HRP20040994A2 - Pharmaceutical combination for the treatment of benign prostatic hyperplasia or for the long-term prevention of acute urinary retention - Google Patents
Pharmaceutical combination for the treatment of benign prostatic hyperplasia or for the long-term prevention of acute urinary retention Download PDFInfo
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- HRP20040994A2 HRP20040994A2 HR20040994A HRP20040994A HRP20040994A2 HR P20040994 A2 HRP20040994 A2 HR P20040994A2 HR 20040994 A HR20040994 A HR 20040994A HR P20040994 A HRP20040994 A HR P20040994A HR P20040994 A2 HRP20040994 A2 HR P20040994A2
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- 206010004446 Benign prostatic hyperplasia Diseases 0.000 title claims abstract description 11
- 208000004403 Prostatic Hyperplasia Diseases 0.000 title claims abstract description 11
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P5/28—Antiandrogens
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
Description
Područje izuma
Prikazani izum se odnosi na farmaceutsku kombinaciju prikladnu za liječenje benigne hiperplazije prostate ili za dugoročnu prevenciju akutne retencije urina.
Pozadina izuma
BHP, benigno, ne kancerogeno povećanje prostate, predstavlja dobro poznati subjektivni simptom kod muškaraca, zbog kojeg se obično javljaju za pomoć liječniku nakon 50 godine života. Približno 50% svih muškaraca u dobi iznad 50 godina i 95% svih muškaraca u dobi iznad 70 godina žale se na navedeni problem. BHP je općenito progresivno stanje koje u teškim slučajevima može ugroziti funkciju bubrega i tada može zahtijevati kiruršku intervenciju. Broj neliječenih bolesnika se kreće oko 37 milijuna širom svijeta. Smanjena brzina protoka i poteškoće (opstruktivne) prilikom pražnjenja mjehura u BHP se općenito smatraju posljedicom dva faktora, povećane prostate (statička komponenta) i tonusa glatkog mišića strome i uretre (dinamička komponenta). Simptomi pohrane (iritativni) su povezani sa disfunkcijom mokraćnog mjehura nastalom sekundarno zbog opstrukcije u istjecanju urina.
Rast i povećan tonus prostate vrši pritisak ili izdužuje uretru, uzrokujući simptome blokade uretre i dovodeći do retencije urina.
Prostata se sastoji od epitelijalinih glandularnih cjevčica okruženih fibromuskularnom stromom. Hiperplastički rast prostate počinje u dobi od 30 godina u periuretralno smještenim dijelovima žlijezde, takozvanoj prijelaznoj zoni. Pored učinaka starenja, androgeni hormoni predstavljaju ključni stimulus rasta prostate u regulaciji veličine žlijezde nakon puberteta. U normalnoj prostati, enzim 5α-reduktaza u epitelnim stanicama pretvara androgeni hormon testosteron (T) u dihidrotestosteron (DHT). DHT, aktivni androgeni metabolit prostate, veže se na citoplazmatske receptore i transportiran se u staničnu jezgru gdje započinje sintezu proteina i RNK i umnažanje stanice. Pretpostavlja se da se BHP javlja kao odgovor na učinke DHT u prostati koja stari i na promjene u stromi i epitelnim stanicama (Steers, Zorn, Dis. Mon., 41(7): 439-497 (1995)).
Promjene ovisne o dobi, serumske koncentracije hormonskog regulacijskog ciklusa u cijelosti (LH, FSH, SHGB, T i DHT) i drugih hormona koji mogu utjecati na navedeni regulacijski ciklus (estrogeni, prolaktin, derivati testosterona), istraživane su kao mogući uzrok BHP. Premda, ne postoji korelacija između hormonskih promjena u serumu ovisnih o dobi i koncentracija hormona u samoj prostati. Jasno je, da je sama prostata odgovorna za regulaciju hormonskog okruženja.
Moguća mjesta za kontroliranje intraprostatičnog hormonskog okruženja predstavljaju 5α-reduktaza (tj. metabolizam androgena), ekspresija hormonskog receptora na stanicama epitela i strome, estrogeni i drugi hormoni, a osobito tip 2 izoforma. Pored toga, brojni peptidni faktori rasta posjeduju parakrino ili autokrino djelovanje na lokalni metabolizam u različitim dijelovima žlijezde, putem kojih se ostvaruje ravnoteža između proliferacije i programirane smrti stanice.
