HRP20020994A2 - Combinations of depeptidyl peptidase iv inhibitors and other antidiabetic agents for the treatment of diabete mellitus - Google Patents
Combinations of depeptidyl peptidase iv inhibitors and other antidiabetic agents for the treatment of diabete mellitus Download PDFInfo
- Publication number
- HRP20020994A2 HRP20020994A2 HR20020994A HRP20020994A HRP20020994A2 HR P20020994 A2 HRP20020994 A2 HR P20020994A2 HR 20020994 A HR20020994 A HR 20020994A HR P20020994 A HRP20020994 A HR P20020994A HR P20020994 A2 HRP20020994 A2 HR P20020994A2
- Authority
- HR
- Croatia
- Prior art keywords
- inhibitor
- pharmaceutically acceptable
- dipeptidyl peptidase
- insulin
- benzyl
- Prior art date
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- 206010012601 diabetes mellitus Diseases 0.000 title claims description 27
- 229940125708 antidiabetic agent Drugs 0.000 title claims description 22
- 239000003112 inhibitor Substances 0.000 title description 18
- 102000035195 Peptidases Human genes 0.000 title 1
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- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 claims description 21
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
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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
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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
- A61P3/06—Antihyperlipidemics
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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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- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Ovaj izum odnosi se na postupak liječenja, posebice na postupak liječenja dijabetesa melitusa, naročito dijabetesa neovisnog o inzulinu (NIDDM) ili dijabetesa tipa 2 i stanja povezanih s dijabetesom melitusom, te na pripravke za primjenu u navedenom postupku.
Dipeptidil peptidaza IV (DPP-IV) je serinska proteaza koja cijepa protein iza prolina ili alanina nađena u različitim tjelesnim tkivima uključujući tkiva bubrega, jetre i crijeva.
Poznato je da inhibitori DPP-IV mogu biti korisni za liječenje smanjene tolerancije na glukozu i dijabetesa melitusa (Međunarodna patentna prijava, broj publikacije W099/61431, Pederson RA et al,. Diabetes. 1998 Aug; 47 (8): 1253-8 and Pauly RP et al, Metabolism 1999 Mar; 48 (3): 385-9). Naročito publikacija W099/61431 otkriva inhibitore DPP IV koji sadrže aminokiselinu i tiazolidinsku ili pirolidinsku grupu te njihove soli, kao što je izoleucil (ili izoleucin) tiazolidid i njegove soli.
Drugi inhibitori DPP-IV uključuju one obznanjene u US patentima broj 6124305 i US 6107317, Međunarodne patentne prijave, brojevi publikacija WO 9819998, WO 9515309 i WO 9818763.
Antihiperglikemici inhibitori alfa glukozidaze (ili inhibitori alfa glukozidaze) i bigvanidni antihiperglikemici (ili bigvanidi) uobičajeno se rabe u liječenju dijabetesa tipa 2. Akarboza, vogliboza, emiglitat i miglitol su primjeri inhibitora alfa glukozidaze. 1, 1-dimetilbigvanidin (ili metformin) je poseban primjer bigvanida.
Inzulinski sekretagogi su spojevi koji potiču povećanu sekreciju inzulina iz beta stanica gušterače. Sulfonilureje su dobro poznati primjeri inzulinskih sekretagoga. Sulfonilureje djeluju kao hipoglikemici i rabe se u liječenju dijabetesa tipa 2. Primjeri sulfonilureja uključuju glibenklamid (ili gliburid), glipizid, gliklazid, glimepirid, tolazamid i tolbutamid.
Europska patentna prijava, broj publikacije 0,306,228 odnosi se na određene derivate tiazolidindiona za koje je otkriveno da imaju antihiperglikemično i hipolipidemično djelovanje. Jedan poseban tiazolidindion obznanjen u EP 0306228 je 5-[4-[2-(N-metil-N-(2-piridil)amino)etoksi]benzil]tiazolidin-2,4-dion (nadalje Spoj (I)).
W094/05659 otkriva određene soli Spoja (I) uključujući maleat u primjeru 1 navedene publikacije.
Spoj (I) je primjer klase antihiperglikemika poznatih kao “inzulinski senzitizatori”. Posebice je Spoj (I) tiazolidindionski inzulinski senzitizator. Spoj (I) je također inzulinski senzitizator agonista aktiviranog proliferatorom peroksisoma (PPARγ).
Europske patentne prijave, brojevi publikacija: 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734,0508740; Međunarodne patentne prijave, brojevi publikacija 92/18501, 93/02079,93/22445 i US brojevi patenata 5104888 i 5478852, također otkrivaju određene tiazolidindionske inzulinske senzitizatore.
Druge serije spojeva općenito prepoznatih da imaju djelovanje kao inzulinski senzitizatori su predočeni kao spojevi obznanjeni u Međunarodnim patentnim prijavama, brojevi publikacija W093/21166 i W094/01420. Ovi spojevi se nadalje nazivaju 'aciklički inzulinski senzitizatori'. Ostali primjeri acikličkih inzulinskih senzitizatora su oni obznanjeni u US patentu broj 5232945 i Međunarodnim patentnim prijavama, brojevi publikacija W092/03425 i W091/19702.
