Chitosan based atorvastatin nanocrystals: effect of cationic charge on particle size, formulation stability, and in-vivo efficacy

Abstract

Cationic charged chitosan as stabilizer was evaluated in preparation of nanocrystals using probe sonication method. The influence of cationic charge densities of chitosan (low CS L , medium CS M , high CS H molecular weights) and Labrasol ® in solubility enhancement and modifying the release was investigated, using atorvastatin (ATR) as poorly soluble model drug. Compared to CS M and CS H ; low cationic charge of CS L acted as both electrostatic and steric stabilizer by significant size reduction to 394 nm with charge of 21.5 meV. Solubility of ATR-CS L increased to 60-fold relative to pure ATR and ATR-L. Nanocrystals were characterized for physiochemical properties. Scanning electron microscopy revealed scaffold-like structures with high surface area. X-ray powder diffractometry and differential scanning calorimetry revealed crystalline to slight amorphous state changes after cationic charge size reduction. Fourier transform-infrared spectra indicated no potent drug-excipient interactions. The enhanced dissolution profile of ATR-CS L indicates that sustained release was achieved compared with ATR-L and Lipitor ® . Anti-hyperlipidemic performance was pH dependent where ATR-CS L exhibited 2.5-fold higher efficacy at pH 5 compared to pH 6 and Lipitor ® . Stability studies indicated marked changes in size and charge for ATR-L compared to ATR-CS L exemplifying importance of the stabilizer. Therefore, nanocrystals developed with CS L as a stabilizer is a promising choice to enhance dissolution, stability, and in-vivo efficacy of major Biopharmaceutical Classification System II/IV drugs.

Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications

“…Recently a research group have reported the use of chitosan as a cationic stabilizer for preparation of itraconazole nanocrystals using the conventional method of HPH method and investigated its stabilization effect. Physical stability of prepared nanocrystals was found to be significantly improved without any changes or new modification observed in crystal structure 94 . Another research group working on chitosan-based atorvastatin nanocrystals investigated the effect of the cationic charge of stabilizer on the nanocrystals particle size and stability.…”

“…Another research group working on chitosan-based atorvastatin nanocrystals investigated the effect of the cationic charge of stabilizer on the nanocrystals particle size and stability. Nanocrystals of the drug were prepared with desired specifications and effect of chitosan as potential stabilizer has been evaluated 94 .…”

In Situ Gel Loaded with Chitosan-Coated Simvastatin Nanoparticles: Promising Delivery for Effective Anti-Proliferative Activity against Tongue Carcinoma

“…When their concentrations are very low, formed nanoparticles show larger particle sizes and even higher concentrations of these factors, resulting in the formation of larger nanoparticles. This might be because of the repulsion of amino groups in chitosan molecules at higher concentrations and the addition of poloxamer 188 might promote further aggregation, which leads to precipitation, forming NPs with larger particle sizes [31]. The size of NPs can affect their distribution, for which lower liver uptake can be observed with smaller particle sizes of 25-50 nm in comparison to 150-300 nm-sized NPs and thus bioavailability.…”

Novel Approaches to Enhance Oral Bioavailability of Poorly Soluble Drugs

“…Nanocrystals are having the atoms size in the range of 10-400 nm, prepared from nanosuspension consisting of the following steps. i) preparation of nanosuspension, ii) wet milling, iii) high pressure homogenization iv) nanocrystallization and v) spray drying [24,25] . Mallesh Kurakula et al, have investigated the efficacy of nanocrystals in enhancing the solubility and dissolution rate of Atorvastatin [26] .…”