Klinički simptomi BHP obuhvaćaju i blokirajuće (otežano pražnjenje, opstrukcija) simptome (npr. oklijevanje pri početku mokrenja, slab ili isprekidan mlaz, nakon pražnjenja mjehura urinarna retencija, akutna urinarna retencija (AUR), prekid mlaza urina) koji nastaju izravno zbog konstrikcije vrata mokraćnog mjehura i prostatičnog dijela uretre hiperplastičnom prostatom, a isto tako i simptome otežanog pohranjivanja (iritativni) , nastale zbog iritacije donjeg urinarnog trakta (napr. povećana frekvencija uriniranja, nikturija, dizurija, urgencija, inkontinencija urina, ureziestezija). Neliječena, BHP može uzrokovati ozbiljne komplikacije urinarnog trakta i bubrega, kao što su npr. akutna retencija urina i hidronefroza (uronefroza).
Tamsulosin hidroklorid predstavlja blokator α-receptora, selektivni antagonist α1-adrenoceptorar a koristi se kao monosupstanca u liječenju funkcionalnih simptoma hiperplazije prostate (BHP) ili simptoma donjeg urinarnog trakta (LUTS) povezanih sa hiperplazijom prostate (BHP). Tamsulosin dovodi do poboljšanja i simptoma otežanog pohranjivanja urina i simptoma otežanog pražnjenja mokraćnog mjehura kod bolesnika sa BHP, a posredovanjem dinamske komponente LUTS. Početak djelovanja je brz, a djelovanje je dugoročno bez obzira na veličinu prostate. Potreba za kirurškim liječenjem BHP i kateterizacijom (uglavnom zbog AUR) je značajno odgođena.
Sinteza tamsulosina i kiselinskih adicijskih soli prvo je opisana u Europskom patentu br. EP 34432, a koji je ovdje obuhvaćen referencom.
Prikladna formulacija za produženo otpuštanje je prikazana, na primjer u US Patentu br. 4,772,475, a koji je isto tako obuhvaćen referencama.
Inhibitori 5α-reduktaze, osobito inhibitori tipa 2 izoforme enzima, isto su tako korišteni u liječenju BHP. Inhibitori 5α-reduktaze mogu smanjiti benigno uvećane prostate (statička komponenta BHP) i tako smanjiti do određenog stupnja simptome nastale zbog otežanog pohranjivanja urina i pražnjenja mokraćnog mjehura. Početak djelovanja je odgođen, no može se smanjiti dugoročan rizik akutne urinarne retencije i potreba za kirurškim zahvatom BHP.
Primjeri navedenih inhibitora predstavljaju spojeve opisane u US Patentu br. 4,760,071, EP 285382, EP 285383 i WO 95/7927, a točnije spoj nazvan finasterid (opisan na primjer u EP 155096 i US Patentu br. 4,760,071) i dutasterid (opisan na primjer u WO 95/7927). Drugi spojevi inhibitornog djelovanja na 5α-reduktazu tip 2, mogu se otkriti primjenom testa opisanog u Primjeru 3 WO 95/10284.
Navedeni spojevi, kao i njihove farmaceutski prihvatljive soli i njihovi optički aktivni izooblici, obuhvaćeni su referencama.
Sažetak izuma
Prikazani izum se odnosi na farmaceutsku kombinaciju koja sadrži tamsulosin i inhibitor 5α-reduktaze testosterona. Kombinacija u skladu s prikazanim izumom je prikladna za liječenje benigne hiperplazije prostate.
Detaljan opis izuma
Iznenađujuće, kombinacija u skladu s prikazanim izumom tamsulosina, ili njegove kiselinske adicijske soli, osobito tamsulosin hidroklorida i inhibitora 5α-reduktaze, osobito inhibitora tipa 2 izooblika navedenog enzima, prikladna je u liječenju benigne hiperplazije prostate i donosi dodatne prednosti u usporedbi sa svakim od navedenih lijekova primjenjenih u monoterapiji.
