Effect of Physicochemical Properties of Emulsions Formed by Self-Emulsifying Drug Delivery Systems (Sedds) on the Solubilization State of Drug: In Vitro Study

Abstract

Objective: Parameters in the oil pre-concentrate which can affect the solvent capacity of the resultant dispersion such as, oil-cosurfactant ratio, type of surfactant used in the system, the inclusion of water soluble co-solvents and the solubilization capacity of native surfactants such as, bile salts and lecithin were studied in an attempt to circumvent crystallization of drug during its passage in the gut.Methods: Different types of self-emulsifying systems representing type II, IIIA and IIIB, were used to probe the influence of the various physicochemical properties of the resultant dispersions on the fate of dissolved model lipophilic drug. This was achieved by studying emulsification behavior of lipid systems in fed and fasted biological fluids, analyzing solubilization/drug crystallization kinetics and oil droplet diameter measurement.Results: Self-micro-emulsifying lipid systems lost solvent capacity on dispersion and were not able to keep the drug in solution at equilibrium. Miglyol 812/Imwitor ratio in the pre-concentrate mixture appeared to influence the kinetics of drug crystallization. Pre-microemulsion systems containing Tagat TO dispersions were found to hold more drugs in solution at equilibrium than in the case of systems containing Cremophor RH40. The inclusion of as little as 10-20% PEG in the lipid mixture accelerated drug precipitation. Bile salt-lecithin mixed micelles appears to some extent enhance the solubilization capacity of these systems after dispersionConclusion: Solvency of emulsions formed by self-emulsifying drug delivery in various emulsification media is a crucial parameter influencing the fate of dissolved drug after the dispersion of the formulations.

Impact of a formulation design on resultant dispersions of self-microemulsifying lipid systems

“…Nano-sized emulsions have a relatively large interfacial area of contact with gut lumen fluids which mimic absorption through augmenting partitioning of drugs from the oil phase to the aqueous phase. Furthermore, it was found that ionic strength and electrolytes present in the emulsification media affect resultant dispersions of lipidic SMEDDS (Hasan, 2014(Hasan, , 2019a. This effect is minimized in the case of using a nonionic surfactant system with a relatively high HLB value > 12.…”

“…At a constant amount of loaded drug, increasing PEG in the oil mixtures has ensued in a corresponding increase in MEDS. Despite the hydrophilic nature of PEG, it has shown low solubilization capacity compared to other hydrophilic cosolvents such as transcutol (Hasan, 2019a). Furthermore, at constant PEG concentrations, increasing the amount of loaded drug in the lipid vehicle results in progressive increases in MEDS.…”

“…Among these are formulationbased factors that control hydrophilicity of vehicle including type and amount of oil (source of triglyceride and/or mixed glycerides), surfactant, and cosolvents. Endogenous-based factors include ionic strength of dispersion media and solubilization capacity of native surfactants such as bile salts and lecithin (Hasan, 2019a). The inclusion of increasing amounts of hydrophilic materials in the lipid mix may prompt drug crystallization in the lumen of gut.…”

“…Hydrophilic components diffuse out from the vehicle after dispersion and thus any amount of drug carried by the hydrophilic constituents will be prone to precipitation. The propensity of drug precipitation during various stages of the dilution process which takes place during passage in the gut was investigated in various reports (Hasan et al, 2015;Hasan, 2019a;Mohsin and Alanazi, 2012;Mohsin et al, 2009;Porter et al, 2004). Despite the in vitro substantiated evidence of the propensity of the drug to come out of solution due to the hydrophilic nature of lipid vehicle, we have marketed products based on cosolvent systems such as Ibuprofen liquigel (Nurofen ® by GSK or Advil ® by Pfizer) (Al Lawati and Jamali, 2016) and free oil system as in Agenerase ® (Rahman et al, 2012).…”

“…Since the advent of Neoral ® , an archetypical SMEDDS reformulation of earlier "Sandimmune" formulation, more than 30 products are now commercially available in the market, which are based on self-emulsifying lipid-based technology (Savla et al, 2017). Formulation design of successful SMEDDS requires lipid mixtures with optimum polarity to ensure fine aqueous dispersions with and without drugs, exhibit enough solubility to dissolve required dose and ability to hold the drug after dispersion, and thus prevent crystallization of drug and the flexibility to free the drug during digestion process to get good absorption profiles (Hasan, 2019a(Hasan, , 2014. In this study, various factors in the lipid mixture which affect dispersion profiles of SMEDDS with and without drug were investigated.…”