Enabling superior drug loading in lipid-based formulations with lipophilic salts for a brick dust molecule: Exploration of lipophilic counterions and in vitro-in vivo evaluation.

Lipid-based formulations (LbFs) are an extensively used approach for oral delivery of poorly soluble drug compounds in the form of lipid suspension and lipid solution. However, the high target dose and inadequate lipid solubility limit the potential of brick dust molecules to be formulated as LbFs. Thus, the complexation of such molecules with a lipophilic counterion can be a plausible approach to improve the solubility in lipid-based solutions via reducing drug crystallinity and polar surface area. The study aimed to enhance drug loading in lipid solution for Nilotinib (Nil) through complexation or salt formation with different lipophilic counterions. We synthesized different lipophilic salts/ complexes via metathesis reactions and confirmed their formation by 1H NMR and FTIR. Docusate-based lipophilic salt showed improved solubility in medium-chain triglycerides (∼7 to 7.5-fold) and long-chain triglycerides (∼30 to 35-fold) based lipids compared to unformulated crystalline Nil. The increased lipid solubility could be attributed to the reduction in drug crystallinity which was further confirmed by the PXRD and DSC. Prototype LbFs were prepared to evaluate drug loading and their physicochemical characteristics. The findings suggested that structural features of counterion including chain length and lipophilicity affect the drug loading in LbF. In addition, physical stability testing of formulations was performed, inferring that aliphatic sulfate-based LbFs were stable with no sign of drug precipitation or salt disproportionation. An in vitro lipolysis-permeation study revealed that the primary driver of absorptive flux is the solubilization of the drug and reduced amount of lipid. Further, the in vivo characterization was conducted to measure the influence of increased drug load on oral bioavailability. Overall, the results revealed enhanced absorption of lipophilic salt-based LbF over unformulated crystalline Nil and conventional LbF (drug load equivalent to equilibrium solubility) which supports the idea that lipophilic salt-based LbF enhances drug loading, and supersaturation-mediated drug solubilization, unlocking the full potential of LbF.

Utilization of Lipophilic Salt and Phospholipid Complex in Lipid-Based Formulations to Modulate Drug Loading and Oral Bioavailability of Pazopanib.

Pazopanib hydrochloride (PAZ) displays strong intermolecular interaction in its crystal lattice structure, limiting its solubility and dissolution. The development of lipid-based formulations (LbFs) resulted in reduced PAZ loading due to solid-state mediated low liposolubility. This study aims to enhance our understanding of PAZ crystallinity by synthesizing a lipophilic salt and phospholipid complex and investigating its impact on the drug loading in LbFs. The synthesized pazopanib lipophilic salt and phospholipid complex were extensively characterized. The solid form of pazopanib docusate (PAZ-DOC) and pazopanib phospholipid complex (PAZ-PLC) indicates a reduction in characteristic diffraction peaks of crystalline PAZ. The lipid formulations were prepared using synthesized PAZ-DOC and PAZ-PLC, where PAZ-DOC demonstrated six fold higher drug solubility than the commercial salt form and twice that of the PAZ-PLC due to differences in the crystallinity. Further, the impact of salt and complex formation was assessed on the aqueous drug solubilization using lipolysis and multimedia dissolution experiments. Moreover, the LbFs showed notably faster dissolution compared to the crystalline PAZ and marketed tablet. In terms of in vivo pharmacokinetics, the PAZ-DOC LbF exhibited a remarkable 11-fold increase in AUC value compared to the crystalline PAZ and a 2.5-fold increase compared to Votrient®. Similarly, PAZ-PLC LbF showed an approximately nine fold increase in drug exposure compared to the crystalline PAZ, and a 2.2-fold increase compared to Votrient®. These findings suggest that disrupting the crystallinity of drugs and incorporating them into LbF could be advantageous for enhancing drug loading and overcoming limitations related to drug absorption.

Supersaturating lipid-based solid dispersion of atazanavir provides enhanced solubilization and supersaturation in the digestive aqueous phase.

Understanding and controlling the drug solubilization in digestive environment is of great importance in the design of lipid based solid dispersion (LBSD) for oral delivery of poorly aqueous soluble drugs. In the current study we determined the extent of drug solubilization and supersaturation of supersaturating lipid based solid dispersion which is governed by formulation variables like drug payload, lipid composition, solid carrier properties and lipid to solid carrier ratio. Initially, the impact of lipid chain length and drug payload on drug solubilization in lipid preconcentrate and dispersibility were evaluated to design liquid LbF of the model antiretroviral drug, atazanavir. The temperature induced supersaturation method enhanced the drug payload in medium chain triglyceride formulation at 60 °C. Further, the selected liquid supersaturated LbF was transformed into solid state LbF by employing different solid carriers including silica (Neusilin® US2 and Aerosil® 200), clay (Montmorillonite and Bentonite) and polymer (HPMC-AS and Kollidon® CL-M). The fabricated LBSDs were evaluated for solid state characterization to identify the physical nature of drug. In vitro digestion studies were conducted using pH-stat lipolysis method to assess the supersaturation propensity in aqueous digestive phase. Results revealed that LBSDs with silica and polymer carriers showed maximum drug solubilization throughout experiment compared to liquid LbF. The ionic interaction between drug-clay particles significantly reduced the ATZ partitioning from clay based LBSDs. LBSDs with dual purpose solid carrier like HPMC-AS and Neusilin® US2 offers the potential to improve drug solubilization of ATZ for physiologically relevant time. Lastly, we conclude that evaluation of formulation variables is crucial to achieve optimal performance of supersaturating LBSD.