U prikladnom ostvarenju prikazanog izuma, tip 2 inhibitora 5α-reduktaze predstavlja finasterid ili dutasterid.
U drugom prikladnom ostvarenju, kombinacija predstavlja, bilo kombinaciju tamsulosina i finasterida ili kombinaciju tamsulosina i dutasterida, a osobito je prikladna za dugoročno liječenje benigne hiperplazije prostate.
U daljnjem prikladnom ostvarenju, kombinacija u skladu s prikazanim izumom sadrži obje aktivne supstance u obliku koji sadrži između 0.1 i 0.8 mg tamsulosin hidroklorida, te između 0.3 i 8 mg tip 2 ihibitora 5α-reduktaze. Aktivni sastojak se može primjeniti oralnim putem.
U daljnjem prikladnom ostvarenju, kombinacija u skladu s prikazanim izumom predstavlja krutu farmaceutsku kombinaciju sadržaja od 0.1 do 0.8 mg tamsulosin hidroklorida i 0.3 do 8 mg tipa 2 inhibitora 5α-reduktaze. Aktivni sastojci se mogu primjeniti oralnim putem.
U daljnjem prikladnom ostvarenju, kombinacija u skladu s prikazanim izumom sadrži obje aktivne supstance u obliku koji sadrži između 0.2 i 0.6 mg tamsulosin hidroklorida i od 0.3 do 8 mg tip 2 inhibitora 5α-reduktaze. Aktivni sastojci se mogu primjeniti oralnim putem.
U daljnjem prikladnom ostvarenju, kombinacija u skladu s prikazanim izumom predstavlja farmaceutsku kombinaciju koja sadrži 0.2 do 0.6 mg tamsulosin hidroklorida i 0.3 do 0.5 mg tip 2 inhibitora 5α-reduktaze. Aktivni sastojak se može primjeniti oralnim putem, u krutom obliku doze.
U daljnjem prikladnom ostvarenju, kombinacija u skladu s prikazanim izumom predstavlja farmaceutsku kombinaciju koja sadrži 0.2 do 0.6 mg tamsulosin hidroklorida i 0.3 do 8 mg tip 2 inhibitora 5α-reduktaze. Aktivni sastojak se može primjeniti oralnim putena u krutom obliku doze.
Slijedeći primjeri formulacija su prikazani u svrhu ilustracije izuma.
Formulacija sadržaja između 0.1 i 0.8 mg tamsulosin hidroklorida, te između 1 i 8. mg finasterida.
Formulacija sadržaja između 0.1 i 0.6 mg tamsulosin hidroklorida, te između 1 i 8 mg finasterida.
Farmaceutska kombinacija sadržaja od 0.2 do 0.4 mg tamsulosin hidroklorida i između 1 i 8 mg finasterida.
Formulacija sadržaja između 0.1 i 0.8 mg tamsulosin hidroklorida, te između 0.3 i 0.5 mg finasterida.
Formulacija sadržaja između 0.1 i 0.6 mg tamsulosin hidroklorida, te između 0.3 i 0.5 mg finasterida.
Farmaceutska kombinacija sadržaja od 0.2 do 0.4 mg tamsulosin hidroklorida i između 0.3 i 0.5 mg finasterida.
Formulacija sadržaja između 0.1 i 0,8 mg tamsulosin hidroklorida, te između 1 i 8 mg dutasterida.
Formulacija sadržaja između 0.1 i 0.6 mg tamsulosin hidroklorida, te između 1 i 8 mg dutasterida.
Farmaceutska kombinacija sadržaja od 0.2 do 0.4 mg tarasulosin hidroklorida i između 1 i 8 mg dutasterida.
Formulacija sadržaja između 0.1 i 0.8 mg tamsulosin hidroklorida, te između 0.3 i 0.5 mg dutasterida.
Formulacija sadržaja između 0.1 i 0.6 mg tamsulosin hidroklorida, te između 0.3 i 0.5 mg dutasterida.
