a gel.
The use of an emulsion, of an ointment, of a cream or of a gel as administration form for a PRASL-containing pharmaceutical form does not, however, appear very suitable for various reasons. Thus, open use of a very potent medicinal substance (PRASL induces pharmacological effects in daily doses of as little as pg upwards) must be regarded as problematic.
Transdermal gels are normally applied to large areas of 25 skin (100-200 cm2). It is known that most of the medicinal substance remains on the surface of the skin for a lengthy time and penetrates completely into lower layers of skin, and is then partly absorbed, only over a period of several hours. However, this is associated 30 with a not inconsiderable risk of contamination of a partner. Relatively large amounts of the active ingredient can be transferred by skin contact and thus lead to uncontrolled treatment of an uninvolved person.
In addition, some of the active ingredient applied openly to the surface of the skin may, for example during showering, enter the drains and thus cause environmental pollution.
_ 3 _ It is furthermore known that the molecular weight of a medicinal substance represents a limiting quantity for its transdermal availability. Active ingredients such as PRASL having a molecular weight of MW ? 500 Da are regarded as having low skin penetration.
It must therefore be assumed that in the case of conventional patches with PRASL a large amount of the active ingredient must be employed in order to attain an effective plasma level.
Description of the invention The present invention is thus based on the object of providing a transdermal patch which achieves a pharmacologically effective plasma level of PRASL
(corresponding to a transdermal administration of about 30-50 ug/d).
In order to avoid the risk of the occurrence of active ingredient-excipient incompatibilities and of irritative skin reactions, these patches should where possible comprise no penetration-enhancing additions of excipients. It was further intended to provide a transdermal patch with the PRASL active ingredient, which releases a maximal proportion of the assimilated active ingredient and accordingly achieves a patch having a low percentage content of the active ingredient in the pharmaceutical form. In order to achieve an increase in the patients' acceptance by reducing the dosage interval, it is further intended to find a transdermal patch with PRASL which enables linear transport of active ingredient over a period of several days.
The object is achieved according to the invention by a transdermal patch comprising the active ingredient of the general formula Ri HO R3 H
Ar R
I
where R1 and R2 are independently of one another H or F, R3 is CH3 or CF3 and AR =
N
O
or .
~
~ O
/
or pharmaceutically suitable derivatives thereof (progesterone A-specific ligands, PRASL), where the transdermal patch consists of a backing layer, of at least one active ingredient-containing adhesive layer which adheres thereto and is based on a silicone polymer, a polyisobutylene polymer (PIB), a polyacrylate polymer or a styrene block copolymer with butadiene or isoprene (SBS or SIS), the active ingredient being present in.a concentration of 0.1-10, based on the total weight of the adhesive matrix, and of a removable protective film.
It is furthermore possible according to the invention for the active ingredient to be present in a concentration of 0.1-5% based on the total weight of the adhesive matrix, preferably in the concentration of 0.1-2% based on the total weight of the adhesive matrix.
It is also possible in the case of the transdermal patch according to the invention to define the solubility of the active ingredient in the adhesive layer from 0.1-5%, preferably from 0.5-2%.
The active ingredient in the transdermal patch according to the invention can be incorporated in the matrix undissolved in less than 50%.
It is possible in this case according to the invention for the undissolved active ingredient to be in the form of a uniform dispersion of microparticles or microdroplets, preferably as nanoparticles or nanodroplets.
The active ingredient is particularly preferably present in amorphous form in the matrix.
The amorphous active ingredient dispersion according to the invention in the adhesive matrix has significant advantages over previously disclosed crystalline dispersions:
- the amorphous dispersion has a particularly large interfacial area of the undissolved active ingredient vis-a-vis the matrix, thus facilitating subsequent dissolving of active ingredient for release from the matrix;
- in the amorphous state it is unnecessary, in contrast to crystals, to provide lattice energies for subsequent dissolving of active ingredient during application, so that this is not limiting for the delivery rate vis-a-vis the release of active ingredient from the matrix;
the amorphous active ingredient dispersion has a homogeneous visual appearance; the user may observe the appearance of spots with a crystalline dispersion, suggesting a poor quality of the transdermal patch to him and thus possibly leading to acceptance problems.
The crystallization inhibitors present in the active ingredient-containing matrix in the case of the transdermal patch according to the invention can be selected from the group comprising N-vinyllactam polymers such as N-vinyl-l-azacycloheptan-2-one homopolymer and N-vinylpiperidin-2-one homopolymer and especially polymers of vinylpyrrolidone such as polyvidone (Kollidon TM), or copolymers of vinylpyrrolidone with vinyl acetate (copovidones).
The crystallization inhibitor can be a copovidone composed of 6 parts of vinylpyrrolidone and 4 parts of vinyl acetate (Kollidon TM VA 64).
The adhesive layer in the transdermal patch according to the invention may comprise a silicone-based adhesive which are notable for a high proportion of polymer in relation to the resin, preferably amine-compatible adhesives with a polymer to resin mass ratio of greater than or equal to 40% or 60%.
The adhesive layer in the transdermal patch according to the invention may furthermore comprise polyisobutylene-based adhesives.