Primjeri ostalih inzulinskih senzitizatora su obznanjeni u Europskoj patentnoj prijavi, broj publikacije 0533933, Japanskoj patentnoj prijavi broj publikacije 05271204 i US patent broj 5264451.
Gore spomenute publikacije ovdje su uključene kao reference.
Ovdje je naznačeno da inhibitori dipeptidil peptidaze IV kao što su spojevi iz publikacije W099/61431, u kombinaciji s ostalim antidijabeticima osiguravaju posebno koristan učinak na kontrolu glikemije, te je sugerirano da je takva kombinacija posebno korisna za liječenje dijabetesa melitusa, naročito dijabetesa tipa 2 i stanja povezanih s dijabetesom melitusom. Takva kombinacija će osigurati bolju regulaciju glukoze u krvi bez uvođenja neprihvatljivih nus pojava.
Prema tome, izum osigurava postupak za liječenje dijabetesa melitusa, naročito dijabetesa tipa 2 i stanja povezanih s dijabetesom melitusom kod sisavaca kao što je čovjek, a koji se sastoji od primjene učinkovitih, netoksičnih i farmaceutski prihvatljivih količina inhibitora dipeptidil peptidaze IV i drugog antidijabetika, sisavcima kojima je to potrebno.
U slijedećem aspektu ovaj izum osigurava inhibitor dipeptidil peptidaze IV i drugi antidijabetik za primjenu u postupku liječenja dijabetesa melitusa, naročito dijabetesa tipa 2 i stanja povezanih s dijabetesom melitusom.
Postupak obuhvaća zajedničku primjenu inhibitora dipeptidil peptidaze IV i drugog antidijabetika ili njihovo uzastopno davanje.
Zajednička primjena uključuje primjenu formulacije koja sadržava i inhibitor DPP-IV i drugi antidijabetik ili uglavnom istovremenu primjenu odvojenih formulacija svake od tvari.
U slijedećem aspektu ovaj izum osigurava uporabu inhibitora dipeptidil peptidaze IV i drugog antidijabetika u proizvodnji pripravka za liječenje pretilosti, dijabetesa melitusa, naročito dijabetesa tipa 2 i stanja povezanih s dijabetesom melitusom.
Prikladno, drugi antidijabetik obuhvaća jedan ili više, obično jedan ili dva, inhibitora alfa glukozidaze, bigvanid, inzulinski sekretagog ili inzulinski senzitizator.
Prikladno, drugi antidijabetik izabran je iz skupine koju čine inhibitor alfa glukozidaze, bigvanid, inzulinski sekretagog ili inzulinski senzitizator.
Slijedeći prikladan antidijabetik je inzulin.
Prikladni inhibitor alfa glukozidaze je akarboza.
Ostali prikladni inhibitori alfa glukozidaze su emiglitat i miglitol. Slijedeći prikladan inhibitor alfa glukozidaze je vogliboza.
Prikladan bigvanid uključuje metformin, buformin ili fenformin, naročito metformin.
Prikladan inzulinski sekretagog uključuje sulfonilureje.
Prikladne sulfonilureje uključuju glibenklamid, glipizid, gliklazid, glimepirid, tolazamid i tolbutamid. Nadalje sulfonilureje uključuju acetoheksamid, karbutamid, klorpropamid, glibornurid, glikvidon, glizentid, glizolamid, glizoksepid, gliklopiamid i glicilamid. Također je uključena sulfonilureja glipentid.
Slijedeći prikladan inzulinski sekretagog je repaglinid. Dodatni inzulinski sekretagog je nateglinid.
Inzulinski senzitizatori uključuju inzulinske senzitizatore agonista PPARγ uključujući spojeve obznanjene u publikaciji WO 97/31907 i naročito 2-(1-karboksi-2-{4-{2-(5-metil-2-fenil-oksazol-4-il)-etoksi]-fenil}-etilamino)-metil ester benzojeve kiseline i 2(S)-(2-benzoil-fenilamino)-3-{4-[2-(5-metil-2-fenil-oksazol-4-il)-etoksi]-fenil}-propionsku kiselinu.
Inzulinski senzitizatori također uključuju tiazolidindionske inzulinske senzitizatore.
Pogodan inzulinski senzitizator je Spoj (I) ili njegov derivat.
Ostali prikladni tiazolidindionski inzulinski senzitizatori uključuju (+)-5-[[4-[(3,4-dihidro-6-hidroksi-2,5,7,8-tetrametil-2H-1-benzopiran-2-il)methoxi]fenil]metil]-2,4-tiazolidindion (ili troglitazon), 5-[4-[(1-metilcikloheksil)metoksi] benzil]tiazolidin-2,4-dione (ili ciglitazon), 5-[4-[2-(5-etilpiridin-2-il)etoksi]benzil]tiazolidin-2,4-dione (ili pioglitazon) ili 5-[(2-benzil-2,3-dihidrobenzopiran)-5ilmetil) tiazolidin-2,4-dion (ili englitazon).
