AU729898B2 - Transdermal therapeutic system having an active compound combination comprising oestriol - Google Patents
Transdermal therapeutic system having an active compound combination comprising oestriol Download PDFInfo
- Publication number
- AU729898B2 AU729898B2 AU40150/97A AU4015097A AU729898B2 AU 729898 B2 AU729898 B2 AU 729898B2 AU 40150/97 A AU40150/97 A AU 40150/97A AU 4015097 A AU4015097 A AU 4015097A AU 729898 B2 AU729898 B2 AU 729898B2
- Authority
- AU
- Australia
- Prior art keywords
- oestriol
- therapeutic system
- transdermal therapeutic
- active compound
- combination
- 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
Links
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 title claims abstract description 40
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 title claims description 12
- 208000001132 Osteoporosis Diseases 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 8
- 239000005557 antagonist Substances 0.000 claims description 5
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
- NXWGWUVGUSFQJC-GFCCVEGCSA-N (2r)-1-[(2-methyl-1h-indol-4-yl)oxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NC[C@@H](O)COC1=CC=CC2=C1C=C(C)N2 NXWGWUVGUSFQJC-GFCCVEGCSA-N 0.000 claims description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 2
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims description 2
- 229960004195 carvedilol Drugs 0.000 claims description 2
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 claims description 2
- 229960003134 mepindolol Drugs 0.000 claims description 2
- 229960000715 nimodipine Drugs 0.000 claims description 2
- -1 pimobendon Chemical compound 0.000 claims description 2
- 229960004605 timolol Drugs 0.000 claims description 2
- 229960001722 verapamil Drugs 0.000 claims description 2
- 239000002876 beta blocker Substances 0.000 claims 2
- 229940097320 beta blocking agent Drugs 0.000 claims 2
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims 1
- 229960000528 amlodipine Drugs 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract 2
- 239000000262 estrogen Substances 0.000 description 5
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 4
- 230000001076 estrogenic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 230000000694 effects Effects 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 229960003399 estrone Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003217 anti-cancerogenic effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- GRXPVLPQNMUNNX-MHJRRCNVSA-N estrane Chemical compound C1CC2CCCC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 GRXPVLPQNMUNNX-MHJRRCNVSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
Abstract
Disclosed is a transdermal therapeutical approach involving oestriol as an active substance, characterized in that oestriol is combined with one or more active substances.
Description
Transdermal therapeutic system having an active compound combination comprising oestriol The invention relates to a transdermal therapeutic system having an active compound combination comprising oestriol.
Oestrogens are steroid hormones which are derived from the tetracyclic C 18 -steroid oestrane. Among the natural oestrogens, oestrone, oestradiol and oestriol are distinguished, oestrone and oestriol counting as the most important physiologically.
Oestriol is one of the metabolic end products of oestradiol metabolism.
It has a number of special pharmacological and biological features which distinguish it from other oestrogens: Even before absorption, it is almost completely conjugated. Only about 1-2 of the oestriol taken appears as free oestriol in the circulation. The quotient of free to conjugated oestriol is 1:500.
At an oral dose of 2 mg, it exerts no proliferating action on the endometrium, since it remains bound to the receptors of the cell nucleus for only a short time. Oestrogenic actions, however, are only triggered when an oestrogenic substance remains in the nucleus for a relatively long period of time. This is only possible with oestriol when it is administered several times a day.
Another special feature of oestriol is that on taking oestriol for several months, the oestrogenic action increases.
After vaginal administration, the proportion of unconjugated oestriol in the serum is 10 to times higher than after oral administration, 1 t, 2 since intestinal metabolization does not take place. With an oestriol dose of 0.5 mg, a high serum level of 100-150 pg/ml can be counted on even 2 hours after vaginal administration. In comparison, for the same effect an oral dose of mg is needed.
The above experiences enable it to be concluded that for oestriol a transdermal therapeutic system (TTS) is pharmaceutically the system of choice. By means of the system it can be ensured that oestriol is delivered to the body continuously over a period of, for example, 7 days.
The active compound oestriol has until now been credited with inadequate therapeutic activity in the context of substitution therapy (HRT). This applies particularly to the use of oestriol for the prevention of osteoporosis. Thus, in an official statement of the German Endocrinology Society the inactivity of oestriol for osteoporosis prophylaxis was specifically emphasized (cf. Deutsches Arzteblatt Arztliche Mitteilungen, 85, 1322-1325, (1988)).
