Tirzepatide Oral ntsiav tshuaj is an orally administered GIP/GLP-1 receptor dual agonist, belonging to the class of intestinal insulinotropic drugs. Its active ingredient, Tirzepatide, simulates the effects of two naturally occurring intestinal insulinotropic hormones in the human body - glucose dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (GLP-1) - while activating GIP receptors and GLP-1 receptors, exerting synergistic physiological effects. GLP-1 plays a leading role in blood glucose regulation and weight control, while the role of GIP is relatively limited, and even may fail in patients with type 2 diabetes. However, recent studies have found that the combined activation of GIP and GLP-1 can produce a synergistic effect of "1+1>2 ", txhim kho insulin secretion, inhibiting glucagon tso tawm, thiab txhim kho insulin rhiab heev, thaum tswj kev noj qab haus huv los ntawm lub hauv nruab nrab lub paj hlwb thiab txo qis zog.
Peb tsis tsuas yog muab cov hmoov ntshiab thiab cov tshuaj ntsiav, tab sis kuj muaj lwm cov ntaub ntawv noj. Yog tias tsim nyog, thov hu rau peb pab neeg muag khoom.
Peb cov khoom
Tirzepatide COA
Tirzepatide, raws li lub ntiaj teb thawj dual GIP / GLP-1 receptor agonist, tau tawm sai sai los ua cov tshuaj siv hauv kev kho cov kab mob metabolic txij li nws cov tshuaj txhaj tshuaj tau pom zoo los ntawm US FDA xyoo 2022. Los ntawm kev ua kom cov piam thaj ib txhij -dependent insulinotropic GIP-1 peptide thiab insulinotropic polypeptide. (GLP-1) receptors, nws ua tiav cov qabzib muaj zog, txo qhov hnyav, thiab kev txhim kho metabolic. Nrog kev ua haujlwm thev naus laus zis,Tirzepatide Oral ntsiav tshuaj(Qhov ncauj Rapid Dissolve Tablets, RDT) tau nkag mus rau hauv kev tshawb fawb thiab kev loj hlob pipeline raws li ib tug tsis yog - txhaj tshuaj. Txawm hais tias nws tseem tsis tau raug pom zoo los ntawm FDA, nws cov txheej txheem tsim khoom, tshuaj siv tshuaj, thiab kev kho mob muaj peev xwm tau txais kev saib xyuas thoob plaws.
Molecular tsim: Lub leap los ntawm txhaj rau qhov ncauj npaj
Cov tshuaj txhaj tshuaj ntawm Tirzepatide yog cov tshuaj polypeptide uas muaj 39 amino acids. Nws cov qauv tseem ceeb suav nrog:
GIP receptor agonist domain: mimics natural GIP hormone los txhim kho insulin secretion;
GLP-1 receptor agonist domain: prolongs gastric emptying lub sij hawm thiab suppresses qab los noj mov;
Fatty acid side chain: Los ntawm kev sib txuas eicosanedioic acid nrog glutamic acid thiab polyethylene glycol units los tsim ib tug ntev - chain modification, binding peev xwm ntawm cov tshuaj rau plasma albumin yog ho txhim khu kev qha, ncua ib nrab - lub neej mus rau 5 hnub, ua rau ib zaug - kev tswj hwm txhua lub lim tiam.
Cov kev sib tw thiab kev sib tw hauv qhov ncauj Formulations
Cov tshuaj peptide ntawm qhov ncauj ntsib ob qho teeb meem tseem ceeb. Ua ntej, kev zom zaub mov hauv plab, raws li gastric acid thiab digestive enzymes (xws li pepsin thiab trypsin) tuaj yeem ua rau cov qauv peptide tau yooj yim puas; Ntxiv mus, nws muaj tsawg permeability, siab molecular hnyav ntawm peptides, thiab muaj zog hydrophilicity, ua rau nws nyuaj rau nkag mus rau lub plab hnyuv mucosal barrier. Kom kov yeej cov teeb meem no,Tirzepatide qhov ncauj ntsiav tshuajsiv cov thev naus laus zis sai sai los npaj cov ntsiav tshuaj sublingual instant ntsiav tshuaj (RDT) los ntawm microcrystallization, nanomaterialization, lossis khov- cov txheej txheem ziab, hla thawj qhov tshwm sim hauv plab hnyuv thiab ncaj qha absorbed los ntawm sublingual mucosa; Penetration enhancers tuaj yeem muab ntxiv nrog cov kua tsib ntsev (xws li sodium deoxycholate), fatty acid esters (xws li glycerol caprylate), los yog polymers (xws li chitosan) kom qhib kev sib tshuam ntawm cov hlwb thiab txhawb cov tshuaj transmembrane thauj; Enzyme inhibitors yog siv ua ke nrog protease inhibitors (xws li aprotinin) lossis pH regulators (xws li sodium bicarbonate) los tiv thaiv cov tshuaj los ntawm enzymatic hydrolysis.
