Explicating the molecular level drug-polymer interactions at the interface of supersaturated solution of the model drug: Albendazole.

Supersaturation as a formulation principle relates to the aqueous solubility of poorly soluble drugs in solution . However, supersaturation state of drugs tends to crystallize because of its thermodynamic instability thereby compromising the solubility and biopharmaceutical performance of drugs. The present study aims to investigate the supersaturation potential of albendazole (ABZ) and its precipitation via nucleation and crystal growth. We hypothesized the use of polymers will avoid ABZ precipitation by interacting with drug molecules. The drug polymer interactions are characterized using conventional methods of Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR) and Polarized light microscopy (PLM). We have used a novel approach of sum frequency generation (SFG) vibrational spectroscopic in exploring the drug polymer interactions at air-water interface. Recently we have reported the SFG for e rifaximin-polymer interactions (Singh et al., 2021). The supersaturation assay, saturation solubility studies and nucleation induction time analysis revealed polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP K30) as effective precipitation inhibitors thereby enhancing the ABZ equilibrium solubility and in vitro supersaturation maintenance of ABZ. Further, modification in the solid state of ABZ has confirmed the influence of polymers on its precipitation behaviour. We conclude that PVA and PVP K30 act as nucleation and crystal growth inhibitor, respectively for the precipitation inhibition of ABZ.

Combination of Phospholipid Complex and Matrix Dispersion.

Phospholipid complexation, despite being a successful, versatile, and burgeoning strategy, stickiness of phospholipids leads to suboptimal dissolution rate of drugs. This work was undertaken to fabricate simvastatin-phospholipid complex (SIM-PLC)-loaded matrix dispersion (SIM-PLC-MD) using Soluplus® as carrier material, to augment dispersibility and dissolution of SIM-PLC without altering complexation between simvastatin (SIM) and phospholipid. SIM-PLC and SIM-PLC-MD were prepared using solvent evaporation and discontinuous solvent evaporation techniques, respectively. The successful complexation was substantiated by FTIR method. Besides, PXRD and SEM studies disclosed the absence of crystallinity of SIM in both SIM-PLC and SIM-PLC-MD. The TEM analysis monitored the self-assembly of SIM-PLC and SIM-PLC-MD into colloidal structures, which could be correlated with redispersion in GIT fluids upon oral administration. The considerable increase in hydrophilicity of SIM-PLC-MD and SIM-PLC as evident from partition coefficient experiment can further be correlated with their remarkably improved solubility profiles in the following pattern: SIM-PLC-MD˃SIM-PLC˃SIM. Correspondingly, improved dispersibility of SIM-PLC-MD in comparison to SIM-PLC can be accountable for accelerated dissolution rate by 2.53-fold and 1.5-fold in pH 1.2 and 6.8 conditions, respectively. The oral pharmacokinetic evaluation in Sprague Dawley (SD) rats revealed 3.19-fold enhancement in oral bioavailability of SIM through SIM-PLC-MD when compared with plain SIM, whereas 1.83-fold increment was observed in the case of SIM-PLC. Finally, the efficacy experimentation in SD rats revealed that SIM-PLC-MD significantly reduced triglycerides and cholesterol levels in comparison to SIM and SIM-PLC. These outcomes suggest that a matrix dispersion strategy improves oral bioavailability and hypolipidemic activity of SIM.

Elucidating the Molecular Mechanism of Drug-Polymer Interplay in a Polymeric Supersaturated System of Rifaximin.

Supersaturated drug delivery system (SDDS) enables the solubility and sustained membrane transport of poorly water-soluble drugs. SDDS provides higher drug concentration in the dispersed phase and equilibrium in the continuous phase, which corresponds to amorphous solubility of the drug. Rifaximin (RFX) is a nonabsorbable BCS class IV drug approved for the treatment of irritable bowel syndrome and effective against Helicobacter pylori. RFX shows slow crystallization and precipitation in an acidic pH of 1.2-2, leading to obliteration of its activity in the gastrointestinal tract. The objective of the present study is to inhibit the precipitation of RFX, involving screening of polymers at different concentrations, using an in-house developed microarray plate method and solubility studies which set forth hydroxypropyl methylcellulose (HPMC) E15, Soluplus, and polyvinyl alcohol to be effective precipitation inhibitors (PIs). Drug-polymer precipitates (PPTS) are examined for surface morphology by scanning electron microscopy, solid-phase transformation by hot stage microscopy, the nature of PPTS by polarized light microscopy, and drug-polymer interactions by Fourier transform infrared and nuclear magnetic resonance spectroscopy. Besides, the unfathomed molecular mechanism of drug-polymer interplay is discerned at the air-water interface using sum-frequency generation spectroscopy to correlate the interfacial hydrogen bonding properties in bulk water. Surprisingly, all studies disseminate HPMC E15 and Soluplus as effective PIs of RFX.

