HRP20041127A2 - Use of new etonogestrel esters - Google Patents
Use of new etonogestrel esters Download PDFInfo
- Publication number
- HRP20041127A2 HRP20041127A2 HR20041127A HRP20041127A HRP20041127A2 HR P20041127 A2 HRP20041127 A2 HR P20041127A2 HR 20041127 A HR20041127 A HR 20041127A HR P20041127 A HRP20041127 A HR P20041127A HR P20041127 A2 HRP20041127 A2 HR P20041127A2
- Authority
- HR
- Croatia
- Prior art keywords
- etonogestrel
- contraceptively
- effective amount
- ester
- therapeutically effective
- Prior art date
Links
- GCKFUYQCUCGESZ-BPIQYHPVSA-N etonogestrel Chemical class O=C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 GCKFUYQCUCGESZ-BPIQYHPVSA-N 0.000 title claims description 108
- 229960002941 etonogestrel Drugs 0.000 claims description 133
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- YSGQGNQWBLYHPE-CFUSNLFHSA-N (7r,8r,9s,10r,13s,14s,17s)-17-hydroxy-7,13-dimethyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical group C1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2[C@H](C)CC3=CC(=O)CC[C@@H]3[C@H]21 YSGQGNQWBLYHPE-CFUSNLFHSA-N 0.000 claims description 49
- -1 etonogestrel ester Chemical class 0.000 claims description 48
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- 238000000034 method Methods 0.000 claims description 24
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 18
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- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
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Description
Polje izuma
Predmet izuma se odnosi na područje kontracepcije (muškaraca i žena), na hormonsku zamjensku terapiju (HRT) i na terapiju/prevenciju ginekoloških promjena.
Pozadina izuma
Kontracepcijske metode za muškarce i žene važne su za sveopće reproduktivno zdravlje.
Međutim, efektivna i eficijentna metoda za mušku kontracepciju još uvijek nije pristupačna.
Muška se kontracepcija bazira na zaustavljanju spermatogeneze preko supresije gonadotropin-luteinizacijskog hormona (LH) i folikularno-stimulirajućeg hormona (FSH). To rezultira deplecijom intratestikularnog testosterona i prestanka spermatogeneze. Davanje progestagena rezultira dozno ovisnom supresijom hipofiznih gonadotropina, a kao posljedica toga javlja se pad u razini testosterona i reverzibilna inhibicija spermatogeneze. Egzogeni androgen je potreban kako bi kompenzirao smanjenu razinu testosterona. Na isti se način može HRT muškaraca izvesti rezultirajući zamjenom testosterona s egzogenim androgenom koji je sigurniji za prostatu nego endogeni testosteron.
Poznata je upotreba progestogena zajedno s androgenima kao kontraceptiva za muškarce i za HRT (Guerin i Rollet (1988), International Journal of Andrology 11, 187-199).
Međutim, do sada još nije opisana upotreba specifičnih etonogestrel estera za kontracepciju muškaraca i HRT.
Dodatno, poznata je upotreba progestogena zajedno s estrogenima u kontracepciji žena i HRT (M. Tausk, J.H.H. Thijssen, Tj.B. van Wimersma Greidanus, “Pharmakologie der Hormone”, Georg Thieme Verlag, Stuttgart, 1986).
Progestageni su široko upotrebljivi u kontracepciji i HRT-i kod žena. U kontracepciji je u najširoj upotrebi kombinacija progestagen-estrogen koja se primjenjuje oralno. Davanje takve kombinacije rezultira brojnim efektima: blokira ovulaciju, ulazi u interakciju s faznim razvojem endometrija što smanjuje šansu uspješne implantacije i uzrokuje viskoznost mukusa maternice čime se sprječava penetracija sperme. Većina tableta koje sadrže samo progestagen (POP’s) bazira se na posljednjem spomenutom efektu.
Ženska HRT je usmjerena na dodatak endogenog estrogena za tretman pred- i postmenopauznih tegoba (navale vrućine, vaginalna suhoća) i za prevenciju simptoma dugotrajnog nedostatka estrogena. Posljednje uključuje osteporezu, bolest koronarne arterije, urogenitalna inkontinencija i vjerojatno Alzheimerova bolest i kolorektalni tumor. Povlačenjem dugotrajne, nesmetane primjene estrogena povezano je s povećanom proliferacijom endometrija što pak može povećati opasnost od tumora endometrija. Iz tog se razloga progestageni daju zajedno u dugotrajnom propisanom postupku zato što imaju sposobnost smanjenja proliferativne aktivnosti epitela endometrija i što induciraju sekretornu konverziju.
Međutim, nije opisana upotreba specifičnih etonogestrel estera za kontracepciju žena, žensku HRT-u i tretman/prevenciju ginekoloških promjena.
Predmet izuma opisuje etonogestrel estere s C7-C15 dugim lancima masnih kiselina, posebice C10-C12, koje imaju dobar farmakokinetički profil i omogućuju davanje, u obliku jedne doze, progestogena s dugotrajnim djelovanjem.
Predmet izuma omogućava kontraceptivni i /ili HRT kit, za muškarce i žene, koji sadrži kontraceptivno i/ili terapeutski djelotvornu količinu etonogestrel estera s lancima masnih kiselina dužine C7-C15, posebice C10-C12.
Dodatno, preporučljiva je također upotreba tih estera za tretman i prevenciju ženskih ginekoloških promjena kao npr. endometrioza, menoragija, menometroragija, premenstrualni sindrom i dismenoreja.
Slike
Slika 1
Kemijska struktura etonogestrel heptanoata (etonogestrel enantata), etonogestrel nananoata, etanogestrel dekanoata, etanogestrel undekanoata, etonogestrel dodekanoata, etonogestrel tridekanoata i etonogestrel pentadekanoata.
