title: Facilitating gastrointestinal solubilisation and enhanced oral absorption of SN38 using a molecularly complexed silica-lipid hybrid delivery system.
abstract: SN38 (7-ethyl-10-hydroxycamptothecin) is a highly potent anti-cancer compound. However, it is poorly soluble in pharmaceutically acceptable excipients, thus the direct formulation and delivery are restricted. The current study focused on lipid-based formulation design to enable oral delivery of SN38 at high doses and at therapeutic levels. The pH dependent ionisation property of SN38 was utilised to form a molecular complex with the cationic surfactant, oleylamine and this increased (>200-fold) solubility/loading in Labrasol (the optimally determined lipid carrier). A SN38 loaded silica-lipid hybrid (SN38-SLH) particle delivery system was prepared by lyophilisation of mesoporous silica nanoparticle stabilised lipid emulsions. The subsequent free-flowing, SLH solid dosage form contained high loading levels of molecularly dispersed SN38 (5%w/w) and significantly enhanced in vitro dissolution in simulated gastrointestinal media. Furthermore, SN38 was chemically stable for at least 12months at 25°C. Orally dosed pharmacokinetics in a rat model demonstrated a 176% increase in SN38 blood plasma exposure in comparison with a raw drug suspension and a significant increase in the period where therapeutic levels are established. SN38-SLH shows potential for enabling injection-to-oral transformation in cancer chemotherapy.
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Vaskor
authors.initials: V
authors.lastname: Bala
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Shasha
authors.initials: S
authors.lastname: Rao
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia. Electronic address: clive.prestidge@unisa.edu.au.
authors.forename: Clive A
authors.initials: CA
authors.lastname: Prestidge
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism*; D000077146:Irinotecan; D008055:Lipids / Q000737:chemistry*; D051381:Rats; D012822:Silicon Dioxide / Q000737:chemistry*; D012995:Solubility
chemical_list: D008055:Lipids; D012822:Silicon Dioxide; D000077146:Irinotecan; D002166:Camptothecin
keywords: 7-Ethyl-10-hydroxycamptothecin (SN38); Lipid-based drug delivery; Oral chemotherapy; Pharmacokinetics; SLH