Izinto eziphakathi ziwuhlobo olubaluleke kakhulu lwemikhiqizo yamakhemikhali emihle. Empeleni, ziwuhlobo “lwemikhiqizo eqediwe kancane”, esetshenziswa kabanzi ekuhlanganiseni imithi, izibulala-zinambuzane, izimbozo, udayi nezinongo.

Kwezokwelapha, ama-intermediate asetshenziswa ukukhiqiza ama-API.

Ngakho-ke iyini imboni eyinhloko yabaxhumanisi bemithi?

01

Lokhu okubizwa ngokuthi ama-pharmaceutical intermediates empeleni kungenye yezinto zokusetshenziswa zamakhemikhali noma imikhiqizo yamakhemikhali esetshenziswa enqubweni yokwenziwa kwezidakamizwa.
Ikhemikhali, engadingi ilayisensi yokukhiqiza izidakamizwa, ingakhiqizwa esitshalweni samakhemikhali esivamile futhi, uma ifinyelela amazinga athile, ingasetshenziswa ekuhlanganiseni izidakamizwa.

Isithombe

Njengamanje, izinhlobo ezithembisayo kakhulu zemithi ephakathi yilezi ezilandelayo:

Izixhumi ze-Nucleoside.
Lolu hlobo lokwenziwa kwemithi yokulwa nengculazi oluphakathi nendawo luyi-zidovudine, evela e-United States Glaxo.
I-Wellcome ne-Bristol-Myers Squibb baphumelele.

Izifo zenhliziyo.
Isibonelo, ama-sartans okwenziwa asetshenziswa kabanzi ekwelapheni umfutho wegazi ophakeme ngenxa yomphumela wawo ophelele wokulwa nomfutho wegazi ophezulu, imiphumela emibi embalwa, ukusebenza kahle isikhathi eside (ukulawulwa okuzinzile komfutho wegazi amahora angama-24) kanye nekhono lokusetshenziswa kanye namanye ama-sartans.
Ngokwezibalo, ngo-2015, isidingo somhlaba wonke sezinto ezisebenzayo zemithi ye-sartan (i-losartan potassium, i-olmesartan, i-valsartan, i-irbesartan, i-telmisartan, i-candesartan) safinyelela kumathani angu-3,300.
Isamba sentengiso sasingu-$21.063 billion.

Izithako eziphakathi ezifakwe i-fluorine.
Imithi efakwe i-fluorinated eyenziwe ngezinto ezinjalo ithuthuke ngokushesha eminyakeni yamuva nje ngenxa yokusebenza kwayo okuhle kakhulu. Ngo-1970, yi-2% kuphela yemithi efakwe i-fluorinated eyayisemakethe; ngo-2013, yi-25% yemithi efakwe i-fluorinated eyayisemakethe.
Imikhiqizo emele efana nemithi yokulwa nokutheleleka nge-fluoroquinolone, i-antidepressant fluoxetine kanye ne-antifungal fluconazole inengxenye enkulu ekusetshenzisweni kwezokwelapha, phakathi kwayo imithi yokulwa nokutheleleka nge-fluoroquinolone ithatha cishe u-15% wesabelo semakethe yomhlaba wonke semithi yokulwa nokutheleleka.
Ngaphezu kwalokho, i-trifluoroethanol iyinto ebalulekile ekwakhiweni kwemithi yokubulala izinzwa, kuyilapho i-trifluoromethylaniline iyinto ebalulekile ekwakhiweni kwemithi yokulwa nomalaleveva, imithi yokulwa nokuvuvukala kanye nemithi yokunciphisa ubuhlungu, imithi yokulwa nendlala kanye nemithi yokunciphisa ukucindezeleka, futhi amathuba emakethe abanzi kakhulu.

Ama-intermediate e-Heterocyclic.
Njengoba i-pyridine ne-piperazine zimelela, isetshenziswa kakhulu ekwakhiweni kwemithi yokulwa nezilonda, imithi eminingi yesisu, imithi yokulwa nokuvuvukala kanye nemithi yokulwa nokutheleleka, imithi yokulwa nomfutho wegazi ophakeme esebenza kahle kakhulu kanye nemithi emisha yokulwa nomdlavuza webele i-letrozole.