Slika 2a
Učinak jedne intramuskularne injekcije (IM) etonogestrela, etonogestrel heptanoata (etonogestrel anantata), etonogestrel nananoata i etonogestrel undekanoata na plazmatsku razinu etonogestrela u nedirnutim muškim miševima. Srednja vrijednost i SEM od N=3.
Slika 2b
Učinak jedne intramuskularne injekcije (IM) etonogestrela, etonogestrel heptanoata (etonogestrel anantata), etonogestrel nananoata i etonogestrel undekanoata, etonogestrel dodekanoata, etonogestrel tridekanoata na plazmatsku razinu etonogestrela nedirnutih muških miševa. Srednja vrijednost i SEM od N=3.
Slika 3
Kemijska struktura MENT undekanoata, MENT buciklata, testosteron heptanoata (testosteron enantata) i testosteron undekanoata.
Slika 4
Vremenski ovisni učinci jedne s.c. injekcije 20 mg/kg MENT undekanoata (MENT-U), MENT buciklata (MENT-B), testosteron heptanoata (testosteron enantata, TE) i testosteron undekanoata (TU) na plazmatski MENT ili testosteron (T) u kastriranim muškim miševima. Rezultati su srednja vrijednost N=3.
Slika 5
Farmakokinetike testosteron enantata, testosteron undekanoata i testosteron buciklata nakon jedne IM injekcije injektirane u muškog hipogonadnog čovjeka s naznačenim dozama plazmatske razine serumskog testosterona. Normalna razina serumskog testosterona prikazana je isprekidanom linijom. Dobiveno od E. Nieschlag i H.M.Bhre. Testosteron terapija. U: Andrology, Male reproductive health and dysfunction., urednik E. Nieschlag i H.M.Behre, Berlin, Heidelberg i New York: Springer-Verlag, 1997, p. 297-309.
Detaljan opis izuma
Predmet izuma osigurava kontraceptivni i/ili HRT kit sastavljen od kontraceptivno i/ili terapeutski djelotvorne količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina dužine C7-C15, posebice C10-C12.
U jednom ostvarenju, kit obuhvaća kontraceptivno i/ili terapeutski djelotvornu količinu androgen estera, posebice MENT undekanoata.
U drugom ostvarenju kit dalje podrazumijeva kontraceptivno i/ili terapeutski djelotvornu količinu estrogena, kao što su mestranol, etinilestradiol, etinilestradiol sulfonat, estradiol, estradiol velerate, estriol, estriol sucinat, kvinestrol, estropipat, natrij estron sulfat ili natrij ekvilin sulfat.
Predmet izuma podrazumijeva dalje upotrebu kontraceptivno i/ili terapeutski djelotvorne količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina duljine C7-C15, posebice C10-C12, za pripremu medikamenta za kontracepciju i/ili HRT.
U jednom ostvarenju etonogestrel ester se upotrebljava u kombinaciji s kontraceptivno i/ili terapeutski djelotvornom količinom androgen estera za pripremu medikamenta za kontracepciju kod muškaraca i/ili mušku HRT. Dugodjelujući androgen ester je prvenstveno MENT undekanoat.
U drugom ostvarenju etonogestrel se upotrebljava u kombinaciji s kontraceptivno i/ili terapeutski djelotvornom količinom estrogena za pripremu medikamenta za kontracepciju kod žena i/ili žensku HRT i/ili za tretman i/ili prevenciju ginekoloških promjena kod žena kao što su endometrioza, menoragija, menometroragija, premenstrualni sindrom i dismenoreja.
Predmet izuma također obuhvaća metodu kontracepcije i/ili HRT sastavljenu od davanja kontraceptivno i/ili terapeutski djelotvorne količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina duljine C7-C15, posebice C10-C12.
U jednom ostvarenju kontraceptivno i/ili terapeutski djelotvorna količina dugodjelujućeg androgen estera, posebice MENT undekanoata, se daje u kombinaciji s etonogestrel esterom.
U drugom ostvarenju kontraceptivno i/ili terapeutski djelotvorna količina estrogena se daje u kombinaciji s etonogestrel esterom.
Predmet izuma dalje osigurava metodu tretiranja i/ili prevencije ginekoloških promjena kod žena sastavljene od davanja terapeutski djelotvorne količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina dužine C7-C15, posebice C10-C12, djelotvorne za tretiranje i/ili sprječavanje bolest kod žena kao objekata.
U gornjim aspektima predmeta izuma kontraceptivno i/ili terapeutski djelotvorna količina MENT undekanoata je 50-400 mg, a kontraceptivno i/ili terapeutski djelotvorna količina etonogestrel estera je 25-200 mg.
U preferiranom ostvarenju kontraceptivno i/ili terapeutski djelotvorna količina MENT undekanoata je 50-200 mg, a kontraceptivna i/ili terapeutski djelotvorna količina etonogestrel estera je 50-100 mg.
U specijalno preferirajućem ostvarenju kontraceptivno i/ili terapeutski djelotvorna količina MENT undekanoata je 100 mg, a kontraceptivno i/ili terapeutski djelotvorna količina etonogestrel estera je 50 mg.
Progestogen i testosteron esteri mogu biti pripremljeni njihovim otapanjem u pogodnoj količini uljnog medija, kao što je ulje kikirikija, oleinska kiselina, ricinusovo ulje, etil undekanoat, bademovo ulje, sezamovo ulje, kokosovo ulje, maslinovo ulje, sojino ulje, (očišćen) triglicerid, propilen glikol esteri, etil oleat i slično, uključujući mješavine ulja. Količina estera koji mogu biti otopljeni razlikuje se s obzirom na izabrani medij, ali će generalno biti u okviru 100-400 mg. Preferirajući ulje je ulje kikirikija ili etil undekanoat.