The transdermal patch according to the invention may in addition also comprise an oestrogen which is selected from the group comprising 17-beta-estradiol, ethinylestradiol, estradiol valerate, estradiol cypionate, estradiol acetates and estradiol benzoates.
It is furthermore possible with the transdermal patch according to the invention for more than 30%, preferably more than 50% of the loading of its active ingredient to be released within a 7-day use cycle.
The transdermal patch according to the invention can furthermore be produced by taking up the appropriate active ingredient in a combination of at least two process solvents, one of which has a low solvent power for the active ingredient and another has a high solvent power for the active ingredient, where the latter is removed from the batch first by drying processes after blending with the adhesive matrix.
In this connection, the solvent with low solvent power for the active ingredient may be 1,4 dioxane, and the solvent with high solvent power may be heptane.
The following formulation strategy according to the invention which is listed in detailed steps characterizes the production of the PRASL-containing patches:
1. selection of adhesive matrices having optimized dissolving properties for PRASL, 2. a suitable production method and 3. by the selection of suitable stabilizing additions for the matrix from.
1. Selection of the adhesive matrices Suitable adhesive matrices are selected on the basis of their dissolving properties for PRASL. Suitable adhesive matrices in the context of the present invention are those in which the solubility for PRASL
is between 0.1-5%. Adhesive matrices which have proved to be particularly suitable are those in which the solubility of PRASL is between 0.1-2%.
Examples of medically acceptable adhesives which can be employed in this adhesive matrix are silicone, polyacrylate or polyisobutylene adhesives. However, it is also possible in addition to employ polyurethanes, styrene-based block copolymers and further organic polymers.
Particular preference is given in the context of the present invention to silicone adhesives which are suitable for medical use and have a maximal proportion of polymer compared with the resin and in this connection especially those which are amine-compatible, such as, for example, the Bio PSAO series from Dow Corning, and polyisobutylene-containing adhesive preparations such as, for example, a preparation from the following components, which is produced in a known manner:
Example of a polyisobutylene-containing adhesive matrix according to the invention.
Component Proportion by weight in the dried adhesive matrix Oppanol B100 10 Oppanol B 12 SFN 52.2 Indopol H 2100 35 2. Production method for incorporating PRASL in the matrix PRASL is taken up during the production process in a combination of at least two process solvents, one of which has a low solvent power for the active ingredients (e.g. heptane) and another has a high solvent power for the active ingredients (i.e. 1,4 dioxane) . It is moreover possible for one of the two solvents also to be a component of the volatile constituents of the adhesive matrix. After blending of the PRASL solution with the adhesive matrix, the solvent having good dissolving properties for PRASL is removed from the batch first by drying processes.
During the subsequent film formation there is, surprisingly, spontaneous precipitation of part of the active ingredient in the form of an amorphous dispersion whose particles predominantly have the size of nanoparticles. The precondition for precipitation of this amorphous dispersion is the use of adhesive matrices having the dissolving properties for PRASL
described above.
If the solvent power of the adhesive matrix used for PRASL is greater than 2-5%, as for example in the case of the acrylate adhesive matrix DuroTak 387-2287, the entire amount of active ingredient remains dissolved even after the film formation, and the advantages of an amorphous active ingredient dispersion according to the invention cannot be utilized.
3. Selection of suitable stabilizing additions for the matrix Crystallization inhibitors can be added to stabilize this amorphous dispersion of the active ingredient in the adhesive matrix. These take the form of pharmaceutical excipients which are known to the skilled person and which are suitable as complexing agents to form for example solid solutions with active ingredients, increase the surface solubility for the active ingredient and reduce the tendency of the active ingredient to recrystallize after removal of one process solvent or lowering of the temperature.
Addition of crystallization inhibitors makes it possible to stabilize the amorphous dispersion of the active ingredient in the adhesive matrix by preventing further precipitation of the dissolved proportion of active ingredient and additionally blocking conversion of the amorphous particles in the crystalline particles.
Exemplary embodiment The invention is explained in detail by the following example Matrix composition of transdermal patches according to the invention Ex- Components Propor- Comments ample tion by weight in dried adhesive matrix in [%]
1 -(R)-3-{1-[2-Fluoro-5- 0.25 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-trifluoromethyl)- to the invention propanamide 99.75 in the adhesive -BioPSA 4302 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation 2 -(R)-3-{1-[2-Fluoro-5- 0.5 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 99.5 in the adhesive -BioPSA 4302 matrix is possible.
where R1 and R2 are independently of one another H or F, R3 is CH3 or CF3 and AR =
N
O
or .
~
~ O
/
or pharmaceutically suitable derivatives thereof (progesterone A-specific ligands, PRASL), where the transdermal patch consists of a backing layer, of at least one active ingredient-containing adhesive layer which adheres thereto and is based on a silicone polymer, a polyisobutylene polymer (PIB), a polyacrylate polymer or a styrene block copolymer with butadiene or isoprene (SBS or SIS), the active ingredient being present in.a concentration of 0.1-10, based on the total weight of the adhesive matrix, and of a removable protective film.
It is furthermore possible according to the invention for the active ingredient to be present in a concentration of 0.1-5% based on the total weight of the adhesive matrix, preferably in the concentration of 0.1-2% based on the total weight of the adhesive matrix.