Posebni tiazolidindionski inzulinski senzitizator je 5-[4-[2-(5-etilpiridin-2-il)etoksi]benzil]tiazolidin-2,4-dion (ili pioglitazon).
Posebni tiazolidindionski inzulinski senzitizator je (+)-5-[[4-[(3,4-dihidro-6-hidroksi-2,5,7,8-tetrametil-2H-1-benzopiran-2-il)metoksi]fenil]metil]-2,4-tiazolidindion (ili troglitazon).
Posebni inhibitori DPP-IV uključuju specifične primjere obznanjene u publikaciji W099/61431, kao što su L-treo-izoleucil pirolidid, L-alo-izoleucil tiazolidid, L-alo-izoleucil pirolidid i njihove soli. Posebni inhibitor DPP-IV je izoleucin tiazolidid i njegove soli.
Daljnji inhibitori DPP-IV uključuju specifične primjere obznanjene u US patentima broj 6124305 i US 6107317, Međunarodnim patentnim prijavama, brojevi publikacija WO 9819998, WO 9515309 i WO 9818763 ; kao što su 1[2-[(5-cijanopiridin-2-il)aminoetilamino]acetil-2-cijano-(S)-pirolidin i (2S)-1-[(2S)-2-amino-3,3-dimetilbutanoil]-2-pirolidinkarbonitril.
Za izbjegavanje sumnje, primjeri obznanjeni u svakoj od gore spomenutih publikacija specifično su uključeni kao reference, kao pojedinačno obznanjeni spojevi.
Podrazumijeva se da su inhibitor DPP-IV i drugi antidijabetik davani u farmaceutski prihvatljivom obliku, uključujući farmaceutski prihvatljive derivate kao što su njihove farmaceutski prihvatljive soli, esteri i solvati, prikladne za relevantnu djelatnu tvar. U nekim ovdje navedenim primjerima, imena korištena za druge antidijabetike mogu se odnositi na određeni farmaceutski oblik relevantne djelatne tvari: Podrazumijeva se da su ovim izumom obuhvaćeni svi farmaceutski prihvatljivi oblici djelatne tvari za sebe.
Prikladni farmaceutski prihvatljivi oblici antidijabetika ovise o tome koja se djelatna tvar koristi, ali uključuju poznate farmaceutski prihvatljive oblike izabrane tvari. Takvi derivati su pronađeni ili citirani u standardnim referentnim tekstovima kao što su Britanska i Američka farmakopeja, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (na primjer vidjeti 31. izdanje stranica 341 i tamo citirane stranice) ili gore spomenute publikacije.
Prikladni farmaceutski prihvatljivi oblici inhibitora DPP-IV uključuju soli i solvate, uključujući one opisane u publikaciji WO 99/61431, na primjer fumarat.
Inhibitor DPP-IV pripravljen je u skladu s objavljenim metodama, na primjer kada je inhibitor DPP-IV spoj iz publikacije WO 99/61431 ili njegov derivat, kao što je njegova farmaceutski prihvatljiva sol ili njegov farmaceutski prihvatljiv solvat, tada se pripravlja u skladu s tamo obznanjenim metodama. Slično je za spojeve iz US patenata broj 6124305 i US 6107317 i one iz Međunarodnih patentnih prijava, brojevi publikacija WO 9819998, WO 9515309 i WO 9818763.
Neki od ovdje spomenutih spojeva mogu sadržavati jedan ili više kiralnih ugljikovih atoma te tako mogu postojati u dvije ili više izomernih formi, koje su sve obuhvaćene ovim izumom, kao pojedinačni izomeri ili kao smjese izomera, uključujući racemate. Neki od ovdje spomenutih spojeva, posebice tiazolidindioni kao što je Spoj (I), koji mogu postojati u jednoj od nekoliko tautomernih formi, obuhvaćeni su ovim izumom kao pojedinačne tautomerne forme ili njihove smjese.
Inhibitor DPP-IV i drugi antidijabetik po izboru pripravljeni su u skladu s poznatim metodama, a koje su pronađene ili citirane u standardnim referentnim tekstovima, kao što su Britanska i Američka farmakopeja, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (na primjer vidjeti 31. izdanje stranica 341 i tamo citirane stranice) ili gore spomenute publikacije.
Kada se ovdje rabi pojam “stanja povezana sa dijabetesom” on uključuje stanja povezana s pre-dijabetičkim stanjem, stanjima povezanim sa samim dijabetesom melitusom i komplikacije povezane s dijabetesom melitusom.
Kada se ovdje rabi pojam “stanja povezana s pre-dijabetičkim stanjem”' on uključuje stanja kao što su inzulinska rezistencija, uključujući nasljednu inzulinsku rezistenciju, smanjenu toleranciju na glukozu i hiperinzulinemiju.
