There is a growing pharmaceutical interest in supersaturated lipid-based formulations (Super-LbF) as an innovative strategy to enhance drug loading capacities while simultaneously reducing pill burden. This approach involves increasing the drug concentration above its equilibrium solubility in a lipid solution, achieved through temperature-induced supersaturation or the dissolution of lipophilic ionic salts. However, the physical instability and potential drug precipitation upon the dispersion of LbF remain critical.
View Article and Find Full Text PDFUnderstanding the mechanisms underlying the dispersion and digestion process is vital in the development of oral lipid-based formulations (LBFs). In vitro lipolysis models mimic the digestion process in the stomach and intestine to explore the fundamental mechanism of supersaturation, solubilization, and precipitation of drugs within the LBFs. The lipid digestion is controlled by the in vitro experimental conditions, and constitution of the lipid formulations.
View Article and Find Full Text PDFLipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility.
View Article and Find Full Text PDFPretomanid (PTM), an oral antibiotic used in the treatment of adults with pulmonary extensively drug-resistant, nonresponsive multidrug-resistant tuberculosis (MDR-TB). It is a poor glass former, that shows high recrystallization tendency from the amorphous and supersaturated state, resulting in low aqueous solubility and suboptimal absorption through the gastrointestinal tract. The present investigation aimed to develop high drug loaded ternary amorphous solid dispersions (ASDs) of PTM with improved stability and enhanced biopharmaceutical performance by utilizing a combination of polymers.
View Article and Find Full Text PDFLipid-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.
View Article and Find Full Text PDFPazopanib 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.
View Article and Find Full Text PDFThe propensity of poorly water-soluble drugs to aggregate at supersaturation impedes their bioavailability. Supersaturated amorphous drug-salt-polymer systems provide an emergent approach to this problem. However, the effects of polymers on drug-drug interactions in aqueous phase are largely unexplored and it is unclear how to choose an optimal salt-polymer combination for a particular drug.
View Article and Find Full Text PDFLignin, a versatile and abundant biomass-derived polymer, possesses a wide array of properties that makes it a promising material for biotechnological applications. Lignin holds immense potential in the biotechnology and pharmaceutical field due to its biocompatibility, high carbon content, low toxicity, ability to be converted into composites, thermal stability, antioxidant, UV-protectant, and antibiotic activity. Notably, lignin is an environmental friendly alternative to synthetic plastic and fossil-based materials because of its inherent biodegradability, safety, and sustainability potential.
View Article and Find Full Text PDF"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.
View Article and Find Full Text PDFUnderstanding 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.
View Article and Find Full Text PDFCombination drug therapy (CDT) plays an immense role in the treatment of various diseases such as malaria, hypertension, cancer, HIV-AIDS, helminthiasis, and many more. However, in vitro drug-drug interaction (DDI) is not well reported for better efficacy of CDT. In DDI one drug may enhance the precipitation of other drugs thereby reducing the advantage of CDT.
View Article and Find Full Text PDFSupersaturation 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.
View Article and Find Full Text PDFSupersaturating 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).
View Article and Find Full Text PDFPhospholipid 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.
View Article and Find Full Text PDFNumerous amorphous solid dispersion (ASD) formulations of celecoxib (CEL) have been attempted for enhancing the solubility, dissolution rate, and in vivo pharmacokinetics via high drug loading, polymer combination, or by surfactant addition. However, physical stability for long-term shelf life and desired in vivo pharmacokinetics remains elusive. Therefore, newer formulation strategies are always warranted to address poor aqueous solubility and oral bioavailability with extended shelf life.
View Article and Find Full Text PDFCo-amorphous (CAM) systems are promising drug-delivery systems in the arena of therapeutic drug delivery, addressing the poor aqueous solubility of drugs by enhancing solubility and thereby improving the oral bioavailability and therapeutic effect of the drug. A CAM system is a single-phase homogeneous blend of two or more low molecular weight molecules that can be drug-drug or drug-co-former, stabilized via intermolecular interactions, adding the benefit of thermodynamic stability. This review covers the fundamentals of CAM systems and recent advances in formulation development.
View Article and Find Full Text PDFSupersaturated 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 RFX shows slow crystallization and precipitation in an acidic pH of 1.
View Article and Find Full Text PDFRationale: Nintedanib, an oral, triple angiokinase inhibitor, is used alongside docetaxel in the management of locally recurrent non-small-cell lung cancer and idiopathic pulmonary fibrosis. The present study deals with the identification and characterization of in vitro and in vivo stable and reactive (if any) metabolites of nintedanib and sheds light on some novel metabolites of the drug which have not been reported previously.
Methods: The study involved an oral administration of the drug to male Wistar rats, followed by collection of the biological matrices (urine, plasma and feces) at specific intervals for determination of in vivo metabolites.
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.
View Article and Find Full Text PDFCetilistat (CET) is a pancreatic lipase inhibitor approved for management of obesity after the serious adverse effects exhibited by its analogue orlistat. Exhaustive literature review reveals lack of comprehensive reports on its biotransformation. With a view to study the same, the present study reports the identification and characterization of metabolites of CET in rats using UPLC-MS/MS.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFPoorly soluble weak bases form a significant proportion of the drugs available in the market thereby making it imperative to understand their absorption behavior. This work aims to mechanistically understand the oral absorption behavior for a weakly basic drug, Irbesartan (IRB), by investigating its pH dependent solubility, supersaturation, and precipitation behavior. Simulations performed using the equilibrium solubility could not accurately predict oral absorption.
View Article and Find Full Text PDFSupersaturating drug delivery systems (SDDS) have dominated the commercial and academic spheres owing to their potential in overcoming the solubility issue of poorly soluble drugs. Precipitation inhibitors are used as excipients in such formulations which has necessitated the development of supersaturation assays that evaluate their precipitation-inhibition efficacy. Such assays are able to give relative estimates of polymer efficacy ceteris paribus within a given set-up.
View Article and Find Full Text PDFThere is an overgrowing emphasis on supersaturating drug delivery systems (SDDS) with increase in number of poorly water-soluble compounds. However, biopharmaceutical performance from these formulations is limited by phase transformation to stable crystalline form due to their high-energy physical form. In the present study, in vitro kinetic solubility in water and dissolution in biorelevant medium integrated with in silico physiologically based pharmacokinetic (PBPK) modeling was used to predict biopharmaceutical performance of SDDS of poorly water-soluble compound, carbamazepine (CBZ).
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