Formulation and <i>in Vitro</i> Evaluation of Self-microemulsifying Drug Delivery System Containing Fixed-Dose Combination of Atorvastatin and Ezetimibe

Abstract

This paper focuses on the development and physicochemical characterization of a self-microemulsifying drug delivery system (SMEDDS) containing a fixed-dose combination of atorvastatin (ATR) and ezetimibe (EZT). The solubility of both drugs was determined in excipient screening studies. Ternary-phase diagrams were drawn for 27 systems composed of different surfactants, cosurfactants, and oils at different surfactantto-cosurfactant (S/CoS) ratios, and the system exhibiting the largest percentage area of the self-microemulsifying region was selected. The optimum oil ratio in the SMEDDS was selected by evaluating the mean droplet size of the resultant microemulsions. The underlying mechanism of the lower ATR loading capacity compared with EZT was elucidated by measurement of the zeta potential and UV absorption analysis. The results implied that ATR was located exclusively in the surfactant-cosurfactant layer, whereas EZT was located both in the microemulsion core and the surfactant-cosurfactant layer. In vitro dissolution studies showed that the SMEDDS had higher initial dissolution rates for both drugs when compared with marketed products. More importantly, EZT had a significantly increased dissolution profile in distilled water and pH 4.0 acetate buffer, implying enhanced bioavailability.Key words self-microemulsifying drug delivery system; fixed-dose combination; ezetimibe; atorvastatin calcium; solubilization Atorvastatin (ATR) is a fully synthetic drug that lowers cholesterol level by competitively blocking 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. However, it has an absolute bioavailability of only 14% due to rapid clearance by CYP3A4 in gastrointestinal mucosa and liver. 1) Ezetimibe (EZT) is a lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. However, EZT has a very low solubility and dissolution rate resulting in highly variable bioavailability, which is also in part due to extensive efflux by p-glycoprotein (P-gp). 2,3)When co-administered with statins, EZT provides significant incremental reductions in low density lipoprotein (LDL)-cholesterol and triglycerides and increases in high density lipoprotein (HDL)-cholesterol when compared with statin monotherapy.4) Co-administration of EZT and ATR is well tolerated with no serious adverse effects. 5) Therefore, the addition of 10 mg EZT to low-dose ATR therapy may significantly reduce the risk of severe side effects, such as myopathy, while increasing its efficacy.Despite the clear synergism of the two drugs, incorporating both drugs in one drug delivery system poses some challenges due to different physicochemical properties. ATR is a weak acid with a solubility of 0.8 mg/mL and pK a of 4.46. 6) On the contrary, EZT is a practically insoluble and weakly basic compound with solubility of 0.012 mg/mL, and pK a of 9.75. 7)Therefore, it may be difficult for both drugs to be solubilized using a single solubilizing agent or strategy (e.g., pH-modifying...

Self Nanoemulsifying Drug Delivery System: A Comrhensive Review

“…Determination of Chemical Substances Using Reverse Phase HPLC Methods Using Chromatography Columns with Different Porosity. [35] ISSN: 2320-4850…”

“…or less. [21] This emulsion forms spontaneously in the intestinal tract, allowing the drug to dissolve. SNEDDS is also important to create a wide interface for distributing the hydrophobic drug between the oil and aqueous phase, increasing the overall bioavailability of the drug.…”

“…SNEDDS is also important to create a wide interface for distributing the hydrophobic drug between the oil and aqueous phase, increasing the overall bioavailability of the drug. Typical structure of SNEDDS [10] Nanoemulsion Types [35] Nanoemulsions are divided into three groups according to their composition. Mechanism of SNEDDS [12] Self-emulsification is a phenomenon that occurs during the formation SEDDS.This occurs when the entropy change favoring dispersion exceeds the energy required to form an emulsion surface.…”

“…100nm, It should be optically transparent after dispersion and HLBvalueshould be higher than 12 [10][11] . [35] Nanoemulsion has three main components: 2).…”