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Type: Journal article
Title: Enabling oral SN38-based chemotherapy with a combined lipophilic prodrug and self-microemulsifying drug delivery system
Author: Bala, V.
Rao, S.
Bateman, E.
Keefe, D.
Wang, S.
Prestidge, C.
Citation: Molecular Pharmaceutics, 2016; 13(10):3518-3525
Publisher: American Chemical Society
Issue Date: 2016
ISSN: 1543-8384
Statement of
Vaskor Bala, Shasha Rao, Emma Bateman, Dorothy Keefe, Shudong Wang and Clive A. Prestidge
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 selfmicroemulsifying 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.
Keywords: 7-ethyl-10-hydroxycamptothecin (SN38); SMEDDS, lipophilic prodrugs; lipid-based formulations; oral delivery; chemotherapy; pharmacokinetics (PK)
Rights: © 2016 American Chemical Society
DOI: 10.1021/acs.molpharmaceut.6b00591
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