Dodaci koji se dodaju obično injekcijskoj tekućini mogu biti dodani otopini po želji. Stručnoj osobi su poznati pogodni aditivi. Mogući aditivi uključuju tekućine koje služe za smanjenje viskoznosti sastava, npr. benzilni alkohol, benzil benzoat, benzil propionat, etil oleat ili etil undekanoat.
Komponente predmeta izuma mogu se principijelno davati preko bilo kojeg pogodnog načina poznatog stručnoj osobi.
U slučaju oralnog davanja solidna jedinica doze može biti tableta ili kapsula. Komponenta izuma može se formulirati s farmakološki prihvatljivim nosačem, kao što je opisano u standardnim referencama, Gennaro i sur., Remmington: The Science and Practice of Pharmacy, (20th urednik: Lippincott Williams & Wilkins, 2000, posebno vidi dio 5: Pharmaceutical Manufacturing). Komponente izuma i farmaceutski prihvatljiv nosač mogu se kompresirati u solidnu jedinicu doze, kao što su pilule, tablete, ili mogu biti procesirane u kapsule ili čepiće. S obzirom na postojeće farmaceutski pogodne tekućine, tvari se mogu davati i kao injekcijski pripravak u obliku otopine, suspenzije, emulzije, ili kao sprej, npr. sprej za nos. Za izradu doza, npr. tableta, upotrebljavaju se konvencionalni dodaci kao što su punjači, obojenja, polimerski vezači, lubrikanti, tekući pojačivači, sredstva za klizanje i slično. Generalno se može koristiti bilo koji farmaceutski prihvatljiv dodatak koji ne ulazi u interakcije s funkcijom aktivne komponente. Komponenta izuma može također biti uključena u implantat, vaginalni prsten, flaster, gel i slično.
Pogodni nosači s kojima se kompozicije mogu davati uključuju laktozu, škrob, derivate celuloze i slično, ili smjese ovih u odgovarajućim količinama. Doza i propisan način davanja komponente izuma, ili iz toga dobiveni farmaceutski pripravak, će ovisiti o terapeutskom efektu koji treba postići i varirati će ovisno o načinu davanja, te će također ovisiti o starosnim uvjetima individue kojoj se medikament daje i/ili o specifičnom kontraceptivu ili HRT.
Tipična količina doze je 0.001-5 mg po kg tjelesne težine.
Izum je dalje opisan kroz sljedeće primjere koji niti u kom slučaju nisu namjera da se ograniči njegov domet.
Primjeri
Primjer 1- Kinetika etonogestrel C7, C9, C10, C11, C12 i C13 estera u zečevima
Sljedeći etonogestrel esteri su pripremljeni i testirani u zečevima:
etonogestrel heptanoat
etonogestrel nananoat
etonogestrel dekanoat
etonogestrel dodekanoat
etonogestrel tridekanoat
Također je pripremljen etonogestrel pentadekanoat.
Slika 1 prikazuje kemijske strukture tih komponenata.
Kao referenca je uključen i etonogestrel.
Priprema etonogestrel estera
Opća metodologija pripremanja estera iz alkohola može se naći u npr. Greene, T.W. i sur., “Protective groups in organic synthesis", John Wiley & Sons, NY, 1999 (treće izdanje). Priprema estera iz tercijarnih alkohola (kao etonogestrel) može se raditi s nekoliko tehnika, kao npr: 1) tercijarni alkohol, karboksilna kiselina, trifluorooctena kiselina-anhidrid, D 1013284 (1956); 2) tercijarni alkohol, kiseli klorid, piridin, Watson, T.G. i sur., Steroids 41, 255 (1983); 3) tercijarni alkohol, kiseli klorid, TlOEt, Shafiee, A.i sur., Steroids 41, 349 (1983), 4) tercijarni alkohol, anhidrid karboksilne kiseline, TsOH, benzen, Johnson, A.L., Steroids, 20, 263 (1972); i 5) tercijarni alkohol, anhidrid karboksilne kiseline, DMAP, CH2Cl2, Shafiee, A. i sur., Steroids 41, 349 (1983).
Priprema (17α)-13-etil-11-metilen-17-[[(1-oksononil)oxi]-18,19-dinopreg-4-en-20-in-3-ona (etonogestrel nonanoat)
a) Otopina pelargonske kiseline (1.95 g) u suhom toluenu (8 ml) je ohlađena na 0° C i tretirana s anhidridom trifluorooctene kiseline (2.6 g). Nakon 30 min miješanja, (17α)-13-etil-11-metilen-17-[[(1-oksononil) oxi]-18,19-dinopreg-4-en-20-in-3-on (etonogestrel, 2.0 g) je dodan u suhi toluen (15 ml) i reakcijska smjesa je miješana 17 h pri sobnoj temperaturi. Reakcijska smjesa je isprana vodom, saturiranom vodenom otopinom natrij hidrogen karbonata, vode i slanom vodom. Organska faza je osušena preko natrij sulfata i koncentrirana pod smanjenim tlakom. Jedinica je očišćena preko kolonske kromatografije (toluen/etilni acetat 95:5). Produkt (2.08 g) je otopljen u etil acetatu (40 ml), ohlađen na 0° C, te miješan s vodenim natrij hidroksidom (1 M, 13 ml) 2 h. Smjesa je ekstrahirana s etil acetatom; vezane organske faze su isprane s ledeno hladnim natrij hidroksidom (1 M), vodom i slanom vodom, te je osušena i koncentrirana pod smanjenim tlakom. Kolonska kromatografija rezultira (17α)-13-etil-11-metilen-17-[[(1-oksononil)oxi]-18,19-dinopreg-4-en-20-in-3-on-om (1.25 g). 1H-NMR (CDCl3): δ 5.89 (m, 1H), 5.08 (bs, 1H), 4.85 (bs, 1H), 2.82 (ddd, 1H, J=14.8, 9.5 i 6.3 Hz), 2.73 (d, 1H, J=12.8 Hz), 2.69-2.19 (m), 2.63 (s, 1H), 2.11 8m, 1H9, 1.90-1.21 (m), 1.15 (m, 1H), 1.05 (t, 3H, J=7.5 Hz), 0.88 (t, 3H, J=7.1 Hz). Mjerena masa [M+H]+ 465.3358. Kalkulirana masa [M+H]+ 465.3363.