“Stanja povezana sa samim dijabetesom melitusom” uključuju hiperglikemiju, inzulinsku rezistenciju, uključujući stečenu inzulinsku rezistenciju i pretilost. Slijedeća stanja povezana sa samim dijabetesom melitusom uključuju hipertenziju i bolesti kardiovaskularnog sustava, naročito aterosklerozu i stanja povezana sa inzulinskom rezistencijom. Stanja povezana sa inzulinskom rezistencijom uključuju sindrom policističnih jajnika, inzulinsku rezistenciju induciranu steroidima te dijabetes u trudnoći.
“Stanja povezana s dijabetesom melitusom” uključuju bubrežne bolesti, naročito bubrežne bolesti povezane s dijabetesom tipa 2, neuropatiju i retinopatiju.
Bubrežne bolesti povezane s dijabetesom tipa 2 uključuju nefropatiju, glomerulonefritis, glomerularnu sklerozu, nefrotički sndrom, hipertenzivna nefroskleroza i posljednji stadij bubrežne bolesti.
Pojam “farmaceutski prihvatljivo” kao što se ovdje rabi, obuhvaća i humanu i veterinarsku primjenu: na primjer pojam “farmaceutski prihvatljivo” obuhvaća veterinarski prihvatljiv spoj.
Pod pojmom dijabetes melitus najčešće se misli na dijabetes tipa 2.
Prikladno, posebno koristan učinak na kontrolu glikemije osiguran postupkom liječenja navedenom u izumu, ima poboljšan terapijski odnos za kombinaciju iz ovog izuma, u odnosu na jedan spoj iz kombinacije, kada se koristi sam i u dozi koja osigurava učinkovitost ekvivalentnu kombinaciji iz ovog izuma.
U preferiranom aspektu, naznačeno je da je posebno koristan učinak na kontrolu glikemije, osiguran postupkom liječena opisanom u izumu, sinergistički učinak u odnosu na očekivani iz učinaka pojedinih djelatnih tvari.
U slijedećem aspektu ovog izuma, kombinirane doze inhibitora DPP-IV i drugog antidijabetika proizvest će veći koristan učinak nego što se može postići za svaku pojedinu tvar u dozi dvostrukoj od korištene za tu tvar u kombinaciji.
Kontrola glikemije može biti karakterizirana uporabom konvencionalnih metoda, na primjer mjerenjem uobičajeno korištenog indeksa kontrole glikemije kao što je razina glukoze u plazmi nakon gladovanja ili glikolizirani hemoglobin (Hb Alc). Takve vrijednosti određene su uporabom standardne metodologije, na primjer one opisane u: Tuescher A, Richterich, P.,Schweiz. med. Wschr. 101 (1971), 345 and 390 and Frank P.,'Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements', Clinical Products 1988.
U preferiranom aspektu, doza svake od djelatnih tvari, kada se primjenjuje u skladu s postupkom liječenja opisanom u izumu, bit će manja od zahtjevanih iz čistog aditivnog efekta u kontroli glikemije.
Također se smatra da će postupak liječenja opisan u izumu utjecati na poboljšanje, u odnosu na pojedine tvari, razine ubrzanja glikozilacije konačnih produkata (AGEs) i serumskih lipida koji uključuju ukupni kolesterol, HDL-kolesterol, LDL-kolesterol, uključujući poboljšanja u njihovom međusobnom omjeru, posebice poboljšanja kod serumskih lipida koji uključuju ukupni kolesterol, HDL-kolesterol, LDL-kolesterol, uključujući poboljšanja u njihovom međusobnom odnosu.
U postupku liječenja opisanom u izumu, ljekovite tvari se pogodno primjenjuju u obliku farmaceutskog pripravka. Kao što je gore navedeno, takvi pripravci mogu uključivati više ljekovitih tvari ili samo jednu.
Prema tome, ovaj izum u jednom aspektu također osigurava farmaceutski pripravak koji sadrži inhibitor dipeptidil peptidaze IV i drugi antidijabetik te farmaceutski prihvatljiv nosač.
Stoga, u slijedećem aspektu izum također osigurava postupak dobivanja farmaceutskog pripravka koji sadrži inhibitor dipeptidil peptidaze IV, drugi antidijabetik i farmaceutski prihvatljiv nosač, a koji obuhvaća miješanje inhibitora dipeptidil peptidaze IV, drugog antidijabetika i farmaceutski prihvatljivog nosača.
Pogodno je da su pripravci u jediničnom obliku u količini prikladnoj za relevantno dnevno doziranje.
Prikladno doziranje, uključujući naročito jedinično doziranje inhibitora DPP-IV i drugog antidijabetika uključuje poznata doziranja uključujući jedinične doze ovih spojeva kako je opisano ili citirano u referentnom tekstu kao što je Britanska i Američka farmakopeja, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (na primjer vidjeti 31. izdanje stranicu 341 i tamo citirane stranice) ili gore spomenute publikacije.