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.

Successful oral delivery of fexofenadine hydrochloride by improving permeability via phospholipid complexation.

The present work aimed to enhance liposolubility along with intestinal permeability of BCS class III drug fexofenadine (FEX) via phospholipid complexation strategy in order to improve its oral bioavailability. This work demonstrated the minimized P-gp efflux and augmented absorption of FEX when fabricated as phospholipid complex. The fexofenadine-phospholipid complex (FEX-PLC) was prepared using widely used solvent evaporation method. Among three phospholipids, Phospholipon® 90 H was screened out for further studies due to high drug content and physical form. The FTIR spectra demonstrated the disappearance of characteristic peaks of FEX which could be attributed to shielding by phospholipid due to molecular interactions between FEX and phospholipid. The differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) revealed the amorphous state of FEX in the complex. The partition coefficient study indicated the increased in lipophilicity which can further be correlated with 1.85 ± 0.850 fold enhancement in intestinal permeability of FEX-PLC in comparison to FEX in Caco-2 permeability assay. Furthermore, efflux ratio of FEX was decreased significantly from 4.04 (FEX) to 1.34 (FEX-PLC) which indicated inhibition of P-gp efflux of FEX. The in vivo evaluation in Wistar rats presented 3.38 fold increment in oral bioavailability of FEX-PLC as compared to FEX. In summary, the phospholipid complexation demonstrated as a simple and promising approach to tackle oral bioavailability hurdles of BCS class III drugs and convert them to BCS class I drugs.

Enhanced Biopharmaceutical Performance of Rivaroxaban through Polymeric Amorphous Solid Dispersion.

Rivaroxaban (RXB) is an orally active direct inhibitor of the activated serine protease Factor Xa, given as monotherapy in the treatment of venous thromboembolism (VTE). It has been characterized in vitro as a substrate for the active, nonsaturable efflux via P-gp transporter, limiting its high permeability. Therefore, the role of P-gp inhibiting polymers in enhancing the biopharmaceutical performance of RXB by preparing polymeric amorphous solid dispersion and subsequent improvement in solubility and permeability was investigated. Initially, solubility parameter and Flory-Huggins interaction parameter were determined for miscibility studies between drug and polymers. Binary dispersions were prepared by dissolving drug with polymers eudragit S100, eudragit L100, and soluplus in common solvent (5% v/v water in tetrahydrofuran) using spray dryer. Prepared binary dispersions were analyzed by differential scanning calorimetry (DSC), microscopy, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR), dynamic vapor sorption (DVS), and solution nuclear magnetic resonance (NMR) spectroscopy. Superior performance of binary dispersions was observed upon dissolution and solubility studies over micronized active pharmaceutical ingredient. Amorphous solid dispersion (ASD) prepared with soluplus showed 10-fold increase in apparent solubility and maintenance of supersaturation for 24 h compared to the crystalline RXB. Further, pharmacokinetic study performed in animals was in good correlation with the solubility data. Increases of 5.7- and 6.7-fold were observed in AUC and Cmax, respectively, for ASDs prepared with soluplus compared to those with crystalline RXB. FTIR and NMR spectroscopy unveiled the involvement of N-H group of RXB with C═O group of polymers in intermolecular interactions. The decreased drug efflux ratio was observed for ASDs prepared with eudragit S100 and soluplus in Caco-2 transport study suggesting improvement in the absorption of RXB. Hence, the present study demonstrates ASD using soluplus as a promising formulation strategy for enhancing the biopharmaceutical performance of RXB by increasing the solubility and circumventing the P-gp activity.

Freeze dried solid dispersion of exemestane: A way to negate an aqueous solubility and oral bioavailability problems.

This study was envisaged to demonstrate the potential of exemestane loaded phospholipid/sodium deoxycholate solid dispersions (EXE-PL/SDC-SDs) on the solubility and oral bioavailability of EXE. Initial studies were performed to screen the best suitable phospholipid among lysophosphatidylcholine, Phospholipon® P80H and Lipoid® E80S for solid dispersion preparation. Further studies were carried out to optimize the molar concentration of phospholipid and sodium deoxycholate (SDC) for EXE-PL/SDC-SDs preparation. Optimized EXE-PL/SDC-SDs was prepared using Lipoid® E80S and SDC in 1:4M concentration, respectively and lyophilized using 10% w/w 2-hydroxypropyl-ß-cyclodextrin (2-HPCD). The physical state of EXE in lyophilized formulation was confirmed by DSC and PXRD. Lyophilized formulation exhibits a significant increase in solubility and dissolution rate as compared to free drug EXE. Apparent permeability study was performed on Caco-2 cell line for 2h. The lyophilized EXE-PL/SDC-SDs exhibits 4.6-fold increase in absorptive transport as compared to EXE. Pharmacokinetic study in fasted female Sprague-Dawley rats revealed a 2.3-fold increase in AUC0-72h. Thus, the results suggest that PL/SDC-SDs is a promising carrier for EXE delivery.

