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https://hdl.handle.net/2440/102810
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dc.contributor.author | Bala, V. | - |
dc.contributor.author | Rao, S. | - |
dc.contributor.author | Bateman, E. | - |
dc.contributor.author | Keefe, D. | - |
dc.contributor.author | Wang, S. | - |
dc.contributor.author | Prestidge, C. | - |
dc.date.issued | 2016 | - |
dc.identifier.citation | Molecular Pharmaceutics, 2016; 13(10):3518-3525 | - |
dc.identifier.issn | 1543-8384 | - |
dc.identifier.issn | 1543-8392 | - |
dc.identifier.uri | http://hdl.handle.net/2440/102810 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Vaskor Bala, Shasha Rao, Emma Bateman, Dorothy Keefe, Shudong Wang and Clive A. Prestidge | - |
dc.language.iso | en | - |
dc.publisher | American Chemical Society | - |
dc.rights | © 2016 American Chemical Society | - |
dc.source.uri | http://dx.doi.org/10.1021/acs.molpharmaceut.6b00591 | - |
dc.subject | 7-ethyl-10-hydroxycamptothecin (SN38); SMEDDS, lipophilic prodrugs; lipid-based formulations; oral delivery; chemotherapy; pharmacokinetics (PK) | - |
dc.title | Enabling oral SN38-based chemotherapy with a combined lipophilic prodrug and self-microemulsifying drug delivery system | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1021/acs.molpharmaceut.6b00591 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1026382 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Bateman, E. [0000-0003-1665-102X] | - |
dc.identifier.orcid | Keefe, D. [0000-0001-9377-431X] | - |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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