Tom ntej: Octreotide API CAS 79517-01-4

Octreotide API CAS 79517-01-4|Octreotide acetate cGMP ntau lawm|Acromegaly/neuroendocrine qog API|Science-Peptide

Octreotide API CAS 79517-01-4 - Peptide API rau acromegaly, neuroendocrine qog.Science-Peptide muab Octreotide Acetate uas ua tau raws li tus qauv cGMP, nrog cov txheej txheem paub tab, ntshiab impurity profiles, kev txhawb nqa rau Tuam Tshoj, Tebchaws USA thiab Europe tshaj tawm, thiab tuaj yeem tso cai rau DMF.Zoo siab txais tos hu rau peb.

Octreotide yog ib qho zoo tshaj plaws paub txog kev loj hlob inhibitor analogs. Acromegaly, neuroendocrine qog (NETs), esophageal variceal hemorrhage, pancreatitis - nws ua haujlwm, thiab nws muaj nyob rau hauv ntau hom tshuaj: kev txhaj tshuaj tsis tu ncua, ntev - ua haujlwm microspheres (txhua 4 lub lis piam), thiab rau cov cim qhia txog kev siv tshuaj endocrinology, thiab oncology.

Nws cov txheej txheem ntawm kev ua haujlwm zoo ib yam li cov tshuaj tiv thaiv kev loj hlob, tab sis ib nrab - lub neej ntev dua (kwv yees 1.5-2 teev vs . 1-3 feeb rau kev loj hlob inhibitors), yog li nws yooj yim dua rau kev siv tshuaj kho mob. Hauv cov neeg mob acromegaly, octreotide tuaj yeem tswj cov qib ntawm cov tshuaj hormones loj hlob thiab IGF-1; nyob rau hauv gastroenteropancreatic neuroendocrine qog, nws tuaj yeem inhibit qhov tso tawm ntawm cov tshuaj hormones thiab tswj cov qog nqaij hlav.

Kev tshawb fawb-Peptide tau ua haujlwm ntawm peptide API rau ntau tshaj 20 xyoo, thiab octreotide yog ib hom tsiaj uas peb nkag mus rau thaum ntxov. Octreotide yog ib qho 8-peptide nrog ib khub ntawm disulfide daim ntawv cog lus, uas yog me ntsis nyuaj rau kev sib txuas, tab sis nws yuav tsum muaj kev paub tshwj xeeb kom ua tiav qhov tsis huv tsis huv, zoo batch sib xws, thiab kev tswj zoo ntawm cov ntsuas tshwj xeeb (xws li particle loj thiab hnyav residue) rau APIs siv nyob rau hauv ntev - microspheres. Peb cov Octreotide Acetate API tuaj yeem ruaj khov los ntawm grams mus rau kilograms, tau ua tiav FDA DMF daim ntawv, thiab txhawb nqa Tuam Tshoj, Tebchaws Asmeskas thiab Europe tshaj tawm. Tshwj xeeb tshaj yog rau cov ntaub ntawv raw siv nyob rau hauv ntev-acting microsphere formulations, peb tau optimized cov txheej txheem purification thiab nruj me ntsis tswj cov residual solvents thiab ya raws.

Octreotide yog ib qho octapeptide uas tsim ib lub voj voog los ntawm disulfide daim ntawv cog lus ntawm 2- thiab 7- txoj hauj lwm cysteine, nrog threoninol ntawm C-terminus. Nws muaj ob hom D-hom amino acids (D-Phe, D-Trp) nyob rau hauv nws cov qauv, uas ua rau kom nws ruaj khov rau proteases thiab yog li ntawd muaj ib nrab neej ntev dua li natural growth inhibitors.

