Many highly effective chemotherapeutic agents can only be administered intravenously as their oral delivery is compromised by low gastro-intestinal solubility and permeability. ) is one such drug; however, recently synthesized lipophilic prodrugs offer a potential solution to the low oral bioavailability issue. Here we introduce a microfluidic-based intestine-on-a-chip (IOAC) model, which has the potential to provide new insight into the structure− permeability relationship for lipophilic prodrugs. More specifically, the IOAC model utilizes external mechanical cues that induce specific differentiation of an epithelial cell monolayer to provide a barrier function that exhibits an undulating morphology with microvilli expression on the cell surface; this is more biologically relevant than conventional Caco-2 Transwell models. IOAC permeability data for SN38 modified with fatty acid esters of different chain lengths and at different molecular positions correlate excellently with water−lipid partitioning data and have the potential to significantly advance their preclinical development. In addition to advancing mechanistic insight into the permeability of many challenging drug candidates, we envisage the IOAC model to also be applicable to nanoparticle and biological entities.
SN38 (7-ethyl-10-hydroxy camptothecin) is a potent anticancer agent belonging to the camptothecin family; however, its oral delivery is extensively restricted by poor solubility in pharmaceutically acceptable excipients and low transmucosal permeability. Lipid-based carriers are well-known for their ability to improve oral absorption and bioavailability of lipid soluble and highly permeable compounds. Thus, this study has focused on improving solubility in lipid excipients, controlling stability, and enhancing transmucosal permeability of SN38 by specific chemical modification. To achieve these aims, a series of lipophilic prodrugs were designed and synthesized by esterification at the C10 and/or C20 positon(s) of SN38 with dietary fatty acids of diverse hydrocarbon chain lengths. The solubility of these novel prodrugs in long-chain triglycerides was increased up to 444-fold, and cytotoxicity was significantly reduced in comparison to SN38. The prodrugs were stable in simulated gastric fluids but exhibited different rates of hydrolysis (t1/2 < 5 min to t1/2 > 2 h) in simulated intestinal fluids (in the presence of enzymes) depending on the alkyl chain length and the position modified. A predictable reconversion of prodrugs to SN38 in plasma was also confirmed. On the basis of these studies, SN38-undecanoate (C20) was identified as the optimal prodrug. Finally, in vitro permeability and uptake studies in rat intestinal mucosal membrane using an Ussing chamber showed significant improvement in transepithelial drug transport and cellular uptake. Together, these results indicate that well designed lipophilic prodrugs have potential for the efficacious and safe oral delivery of SN38.
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 (AUC) 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.
Abstract:The methanol extract of the dried leaves of Cleome viscosa L., Cleomaceae, was investigated for its possible antinociceptive, cytotoxic and antibacterial activities in animal models. The extract produced significant writhing inhibition in acetic acid-induced writhing in mice at the oral doses of 250 and 500 mg/kg body weight (p<0.001) comparable to the standard drug diclofenac sodium at the dose of 25 mg/kg of body weight (p<0.001). The crude extract produced the most prominent cytotoxic activity against brine shrimp Artemia salina (LC50 28.18 µg/mL and LC90 112.20 µg/mL). The extract of C. viscosa L. exhibited significant in vitro antibacterial activity against Staphylococcus saprophyticus, Shigella sonnie, Salmonella typhi, Vibrio cholera, Streptococcus epidermidis, Shigella flexneri and Staphylococcus aureus with the zones of inhibition ranging from 10.76 to 16.34 mm. The obtained results provide a support for the use of this plant in traditional medicine and its further investigation.
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