Stoga, prikladna doziranja za inhibitor DPP-IV navedena u WO 99/61431 i uključivo doziranja tamo otkrivena, na primjer 0.01 do 30 mg na dan ili 0.01 do 10 mg po kilogramu tjelesne mase. Također, prikladne doze drugih ovdje spomenutih inhibitora DPP-IV uključuju one spomenute u gore navedenim relevantnim publikacijama.
Za inhibitor alfa glukozidaze, prikladna količina akarboze je u području od 25 to 600 mg, uključujući 50 to 600 mg, na primjer 100 mg ili 200mg.
Za bigvanid, prikladno doziranje metformina je između 100 do 3000 mg, na primjer 250, 500 mg, 850 mg ili 1000 mg.
Za inzulinski sekretagog, prikladna količina glibenklamida je u području od 2,5 do 20 mg, na primjer 10 mg ili 20 mg; prikladna količina glipizida je u području od 2,5 do 40 mg; prikladna količina gliklazida je u području od 40 do 320 mg ; prikladna količina tolazamida je u području od 100 to 1000 mg; prikladna količina tolbutamida je u području od 1000 to 3000 mg; prikladna količina klorpropamida je u području od 100 to 500 mg; i prikladna količina glikvidona je u području od 15 to 180 mg. Također, prikladna količina glimepirida je 1 do 6mg i prikladna količina glipentida je 2,5 do 20 mg.
Prikladna količina repaglinida je u području od 0.5 mg do 20 mg, na primjer 16 mg. Također, prikladna količina nateglinida je 90 do 360 mg, na primjer 270 mg.
U posebnom aspektu, pripravak sadržava 2 do 12 mg Spoja (I).
Prikladno je da pripravak sadržava 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ili 12 mg Spoja (I).
Posebice, pripravak sadržava 2 do 4, 4 do 8 ili 8 do 12 mg Spoja (I).
Posebice, pripravak sadržava 2 do 4 mg Spoja (I).
Posebice, pripravak sadržava 4 do 8 mg Spoj (I).
Posebice, pripravak sadržava 8 do 12 mg Spoja (I).
Pogodno je da pripravak sadržava 2 mg Spoja (I).
Pogodno je da pripravak sadržava 4 mg Spoja (I).
Pogodno je da pripravak sadržava 8 mg Spoja (I).
Prikladno jedinično doziranje drugih inzulinskih senzitizatora uključuje doze od 100 do 800 mg troglitazona kao što su 200, 400, 600 ili 800mg ili doze od 5 do 50 mg uključujući 10 do 40 mg pioglitazona, kao što su 20, 30 ili 40 mg te također 15, 30 i 45 mg pioglitazona.
Prikladna doziranja drugih inzulinskih senzitizatora agonista PPARγ uključuju objavljene za agonist naveden u gore spomenutim patentnim prijavama, na primjer 2-(1-karboksi-2-{4-{2-(5-metil-2-fenil-oksazol-4-il)-etoksi]-fenil}-etilamino)-metil ester benzojeve kiseline i 2(S)-(2-benzoil-fenilamino)-3-{4-[2-(5-metil-2-fenil-oksazol-4-il)-etoksi]-fenil}-propionska kiselina je prikladno dozirana u skladu s doziranjem objavljenim u publikaciji WO 97/31907.
U liječenju se lijekovi mogu primjenjivati 1 do 6 puta na dan, ali najpogodnije je 1 ili 2 puta na dan.
Također, doza svake pojedine djelatne tvari u bilo kojem danom pripravku može, kao što se zahtijeva, varirati unutar poznatih zahtjevanih raspona doza, u odnosu na prihvaćen režim doziranja za taj spoj. Doze svake pojedine tvari također mogu biti prilagođene, kao što se zahtijeva, uzimajući u obzir povoljan učinak kombiniranja tvari kako je ovdje navedeno.
Podrazumijeva se da su inhibitor DPP-IV i drugi antidijabetik u farmaceutski prihvatljivom obliku, uključujući farmaceutski prihvatljive derivate kao što su njihove farmaceutski prihvatljive soli, esteri i solvati, prikladne za izabranu relevantnu farmaceutski aktivnu tvar. U nekim ovdje navedenim slučajevima nazivi koji se koriste za antidijabetike mogu se odnositi na određeni farmaceutski oblik relevantne djelatne tvari: Podrazumijeva se da su svi farmaceutski prihvatljivi oblici djelatnih tvari po sebi obuhvaćeni ovim izumom.
Ovaj izum također osigurava farmaceutski pripravak koji sadržava inhibitor dipeptidil peptidaze IV, drugi antidijabetik i farmaceutski prihvatljiv nosač, za primjenu kao terapijski aktivnu tvar.
Posebice, ovaj izum osigurava farmaceutski pripravak koji obuhvaća inhibitor dipeptidil peptidaze IV, drugi antidijabetik i farmaceutski prihvatljiv nosač za primjenu u liječenju dijabetesa melitusa, naročito tipa 2 dijabetesa i stanja povezanih s dijabetesom melitusom.