Cov ntawv thov kev kho mob tseem ceeb:

• Acromegaly: inhibit kev loj hlob hormone secretion, tswj cov tsos mob, txo IGF-1 qib. Kev txhaj tshuaj tsis tu ncua yog siv rau kev kho thawj zaug lossis hloov koob tshuaj, thiab ntev - ua haujlwm microspheres yog siv rau kev saib xyuas mus ntev.
• Neuroendocrine qog (NETs): tswj kev mob raws plab thiab yaug hauv cov kab mob carcinoid, inhibits cov tshuaj hormone secretion hauv NETs ua haujlwm, thiab tseem muaj qee yam kev tiv thaiv kab mob.
• Mob plab hnyuv variceal los ntshav: txuas mus rau endoscopic ligation kom txo qhov siab ntawm lub portal, zoo ib yam li kev loj hlob inhibitors.
• Pancreatitis, pancreatic fistula: inhibit pancreatic enzyme secretion, txhawb kev kho ntawm fistula.

Los ntawm API qhov kev xav, kev ua lag luam rau octreotide yog qhov loj dua li ntawm kev loj hlob inhibitors - vim tias nws ntev - ua yeeb yam microsphere ntau npaum li cas (Xanlong) yog ntau yam hnyav, thiab muaj kev thov rau cov tshuaj generic. Cov kev cai rau APIs kuj tseem siab dua: ntxiv rau cov purity ib txwm thiab impurities, microsphere formulations kuj yuav tsum tau tsom rau cov particle loj faib ntawm API, residual solvents, noo noo thiab lwm yam ntsuas.

Peb tau ua haujlwm nrog cov neeg siv khoom uas ua kom ntev - microspheres kav ntev, thiab peb paub tias lawv txhawj xeeb txog dab tsi: siab batch-rau-batch sib xws, ruaj khov impurity profiles, residual solvents raws li ICH Q3C, thiab tswj cov dej noo, txwv tsis pub cov txheej txheem kho ntawm microspheres yuav muaj teeb meem.

1. Kev siv tshuab mature, optimized tshwj xeeb tshaj yog rau microsphere dosage forms
Txoj kev synthesis ntawm octreotide tsis nyuaj - khoom -theem synthesis ntawm linear precursors, kua-phase cyclization los ua disulfide bonds. Txawm li cas los xij, txhawm rau kom ua tiav siab purity, tsis muaj impurity thiab haum rau microsphere formulation, peb tau siv zog ntau yam:

• Linear precursor: Fmoc solid-theem synthesis, vim tias muaj D-hom amino acids thiab C-terminal threoninol (tsis yog cov qauv amino acids) nyob rau hauv qhov sib lawv liag, cov coupling tej yam kev mob yuav tsum tau optimized. Peb tau ua qhov no rau ntau xyoo thiab cov txiaj ntsig ntawm crude peptide ruaj khov.
• Cyclization: Me me oxidation nyob rau hauv cov kua theem, meej tsim ntawm 2-7 disulfide daim ntawv cog lus. Peb nruj me ntsis tswj tus nqi ntawm oxidizing tus neeg saib xyuas thiab pH, thiab lub cyclization efficiency yog ruaj khov ntawm ntau tshaj 95%, nrog rau cov ntsiab lus tsawg heev ntawm mismatched isomers.
• Purification: Multi-pab HPLC kev npaj: Rau kev tsim cov microsphere, peb ntxiv cov txheej txheem tshem tawm cov khoom seem ntawm qhov kawg ntawm kev ua kom huv los xyuas kom meej tias cov seem ntawm acetonitrile, TFA, thiab lwm yam. ua raws li ICH Q3C (tsawg dua lossis sib npaug rau 410ppm acetonitrile).
• Txias- ziab thiab pulverization: Tom qab khov- ziab, qhov loj me me ntawm cov hmoov yog tswj raws li qhov xav tau. Microsphere cov neeg siv khoom feem ntau xav tau qee qhov loj me me, peb tuaj yeem kho cov txheej txheem pulverization raws li qhov xav tau.

Cov txheej txheem validation cov ntaub ntawv qhia tau hais tias lub purity yog stabilized ntawm ntau tshaj 99.0% nrog heev overlapping impurity profiles nyob rau hauv successive batch.

2. Kev tswj kom zoo, npog cov hom phiaj tshwj xeeb rau cov qauv tsim microsphere
Txhua pawg ntawm Octreotide API raug tso tawm raws li cGMP cov kev cai, thiab cov khoom xeem suav nrog cov kev ntsuas dav dav thiab cov txiaj ntsig ntawm kev txaus siab rau kev npaj microsphere:

• Cov ntsiab lus: 95.0% -105.0% raws li tsis muaj dej thiab hnyav, raws li USP / EP.
• Purity: HPLC Ntau dua lossis sib npaug rau 99.0%, qhov tseeb batch feem ntau yog 99.2% -99.5%.
• Cov khoom muaj feem xyuam: ib qho impurity Tsawg dua lossis sib npaug li 0.15%, tag nrho impurity Tsawg dua lossis sib npaug li 1.0%.
• Cov impurities tseem ceeb: disulfide bond mismatch isomers, oxidized impurities (tryptophan, methionine?), peptides uas ploj lawm, dimers, D-Trp differential isomers. Octreotide tsis muaj Met, tab sis Trp yog yooj yim oxidized), peptides ploj, dimers, D-Trp txawv isomers, tag nrho nrog kev tswj thiab kom muaj nuj nqis.
• Cov kuab tshuaj seem: acetonitrile, TFA, methanol, thiab lwm yam raws li ICH Q3C.
• Moisture: Tsawg dua lossis sib npaug li 5.0%, tuaj yeem tswj tau ntawm qib qis (xws li Tsawg dua lossis sib npaug li 2.0%) ntawm qhov kev thov ntawm cov neeg siv khoom.
• Particle loj faib (ntawm kev thov): D90, D50, thiab lwm yam.
• Kev nyab xeeb ntsuas: endotoxin<0.25 EU/mg, microbial limit in accordance with the Pharmacopoeia.

Kev ruaj ntseg yog ntev -lub sij hawm thiab ceev, txhawb 24-36 lub hlis rov kuaj dua. Cov txheej txheem tshuaj ntsuam xyuas tau raug lees paub thiab ua raws li ICH Q2 thiab USP / EP.

3. Ua tiav cov ntaub ntawv thiab DMF ua ntaub ntawv
Octreotide muaj txoj hauv kev ua kom paub tab, thiab cov ntaub ntawv peb muab tuaj yeem siv ncaj qha rau ANDA lossis cov ntaub ntawv hauv tsev:

• Txheej txheem kev txhim kho daim ntawv qhia (nrog rau qhov tseem ceeb tsis, tshwj xeeb tshaj yog cyclization tej yam kev mob, residual kuab tshuaj tswj)
• Cov txheej txheem validation cov kev pab cuam thiab cov ntawv ceeb toom (ntau- cov ntaub ntawv batch) analytical method validation reports
• Cov ntaub ntawv ruaj ntseg (ntev-lub sijhawm, nrawm, cuam tshuam)
• Heterogeneous mass spectrometry report (nrog kev pom zoo)
• Cov ntaub ntawv corroboration (NMR, MS, IR) batch ntau lawm cov ntaub ntawv
• Ua ke nrog rau ntawm - kev tshuaj xyuas qhov chaw

Peb cov Octreotide API tau ua tiav FDA DMF cov ntaub ntawv, thiab tuaj yeem tso cai siv hauv Suav teb, Tebchaws Meskas thiab Europe tshaj tawm. Yog tias koj xav tau European CEP, peb kuj tuaj yeem koom tes nrog koj.

4. Cov saw hlau ruaj khov nrog cov ntaub ntawv tseem ceeb
Ntawm cov amino acids siv rau octreotide, muaj ntau yam khoom tshwj xeeb (Fmoc-D-Phe-OH, Fmoc-D-Trp(Boc)-OH, threoninol derivatives), uas muaj lub voj voog mus ntev. Peb tau ua ntau yam:

• Tsawg kawg yog ob tus neeg muag khoom tsim nyog rau cov ntaub ntawv tseem ceeb, kev tshawb xyuas lub Hoobkas tsis tu ncua.
• Tsim kom muaj kev ruaj ntseg cov khoom lag luam rau cov khoom siv nrog lub sijhawm ua khoom siv ntev.
• Ntau cov kab ntau lawm nrog kev teem caij sib luag.
• Kev koom tes hom: API kev muag khoom, kev tso cai DMF, thev naus laus zis hloov pauv, ntim khoom ntim.

General txhaj tshuaj ntau lawm:kev noj ncaj qha, zoo solubility, aseptic filling tsis muaj teeb meem.
Ntev -koom microsphere formulation kev txhim kho / ntau lawm:Peb optimize cov residual hnyav thiab noo noo tswj rau peb cov neeg siv khoom microsphere, thiab muab cov ntaub ntawv me me. Ib tus neeg siv khoom tau ua qhov kev sim ntsuas microsphere nrog peb cov khoom siv raw thiab cov ntaub ntawv tso tawm yog du.
General ntaub ntawv:Npaj rau ANDA lossis cov ntaub ntawv hauv tsev, xav tau ib pob API tag nrho. Peb muab DMF tso cai thiab cov ntaub ntawv pov thawj.
Kev ntsuas qhov sib xws:cov npe ntau yam los ua qhov kev ntsuam xyuas sib xws, peb muab nrog cov kev tshawb fawb thawj zaug zoo ib yam nrog API thiab impurity profile piv cov ntaub ntawv.
R & D thiab Pilot:Muab me me, ob peb grams mus rau kaum grams.

• Chaw tsim khoom 10 daim av, cGMP tus qauv, FDA, EMA, NMPA raws, ISO 9001: 2015 tau ntawv pov thawj.
• Synthesis cog: automated solid-phase synthesis, 100 kg peev
• Purification cog: Ntau pawg ntawm kev npaj HPLC nrog txhim kho elution rau cov kuab tshuaj residual
• Txias-rhiav ziab khaub ncaws: 30 square metres +, muaj khov kho- tshuab ziab khaub ncaws, tuaj yeem tswj tau qhov loj me
• Qhov chaw huv: ISO 7/8
• QC Lab: HPLC, UPLC, LC-MS, GC, Moisture meter
• Kev Tswjhwm Zoo: Kev Hloov Kho, Kev Tswj Xyuas Kev Sib Dev, CAPA, Kev Tshawb Fawb Txog Kev Lag Luam, Kev Tshuaj Xyuas Txhua Xyoo, FDA, EMA, NMPA Kev Tshawb Fawb Hauv Chaw.

Cov neeg siv khoom A, lub tuam txhab tshuaj hauv tsev, ntev - qhov project microsphere ntev: lawv tab tom tsim octreotide microspheres, thiab cov residual hnyav fluctuation ntawm raw khoom siv ua ntej yog loj, uas ua rau inconsistency ntawm microsphere curing batch rau batch. Raws li lawv cov kev xav tau, peb tswj cov acetonitrile residue hauv qab 200ppm (deb hauv qab tus qauv ICH) thiab cov dej noo hauv qab 2%. Lawv tau khiav peb qhov kev sim ntawm kev sim nrog peb cov ntaub ntawv raw, thiab qhov kev tso tawm nkhaus tau zoo ib yam, thiab tam sim no qhov project tau nkag mus rau kev kho mob ntau lawm.

Octreotide yog lub hauv paus tseem ceeb ntawm kev loj hlob inhibitor analogs, uas yog qhov xav tau zoo hauv kev ua lag luam, tshwj xeeb tshaj yog ntev - ua daim ntawv microsphere ntau npaum li cas yuav tsum muaj siab rau APIs. Peb tau sau ntau tshaj 10 xyoo ntawm kev paub nyob rau hauv cov khoom no, nrog rau mature technology, zoo impurity tswj, thiab optimized residual hnyav thiab noo noo tswj tshwj xeeb tshaj yog rau microsphere cov neeg muas zaub. Yog tias koj tab tom tsim cov qauv octreotide, txawm tias nws yog kev txhaj tshuaj dav dav lossis ntev - ua microspheres, thiab xav tau tus neeg xa khoom ruaj khov thiab ua raws API, txais tos nrog tham nrog peb.