Na analogan način postupku opisanom gore pripremljeni su: etonogestrel heptanoat, etonogestrel dekanoat, etonogestrel undekanoat, etonogestrel dodekanoat, etonogestrel tridekanoat i etonogestrel pentadekanoat:
b) (17α)-13-etil-11-metilen-17-[[(1-oksononil)oxi]-18,19-dinopreg-4-en-20-in-3-on (etonogestrel heptanoat). 1H-NMR (CDCl3): δ 5.89 (m, 1H), 5.08 (bs, 1H), 4.85 (bs, 1H), 2.82 (ddd, 1H, J=14.8, 9.5 i 6.3 Hz), 2.73 (d, 1H, J=12.6 Hz), 2.68-2.19 (m), 2.63 (s, 1H), 2.11 (m, 1H), 1.90-1.24 (m), 1.15 (m, 1H), 1.90-1.24 (m), 1.15 (m, 1H), 1.05 (t, 3H, J=7.5 Hz), 0.89 (t, 3H, J=7.1 Hz). Mjerena masa [M+H]+ 437.3050. Kalkulirana masa [M+H]+ 437.3050.
c) (17α)-13-etil-11-metilen-17-[[(1-oksononil)oxi]-18,19-dinopreg-4-en-20-in-3-on (etonogestrel dekanoat). 1H-NMR (CDCl3): δ5.89 (bs, 1H), 5.08 (bs, 1H), 4.84 (bs, 1H), 2.82 (m, 1H), 2.73 (d, 1H, J=12.6 Hz), 2.67-2.18 (m), 2.63 (s, 1H), 2.11 (m, 1H), 1.90-1.21 (m), 1.15 (m, 1H), 1.06 (t, 3H, J=7.5 Hz), 0.88 (t, 3H, J=7.1 Hz). Mjerena masa [M+H]+ 479.3508. Kalkulirana masa [M+H]+ 479.3519.
d) (17α)-13-etil-11-metilen-17-[[(1-oksononil)oxi]-18,19-dinopreg-4-en-20-in-3-on (etonogestrel dekanoat). 1H-NMR (CDCl3): δ5.89 (m, 1H), 5.08 (bs, 1H), 4.85 (bs, 1H), 2.82 (ddd, 1H, J=14.8, 9.5 i 6.3 Hz), 2.73 (d, 1H, J=12.6 Hz), 2.68-2.18 (m), 2.63 (s, 1H), 2.11 (m, 1H), 1.90-1.21 (m), 1.06 (t, 3H, J=7.5 Hz), 1.06 (t, 3H, J=7.5 Hz), 0.88 (t, 3H, J=7.1 Hz). Mjerena masa [M+H]+ 493.3664. Kalkulirana masa [M+H]+ 493.3676.
e) (17α)-13-etil-11-metilen-17-[[(1-oksononil)oxi]-18,19-dinopreg-4-en-20-in-3-on (etonogestrel dekanoat). 1H-NMR (CDCl3): δ5.89 (bs, 1H), 5.08 (bs, 1H), 4.85 (bs, 1H), 2.82 (m, 1H), 2.73 (d, 1H, J=12.6 Hz), 2.65-2.18 (m), 2.64 (s, 1H), 2.11 (m, 1H), 1.90-1.20 (m), 1.15 (m, 1H), 1.06 (t, 3H, J=7.5 Hz), 0.88 (t, 3H, J=7.1 Hz). Mjerena masa [M+H]+ 507.3829. Kalkulirana masa [M+H]+ 507.3832.
f) (17α)-13-etil-11-metilen-17-[[(1-oksononil)oxi]-18,19-dinopreg-4-en-20-in-3-on (etonogestrel dekanoat). 1H-NMR (CDCl3): δ5.89 (bs, 1H), 5.08 (bs, 1H), 4.85 (bs, 1H), 2.82 (m, 1H), 2.73 (d, 1H, J=12.6 Hz), 2.65-2.18 (m), 2.64 (s, 1H), 2.11 (m, 1H), 1.90-1.20 (m), 1.15 (m, 1H), 1.06 (t, 3H, J=7.5 Hz), 0.89 (t, 3H, J=7.1 Hz). Mjerena masa [M+H]+ 521.4007. Kalkulirana masa [M+H]+ 521.3938.
g) (17α)-13-etil-11-metilen-17-[[(1-oksononil)oxi]-18,19-dinopreg-4-en-20-in-3-on (etonogestrel dekanoat). 1H-NMR (CDCl3): δ5.89 (bs, 1H), 5.08 (bs, 1H), 4.85 (bs, 1H), 2.82 (m, 1H), 2.73 (d, 1H, J=12.6 Hz), 2.65-2.19 (m), 2.63 (s, 1H), 2.11 (m, 1H), 1.90-1.20 (m), 1.15 (m, 1H), 1.06 (t, 3H, J=7.5 Hz), 0.89 (t, 3H, J=7.1 Hz). Mjerena masa [M+H]+ 549.4278. Kalkulirana masa [M+H]+ 549.4302.