Farmaceutska kombinacija sadržaja od 0.2 do 0.4 mg tamsulosin hidroklorida i između 0.3 i 0.5 mg dutasterida.
Navedeni primjeri formulacija mogu doći u krutom obliku farmaceutske doze, a mogu se primjeniti oralnim putem.
Prikladni uobičajeni pripravci obuhvaćaju, na primjer, inertne standardne nosače i/ili diluense, npr. kukuruzni škrob, laktozu, glukozu, mikrokristalinicnu celulozu, magnezijev stearat, polivinilpirolidon, limunsku kiselinu, vinsku kiselinu, vodu, vodu/etanol, vodu/glicerol, vodu/sorbitol, vodu/polietilenglikol, propilenglikol, cetilstearilni alkohol, karboksimetilcelulozu ili masne supstance kao što je kruta mast ili njihove prikladne smjese, inkorporirane u uobičajenim galenskim pripravcima kao što su obične ili obložene tablete, kapsule, prašci, suspenzije ili supozitoriji.
Aktivni sastojci se mogu primjeniti oralnim putem u raličitim oblicima doze: na primjer, mogu biti formulirani zajedno sa raznim farmaceutski prihvatljivim inertnim nosačima u obliku tableta, kapsula, patila, lozenga, krutih zaslađivača, praškova, vodenih suspenzija, eliksira, sirupa i slično. Takvi nosači sadrže, na primjer, krute diluense ili filere, sterilne vodene medije i različite ne toksične solvente. Pored toga, oralne formulacije takve vrste mogu biti prikladno zaslađene i/ili pomiješane sa različitim tvarima za poboljšanje okusa.
Općenito, aktivni sastojci su prisutni u dozažnim oblicima za oralnu primjenu u koncentraciji od 0.5% masenog udjela do približno 90% masenog udjela, izračunatog na osnovi mase ukupnog pripravka, a u količinama dovoljnim za proizvodnju željenih dozažnih jedinica. Drugi oblici doza aktivnih sastojaka obuhvaćaju formulacije za kontrolirano otpuštanje i primjenu sredstava dobro poznatih osobama iz struke.
Prikladno, dva aktivna sastojka su prisutna u obliku formulacije sa odgođenim otpuštanjem.
U prikazanom izumu, dva aktivna sastojka mogu biti prisutna, ili u istoj ili u dvije različite formulacije. U posljednjem slučaju, formulacije koje sadrže sastojke se mogu primjeniti istovremeno ili u slijedu.
U skladu s izumom, naziv dugoročna terapija označava medicinsku primjenu kombinacije dva aktivna sastojka u jednoj ili dvije formulacije tijekom najmanje 3 mjeseca, odnosno kroz dulje vrijeme.
Kombinacije u skladu s prikazanim izumom, osobito su prikladne za liječenje bolesnika sa izrazito povećanom prostatom, a kod kojih su prisutni simptomi donjeg urinarnog trakta (LUTS) i/ili bolesnika s povećanim rizikom od napredovanja bolesti, kao što je dugoročna prevencija akutne urinarne retencije (AUR).
Claims (8)
1. Farmaceutska kombinacija, naznačena time, da sadrži kombinaciju tamsulosina ili njegove kiselinske adicijske soli, sa inhibitorom 5α-reduktaze.
2. Farmaceutska kombinacija u skladu sa zahtjevom 1, naznačena time, da inhibitor 5α-reduktaze predstavlja inhibitor tipa 2 izooblika enzima 5α-reduktaze.
3. Farmaceutska kombinacija u skladu sa zahtjevom 1 ili 2, naznačena time, da sadrži tamsulosin hidroklorid.
4. Farmaceutska kombinacija u skladu sa bilo kojim od zahtjeva 1 do 3, naznačena time, da je inhibitor 5α-reduktaze finasterid.
5. Farmaceutska kombinacija u skladu sa bilo kojim od zahtjeva 1 do 3, naznačena time, da je inhibitor 5α-reduktaze dutasterid.
6. Farmaceutska kombinacija u skladu sa bilo kojim od zahtjeva 1 do 5, naznačena time, da je za liječenje benigne hiperplazije prostate.
