Chronotherapeutically Modulated Pulsatile System of Valsartan Nanocrystals—an In Vitro and In Vivo Evaluation

Abstract

The objective was to improve the dissolution of valsartan by developing valsartan nanocrystals and design a pulsed release system for the chronotherapy of hypertension. Valsartan nanocrystals were prepared by sonication-anti-solvent precipitation method and lyophilized to obtain dry powder. Nanocrystals were directly compressed to minitablets and coated to achieve pulsatile valsartan release. Pharmacokinetic profiles of optimized and commercial formulations were compared in rabbit model. The mean particle size and PDI of the optimized nanocrystal batch V4 was reported as 211 nm and 0.117, respectively. DSC and PXRD analysis confirmed the crystalline nature of valsartan in nanocrystals. The dissolution extent of valsartan was markedly enhanced with both nanocrystals and minitablets as compared to pure valsartan irrespective of pH of the medium. Core minitablet V4F containing 5% w/w polyplasdone XL showed quickest release of valsartan, over 90% within 15 min. Coated formulation CV4F showed two spikes in release profile after successive lag times of 235 and 390 min. The pharmacokinetic study revealed that the bioavailability of optimized formulation (72.90%) was significantly higher than the commercial Diovan tablet (30.18%). The accelerated stability studies showed no significant changes in physicochemical properties, release behavior, and bioavialability of CV4F formulation. The formulation was successfully designed to achieve enhanced bioavailability and dual pulsatile release. Bedtime dosing will more efficiently control the circadian spikes of hypertension in the morning.

Extemporaneous Compounding and Physiological Modeling of Amlodipine/Valsartan Suspension

“…is decrease in the dissolution rates with the reduction in the media pH reflects the pH-dependent solubility of VAL, where the IR tablet was the reference and the extemporaneous suspension was the test. ese findings are in agreement with previous studies which reported a reduction in VAL solubility at lower pH values [32][33][34]. e results of similarity were more than 50 for each dissolution showed latency in 85% within 15 minutes indicating the similarity in the release from both formulations.…”

“…Weight uniformity of the subdivided tablets cannot be guaranteed all the time even for scored tablets; this may lead to serious complications especially in case of narrow therapeutic window drugs [2]. Moreover, crushed tablets that are used for preparing an extemporaneous suspension do not follow any stability or bioavailability testing [34], which may lead to further confusion whether these crushed tablets preserve their efficacy or safety issues which may lead to serious complications.…”

Systems Chronotherapeutics

“…Indeed, most drugs against hypertension achieved both greater improvement of blood pressure circadian profile and lower risks of cardiovascular events, following their oral intake at bedtime compared with morning administration (Smolensky et al, 2016). Several physico-chemical studies further developed modified release formulation of valsartan to achieve late night/early morning exposure after a bedtime administration (Kshirsagar et al, 2011; Biswas and Kuotsu, 2017). Classic PK-PD models have been developed for cardiovascular medications linking drug dose or plasma concentration to their effect on the QT interval in an empirical manner, and modeling efforts have been made to extend them to account for the circadian control of the drug effect (Piotrovsky, 2005; Huh and Hutmacher, 2015).…”

Development of docetaxel nanocrystals surface modified with transferrin for tumor targeting

“…Recently, significant advancement has been made in the field of drug NCs because of numerous studies on the development of NCs of drugs such as DTX,30 PTX,31 curcumin,32 aceclofenac,15 valsartan,33 and quercetin 34. Drug NCs are usually prepared by two methods, top-down and bottom-up methods 35,36.…”