Parmakokinetičke studije u zecu
Za određivanje farmakokinetičkog profila različitih etonogestrel estera nakon roditeljske aplikacije, umjesto s.c izabrana je i.m. aplikacija u kastriranog zeca kao modela. Ukratko, zečevi su injicirani jednom (dan 1) s navedenim etonogestrel esterima na 20 mg/kg u ulju kikirikija (s koncentracijom od 40 mg/ml). Na dan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 21, 28, 35, 49, 63, 77, 92, 106, 120 i 133 iz ušne arterije sakupljana je krv u epruvete s EDTA. Pripremljena EDTA plazma (1500 g, 15 min) je spremljena pri -20° C. Sa LC-MSMS određena je količina roditeljske komponenate (etonogestrel) u tim uzorcima. Niži limit ove nove metode je 0.5 nmol/l, iz 0-250 nmol/l postignuta je linearna krivulja s korelacijskim koeficijentom od 0.9998.
Kao što je prikazano na slici 2a, sam etonogestrel rezultira veoma visokim pikom (200 nmol/l) koji pada 28 dana ispod 1 nmol/l.
Etonogestrel heptanoat također raste prema visokom piku etonogestrela (120 nmol/l). Etonogestrel nonanoat daje nižu razinu pika i produženo djelovanje s razinom etonogestrela u krvi iznad 1 nmol/l. Ukoliko se usporedi s ostala dva estera na slici 2a, etonogestrel undekanoat daje najoptimalniju ravnotežu između početne razine pika (maksimum od 13 nmol/l nakon osam dana) i trajanja djelovanja (više od 92 dana iznad 1 nmol/l).
Kao što je pokazano na slici 2b, etonogestrel dekanoat daje početnu razinu pika od 24 nmol/l nakon 5 dana dok etonogestrel dodekanoat daje početnu razinu pika od 9 nmol/l nakon 8 dana. S etonogestrel tridekanoatom, nisu uočene početne razine etonogestrela.
Iz slika 2a i 2b može se vidjeti da su preferirani etonogestrel esteri etonogestrel dekanoat, etenogestrel undekanoat i etonogestrel dodekanoat.
Primjer 2- Kinetika dva MENT estera u zečevima
Farmakokinetički profil MENT undekanoata i MENT buciklata je uspoređena s testosteron enantanom i testosteron undekanoatom.
Slika 3 prikazuje kemijske strukture tih androgen estera.
MENT undekanoat je pripremljen zapravo kao što je opisano u WO 99/67271. MENT buciklat je pripremljen kao što je opisano u WO 99/67270. Testosteron enantat i undekanoat su komercijalno dobiveni od Diosynth, Oss, Nizozemska.
Parmakokinetičke studije u zecu
Za određivanje farmakokinetičkog profila različitih androgenih estera nakon s.c. aplikacije, kastrirani zec izabrana je kao model zbog sličnosti s ljudima. Ukratko, zečevi su injicirani jednom (dan 1) s navedenim androgenim esterima na 20 mg/kg u ulju kikirikija (s koncentracijom od 100 mg/ml). Na dan 2, 3, 4, 5, 8, 15, 22, 36, 44 i 58 iz ušne arterije sakupljana je krv u epruvete s EDTA. Pripremljena EDTA plazma (1500 g, 15 min) je spremljena pri -20° C. Sa LC-MSMS određena je količina roditeljske komponenate (testosteron ili MENT) u tim uzorcima. Niži limit ove nove metode je 2 nmol/l, iz 0-500 nmol/l postignuta je linearna krivulja s korelacijskim koeficijentom od 0.9998.
Kao što je pokazano na slici 4, i s MENT undekanoatom i s MENT buciklatom nađen je farmakokinetički profil otpuštanja MENTa koji je sličan onom referentne komponente testosteron undekanoata u odnosu na otpušten testosteron. Testosteron enantat rezultira s visokim pikom testosterona dva dana nakon injekcije.
Stoga, u zecu, s oba MENT estera nije uočen početan rast MENTa s jedne strane, ali je uočeno prolongirano otpuštanje s druge strane, što ukazuje na optimalnije farmakokinetičko ponašanje u odnosu na trenutno standardni testosteron enantat.
U ljudi, optimalna farmakokinetika je postignuta s testosteron undekanoatom: niže početno otpuštanje i stabilna razina dugog trajanja (Slika 5). S obzirom da je farmakokinetički profil dva MENT estera veoma sličan onom testosteron undekanoata (Slika 4), očekivana je optimalna farmakokinetika s oba MENT estera u ljudi.
Primjer 3-Topivost i viskoznost MENT undekanoata i etonogestrel undekanoata u različitim otapalima
Za određivanje topivosti i viskoznosti MENT undekanoata i etonogestrel undekanoata, upotrijebljena su četiri različita otapala:
etil undekanoat
etil undekanoat + 50% benzil benzoat
ulje kikirikija
ulje kikirikija + 50% benzil benzoat
Upotrebom tih otapala, pripremljene su slijedeće otopine:
100 mg/ml etonogestrel undekanoata u različitim otapalima
50 mg/ml etonogestrel undekanoata u različitim otapalima
200 mg/ml MENT undekanoata u različitim otapalima
100 mg/ml MENT undekanoat u različitim otapalima
50 mg/ml etonogestrel undekanoata + 100 mg/ml MENT undekanoata u različitim otapalima
Dva kombinirana otapala su pripremljena dodavanjem 50 grama etil undekanoata ili ulja kikirikija u 50 grama benzil benzoata. Otopina etil undekanoat + 50% benzil benzoata je filtrirana preko 0.22 μm Durapore filtera kako bi se dobila čista i prozirna otopina. Otopina ulja kikirikija + 50% benzil benzoata nije filtrirana.
Topivost komponenata u otapalima je određena vizualno. Viskozitet je određen upotrebom Brookfield modela DV-III. Gustoća otopina je određena upotrebom Mettler Toledo DA-100M density meter.
Tabela 1. Izgled, viskozitet i gustoća otapala
[image]
Etil undekanoat, etil undekanoat + 50% benzil benzoat i ulje kikirikija + 50% benzil benzoat nije potrebno zagrijati. Da bi se otopilo 200 mg/ml MENT undekanoata u ulju kikirikija, potrebno je zagrijavanje pri oko 50° C.