02

Izinkampani zokwelapha ezihlanganisa imithi ziyisixhumanisi esibalulekile ochungechungeni lwezimboni zemithi.

Isithombe

Phezulu kukhona izinto eziyisisekelo zamakhemikhali, eziningi zazo eziyimikhiqizo ye-petrochemical, njenge-acetylene, i-ethylene, i-propylene, i-butene ne-butadiene, i-toluene ne-xylene.

Izakhi zemithi zihlukaniswe zibe yizakhi zemithi eziyinhloko kanye nezakhi zemithi ezithuthukisiwe.
Phakathi kwabo, abahlinzeki abaphakathi abayinhloko bangahlinzeka kuphela ngokukhiqiza okulula okuphakathi futhi baphambili ochungechungeni lwezimboni abanengcindezi enkulu yokuncintisana kanye nengcindezi yentengo. Ngakho-ke, ukuguquguquka kwentengo yezinto zokusetshenziswa zamakhemikhali eziyisisekelo kunomthelela omkhulu kubo.

Ngakolunye uhlangothi, abahlinzeki abaphakathi abathuthukile abanawo nje amandla amakhulu okuxoxisana ngabahlinzeki abayinhloko, kodwa okubaluleke kakhulu, ngoba benza ukukhiqizwa kwabaphakathi abathuthukile abanokuqukethwe okuphezulu kobuchwepheshe futhi bagcina ukuxhumana okuseduze nezinkampani zamazwe ngamazwe, abathinteki kakhulu ekushintsheni kwentengo yezinto zokusetshenziswa.

Izindawo eziphakathi nendawo zingaphansi kwemboni yamakhemikhali emithi.
Abakhiqizi bezinkampani ezisebenza ngemithi bahlanganisa izinkampani ezisebenza ngemithi noma ama-API aluhlaza, bese bethengisa imikhiqizo ngendlela yemikhiqizo yamakhemikhali ezinkampanini zemithi, ezizihlunga bese ziyithengisa njengemithi.

Izinkampani ezihlanganisa imithi zihlanganisa imikhiqizo ejwayelekile kanye nemikhiqizo eyenziwe ngokwezifiso. Ngokwezigaba ezahlukene zesevisi yokuthumela ngaphandle, amamodeli ebhizinisi enziwe ngokwezifiso ezinkampani ezihlanganisa imithi ngokuvamile angahlukaniswa nge-CRO (ucwaningo lwenkontileka kanye nokuthuthukiswa kokukhipha ngaphandle) kanye ne-CMO (ukukhishwa ngaphandle kokukhiqiza inkontileka).

Esikhathini esidlule, imodi yokudlulisela imisebenzi yebhizinisi le-CMO yayisetshenziswa kakhulu kuma-medicine intermediates.
Ngaphansi kwemodeli ye-CMO, izinkampani zemithi zithumela umkhiqizo kwabanye ozakwethu.
Ngakho-ke, uchungechunge lwebhizinisi luvame ukuqala ngezinto zokusetshenziswa ezikhethekile zemithi.
Izinkampani zezimboni zidinga ukuthenga izinto eziyisisekelo zamakhemikhali bese zihlela futhi zicubungule zibe izinto ezikhethekile zokwenziwa kwemithi, bese zicubungulwa kabusha zibe izinto zokuqala ze-API, ama-intermediate e-cGMP, ama-API kanye namalungiselelo.

Kodwa, njengoba izinkampani zemithi zidinga ukulawula izindleko kanye nokusebenza kahle, izinsizakalo ezilula zokuthumela ngaphandle komkhiqizo azikwazanga ukuhlangabezana nesidingo sebhizinisi, imodi ye-CDMO (ucwaningo lokukhiqiza kanye nokuthumela ngaphandle kokuthuthukiswa) ivela ngesikhathi esibalulekile, i-CDMO idinga ukwenza ngokwezifiso amabhizinisi okukhiqiza ukuze ahlanganyele kumakhasimende enkambisweni yocwaningo kanye nokuthuthukiswa, ukuhlinzeka ngokuthuthukiswa kwenqubo noma ukwenza ngcono, ukuqaphela ikhwalithi yokukhiqiza enkulu, ukunciphisa izindleko zokukhiqiza,
Inenzuzo ephezulu kunemodeli ye-CMO.

