Combining lipid based drug delivery and amorphous solid dispersions for improved oral drug absorption of a poorly water-soluble drug

Two widely applied enabling drug delivery approaches, self-nanoemulsifying drug delivery systems (SNEDDS) and amorphous solid dispersions (ASD), were combined, with the aim of enhancing physical stability, solubilization and absorption of the model drug ritonavir. Ritonavir was loaded at a concentration above its saturation solubility (Seq) in the SNEDDS (superSNEDDS, 250% of Seq). An ASD of ritonavir with polyvinylpyrrolidone-vinyl acetate copolymers (Kollidon® VA64) was prepared by ball milling. Relevant control formulations, which include conventional SNEDDS (90% of Seq), superSNEDDS with a physical mix of Kollidon® VA64 and ritonavir (superSNEDDS+PM) and an aqueous suspension of ritonavir were used. A pharmacokinetic (PK) study in rats was performed to assess the relative bioavailability of ritonavir after oral administration. This was followed by evaluating the formulations in a novel two-step in vitro lipolysis model simulating rat gastric and intestinal conditions. The addition of a ritonavir containing ASD to superSNEDDS increased the degree of supersaturation from 250% to 275% Seq in the superSNEDDS and the physical stability (absence of drug recrystallization) of the system from 48 h to 1 month under ambient conditions. The PK study in rats displayed significantly higher Cmax and AUC0-7h (3-fold increase) and faster Tmax for superSNEDDS+ASD compared to the conventional SNEDDS whilst containing 3 times less lipid than the latter. Furthermore, superSNEDDS+ASD were able to keep the drug solubilised during in vitro lipolysis to the same degree as the conventional SNEDDS. These findings suggest that dissolving an ASD in a superSNEDDS can contribute to the development of novel oral delivery systems with increased bioavailability for poorly water-soluble drugs.

Materials

Kollidon® VA64 (polyvinylpyrrolidone-vinyl acetate copolymers; PVP-VA64), Kolliphor RH 40 and ritonavir were kindly provided by BASF (Ludwigshafen, Germany). Maisine® CC (glyceryl monolinoleate) was kindly donated by Gattefossé (Saint-Priest, France). Lipoid lyso-phospatidylcholine (LPC) (from soybean, containing 80.0% LPC) was kindly donated by Lipoid GmbH (Ludwigshafen, Germany). Ethylenediaminetetraacetic acid (EDTA) tripotassium salt dihydrate coated plasma tubes were obtained from Sarstedt (Nümbrecht, Germany). Soybean oil, porcine pancreatic lipase extract, tris (hydroxymethyl) aminomethane (Tris), maleic acid, bile extract (bovine) (B-3883), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pepsin and lipase (from Rhizopus oryzae) were obtained from Sigma-Aldrich (St Louis, MO, USA). Deionized water was obtained from an SG Ultraclear water system (SG Water GmbH, Barsbüttel, Germany). Ethanol (Ph. Eur. Grade) was purchased from VWR (Herlev, Denmark). All other reagents used were of analytical grade.

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Georgia-Ioanna Nora, Ramakrishnan Venkatasubramanian, Sophie Strindberg, Scheyla Daniela Siqueira-Jørgensen, Livia Pagano, Francis S. Romanski, Nitin K. Swarnakar, Thomas Rades, Anette Müllertz, Combining lipid based drug delivery and amorphous solid dispersions for improved oral drug absorption of a poorly water-soluble drug, Journal of Controlled Release, Volume 349, 2022, Pages 206-212, ISSN 0168-3659,
https://doi.org/10.1016/j.jconrel.2022.06.057.

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