Testirane koncentracije su bile 100 mg/ml etonogestrel undekanoata, 200 mg/ml MENT undekanoata i 50 mg/ml etonogestrel undekanoata + 100 mg/ml MENT undekanoata u različitim otapalima. Rezultati su sažeti u tabeli 2.
Tabela 2. Izgled, viskoznost i gustoća finalnih otopina
[image]
Kombinacija etonogestrel undekanoata i MENT undekanoata je vizualno otopljena na željenu koncentraciju od 50 mg/ml etonogestrel undekanoata i 100 mg/ml MENT undekanoata u sva četiri otapala. Oba etonogestrel undekanoat i MENT undekanoat mogu biti otopljeni dva puta do željene koncentracije u sva četiri testirana otapala. Kada su 50 mg/ml etonogestrel undekanoat i 100 mg/ml MENT undekanoat otopljeni u sva četiri otapala pri sobnoj temperaturi nije došlo do stvaranja precipitata.
Viskozitet etil undekanoata i etil undekanoata + 50% benzil benzoata bio je značajno niži nego viskozitet ulja kikirikija i ulja kikirikija + 50% benzil benzoata. Viskozitet željene formulacije 50 mg/ml etonogestrel undekanoata + 100 mg/ml MENT undekanoata u četiri različita otapala je bila najniža (4 cps) za otopinu etil undekanoata, koju je zatim sljedila otopina etil undekanoata + 50% benzil benzoata (7 cps) i ulja kikirikija + 50% benzil benzoata (39 cps). Viskozitet otopine ulja kikirikija je bila signifikantno viša nego viskozitet drugih otopina (100 cps).
Primjer 4- Farmakolološko djelovanje etonogetsrel estera u mužjaka
Farmakološko djelovanje etonogestrel estera u mužjaka je određeno za supresivno djelovanje etonogestrel testosterona u zecu kao što je opisano u Wu, F.C., Balasubramanian, R., Mulders, T.M. i Coelingh-Bennink, H.J., Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism, J. Clin. Endocrinol. Metab 84 (1):112-122, 1999. Ukratko, na dan sedam biti će promatran efekt jedne sc/im injekcije različitih etonogestrel estera na testosteron seruma zrelih mužjaka zečeva.
Primjer 5-Farmakološko djelovanje etonogestrel estera kod ženke
Farmakološko djelovanje etonogestrel estera u ženka je testirano klasičnim Clauberg testom. Ukratko, nezrele ženke zečeva, pripremljen s ostradiolom za 8 dana, su jednom tretirane sa sc/im različitih etonogestrel estera (dan 8 popodne). Autopsija je napravljena popodne na dan 13 i progestageničko djelovanje je izvršeno na sekcijama uterusa na temelju podataka u McPhail i sur., The assay of progestin. J of Physiolgy, 1934, 83: 145-156.
Claims (31)
1. Kontraceptivni i/ili HRT kit, naznačen time, da je sastavljen od kontraceptivno i/ili terapeutski učinkovite količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina od C7-C15.
2. Kit, prema zahtjevu 1, naznačen time, da je etonogestrel ester ili etonogestrel undekanoat i/ili etonogestrel dekanoat i/ili etonogestrel dodekanoat.
3. Kit prema zahtjevu 1 ili 2, naznačen time, da se sastoji od kontraceptivno i/ili terapeutski učinkovite količine androgen estera.
4. Kit prema zahtjevu 3, naznačen time, da je androgen ester MENT undekanoat.
5. Kit prema zahtjevu 4, naznačen time, da je kontraceptivno i/ili terapeutski učinkovita količina MENT undekanoata 50-400 mg, a da je kontraceptivno i/ili terapeutski učinkovita količina etonogestrel estera 25-200 mg.
6. Kit prema zahtjevu 5, naznačen time, da je kontraceptivno i/ili terapeutski učinkovita količina MENT undekaoata 50-200 mg, a kontraceptivno i/ili terapeutski učinkovita količina etonogestrel estera 50-100 mg.
7. Kit prema zahtjevu 6, naznačen time, da je kontraceptivno i/ili terapeutski učinkovita količina MENT undekaoata 100 mg, a kontraceptivno i/ili terapeutski učinkovita količina etonogestrel estera 50 mg.
8. Kit prema zahtjevu 1 ili 2, naznačen time, da se dalje sastoji od kontraceptivno i/ili terapeutski učinkovite količine estrogena.
9. Upotreba kontraceptivno i/ili terapeutski učinkovite količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina dužine C7-C15, naznačena time, da služi za pripremu pripravka za kontracepciju i/ili HRT.
10. Upotreba prema zahtjevu 9, naznačena time, da je ester ili etonogestrel undekanoat i/ili etonogestrel dekanoat i/ili etonogestrel dodekanat.
11. Upotreba kontraceptivno i/ili terapeutski učinkovite količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina dužine C7-C15 u vezi s kontraceptivno i/ili terapeutski učinkovitom količinom dugodjelujućeg androgen estera, naznačena time, da služi za pripremu pripravka za mušku kontracepciju i/ili mušku HRT.
12. Upotreba prema zahtjevu 11, naznačena time, da je etonogestrel ili ester etonogestrel undekanoat i/ili etonogestrel dekanoat i/ili etonogestrel dodekanoat, a androgen ester je MENT undekanoat.
13. Upotreba prema zahtjevu 12, naznačena time, da je kontraceptivno i/ili terapeutski učinkovita količina MENT undekanoata 50-400 mg, a kontraceptivno i/ili terapeutski učinkovita količina etonogestrel estera 25-200 mg.
14. Upotreba prema zahtjevu 13, naznačena time, da je kontraceptivno i/ili terapeutski učinkovita količina MENT undekanoata 50-200 mg, a kontraceptivno i/ili terapeutski učinkovita količina etonogestrel estera 50-100 mg.
