Octreotide acetate yog cov tshuaj siv tshuaj, cov khoom tseem ceeb yog octreotide, thiab cov tshuaj formula yog c49h66n10o10s2. Dawb crystal hmoov. Nws yog qhov tsim nyog rau acromegaly, kab mob hauv plab thiab kab mob neuroendocrine uas xav tau kev tswj hwm mus sij hawm ntev. Cov khoom no tsuas yog siv rau kev sim, tsis yog rau lwm lub hom phiaj.
Synthesis ntawm octreotide acetate:
Compound (I) tau hydrogenated kom tshem tawm cov benzyl tiv thaiv pab pawg, thiab tom qab ntawd ua ke nrog (II) hauv dimethylformamide, Dicyclohexylcarbodiimide (DCC) thiab HOBt kom tau cov compound (III). (III) benzyl tiv thaiv pab pawg raug tshem tawm los ntawm hydrogenation ua ntej, thiab tom qab ntawd hauv dimethylformamide, DCC thiab HOBt react nrog (IV) kom tau txais (V). (5) Thiab hydrazine hloov mus rau (Ⅵ).
Tsis tas li ntawd, (VII) thiab (VIII) yog ua ke kom tau txais (IX). (IX) tom qab tshem tawm tert butyl tiv thaiv pab pawg, nws yog ua ke nrog (VI) kom tau txais (x). (10) Nws reacts nrog trifluoroacetic acid, benzyl sulfide, boron trifluoroacetic acid thiab trifluoroacetic acid kom tshem tawm cov pab pawg neeg tiv thaiv, thiab thaum kawg oxidizes thiab cyclizes nrog huab cua kom tau octreotide.
Cov kws sim cuam tshuam tau ua cov kev sim tsiaj txhawm rau txheeb xyuas cov txiaj ntsig ntawm cov khoom tiav. Cov kev sim no muaj raws li hauv qab no: amale PCK nas (n=24) tau muab tso rau ib qho ntawm plaub pawg (n=6 hauv txhua pab pawg): kev kho mob subcutaneous ib zaug txhua plaub lub lis piam, octreotide LAR ib leeg tau siv, pas-lar ib leeg tau siv, thiab octreotide thiab pas-lar ib leeg tau siv. Los ntawm 4 mus rau 16 lub lis piam ntawm hnub nyoog, 8mg / kg octreotide thiab 8mg / kg PAS tau muab ua ke, los yog lub tsheb (cov kua paug; cont). Cov cab kuj muaj copolymer microparticles uas muaj polylactic acid co glycolic acid (PLGA). Lub plawv dhia (HR), diastolic ntshav siab (DBP) thiab systolic ntshav siab (SBP) tau ntsuas los ntawm tus Tsov tus tw cuff sphygmomanometer hauv 4- lub lis piam-hnub nyoog thiab 15 lub lis piam tsis nco qab nas. Nees nkaum plaub teev tso zis thiab noj zaub mov tau ntsuas los ntawm kev siv cov kab mob metabolic tom qab 15.5 lub lis piam ntawm hnub nyoog. Tom qab ntsuas lub cev hnyav, cov tsiaj tau muab tshuaj loog nrog sodium pentobarbital thaum muaj hnub nyoog 16 lub lis piam, thiab lub raum thiab daim siab raug tshem tawm sai, ua rau los ntshav tuag. Tag nrho lub raum ntub dej hnyav thiab lub siab ntub dej tau raug ntsuas, thiab cov qauv ntshav tau sau los ntsuas cov ntshav urea nitrogen (sun), aspartate aminotransferase (AST), alanine aminotransferase (ALT), insulin zoo li kev loj hlob zoo li -1 (IGF{ {16}})), qabzib, insulin, glucagon, thiab cortisol.
Cov khoom tiav ntawm cov khoom no tau sau tseg hauv Suav Pharmocopoeia:
Cov khoom yog d-phenylalanyl-l-cysteineyl-l-phenylalanyl-d-tryptophan-l-lysinyl-l-threoniyl-n - [2-}hydroxy-1 - (hydroxymethyl) propyl] - l-cysteamine nplhaib (2 → 7) - disulfide daim ntawv cog lus acetate, thiab cov ntsiab lus ntawm octreotide (c49h66n10o10s2) yuav tsum yog 95.0 feem pua ~ 102.0 feem pua raws li anhydrous thiab acetic acid dawb tshuaj.
tus cwj pwm:
1. Cov khoom yog dawb los yog tawm dawb lyophilized hmoov.
2. Cov khoom yog soluble hauv dej thiab glacial acetic acid, tab sis insoluble hauv ether.
3. Kev sib hloov tshwj xeeb: nqa cov khoom, ntsuas kom raug, ua cov tshuaj uas muaj 5mg ib 1ml nrog glacial acetic acid, thiab ntsuas raws li txoj cai (Appendix VI E). Qhov kev sib hloov tshwj xeeb yuav tsum yog - 66.0 degree rau - 76.0 degree raws li kev suav cov tshuaj tsis muaj dej thiab acetic acid.
kev txheeb xyuas:
(1) noj li 1mg ntawm cov khoom, ntxiv 1ml dej kom yaj nws, thiab ntxiv 1ml ntawm alkaline tooj liab tartrate test tov kom pom xiav ntshav.
(2) nyob rau hauv lub chromatogram sau tseg nyob rau hauv cov ntsiab lus kev txiav txim cov khoom, lub sij hawm khaws cia ntawm lub ntsiab ncov ntawm qhov kev tshuaj ntsuam yuav tsum tau raws li cov kev siv tshuaj.
kev tshuaj xyuas:
Acidity: noj cov khoom no thiab ntxiv dej los npaj cov tshuaj uas muaj {{0}}.125mg ib 1ml. Ntsuas raws li txoj cai (Appendix VI h). Tus nqi pH yuav tsum yog 5.0-7.0.
Clarity thiab xim ntawm cov tshuaj: coj cov khoom no thiab ntxiv dej los ua cov tshuaj uas muaj 0.125mg ib 1ml. Cov tshuaj yuav tsum yog ntshiab thiab tsis muaj xim. Yog hais tias nws yog turbid, nws yuav tsum tsis txhob thicker tshaj No.1 turbidity standard tov (Appendix IX b); Yog tias cov xim raug tsim, nws yuav tsum tsis txhob tob dua li Yellow No. 1 standard colorimetric solution (Appendix IX a method I).
Amino acid ratio: noj cov khoom tsim nyog, ntxiv 6 mol / L hydrochloric acid tov, hloov cov cua nrog nitrogen, yaj thiab foob, hydrolyze ntawm 110 degree rau 24 teev, txias, unseal, nqus tsev vacuum qhuav. , ntxiv 0.1mol/l hydrochloric acid tov kom yaj thiab npaj txog 1mg tov ib 1ml. Noj 100 µ l ntawm cov tshuaj no, ntxiv 10 feem pua dithiodipropionic acid tov (noj 1g ntawm dithiodipropionic acid, ntxiv 10ml ntawm 0.4mol/l borate buffer (ph10.2) kom yaj nws, kho pH rau 10.4. nrog 40 feem pua sodium hydroxide tov), sib tov zoo, noj 80 degree dej da dej rau 10 feeb, txias nws, thiab ua hauj lwm raws li cov tshuaj ntsuam xyuas. Tsis tas li ntawd, noj cystine, threonine, phenylalanine, lysine thiab threonine siv cov ntaub ntawv, thiab siv 0.1mol / l hydrochloric acid tov los npaj cov tshuaj nrog cov concentration sib xws rau cov qauv kuaj raws li kev siv tshuaj. Txiav txim siab raws li txoj kev tsom xam cov amino acid (Appendix XX, method 1). Cov ntsiab lus ntawm txhua cov amino acid raug xam los ntawm thaj chaw ncov raws li tus qauv txheej txheem sab nraud.
Noj 1/3 ntawm tag nrho cov moles ntawm phenylalanine thiab lysine li 1 los xam cov txheeb ze ntawm txhua tus amino acid, thiab tus nqi yuav tsum nyob rau hauv cov nram qab no ntau yam:
Cysteine 1.7-2.3, threonine 0.8-1.2, phenylalanine 1. 1; Threonine tam sim no.
Cov tshuaj muaj feem cuam tshuam yuav tsum raug txiav txim siab raws li txoj hauv kev hauv kev txiav txim siab cov ntsiab lus, thiab suav raws li qhov chaw siab tshaj qhov qub, tshwj tsis yog qhov hnyav ncov thiab acetic acid ncov, thaj tsam ntawm ib qho impurity ncov yuav tsum tsis pub tshaj 1.0 feem pua , thiab tag nrho cheeb tsam ntawm txhua qhov impurity ncov yuav tsum tsis pub tshaj 2.0 feem pua .
Acetic acid: noj cov khoom tsim nyog thiab ntsuas kom raug. Raws li txoj kev txiav txim siab ntawm acetic acid hauv hluavtaws polypeptide, cov ntsiab lus ntawm acetic acid yuav tsum yog 5.0 feem pua ~ 12.0 feem pua .
Moisture: coj cov khoom no thiab ntsuas nws raws li txoj kev ntsuas dej noo, thiab cov dej noo yuav tsum tsis pub tshaj 10.0 feem pua.
kev txiav txim siab cov ntsiab lus:
Txiav txim siab los ntawm kev ua haujlwm siab ua kua chromatography.
Chromatographic tej yam kev mob thiab system adaptability octadecylsilane bonded silica gel tau siv los ua muab tub lim; Gradient elution tau ua nrog 10 feem pua tetramethylammonium hydroxide kua dej acetonitrile (2:88:10) (kho pH rau 5.4 nrog 10 feem pua phosphoric acid tov) raws li mobile theem A thiab 10 feem pua tetramethylammonium hydroxide tov dej (acetonitrile) 2: 38: 60) (hloov pH rau 5.4 nrog 10 feem pua phosphoric acid tov) raws li mobile theem B; Kev tshawb pom wavelength yog 210nm; Noj ib qho tsim nyog ntawm destriothrin octreotide thiab octreotide siv tshuaj, yaj lawv nrog dej thiab npaj rau hauv cov tshuaj uas muaj li 10 feem pua ntawm destriothrin octreotide ib 1ml μ G thiab octreotide 0.1mg, thiab 20 μ L txhaj rau hauv cov kua chromatograph thiab sau cov ntaub ntawv. chromatogram. Lub theoretical phaj naj npawb yuav tsum tsis pub tsawg tshaj 3000 raws li lub ncov ntawm octreotide acetate; Qhov kev daws teeb meem ntawm lub ncov ntawm octreotide thiab octreotide yuav tsum ua tau raws li qhov yuav tsum tau ua.
Txoj kev txiav txim siab: noj cov khoom tsim nyog, ntsuas kom raug, thiab npaj cov tshuaj uas muaj txog 0.125mg ib 1ml nrog dej. Ua kom raug ntsuas 20 μ L txhaj rau hauv cov kua chromatograph thiab sau cov chromatogram; Noj cov tshuaj octreotide acetate uas tsim nyog thiab txiav txim siab los ntawm tib txoj kev. Muab xam los ntawm thaj chaw ncov raws li tus qauv txheej txheem sab nraud.