Obično su pripravci prilagođeni za oralnu primjenu. Međutim, mogu biti prilagođeni za druge načine primjene, na primjer parenteralnu primjenu, sublingvalnu ili transdermalnu primjenu.
Pripravci mogu biti u obliku tableta, kapsula, prašaka, granula, pastila, supozitorija, prašaka za pripremu otopine/suspenzije ili tekućih pripravaka, kao što su oralne ili sterilne parenteralne otopine ili suspenzije.
Za postizanje ujednačenosti primjene pogodno je da pripravak navedenog izuma bude u jediničnom obliku.
Jedinični oblici za oralnu primjenu mogu biti tablete ili kapsule i mogu ako je potrebno sadržavati uobičajene pomoćne tvari kao što su veziva, punila, lubrikanti, glidanti, sredstva za raspadanje i sredstva za vlaženje.
Kruti oralni pripravci mogu biti pripravljeni uobičajenim metodama miješanja, punjenja ili tabletiranja. Ponovljene operacije miješanja mogu se koristiti za potpuniju distribuciju djelatne tvari u pripravku koji ima veliku količinu punila. Takve su operacije naravno poznate u stanju tehnike. Tablete se mogu oblagati u skladu s metodama poznatim u normalnoj farmaceutskoj praksi, posebice ovojnicom koja se razgrađuje u crijevnom soku.
Tekući oralni pripravci mogu biti u obliku na primjer, emulzija, sirupa, ili eliksira, ili u obliku suhih preparata koji se prije primjene rekonstituiraju s vodom ili drugim prikladnim vehiklom. Takvi tekući pripravci mogu sadržavati uobičajene aditive kao što su sredstva za suspendiranje, na primjer sorbitol, sirup, metilceluloza, želatina, hidroksietilceluloza, karboksimetilceluloza, gel aluminij-stearata, hidrogenirane jestive masnoće; emulgatore, na primjer lecitin, sorbitan monooleat, ili arapska guma; nevodene vehikle (koji mogu uključivati jestiva ulja), na primjer bademovo ulje, frakcionirano kokosovo ulje, uljne estere kao što su esteri glicerola, propilen-glikola, ili etanola; konzervanse, na primjer metil ili propil p-hidroksibenzoat ili sorbinsku kiselinu; te ako je potrebno uobičajene korigense okusa ili boje.
Za parenteralnu primjenu, tekući jedinični oblici pripravljaju se od spoja i sterilnog vehikla, te ovisno o korištenoj koncentraciji, mogu biti suspendirani ili otopljeni u vehiklu. U pripravljanju otopina, spoj se može otopiti u vodi za injekcije i sterilizirati filtracijom prije punjenja u prikladne bočice ili ampule i zatvaranja. Pogodno je da pomoćne tvari kao što su lokalni anestetik, konzervans i pufer mogu biti otopljeni u vehiklu. U svrhu povećanja stabilnosti, pripravak može biti zamrznut nakon punjenja u bočicu i voda uklonjena pod vakuumom. Parenteralne suspenzije pripravljaju se u osnovi na isti način, osim što je djelatni spoj suspendiran umjesto otopljen u vehiklu, i sterilizacija ne može biti provedena filtracijom. Spoj može biti steriliziran izlaganjem etilen-oksidu prije suspendiranja u sterilnom vehiklu. Pogodno je da su sredstvo za povećanje površinske napetosti ili sredstvo za vlaženje u sastavu pripravka kako bi se omogućila ujednačena distribucija spoja.
Pripravci mogu sadržavati djelatnu tvar u količini od 0.1% do 99% masenih, pogodnije od 10-60% masenih, ovisno o načinu primjene.
Primjeri veziva uključuju arapsku gumu, alginsku kiselinu, kalcij-karboksimetilcelulozu, natrij-karboksimetilcelulozu, dekstrate, dekstrin, dekstrozu, etilcelulozu, želatinu, glukozni sirup, guar gumu, hidroksietilcelulozu, hidroksipropilcelulozu, hidroksipropilmetilcelulozu, magnezij aluminij-silikat, maltodekstrin, metilcelulozu, polimetakrilate, polivinilpirolidon, preželatinizirani škrob, natrij-alginat, sorbitol, škrob, sirup, tragakant.
Primjeri punila uključuju kalcij-karbonat, kalcij-fosfat, kalcij-sulfat, kalcij-karboksimetilcelulozu, natrij-karboksimetilcelulozu, šećer koji se može komprimirati, konzumni šećer, dekstrate, dekstrin, dekstrosu, dibazični kalcij-fosfat dihidrat, dibazični kalcij-fosfat, fruktozu, gliceril palmitostearat, glicin, hidrogenirano biljno ulje-tip 1, kaolin, laktozu, kukuruzni škrob, magnezij-karbonat, magnezij-oksid, maltodekstrin, manitol, mikrokristalnu celulozu, polimetakrilate, kalij-klorid, praškastu celulozu, preželatinizirani škrob, natrij-klorid, sorbitol, škrob, saharozu, šečerne pelete, talk, tribazični kalcij-fosfat, ksilitol.
Primjeri lubrikanata uključuju kalcij-stearat, gliceril monostearat, gliceril palmitostearat, magnezij-stearat, mikrokristalnu celulozu, natrij-benzoat, natrij-klorid, natrij-laurilsulfat, stearinsku kiselinu, natrij-stearilfumarat, talk, cink-stearat.
Primjeri glidanata uključuju koloidni silicij-dioksid, praškastu celulozu, magnezij-trisilikat, silicij-dioksid, talk.
Primjeri sredstava za raspadanje uključuju alginsku kiselinu, kalcij-karboksimetilcelulozu, natrij-karboksimetilcelulozu, koloidni silicij-dioksid, kroskarmelozu-natrij, krospovidon, guar gumu, magnezij aluminij-silikat, mikrokristalnu celulozu, metilcelulozu, polivinilpirolidon, kalij-polakrilin, preželatinizirani škrob, natrij-alginat, natrij-laurilsulfat, natrij škrob glikolat.
Primjer farmaceutski prihvatljivog sredstva za vlaženje je natrij-laurilsulfat.
Pripravci su pripravljeni i oblikovani u skladu s uobičajenim metodama, kao što su one obznanjene u standardnim referentnim tekstovima, na primjer Britanskoj i Američkoj farmakopeji, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (na primjer vidi 31. izdanje stranicu 341 i tamo citirane stranice) i Harry's Cosmeticology (Leonard Hill Books) ili gore spomenutim publikacijama.
Na primjer, kruti oralni pripravci mogu se pripraviti uobičajenim metodama miješanja, punjenja ili tabletiranja. Ponovljena operacija miješanja može se koristiti za potpuniju distribuciju djelatne tvari u pripravku koji ima veliku količinu punila. Takve su operacije naravno poznate u stanju tehnike. Tablete se mogu oblagati u skladu s dobro poznatim metodama u normalnoj farmaceutskoj praksi.
Pripravci mogu, ako je potrebno, biti u kutiji zajedno s pisanom ili otisnutom uputom za primjenu.
Očekuje se da pripravci i postupci opisani u ovom izumu nemaju nepovoljne toksikološke učinke u gore spomenutom području doziranja.
Farmakološki podaci
ZDF fa/fa štakori (Genetic Models, Inc., Indianapolis, IN) muškog spola, jednaki po starosti i masi smješteni su pojedinačno na 72°F i 50% relativne vlage sa 12-satnim ciklusima svjetlosti/mraka i hranjeni s PMI 5008 Formula Diet (PMI Nutrition International, Saint Louis, MO).
Životinje su dozirane oralno dva puta dnevno tijekom ciklusa mraka tijekom jednog tjedna s vehiklom (0.5% hidroksi-propilmetilceluloza (HPMC) i 0.1% Tween 80), 100 mg/kg izoleucin tiazolidida (Spoj (II)), 5 mg/kg Spoja (I) u vehiklu, ili 5 mg/kg Spoja (I) sa 100 mg/kg Spoja (II) u vehiklu.
Za mjerenje tolerancije na glukozu, štakori su tretirani ispitivanim spojem 7 dana uz davanje intraperitonealne injekcije otopine glukoze u fiziološkoj otopini 30 minuta nakon posljednje doze ispitivanog spoja.
Štakori su anestezirani izofluranom u svrhu skupljanja krvi iz srca 30 minuta nakon primjene otopine glukoze. Kemijska mjerenja seruma provedena su korištenjem automatiziranog kemijskog analizatora (ILab600, Instrument Laboratory, Lexington, MA).
Aktivnost DPP-IV mjerena je korištenjem fluorogenskog supstrata Gly-Pro-AMC (50 mM) u skladu s proizvođačevim specifikacijama (Enzyme System Products, Livermore CA). Supstrat je pomiješan s 50 mM Trisa, uz pH 7.8 u plazmi (20% konačnih v/v), te su uzorci inkubirani 5-20 min pri 30°C. Aktivnost DPP-IV određena je mjerenjem fluorescencije korištenjem citofluor spectrofluorometra s filterima podešenim na 360 nm za ekscitaciju i 460 nm za emisiju.
Rezultati svake grupe (n=6) iskazani su prosječno i uspoređeni sa rezultatima za štakore tretirane vehiklom kako bi se odredila signifikantnost te su prikazani u tablici I.
Slijedeći podaci prikazuju ovaj izum ali ga ne ograničavaju ni na koji način.
TABLICA I
ZDF štakori, tretirani BID-om tijekom 7 dana
[image]
*P.0.05
Claims (14)
1. Postupak za liječenje dijabetesa melitusa, naročito dijabetesa tipa 2 i stanja povezanih s dijabetesom melitusom kod sisavaca kao što je čovjek, naznačena time da se sastoji od primjene učinkovite, netoksične i farmaceutski prihvatljive količine inhibitora dipeptidil peptidaze IV i drugog antidijabetika sisavcima kojima je to potrebno.
2. Postupak prema zahtjevu 1, naznačen time da je dipeptidil peptidaza IV izabrana iz: L-treo-izoleucil pirolidida, L-alo-izoleucil tiazolidida, L-alo-izoleucil pirolidida i njihovih soli ili 1[2-[(5-cijanopiridin-2-il)aminoetilamino]acetil-2-cijano-(S)-pirolidin i (2S)-1-[(2S)-2-amino-3,3-dimetilbutanoil]-2-pirolidinkarbonitril.
3. Postupak prema zahtjevu 1 ili zahtjevu 2, naznačen time da drugi antidijabetik obuhvaća jedan ili više inhibitora alfa glukozidaze, bigvanida, inzulinskih sekretagoga ili inzulinskih senzitizatora.
4. Postupak prema zahtjevu 3, naznačen time da je inhibitor alfa glukozidaze izabran iz skupine koju čine akarboza, emiglitat, miglitol i vogliboza.
5. Postupak prema zahtjevu 3 naznačen time da je bigvanid izabran iz skupine koju čine metformin, buformin i fenformin.
6. Postupak prema zahtjevu 3, naznačen time da je inzulinski sekretagog sulfonilureja izabrana iz skupine koju čine: glibenklamid, glipizid, gliklazid, glimepirid, tolazamid i tolbutamid, acetoheksamid, karbutamid, klorpropamid, glibornurid, glikvidon, glizentid, glizolamid, glizoksepid, gliklopiamid, glicilamid i glipentid.
7. Postupak prema zahtjevu 3, naznačen time da je inzulinski sekretagog repaglinid ili nateglinid.
8. Postupak prema zahtjevu 3, naznačen time da je inzulinski senzitizator tiazolidindion.
9. Postupak prema zahtjevu 7, naznačen time da je tiazolidindion izabran iz skupine koju čine: (+)-5-([4-[(3,4-dihidro-6-hidroksi-2,5,7,8-tetrametil-2H-1-benzopiran-2-il)metoksi]fenil]metil]-2,4-tiazolidindion (ili troglitazon), 5-[4-[(1-metilcikloheksil)metoksi]benzil]tiazolidin-2,4-dione (ili ciglitazon), 5-[4-[2-(5-etilpiridin-2-il)etoksi]benzil tiazolidin-2,4-dion (ili pioglitazon) ili 5-[(2-benzil-2,3-dihidrobenzopiran)-5-ilmetil)tiazolidin-2,4-dion (ili englitazon).
10. Postupak prema zahtjevu 7, naznačen time da je tiazolidindion 5-[4-[2-(N-metil-N-(2-piridil)amino)etoksi] benzil]tiazolidin-2,4-dion, 5-[4-[2-(5-etilpiridin-2-il)etoksi]benzil]tiazolidin-2,4-dion (ili pioglitazon); ili njihov farmaceutski prihvatljiv derivat.
11. Farmaceutski pripravak, naznačen time da sadržava inhibitor dipeptidil peptidaze IV i drugi antidijabetik te farmaceutski prihvatljiv nosač.
12. Postupak za izradu farmaceutskog pripravka, naznačen time da sadržava inhibitor dipeptidil peptidaze IV, drugi antidijabetik i farmaceutski prihvatljiv nosač, a obuhvaća miješanje inhibitora dipeptidil peptidaze IV, drugog antidijabetika i farmaceutski prihvatljivog nosača.
13. Farmaceutski pripravak, naznačen time da sadržava inhibitor dipeptidil peptidaze IV, drugi antidijabetik i farmaceutski prihvatljiv nosač za primjenu kao aktivna terapijska supstancija.
14. Farmaceutski pripravak, naznačen time da sadržava inhibitor dipeptidil peptidaze IV, drugi antidijabetik i farmaceutski prihvatljiv nosač za primjenu u liječenju dijabetesa melitusa, naročito dijabetesa tipa 2 i stanja povezanih s dijabetesom melitusom.
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| US6107317A (en) | 1999-06-24 | 2000-08-22 | Novartis Ag | N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| SG149676A1 (en) * | 1999-12-23 | 2009-02-27 | Novartis Ag | Use of hypoglycemic agent for treating impaired glucose metabolism |
| ATE346613T1 (de) * | 2000-01-21 | 2006-12-15 | Novartis Pharma Gmbh | Zusammensetzungen bestehend aus dipeptidylpeptidase-iv inhibitoren und antidiabetica |
| US7078397B2 (en) * | 2000-06-19 | 2006-07-18 | Smithkline Beecham Corporation | Combinations of dipeptidyl peptidase IV inhibitors and other antidiabetic agents for the treatment of diabetes mellitus |
| GB0014969D0 (en) * | 2000-06-19 | 2000-08-09 | Smithkline Beecham Plc | Novel method of treatment |
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2000
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