Clopidogrel Napadisilate Monohydrate Loaded Surface-Modified Solid Dispersion: Physicochemical Characterization and <i>in Vivo</i> Evaluation

Abstract

To develop a novel solid dispersion of clopidogrel napadisilate monohydrate (CNM) with improved stability and oral bioavailability, surface-modified solid dispersions were prepared by spray-drying using water as a solvent, Tween 80 as a surfactant, and hydroxypropylmethyl cellulose (HPMC) as a hydrophilic polymer, and optimized according to drug solubility. Its solid-state characterization was evaluated by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The stability study was performed at 50°C/75% RH over a period of 6 weeks. Its dissolution profiles and oral bioavailability in rats were also compared with that of CNM and clopidogrel bisulfate (CB). The solid dispersion, composed of CNM/HPMC/Tween80 at a weight ratio of 10/2.5/2.5, in which CNM was in the crystalline state, increased the drug solubility approximately 4.6-fold. It showed a significantly better dissolution profile than that of CNM in all the dissolution media, and gave either similar or higher dissolution compared to that of CB. This solubility and dissolution enhancement was attributed to improved wetting and solubilization of CNM crystals due to hydrophilic carriers attached on the drug surface. It had excellent stability, thereby addressing the stability problem of CB powder. Furthermore, it increased the area under curve (AUC) values by about 4-fold and 1.6-fold compared to CNM and CB, respectively, suggesting that it improved the oral bioavailability of the drug in rats. Thus, this solid dispersion system prepared with water, HPMC and Tween 80 can be used to enhance the bioavailability of CNM as well as to solve the stability problem of CB.Key words clopidogrel napadisilate monohydrate; surface-modified solid dispersion; water; stability; bioavailability Clopidogrel, a non-competitive inhibitor of adenosine diphosphate in platelets is an orally administered antiplatelet agent prescribed for cerebral and peripheral vascular diseases and for the early and long term secondary prevention of atherothrombotic events in patients with acute coronary syndromes.1) This drug is practically insoluble in water; hence, its commercial salt form, clopidogrel bisulfate (CB) has been widely used in the pharmaceutical industry. CB is highly soluble in water and rapidly absorbed in vivo; however, this salt form is slightly hygroscopic and has been reported not stable under accelerated heat and moisture conditions, producing severe amounts of degradants.2) Thus, to increase the stability of the drug, a new salt form, clopidogrel napadisilate monohydrate (CNM), has been prepared with improved stability.3) Even though CNM demonstrated increased stability, this salt showed poor aqueous solubility compared to the CB salt.3) Therefore, a novel formulation strategy is needed to resolve the solubility issue of stable CNM.Drug solubility remains one of the most challenging aspects of formulation development because it results in poor bioavailability of the drug. Among the various approaches to improve the ...

Vitamin D3/vitamin K2/magnesium-loaded polylactic acid/tricalcium phosphate/polycaprolactone composite nanofibers demonstrated osteoinductive effect by increasing Runx2 via Wnt/β-catenin pathway

“…EE was lower for D 3 and K 2 than Mg due to their low solubility in PBS, although Tween 80 was added to PBS to increase the solubility of D 3 and K 2 . [53] The drug-to-polymer ratio or low concentration of emulsifier may be another reason that influences the drug loading. [24] The drug release analysis was performed to investigate the release kinetics of drugs encapsulated in the fibers for 144 h with PBS that mimics the physical conditions of living organisms.…”