title: Enabling Oral SN38-Based Chemotherapy with a Combined Lipophilic Prodrug and Self-Microemulsifying Drug Delivery System.
abstract: Oral chemotherapy with SN38 is restricted by its poor solubility in gastrointestinal (GI) fluids and low permeability. Here we report the oral delivery of SN38 by a combined lipophilic prodrug and lipid-based formulation strategy. A lead lipophilic prodrug of SN38, SN38-undecanoate (SN38-unde20), was incorporated into a self-microemulsifying drug delivery system (SMEDDS) for improved in vitro and in vivo performance. The formulation was purposefully designed and optimized with long chain lipids and lipid-based nonionic surfactants to maximize drug solubilization in GI conditions, facilitate trans-membrane permeation, and hence improve oral absorption. SN38-unde20-SMEDDS significantly increased (>7 fold) drug solubilization in the aqueous phase compared to unformulated drug during in vitro lipolysis and drug solubilization studies. In an orally dosed in vivo pharmacokinetics study in a Dark Agouti rat model, the SN38-unde20-SMEDDS formulation confirmed oral absorption of SN38-unde20 and subsequent reconversion to SN38. Importantly, the overall plasma exposure of SN38 (AUC0→∞) was equivalent for orally dosed SN38-unde20-SMEDDS in comparison with a parenteral dose of SN38-unde20-SMEDDS and SN38 at an identical dose (10 mg/kg). The combination of lipophilic prodrug along with an optimal delivery carrier is demonstrated to enable effective oral delivery of challenging chemotherapeutic compounds that are conventionally dosed by injection.
authors: School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, SA 5001, Australia.
authors: Vaskor
authors: V
authors: Bala
authors: School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, SA 5001, Australia.
authors: Shasha
authors: S
authors: Rao
authors: Mucositis Research Group, School of Medicine, University of Adelaide , Adelaide, SA 5001, Australia.
authors: Emma
authors: E
authors: Bateman
authors: Mucositis Research Group, School of Medicine, University of Adelaide , Adelaide, SA 5001, Australia.
authors: Dorothy
authors: D
authors: Keefe
authors: School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, SA 5001, Australia.
authors: Shudong
authors: S
authors: Wang
authors: School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, SA 5001, Australia.
authors: Clive A
authors: CA
authors: Prestidge
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions / Q000737:chemistry; D005079:Excipients / Q000737:chemistry; D005260:Female; D000077146:Irinotecan; D015394:Molecular Structure; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D053719:Tandem Mass Spectrometry
chemical_list: D004655:Emulsions; D005079:Excipients; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin
keywords: 7-ethyl-10-hydroxycamptothecin (SN38); SMEDDS; chemotherapy; lipid-based formulations; lipophilic prodrugs; oral delivery; pharmacokinetics (PK)