7. Farmaceutska kombinacija u skladu sa bilo kojim od zahtjeva 1 do 6, naznačena time, da je za dugoročno liječenje benigne hiperplazije prostate.
8. Farmaceutska kombinacija u skladu sa bilo kojim od zahtjeva 1 do 5, naznačena time, da je za dugoročnu prevenciju akutne retencije urina.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2002118392 DE10218392A1 (de) | 2002-04-24 | 2002-04-24 | Verwendung von Arzneimittelkombinationen zur Behandlung von benigner Prostatahyperplasie |
| DE2002118611 DE10218611A1 (de) | 2002-04-25 | 2002-04-25 | Verwendung einer Tamsulosin enthaltenden Arzneimittelkombination zur Behandlung von benigner Prostatahyperplasie |
| PCT/EP2003/004034 WO2003090753A1 (en) | 2002-04-24 | 2003-04-17 | Pharmaceutical combination for the treatment of benign prostatic hyperplasia or for the long-term prevention of acute urinary retention |
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| HRP20040994A2 true HRP20040994A2 (en) | 2005-02-28 |
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| HR20040994A HRP20040994A2 (en) | 2002-04-24 | 2004-10-22 | Pharmaceutical combination for the treatment of benign prostatic hyperplasia or for the long-term prevention of acute urinary retention |
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| EP (2) | EP1501517B1 (hr) |
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| BR0309435A (pt) * | 2002-04-24 | 2005-02-15 | Boehringer Ingelheim Pharma | Combinação farmacêutica para o tratamento de hiperplasia prostática benigna ou para a prevenção a longo prazo de retenção urinária aguda |
| KR20060124603A (ko) * | 2003-11-03 | 2006-12-05 | 베링거 인겔하임 인터내셔날 게엠베하 | 베타-3-아드레날린 수용체 효능제 및 알파 길항제 및/또는5-알파-리덕타제 억제제를 함유하는 약제학적 조성물 |
| US7601994B2 (en) * | 2003-11-14 | 2009-10-13 | Semiconductor Energy Laboratory Co., Ltd. | Display device and method for manufacturing the same |
| WO2006055659A2 (en) * | 2004-11-15 | 2006-05-26 | Smithkline Beecham Corporation | Fixed dose combination op dutasteride and tamsulosin |
| CN102309495A (zh) * | 2010-06-30 | 2012-01-11 | 北京润德康医药技术有限公司 | 一种复方制剂及其制备方法 |
| WO2012110092A1 (en) | 2011-02-17 | 2012-08-23 | Synthon Bv | Tamsulosin derivatives |
| BRPI1103204A2 (pt) * | 2011-06-03 | 2014-02-25 | Eurofarma Lab S A | Composição farmacêutica para o tratamento de hiperplasia prostática benigna |
| WO2013123965A1 (en) | 2012-02-20 | 2013-08-29 | Synthon Bv | A fixed dose pharmaceutical formulation |
| US10596127B2 (en) | 2013-03-14 | 2020-03-24 | Wellesley Pharmaceuticals, Llc | Composition for reducing the frequency of urination, method of making and use thereof |
| BR102013020508B1 (pt) * | 2013-08-12 | 2021-01-12 | Ems S/A. | Forma de dosagem que compreende um inibidor de esteroide 5-alfa-redutase e um bloqueador alfa, processo para a preparaçãode uma forma de dosagem e uso da forma de dosagem |
| ES2555485T1 (es) | 2014-05-26 | 2016-01-04 | Galenicum Health S.L. | Composiciones farmacéuticas que contienen un agente activo |
| AU2016331879A1 (en) * | 2015-09-30 | 2018-05-17 | Wellesley Pharmaceuticals, Llc | Composition for reducing the frequency of urination, method of making and use thereof |
| US10172910B2 (en) * | 2016-07-28 | 2019-01-08 | Nymox Corporation | Method of preventing or reducing the incidence of acute urinary retention |
