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.

Supersaturable diacyl phospholipid dispersion for improving oral bioavailability of brick dust molecule: A case study of Aprepitant.

This study aims to investigate the potential use of polymer inclusion in the phospholipid-based solid dispersion approach for augmenting the biopharmaceutical performance of Aprepitant (APT). Initially, different polymers were screened using the microarray plate method to assess their ability to inhibit drug precipitation in the supersaturated solution and HPMCAS outperformed the others. Later, the binary (BD) and ternary (TD) phospholipid dispersions were prepared using the co-solvent evaporation method. Solid-state characterization was performed using SEM and PXRD to examine the physical properties, while molecular interactions were probed through FTIR and NMR analysis. In vitro dissolution studies were performed in both fasted and fed state biorelevant media. The results demonstrated a substantial increase in drug release from BD and TD, approximately 4.8 and 9.9 times higher compared to crystalline APT in FaSSIF. Notably, TD also showed a lowered dissolution difference between fed and fasted states in comparison to crystalline APT, indicating a reduction in the positive food effect of APT. Moreover, we assessed the impact of polymer inclusion on permeation under in vitro biomimetic conditions. In comparison with the crystalline APT suspension, both BD and TD demonstrated approximately 3.3 times and 14 times higher steady-state flux (Jss values), respectively. This can be ascribed to the supersaturation and presence of drug-rich submicron particles (nanodroplets) along with the multiple aggregates of drug with phospholipids and polymer in the donor compartment, consequently resulting in a more substantial driving force for passive diffusion. Lastly, in vivo pharmacokinetic evaluation demonstrated the enhanced absorption of both TD and BD over the free drug suspension in the fasted state. This enhancement was evident through a 2.1-fold and 1.3-fold increase in Cmax and a 2.3-fold and 1.4-fold increase in AUC0-t, respectively. Overall, these findings emphasize the potential of polymer-based phospholipid dispersion in enhancing the overall biopharmaceutical performance of APT.

Enhanced biopharmaceutical performance of brick dust molecule nilotinib via stabilized amorphous nanosuspension using a facile acid-base neutralization approach.

"Brick dust" compounds have high lattice energy as manifested by the poor aqueous solubility and suboptimal bioavailability. Nilotinib being a weakly basic brick dust molecule exhibits erratic and limited absorption during gastrointestinal transit, attributed to pre-absorptive factors like pH-dependent solubility, poor dissolution kinetics, and post-absorptive factors including P-gp-mediated drug efflux. In our study, these problems are addressed holistically by the successful fabrication of amorphous nanosuspension by an acid-base neutralization approach. The nanosuspension was obtained via rapid precipitation of nilotinib in an amorphous form and the generated in situ sodium chloride salt assisted in stabilizing the drug-loaded nanosuspension in a cage of salt and micellar stabilizer. Soluplus® and hypromellose acetate succinate (HPMCAS) were employed as a novel combination of stabilizers. Systematic optimization was carried out by employing the I-optimal method using Design Expert® software with a concentration of HPMCAS and Soluplus® as independent variables and evaluating them for responses viz particle size, polydispersity index (PDI), and zeta potential. The resultant nanosuspension showed a mean particle size of 130.5 ± 1.22 nm with a PDI value of 0.27 ± 0.01, and a zeta potential of - 5.21 ± 0.91 mV. The nanosuspension was further characterized for morphology, dissolution, and in vivo pharmacokinetics study. X-ray powder diffraction study of the nano-formulation displayed a halo pattern revealing the amorphous form. Stability studies showed that the nanosuspension remained stable at 40 °C ± 2 °C and 75% RH ± 5% RH for a period of three months. In vitro drug release and solubility study showed threefold and 36-fold enhancement in dissolution and solubility of the nanosuspension. Furthermore, an in vivo pharmacokinetic study in Sprague-Dawley rats following oral administration displayed a 1.46-fold enhancement in the relative bioavailability of the nanosuspension in contrast to neat nilotinib.

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.

Biorelevant dissolution testing and physiologically based absorption modeling to predict in vivo performance of supersaturating drug delivery systems.

Supersaturating drug delivery systems (SDDS) enhance the oral absorption of poorly water-soluble drugs by achieving a supersaturated state in the gastrointestinal tract. The maintenance of a supersaturated state is decided by the complex interplay among inherent properties of drug, excipients and physiological conditions of gastrointestinal tract. The biopharmaceutical advantage through SDDS can be mechanistically investigated by coupling biopredictive dissolution testing with physiologically based absorption modeling (PBAM). However, the development of biopredictive dissolution methods possess challenges due to concurrent dissolution, supersaturation, precipitation, and possible redissolution of precipitates during gastrointestinal transit of SDDS. In this comprehensive review, our effort is to critically assess the current state-of-knowledge and provide future directions for PBAM of SDDS. The review outlines various methods used to retrieve physiologically relevant values for input parameters like solubility, dissolution, precipitation, lipid-digestion and permeability of SDDS. SDDS-specific parameterization includes solubility values corresponding to apparent physical form, dissolution in physiologically relevant volumes with biorelevant media, and transfer experiments to incorporate precipitation kinetics. Interestingly, the lack of experimental permeability values and modification of absorption flux through SDDS possess the additional challenge for its PBAM. Supersaturation triggered permeability modifications are reported to fit the observed plasma concentration-time profile. Hence, the experimental insights on good fitting with modified permeability can be potential area of future research for the development of in vitro methods to reliably predict oral absorption of SDDS.

Polymeric micelles based on amphiphilic oleic acid modified carboxymethyl chitosan for oral drug delivery of bcs class iv compound: Intestinal permeability and pharmacokinetic evaluation.

Chemical modification of chitosan derivatives with hydrophobic fatty acids to enhance their self-aggregation behavior is well established. Previously our group reported low molecular weight carboxymethyl chitosan (CMCS) which showed enhancement in apparent permeability of hydrophobic drug, tamoxifen. Further extension to this work, herein we synthesize a new polymer of oleic acid grafted low molecular weight carboxymethyl chitosan (OA-CMCS) for maneuvering biopharmaceutical performance of poorly water soluble drugs. This polymer was designed and synthesized via amidation reaction and well characterized by analytical tools like 1H-NMR and FT-IR spectroscopy. OA-CMCS conjugate easily self-organized into micelles like structure in an aqueous medium and showed a low critical micellar concentration of 1 µg/mL. Poorly water-soluble drug, docetaxel (DTX) was used as a model drug in this study. Optimization of variables resulted in the formation of spherical DTX loaded OA-CMCS micelles in the size range of 213.4 ± 9.6 nm with an entrapment efficiency of 57.26 ± 1.25%. DTX loaded OA-CMCS micelles showed slow and sustained DTX release behavior in simulated body fluid during in vitro release study. The permeability of DTX loaded OA-CMCS micelles across the gastrointestinal tract were investigated by in vitro Caco-2 cells model. The apparent permeability of DTX loaded OA-CMCS micelles improved up to 6.57-fold in comparison to free DTX suspension which indicates the increase in paracellular absorption of DTX. Additionally, in vivo pharmacokinetic study demonstrates an increase in Cmax (1.97-fold) and AUC (2.62-fold) for DTX loaded OA-CMCS micelles compared to free DTX suspension. Hence, we propose OA-CMCS as a promising cargo to incorporate drugs for enhancement of biopharmaceutical performance.