HRP20090198A9 - Upotreba poliola za dobivanje stabilnih oblika rifaksimina - Google Patents
Upotreba poliola za dobivanje stabilnih oblika rifaksimina Download PDFInfo
- Publication number
- HRP20090198A9 HRP20090198A9 HR20090198A HRP20090198A HRP20090198A9 HR P20090198 A9 HRP20090198 A9 HR P20090198A9 HR 20090198 A HR20090198 A HR 20090198A HR P20090198 A HRP20090198 A HR P20090198A HR P20090198 A9 HRP20090198 A9 HR P20090198A9
- Authority
- HR
- Croatia
- Prior art keywords
- rifaximin
- polyols
- reported
- residual water
- water content
- Prior art date
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- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical compound OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 title claims abstract description 71
- 229960003040 rifaximin Drugs 0.000 title claims abstract description 62
- 229920005862 polyol Polymers 0.000 title claims abstract description 40
- 150000003077 polyols Chemical class 0.000 title claims abstract description 40
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 238000001035 drying Methods 0.000 claims description 17
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- 239000002253 acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
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- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
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- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
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- 238000001159 Fisher's combined probability test Methods 0.000 description 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- BUBBEHCXSMCYNY-CVEARBPZSA-N [3-hydroxy-5-methyl-4-[(2S,3R)-2,3,4-trihydroxybutoxy]carbonylphenyl] 2,4-dihydroxy-6-methylbenzoate Chemical compound CC1=CC(O)=CC(O)=C1C(=O)OC1=CC(C)=C(C(=O)OC[C@H](O)[C@H](O)CO)C(O)=C1 BUBBEHCXSMCYNY-CVEARBPZSA-N 0.000 description 1
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- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
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- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
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- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
Polioli stabiliziraju polimorfni oblik rifaksimina, posebice oblik ß. Kada su polioli koji imaju najmanje dvije hidroksilne skupine dodani praškastom rifaksiminu, polimorf ß ostaje stabilan u vremenu neovisno o vlazi u okolini. U ovom izumu je opisana metoda priprave formulacija koji sadrže čiste stabilne polimorfne oblike koji mogu dati farmaceutske produkte.
Description
Dosadašnja spoznaje
Aktivni sastojci sadržani u medicinskim produktima mogu biti raspoloživi u polimorfnim oblicima koji imaju različita kemijsko-fizička svojstva, kao što je primjerice topljivost i kemijska stabilnost.
Kod medicinskih produkata su oba ova svojstva kritična za in vivo apsorpciju aktivne tvari, te stoga za učinkovitost i sigurnost produkta nakon davanja ljudima ili životinjama.
Postoji veliki broj znanstvenih radova o ovoj temi. Neki članci su primjerice o sljedećim: doksazosin (Sohn Y.T. et al., Arch. Pharm. Res., 2005; 28, 730-735), tranilast (Vogt F.G. et al., J. Pharm. Sci., 2005, 94,651-65), klopidogrel (Koradia V., et al., Ada. Pharm., 2004, 54 (3),193-204), celekoksib (Chawla G. et al., Pharm. Dev. Technol., 2004, 9 (4), 41933), ketorolak (Sohn Y.T. et at., Arch. Pharm. Res. 2004, 27 (3), 357-60), flukonazol (Caira M.R. et al., J. Pharm. Sci., 2004, 93 (3), 601-11); piroksikam (Vrecer F. et al., int. J. Pharm., 2003, 256 (1-2), 3-15), teofilin (Airaksinen S. et al., int. J. Pharm., 2004, 276 (1-2), 129-41).
Zbog gore spomenutih razloga su medicinski stručnjaci odgovorni za odobravanje stavljanja na tržište medicinskih produkata za koje se traži informacija o svojstvima i konzistencija u proizvodnji polimorfnih aktivnih tvari u čvrstom stanju. Važno je izbjeći modifikaciju polimorfnog oblika tijekom stupnja proizvodnje farmaceutskog pripravka. Za tu svrhu je važno da se među mogućim polimorfnim oblicima izaberu oni koji imaju veću stabilnost u vremenu, kao što je opisano od Rodriquez-Spong B et al. u Adv. Drug Del. Rev., 2006, 56(3), 241-74.
Da se dobije stabilniji polimorfni oblik, koriste se aktivni sastojci u fiziološkoj otopini, kao što je opisano u Adv. Drug Del. Rev., 2006, 56, 231-334.
Rifaksimin je antibiotik koji spada u obitelj rifampicina na tržištima Europe U.S.A. i mnogih drugih država je na raspolaganju je u tabletama, granulama za oralnu suspenziju i mastima.
Rifaksimin može postojati i polimorfnim oblicima α, β i γ opisanih od Viscomi G. C. et al. u IT MI2003 A 002144, (2003) i US 7,045,620 B1, (2003), te u polimorfnim oblicima δ i ε opisanih od Viscomi G. C. et al. u EP 1698630 (2005). Ti polimorfni oblici su vrlo važni jer mogu promijeniti intrinzičko raspadanje približno deset puta, a bioraspoloživost rifaksimina skoro šesto puta, kao što je opisano od Viscomi et al. u WO 2005104.4823 (2004). Te promjene mogu imati veliki učinak na učinkovitost i sigurnost produkta.
Štoviše, poznato je iz US 7,045,620 B1 (2003) i EP 1698630 (2005) da rifaksimin u polimorfnim oblicima može lako preći u druge oblike ovisno o mogućnosti dobivanja ili gubitka vode. Te transformacije se također mogu desiti u čvrstom stanju zbog promjena vlage i temperaturnih uvjeta. Primjerice u okolišu s relativnom vlagom oko 50% ili višom, polimorfni oblik α prelazi u polimorfni oblik β. Sljedeći primjer je predstavljen polimorfnim oblikom ε koji se može dobiti sušenjem polimorfa δ, kao što je opisano u EP 1698630 (2005), a koji pokazuje smanjivanje bioraspoloživosti dvadeset puta u usporedbi s oblikom δ.
Različiti polimorfni oblici rifaksimina se mogu pogodno koristiti kao homogeni čisti produkti za pripravu medicinskih produkata koji sadrže rifaksimin, a učinkovitost i sigurnost produkta se može modulirati upotrebom pravog polimorfnog oblika.
Prethodna saznanja dozvoljavaju razumijevanje važnosti uvjeta priprave medicinskih produkata koji sadrže rifazkimin, koji, ako ih nije moguće kontrolirati, mogu dati neželjene transformacije polimorfnih oblika rifaksimina.
Štoviše, radna faza korištena tijekom priprave farmaceutskog produkta obuhvaća upotrebu vode, primjerice granuliranje praška u vlažnim uvjetima, oblaganje filmom uz vodu kao otapalo, sušenje, može modificirati polimorfni oblik odabranog rifaksimina. Također skladištenje rifaksimina i medicinskog produkta koji ga sadrži može uzrokovati probleme jer vlaga može modificirati polimorfni oblik tijekom vremena i stoga se mora obratiti posebna pažnja na pripravu.
Kao što je prethodno opisano, s industrijskog stajališta je pogodno imati amorfne oblike rifaksimina pod uvjetima koji nisu ovisni o vlazi u okolini, a da se omogući priprava uz uklanjanje vode bez modifikacije polimorfizma.
Mi smo iznenađujuće našli da je pravi predmet ovog izuma taj da dodatak spojeva koji imaju najmanje dvije hidroksilne skupine, koji se nadalje navode kao polioli, daje stabilnost polimorfnom obliku rifaksimina.
Prema ovom izumu "polioli" označava polialkohole (kao što je etilen-glikol, proprandiol, butandiol, prentandiol, ertirtiol, pentaeritriol, itd.), monosaharide, polisaharide, kao što je fruktoza, dekstroza, saharoza, škrob, celuloza i njihovi derivati (hidroksipropil-celuloza, hidroksietil-celuloza, karbonskmetil-celuloza, itd.) maltodekstrin, dekstrin, guma ksantan i slično, dihidroksi kiselina i polihidroksi kiseline (kao što je jabučna, vinska, limunska kiselina, itd.).
Preferirani kemijski spojevi predstavljeni su formulom I
H-[O-CH-(X)-CH2]n-OH (I)
u kojoj X jest vodik ili niži alkil a n može biti u rasponu od 1 do 20 ili 1,2,3-proprantriol i 1,2-prorandiol.
Određenije, kad se polioli dodaju u jedan od polimorfa rifaksimina, a zapravo polimorfa β, ti polimorfni oblici ne mijenjaju svoj kristalinični oblik čak i pod uvjetima za koje je do sada poznato da su te promjene opažene. Nakon sušenja, sadržaj vode u rifaksiminu poliformfa β, prikazanog u US 7,045,620 B1 se smanjuje na niže od 4.5 % po masi, a polimorf se prevodi u polimorf α. Kada su rifaksiminu β dodani polioli, on je stabilan čak kad je sadržaj zaostale vode u čvrstom obliku niži od 4.5%, štoviše čuvanje tog polimorfa je neovisno o relativnoj vlažnosti sredine.
Među polimorfina rifaksimina, oblik β je vrlo važan jer je najmanje apsorbiran od svih polimorfnih oblika rifkasimina, kao što je pokazano od Viscomi G. C. et al. u WO 2005/044823 (2004) i EP 1698630 (2005). Za rifaksimin je niska apsorpcija vrlo važna, jer ima učinkovitu antibakterijsku aktivnost u gastrointestinalnom traktu prema velikom spektru mikroorganziama odgovornih za infektivne proljeve, pokazujući izvrstan profil sigurnosti jer nije apsorbiran kod ljudi, kao što je prikazano od Sascombe J. J. et al. u Int. J. Clin. Pharnacol., Res. 1994, 14 (2), 51-56. Pokazano je u WO 2005/044823 te u EP 1698630 (2005) da apsorpcija rifaksimina ovisi samo o polimorfizmu i moguće je dobiti razlike u apsorpciji skoro šeto puta među polimorfima, stoga je upotreba polimorfa β, koji se najmanje apsorbira, vrlo pogodna. U stvari, indukcija bakterijskih vrsta koje su rezistentne na antibiotik je mogući nepovoljni učinak povezan s antibioticima., To je posebno važno u slučaju rifaksimina jer rifaksimin spada u obitelj rifampicina koji se uvelike koristi za tretman tuberkuloza, patologije koja se ponovo pojavila, kao što je opisano od Kremer L et al. u Expert Opin. Investig. Drugs, 2002, 11 (2), 153-157.
Prema ovom izumu, među raspoloživim poliolima oni formule H-[O-CH2-CH2]n-OH i njihova smjesa (gdje n može biti između 2 i 16), kao i spojevi 1,2,3-propantriol i 1,2-propandiol su vrlo važni jer se svi koriste u pripravi farmaceutskih formulacija za ljude i životinje, te štoviše imaju omekšavajuća svojstva koja ih čine korisnim za aditive u farmaceutskim pripravcima koji obuhvaćaju oblaganje, kao što su granule i tablete.
Nađeno je da se stvarni predmet ovog izuma, spojevi formule H-[O-CH2-CH2]n-OH i njihova smjesa (gdje n može biti između 2 i 16) i spojevi 1,2,3-propantriol i 1,2-propandiol, može djelovati kao stabilizator za polimorfni oblik β te kao plastifikator za postupak tvorbe ovojnice koja je također gastrorezistentna (upotrebom celuloze ili derivata akrilne ili metakrilne kiseline, a mogu biti ovojnice granula i tableta, upotrebom vodenih otopina poliola pri koncentraciji u rasponu od 5% (w/w do 50% (w/w, preferirano između 10% (w/w) i 30% (w/w)), a zatim se suvišak vode uklanja te dobiva i čuva polimorfni oblik β.
Opis izuma
Kao što je prije opisano, predmet ovog izuma je upotreba gore opisanih poliola za stabilizaciju polimorfnih oblika rifaksimina, posebice β oblika prikazanog od Viscomi G. C. et al. u US 7,045,620 B1 (2003), a da se dobije farmaceutski prirpavak koji sadrži β oblik rifaksimina, u kojem je sadržaj zaostale vode u aktivnoj tvari, rifaksiminu, niži od 4.5% (w/w), te za održavanje nepromijenjenog polimorfa β tijekom stupnja priprave koja može izravno ili neizravno voditi sušenju rifaksimina, a koja pod uvjetima bez upotrebe poliola ne bi omogućavala konzerviranje oblika β, jer bi taj doista bio transformiran u drugi polimorfni oblik rifaksimina, ovisno o drastičnosti primijenjenih uvjet pri sušenju.
Mi smo našli da se dovođenjem u kontakt rifaksimina β s vodenom otopinom poliola pri koncentraciji od 5% (w/w) do 50% (w/w), preferirano između 10% (w/w) i 30% (w/w) u periodu vremena koje je općenito od 1 do 24 sata, dobiva rifaksimin oblika β�� koji je stabilan čak i kad se sadržaj zaostale vode u čvrstom obliku dovede na vrijednost manju od 4.5 % (w/w).
Gore opisani polioli ili njihova smjesa, koji su predmet ovog izuma, se mogu dodati rifaksiminu β sami ili miješani s nekom količinom razrjeđivača poznatog u farmaceutskoj tehnologiji za poboljšanje mekoće i okusa i interakciji s poliolima ili s njihovom smjesom. Za tu svrhu se mogu koristiti tvari kao što je koloidni silikagel (primjerice koloidni silikagel poznat kao Aerosil®) koji mogu biti dodani aktvnoj tvari u rasponu između 1% (w/w) i 20% (w/w), a preferirano između 0.2% (w/w) i 5% (w/w).
Proces interakcije između jednog od tih gore opisanih poliola ili njihove smjese i rifaksimina se može dobiti bilo kojim postupkom koji je poznat u polju farmaceutske tehnologije što omogućuje dobro miješnja komponenata.
Jedan od tih poliola, ili njihova smjesa, se može primijeniti nakon pogodnog razrjeđivanja vodom uz postupak granulacije u kojem se prašku može dodati voda koja sadrži aktivnu tvar ili sama tvar, a uz pogodno miješanje. Operacija se može provesti u tradicionalnom granulatoru ili u granulatoru velike brzine u kojem snabjeven rotirajućim sjekačem i razbijačem prisutnim za pogodno miješanje kompnenata.
Dodatak otopine jednog ili više poliola smjesi prašaka se može provesti ručno, pazeći da se otopina dodaje prašku ili smjesi prašaka polako da se omogući interakcija komponenata, ili se pogodnije može provesti u pogodnom sustavu za pumpanje upotrebom raspršivača koji omogućuje raspršivanje otopine i stoga dovodi do bolje iterakcije komponenata.
Kad je granuliranje provedeno, suvišak vode se može eliminirati upotrebom tradicionalnog sustava za sušenje poznatog u polju farmaceutske tehnologije, sušenjem u statičkom sušioniku ili sušenjem u fluidizatoru. Temperatura sušenja može biti u rasponu između 30 °C i 90 °C, preferirano između 40 °C i 80 °C. Vrijeme sušenja ovisi o korištenom aparatu, o količini praška koji se suši te o željenoj zaostaloj vlažnosti.
Primjena otopine koja sadrži jedan od gore spomenutih poliola ili njihovu smjesi, se također može provesti u fluidizatoru. U tom slučaju je prašak koji sadrži aktivni sastojak ili samo njega, održavan u suspenziji pomoću vrućeg protoka zraka, a istovremeno je otopina koja sadrži jedan od gore spomenutih poliola ili njihovu smjesu, fino raspršena na prašak. U tom slučaju dobrog miješanje otopine koja sadrži poliole ili njihovu smjesu sa čvrstim rifaksiminom se događa istovremeno s postupkom sušenja.
Stručnjak za farmaceutsku tehnologiju može dobiti produkt s željenom zaostalom vodom mijenjanjem kritičnih parametara, kao što je ulazna temperatura, ulazni kapacitet zraka te primijenjena brzina otopine. Ulazna temperatura je općenito između 20 °C i 90 °C, preferirano između 30 °C i 80 °C.
Primijenjena brzina otopine je povezana s temperaturom zraka koji održava prašak u suspenziji. Cilj, koji je dobro poznat stručnjaku, je održavanje temperature smjese konstantnom tijekom cijelog postupka. U stvari, primijenjena brzina koja je prevelika će voditi znatnom ovlaživanju uz aglomeraciju praška, što će spriječiti nastajanje smjese neophodne za učinkovito djelovanje na prašku, dok premala primijenjena brzina uzrokuje povećavanje temperature smjese uz mogući raspad aktivne tvari.
Ovaj izum se može dobiti putem bilo kojeg farmaceutskog postupka kojem se dobiva dobro miješanje otopine koja sadrži gore spomenute poliole ili njihovu smjesu, a zatim sušenje.
Preferirani spojevi, koji imaju formulu H-[O-CH2-CH2]n-OH (gdje n može biti između 2 i 10) i njihova smjesa, te spojevi 1,2,3-propantriol i 1,2-propandiol, mogu se dodati pri koncentracijama između 5% (w/w) i 50% (w/w), preferiranije između 10% (w/w) i 30% (w/w), kao komponente vodenih smjesa pogodnih za oblagaje filmom čvrstih oralnih farmaceutskih pripravaka, a koji mogu kontrolirano oslobađati tvar ili biti gastrorezistentni.
Izum je ilustriran sljedećim neograničavajućim primjerima.
Primjer 1
Prirpava rifaksimina oblika β sa sadržajem zaostale vode niže od 4.5%
199 g rifaksimina oblika β je miješano 5 minuta u fluidizatoru koji ima ulaznu temperaturu od 80 °C sa 1 g Aerodila®.
Suspenzija koja se sastoji od 390 g vode i 13 g 1,2-propandiola je sprejana na smjesu rifaksimina oblika β u fluidizatoru upotrebom peristaltičke pumpe kapaciteta 11 g/min, a temperatura je održavana pri konstantnoj vrijednosti od 80 °C tijekom cijelog postupka. Smjesa je sušena pri 80 °C i sušenje je nastavljeno do konstantne mase. Određen je sadržaj zaostale vode u mikrogranulama (Karl Fisher) i iznosi 2.2%. Tako dobivene mikrogranule su podvrgnute spektroskopiji x-zraka, a difraktogram, koji je prikazan na slici 1, odgovara polimorfnom obliku β rifaksimina.
Isti rezultati su dobiveni kada je 1,2-propandiol zamijenjen eritrinom ili manitolom.
Komparativni Primjer 2
Ovaj primjer pokazuje da u odsutnosti poliola, rifaksimin sa sadržajem zaostale vode niže od 4.5% nema polimorfni oblik β, te da dodatak poliola omogućuje dobivanje rifaksimina u čvrstom stanju oblika β sa sadržajem vode koji je manji od 4.5% (postupci su isti kao oni opisani u primjeru 1, pri čemu sprejana otopina ne sadrži 1,2-propandiol).
199 g rifaksimina oblika β je miješano 5 minuta u fluidizatoru koji ima ulaznu temperaturu od 80 °C sa 1 g Aerodila®.
400 g vode je sprejano na smjesu rifaksimina oblika β u fluidizatoru upotrebom peristaltičke pumpe kapaciteta 11 g/min i tempertura je održavana pri konstantnoj vrijednosti od 80 °C tijekom cijelog postupka. Smjesa je sušena pri 80 °C i sušenje je nastavljeno do konstantne mase. Određen je sadržaj zaostale vode u mikrogranulama (Karl Fisher) i iznosi 1.1%. Tako dobivene mikrogranule su podvrgnute spektroskopiji x-zraka a difraktogram, koji je prikazan na slici 2, odgovara polimorfnom obliku α rifaksimina.
Komparativni Primjer 3
Ovaj primjer pokazuje važnost prisutnosti hidroksilne skupine u poliolu za dobivanje rifaksimina polimorfnog oblika β sa sadržajem vode koja je manji od 4.5%. Postupci su isti kao oni opisani u primjeru 1, u kojem je otopina 1,2-propandiola zamijenjena s poliolom koji ima esterificiranu hidroksilnu skupinu, primjerice 1,2,3-propantriol.
199 g rifaksimina oblika β je miješano 5 minuta u fluidizatoru koji ima ulaznu temperaturu od 80 °C sa 1 g Aerodila®.
Suspenzija koja se sastoji od 382.75 g vode i 12.75 g 1,2,3-propandiol-triacetata je sprejana na smjesu rifaksimina oblika β u fluidizatoru upotrebom peristaltičke pumpe kapaciteta 11 g/min, a tempertura je održavana pri konstantnoj vrijednosti od 80 °C tijekom cijelog postupka. Smjesa je sušena pri 80 °C i sušenje je nastavljeno do konstantne mase. Određen sadržaj zaostale vode u mikrogranulama (Karl Fisher) iznosi 0.5%. Tako dobivene mikrogranule su podvrgnute spektroskopiji x-zraka a difraktogram, koji je prikazan na slici 3, odgovara polimorfnom obliku α rifaksimina.
Primjer 4
Prirpava rifaksimina oblika β sa sadržajem zaostale vode niže od 4.5% u prisutnosti PEG 400
199 g rifaksimina oblika β je miješano 5 minuta u fluidizatoru koji ima ulaznu temperaturu od 80 °C sa 1 g Aerodila®.
Suspenzija koja se sastoji od 360 g vode i 40 g 1,2-propandiola PEG 400 (poietilenglikol formule H-[O-CH2-CH2]n-OH) je sprejana na smjesu rifaksimina oblika β u fluidizatoru upotrebom peristaltičke pumpe kapaciteta 6 g/min i temperatura je održavana pri konstantnoj vrijednosti od 80 °C tijekom cijelog postupka. Smjesa je sušena pri 80 °C i sušenje je nastavljeno do konstantne mase. Određen je sadržaj zaostale vode u mikrogranulama (Karl Fisher) i iznosi 0.8%.
Tako dobivene mikrogranule su podvrgnute spektroskopiji x-zraka, a difraktogram, koji je prikazan na slici 4, odgovara polimorfnom obliku β rifaksimina. Isti rezultati su dobiveni kada je PEG 400 zamijenjen celulozom ili vinskom kiselinom.
Primjer 5
Priprava gastrorezistentnih mikrogranula rifaksimina β sa sadržajem zaostale vode niže od 4.5% u prisutnosti PEG 1,2-propandiola
Ovaj primjer pokazuje da poliol 1,2-propandiol, dodan rifaksiminu za dobivanje rifaksimina β sa sadržajem zaostale vode niže od 4.5%, može istovremeno djelovati kao omekšivač u pripravi filmova za oblaganje granula, a bez dodatka drugih spojeva koji imaju tu funkciju.
25000 g praška rifaksimina i 125 g Aerodila® koji djeluje kao raspršivač su nanešeni u fluidizator za omatanje aktivne tari s filmom tipa Glatt GPC, snabdjevene s Wirser sustavnom od 18 inča.
Istovremeno je pripravljena suspenzija u mješaču uz miješanje, kao što je prikazano u tablici 1.
Tablica 1
[image]
Čvrste komponente su homogeno dispergirane u demineraliziranoj vodi s homogenizatorom velike brzine Ultra Turrax. Homogenizirana suspenzija je unešena u aparat tipa Wirster s peristaltičkom pumpom te su prašak rifaksimina i Aerosil® raspršeni pri tlaku između 1.0 i 1.5 bar kroz raspršivač otvora 1.8 mm.
Oblaganje filmom je provedeno pod istim uvjetima kao što je opisano u tablici 2.
Tablica 2
[image]
Zaostali sadržaj vlage u tako dobivenim mikrogranulama je određen prema Karl Fisherovoj metodi iznosio je 1.2%.
Difraktogram X-zraka dobiven od mikrogranula prikazan na slici 5 odgovara polimorfu β.
Primjer 6
Farmaceutski pripravak rifaksimina β pripravljen u termički zatvorenim vrećicama
9.12 kg granula gastrorezistentnog rifaksimina pripravljenih prema primjeru 5, 19.58 kg sorbitola, 0.49 kg aspartama, 0.21 kg bezvodne limunske kiseline, 2.10 kg pektina, 2.10 kg manitola, 0.21 kg neohesperidina DC, 1.12 kg okusa trešnje i 0.07 kg silikagela su prosijani preko sita otvora od 0.5 mm te su miješani 20 minuta u V-mješaču. Nastala smjesa je razdijeljena i smještena u termički zatvorene vrećice koje sadrže po 5 g produkta što odgovara 800 mg rifaskimina. Sastav medicinskog pripravka u termički zatvorenim vrećicama je prikazan u sljedećoj Tablici 3.
Tablica 3
[image]
Gastrorezistencija mikrogranula sadržanih u termički zatvorenim vrećicama je procijenjena nakon 12 mjeseci čuvanja pri 25 °C, kako je prikazano u USP 28. izd. str 2417, te su dobiveni isti rezultati kao s mikrogranulama pripravljenim u primjeru 1, a to je da je raspadanje jednako 2.2% u 0.1 M klorovodičnoj kiselini i jednako je 91.1% u puferu kod pH 6.8.
Primjer 7
Farmaceutski pripravak u obliku tableta koji sadrži rifaksimina β pripravljen prema primjeru 5
9.3 kg granula gastrorezistentnog rifaksimina pripravljenih prema primjeru 1, 593 g natrijevog škrob glikolata i 100 g magnezijevog stearata su prosijani preko sita otvora od 0.5 mm te su miješani 20 minuta u V-mješaču. Nastala smjesa je tabletirana upotrebom rotacijskog tabletnog stroja (Fette 1200) snabjevenog ovalnim žigovima 19 × 9 mm dajući konačnu masi od 718 mg, što odgovara 400 mg rifaskimina.
Sastav tablete je prikazan u Tablici 4.
Tablica 4
[image]
Tablete su zatim obložene upotrebom konvencionalnog stroja za oblaganje filom hidroksipropil-metilceluloze da se poboljša izgled te da se maskiraj okus. Sastav filma je prikazan u Tablici 5.
Tablica 5
[image]
Claims (15)
1. Upotreba jednog ili više spojeva (ovdje definirani kao "polioli"), naznačena time da imaju najmanje dvije hidroksilne skupine, za stabilizaciju polimorfnih oblika rifkasimina.
2. Upotreba kako je prijavljena u patentnom zahtjevu 1, naznačena time da su jedan ili više poliola odabrani iz skupine poliola koji sadrže dva do sedam atoma ugljika i dvije do sedam hidroksilnih skupina, monosaharida, disaharida, polisaharida kao što je škrob, celuloza i njihovi derivati, dekstrin i maltodekstrin, guma ksantan, dihidroksi kiseline i polihidroksi kiseline.
3. Upotreba kako je prijavljena u patentnom zahtjevu 1, naznačena time da jedan ili više poliola imaju formulu I
H-[O-CH-(X)-CH2]n-OH (I)
u kojoj X predstavlja vodik ili niži alkil, a n može biti u rasponu od 1 do 20.
