Abstract
Self-emulsifying pellets (SEPs) of Atorvastatin Calcium (AtrCa) were developed and processed into tablets (SETs). Self-emulsifying drug delivery system (SEDDS) composed of oleic acid, Tween 20, Span 80 and N-Methyl-2-pyrolidone gave great solubility improvement and was used as oil in water emulsion for the preparation of SEPs. Due to the high 60% w/w SEDDS content required to achieve a therapeutic dose in the final tablet form, sonication was necessary to improve fluidity and stability. Colloidal silicon dioxide (CSD) and microcrystalline cellulose (MCC) were the solids in the pellet formulation employed at a ratio 7:3, which enabled production of pellets with high SEDDS content and acceptable friability as well. Emulsions were characterized physico-chemically, SEPs for physical properties and reconstitution, and tablets of compressed pellets for mechanical strength, disintegration into pellets and drug release. SEPs compressed with 30% MCC at 60 MPa gave tablets of adequate strength that disintegrated rapidly into pellets within 1 min. Emulsion reconstitution took longer than drug release due to adsorption of SEDDS on CSD, implying dissolution at the pellet surface in parallel to that from the dispersed droplets. Compared to the commercial tablet, drug release from the self-emulsifying forms was faster at pH 1.2 where the drug solubility is poor, but slower at pH 6.8 where the solubility is higher. Permeability and cytotoxicity were also studied using Caco-2 cells. The results showed that drug transport from the apical to basolateral compartment of the test well was 1.27 times greater for SEPs than commercial tablets, but 0.86 times lower in the opposite direction. Statistical analysis confirmed the significance of these results. Toxicity was slightly reduced. Therefore, the increased permeability in conjunction with the protection of the drug being dissolved in the SEDDS droplets, may reduce the overall effect of presystemic metabolism and enhance bioavailability.
Highlights
Hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood.Hypercholesterolemic patients have a high risk of developing a form of heart disease known as coronary artery disease [1]
Atorvastatin is indicated for the reduction of total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B in adult patients with familial hypercholesterolemia, in cases where response to diets and other methods is inadequate [2]
It is used as atorvastatin calcium trihydrate (AtrCa) which according to the Biopharmaceutics Classification System (BCS) is a class 2
Summary
Hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood.Hypercholesterolemic patients have a high risk of developing a form of heart disease known as coronary artery disease [1]. Atorvastatin is indicated for the reduction of total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B in adult patients with familial hypercholesterolemia, in cases where response to diets and other methods is inadequate [2]. It is used as atorvastatin calcium trihydrate (AtrCa) which according to the Biopharmaceutics Classification System (BCS) is a class 2. Processes 2019, 7, 365 drug with low solubility, which together with its high (above 80%) presystemic clearance are the main reasons for its low oral bioavailability (12% after a 40 mg oral dose) [3]. There is scope for increasing the bioavailability of ATrCa by increasing both dissolution and permeability, since reduction of the residence time in the gut and intestine will reduce the effect of presystemic metabolism [4,5].
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