The inactivity of oestriol in bone has meanwhile gone into the relevant textbooks as standard knowledge (Freimut A. Leidenberger, "Klinische Endokrinologie fur Frauenarzte" Springer Verlag 1992, page 356).
The inactivity of oestriol on its own for the treatment of osteoporosis is furthermore pointed out in product information for preparations which contain oestriol as active compound Jenapharm Medicaments: Range and Prices of 01.07.1991 p. 67).
In contrast to this, the sole use of oestriol for the treatment of osteoporosis in the form of a transdermal therapeutic system is presented in the PCT Application WO 93/18774. According to this, the results support oestriol as the oestrogen of choice for continuous hormone substitution therapy and in particular for the therapy of climacteric osteoporosis.
-3 On continuous administration, osteoporosis specifically is effectively treated or prevented on the one hand, while on the other hand the carcinogenic action observed with conventional oestrogens does not take place and an anticarcinogenic action can even be expected.
Starting from this state of medical knowledge, the invention is based on the object of specifying a significantly improved transdermal therapeutic system having an active compound combination comprising oestriol, which, without risks and harmful side effects, displays a particularly high therapeutic efficacy and acceptance in the use of oestriol for the prevention of osteoporosis, arteriosclerosis and/or cardiac insufficiency in old age.
Surprisingly, it has been found that transdermally administered oestriol assists the action of transdermally administered biphosphonates, P-blockers and Ca antagonists, and that transdermally administered oestriol in combination with P-blockers and Ca antagonists can preferably be employed for the treatment of arteriosclerosis or for the treatment of cardiac insufficiency in old age. In combination with e* biphosphonates, it is suitable for the treatment of 25 |osteoporosis by transdermal administration.
P-blockers and Ca antagonists in accordance with the present invention may be chosen from for example amlodopine carvedilol, pimobendon, timolol, mepindolol, verapamil nifredipine and/or nimodipine.
In further applications, it was found that in the treatment of osteoporosis the transdermal administration of biphosphonates in combination with oestriol is more advantageous than oestriol alone. A preferred dose form is one which releases 8 to 16 mg of oestriol in 24 hours and 3 to 7 mg of biphosphonate per
TTS.
According to the invention, all transdermal 5= therapeutic systems having an active compound 4 combination comprising oestriol which guarantee the continuous release of active compound over at least 24 hours are suitable for this. The production of such systems using the appropriate individual substances is known to the person skilled in the art and described in relevant detail.
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 that prior art forms part of the common general knowledge in Australia.
Claims (5)
1. Transdermal therapeutic system having the active compound oestriol, characterized in that it contains a combinationof oestriol with one or more other active compounds from the class of beta-blockers, Ca antagonists or biphosphonates.
2. Transdermal therapeutic system according to Claim 1, characterized in that in combination with oestriol it contains amlodipine, carvedilol, pimobendon, timolol, mepindolol, verapamil, nifredipine and/or nimodipine.
3. Transdermal therapeutic system for the treatment of osteoporosis, characterized in that in combination with oestriol it contains biphosphonate. I
4. Transdermal therapeutic system according to claim 3, characterized by release rates of 8-16 mg of oestriol or 3-7 mg of biphosphonate per day. 25
5. Transdermal therapeutic system for the treatment of cardiac insufficiency in old age or arteriosclerosis, characterized by an active compound combination of oestriol with active compounds from the beta-blocker class and/or Ca antagonists class according to Claim 1 or 2. !DATED THIS 28th day of November, 2000. LTS LOHMANN THERAPIE-SYSTEME GMBH By Its Patent Attorneys DAVIES COLLISON CAVE
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19635883A DE19635883A1 (en) | 1996-09-04 | 1996-09-04 | Transdermal therapeutic system with an active ingredient combination containing estriol |