It is also possible in the case of the transdermal patch according to the invention to define the solubility of the active ingredient in the adhesive layer from 0.1-5%, preferably from 0.5-2%.
The active ingredient in the transdermal patch according to the invention can be incorporated in the matrix undissolved in less than 50%.
It is possible in this case according to the invention for the undissolved active ingredient to be in the form of a uniform dispersion of microparticles or microdroplets, preferably as nanoparticles or nanodroplets.
The active ingredient is particularly preferably present in amorphous form in the matrix.
The amorphous active ingredient dispersion according to the invention in the adhesive matrix has significant advantages over previously disclosed crystalline dispersions:
- the amorphous dispersion has a particularly large interfacial area of the undissolved active ingredient vis-a-vis the matrix, thus facilitating subsequent dissolving of active ingredient for release from the matrix;
- in the amorphous state it is unnecessary, in contrast to crystals, to provide lattice energies for subsequent dissolving of active ingredient during application, so that this is not limiting for the delivery rate vis-a-vis the release of active ingredient from the matrix;
the amorphous active ingredient dispersion has a homogeneous visual appearance; the user may observe the appearance of spots with a crystalline dispersion, suggesting a poor quality of the transdermal patch to him and thus possibly leading to acceptance problems.
The crystallization inhibitors present in the active ingredient-containing matrix in the case of the transdermal patch according to the invention can be selected from the group comprising N-vinyllactam polymers such as N-vinyl-l-azacycloheptan-2-one homopolymer and N-vinylpiperidin-2-one homopolymer and especially polymers of vinylpyrrolidone such as polyvidone (Kollidon TM), or copolymers of vinylpyrrolidone with vinyl acetate (copovidones).
The crystallization inhibitor can be a copovidone composed of 6 parts of vinylpyrrolidone and 4 parts of vinyl acetate (Kollidon TM VA 64).
The adhesive layer in the transdermal patch according to the invention may comprise a silicone-based adhesive which are notable for a high proportion of polymer in relation to the resin, preferably amine-compatible adhesives with a polymer to resin mass ratio of greater than or equal to 40% or 60%.
The adhesive layer in the transdermal patch according to the invention may furthermore comprise polyisobutylene-based adhesives.
The transdermal patch according to the invention may in addition also comprise an oestrogen which is selected from the group comprising 17-beta-estradiol, ethinylestradiol, estradiol valerate, estradiol cypionate, estradiol acetates and estradiol benzoates.
It is furthermore possible with the transdermal patch according to the invention for more than 30%, preferably more than 50% of the loading of its active ingredient to be released within a 7-day use cycle.
The transdermal patch according to the invention can furthermore be produced by taking up the appropriate active ingredient in a combination of at least two process solvents, one of which has a low solvent power for the active ingredient and another has a high solvent power for the active ingredient, where the latter is removed from the batch first by drying processes after blending with the adhesive matrix.
In this connection, the solvent with low solvent power for the active ingredient may be 1,4 dioxane, and the solvent with high solvent power may be heptane.
The following formulation strategy according to the invention which is listed in detailed steps characterizes the production of the PRASL-containing patches:
1. selection of adhesive matrices having optimized dissolving properties for PRASL, 2. a suitable production method and 3. by the selection of suitable stabilizing additions for the matrix from.
1. Selection of the adhesive matrices Suitable adhesive matrices are selected on the basis of their dissolving properties for PRASL. Suitable adhesive matrices in the context of the present invention are those in which the solubility for PRASL
is between 0.1-5%. Adhesive matrices which have proved to be particularly suitable are those in which the solubility of PRASL is between 0.1-2%.
Examples of medically acceptable adhesives which can be employed in this adhesive matrix are silicone, polyacrylate or polyisobutylene adhesives. However, it is also possible in addition to employ polyurethanes, styrene-based block copolymers and further organic polymers.
Particular preference is given in the context of the present invention to silicone adhesives which are suitable for medical use and have a maximal proportion of polymer compared with the resin and in this connection especially those which are amine-compatible, such as, for example, the Bio PSAO series from Dow Corning, and polyisobutylene-containing adhesive preparations such as, for example, a preparation from the following components, which is produced in a known manner:
Example of a polyisobutylene-containing adhesive matrix according to the invention.
Component Proportion by weight in the dried adhesive matrix Oppanol B100 10 Oppanol B 12 SFN 52.2 Indopol H 2100 35 2. Production method for incorporating PRASL in the matrix PRASL is taken up during the production process in a combination of at least two process solvents, one of which has a low solvent power for the active ingredients (e.g. heptane) and another has a high solvent power for the active ingredients (i.e. 1,4 dioxane) . It is moreover possible for one of the two solvents also to be a component of the volatile constituents of the adhesive matrix. After blending of the PRASL solution with the adhesive matrix, the solvent having good dissolving properties for PRASL is removed from the batch first by drying processes.
During the subsequent film formation there is, surprisingly, spontaneous precipitation of part of the active ingredient in the form of an amorphous dispersion whose particles predominantly have the size of nanoparticles. The precondition for precipitation of this amorphous dispersion is the use of adhesive matrices having the dissolving properties for PRASL
described above.
If the solvent power of the adhesive matrix used for PRASL is greater than 2-5%, as for example in the case of the acrylate adhesive matrix DuroTak 387-2287, the entire amount of active ingredient remains dissolved even after the film formation, and the advantages of an amorphous active ingredient dispersion according to the invention cannot be utilized.
3. Selection of suitable stabilizing additions for the matrix Crystallization inhibitors can be added to stabilize this amorphous dispersion of the active ingredient in the adhesive matrix. These take the form of pharmaceutical excipients which are known to the skilled person and which are suitable as complexing agents to form for example solid solutions with active ingredients, increase the surface solubility for the active ingredient and reduce the tendency of the active ingredient to recrystallize after removal of one process solvent or lowering of the temperature.
Addition of crystallization inhibitors makes it possible to stabilize the amorphous dispersion of the active ingredient in the adhesive matrix by preventing further precipitation of the dissolved proportion of active ingredient and additionally blocking conversion of the amorphous particles in the crystalline particles.
Exemplary embodiment The invention is explained in detail by the following example Matrix composition of transdermal patches according to the invention Ex- Components Propor- Comments ample tion by weight in dried adhesive matrix in [%]
1 -(R)-3-{1-[2-Fluoro-5- 0.25 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-trifluoromethyl)- to the invention propanamide 99.75 in the adhesive -BioPSA 4302 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation 2 -(R)-3-{1-[2-Fluoro-5- 0.5 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 99.5 in the adhesive -BioPSA 4302 matrix is possible.
4 -(R)-3-{1-(2-Fluoro-5- 0.75 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 99.25 in the adhesive -BioPSA 4302 matrix is possible.
4 -(R)-3-{1-[2-Fluoro-5- 1 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 99 in the adhesive -BioPSA 4302 matrix is possible.
-(R)-3-{1-[2-Fluoro-5- 1 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 10 in the adhesive - Oppanol B100 52.2 matrix is - Oppanol B 12 SFN 35 possible.
- Indopol H 2100 6 -(R)-3-{1-[2-Fluoro-5- 1 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 99 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation 7 -(R)-3-{l-[2-Fluoro-5- 2 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 98 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation 8 -(R)-3-{1-[2-Fluoro-5- 3 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 97 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation 9 -(R)-3-{1-[2-Fluoro-5- 4 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 96 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation -(R)-3-{l-[2-Fluoro-5- 5 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 95 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation Example 4 is explained in detail below.
A 10% strength solution of the active ingredient according to the invention, (R)-3-{1-[2-fluoro-5-5 (trifluoromethyl)phenyl]cyclopropyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoromethyl)propanamide F HO cF3 H
N O
in dioxane is introduced into a suitable batch container. An aliquot of suitable adhesive matrix (e.g.
BioPSA 4302, Dow Corning) is added to result in a 10 strength mixture based on the solids content of the matrix.
The matrix is homogenized in a known manner. The film is spread on a removable protective layer (e.g. Scotch-pack 97420, 3M) and dried in accordance with pharmaceutical rules. When the solvents are evaporated there is partial precipitation of the active ingredient in the form of uniformly dispersed nanoparticles in the adhesive matrix. Finally, a substantially water vapour-impermeable backing layer (e.g. Hostaphan RN 15 MEDO, Mitsubishi) is used for lamination, and the patches are singulated.
The results of the in vitro liberation for 6 of these patches according to the invention over a period of 24 h is shown below by way of example.
Table 1 Percentage release of (R)-3-{1-[2-fluoro-5-(trifluoro-methyl)phenyl]cyclopropyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoromethyl)propanamide from patches according to the invention with 1% active ingredient in the matrix 1 h 4 h 8 h 24 h lst specimen 39% 72% 80% 81%
2nd specimen 39% 68% 73% 74%
3rd specimen 40% 74% 91% 92%
4th specimen 40% 73% 84% 85%
5th specimen 39% 73% 85% 87%
6th specimen 39% 71% 82% 84%
Average 39% 72% 83% 84%
Surprisingly, the patches according to the invention release by far the greatest part of their load of active ingredient after only after 4 h, and make it availabl.e for treatment. The patches according to the invention are therefore suitable for at least markedly reducing the described problem of overloading of an oral pharmaceutical form with PRASL.
The reduction in the amount of active ingredient employed per pharmaceutical form means that the plasters according to the invention provide an economic advantage by comparison with an oral pharmaceutical form. In addition, the reduction in the amount of active ingredient per pharmaceutical form considerably reduces the environmental risk derived from the pharmaceutical form.
The ability of the patches according to the invention to transport the active ingredient through human skin was investigated by means of permeation studies on exised human skin. The established model of the Franz diffusion cell was employed in this case. 6 patches were likewise investigated, and were loaded in each case with 1% (R)-3-{1-[2-fluoro-5-(trifluoromethyl)phenyl]cyclopropyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoromethyl)propanamide in the matrix.
