Liraglutide ntsiav tshuajcuam tshuam cov metabolism los ntawm kev ua kom GLP-1 receptors thiab tswj cov cAMP PKA txoj hauv kev, xws li ua kom AMPK signaling los txhim kho lub zog metabolism thiab inhibit cell apoptosis. Nws tuaj yeem txhawb kev tsim cov tshuaj insulin thiab tso tawm, inhibit glucagon secretion, txhawb nqa beta cell proliferation thiab rov tsim dua tshiab, thiab inhibit beta cell apoptosis, yog li ua rau cov nyhuv hypoglycemic. Tsis tas li ntawd, Liraglutide tuaj yeem ncua lub plab zom mov, txo cov zaub mov noj, txo cov neeg mob hnyav, txhim kho cov ntshav lipid thiab tswj ntshav siab, thiab tseem muaj cov teebmeem neuroprotective ntawm paj hlwb thiab myocardial hlwb.
Khoom Description
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LiraglutideCOA
Liraglutide ntsiav tshuajyog GLP-1 receptor agonist, tshuaj npe hu ua Arg34 Lys26- (N - ε - ( -} Glu (N - -} hexadecanoyl)) - GLP-1 [7-37], nrog rau molecular formula ntawm molecular H 25 O4 ntawm C172 thiab molecular formula ntawm molecular H 26 O 24 O 2, 1 receptor agonist. 3751.20 Da muab faib ua ob pawg: solid-phase peptide synthesis (SPPS, chemical method) thiab genetic engineering recombinant expression (biological method).
Solid phase synthesis core txheej txheem
Cov khoom thauj khoom theem: 2-Chlorotriphenylmethyl chloride resin (2-CTC resin) yog qhov zoo dua, nrog kev hloov pauv ntawm 0.4-0.6 mmol / g, tus cwj pwm los ntawm qhov tsis muaj zog, yooj yim tawg, thiab kev tawm tsam tsawg kawg nkaus.
Tiv thaiv cov amino acids: siv N-terminal Fmoc tiv thaiv thiab sab saw acid rhiab tiv thaiv cov tswv yim:
Pa amino acids: Fmoc Ala OH, Fmoc Gly OH, Fmoc Thr (tBu) - OH, thiab lwm yam;
Cov amino acid hloov pauv tseem ceeb: Fmoc Lys (N -} ε - (N - - palmitoyl-L - - Glu (Boc))) - OH, ncaj qha nkag mus rau hauv cov roj fatty acid sab saw kom txo tau cov kev hloov pauv tom qab kev tawm tsam.
Khoom theem sib dhos ntawm polypeptide chains (31 amino acid coupling cycles)
Resin loading: Fmoc Gly OH tau ua ke nrog 2-CTC resin nyob rau hauv catalysis ntawm * * DIEA (diisopropylethylamine) * *, thiab reacted ntawm chav tsev kub rau 2 teev. Qhov kawg ntawm cov tshuaj tiv thaiv tau kuaj pom los ntawm txoj kev indene ketone, thiab cov chaw tsis muaj tshuaj tiv thaiv tau thaiv nrog methanol.
Fmoc tshem tawm: Ntxiv 20% piperidine/DMF tov, do hauv chav sov li 15 feeb, rov ua dua ob zaug, tshem tawm N-terminal Fmoc tiv thaiv pab pawg, thiab nthuav tawm cov amino pawg dawb.
Amino acid coupling: siv DIEA + TBTU condensation system (molar ratio 2: 1), tiv thaiv cov amino acids thiab resin amino pawg yog pub nyob rau hauv ib tug ratio ntawm 1.5-2.0: 1, DMF yog siv raws li hnyav, thiab cov tshuaj tiv thaiv yog nqa tawm nyob rau hauv chav tsev kub rau 100-140 feeb; Tom qab txhua kauj ruam txuas, ntxuav ua ke nrog DMF thiab DCM 6 zaug kom tshem tawm cov khoom tsis zoo.