| DE19635883 | 1996-09-04 | ||
| PCT/EP1997/004392 WO1998009631A1 (en) | 1996-09-04 | 1997-08-13 | Transdermal therapeutical approach involving a combination of active substances containing oestriol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU4015097A AU4015097A (en) | 1998-03-26 |
| AU729898B2 true AU729898B2 (en) | 2001-02-15 |
Family
ID=7804611
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU40150/97A Ceased AU729898B2 (en) | 1996-09-04 | 1997-08-13 | Transdermal therapeutic system having an active compound combination comprising oestriol |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0927036B9 (en) |
| JP (1) | JP2000517324A (en) |
| KR (1) | KR20010029451A (en) |
| CN (1) | CN1228702A (en) |
| AT (1) | ATE289818T1 (en) |
| AU (1) | AU729898B2 (en) |
| CA (1) | CA2261655A1 (en) |
| CZ (1) | CZ70099A3 (en) |
| DE (2) | DE19635883A1 (en) |
| ES (1) | ES2239362T3 (en) |
| IL (1) | IL128768A0 (en) |
| NO (1) | NO991047L (en) |
| NZ (1) | NZ334443A (en) |
| PL (1) | PL332035A1 (en) |
| SK (1) | SK25299A3 (en) |
| WO (1) | WO1998009631A1 (en) |
| ZA (1) | ZA977895B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101873859A (en) | 2007-12-10 | 2010-10-27 | 考司美德制药株式会社 | transdermal patch |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992014474A1 (en) * | 1991-02-26 | 1992-09-03 | Norwich Eaton Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis |
| US5614213A (en) * | 1992-03-21 | 1997-03-25 | Entec Gesellschaft Fuer Endokrinologische Technologie M.B.H. | Use of estriol for treatment of climacteric osteoporosis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5474783A (en) * | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| JPH0679002A (en) * | 1993-12-14 | 1994-03-22 | Hisamitsu Pharmaceut Co Inc | Patch device for percutaneous administration |
| DE4405898A1 (en) * | 1994-02-18 | 1995-08-24 | Schering Ag | Transdermal therapeutic systems containing sex steroids |
-
1996
- 1996-09-04 DE DE19635883A patent/DE19635883A1/en not_active Withdrawn
-
1997
- 1997-08-13 CN CN97197615A patent/CN1228702A/en active Pending
- 1997-08-13 JP JP10512160A patent/JP2000517324A/en active Pending
- 1997-08-13 IL IL12876897A patent/IL128768A0/en unknown
- 1997-08-13 ES ES97937573T patent/ES2239362T3/en not_active Expired - Lifetime
- 1997-08-13 CA CA002261655A patent/CA2261655A1/en not_active Abandoned
- 1997-08-13 AT AT97937573T patent/ATE289818T1/en not_active IP Right Cessation
- 1997-08-13 CZ CZ99700A patent/CZ70099A3/en unknown
- 1997-08-13 PL PL97332035A patent/PL332035A1/en unknown
- 1997-08-13 AU AU40150/97A patent/AU729898B2/en not_active Ceased
- 1997-08-13 KR KR1019997001714A patent/KR20010029451A/en not_active Withdrawn
- 1997-08-13 NZ NZ334443A patent/NZ334443A/en unknown
- 1997-08-13 SK SK252-99A patent/SK25299A3/en unknown
- 1997-08-13 DE DE59712215T patent/DE59712215D1/en not_active Expired - Lifetime
- 1997-08-13 EP EP97937573A patent/EP0927036B9/en not_active Expired - Lifetime
- 1997-08-13 WO PCT/EP1997/004392 patent/WO1998009631A1/en not_active Ceased
- 1997-09-03 ZA ZA9707895A patent/ZA977895B/en unknown
-
1999
- 1999-03-03 NO NO991047A patent/NO991047L/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992014474A1 (en) * | 1991-02-26 | 1992-09-03 | Norwich Eaton Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis |
| US5614213A (en) * | 1992-03-21 | 1997-03-25 | Entec Gesellschaft Fuer Endokrinologische Technologie M.B.H. | Use of estriol for treatment of climacteric osteoporosis |
Also Published As
| Publication number | Publication date |
|---|---|
| DE59712215D1 (en) | 2005-04-07 |
| KR20010029451A (en) | 2001-04-06 |
| AU4015097A (en) | 1998-03-26 |
| CA2261655A1 (en) | 1998-03-12 |
| EP0927036A1 (en) | 1999-07-07 |
| ATE289818T1 (en) | 2005-03-15 |
| SK25299A3 (en) | 2000-08-14 |
| EP0927036B9 (en) | 2005-08-10 |
| CZ70099A3 (en) | 1999-07-14 |
| PL332035A1 (en) | 1999-08-16 |
| ES2239362T3 (en) | 2005-09-16 |
| EP0927036B1 (en) | 2005-03-02 |
| JP2000517324A (en) | 2000-12-26 |
| CN1228702A (en) | 1999-09-15 |
| NZ334443A (en) | 1999-08-30 |
| WO1998009631A1 (en) | 1998-03-12 |
| NO991047D0 (en) | 1999-03-03 |
| DE19635883A1 (en) | 1998-03-05 |
| ZA977895B (en) | 1998-03-02 |
| NO991047L (en) | 1999-03-03 |
| IL128768A0 (en) | 2000-01-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |