Surface stabilized atorvastatin nanocrystals with improved bioavailability, safety and antihyperlipidemic potential

Abstract

Atorvastatin, a favored option for hyperlipidemia exhibits the problem of poor gastric solubility and low absolute bioavailability (12%) along with higher pre-systemic clearance (>80%). Therefore, to circumvent these limitations, atorvastatin nanocrystals were prepared using poloxamer-188 as stabilizer via high pressure homogenization technique followed by lyophilization. Various variables like drug to poloxamer-188 ratio, homogenization cycle, homogenization pressure, type and concentration of cryoprotectant were optimized to achieve uniform nanosized crystals with good dispersibility. Solid state characterization by ATR-FTIR and DSC revealed no incompatible physicochemical interaction between drug and excipients in formulation while DSC and PXRD collectively corroborated the reduced crystallinity of drug in nanocrystals. Size analysis and SEM confirmed nanometric size range of nanocrystals (225.43 ± 24.36 nm). Substantial improvement in gastric solubility (~40 folds) and dissolution rate of drug in nanocrystals was observed. Pharmacokinetic study in wistar rats revealed significant improvement in oral bioavailability (~2.66 folds) with atorvastatin nanocrystals compared to pure drug. Furthermore, reduction in serum total lipid cholesterol, LDL and triglyceride content justified the effectiveness of formulation at 50% less dose of atorvastatin along with improved plasma safety profile in comparison of pure drug. In conclusion, atorvastatin nanocrystals are safe and efficacious drug delivery system confirming potent competence in treatment of hyperlipidemic conditions with ease of scalability for commercialization.

Comprehensive Study of Atorvastatin Nanostructured Lipid Carriers through Multivariate Conceptualization and Optimization

“…FTIR spectra of Atorvastatin, the optimized AT-NLC formulation, plain NLC formulation, and physical lipid mixture are shown in Figure 9. The FTIR spectrum of pure AT showed distinctive peaks at 3668.9 cm −1 (non-hydrogen-bonded O-H), 3364.2 cm −1 (N-H stretching), 3250.4 cm −1 (symmetrical O-H stretching), 2968.87 cm −1 (C-H stretching), 2920.66 cm −1 (C-H, aromatic), 1650.77 cm −1 (asymmetric C=O stretching), 1578.45 cm −1 (N-H bending), 1511.92 cm −1 (C-N stretching), 1434.78 cm −1 (O-H bending), and 1380.78 cm −1 (C-O stretching) of the carboxyl group, which were already reported in many studies [11,53]. AT-NLC spectrum revealed the disappearance of the 3668.9 cm −1 (non-hydrogen-bonded O-H) and 3364.2 cm −1 (O-H stretching) AT peaks compared to the pure AT spectrum.…”

“…Additionally, four animals were fed with a normal diet to serve as a negative control. Blood samples were collected from the caudal vein of animals and evaluated for serum lipid levels [ 11 ]. A considerable elevation in serum lipid levels indicated the establishment of hyperlipidemia with the high-fat diet.…”

“…After two weeks of treatment, blood samples were collected and centrifuged at 5000 rpm for 10 min to separate the plasma. The collected plasma samples were assayed for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels using a commercially available diagnostic kit (Span Diagnostic Ltd., Surat, India) [ 11 ].…”

“…Lipid-based formulations have emerged as excellent carriers for oral formulations due to the diverse physicochemical properties of lipids, their biocompatibility, and lymphatic uptake, especially for drugs suffering from first-pass effect and incomplete intestinal absorption [ 7 ]. Several lipid-based formulations have been used to improve the bioavailability of AT such as self-emulsifying drug delivery systems (SEDDS) [ 8 ], a self-nano emulsifying drug delivery system (SNEDDS) [ 9 ], solid lipid nanoparticles (SLNs) [ 10 ], and nanocrystals [ 11 ]. Nanostructured lipid carriers (NLCs) are second-generation solid lipid nanoparticles (SLNs) that combine the advantages of the SLN with high entrapment efficiency and reduced drug leakage throughout storage [ 12 ].…”

Formulation and Evaluation of Atorvastatin Calcium Nanocrystals Containing P-Glycoprotein Inhibitors for Enhancing Oral Delivery

“…It was also observed that the cumulative percentage of drug released in F1 and F2 were not significantly higher than drug (P<0.05) and they took a longer time to dissolve completely proofing that the aggregation hindered the dissolution [23]. These findings indicate that 0.3 % of PEG 300 and PEG 400 were not sufficient to achieve better formulas.…”