Mengqi Yu, Deliang Zhou, Hardeep S Oberoi, Ahmed Hamed Salem, Laura A McKee, Jason R Arnholt, Hitesh S Purohit, Devalina Law
{"title":"口服给药 BCS IV 化合物的 45% 药物负载无定形纳米粒子制剂的放大和临床生物利用度评估。","authors":"Mengqi Yu, Deliang Zhou, Hardeep S Oberoi, Ahmed Hamed Salem, Laura A McKee, Jason R Arnholt, Hitesh S Purohit, Devalina Law","doi":"10.1016/j.xphs.2024.10.014","DOIUrl":null,"url":null,"abstract":"<p><p>A 45% drug loaded (DL) amorphous nanoparticle (ANP) formulation for a BCS IV drug demonstrated promising pharmacokinetics in dogs (Purohit, et al, J. Pharm. Sci. 2023(113)1007-1019). This preclinical data enabled a human proof-of-concept assessment opportunity. The ANP freeze dried powder for oral suspension was prepared using solvent/antisolvent precipitation followed by organic solvent removal and freeze drying (FD). Challenges manifested during scale-up from 50g to 280g. Given the preclinical data, formulation change was restricted, therefore, process modifications were implemented. Cold collection after precipitation prevented particle growth but resulted in 75 nm particles at clinical scale (CS), compared to 150 nm at laboratory scale (LS). This size decrease rendered stabilizer amounts suboptimal for FD operation. Consequently, when FD powder was resuspended in water a smaller fraction of particles was below 450 nm (by filtration), ∼65% for CS compared to ∼85% for LS. Formulation was stable for > 6 months, evaluated by monitoring moisture content, assay, powder X-ray diffraction (PXRD), and redispersion time. Despite ∼65% re-dispersibility, this 45% DL formulation in humans had higher C<sub>max</sub> and AUC ∼73% and ∼46% respectively in fasted-state, and under fed-state it met bioequivalence criteria for AUC but C<sub>max</sub> was 20% lower compared to reference (10% DL ASD tablets) demonstrating advantage of ANP strategy over ASD approach.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Scale-up and Clinical Bioavailability Assessment of a 45% Drug Loaded Amorphous Nanoparticle Formulation of a BCS IV Compound for Oral Delivery.\",\"authors\":\"Mengqi Yu, Deliang Zhou, Hardeep S Oberoi, Ahmed Hamed Salem, Laura A McKee, Jason R Arnholt, Hitesh S Purohit, Devalina Law\",\"doi\":\"10.1016/j.xphs.2024.10.014\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>A 45% drug loaded (DL) amorphous nanoparticle (ANP) formulation for a BCS IV drug demonstrated promising pharmacokinetics in dogs (Purohit, et al, J. Pharm. Sci. 2023(113)1007-1019). This preclinical data enabled a human proof-of-concept assessment opportunity. The ANP freeze dried powder for oral suspension was prepared using solvent/antisolvent precipitation followed by organic solvent removal and freeze drying (FD). Challenges manifested during scale-up from 50g to 280g. Given the preclinical data, formulation change was restricted, therefore, process modifications were implemented. Cold collection after precipitation prevented particle growth but resulted in 75 nm particles at clinical scale (CS), compared to 150 nm at laboratory scale (LS). This size decrease rendered stabilizer amounts suboptimal for FD operation. Consequently, when FD powder was resuspended in water a smaller fraction of particles was below 450 nm (by filtration), ∼65% for CS compared to ∼85% for LS. Formulation was stable for > 6 months, evaluated by monitoring moisture content, assay, powder X-ray diffraction (PXRD), and redispersion time. Despite ∼65% re-dispersibility, this 45% DL formulation in humans had higher C<sub>max</sub> and AUC ∼73% and ∼46% respectively in fasted-state, and under fed-state it met bioequivalence criteria for AUC but C<sub>max</sub> was 20% lower compared to reference (10% DL ASD tablets) demonstrating advantage of ANP strategy over ASD approach.</p>\",\"PeriodicalId\":16741,\"journal\":{\"name\":\"Journal of pharmaceutical sciences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-10-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of pharmaceutical sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xphs.2024.10.014\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of pharmaceutical sciences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.xphs.2024.10.014","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Scale-up and Clinical Bioavailability Assessment of a 45% Drug Loaded Amorphous Nanoparticle Formulation of a BCS IV Compound for Oral Delivery.
A 45% drug loaded (DL) amorphous nanoparticle (ANP) formulation for a BCS IV drug demonstrated promising pharmacokinetics in dogs (Purohit, et al, J. Pharm. Sci. 2023(113)1007-1019). This preclinical data enabled a human proof-of-concept assessment opportunity. The ANP freeze dried powder for oral suspension was prepared using solvent/antisolvent precipitation followed by organic solvent removal and freeze drying (FD). Challenges manifested during scale-up from 50g to 280g. Given the preclinical data, formulation change was restricted, therefore, process modifications were implemented. Cold collection after precipitation prevented particle growth but resulted in 75 nm particles at clinical scale (CS), compared to 150 nm at laboratory scale (LS). This size decrease rendered stabilizer amounts suboptimal for FD operation. Consequently, when FD powder was resuspended in water a smaller fraction of particles was below 450 nm (by filtration), ∼65% for CS compared to ∼85% for LS. Formulation was stable for > 6 months, evaluated by monitoring moisture content, assay, powder X-ray diffraction (PXRD), and redispersion time. Despite ∼65% re-dispersibility, this 45% DL formulation in humans had higher Cmax and AUC ∼73% and ∼46% respectively in fasted-state, and under fed-state it met bioequivalence criteria for AUC but Cmax was 20% lower compared to reference (10% DL ASD tablets) demonstrating advantage of ANP strategy over ASD approach.
期刊介绍:
The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.