Formulation Development and <i>In-Vivo</i>Evaluation of Atorvastatin Calcium Solid Dispersion in Streptozotocin Induced Diabetic Mice

Atorvastatin calcium (ATV) is a selective competitive inhibitor of HMG CoA reductase characterized by poor aqueous solubility leading to inadequate bioavailability. The present study was designed to develop solid dispersion of atorvastatin (SDA) to improve the solubility and dissolution properties of ATV and evaluation of its in-vivo efficiency in streptozotocin (STZ) induced diabetic mice. Formulations of SDA were prepared by solvent evaporation method using PEG-4000 alone and/or mixture of PEG-4000 and Carplex-80 as carrier in different ratios. Solid-state analyses of SDA were performed to characterize the physicochemical properties of newly developed SDA by differential scanning calorimetry (DSC), powder x-ray diffractometry (PXRD), fourier transformed infrared spectra (FTIR) and scanning electron microscopy (SEM). DSC and PXRD showed that the crystallinity of drugs was notably decreased during the preparation of SDA. FTIR and SEM also demonstrated the conversion of ATV from amorphous to crystalline state resulting in improved solubility. Among formulations, SDA-5 showed significant enhancement of in-vitro drug release (around 2 fold higher) as compared to pure ATV. Further, in-vivo study was conducted to evaluate the effects of a newly developed ATV loaded solid dispersion on glycemic control, lipid profile, liver enzyme and histopathology in STZ induced diabetic mice. Oral administration of SDA significantly lowered the blood glucose levels during the course of treatment. Treatment with SDA significantly improved lipid profiles better than ATV alone and the effect was dose-dependent. After one week of SDA treatment significantly decreased liver weights as result of lipid clearance and the hepatocytes regained their normal architecture, and these beneficial effects can be correlated with the reduction of SGPT levels. The results demonstrated that, SDA exerted better glycemic control, lipid lowering effect and organ protection (liver and pancreas) than that of conventional ATV in STZ induced diabetic mice. The mechanism by which SDA conferred better improvement in diabetic conditions can be partially explained by enhancement of solubility and dissolution rate when ATV is loaded in solid dispersion.

Preparation and Antidiabetic Effect of Orally Administered Nifedipine‐Loaded Solid Lipid Nanoparticles in Fructose-Induced Diabetic Rats

The use of Nifedipine (NI), a dihydropyridine calcium channel blocker, is limited due to its poor aqueous solubility. However, NI loaded solid-lipid nanoparticles (NI-SLN) are known to exhibit suitable pharmacokinetic properties and good biocompatibility. The present investigation was designed to evaluate the effects of NI-SLN on glucose homeostasis, lipid metabolism and liver function in fructose-induced diabetic rats. NI-SLN was prepared by high pressure homogenization technique followed by lyophilization with trehalose as cryoprotectant. Diabetes was induced into rats by the administration of fructose (10%) in drinking water for six weeks. After induction of diabetes, rats were divided into four groups for the oral ingestion of NI, NI-SLN and/or vehicles and their effects on blood glucose levels, oral glucose tolerance test (OGTT), lipid profile, biochemical parameters, electrolytes and histopathology were observed. Single dose administration and treatment with NI-SLN showed significant glucose lowering efficacy in fructose-induced diabetic rats. Although NI and NI-SLN did not alter the fasting blood glucose level in normal rats, diabetic rats treated with NI-SLN resulted in significant reduction in glucose level for 24 hr. In OGTT, NI-SLN exhibited significant antihyperglycemic activity in both normal and diabetic rats. So, NI-SLN has better glucose lowering efficacy than that of pure NI in diabetic rats. The survival rates in rats among the treatment groups were 100%. Treatment with NI-SLN significantly improved lipid profiles than NI alone and the effect was dose-dependent. Administration of NI-SLN significantly reduced uric acid, creatinine levels and maintained a good cationic balance. After two weeks of NI-SLN treatment, hepatocytes regained their normal architecture, and the beneficial effect could be correlated with the reduction of SGOT and total bilirubin levels. Therefore, NI-SLN was found to be useful for the enhancement of bioavailability and exhibited profound antidiabetic activity in rats. The results of the study suggested that NI-SLN exerted better improvement in glucose levels, lipid profiles and organ protection than pure NI and might have some beneficial effects in the management of diabetic patients.

<i>In Vivo</i>Pharmacokinetic and Hemocompatible Evaluation of Lyophilization Induced Nifedipine Solid-Lipid Nanoparticle

Nifedipine-solid-lipid nanoparticles lyophilized with trehalose (NI-SLN-Tre) were prepared by the high pressure homogenization of a roll mixture consisting of NI and hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol, and in vivo pharmacokinetic properties and their hemocompatibility were determined and compared with those of a NI-SLN suspension. The resulting pharmacokinetic data demonstrated that although no significant differences were observed between the time of peak concentration (Tmax), peak plasma concentration (Cmax), and the area under the curve (AUC0→∞) values of both administrated samples, NI tended to be absorbed to a much greater extent from the lyophilized NI-SLN-Tre suspensions because of the enhanced solvation of NI-SLN in gastrointestinal fluid, derived from formation of hydrogen bonds between the polar head groups of the lipids and the O-H groups of trehalose. Furthermore, the results of a hemolysis assay revealed that the NI-SLN and NI-SLN-Tre suspensions showed good hemocompatibility properties with hemolysis values of less than 5%. Taken together, the results of this study demonstrate that NI-SLN-Tre exhibits suitable pharmacokinetic properties and good biocompatibility.

Improving Flow Property of Nifedipine Loaded Solid-Lipid Nanoparticles by Means of Silica for Oral Solid Dosage Form

In this study, a new formulation of silica nanocomposite containing nifedipine (NI) loaded freeze-dried solid-lipid nanoparticles (NI-SLNs) and silica have been developed with improved flowability of powders, which can lead to the formulation of a widely acceptable oral dosage form. The stable NI-SLNs were prepared using two phospholipids, hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol mixed with 2.5% w/v trehalose as a cryoprotectant followed by lyophilization. We employed various grades of two types of silica, such as fumed and precipitated. Silica improved the poor flow property of NI-SLNs to good category as per USP-29. In addition, most of the silica nanocomposites showed the satisfactory results in their physicochemical properties such as particle size, polydispersity index, zeta potential, and recovered potency by around 100 nm, 0.3, -50 mV, and 80%, respectively. Furthermore, it was found that NI-SLNs were easily released form nanocomposites within 30 min, therefore, suggesting an improvement of drug dissolutions. Among them, precipitated silica cooperated fairly in improving the powder characteristics as well as the physicochemical, morphological, and pharmaceutical properties.