| CN115969860A (zh) * | 2021-10-14 | 2023-04-18 | 上海汇伦医药股份有限公司 | 一种药物组合物及其用途 |
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| US5391825A (en) * | 1980-02-08 | 1995-02-21 | Yamanouchi Pharmaceutical Co., Ltd. | Sulfamoyl substituted phenethylamine intermediates |
| JPS56110665A (en) | 1980-02-08 | 1981-09-01 | Yamanouchi Pharmaceut Co Ltd | Sulfamoyl-substituted phenetylamine derivative and its preparation |
| US4760071A (en) | 1984-02-27 | 1988-07-26 | Merck & Co., Inc. | 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors |
| IL74365A (en) | 1984-02-27 | 1990-07-26 | Merck & Co Inc | 17beta-(n-t.-butylcarbamoyl)-4-aza-5alpha-androst-1-en-3-one and pharmaceutical compositions containing it |
| US4772475A (en) | 1985-03-08 | 1988-09-20 | Yamanouchi Pharmaceutical Co., Ltd. | Controlled-release multiple units pharmaceutical formulation |
| EP0285383B1 (en) | 1987-04-03 | 1994-03-16 | Merck & Co. Inc. | Treatment of prostatic carcinoma with 17beta-n-monosubstituted-carbamoyl-4-aza-5alpha-androst-1-en-3-ones |
| EP0285382B1 (en) | 1987-04-03 | 1994-04-13 | Merck & Co. Inc. | Treatment of androgenic alopecia with 17beta-n-monosubstituted-carbamoyl-4-aza-5alpha-androst-1-en-3-ones |
| IL101243A (en) * | 1991-03-20 | 1999-12-22 | Merck & Co Inc | Pharmaceutical preparations for the treatment of benign prostatic hyperplasia containing steroid history |
| TW369521B (en) | 1993-09-17 | 1999-09-11 | Smithkline Beecham Corp | Androstenone derivative |
| TW382595B (en) | 1993-10-15 | 2000-02-21 | Merck & Co Inc | Pharmaceutical composition for use in arresting and reversing androgenic alopecia |
| US6423719B1 (en) * | 1999-02-16 | 2002-07-23 | Upsher-Smith Laboratories, Inc. | Method for treating benign prostate hyperplasia |
| WO2001021167A1 (en) * | 1999-09-22 | 2001-03-29 | Merck & Co., Inc. | Treatment of lower urinary tract symptoms and pharmaceutical compositions for use therein |
| BR0309435A (pt) * | 2002-04-24 | 2005-02-15 | Boehringer Ingelheim Pharma | Combinação farmacêutica para o tratamento de hiperplasia prostática benigna ou para a prevenção a longo prazo de retenção urinária aguda |
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Also Published As
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| EP1743656A3 (en) | 2007-03-07 |
| BR0309435A (pt) | 2005-02-15 |
| ATE361075T1 (de) | 2007-05-15 |
| WO2003090753A8 (en) | 2004-11-04 |
| WO2003090753A1 (en) | 2003-11-06 |
| PL371430A1 (en) | 2005-06-13 |
| EP1501517A1 (en) | 2005-02-02 |
| EA200401340A1 (ru) | 2005-06-30 |
| DE60313603D1 (de) | 2007-06-14 |
| US20030225118A1 (en) | 2003-12-04 |
| EA008377B1 (ru) | 2007-04-27 |
| PT1501517E (pt) | 2007-05-31 |
| US20070197666A1 (en) | 2007-08-23 |
| MXPA04010408A (es) | 2005-02-17 |
| DE60313603T2 (de) | 2008-01-03 |
| JP2005524693A (ja) | 2005-08-18 |
| DK1501517T3 (da) | 2007-06-11 |
| CN1646135A (zh) | 2005-07-27 |
| NZ536514A (en) | 2006-11-30 |
| EP1501517B1 (en) | 2007-05-02 |
| CY1107674T1 (el) | 2013-04-18 |
| AU2003227643A1 (en) | 2003-11-10 |
| RS92304A (en) | 2006-10-27 |
| IL163976A0 (en) | 2005-12-18 |
| EP1743656A2 (en) | 2007-01-17 |
| ES2287474T3 (es) | 2007-12-16 |
| NO20044333L (no) | 2004-11-09 |
| CA2479992A1 (en) | 2003-11-06 |
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