Loop extension: Rov qab "deprotection coupling washing" voj voog raws li qhov sib lawv liag ntawm Liraglutide (Nws Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Tyr Leu Glu Gly Gln Ala Ala Lys (palmitoyl Glu) Glu Phe Ile Trp Leu Val Arg Gly Arg sequence.
Cracking thiab sab chain deprotection
Cracking kua system: TFA: EDT: PhSMe: TIS: H ₂ O=85: 5: 4: 2: 4 (Volume ratio), TFA ua tus neeg sawv cev tseem ceeb, EDT thiab PhSMe ua cov dawb radical scavengers, inhibiting oxidation ntawm tryptophan thiab tyrosine.
Cracking tej yam kev mob: Sib tov peptide resin thiab lysis tsis nyob rau hauv ib tug ratio ntawm 1g: 10mL, do nyob rau hauv chav tsev kub rau 2.5 teev; Lim cov resin, ntxiv ua ntej txias anhydrous ether (1:10 ntim piv) rau cov lim, thiab cia nws sawv ntsug rau 2 teev los daws cov peptide crude.
Crude peptide sau: Centrifuge (4000 rpm, 10 feeb) tshem tawm cov supernatant, ntxuav lub precipitate nrog ether peb zaug, nqus cov khoom deliaglutide crude, nrog ib tug purity ntawm txog 75-85%.
Purification thiab khov - ziab ntawm cov khoom siv raw
Chromatographic tej yam kev mob: C18 thim rov qab theem kab (particle loj 10 μ m, pore loj 120 Å), mobile theem A: 0.1% TFA aqueous tov, B: 0.1% TFA acetonitrile tov; Gradient elution (5% → 60% B, 30 feeb), txaus tus nqi 80-100 mL / min, nrhiav wavelength 220 nm.
Step by step collection: Extract the main peak component (purity>98%), tshem tawm pem hauv ntej thiab nram qab peaks uas muaj impurities; Muab cov khoom xyaw ntshiab thiab ua kom pom tseeb hauv kev txo qis (35 degree, nqus tsev kawm ntawv 0.08 MPa) kom tshem tawm acetonitrile.
Desalination thiab Freeze Drying
Desalination: Ultrafiltration membrane (molecular hnyav txiav tawm ntawm 3000 Da) yog siv, thiab cov dej ntshiab yog dialyzed peb zaug kom tshem tawm TFA thiab inorganic ntsev; Concentrate rau ib tug concentration ntawm 1-3 mg / mL thiab lim finely nrog ib tug 0.45 μ m membrane.
Freeze drying txheej txheem:
Ua ntej khov: Ua ntej khov ntawm -45℃rau 3 teev los tsim cov dej khov sib xws;
Sublimation ziab: Gradient cua sov (-45℃→ -20℃→ 0 degree), nqus tsev kawm ntawv ntawm 15 Pa, khaws cia rau 15 teev, tshem tawm cov dej dawb;
Kev tshuaj xyuas kom qhuav: Khaws ntawm 25℃rau 12 teev, tswj cov dej noo<1.0%;
Endpoint: Obtain white loose Liraglutide API powder with purity>99.0% thiab ib qho impurity<0.5%.
Cov ntaub ntawv pov thawj:
- Ib qho khoom siv -theem synthesis txoj kev ntawm liraglutide (CN107033112B);
- Txoj kev npaj liraglutide los ntawm cov khoom sib xyaw ua ke - kua (CN105111303B);
- Technical Specification for Solid Phase Synthesis of Peptide Drugs (2022 Edition).
Raws li tus kab mob metabolic ntev, lub hauv paus tseem ceeb ntawm kev noj qab haus huv ntev - kev tswj hwm kev rog yog nyob rau hauv siab rov muaj dua thiab ntev - ua raws li lub sijhawm.Liraglutide ntsiav tshuaj, raws li daim ntawv tseem ceeb ntawm GLP-1 receptor agonist (GLP-1 RA), tau hloov zuj zus los ua kom tau txais kev noj qab haus huv mus sij hawm ntev thiab kev txhim kho metabolic hauv cov neeg rog dhau los ntawm peb lub tswv yim ntawm kev noj qab haus huv hauv nruab nrab, kev mob plab hnyuv, thiab kho metabolic.
Tus nqi rov qab yog qhov siab heev: tom qab kev cuam tshuam kev ua neej yooj yim, qhov hnyav rov qab nyob rau hauv ib xyoos tuaj yeem ncav cuag 30% txog 50%. Cov tshuaj poob phaus ib txwm muaj kev ua siab ntev thiab tsis muaj txiaj ntsig, ua rau nws nyuaj rau kev ua txhaum ntawm "qhov hnyav rov qab" lub voj voog.
Shortboard ntawm kev ua raws li: Txawm hais tias cov ntawv txhaj tshuaj (xws li 3.0 mg subcutaneous txhaj) muaj cov teebmeem kev kho mob, kev txhaj tshuaj txhua hnub / txhua lub limtiam ua rau ntev -kev ua raws sijhawm tsawg dua 40%, dhau los ua qhov teeb meem tseem ceeb rau lub sijhawm ntev - tswj.
Metabolic comorbidity superposition: Cov neeg rog rog feem ntau muaj cov tshuaj insulin tsis kam, kub siab, thiab dyslipidemia, yuav tsum tau siv ntau yam -cov tshuaj tswj hwm es tsis yog qhov hnyav xwb.
Kev txhim kho thiab kho qhov chaw ntawm qhov ncauj liraglutide npaj
Formulation Evolution: Liraglutide qhov ncauj formulation lov los ntawm lub bottleneck ntawm peptide qhov ncauj nqus los ntawm technologies xws li nanomicelles thiab enteric carriers, thiab nws bioavailability yog 4-13 lub sij hawm ntau dua li unmodified formulations, ua tiav ib zaug ib hnub twg kev tswj qhov ncauj.
Qhov chaw tseem ceeb: Raws li thawj - kab kev xaiv tshuaj rau ntev - lub sij hawm tswj qhov hnyav ntawm qhov hnyav, nws muab cov txiaj ntsig zoo ntawm kev poob phaus, txhim kho cov metabolism, thiab txhim kho kev ua raws, ua raws li qhov sib txawv ntawm cov tshuaj txhaj tshuaj thiab ua tau raws li qhov ntev - tswj cov kev xav tau ntawm kev rog ntev.
Cov ntaub ntawv pov thawj:
- Cov kws tshaj lij pom zoo rau kev soj ntsuam daim ntawv thov ntawm enteropancreatin raws li cov tshuaj poob phaus (2025 version) Chinese Journal of diabetes, 2025
- Quinapanta Castro, et al. Kho: Kev ua tau zoo ntawm Liraglutide rau Kev poob phaus hauv Kev rog rog thiab rog tsis yog- cov neeg laus mob ntshav qab zib. Cureus, Peb 2025.
- Lilly lub qhov ncauj GLP-1, orforglipron, ua kom pom kev poob phaus. NEJ, 2025.