Table 2 Cumulative flux of (R)-3-{1-[2-Fluoro-5-(trifluoro-methyl)phenyl]cyclopropyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoromethyl)propanamide in from patches according to the invention with 1% active ingredient in the matrix through human skin 0 h 6 h 12 h 24 h 30 h 48 h lst n.w. n.w. n.w. 3.60 4.86 8.96 specimen [ug/cm2] [ug/cmZ] [ug/cmZ]
2nd n.w. n.w. n.w. 3.70 5.26 10.40 specimen [ug/cm2] [ug/cmZ] [ug/cmZ]
3rd n.w. n.w. n.w. 3.17 4.36 8.20 specimen [ug/cmZ] [ug/cmZ] [ug/cmZ]
4th n.w. n.w. 0.92 5.45 7.03 11.96 specimen [ug/cm2] [ug/cm2] [ug/cmz] [ug/cm2]
5th n.w. n.w. n.w. 3.35 4.78 9.51 specimen [ug/cm2] [ug/cmZ] [ug/cmZ]
6th n.w. n.w. n.w. 2.94 3.97 7.33 specimen [ug/cm2] [ug/cmZ] [ug/cmZ]
Average W.W. n.w. 0.15 3.70 5.04 9.39 [u9/cm2] [ug/cmZ] [ug/cmz] [ug/cm2]
n.w. = below the limit of detection The results surprisingly show that ,even a patch according to the invention not more than 15 cm2 in size and free of penetration-enhancing excipients is able to transport therapeutically relevant amounts (30-50 pg/d) of (R)-3-{1-[2-fluoro-5-(trifluoromethyl)phenyl]cyclo-propyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoro-methyl)propanamide through the skin.
The small size of a transdermal patch suggests that acceptance by patients will be great. The omission of penetration-enhancing additions reduces the risk of the occurrence of active ingredient-excipient incompatibilities and of irritative skin reactions reduces and thus represents a further advantage of the patches according to the invention.
Owing to the uniform fluxes of the active ingredient, a pharmaceutical form according to the invention additionally makes it possible to reduce the dosage interval from a daily use of the oral pharmaceutical form to a weekly use.
This reduction represents a further advantage of the pharmaceutical form according to the invention.
4 -(R)-3-{1-[2-Fluoro-5- 1 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 99 in the adhesive -BioPSA 4302 matrix is possible.
-(R)-3-{1-[2-Fluoro-5- 1 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 10 in the adhesive - Oppanol B100 52.2 matrix is - Oppanol B 12 SFN 35 possible.
- Indopol H 2100 6 -(R)-3-{1-[2-Fluoro-5- 1 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 99 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation 7 -(R)-3-{l-[2-Fluoro-5- 2 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 98 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation 8 -(R)-3-{1-[2-Fluoro-5- 3 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 97 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation 9 -(R)-3-{1-[2-Fluoro-5- 4 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 96 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation -(R)-3-{l-[2-Fluoro-5- 5 Production of an (trifluoromethyl)- amorphous active phenyl]cyclopropyl}-2- ingredient dis-hydroxy-N-(phthalid-5- persion according yl)-2-(trifluoro- to the invention methyl)propanamide 95 in the adhesive - DuroTak 387-2287 matrix is impossible because the active ingredient remains com-pletely dissolved even after film formation Example 4 is explained in detail below.
A 10% strength solution of the active ingredient according to the invention, (R)-3-{1-[2-fluoro-5-5 (trifluoromethyl)phenyl]cyclopropyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoromethyl)propanamide F HO cF3 H
N O
in dioxane is introduced into a suitable batch container. An aliquot of suitable adhesive matrix (e.g.
BioPSA 4302, Dow Corning) is added to result in a 10 strength mixture based on the solids content of the matrix.
The matrix is homogenized in a known manner. The film is spread on a removable protective layer (e.g. Scotch-pack 97420, 3M) and dried in accordance with pharmaceutical rules. When the solvents are evaporated there is partial precipitation of the active ingredient in the form of uniformly dispersed nanoparticles in the adhesive matrix. Finally, a substantially water vapour-impermeable backing layer (e.g. Hostaphan RN 15 MEDO, Mitsubishi) is used for lamination, and the patches are singulated.
The results of the in vitro liberation for 6 of these patches according to the invention over a period of 24 h is shown below by way of example.
Table 1 Percentage release of (R)-3-{1-[2-fluoro-5-(trifluoro-methyl)phenyl]cyclopropyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoromethyl)propanamide from patches according to the invention with 1% active ingredient in the matrix 1 h 4 h 8 h 24 h lst specimen 39% 72% 80% 81%
2nd specimen 39% 68% 73% 74%
3rd specimen 40% 74% 91% 92%
4th specimen 40% 73% 84% 85%
5th specimen 39% 73% 85% 87%
6th specimen 39% 71% 82% 84%
Average 39% 72% 83% 84%
Surprisingly, the patches according to the invention release by far the greatest part of their load of active ingredient after only after 4 h, and make it availabl.e for treatment. The patches according to the invention are therefore suitable for at least markedly reducing the described problem of overloading of an oral pharmaceutical form with PRASL.
The reduction in the amount of active ingredient employed per pharmaceutical form means that the plasters according to the invention provide an economic advantage by comparison with an oral pharmaceutical form. In addition, the reduction in the amount of active ingredient per pharmaceutical form considerably reduces the environmental risk derived from the pharmaceutical form.
