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 (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.

Lipidic prodrug approach for improved oral drug delivery and therapy

“…Oftentimes, combining multiple approaches can improve results, as can be seen when lipidic prodrugs and formulation approaches were taken together . Moreover, the lipidic moiety of the lipid‐drug conjugate may facilitate loading into the delivery systems through hydrophobic interaction, which can improve formulation stability and drug loading, and prevent drug leakage .…”

“…A recent example of an FA‐based prodrug used SN‐38 (7‐ethyl‐10‐hydroxy camptothecin), an anticancer agent whose mechanism of action is the inhibition of DNA topoisomerase 1. SN‐38 is a BCS class 4 compound with poor solubility in the GI fluids, low intestinal permeability, and overall poor stability, suggesting the need for a lipophilic prodrug approach . SN‐38 modified at the C 20 position with undecanoic acid (Table ) increased intestinal permeability and provided a stable conversion to SN‐38 in plasma.…”

“…In comparison with intraperitoneal administration, the oral formulation resulted in sixfold lower plasma levels of the prodrug with the comparable free drug (SN‐38) plasma levels. Oral delivery of the prodrug resulted in a 100‐fold higher area under the curve (AUC) of SN‐38 compared with oral SN‐38 solution …”

<p>Self-Microemulsifying Drug Delivery System for Improved Oral Delivery and Hypnotic Efficacy of Ferulic Acid</p>

“…Self-microemulsifying drug delivery system (SMEDDS) is a carrier system known for its biocompatibility, stability, controlled release, facilitated absorption, and improved bioavailability. 26,27 SMEDDS decreases the elimination and clearance of drugs by altering their distribution in tissues. 28,29 Thus, we speculated that SMEDDS may be an effective carrier to improve the pharmacokinetic behavior and anti-insomnia efficacy of FA.…”

PEGylation of lipophilic SN38 prodrug with DSPE-mPEG2000 versus cremophor EL: comparative study for intravenous chemotherapy

“…Lipids have been widely conjugated to various hydrophobic drugs to obtain the so-called dually hydrophobic prodrugs (DHPs). By enhancing their loading capacity in the lipid-based nanocarriers, DHPs have been regarded as a feasible strategy to address the solubility problem of hydrophobic chemotherapeutic agents (Lundberg, 2011; Bala et al., 2016; Ren et al., 2016). Recently, DHPs containing particular chemical elements (e.g.…”