Ingxenye engezansi ikakhulukazi imboni yokukhiqiza i-API, kanti i-API isebudlelwaneni bochungechunge lwezimboni oluphezulu noluphansi nokulungiselela.
Ngakho-ke, isidingo sokusetshenziswa kokulungiswa kwemithi okungezansi sizothinta ngqo isidingo se-API, bese sithinta isidingo se-intermediate.

Ngokombono wochungechunge lonke lwezimboni, izinkampani ezisebenza ngemithi zisesesigabeni sokukhula njengamanje, kanti isilinganiso senzuzo iyonke ngokuvamile siyi-15-20%, kuyilapho isilinganiso senzuzo iyonke ye-API singama-20-25%, kanti isilinganiso senzuzo iyonke yemikhiqizo yemithi engezansi siphakeme njengo-40-50%. Ngokusobala, isilinganiso senzuzo iyonke yengxenye engezansi siphakeme kakhulu kunesengxenye engenhla.
Ngakho-ke, amabhizinisi aphakathi kwezemithi angandisa uchungechunge lomkhiqizo, andise inzuzo yomkhiqizo futhi athuthukise ukuzinza kokuthengisa ngokukhiqiza i-API esikhathini esizayo.

03

Intuthuko ephezulu yemboni yezokwelapha eShayina yaqala ngo-2000.

Ngaleso sikhathi, izinkampani zemithi emazweni athuthukile zazinaka kakhulu ucwaningo lomkhiqizo kanye nentuthuko kanye nentuthuko yemakethe njengokuncintisana kwazo okuyinhloko, futhi zasheshisa ukudluliselwa kwezidakamizwa ezisebenzayo kanye nokuhlanganiswa kwemithi okusebenzayo emazweni asathuthuka ngezindleko eziphansi.
Ngakho-ke, imboni yezokwelapha eShayina ithole intuthuko enhle kakhulu ngokusebenzisa leli thuba.
Ngemva kweminyaka engaphezu kweyishumi yentuthuko eqhubekayo, ngokusekelwa kwemithethonqubo kanye nezinqubomgomo zikazwelonke, iShayina isibe yisisekelo esibalulekile sokukhiqiza esiphakathi nendawo ekuhlukanisweni kwemisebenzi emhlabeni wonke embonini yemithi.

Kusukela ngo-2012 kuya ku-2018, umkhiqizo wemboni yezokwelapha yaseShayina ukhuphuke usuka kumathani ayizigidi ezingu-8.1 ngobukhulu bemakethe obungaba yizigidi eziyizinkulungwane ezingu-168.8 zama-yuan kuya kumathani ayizigidi ezingu-10.12 ngobukhulu bemakethe obungaba yizigidi eziyizinkulungwane ezingu-2010.7 zama-yuan.

Isithombe

Imboni yezemithi esezingeni eliphezulu yaseShayina ifinyelele ukuncintisana okuqinile emakethe, futhi ngisho nezinye izinkampani zokukhiqiza ezisezingeni eliphezulu zikwazile ukukhiqiza imikhiqizo esezingeni eliphezulu enesakhiwo esiyinkimbinkimbi sama-molecule kanye nezidingo zobuchwepheshe eziphakeme. Inani elikhulu lemikhiqizo enethonya seliqalile ukubusa imakethe yamazwe ngamazwe.

Kodwa-ke, ngokuvamile, imboni ephakathi eShayina isesesikhathini sokuthuthukiswa kokuthuthukiswa kwesakhiwo somkhiqizo, futhi izinga lobuchwepheshe lisaphansi kakhulu.
Izinkampani eziyinhloko zemithi ziseyimikhiqizo eyinhloko embonini yezinkampani eziyinhloko zemithi, futhi zimbalwa izinkampani ezikhiqiza inani elikhulu lezinkampani ezithuthukile zemithi futhi zisekela imikhiqizo esezingeni eliphakathi yemithi emisha enelungelo lobunikazi.