The ability of the patches according to the invention to transport the active ingredient through human skin was investigated by means of permeation studies on exised human skin. The established model of the Franz diffusion cell was employed in this case. 6 patches were likewise investigated, and were loaded in each case with 1% (R)-3-{1-[2-fluoro-5-(trifluoromethyl)phenyl]cyclopropyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoromethyl)propanamide in the matrix.
Table 2 Cumulative flux of (R)-3-{1-[2-Fluoro-5-(trifluoro-methyl)phenyl]cyclopropyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoromethyl)propanamide in from patches according to the invention with 1% active ingredient in the matrix through human skin 0 h 6 h 12 h 24 h 30 h 48 h lst n.w. n.w. n.w. 3.60 4.86 8.96 specimen [ug/cm2] [ug/cmZ] [ug/cmZ]
2nd n.w. n.w. n.w. 3.70 5.26 10.40 specimen [ug/cm2] [ug/cmZ] [ug/cmZ]
3rd n.w. n.w. n.w. 3.17 4.36 8.20 specimen [ug/cmZ] [ug/cmZ] [ug/cmZ]
4th n.w. n.w. 0.92 5.45 7.03 11.96 specimen [ug/cm2] [ug/cm2] [ug/cmz] [ug/cm2]
5th n.w. n.w. n.w. 3.35 4.78 9.51 specimen [ug/cm2] [ug/cmZ] [ug/cmZ]
6th n.w. n.w. n.w. 2.94 3.97 7.33 specimen [ug/cm2] [ug/cmZ] [ug/cmZ]
Average W.W. n.w. 0.15 3.70 5.04 9.39 [u9/cm2] [ug/cmZ] [ug/cmz] [ug/cm2]
n.w. = below the limit of detection The results surprisingly show that ,even a patch according to the invention not more than 15 cm2 in size and free of penetration-enhancing excipients is able to transport therapeutically relevant amounts (30-50 pg/d) of (R)-3-{1-[2-fluoro-5-(trifluoromethyl)phenyl]cyclo-propyl}-2-hydroxy-N-(phthalid-5-yl)-2-(trifluoro-methyl)propanamide through the skin.
The small size of a transdermal patch suggests that acceptance by patients will be great. The omission of penetration-enhancing additions reduces the risk of the occurrence of active ingredient-excipient incompatibilities and of irritative skin reactions reduces and thus represents a further advantage of the patches according to the invention.
Owing to the uniform fluxes of the active ingredient, a pharmaceutical form according to the invention additionally makes it possible to reduce the dosage interval from a daily use of the oral pharmaceutical form to a weekly use.
This reduction represents a further advantage of the pharmaceutical form according to the invention.
Claims (14)
1. Transdermal patch comprising the active ingredient of the general formula where R1 and R2 are independently of one another H
or F, R3 is CH3 or CF3 and AR is.
or pharmaceutically suitable derivatives thereof (progesterone A-specific ligands, PRASL), characterized in that the transdermal patch consists of a backing layer, of at least one active ingredient-containing adhesive layer which adheres thereto and is based on a silicone polymer, a polyisobutylene polymer (PIB), a polyacrylate polymer or a styrene block copolymer with butadiene or isoprene (SBS or SIS), the active ingredient being present in a concentration of 0.1-10%, based on the total weight of the adhesive matrix, and of a removable protective film.
or F, R3 is CH3 or CF3 and AR is.
or pharmaceutically suitable derivatives thereof (progesterone A-specific ligands, PRASL), characterized in that the transdermal patch consists of a backing layer, of at least one active ingredient-containing adhesive layer which adheres thereto and is based on a silicone polymer, a polyisobutylene polymer (PIB), a polyacrylate polymer or a styrene block copolymer with butadiene or isoprene (SBS or SIS), the active ingredient being present in a concentration of 0.1-10%, based on the total weight of the adhesive matrix, and of a removable protective film.
2. Transdermal patch according to Claim 1, characterized in that the active ingredient is present in a concentration of 0.1-5% based on the total weight of the adhesive matrix, preferably in the concentrations of 0.1-2% based on the total weight of the adhesive matrix.
3. Transdermal patch according to Claims 1 and 2, characterized in that the solubility of the active ingredient in the adhesive layer is defined from 0.1-5%, preferably from 0.5-2%.
4. Transdermal patch according to one or more of Claims 1 to 3, characterized in that the active ingredient is incorporated in the matrix undissolved in less than 50%.
5. Transdermal patch according to Claim 4, characterized in that the active ingredient is present in the form of microparticles and microdroplets, preferably as nanoparticles or nanodroplets, uniformly dispersed in the matrix.
6. Transdermal patch according to Claims 4 and 5, characterized in that the active ingredient is present in amorphous form in the matrix.
7. Transdermal patch according to one of more of Claims 1 to 6, characterized in that the active ingredient-containing matrix comprises a crystallization inhibitor which is selected from the group comprising N-vinyllactam polymers such as N-vinyl-1-azacycloheptan-2-one homopolymer and N-vinylpiperidin-2-one homopolymer and especially polymers of vinylpyrrolidone such as polyvidone (Kollidon TM), or copolymers of vinylpyrrolidone with vinyl acetate (copovidones).