Kev npaj ntawm qhov ncauj tuaj yeem cuam tshuam zoo - kho ntawm Tirzepatide molecule, xws li:
Shortening sab saw ntev: Txo cov pa roj carbon atoms nyob rau hauv fatty acid sab saw, txo qhov hnyav molecular, thiab txhim kho permeability;
Taw qhia D-amino acids: hloov qee cov L-amino acids los txhim kho kev tiv thaiv enzymatic hydrolysis;
Cyclization modification: Tsim cov qauv cyclic los ntawm disulfide bonds los yog tshuaj crosslinking kom stabilize cov molecular conformation.
Formulation development: Txoj kev txhais lus los ntawm chav kuaj mus rau kev kho mob
Cov txheej txheem tseem ceeb ntawm Tirzepatide qhov ncauj ntsiav tshuaj suav nrog:
Cov khoom xyaw nquag: Tirzepatide (Cov koob tshuaj ntau npaum li cas yuav yog 2.5mg-15mg, zoo ib yam li cov tshuaj txhaj tshuaj);
Disintegrant: croscarmellose sodium (CCNa), crospovidone (PVPP), lossis qis- hloov hydroxypropyl cellulose (L-HPC), ua kom cov ntsiav tshuaj tawg sai sai hauv qab tus nplaig;
Penetration enhancers: xws li sodium deoxycholate (5% -10%), caprylic acid glyceride (2% -5%);
Stabilizer: mannitol, sucrose, lossis trehalose, los tiv thaiv cov tshuaj noo noo los yog crystallization;
Lubricant: Magnesium stearate los yog silicon dioxide, los txhim kho cov flowability ntawm cov ntsiav tshuaj compressed;
Flavoring neeg sawv cev: menthol, aspartame, los npog qhov iab saj ntawm cov tshuaj.
Txheej Txheem Flow
Preprocessing theem
Kev sib tsoo ntawm cov khoom siv tshuaj nquag: Tirzepatide cov khoom siv tshuaj nquag yog crushed los ntawm airflow los yog ntub sib tsoo kom tau txais cov hmoov micronized nrog cov particle loj D90 < 50 μm;
Kev sib xyaw: Sib tov cov tshuaj micronized hmoov nrog disintegrant thiab stabilizer nyob rau hauv V- hom tov khoom raws li qhov piv txwv rau 15-30 feeb;
Granulation: ntub granulation los yog fluidized txaj granulation yog ua hauj lwm, nrog rau ntxiv ntawm ib tug binder (xws li povidone K30 tov) los tsim ib yam khoom hais.
Tableting theem
Kev ziab: ziab cov khoom ntub dej hauv lub tshuab ziab khaub ncaws ntawm 40-60℃kom txog thaum cov dej noo tsawg dua 3%;
Tag Nrho granulation: Tau txais cov khoom me me los ntawm kev tshuaj xyuas los ntawm kev co granulator;
Kev sib xyaw tseem ceeb: Ntxiv cov roj nplua nyeem, kev nkag mus rau kev txhim kho, thiab tus neeg sawv cev flavoring, thiab sib tov rau 10-20 feeb;
Tabletting: Siv cov ntsiav tshuaj teb xovxwm, tswj cov ntsiav tshuaj qhov sib txawv kom tsawg dua 5%, thiab teem lub hardness rau 30-50N, xyuas kom meej tias cov ntsiav tshuaj disintegrate tsis pub dhau 30 vib nas this hauv qab tus nplaig.