Njengamanje, izinkampani ezincintisana kakhulu ngesabelo se-A embonini ephakathi yiYaben Chemical, Lianhua Technology, Boten, kanye neWanrun, ehlela ukutshala ama-yuan ayizigidi ezingu-630 ekwakhiweni kwezinkampani zokwelapha ezihlanganisa imithi kanye namaphrojekthi e-API anomthamo we-A ongamathani angu-3,155 ngonyaka.
Bayaqhubeka nokuthuthukisa imikhiqizo ehlukahlukene ngocwaningo nentuthuko, ukuze bathole izindlela ezintsha.

I-Yaben Chemical Co., Ltd. (300261): Imikhiqizo yethu eyinhloko ifaka phakathi izidakamizwa zokulwa nomdlavuza, izidakamizwa zokulwa nesifo sokuwa kanye nezidakamizwa zokulwa namagciwane.
Phakathi kwazo, i-ABAH, umuthi osiza ekulweni nesifo sokuwa, yasungulwa ngokusemthethweni ngo-Okthoba 2014, inamandla okuthwala amathani ayi-1,000.
Ubuchwepheshe bokuvutshelwa kwama-enzyme bethulwe ngempumelelo ezinhlotsheni zenhliziyo ukuze kuthuthukiswe ukuncintisana kwemikhiqizo.
Ngo-2017, inkampani yathenga i-ACL, inkampani yemithi esebenzayo eMalta, yasheshisa ukwakheka kwayo emakethe yezokwelapha yamazwe ngamazwe futhi yaqhuba ukuguqulwa nokuthuthukiswa kwesisekelo sasekhaya.

I-BTG (300363): igxile ebhizinisini le-CMO elenziwe ngokwezifiso ze-API, imikhiqizo eyinhloko iyimithi elwa ne-hepatitis C, i-AIDS, i-hypolipidemia kanye ne-analgesia, futhi ingumhlinzeki oyinhloko we-Sofebuvir imithi elwa ne-hepatitis C yaseGilead.
Ngo-2016, imali engenayo iyonke yezidakamizwa ezilwa nesifo sikashukela kanye ne-anti-hepatitis C yafinyelela ku-660 million, okwenza u-50% wemali engenayo iyonke.
Kodwa-ke, kusukela ngo-2017, ngenxa yokwelashwa kancane kancane kweziguli ze-hepatitis C kanye nokuncipha kwenani leziguli, ukuthengiswa kwe-Gilead kwemithi ye-hepatitis C kwaqala ukwehla. Ngaphezu kwalokho, ngokuphelelwa yisikhathi kwamalungelo obunikazi, kwaqalwa imithi eminingi yokulwa ne-hepatitis C, futhi umncintiswano waqhubeka nokuqina, okwaholela ekwehleni kwama-oda aphakathi kanye nemali engenayo.
Njengamanje, inkampani isishintshe kusukela ebhizinisini le-CMO kuya ebhizinisini le-CDMO ukuze yakhe ipulatifomu yesevisi yomhlaba wonke ehamba phambili yamabhizinisi emithi.

Ubuchwepheshe be-Alliance (002250):
Imikhiqizo yemithi ephakathi ihileleke kakhulu emithini yokulwa nomdlavuza, imithi yokuzivikela komzimba, imithi yokukhunta, imithi yenhliziyo, imithi yesifo sikashukela, imithi yokucindezeleka, imithi yokukhunta, imithi yokulwa nomfutho wegazi ophakeme, imithi yokulwa nomkhuhlane, njengemithi eyisisekelo, konke lokhu kutholakala ezindaweni zokwelapha zemakethe ethandwa kakhulu futhi ebanzi emhlabeni, ukukhula okusheshayo eminyakeni yamuva, izinga lokukhula kwe-compound elihlanganisiwe elingama-50%.
Phakathi kwazo, “umkhiqizo waminyaka yonke wamathani angu-300 e-Chunidine, amathani angu-300 e-Fluzolic Acid kanye namathani angu-200 e-Cyclopyrimidine Acid Project” usetshenziswe ngokulandelana kusukela ngo-2014.