8. Transdermal patch according to one or more of claims 1 to 7, characterized in that the active ingredient-containing matrix comprises as crystallization inhibitor a copovidone composed of 6 parts of vinylpyrrolidone and 4 parts of vinyl acetate (Kollidon TM VA 64).
9. Transdermal patch according to one or more of Claims 1 to 8, characterized in that the adhesive layer comprises a silicone-based adhesive which are distinguished by a high proportion of polymer in relation to the resin, preferably amine-compatible adhesives with a polymer to resin mass ratio of greater than or equal to 40% to 60%.
10. Transdermal patch according to one or more of Claims 1 to 8, characterized in that the adhesive layer comprises polyisobutylene-based adhesives.
11. Transdermal patch according to one or more of Claims 1 to 10, characterized in that it comprises an oestrogen which is selected from the group comprising 17-beta-estradiol, ethinylestradiol, estradiol valerate, estradiol cypionate, estradiol acetate and estradiol benzoate.
12. Transdermal patch according to one or more of Claims 1 to 11, characterized in that it releases more than 30%, preferably more than 50% of its loading with the active ingredient defined in Claim 1 within a 7-day use cycle.
13. Process for producing the transdermal patch according to one or more of Claims 1-12, characterized in that the appropriate active ingredient is taken up in a combination of at least two process solvents, one of which has a low solvent power for the active ingredient and another has a high solvent power for the active ingredient, where the latter is removed from the batch first by drying processes after blending with the adhesive matrix.
14. Process for producing the transdermal patch according to Claim 13, characterized in that the solvent with low solvent power for the active ingredient is 1,4 dioxane and the solvent with high solvent power is heptane.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102004062182A DE102004062182B4 (en) | 2004-12-20 | 2004-12-20 | Transdermal patch with progesterone A-specific ligands (PRASL) as active ingredient |
| DE102004062182.9 | 2004-12-20 | ||
| PCT/EP2005/013480 WO2006066788A1 (en) | 2004-12-20 | 2005-12-15 | Transdermal plaster with progesterone a-specific ligands (prasl) as an active ingredient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2591076A1 true CA2591076A1 (en) | 2006-06-29 |
Family
ID=35559357
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002591076A Abandoned CA2591076A1 (en) | 2004-12-20 | 2005-12-15 | Transdermal plaster with progesterone a-specific ligands (prasl) as an active ingredient |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1671626A1 (en) |
| JP (1) | JP2008524144A (en) |
| KR (1) | KR20070089241A (en) |
| CN (1) | CN101102754A (en) |
| AR (1) | AR052168A1 (en) |
| AU (1) | AU2005318548A1 (en) |
| BR (1) | BRPI0519143A2 (en) |
| CA (1) | CA2591076A1 (en) |
| CR (1) | CR9207A (en) |
| DE (1) | DE102004062182B4 (en) |
| EA (1) | EA200701222A1 (en) |
| IL (1) | IL183935A0 (en) |
| MX (1) | MX2007007418A (en) |
| NO (1) | NO20073768L (en) |
| PA (1) | PA8657401A1 (en) |
| PE (1) | PE20060841A1 (en) |
| TW (1) | TW200633732A (en) |
| UY (1) | UY29263A1 (en) |
| WO (1) | WO2006066788A1 (en) |
| ZA (1) | ZA200705991B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0913214B1 (en) * | 2008-05-30 | 2022-05-17 | Mylan Laboratories Inc | Transdermal drug delivery device and method of manufacturing same |
| DE102010040299A1 (en) | 2010-09-06 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Transdermal therapeutic systems with crystallization-inhibiting protective film (release liner) |
| CN103893189B (en) * | 2012-12-26 | 2019-04-23 | 江苏康倍得药业股份有限公司 | Pharmaceutical composition and its preparation and application containing estradiol |
| CN113795323B (en) * | 2019-05-13 | 2023-11-28 | 东洋纺Mc株式会社 | Filter materials and filters for filters |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU644815B2 (en) * | 1989-09-08 | 1993-12-23 | Ortho-Mcneil Pharmaceutical, Inc. | Solid matrix system for transdermal drug delivery |
| DE4309830C1 (en) * | 1993-03-26 | 1994-05-05 | Lohmann Therapie Syst Lts | Transdermal patches for oestradiol admin. - contg. isopropylidene mono- or di-glycerol as penetration enhancer |
| DE19723722A1 (en) * | 1997-05-30 | 1998-12-10 | Schering Ag | Nonsteroidal progestogens |
| DE19830732B4 (en) * | 1998-07-09 | 2008-11-13 | Lts Lohmann Therapie-Systeme Ag | Composition containing at least one substance influencing blood lipid levels and its use |
| DE19830649C2 (en) * | 1998-07-09 | 2003-04-10 | Lohmann Therapie Syst Lts | Topical patch with nonsteroidal anti-inflammatory drugs with acid group |
| DE10012908B4 (en) * | 2000-03-16 | 2005-03-17 | Lts Lohmann Therapie-Systeme Ag | Stabilized supersaturated transdermal therapeutic matrix systems and methods for their preparation |