- National Medical Products Administration Drug Review Center. Cov Lus Qhia rau Kev Tshawb Fawb Kev Tsim Kho ntawm Liraglutide rau Kev Tswj Xyuas Qhov hnyav, 2022
Pharmacokinetics thiab mechanism ntawm kev txiav txim ntawm qhov ncauj liraglutide npaj
Cov yam ntxwv ntawm cov tshuaj pharmacokinetic: qhov ncauj nqus thiab ua haujlwm ntev -
| Yam ntxwv parameter | Cov ntaub ntawv tshwj xeeb | Clinical tseem ceeb |
| Bioavailability | Optimized formula nce mus txog 5% mus rau 10% (4-13 npaug ntau dua li cov ntawv tsis hloov pauv) | Ua kom muaj txiaj ntsig zoo ntawm cov tshuaj ntshav rau kev tswj hwm qhov ncauj thiab tsis txhob txhaj tshuaj tiv thaiv |
| Peak sij hawm | Peak concentration (Cmax) mus txog 2-4 teev tom qab noj qhov ncauj | Synchronize nrog postprandial qab los noj mov ncov, yog suppress noj impulse |
| Ib nrab -lub neej | Kwv yees li 12-18 teev, muab tshuaj ib zaug ib hnub kom tswj tau lub xeev khov kho rau 24 teev | Ua kom tiav - cov kev cai ncua sij hawm, txo kev siv tshuaj ntau zaus, thiab txhim kho kev ua raws cai |
| Qhov chaw nqus | Feem ntau absorbed los ntawm sab sauv ntawm cov hnyuv, thiab tiv thaiv los ntawm enteric cab rau molecular degradation | Tsis txhob siv lub plab acid thiab enzymatic hydrolysis los xyuas kom meej cov tshuaj ua haujlwm |
| Txoj kev metabolic | Feem ntau degraded los ntawm proteases, nrog ib tug me me npaum li cas los ntawm lub raum | Cov neeg mob uas muaj lub siab thiab lub raum tsis ua haujlwm yuav tsum tau kho cov tshuaj, thiab kev nyab xeeb yog tswj tau |
Triple Core Mechanism ntawm Long-term Weight Management
1. Kev tswj hwm lub paj hlwb hauv nruab nrab: Txo kev qab los ntawm cov hauv paus hniav
Qhov ncaujLiraglutide ntsiav tshuajnkag mus rau hauv cov ntshav- hlwb teeb meem, qhib GLP-1 receptors nyob rau hauv hypothalamic arcuate nucleus (ARC), upregulates opioid peptide melanocortinogen (POMC) (qab los noj mov), thiab downregulates neuropeptide Y (NPY) / agouti txuam nrog protein (AgRP) (qab los noj mov).
Kev ua kom lub sij hawm ntev tuaj yeem hloov kho qhov rhiab heev ntawm qhov chaw qab los noj mov, txo qis qhov qab los noj mov, txo qis "kev noj mov" tus cwj pwm, thiab ua tiav qhov tsis zoo ntawm qhov ntev - lub zog kom tsawg.
2. Kev tswj lub plab zom mov: ncua kev tshem tawm thiab ua kom satiety
Inhibit gastric emptying npaum li cas los ntawm 30% ~ 50%, ncua lub sij hawm nyob rau hauv cov zaub mov nyob rau hauv lub plab hnyuv ib ntsuj av, txhim khu lub stimulation ntawm gastric phab ntsa nro receptors, thiab ua kom satiety.
Ua rau me me plab hnyuv peristalsis, txhawb kev nqus cov ntsiab lus, txo ghrelin secretion, thiab ntev lub sij hawm satiety (los ntawm 2-3 teev mus rau 6-8 teev).
3. Metabolic remodeling: txhim kho insulin tsis kam thiab rog rog
Ua kom cov nqaij peripheral GLP-1 receptors, txhim kho insulin rhiab heev (txhim kho cov ntaub so ntswg peripheral insulin tsis kam los ntawm 20% ~ 30%), thiab txo cov rog.
Txhawb lipolysis ntawm cov ntaub so ntswg adipose, inhibit fatty synthesis, txo cov roj visceral cov ntsiab lus (visceral rog txo ntawm 15% ~ 25%), thiab txhim kho cov kab mob metabolic.
Inhibit glucagon secretion, txo cov ntshav qabzib hauv siab, ua haujlwm kom poob phaus, thiab txo qhov kev pheej hmoo ntawm metabolic comorbidities.
Cov ntaub ntawv pov thawj:
- Liraglutide activates lub hlwb tseem ceeb circuits los ua kom poob phaus hauv kev rog. Xov xwm-Kev kho mob, 2024.
- Qhov ncauj liraglutide nanomicelle formulation conferring txo cov insulin{0}}kuj. Pub Med, 2025.
- Cov teebmeem ntawm Liraglutide ntawm Kev Ua Haujlwm ntawm plab hnyuv thiab qhov hnyav hauv kev rog. PIB, 2025.
- Suav Journal of Endocrinology thiab Metabolism Cov txheej txheem metabolic ntawm GLP-1 receptor agonists hauv cov tib neeg rog rog, 2024
Cim npe nrov: Tuam Tshoj liraglutide ntsiav tshuaj manufacturers, lwm tus neeg