Txheej thiab ntim
Txheej: Siv cov txheej txheem zaj duab xis, txau hydroxypropyl methylcellulose (HPMC) los yog polyvinyl cawv (PVA) txheej tov los tsim ib tug du nto, txo kev sib txhuam ntawm cov tshuaj thiab qhov ncauj mucosa;
Ntim: Siv aluminium- ntim cov hnab yas ntim lossis siab -cov hnab polyethylene ntom ntom, nrog cov desiccant sab hauv kom cov ntsiav tshuaj ruaj khov.
Cov txheej txheem ntau lawm: scaling li los ntawm chav kuaj ntsuas mus rau industrial ntau lawm
Laboratory nplai (1-10kg / batch)
Khoom siv: Me V- hom tov khoom (5L), ntub dej granulation tshuab (10L), fluidized txaj tshuab (20L), cov ntsiav tshuaj teb xovxwm (16 chaw nres tsheb)
Cov yam ntxwv tseem ceeb: sib tov lub sij hawm, granulation kua ntws tus nqi, ziab kub thiab lub sij hawm, ntsiav tshuaj nias ceev thiab siab;
Kev Tswjhwm Zoo: Cov khoom loj me me yog kuaj pom los ntawm laser diffraction, ntsiav tshuaj hardness yog ntsuas siv lub hardness tester, thiab lub sij hawm disintegration yog xyuas los ntawm ib tug disintegrator.
Pilot nplai (10-100kg / batch)
Cov khoom siv hloov kho dua tshiab: nruab nrab- qhov loj me (50L), fluidized txaj granulator (100L), siab- ceev ceev cov ntsiav tshuaj xovxwm (32 chaw nres tsheb);
Cov txheej txheem optimization: txiav txim siab cov txheej txheem zoo tshaj plaws los ntawm kev sim tsim (DOE), xws li cov concentration ntawm granulating tov, tshuaj tsuag siab, thiab cov ntsiav tshuaj nias ceev;
Kev tshawb fawb txog kev ruaj ntseg: Ua cov kev ntsuam xyuas nrawm (40℃/ 75% RH) thiab ntev - cov kev ntsuam xyuas lub sij hawm (25℃/ 60% RH) los soj ntsuam cov kev hloov pauv hauv cov ntsiav tshuaj cov ntsiab lus, cov khoom muaj feem xyuam, thiab kev sib cais nyob rau lub sijhawm 6 lub hlis.
Industrial production (>100kg / batch)
Nruam ntau lawm: txais kev sib xyaw ua ke, granulation, ziab, thiab ntsiav tshuaj xovxwm tshuab los txhim kho kev tsim khoom;
Kev tswj tsis siv neeg: Kev saib xyuas lub sijhawm ntawm qhov tseem ceeb xws li qhov kub thiab txias, av noo, thiab siab los ntawm kev tswj hwm kev faib tawm (DCS) kom paub meej cov txheej txheem rov ua dua tshiab;
Kev kuaj xyuas tu: Txais cov txheej txheem kev kuaj xyuas kev ntxuav tu (xws li kev kuaj TOC) txhawm rau tiv thaiv kev sib kis;
Ntim kab kev koom ua ke: ua tiav automation ntawm blister ntim lossis bottling, txo cov kev ua haujlwm yuam kev.
Kev Tswjhwm Zoo: nruj saib xyuas los ntawm raw khoom mus rau cov khoom tiav
Kev tswj zoo ntawm cov khoom siv raw
Kev txheeb xyuas: Kev ua haujlwm siab ua kua chromatography-mass spectrometry (HPLC-MS) tau siv los lees paub qhov hnyav thiab cov qauv;
Purity: Txiav txim siab cov ntsiab lus ntawm cov khoom muaj feem xyuam (xws li peptides ploj lawm thiab oxidized peptides) los ntawm HPLC, nrog rau tag nrho cov impurities<1.0%;
Kev txiav txim siab txog cov ntsiab lus: Siv ultraviolet spectrophotometry (UV) lossis HPLC los txiav txim siab cov ntsiab lus ntawm Tirzepatide, xws li 95.0% txog 105.0%;
Cov ntsiab lus noo noo: txiav txim siab los ntawm Karl Fischer txoj kev,<5.0%;
Cov hlau hnyav: Atomic absorption spectroscopy (AAS) tau siv los kuaj xyuas cov hlau hnyav xws li txhuas, arsenic, thiab mercury, tag nrho cov uas yog<10ppm.
