Facilitating gastrointestinal solubilisation and enhanced oral absorption of SN38 using a molecularly complexed silica-lipid hybrid delivery system

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 105; pp. 32 - 39
• Main Authors: Bala, Vaskor, Rao, Shasha, Prestidge, Clive A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2016
• Subjects: 7-Ethyl-10-hydroxycamptothecin (SN38); Administration, Oral; Animals; Biological Availability; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - blood; Camptothecin - pharmacokinetics; Drug Delivery Systems; Female; Gastrointestinal Tract - metabolism; Lipid-based drug delivery; Lipids - chemistry; Oral chemotherapy; Pharmacokinetics; Rats; Silicon Dioxide - chemistry; SLH; Solubility; Lipid-based drug delivery; Pharmacokinetics; 7-Ethyl-10-hydroxycamptothecin (SN38); Oral chemotherapy; SLH
• ISSN: 0939-6411; 1873-3441; 1873-3441
• DOI: 10.1016/j.ejpb.2016.05.021

[Display omitted] 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.