4. Upotreba kako je prijavljena u patentnom zahtjevu 1, naznačena time da je 1,2,3-proprantriola.
5. Upotreba kako je prijavljena u patentnom zahtjevu 2, naznačena time da je poliola koji ima opću formulu H-[O-CH2-CH2]n-OH, u kojoj n može biti u rasponu između 2 i 14.
6. Upotreba kako je prijavljena u patentnom zahtjevu 2, naznačena time da je 1,2-prorandiola.
7. Upotreba kako je prijavljena u patentnom zahtjevu 1, naznačena time da je poliola za dobivanje rifaksimina u čvrstom stanju polimorfnog oblika β� koji ima sadržaj zaostale vode niži od 4.5%.
8. Polimorfni oblici rifaksimina u čvrstom stanju, naznačeni time da su stabilizirani upotrebom jednog ili više poliola kako su prijavljeni u patentnim zahtjevima 1 do 6, a neovisno o sadržaju zaostale vode.
9. Polimorf β rifaksimina u čvrstom stanju, naznačen time da je stabiliziran upotrebom jednog ili više poliola kako su prijavljeni u patentnim zahtjevima 1 do 6, a neovisno o sadržaju zaostale vode.
10. Oralni ili topički medicinski pripravci, naznačeni time da sadrže rifaksimin u polimorfnom obliku β koji je je stabiliziran upotrebom jednog ili više poliola kako su prijavljeni u patentnim zahtjevima 1 do 6, a neovisno o sadržaju zaostale vode, skupa s ekscipijensoma dobro poznatim u struci, kao što su razrjeđivači, ligandi, lubrikanti, dezintegrirajuća sredstva, boje, sredstva za poboljšanje okusa, zaslađivači, a za tretman pataloloških stanja koji imaju potrebu za antibiotskom terapijom.
11. Mikroganule gastrorezistentnog rifaksimina β, naznačene time da je polimorf β stabiliziran upotrebom jednog ili više poliola kako su prijavljeni u patentnim zahtjevima 1 do 6, a neovisno o sadržaju zaostale vode.
12. Rifaksimin β u termički zatvorenom vrećicama, naznačen time da je polimorf β stabiliziran upotrebom jednog ili više poliola kako su prijavljeni u patentnim zahtjevima 1 do 6, a neovisno o sadržaju zaostale vode.
13. Rifaksimin β u u obliku tablete, naznačen time da je polimorf β stabiliziran upotrebom jednog ili više poliola kako su prijavljeni u patentnim zahtjevima 1 do 6, a neovisno o sadržaju zaostale vode.
14. Postupak priprave rifaksimina u polimorfnom obliku β prema patentnom zahtjevu 9, naznačen time da je rifaksimin u čvrstom stanju doveden u kontakt s vodenom otopinom jednog ili više poliola kako su prijavljeni u patentnim zahtjevima 1 do 6, pri koncentraciji od 5% do 59% (w/w) pri temperaturi između 30 °C i 90 °C u periodu vremena između 1 i 24 sata, te time da je nakon odvajanja krutina sušena pri temperaturi između 30 i 80 °C pri atmosferskom tlaku ili u vakuumu u periodu vremena između 2 i 72 sata.
15. Postupak priprave rifaksimina u polimorfnom obliku β prema patentnom zahtjevu 9, naznačen time da je vodena otopina jednog ili više poliola kako su prijavljeni u patentnim zahtjevima 1 do 6, pri koncentraciji od 5% do 50% (w/w) sprejana na rifaksimin β u čvrstom stanju u fluidizatoru s ulaznom temperaturom između 40 °C i 90 °C i tako dobivena smjesa je podvrgnuta sušenju uz protok zraka pri temperaturi između 40 °C i 90 °C.
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PCT/IB2007/002199 WO2008029208A1 (en) | 2006-09-05 | 2007-07-31 | Use of polyols to obtain stable polymorphous forms of rifaximin |
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