Potential of amphiphilic graft copolymer α-tocopherol succinate-g-carboxymethyl chitosan in modulating the permeability and anticancer efficacy of tamoxifen.

Recent studies showed an enhanced oral bioavailability of tamoxifen (TMX) by hydrophobically modified α-tocopherol succinate-g-carboxymethyl chitosan (Cmc-TS) micelles. As a continued effort, here we evaluated TMX-loaded polymeric micelles (TMX-PMs) for its enhanced permeability with increased anticancer efficacy and decreased hepatotoxicity. We employed co-solvent evaporation technique to encapsulate TMX into Cmc-TS. Apparent permeability assay of TMX-PMs was performed on Caco-2 cell line. The absorptive transport of TMX increased significantly about 3.8-fold when incorporated into Cmc-TS PMs. Cytotoxicity of Cmc-TS PMs was studied on MCF-7 cell line by MTT and; confocal microscopy was used for cellular uptake. Confocal microscopy revealed that Cmc-TS PMs could effectively accumulate in the cytosol of MCF-7 cell lines. In vitro data was further validated using N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model in Sprague-Dawley rats. Hepatotoxicity profiles of TMX-PMs at three different doses were also evaluated against the free drug TMX. TMX-PMs were more effective in suppressing breast tumor in MNU-induced mammary carcinoma model than free TMX with better safety profile. In addition, histological data shows that tumors are "benign" in TMX-PMs treated group compared with "malignant" tumors in free TMX treated and control groups. Overall, the results implicate that our Cmc-TS PMs may serve as a promising carrier for the intracellular delivery of anticancer drug molecules via oral route.

Alpha-lipoic acid-stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study.

OBJECTIVES: This study was designed to demonstrate the potential of novel α-lipoic acid-stearylamine (ALA-SA) conjugate-based solid lipid nanoparticles in modulating the pharmacokinetics and hepatotoxicity of tamoxifen (TMX). METHODS: α-lipoic acid-stearylamine bioconjugate was synthesized via carbodiimide chemistry and used as a lipid moiety for the generation of TMX-loaded solid lipid nanoparticles (TMX-SLNs). TMX-SLNs were prepared by solvent emulsification-diffusion method and optimized for maximum drug loading using rotatable central composite design. The optimized TMX-SLNs were stabilized using 10% w/w trehalose as cryoprotectant. In addition, pharmacokinetics and hepatotoxicity of freeze-dried TMX-SLNs were also evaluated in Sprague Dawley rats. KEY FINDINGS: Initial characterization with transmission electron microscopy revealed spherical morphology with smooth surface having an average particle size of 261.08 ± 2.13 nm. The observed entrapment efficiency was 40.73 ± 2.83%. In-vitro release study showed TMX release was slow and pH dependent. Pharmacokinetic study revealed a 1.59-fold increase in relative bioavailability as compared to TMX suspension. A decrease in hepatotoxicity of TMX is evidenced by the histopathological evaluation of liver tissues. CONCLUSIONS: α-lipoic acid-stearylamine conjugate-based SLNs have a great potential in enhancing the oral bioavailability of poorly soluble drugs like TMX. Moreover, this ALA-SA nanoparticulate system could be of significant value in long-term anticancer therapy with least side effects.

Injectable photocrosslinkable nanocomposite based on poly(glycerol sebacate) fumarate and hydroxyapatite: development, biocompatibility and bone regeneration in a rat calvarial bone defect model.

AIM: An injectable, photocrosslinkable nanocomposite was prepared using a fumarate derivative of poly(glycerol sebacate) and nanohydroxyapatite. MATERIALS & METHODS: Polymers with varying physical and mechanical properties were synthesized. Furthermore, nanocomposites were developed using a homogenization process by combining nanohydroxyapatite within poly(glycerol sebacate) matrix via photocrosslinking and evaluated both in vitro and in vivo. RESULTS & DISCUSSION: The nanocomposites were injectable, highly bioactive and biocompatible. Addition of nanohydroxyapatite led to enhanced mechanical properties with an ultimate strength of 8 MPa. The optimized nanocomposite showed good in vitro cell attachment, proliferation and differentiation of rat bone marrow-derived mesenchymal stem cells. The in vivo evaluation in a rat calvarial bone defect model showed significantly high alkaline phosphatase activity and bone regeneration. CONCLUSION: This injectable, biocompatible and bioactive in situ hardening composite graft was found to be suitable for load-bearing bone regeneration applications using minimally invasive surgery.