Hoʻomaka i nā lāʻau mRNA
ʻO Messenger RNA (mRNA) he kaʻina o nā nucleotides e hoʻopili i kahi protein, a i loko o ka cytoplasm hiki ke hoʻohana i nā organelles e hōʻike i ka protein i hoʻopili ʻia. Hoʻololi ʻia nā lāʻau lapaʻau mRNA ma muli o ke koho ʻana i nā pahuhopu a i ʻole antigens a komo i ka cytoplasm ma o kahi ʻōnaehana hāʻawi kikoʻī (e laʻa, LNP), kahi e hana ai lākou i kahi protein kikoʻī (e pili ana i ke kumu o ka hoʻolālā hoʻololi kemika), a loaʻa ka hopena i loko o ka intracellularly a ma hope o ka huna ʻana i loko o ke keʻena extracellular (Fig. 1). Hiki ke unuhi ʻia ka mRNA i loko o kekahi pūmua, a hiki ke hoʻololi ʻia nā lāʻau lapaʻau e hoʻohana ana i nā protein e like me ka therapeutics e nā mRNA therapies.
Fig. 1. Nā hiʻohiʻona o nā lāʻau lapaʻau mRNA a me ke kaʻina hana e hoʻokō ai lākou i ko lākou pono.
Nā hoʻolālā no nā haʻawina pharmacokinetic o nā lāʻau lapaʻau mRAN
E pili ana i ka noiʻi pharmacokinetic preclinical o nā lāʻau lapaʻau mRNA, hiki ke hoʻokaʻawale ʻia i ʻekolu mau ʻāpana o nā haʻawina e kuhikuhi ana i nā kano mRNA, mRNA therapeutics a me nā mea hoʻohana lāʻau lapaʻau hou. Wahi a ka lāʻau - nā alakaʻi ʻenehana pili i hoʻopuka ʻia e FDA a me NMPA, ʻaʻole pono nā lāʻau lapaʻau i nā haʻawina pharmacokinetic maʻamau, akā pono e aʻo ʻia kekahi mau lāʻau lapaʻau kūikawā no ka biodistribution. No nā lāʻau lapaʻau kūikawā ka mRNA, e koi ana i nā haʻawina biodistribution. A ʻo ka haʻawina pharmacokinetic o nā lāʻau lapaʻau mRNA hiki ke kōkua i ka hoʻomaopopo ʻana i ka nui - hopena pili o nā lāʻau lapaʻau. No nā mea hoʻohana lāʻau lapaʻau hou, e like me ka cationic lipids a i ʻole nā mea ʻē aʻe i loko o nā ʻōnaehana hāʻawi LNP he mau mea hoʻohui lāʻau hou, in vitro, in vivo a me nā haʻawina pili lāʻau e koi ʻia e like me ka "Guidelines for Non-clinical Safety Evaluation of New Pharmaceutical Excipients".Loaʻa i ka haʻawina in vitro ke kūpaʻa metabolic a me ka ʻike metabolite o nā ʻōnaehana like ʻole, a aia ka haʻawina in vivo i ka absorption, distribution, metabolism and excretion study i loko o nā holoholona e hoʻoholo ai i ke kaʻina in vivo ADME o ka excipient. Nānā ʻia nā hui lāʻau-lāʻau o nā mea hoʻohui hou ma muli o ke kiʻekiʻe o ka pilikia.
Nā Huahana Pili IPHASE
ʻO Messenger RNA (mRNA) he kaʻina o nā nucleotides e hoʻopili i kahi protein, a i loko o ka cytoplasm hiki ke hoʻohana i nā organelles e hōʻike i ka protein i hoʻopili ʻia. Hoʻololi ʻia nā lāʻau lapaʻau mRNA ma muli o ke koho ʻana i nā pahuhopu a i ʻole antigens a komo i ka cytoplasm ma o kahi ʻōnaehana hāʻawi kikoʻī (e laʻa, LNP), kahi e hana ai lākou i kahi protein kikoʻī (e pili ana i ke kumu o ka hoʻolālā hoʻololi kemika), a loaʻa ka hopena i loko o ka intracellularly a ma hope o ka huna ʻana i loko o ke keʻena extracellular (Fig. 1). Hiki ke unuhi ʻia ka mRNA i loko o kekahi pūmua, a hiki ke hoʻololi ʻia nā lāʻau lapaʻau e hoʻohana ana i nā protein e like me ka therapeutics e nā mRNA therapies.
Fig. 1. Nā hiʻohiʻona o nā lāʻau lapaʻau mRNA a me ke kaʻina hana e hoʻokō ai lākou i ko lākou pono.
Nā hoʻolālā no nā haʻawina pharmacokinetic o nā lāʻau lapaʻau mRAN
E pili ana i ka noiʻi pharmacokinetic preclinical o nā lāʻau lapaʻau mRNA, hiki ke hoʻokaʻawale ʻia i ʻekolu mau ʻāpana o nā haʻawina e kuhikuhi ana i nā kano mRNA, mRNA therapeutics a me nā mea hoʻohana lāʻau lapaʻau hou. Wahi a ka lāʻau - nā alakaʻi ʻenehana pili i hoʻopuka ʻia e FDA a me NMPA, ʻaʻole pono nā lāʻau lapaʻau i nā haʻawina pharmacokinetic maʻamau, akā pono e aʻo ʻia kekahi mau lāʻau lapaʻau kūikawā no ka biodistribution. No nā lāʻau lapaʻau kūikawā ka mRNA, e koi ana i nā haʻawina biodistribution. A ʻo ka haʻawina pharmacokinetic o nā lāʻau lapaʻau mRNA hiki ke kōkua i ka hoʻomaopopo ʻana i ka nui - hopena pili o nā lāʻau lapaʻau. No nā mea hoʻohana lāʻau lapaʻau hou, e like me ka cationic lipids a i ʻole nā mea ʻē aʻe i loko o nā ʻōnaehana hāʻawi LNP he mau mea hoʻohui lāʻau hou, in vitro, in vivo a me nā haʻawina pili lāʻau e koi ʻia e like me ka "Guidelines for Non-clinical Safety Evaluation of New Pharmaceutical Excipients".Loaʻa i ka haʻawina in vitro ke kūpaʻa metabolic a me ka ʻike metabolite o nā ʻōnaehana like ʻole, a aia ka haʻawina in vivo i ka absorption, distribution, metabolism and excretion study i loko o nā holoholona e hoʻoholo ai i ke kaʻina in vivo ADME o ka excipient. Nānā ʻia nā hui lāʻau-lāʻau o nā mea hoʻohui hou ma muli o ke kiʻekiʻe o ka pilikia.
Nā Huahana Pili IPHASE
| Māhele | Hoʻokaʻawale |
| Māhele subcellular | lysosome o ka ate |
| Acidified ate homogenate | |
| ʻĀpaʻu/ ʻōpū/ ʻāʻī/māmā S9 | |
| Nā microsomes ate/intestinal/kidney/lung | |
| ʻO ka ate/intestinal/renal/lung cytoplasmic fluid | |
| Hepatocytes mua | Hoʻokuʻu ʻia nā Hepatocytes |
| Hepatocytes paʻa | |
| ʻO ka plasma kūʻokoʻa | Paʻa paʻa plasma |
| ʻO ka hoʻopaʻa ʻana i ka protein plasma | |
| ʻO ke koko holoʻokoʻa | Kanaka/Monkey/Canine/Iole/Iole/Rabbit/Puaa Koko Kakau |
Ka manawa hoʻouna: 2024-08-25 19:54:01