15. Upotreba prema zahtjevu 14, naznačena time, da je kontraceptivno i/ili terapeutski učinkovita količina MENT undekanoata 10 mg, a kontraceptivno i/ili terapeutski učinkovita količina etonogestrel estera 50 mg.
16. Upotreba kontraceptivno i/ili terapeutski učinkovite količine dugodjelujućeg etonogestrel estera s lancima masnih kiselina dužine C7-C15 u vezi s kontraceptivno i/ili terapeutski učinkovitom količinom estrogena, naznačena time, da služi za pripremu pripravka za žensku kontracepciju i/ili žensku HRT.
17. Upotreba prema zahtjevu 16, naznačena time, da je etonogestrel ester ili etonogestrel undekanoat i/ili etonogestrel dekanoat i/ili etonogestrel dodekanoat.
18. Metoda kontracepcije i/ili HRT, naznačena time ,da se sastoji od davanja kontraceptivno i/ili terapeutski djelotvorne količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina od C7-C15.
19. Metoda prema zahtjevu 18, naznačena time, da je ester ili etonogestrel undekanoat i/ili etonogestrel dekanoat i/ili etonogestrel dodekanoat.
20. Metoda prema zahtjevu 18, naznačena time, da je kontraceptivna i/ili terapeutski učinkovita količina dugodjelujućeg androgen estera u vezi s etonogestrel esterom.
21. Metoda prema zahtjevu 20, naznačena time, da je etonogestrel ester ili etonogestrel undekanoat i/ili etonogestrel dekanoat i/ili etonogestrel dodekanoat, a da je androgen ester MENT undekanoat.
22. Metoda prema zahtjevu 21, naznačena time, da je kontraceptivno i/ili terapeutski učinkovita količina MENT undekanoata 50-400 mg, a kontraceptivno i/ili terapeutski učinkovita količina etonogestrel estera 25-200 mg.
23. Metoda prema zahtjevu 22, naznačena time, da je kontraceptivno i/ili terapeuski učinkovita količina MENT undekanoata 50-200 mg, a kontraceptivno i/ili terapeutski učinkovita količina etonogestrel estera 25-100 mg.
24. Metoda prema zahtjevu 23, naznačena time, da je kontraceptivno i/ili terapeutski učinkovita količina MENT undekanoata 100 mg, a kontraceptivno i/ili terapeutski učinkovita količina etonogestrel estera 50 mg.
25. Metoda prema zahtjevu 18 ili 19, naznačena time, da je kontraceptivno i/ili terapeutski učinkovita količina estrogena davana u kombinaciji s etonogestrel esterom.
26. Upotreba kontraceptivno i/ili terapeutski učinkovite količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina dužine C7-C15, naznačena time, da služi za pripremu medikamenta za tretman i/ili prevenciju ženskih ginekoloških promjena.
27. Upotreba prema zahtjevu 26 , naznačena time, da je etonogestrel ester ili etonogestrel undekaoat i/ili etonogestrel dekanoat i/ili etonogestrel dodekanoata.
28. Upotreba prema zahtjevu 26 ili 27, naznačena time, da se pod ženskim ginekološkim promjenama podrazumijevaju endometroza, menoragija, menometroragija, premenstrualni sindrom i dismenoreja.
29. Metoda tretiranja i/ili prevencije ženskih ginekoloških promjena, naznačena time, da se sastoji od davanja kontraceptivno i/ili terapeutski učinkovite količine dugodjelujućeg etonogestrel estera s lancem masnih kiselina C7-C15 učinkovitih u tretmanu i/ili prevenciji promjena.
30. Metoda prema zahtjevu 29, naznačena time, da je etonogestrel ester ili etonogestrel undekanoat i/ili etonogestrel dekanoat i/ili etonogestrel dodekanoat.
31. Metoda prema zahtjevu 29 ili 30, naznačena time, da su ženske ginekološke promjene izabrane iz grupe sastavljene od endometroze, menoragije, menometroragije, premenstrualnog sindroma i dismenoreje.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02077118 | 2002-05-30 | ||
| PCT/EP2003/050188 WO2003101374A2 (en) | 2002-05-30 | 2003-05-22 | Use of new etonogestrel esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20041127A2 true HRP20041127A2 (en) | 2005-02-28 |
Family
ID=29595013
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| HR20041127A HRP20041127A2 (en) | 2002-05-30 | 2004-11-25 | Use of new etonogestrel esters |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US20050222114A1 (hr) |
| EP (1) | EP1513588B1 (hr) |
| JP (1) | JP2005532336A (hr) |
| KR (1) | KR20050005507A (hr) |
| CN (1) | CN1655848A (hr) |
| AR (1) | AR040129A1 (hr) |
| AT (1) | ATE394140T1 (hr) |
| AU (1) | AU2003246740B2 (hr) |
| BR (1) | BR0311248A (hr) |
| CA (1) | CA2487293A1 (hr) |
| DE (1) | DE60320786D1 (hr) |
| ES (1) | ES2305498T3 (hr) |
| HK (1) | HK1072568A1 (hr) |
| HR (1) | HRP20041127A2 (hr) |
| IL (1) | IL165125A0 (hr) |
| IS (1) | IS7537A (hr) |
| MX (1) | MXPA04011798A (hr) |
| NO (1) | NO20044903L (hr) |
| NZ (1) | NZ536618A (hr) |
| PE (1) | PE20040042A1 (hr) |
| PL (1) | PL373295A1 (hr) |
| RS (1) | RS101004A (hr) |
| RU (1) | RU2322986C2 (hr) |
| TW (1) | TW200400041A (hr) |