| BR0308394A (en) * | 2002-03-11 | 2005-01-25 | Schering Ag | 5- {2-Hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropyl] -propionylamino} -phthalide and progesterone receptor modulating activity-related compounds for use in fertility control and hormone replacement therapy |
| EP1535618A1 (en) * | 2003-11-26 | 2005-06-01 | Schering Aktiengesellschaft | Pharmaceutical preparation for continuous hormonal treatment over a period of longer than 21-28 days comprising two estrogen and/or progestin compositions |
-
2004
- 2004-12-20 DE DE102004062182A patent/DE102004062182B4/en not_active Expired - Fee Related
-
2005
- 2005-12-15 EA EA200701222A patent/EA200701222A1/en unknown
- 2005-12-15 CN CNA2005800469009A patent/CN101102754A/en active Pending
- 2005-12-15 BR BRPI0519143-2A patent/BRPI0519143A2/en not_active Application Discontinuation
- 2005-12-15 WO PCT/EP2005/013480 patent/WO2006066788A1/en not_active Ceased
- 2005-12-15 KR KR1020077016518A patent/KR20070089241A/en not_active Withdrawn
- 2005-12-15 AU AU2005318548A patent/AU2005318548A1/en not_active Abandoned
- 2005-12-15 CA CA002591076A patent/CA2591076A1/en not_active Abandoned
- 2005-12-15 JP JP2007545947A patent/JP2008524144A/en active Pending
- 2005-12-15 MX MX2007007418A patent/MX2007007418A/en unknown
- 2005-12-15 EP EP05027489A patent/EP1671626A1/en not_active Withdrawn
- 2005-12-16 PE PE2005001484A patent/PE20060841A1/en not_active Application Discontinuation
- 2005-12-16 AR ARP050105301A patent/AR052168A1/en not_active Application Discontinuation
- 2005-12-20 PA PA20058657401A patent/PA8657401A1/en unknown
- 2005-12-20 UY UY29263A patent/UY29263A1/en not_active Application Discontinuation
- 2005-12-20 TW TW094145401A patent/TW200633732A/en unknown
-
2007
- 2007-06-14 IL IL183935A patent/IL183935A0/en unknown
- 2007-06-25 CR CR9207A patent/CR9207A/en not_active Application Discontinuation
- 2007-07-19 ZA ZA200705991A patent/ZA200705991B/en unknown
- 2007-07-19 NO NO20073768A patent/NO20073768L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006066788A1 (en) | 2006-06-29 |
| IL183935A0 (en) | 2007-10-31 |
| PA8657401A1 (en) | 2006-07-03 |
| BRPI0519143A2 (en) | 2008-12-30 |
| DE102004062182B4 (en) | 2007-06-06 |
| EA200701222A1 (en) | 2007-12-28 |
| CN101102754A (en) | 2008-01-09 |
| MX2007007418A (en) | 2007-08-17 |
| ZA200705991B (en) | 2009-01-28 |
| DE102004062182A1 (en) | 2006-06-29 |
| AR052168A1 (en) | 2007-03-07 |
| AU2005318548A1 (en) | 2006-06-29 |
| JP2008524144A (en) | 2008-07-10 |
| PE20060841A1 (en) | 2006-09-14 |
| NO20073768L (en) | 2007-07-19 |
| EP1671626A1 (en) | 2006-06-21 |
| UY29263A1 (en) | 2006-06-30 |
| KR20070089241A (en) | 2007-08-30 |
| TW200633732A (en) | 2006-10-01 |
| CR9207A (en) | 2007-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0275716B1 (en) | Transdermal estrogen/progestin dosage unit, and fertility control kit comprising said dosage unit. | |
| US20060134188A1 (en) | Transdermal pharmaceutical preparation with a progesterone A-specific ligand (PRASL) as active ingredient | |
| US4906169A (en) | Transdermal estrogen/progestin dosage unit, system and process | |
| US9005653B2 (en) | Transdermal delivery of hormones with low concentration of penetration enhancers | |
| JP2974969B2 (en) | Solid matrix system for transdermal drug delivery | |
| JP5134187B2 (en) | Device for transdermal administration of rotigotine base | |
| CN1188189C (en) | Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with estrogen | |
| AU2002365624B2 (en) | Transdermal therapeutic systems containing steroid hormones and propylene glycol monocaprylate | |
| JP2007524648A (en) | Transdermal hormone delivery system: compositions and methods | |
| JP5111710B2 (en) | Stabilized supersaturated transdermal therapeutic substrate system | |
| CA2387143C (en) | Transdermal therapeutic system containing tulobuterol hydrochloride for administering the bronchodilator tulobuterol via the skin | |
| EP2138169B1 (en) | Transdermal delivery system of hormones without penetration enhancers | |
| CA2549916C (en) | Transdermal delivery system of hormones without penetration enhancers | |
| CA2591076A1 (en) | Transdermal plaster with progesterone a-specific ligands (prasl) as an active ingredient | |
| CN1187042C (en) | Plaster which contains steroids, and method for the production and use thereof | |
| EP3448778B1 (en) | Transdermal delivery system containing methylphenidate or its salts and methods thereof | |
| CA2494915C (en) | Female hormone-containing patch | |
| HK1132682B (en) | Transdermal delivery system of hormones without penetration enhancers | |
| HK1074801B (en) | Transdermal delivery system of gestodene | |
| HK1031828A (en) | Therapeutical system for transdermal delivery of levonorgestrel |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |