HRP20010421A2 - Controlled release formulation comprising gnrh-ii - Google Patents
Controlled release formulation comprising gnrh-ii Download PDFInfo
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- HRP20010421A2 HRP20010421A2 HR20010421A HRP20010421A HRP20010421A2 HR P20010421 A2 HRP20010421 A2 HR P20010421A2 HR 20010421 A HR20010421 A HR 20010421A HR P20010421 A HRP20010421 A HR P20010421A HR P20010421 A2 HRP20010421 A2 HR P20010421A2
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- polymer
- osteoporosis
- peptide
- treatment
- prostate
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
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- Peptides Or Proteins (AREA)
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Description
Područje tehnike
Ovaj izum se odnosi na farmaceutski pripravak koji oslobađa terapijsko sredstvo tijekom produljenog razdoblja.
Stanje tehnike
Ispitivanja fiziologije osovine hipotalamus-hipofiza-gonade dovelo je do otkrića hormona koji oslobađa gonadotropin (GnRH, poznat i kao hormon koji oslobađa luteinizirajući hormon, LHRH) kao ključnog regulacijskog hormona. GnRH se izlučuje iz hipotalamusa i djeluje na hipofizu na način da potiče otpuštanje luteinizirajućeg hormona (LH) i folikul-stimulirajućeg hormona (FSH). U posljednje vrijeme, otkrivEn je peptid koji je homologan GnRH (White i sur., Proc. Natl. Acad. Sci. USA 95 305-309, 1998). Ovaj peptid nazvan je GnRH-II. Dolje je prikazana usporedba slijedova dvaju peptida.
GnRH piroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 (SEQ I.D. br. 5)
GnRH-II piroGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (SEQ I.D. br. 5)
Naziv “GnRH-II” je u određenoj mjeri zbunjujući. Novi peptid je proizvod posebnog gena i jasno se razlikuje od GnRH prema svojoj tkivnoj raspodjeli. Malo je vjerojatno da GnRH-II djeluje kao endogeni poticatelj oslobađanja LH i FSH. Kako još nije nađen jasan dokaz za fiziološku ulogu GnRH-II, nije polagana pozornost na praktične aspekte primjene ovog peptida kao terapijskog sredstva.
Izlaganje biti izuma
Otkrili smo kako GnRH-II ima važnu ulogu u djelovanju brojnih organa. Na primjer, utječe na osteogenezu i modulira proliferaciju epitelnih stanica prostate. Zato smo razmatrali prilike u kojima bi se to sredstvo i njegovi analozi mogli korisno primijeniti u kliničkim okolnostima, pa je stoga svrha ovog izuma dobivanje prikladnih pripravaka za postizanje ove svrhe. Pripravci prema ovom izumu oslanjaju se na uporabu biorazgradivog polimera koji bi držao peptid u depou, iz kojeg bi bio otpuštan u sustavni krvotok kontroliranom brzinom. Ovi pripravci sadrže dva ključna elementa, i to biološki aktivni peptid i biorazgradivi polimer. Biološki aktivni peptid je dekapeptid čiji je slijed
piroGlu-His-Trp-Ser-Xaa1-Gly-Xaa2-Xaa3-Pro-Gly-NH2 (SEQ I.D. br. 7)
pri čemu Xaa1 je His ili Tyr,
Xaa2 je Trp ili Leu, a
Xaa3 je Tyr ili Arg,
s time da kada je Xaa1 Tyr, a Xaa2 je Leu, Xaa3 ne bude Arg. Polimer je svaki farmaceutski prihvatljivi biorazgradivi polimer, preporučljivo kopolimer glikolne i mliječne kiseline. Izum nadalje obuhvaća uporabu pripravaka za liječenje patoloških stanja u ljudi.
Opis slike
Slika 1 prikazuje učinak povećanih doza GnRH-II na serumske koncentracije kalcija u štakora kojima su uklonjeni jajnici.
Opis izuma
U ovdje korištenom značenju, kratice koje se odnose na aminokiseline imaju svoja uobičajena značenja i predstavljaju prirodni L-izomer (osim akiralne aminokiseline glicina).
U prvom aspektu, izum obuhvaća farmaceutski pripravak koji otpušta terapijski peptid kontroliranom brzinom i tijekom produljenog vremenskog razdoblja (na pr. tijekom najmanje jednog dana, preporučljivo nekoliko dana, još preporučljivije barem tijekom jednog tjedna), osobito za liječenje bolesti kostiju i prostate. Terapijski peptid je dekapeptid čiji je slijed
piroGlu-His-Trp-Ser-Xaa1-Gly-Xaa2-Xaa3-Pro-Gly-NH2 (7)
pri čemu je Xaa1 His ili Tyr, Xaa2 je Trp ili Leu, a Xaa3 je Tyr ili Arg, s time da kada je Xaa1 Tyr, a Xaa2 je Leu, Xaa3 ne bude Arg. Preporučljivo, Xaa1 je His, Xaa2 je Trp, a Xaa3 je Tyr. Treba uvidjeti kako takav peptid može tvoriti soli s kiselinama (na primjer, acetate, trifluoroacetate, benzoate, kloride, fosfate i druge). Do mjere u kojoj se takve soli tvore s farmaceutski prihvatljivim kiselinama, uključene su u područje izuma.
Drugi temeljni sastojak pripravka je biorazgradivi, farmaceutski prihvatljivi polimer. Takvi su polimeri poznati u struci. Oni mogu biti ili homopolimeri (tj. polimeri od jednog monomera) ili kopolimeri (tj. sastavljeni od dvaju ili više različitih monomera). Prikladni monomeri uključuju amino i hidroksi derivate karboksilnih kiselina. U preporučenom obliku ovog izuma, polimer je sastavljen od hidroksiacilnih monomernih jedinica, a još preporučljivije od α-hidroksiacilnih jedinica. Najpreporučljivije, polimer je poli(glikolna kiselina), poli(mliječna kiselina) ili kopolimer glikolne i mliječne kiseline. Slijedi prikaz kemijske strukture takvog polimera.
[image]
pri čemu je R vodik u poli(glikolnoj kiselini), metil u poli(mliječnoj kiselini), i slučajno vodik ili metil u kopolimeru.
Mogu se razlikovati dva komplementarna postupka za izradu pripravka ovog izuma. Peptid može biti ili uklopljen u matriks polimera, ili, preporučljivije, može biti obložen (inkapsuliran) polimerom. U drugom slučaju, peptid koji je obložen može biti u krutom obliku ili kao otopina. Preporučuje se da peptid bude u krutom obliku.
Ovaj je pripravak koristan u liječenju bolesnih stanja u ljudi, uključujući poremećaje rasta kostiju (uključujući involucijsku osteoporozu, kao i osteoporozu povezanu s postmenopauzalnim hormonskim statusom, primarnom i sekundarnom hiperparatireozom, osteoporozom zbog mirovanja, osteoporozom vezanom s dijabetesom i osteoporozom vezanom s glukokortikoidima) i rasta prostate (uključujući benignu hiperplaziju prostate i rak prostate).
U drugom aspektu, izum obuhvaća postupak za liječenje osobe koja pati od poremećaja rasta kostiju ili prostate, ili se smatra da ima rizik od takvog poremećaja. Ovaj postupak liječenja obuhvaća primjenu na spomenutu osobu terapijski učinkovite količine pripravka koji sadrži, kao svoj aktivni dio, peptid čiji je slijed
piroGlu-His-Trp-Ser-Xaa1-Gly-Xaa2-Xaa3-Pro-Gly-NH2 (7)
ili njegovu farmaceutski prihvatljivu sol, pri čemu su Xaa1, Xaa2 i Xaa3 kao što su ranije definirani, te, kao svoj drugi sastojak, farmaceutski prihvatljivi biorazgradivi polimer, pri čemu taj pripravak, raspadanjem polimera, otpušta peptid u sistemski krvotok. Postupak za liječenje može obuhvaćati jednokratnu primjenu pripravka, ali je vjerojatnije da sadrži kuru ponovljenih primjena. Učestalost primjena može biti od jedne na dan, pa do jedne na mjesec. Količina aktivnog peptida u svakoj dozi ovisit će o rasporedu doziranja i putu primjene. Općenito, kretat će se u rasponu od jednog miligrama (1 mg) do jednog grama (1 g). Ordinarijus će odrediti točnu dozu ovisno o parametrima koji se inače, u struci, smatraju važnima. Pripravak se primjenjuje intramuskularnim ili potkožnim injiciranjem.
Peptidi koji predstavljaju aktivna sredstva pripravaka ovog izuma mogu se pripraviti postupcima koji su općenito poznati u struci. Na primjer, peptidi se mogu pripraviti sintezom u krutoj fazi. Ovo uključuje uzastopno dodavanje aminokiselinskih ostataka u međuspoj vezan na smolu, prema slijedećoj strategiji.
1. Stvaranje prvog međuspoja vezanog na smolu
PG-Aaa-OH + FG-Res →PG-Aaa-L-Res
Aaa = aminokiselina
PG = zaštitna skupina
FG = funkcijska skupina
Res = polimerska smola
L = vezna skupina (-O- ili -NH-)
2. Deprotekcija
PG-Aaa-L-Res → H-Aaa-L-Res
3. Istezanje lanca
PG-Bbb-OH + H-Aaa-L-Res → PG-Bbb-Aaa-L-Res
4. Ponavljanje koraka 2 i 3 po potrebi
PG-Bbb-Aaa-L-Res --- PG-Nnn- _ -Bbb-Aaa-L-Res
5. Cijepanje/deprotekcija
PG-Nnn- _ -Bbb-Aaa-L-Res - H-Nnn- _ -Bbb-Aaa-OH (ili -NH2)
U prvom koraku, zaštićena aminokiselina reagira s funkcionaliziranom smolom. Zaštitna skupina (PG) je najčešće terc-butiloksikarbonil (Boc) ili 9-fluorenilmetiloksikarbonil (Fmoc). Funkcijska skupina na smoli (FG) je obično kloroalkilna skupina, hidroksilna skupina ili aminska skupina. Kada je FG kloroalkilna ili hidroksilna skupina, vezna skupina (L) je atom kisika (-O-). Kada je FGg aminska skupina, L je -NH-.
U drugom koraku, zaštitna skupina (PG) se uklanja s α-amino skupine. Kada je PG Boc, to se može postići obradom smole s kiselinama kao što su trifluorooctena kiselina ili klorovodik u diklorometanu. Kada je PG Fmoc, deprotekcija se može postići obradom smole bazama kao što je piperidin.
U trećem koraku, peptidni lanac se isteže za jedan aminokiselinski ostatak. Zaštićena aminokiselina se veže na aminsku skupinu oslobođenu u drugom koraku. U struci su poznati mnogi reagensi za postizanje ovog prevođenja. Jedna kombinacija je dicikloheksilkarbodiimid (DCC) i hidroksibenzotriazol (HOBt). Općenito, potrebna je i baza. Prikladne baze uključuju trietilamin i N,N-diizopropiletilamin. Općenito, otapalo će biti diklorometan, dimetilformamid ili njihova smjesa.
Ako pobočni lanci aminokiselina (Aaa-Nnn) sadrže reaktivne skupine (na primjer, amino skupine, skupine karboksilne kiseline, hidroksilne skupine), trebat će ih zaštititi. Zaštitne skupine odabrane za pobočne lance općenito su one koje su stabilne u uvjetima potrebnim za uklanjanje zaštitne skupine (PG) s α-amino skupine. Ako je PG Fmoc, tada je zgodno da zaštitne skupine pobočnog lanca budu na temelju terc-butila. S druge strane, ako je PG Boc, zaštitne skupine pobočnog lanca mogu se temeljiti na fluorenilmetilu. Mogu se koristiti i druge zaštitne skupine poznate u struci.
U četvrtom koraku, ciklus deprotekcije/istezanja lanca se ponavlja do stvaranja željenog peptidnog slijeda.
U petom koraku, dovršeni peptid se oslobađa iz smole. Zaštitne skupine se uklone sa pobočnih lanaca prije ili nakon cijepanja. Kada je L -NH-, oslobođeni peptid je u obliku C-terminalnog amida. Kada je L -O-, oslobođeni peptid je često C-terminalna slobodna kiselina, pa je potreban drugi korak za stvaranje C-terminalnog amida.
Peptidi se također mogu pripraviti sintezom u fazi otopine, što može biti zgodnije kada su potrebne velike količine tvari.
Polimeri potrebni za pripravak općenito su dobro poznati u struci. Kao što je prethodno rečeno, pripravak može imati oblik jednostavne disperzije peptida u matriksu polimera, ili peptid može biti mikroinkapsuliran polimerom. Disperzije se mogu pripraviti miješanjem peptida (u krutom obliku) i polimera do homogeniziranja, a potom tlačenjem smjese do stvaranja krute mase. Može biti nužno dodavanje vežućeg sredstva u smjesu, kako bi se dobio sastav prikladne kohezivnosti. Masa se potom može samljeti, čime se dobiju čestice prikladne za suspendiranje u biološki kompatibilnoj tekućini (poput vode ili fiziološke otopine) i injiciranje.
Mikroinkapsulirani pripravci mogu se pripraviti ili od krutog peptida (u obliku praška) ili iz otopine, osobito vodene otopine, peptida. Polimer se prvo otopi u prikladnom organskom otapalu. Peptid se zatim doda ovoj otopini i smjesa se energično miješa kako bi se peptid dispergirao u organskoj fazi. Potom se doda drugo organsko otapalo. Ovo drugo otapalo se odabere tako da smanji topljivost polimera u organskoj fazi. Polimer izlazi iz otopine da bi oblikovao obložni sloj oko čestica krutog peptida (ili oko kapljica dispergirane vodene otopine). Nastale mikrokapsule potom se otvrdnu ispiranjem, kako bi se uklonili tragovi organskih otapala. Potom su spremne za suspendiranje u odgovarajućoj tekućini radi primjene.
Gornji općeniti opis u nastavku je potkrijepljen brojnim primjerima. Namjera im je prikaz pojedinih aspekata izuma. Nije im svrha na bilo koji način ograničiti izum.
PRIMJERI
Primjer 1 - Sinteza GnRH-II
1A. Priprava zaštićenog peptida vezanog na smolu
piroGlu-His(Bom)-Trp(CHO)-Ser(Bzl)-His(Bom)-Gly-Trp(CHO)-Tyr(Bzl)-Pro-Gly-Ores
Ovaj se peptid pripravi pomoću uobičajenih postupaka krute faze, počevši od Boc-Gly-esterificirane Merrifield smole (60 g, 1 mmol/g). Sinteza se provede u ručnom sintetizatoru, s ukupnim volumenom otapala i reagensa od 300 mL za svaki zahvat. Standardni protokol deprotekcija/ispiranje/vezanje sažet je u Tablici 1.
Tablica 1
[image]
Benzotriazolil esteri se koriste kao aktivirani esteri tijekom sinteze. Priprave se od odgovarajućih zaštićenih aminokiselina reakcijom s 1-hidroksibenzotriazolom (1 eq.) i dicikloheksilkarbodiimidom (1 eq.). Korištene količine ( u odnosu na supstitucijski kapacitet smole) navedene su u Tablici 2.
Tablica 2
[image]
Nakon završnog spajanja, smola se ispire diklorometanom (3 x 3 L) i suši pri smanjenom tlaku na +40°C do postizanja stalne težine.
Analiza aminokiselina: U skladu s pretpostavljenim slijedom
18. Cijepanje i deprotekcija
piroGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (6)
Peptidosmola pripravljena u Primjeru 1A stavi se u platnenu vrećicu u tlačnu posudu. Posuda se potom puni plinovitim amonijakom do konačnog tlaka od 4 atm. Nakon 72 h, višak amonijaka se ispusti, a smola se ekstrahira s octenom kiselinom (3 x 100 mL) i etanolom (3 x 100 mL). Pomiješani ekstrakti se otplinjuju dušikom, doda se 10%-tni paladij na ugljiku i smjesa se miješa u atmosferi vodika. Kada se reakcija dovrši (procijeni se pomoću HPLC), smjesa se filtrira i filtrat se ispari. Ostatak se pročisti pomoću HPLC obrnute faze, čime se dobije naslovni spoj.
Primjer 2 - mikroinkapsulacija peptida
Koristi se kopoli(D,L-mliječna kiselina, glikolna kiselina) s omjerom mliječne kiseline/glikone kiseline 50/50. Otopini ovog polimera (3.7 g) u diklorometanu (100 mL) u reakcijskoj posudi opremljenoj s miješalom se doda GnRH-II acetat (0.15 g, pripravi se otapanjem peptida iz primjera 1 u octenoj kiselini i liofiliziranjem dobivene otopine). Smjesa se miješa na 500 okretaja u minuti, a zatim se tijekom 10 minuta dodaje silikonsko ulje (Dow Corning 360 Medical Fluid®, 45 g). Smjesa se potom u obliku tankog mlaza uvede u kaprilinsku-kaprilnu kiselinu-triglicerid (Miglyol® 812, 3.3 L) uz trajno miješanje pri 1000 okretaja u minuti. Po dovršetku dodavanja, miješanje se nastavi 1 sat, potom se mikrokapsule prikupe filtriranjem, ispiru dva puta s izopropanolom i na kraju osuše.
Primjer 3 - Analiza učinaka GnRH-II i analoga na populacije osteogenih stanica in vitro
(a) Ljudski osteoblasti se izoliraju iz kancerozne kosti dobivene ortopedskim kirurškim zahvatima (Nilsson i sur., 1995) pomoću uobičajenih postupaka poznatih u struci. Koštani eksplantati se samelju na male komadiće kosti i potom obilno ispiru u Dulbeccoovom modificiranom Eagleovom mediju (DMEM)/F12 (1:1 Gibco, Paisley, UK). Ove stanice nalik na osteoblaste, mišji osteoblasti MC3T3-E1 i ljudske klonalne stanične linije osteosarkoma MG-63 (nemineralizirajuće) i SaOS-2 (mineralizirajući osteosarkom) se kultiviraju u DMEM:F12, 1:1, uz dodavanje 10% fetalnog telećeg seruma (FCS, Gibco), fungizona (500 mg/L), gentamicin sulfata (50 mg/L), L-glutamina (2 mM) i L-askorbinske kiseline (100 mg/L) u vlažnoj CO2 komori na 37°C.
(b) Stromalne stanice ljudske koštane srži izoliraju se iz koštanih ulomaka ispranih u fosfatom puferiranoj fiziološkoj otopini. Stanice koštane srži se prikupe i provedu kroz kolonu Ficoll Hypaque (Kimble i sur., J Clin Invest 93 1959-1967, 1994). Stanice i međupovršina se peletiraju, broje i zasiju u tikvice od 75 cm2. Stanice se inkubiraju u vlažnoj CO2 komori na 37°C i medij se tjedno mijenja. Kada se počnu stapati, stanice se žanju pomoću tripsin EDTA i ponovno zasiju u α-minimalnom esencijalnom mediju (α-MEM) obogaćenom s 10% fetalnog telećeg seruma (FCS, Gibco), penicilinom (100 U/mL), streptomicinom (100 mg/mL), fungizonom i L-glutaminom (2 mM).
(c) Sve stanice se ostave na serumu 48 h prije dodavanja GnRH-I i GnRH-II. Stanice se stave u DMEM bez fenolnog crvenila (kako bi se izbjegli estrogenski učinci fenolnog crvenila) koji sadrži na 10% drvenog ugljena ogoljen serum, tijekom 48 h, na ploče s 12 jamica. Promatraju se o dozi ovisni učinci GnRH-I i GnRH-II i analoga peptida nastali nakon dodavanja peptida u konačnim koncentracijama u rasponu od 10-9 do 10-5 M. 1 mM dibutiril cAMP je korišten kao kontrola. Stanice su inkubirane 24, 48 i 96 h, s time da je peptid mijenjan svaka 24 sata.
(d) Za procjenu učinaka peptida na proliferaciju stanica, doda se [3H]timidin, 1 mCi/mL dodatnih 24 sata i određivano je ugrađivanje [3H]timidina. Ugrađivanje radioizotopa određivano je pomoću scintilacijskog brojača, a rezultati su izračunati kao cpm/mg ukupnih proteina.
(e) Također je određivana ekspresija biljega diferencijacije osteoblasta (Tintut Y i sur., J Biol Chem 273 7547-53, 1998). Ukupna RNA izolirana je u nekoliko stadija prije liječenja, 24, 48, 72 i 96 sati nakon dodavanja peptida. Ekspresija prokolagena tipa I, osteopontina i 28S RNA (korištena kao interna kontrola) određena je pomoću Northern blot analize. Alkalna fosfataza, matriks GLA protein, osteoklastin i GAPDH (kao interna kontrola) određeni su pomoću RT-PCR, sa specifičnim primerima pripravljenima za svaki gen.
Peptidi izuma pokazali su značajne učinke pri koncentracijama ispod 100 μM.
Primjer 4 - Analiza učinaka GnRH-II i analoga na populacije ostaoklasta in vitro
(a) Ljudske klonalne stanične linije prekursora osteoklasta (FLG 29.1) korištene su kao in vitro model diferencijacije osteoklasta (Gattei V i sur., Cell Growth Differ 7 753-63, 1996). Pored toga, ispitivane su migracijske, adhezijske, citokemijske, morfološke i biokemijske promjene su-kultura FLG 29.1 i osteoblastnih stanica (Saos-2). Promatraju se o dozi ovisni učinci GnRH-I i GnRH-II i analoga peptida nastali nakon dodavanja u konačnim koncentracijama u rasponu od 10-9 do 10-5 M na FLG 29.1 kulture i na su-kulture. Paratireoidni hormon se doda kao kontrola. Mjereni su potenciranje (ili inhibiranje) diferencijacije preosteoklasta (stapanje u velike multinuklearne elemente) i brojni drugi činitelji (Orlandini i sur., Cell Tissue Res 281 33-42, 1995). Ovo uključuje:
1. Pozitivno bojanje na kiselu fosfatazu otpornu na tartarat u FLG 29.1 stanicama
2. Smanjenje aktivnosti alkalne fosfataze koju eksprimiraju Saos-2 stanice
3. Pojava tipičnih ultrastrukturnih svojstava zrelih osteoklasta u FLG 29.1 stanicama
4. Otpuštanje granulocitnog-makrofagnog čimbenika stimulacije kolonija u medij kulture
5. Za procjenu učinaka peptida na proliferaciju stanica, doda se [3H]timidin, 1 mCi/mL, dodatnih 24 sata, i ugrađivanje [3H]timidina se određuje na gore opisani način.
(b) Stanice koštane srži izdvojene iz ulomaka ljudskih kostiju kultivirane su u nazočnosti 10 nM 1,25-(OH)2 vitamina D3 tijekom sedam dana, kako bi se dobili multinuklearni osteoklasti, uobičajenim tehnikama poznatima u struci (Takahashi i sur., Endocrinol 122 1473-1482, 1988). Medij kulture (α-MEM) se ukloni i zamijeni svježim medijem bez fenolnog crvenila obogaćenim s antibioticima i s 10% drvenog ugljena ogoljenog toplinski inaktiviranog FCS koji sadrži GnRH-I, GnRH-II ili analoga, i kulture su održavane daljnjih 24 sata. Plutajuće stanice se žanju i osteoklasti se boje na ekspresiju kisele fosfataze otporne na tartarat (TRAP), biljega za diferencijaciju osteoklasta (Hughes i sur., Nat Med 2 1132-1135, 1996).
1. Stanice se inkubiraju u 0.2 M acetatnom puferu, pH 4.7-5.0 koji sadrži vinsku kiselinu i 2% naftol AS-BI fosfat (otopljen, 20 mg/mL u etilen glikol monometil eteru) tijekom 15 minuta na 37°C. Stanice se potom prenesu u drugu otopinu koja se sastoji od istog pufera i koncentracije vinske kiseline s 0.1% pararozanoilin klorida (heksazotiran miješanjem jednakog volumena 4% natrij nitrita, 5 minuta, na sobnoj temperaturi) tijekom 10 min. na 37°C. Ovo liječenje uzrokuje crveno obojenje citoplazme u stanica koje eksprimiraju TRAP. Harrisov hematoksilin je korišten kao kontrastna boja za jezgru.
2. Apoptotički multinuklearni osteoklasti su identificirani prema jakoj ekspresiji TRAP-a, opsežnijoj od pripadajućih živih TRAP-pozitivnih stanica. Potvrda apoptoze provedena je uporabom akridinske narančaste boje. Živi osteoklasti brojani su nakon fiksiranja u 95%-tnom etanolu i TRAP hematoksilinskog bojenja; apoptotični osteoklasti su izraženi kao postotak ukupnog broja multinuklearnih osteoklasta (živih i apoptotičnih) u svakoj jamici kulture.