| UA (1) | UA80703C2 (hr) |
| WO (1) | WO2003101374A2 (hr) |
| ZA (1) | ZA200409498B (hr) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200403065A (en) * | 2002-05-30 | 2004-03-01 | Akzo Nobel Nv | New etonogestrel esters |
| US20130123523A1 (en) * | 2011-11-10 | 2013-05-16 | Klaus Nickisch | Methods for the preparation of etonogestrel and desogestrel |
| DE102012211511A1 (de) * | 2012-07-03 | 2014-01-09 | Siemens Aktiengesellschaft | Bestimmung der Eignung einer Ressource |
| EP3697421B1 (en) * | 2017-10-19 | 2024-04-17 | Evestra, Inc. | Longer-acting progestin prodrug contraceptives |
| CN111057120B (zh) * | 2019-12-27 | 2021-04-27 | 苏州翔实医药发展有限公司 | 一种依托孕烯衍生物a及其制备方法和用途 |
| EP4164743A2 (en) * | 2020-06-11 | 2023-04-19 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Monomeric and oligomeric compound embodiments as contraceptives and therapies and methods of making and using the same |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4227989A1 (de) * | 1992-08-21 | 1994-06-09 | Schering Ag | Mittel zur transdermalen Applikation enthaltend 3-Keto-desogestrel |
| DE4240806A1 (de) * | 1992-12-01 | 1994-06-09 | Schering Ag | Mittel zur transdermalen Applikation enthaltend 14alpha,17alpha-Ethanoestra-1,3,5(10)-trien-3,17beta-diol |
| JPH07101884A (ja) * | 1993-10-01 | 1995-04-18 | Sanei Gen F F I Inc | 水溶性ヘミセルロースを含有する製剤 |
| AU692504B2 (en) * | 1993-12-27 | 1998-06-11 | Akzo Nobel N.V. | Percutaneously absorbable preparation |
| WO1997003709A1 (de) * | 1995-07-17 | 1997-02-06 | Schering Aktiengesellschaft | Mittel zur transdermalen applikation enthaltend ester des 3-ketodegestrel |
| PT1087986E (pt) * | 1998-06-19 | 2002-08-30 | Akzo Nobel Nv | Undecanoato de 7alfa-metil-19-nortestosterona com actividade androgenica |
| AU4513099A (en) * | 1998-06-19 | 2000-01-10 | Akzo Nobel N.V. | Cycloalkyl-carboxylic acid esters of 7.alpha.methyl-estr-4-en-3-one 17.beta.-ol (19-nor 7.alpha.-methyltestosterone) |
| US6180682B1 (en) * | 1999-01-26 | 2001-01-30 | Virgil A. Place | Buccal drug delivery system for use in male contraception |
| TW200403065A (en) * | 2002-05-30 | 2004-03-01 | Akzo Nobel Nv | New etonogestrel esters |
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2003
- 2003-05-19 TW TW092113492A patent/TW200400041A/zh unknown
- 2003-05-22 MX MXPA04011798A patent/MXPA04011798A/es unknown
- 2003-05-22 UA UA20041109285A patent/UA80703C2/uk unknown
- 2003-05-22 DE DE60320786T patent/DE60320786D1/de not_active Expired - Fee Related
- 2003-05-22 US US10/517,362 patent/US20050222114A1/en not_active Abandoned
- 2003-05-22 KR KR10-2004-7019327A patent/KR20050005507A/ko not_active Application Discontinuation
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- 2003-05-22 WO PCT/EP2003/050188 patent/WO2003101374A2/en active IP Right Grant
- 2003-05-22 CN CNA038123657A patent/CN1655848A/zh active Pending
- 2003-05-22 NZ NZ536618A patent/NZ536618A/en unknown
- 2003-05-22 EP EP03755980A patent/EP1513588B1/en not_active Expired - Lifetime
- 2003-05-22 AT AT03755980T patent/ATE394140T1/de not_active IP Right Cessation
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- 2003-05-22 AU AU2003246740A patent/AU2003246740B2/en not_active Ceased
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- 2003-05-22 RU RU2004138809/15A patent/RU2322986C2/ru active
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- 2003-05-26 PE PE2003000508A patent/PE20040042A1/es not_active Application Discontinuation
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Also Published As
| Publication number | Publication date |
|---|---|
| UA80703C2 (en) | 2007-10-25 |
| US20050222114A1 (en) | 2005-10-06 |
| PE20040042A1 (es) | 2004-01-31 |
| IL165125A0 (en) | 2005-12-18 |
| WO2003101374A3 (en) | 2004-02-26 |
| AR040129A1 (es) | 2005-03-16 |
| IS7537A (is) | 2004-11-18 |
| BR0311248A (pt) | 2005-03-15 |
| WO2003101374A2 (en) | 2003-12-11 |
| MXPA04011798A (es) | 2005-03-31 |
| CA2487293A1 (en) | 2003-12-11 |
| PL373295A1 (en) | 2005-08-22 |
| AU2003246740A1 (en) | 2003-12-19 |
| NZ536618A (en) | 2007-06-29 |
| RU2322986C2 (ru) | 2008-04-27 |
| RS101004A (en) | 2006-10-27 |
| TW200400041A (en) | 2004-01-01 |
| DE60320786D1 (de) | 2008-06-19 |
| EP1513588B1 (en) | 2008-05-07 |
| CN1655848A (zh) | 2005-08-17 |
| NO20044903L (no) | 2005-02-25 |
| HK1072568A1 (en) | 2005-09-02 |
| RU2004138809A (ru) | 2005-06-10 |
| KR20050005507A (ko) | 2005-01-13 |
| JP2005532336A (ja) | 2005-10-27 |
| ZA200409498B (en) | 2006-05-31 |
| EP1513588A2 (en) | 2005-03-16 |
| ES2305498T3 (es) | 2008-11-01 |
| ATE394140T1 (de) | 2008-05-15 |
| AU2003246740B2 (en) | 2009-01-08 |
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