Kev tswj kom zoo ntawm cov formulations
Cov tsos thiab yam ntxwv
Ntsiav tshuaj zoo li: dawb los yog tawm dawb, du nto, tsis muaj kab nrib pleb, ploj lawm ces kaum los yog txawv teb chaws khoom;
Disintegration lub sij hawm txwv: Sublingual ntsiav tshuaj yuav tsum disintegrate kiag li nyob rau hauv 30 vib nas this thiab tsis muaj seem seem;
Hardness: 30-50N, kom ntseeg tau tias nws tsis yooj yim tawg thaum thauj thiab khaws cia.
Cov ntsiab lus sib xws
Txoj kev ntsuas: Siv 10 ntsiav tshuaj thiab ntsuas cov ntsiab lus sib cais. Xam qhov txheeb ze tus qauv sib txawv (RSD), uas yuav tsum tsawg dua 5.0%;
Dissolution tus nqi: Siv txoj kev paddle (50rpm, 900mL pH 6.8 phosphate buffer), tus nqi tawg yuav tsum ntau dua lossis sib npaug li 80% hauv 15 feeb.
Cov khoom muaj feem xyuam
Txoj kev txiav txim siab: HPLC txoj kev, mobile theem yog acetonitrile dej (muaj 0.1% trifluoroacetic acid), gradient elution;
Txwv: Tus kheej impurities<0.5%, total impurities<1.5%.
Microbial txwv
Tag nrho cov kab mob aerobic suav:<1000 CFU/g;
Tag nrho cov pwm thiab cov poov xab:<100 CFU/g;
Escherichia coli: Tsis pom.
Daim ntawv thov kev cia siab rau kev kho mob: los ntawm lwm txoj kev txhaj tshuaj mus rau kev nthuav qhia
Advantage Analysis
Kev ua raws li tus neeg mob: cov ntsiav tshuaj ntawm qhov ncauj tshem tawm kev ntshai, tshwj xeeb tshaj yog rau cov menyuam yaus, cov neeg laus, thiab cov neeg mob uas muaj koob phobia;
Kev siv tshuaj yooj yim: Tsis xav tau lub tub yees cia (qee cov ntawv sau tuaj yeem khaws cia hauv chav sov), yooj yim nqa thiab mus ncig;
Tus nqi ua tau zoo: Yog tias tsim los ntawm qhov loj, tus nqi ntawm cov tshuaj yuav qis dua li ntawm cov ntawv txhaj tshuaj, txo qis kev lag luam rau cov neeg mob.
Muaj peev xwm sib tw
Bioaccumulation: Lub bioavailability ntawm sublingual absorption yuav qis dua li ntawm daim ntawv txhaj tshuaj (kwv yees li 80% bioavailability ntawm daim ntawv txhaj tshuaj), thiab yuav tsum tau hloov ntau npaum li cas los yog txheej txheem optimization yuav tsum tau ua kom muaj kev ua tau zoo;
Kev sib txawv ntawm tus kheej: Cov mob ntawm qhov ncauj mucosa (xws li dryness thiab o) tuaj yeem cuam tshuam rau kev nqus tshuaj thiab yuav tsum tau siv tshuaj kho tus kheej;
Kev pom zoo raws li txoj cai: Kev tshuaj xyuas nruj los ntawm FDA lossis EMA yog xav tau, nrog rau cov tshuaj pharmacokinetic txaus (PK), pharmacodynamic (PD), thiab cov ntaub ntawv kev nyab xeeb muab.
Kev nthuav qhia
Ua ntej ntshav qab zib: kev cuam tshuam ntxov tuaj yeem ncua kev nce qib ntawm ntshav qab zib hom 2;
Tsis haus dej cawv steatohepatitis (NASH): Kho daim siab mob thiab fibrosis los ntawm kev txo qhov hnyav thiab txhim kho cov ntsuas metabolic;
Kab mob plawv: txo cov ntshav siab, txhim kho cov ntshav lipids, thiab txo cov kev pheej hmoo ntawm cov hlab plawv;
Polycystic zes qe menyuam syndrome (PCOS): tswj cov tshuaj insulin thiab qib tshuaj hormones, txhim kho kev ua me nyuam.
Cim npe nrov: Tuam Tshoj tirzepatide qhov ncauj ntsiav tshuaj manufacturers, lwm tus neeg