Peptidi izuma postigli su značajne učinke pri koncentracijama ispod 100 μM.
Primjer 5 - Ekspresijska analiza GnRH mRNA u osteogeničkim i osteoklastnim staničnim populacijama
Ukupna RNA je ekstrahirana iz stanica kultiviranih na gore opisani način:
1. stanice slične osteoblastima, izolirane iz kancerozne kosti
2. mišje osteoblastične MC3T3-E1 stanice
3. MG-63 (nemineralizirajuće)
4. SaOS-2 (mineralizirajući osteosarkom)
5. ljudske stromalne stanice koštane srži
6. ljudske FLG 29.1 stanice prekursori osteoklasta
7. multinuklearni osteoklasti dobiveni iz koštane srži
Ekspresija GnRH-I i GnRH-II određena je pomoću RT-PCR pomoću PCR primera navedenih u SEQ. I.D. br. 1-4. Cjelovitost dobivene cDNA određena je procjenom relativne razine amplifikacije aktina.
Primjer 6 - Učinak GnRH-II na mineralnu gustoću kostiju u štakora kojem su uklonjeni jajnici
(a) Odraslim (8 tjedana, 200-215 g) Sprague Dawley štakoricama su uklonjena oba jajnika (OVX). Životinje su držane 4 tjedna nakon zahvata prije započinjanja liječenja. Purina hrana za štakore (1.00% kalcija, 0.61% fosfora) i voda ponuđeni su u količini po želji. Svako se ispitivanje sastojalo od 6 skupina grupiranih po težini (n=8/skupini).
(b) Liječenje je započeto 4 tjedna nakon OVX. Nakon 4 tjedna, bazalna kontrolna OVX skupina je žrtvovana (Skupina A). Preostalim skupinama su jednom dnevno injicirani nosač (Skupina B), 1μg/kg tjelesne težine (Skupina C), 10 μg/kg tjelesne težine (Skupina D), odnosno 100 μg/kg tjelesne težine (Skupina E) GnRH-II, te 80 μg/kg tjelesne težine (Skupine F) hPTH (1-34).
(c) Svi štakori su vagani svakog četvrtog dana i doze su prilagođene na 50 g povećanja prosječne težine skupine. Štakorima su naizmjenično davane potkožne injekcije kalceina (30 mg/kg) ili tetraciklina (30 mg/kg) u 2% natrij bikarbonat/fiziološkoj otopini, prema oznakama mineralizacijskih površina u dane 10, 19 i 26 nakon primjene lijeka. Mineralna gustoća kostiju procijenjena je apsorptometrijom x-zraka dvojne energije (DEXA). Na dan 28, određene su serumske razine kalcija, kolorimetrijskim testom, pomoću komercijalnog kita.
(d) Uspjeh OVX potvrđen je obdukcijom, nemogućnošću prepoznavanja tkiva jajnika i nalazom značajne atrofije rogova maternice. Obje su noge amputirane u zglobu kuka. Lijeva tibija i femur su očišćeni od viška mišića i mekih tkiva i smještene u 70%-tni etanol. Prednja eminencija metafize desne tibije obrijana je britvom, tako da se prikaže gola koštana srž. Desni femur i tibija su zatim smješteni u 10% fosfat-puferirani formalin tijekom 24 h, a potom preneseni u 70%-tni etanol.
U ovariektomiranih životinja liječenih dnevno s 10 i 100 μg/kg GnRH-II i 80 μg/kg PTH tijekom 28 dana javila se jaka hiperkalcemija. Rezultati su prikazani na Slici 1.
Primjer 7 - Stanična lokalizacija GnRH-II u parafinskim rezovima normalne štakorske i ljudske kosti
(a) Zamrznuti i/ili u parafin uklopljeni rezovi ljudske i štakorske kosti fiksirani su 3-36 h, ovisno o veličini (3-5 h na sobnoj temperaturi, potom otprilike 24 h na 4°C) i zatim potopljeni u 0.1 M Tris + 5% EDTA (12.11 g + 50 g EDTA) pH 7.3 do dekalcificiranja.
(b) Rezovi su zatim pripravljeni za bojanje protutijelima (kunićje poliklonalno protu-GnRH-II protutijelo) uobičajenim tehnikama.
Bojanje na GnRH-II je zamijećeno u trombocitima, megakariocitima na ploči za rast (osobito proliferirajući hondrociti). Neka su bojanja također viđena u stanicama koje tvore kost, osobito u aktivnim osteoblastima,kao i u novom osteoidu.
Primjer 1 prikazuje pripravu peptida izuma,koji potom mogu biti formulirani kao što je prikazano u Primjeru 2. Primjeri 3 do 7 prikazuju biološko djelovanje promatranih peptida. Ograničavanje područja izuma u bilo kojem obliku nije namjera ovih Primjera. Napose, treba uvidjeti kako se različiti pripravci ovih peptida s kontroliranim otpuštanjem mogu pripraviti mijenjanjem polimera i/ili fizikalne prirode kombinacija peptida i polimera. Međutim, ove varijacije daju pripravke s ekvivalentnim biološkim svojstvima, pa se prema tome nalaze unutar područja izuma definiranog prema slijedećim Zahtjevima.
SEQ I.D. br. 1 do 4 spomenuti u Primjeru 5 su slijedeći:
[image]
Claims (13)
1. Farmaceutski pripravak za kontrolirano otpuštanje terapijskog peptida ili njegove soli, naznačen time, što peptid ima slijed
piroGlu-His-Trp-Ser-Xaa1-Gly-Xaa2-Xaa3-Pro-Gly-NH2
pri čemu Xaa1 je His ili Tyr,
Xaa2 je Trp ili Leu, a
Xaa3 je Tyr ili Arg,
s time da kada je Xaa1 Tyr, a Xaa2 je Leu, Xaa3 ne bude Arg,
pri čemu pripravak nadalje obuhvaća farmaceutski prihvatljiv biorazgradivi polimer.
2. Farmaceutski pripravak prema Zahtjevu 1, naznačen time, što je peptid
piroGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2.
3. Pripravak prema Zahtjevu 1, naznačen time, što je polimer polimer od hidroksiderivata karboksilne kiseline ili kopolimer takvih derivata.
4. Pripravak prema Zahtjevu 3, naznačen time, što je polimer polimer od glikolne kiseline, polimer od mliječne kiseline, ili kopolimer mliječne i glikolne kiseline.
5. Pripravak prema Zahtjevu 1, naznačen time, što je peptid mikroinkapsuliran polimerom.
6. Postupak za liječenje medicinskog stanja u ljudi, naznačen time, što obuhvaća primjenu na osobu kojoj je takvo liječenje potrebno terapijski učinkovite količine pripravka s kontroliranim otpuštanjem peptida prema bilo kojem od prethodnih Zahtjeva.
7. Pripravak prema bilo kojem od Zahtjeva 1 do 5, naznačen time, što je za liječenje ili zaštitu od poremećaja rasta kostiju ili poremećaja rasta prostate.
8. Uporaba peptida ili soli definiranih u Zahtjevu 1 ili 2, zajedno s farmaceutski prihvatljivim biorazgradivim polimerom, naznačena time, što je u svrhu priprave lijeka s kontroliranim otpuštanjem za liječenje ili zaštitu od poremećaja rasta kostiju ili poremećaja rasta prostate.
9. Uporaba prema Zahtjevu 8, naznačena time, što je spomenuti polimer
[a] polimer od hidroksiderivata karboksilne kiseline ili kopolimer takvih derivata, ili
[b] polimer od glikolne kiseline, polimer od mliječne kiseline, ili kopolimer mliječne i glikolne kiseline.
10. Uporaba prema zahtjevu 8 ili 9, naznačena time, što je spomenuti poremećaj odabran između involucijske osteoporoze, osteoporoze povezane s postmenopauzalnim hormonskim statusom, primarnom i sekundarnom hiperparatireozom, osteoporoze zbog mirovanja, osteoporoze povezane s dijabetesom, osteoporoze povezane s glukokortikoidima, benigne hiperplazije prostate i raka prostate.
11. Pripravak prema zahtjevu 7, naznačen time, što ima svrhu liječenja ili zaštite od poremećaja odabranog između involucijske osteoporoze, osteoporoze povezane s postmenopauzalnim hormonskim statusom, primarnom i sekundarnom hiperparatireozom, osteoporoze zbog mirovanja, osteoporoze povezane s dijabetesom, osteoporoze povezane s glukokortikoidima, benignom hiperplazijom prostate i rakom prostate.
12. Postupak za liječenje ili zaštitu od poremećaja rasta kostiju ili poremećaja rasta prostate u ljudi, naznačen time, što obuhvaća primjenu na osobu, kojoj je potrebno takvo liječenje ili zaštita, terapijski učinkovite količine pripravka prema bilo kojem od Zahtjeva 1 do 5.
13. Postupak prema zahtjevu 12, naznačen time, što je spomenuti poremećaj odabran između involucijske osteoporoze, osteoporoze povezane s postmenopauzalnim hormonskim statusom, primarnom i sekundarnom hiperparatireozom, osteoporoze zbog mirovanja, osteoporoze povezane s dijabetesom, osteoporoze povezane s glukokortikoidima, benigne hiperplazije prostate i raka prostate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9826662A GB2344287A (en) | 1998-12-03 | 1998-12-03 | Controlled release pharmaceutical formulation |
| PCT/GB1999/004045 WO2000032218A1 (en) | 1998-12-03 | 1999-12-02 | Controlled release formulation comprising gnrh-ii |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20010421A2 true HRP20010421A2 (en) | 2002-06-30 |
Family
ID=10843631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20010421A HRP20010421A2 (en) | 1998-12-03 | 2001-06-01 | Controlled release formulation comprising gnrh-ii |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP1140133A1 (hr) |
| JP (1) | JP2002531411A (hr) |
| KR (1) | KR20010089538A (hr) |
| CN (1) | CN1332635A (hr) |
| AU (1) | AU770676B2 (hr) |
| BR (1) | BR9915943A (hr) |
| CA (1) | CA2353798A1 (hr) |
| CZ (1) | CZ20011893A3 (hr) |
| EE (1) | EE200100293A (hr) |
| GB (1) | GB2344287A (hr) |
| HR (1) | HRP20010421A2 (hr) |
| HU (1) | HUP0104943A3 (hr) |
| IL (1) | IL143496A0 (hr) |
| MX (1) | MXPA01005543A (hr) |
| NO (1) | NO20012636L (hr) |
| NZ (1) | NZ511984A (hr) |
| PL (1) | PL348575A1 (hr) |
| RU (1) | RU2233170C2 (hr) |
| SK (1) | SK7552001A3 (hr) |
| TR (1) | TR200102273T2 (hr) |
| WO (1) | WO2000032218A1 (hr) |
| ZA (1) | ZA200104530B (hr) |
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| ES2575160T3 (es) | 2010-03-15 | 2016-06-24 | The Board Of Trustees Of The University Of Illinois | Inhibidores de las interacciones que unen la subunidad alfa de la beta integrina-proteína G |
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| WO1997047743A1 (en) * | 1996-06-13 | 1997-12-18 | Zymogenetics, Inc. | Human type ii gonadotropin-releasing hormone receptor |
-
1998
- 1998-12-03 GB GB9826662A patent/GB2344287A/en not_active Withdrawn
-
1999
- 1999-12-02 PL PL99348575A patent/PL348575A1/xx not_active Application Discontinuation
- 1999-12-02 IL IL14349699A patent/IL143496A0/xx unknown
- 1999-12-02 KR KR1020017006883A patent/KR20010089538A/ko not_active Application Discontinuation
- 1999-12-02 TR TR2001/02273T patent/TR200102273T2/xx unknown
- 1999-12-02 EE EEP200100293A patent/EE200100293A/xx unknown
- 1999-12-02 JP JP2000584909A patent/JP2002531411A/ja active Pending
- 1999-12-02 BR BR9915943-0A patent/BR9915943A/pt not_active IP Right Cessation
- 1999-12-02 HU HU0104943A patent/HUP0104943A3/hu unknown
- 1999-12-02 WO PCT/GB1999/004045 patent/WO2000032218A1/en not_active Application Discontinuation
- 1999-12-02 EP EP99958357A patent/EP1140133A1/en not_active Withdrawn
- 1999-12-02 NZ NZ511984A patent/NZ511984A/xx unknown
- 1999-12-02 CA CA002353798A patent/CA2353798A1/en not_active Abandoned
- 1999-12-02 RU RU2001118040/15A patent/RU2233170C2/ru not_active IP Right Cessation
- 1999-12-02 CN CN99815183A patent/CN1332635A/zh active Pending
- 1999-12-02 AU AU15732/00A patent/AU770676B2/en not_active Ceased
- 1999-12-02 MX MXPA01005543A patent/MXPA01005543A/es unknown
- 1999-12-02 CZ CZ20011893A patent/CZ20011893A3/cs unknown
- 1999-12-02 SK SK755-2001A patent/SK7552001A3/sk unknown
-
2001
- 2001-05-29 NO NO20012636A patent/NO20012636L/no not_active Application Discontinuation
- 2001-06-01 HR HR20010421A patent/HRP20010421A2/hr not_active Application Discontinuation
- 2001-06-01 ZA ZA200104530A patent/ZA200104530B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PL348575A1 (en) | 2002-06-03 |
| CN1332635A (zh) | 2002-01-23 |
| MXPA01005543A (es) | 2003-07-14 |
| ZA200104530B (en) | 2002-06-04 |
| CA2353798A1 (en) | 2000-06-08 |
| WO2000032218A1 (en) | 2000-06-08 |
| IL143496A0 (en) | 2002-04-21 |
| EP1140133A1 (en) | 2001-10-10 |
| NO20012636L (no) | 2001-07-12 |
| BR9915943A (pt) | 2001-08-21 |
| JP2002531411A (ja) | 2002-09-24 |
| HUP0104943A2 (en) | 2002-06-29 |
| EE200100293A (et) | 2002-08-15 |
| NZ511984A (en) | 2002-11-26 |
| GB2344287A (en) | 2000-06-07 |
| AU1573200A (en) | 2000-06-19 |
| SK7552001A3 (en) | 2002-02-05 |
| GB9826662D0 (en) | 1999-01-27 |
| CZ20011893A3 (cs) | 2002-05-15 |
| NO20012636D0 (no) | 2001-05-29 |
| RU2233170C2 (ru) | 2004-07-27 |
| HUP0104943A3 (en) | 2002-08-28 |
| TR200102273T2 (tr) | 2001-12-21 |
| AU770676B2 (en) | 2004-02-26 |
| KR20010089538A (ko) | 2001-10-06 |
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