RESUMEN

Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids, and/or surfactants/cosolvents, hereby avoiding the rate-limiting dissolution step. According to the Lipid formulation classification system, proposed by Pouton in 2006, in type II LBFs a surfactant with an HLB-value lower than 12 is added to the lipids. If high drug doses are required, e.g. for preclinical toxicity studies, supersaturated LBFs prepared at elevated temperatures may be a possibility to increase drug exposure. In the present study, the impact of digestion on drug absorption in rats was studied by pre-dosing of the lipase inhibitor orlistat. The lipid chain length of the type II LBFs was varied by administration of a medium-chain- (MC) and a long-chain (LC)-based formulation. Different drug doses, both non-supersaturated and supersaturated, were applied. Due to an inherent precipitation tendency of cinnarizine in supersaturated LBFs, the effect of the addition of the precipitation inhibitor Soluplus® was also investigated. The pharmacokinetic results were also evaluated by multiple linear regression. In most cases LC-based LBFs did not perform better in vivo, in terms of a higher area under the curve (AUC0-24 h) and maximal plasma concentration (Cmax), than MC-based LBFs. The administration of supersaturated LBFs resulted in increased AUC0-24 h (1.5 - 3.2-fold) and Cmax (1.1 - 2.6-fold)-values when compared to the non-supersaturated equivalents. Lipase inhibition led to a decreased drug exposure in most cases, especially for LC formulations (AUC0-24 h reduced to 47 - 67%, Cmax to 46 - 62%). The addition of Soluplus® showed a benefit to drug absorption from supersaturated type II LBFs (1.2 - 1.7-fold AUC0-24 h), due to an increased solubility of cinnarizine in the formulation. Upon dose-normalization of the pharmacokinetic parameters, no beneficial effect of Soluplus® could be demonstrated.

Asunto(s)

Cinarizina , Lípidos , Cinarizina/química , Cinarizina/farmacocinética , Cinarizina/administración & dosificación , Animales , Masculino , Lípidos/química , Solubilidad , Lactonas/química , Lactonas/farmacocinética , Lactonas/administración & dosificación , Ratas Wistar , Orlistat/administración & dosificación , Orlistat/farmacocinética , Absorción Intestinal , Ratas , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Lipasa/antagonistas & inhibidores , Polivinilos/química , Precipitación Química , Tensoactivos/química , Química Farmacéutica/métodos

RESUMEN

Enabling formulations, such as lipid-based formulations (LBFs), are means to deliver challenging-to-formulate, poorly soluble drugs. LBFs may be composed of lipids, surfactants and/or cosolvents and can be classified depending on the proportions of the components and the hydrophilicity of the surfactant according to the Lipid Formulations Classification System, ranging from type I (very lipophilic) to type IV (hydrophilic). In cases where drug solubility in LBFs does not suffice, e.g. for preclinical toxicity studies, supersaturated LBFs can be used in order to increase the drug load. However, the effect of digestion on drug absorption from supersaturated type I formulations (consisting exclusively of lipids) still remains relatively unexplored and unclear. In the present study, the impact of lipid digestion on absorption of cinnarizine-loaded supersaturated lipid-based formulations of type I was investigated in rats by pre-dosing of the lipase inhibitor orlistat. The lipid chain length and the drug dose were varied by testing medium-chain triglycerides (MCT) and long-chain triglycerides (LCT), both supersaturated and non-supersaturated. Due to the physical instability of supersaturated formulations of cinnarizine, i.e. a potential of precipitation of cinnarizine, the impact of the addition of the amphiphilic polymer Soluplus®, as a potential precipitation inhibitor, was also investigated. The supersaturated systems resulted in a 2.3 - 3.3-fold higher Area Under the Curve (AUC0-24 h, not dose-normalized) and 1.4 - 2.2-fold higher maximum plasma concentration (Cmax, not dose-normalized) than non-supersaturated formulations (statistically significant with p = 0.05), whereas the addition of Soluplus® did not reveal any benefit. Results indicated that lipase inhibition affected the in vivo performance of LBFs: Co-administration of the lipase inhibitor significantly reduced Cmax and AUC0-24 h (both to 33-39 %, not dose-normalized) for the LCT formulations and, though not significant, a similar trend was observed for the AUC0-24 h of the MCT formulations (to 53-87 %), suggesting a higher dependency on lipolysis for LCT. Also, tmax tended to decrease to 20-60 % when compared to the animals not dosed with orlistat but lacking statistical significance. Without lipase inhibition, the LCT in general lead to better absorption of cinnarizine as compared to MCT, with 1.2-1.7-fold higher AUC0-24 h and 1.4-1.8-fold higher Cmax, but without showing statistical significance. Overall, the study revealed that lipolysis plays a major role in drug absorption from supersaturated lipid-based formulations type I.

Asunto(s)

Cinarizina , Ratas , Animales , Orlistat , Preparaciones Farmacéuticas , Triglicéridos , Solubilidad , Tensoactivos , Lipasa , Digestión , Administración Oral

RESUMEN

In response to the increasing application of machine learning (ML) across many facets of pharmaceutical development, this pilot study investigated if ML, using artificial neural networks (ANNs), could predict the apparent degree of supersaturation (aDS) from two supersaturated LBFs (sLBFs). Accuracy was compared to partial least squares (PLS) regression models. Equilibrium solubility in Capmul MCM and Maisine CC was obtained for 21 poorly water-soluble drugs at ambient temperature and 60 °C to calculate the aDS ratio. These aDS ratios and drug descriptors were used to train the ML models. When compared, the ANNs outperformed PLS for both sLBFCapmulMC (r2 0.90 vs. 0.56) and sLBFMaisineLC (r2 0.83 vs. 0.62), displaying smaller root mean square errors (RMSEs) and residuals upon training and testing. Across all the models, the descriptors involving reactivity and electron density were most important for prediction. This pilot study showed that ML can be employed to predict the propensity for supersaturation in LBFs, but even larger datasets need to be evaluated to draw final conclusions.

RESUMEN

Increasing numbers of beyond Rule-of-Five drugs are emerging from discovery pipelines, generating a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. However, many drug candidates display insufficient lipid solubility, leading to dose-loading limitations in LBFs. The aim of this study was to explore the potential of supersaturated LBFs (sLBF) for the beyond Rule-of-Five drug venetoclax. Temperature-induced sLBFs of venetoclax were obtained in olive oil, Captex® 1000, Peceol® and Capmul MCM®, respectively. A Peceol®-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol®-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol®-based suspension and an aqueous suspension. A subsequent bioavailability study in pigs demonstrated for sLBF a 3.8-fold and 2.1-fold higher bioavailability compared to the drug powder and Peceol®-based suspension, respectively. In conclusion, sLBF is a promising bio-enabling formulation approach to enhance in vivo exposure of beyond Rule-of-Five drugs, such as venetoclax. The in vitro lipolysis results correctly predicted a higher exposure of the sLBF in vivo. The findings of this study are of particular relevance to pre-clinical drug development, where maximum exposure is required.