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      Soluplus micelles for improving the oral bioavailability of scopoletin and their hypouricemic effect in vivo

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          Abstract

          Scopoletin is an active coumarin possessing a variety of pharmacological activities, including anti-hyperuricemic effect, but with poor solubility. To improve its oral bioavailability, we attempted to encapsulate scopoletin into Soluplus micelles (Soluplus-based scopoletin micelles, Sco-Ms) and evaluated the hypouricemic action of Sco-Ms. Sco-Ms were prepared using a thin-film hydration method. Sco-Ms displayed near spherical shapes with an average size of 59.4±2.4 nm (PDI=0.08±0.02). The encapsulation efficiency of scopoletin was 87.3%±1.5% with a loading capacity of 5.5%±0.1%. Sco-Ms were further characterized using transmission electron microscopy, powder X-ray diffraction, Fourier transform infrared techniques and scanning electron microscopy. After oral administration in rats, Sco-Ms exhibited significantly improved absorption in each intestinal segment compared to free scopoletin, with the duodenum and jejunum being the main absorption regions. In rats administered Sco-Ms (at an equivalent dose of free scopoletin of 100 mg/kg, po), the AUC 0–∞ and C max of Sco-Ms were 4.38- and 8.43-fold, respectively, as large as those obtained following administration of free scopoletin. After oral administration in rats, Sco-Ms did not alter the tissue distributions of scopoletin, but significantly increased the scopoletin levels in the liver. In potassium oxonate-induced hyperuricemic mice, oral administration of Sco-Ms (at an equivalent dose of free scopoletin of 300 mg/kg) reduced the serum uric acid concentration to the normal level. The results suggest that Soluplus-based micelle system greatly improves the bioavailability of poorly water-soluble drugs, such as scopoletin, and represents a promising strategy for their oral delivery.

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          Most cited references28

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          Prepare dispersed CIS nano-scale particles and spray coating CIS absorber layers using nano-scale precursors

          In this study, the Mo-electrode thin films were deposited by a two-stepped process, and the high-purity copper indium selenide-based powder (CuInSe2, CIS) was fabricated by hydrothermal process by Nanowin Technology Co. Ltd. From the X-ray pattern of the CIS precursor, the mainly crystalline phase was CIS, and the almost undetectable CuSe phase was observed. Because the CIS powder was aggregated into micro-scale particles and the average particle sizes were approximately 3 to 8 μm, the CIS power was ground into nano-scale particles, then the 6 wt.% CIS particles were dispersed into isopropyl alcohol to get the solution for spray coating method. Then, 0.1 ml CIS solution was sprayed on the 20 mm × 10 mm Mo/glass substrates, and the heat treatment for the nano-scale CIS solution under various parameters was carried out in a selenization furnace. The annealing temperature was set at 550°C, and the annealing time was changed from 5 to 30 min, without extra Se content was added in the furnace. The influences of annealing time on the densification, crystallization, resistivity (ρ), hall mobility (μ), and carrier concentration of the CIS absorber layers were well investigated in this study.
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            Poly(lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel.

            Four systems of nanoparticles of biodegradable polymers were developed in this research for oral delivery of anticancer drugs with Docetaxel used as a model drug, which include the poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), the poly(lactide)-vitamin E TPGS nanoparticles (PLA-TPGS NPs), the poly(lactic-co-glycolic acid)-montmorillonite nanoparticles (PLGA/MMT NPs) and the poly(lactide)-vitamin E TPGS/montmorillonite nanoparticles (PLA-TPGS/MMT NPs). Vitamin E TPGS stands for d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), which is a water-soluble derivative of natural vitamin E formed by esterification of vitamin E succinate with polyethylene glycol (PEG) 1000. The design was made to take advantages of TPGS in nanoparticle technology such as high emulsification effects and high drug encapsulation efficiency, and those in drug formulation such as high cellular adhesion and adsorption. MMT of similar effects is also a detoxifier, which may cure some side effects caused by the formulated drug. The drug-loaded NPs were prepared by a modified solvent extraction/evaporation method and then characterized for their MMT content, size and size distribution, surface charge and morphology, physical status and encapsulation efficiency of the drug in the NPs, and in vitro drug release profile. Cellular uptake of the coumarin 6-loaded NPs was investigated. In vitro cancer cell viability experiment showed that judged by IC(50), the PLA-TPGS/MMT NP formulation was found 2.89, 3.98, 2.12-fold more effective and the PLA-TPGS NP formulation could be 1.774, 2.58, 1.58-fold more effective than the Taxotere((R)) after 24, 48, 72h treatment, respectively. In vivo PK experiment with SD rats showed that oral administration of the PLA-TPGS/MMT NP formulation and the PLA-TPGS NP formulation could achieve 26.4 and 20.6 times longer half-life respectively than i.v. administration of Taxotere((R)) at the same 10mg/kg dose. One dose oral administration of the NP formulations could realize almost 3 week sustained chemotherapy in comparison of 22h of i.v. administration of Taxotere((R)). The oral bioavailability can be enhanced from 3.59% for Taxotere((R)) to 78% for the PLA-TPGS/MMT NP formulation and 91% for the PLA-TPGS NP formulation respectively. Oral chemotherapy by nanoparticles of biodegradable polymers is feasible.
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              Nanoemulsion improves the oral absorption of candesartan cilexetil in rats: Performance and mechanism.

              Candesartan cilexetil (CC), an inactive prodrug of candesartan, was rapidly hydrolyzed into active candesartan during absorption in the gastrointestinal (GI) tract to achieve antihypertensive effects. However, CC exhibited incomplete intestinal absorption with low oral bioavailability due to its poor aqueous solubility. In this work, a novel CC loaded nanoemulsion (CCN) was designed to improve the intestinal absorption. CCN was prepared by a modified emulsification-solvent evaporation technique. The physicochemical characteristics of CCN were characterized, and the intestinal absorption was investigated as well. The experimental results indicated that CCN was nanometer-sized droplets (35.5±5.9nm) with negative potential (-6.45±0.36mV), and the absorption of CCN was significantly improved in total intestinal tract compared with free CC solution. Moreover, CCN could be internalized into the enterocytes by clathrin-mediated endocytosis pathway, and thereafter transported into systemic circulation via both portal vein and lymphatic pathway. The concentration of active candesartan in rat plasma was determined by LC-MS-MS method. The experimental results showed that the area under the concentration-time curve (AUC(0-t)) of candesartan was improved over 10-fold after CC was incorporated into CCN. The overall results implicated that the nanoemulsion was very effective for enhancing the oral absorption of insoluble CC, and CCN showed the great potential for clinical application. Copyright © 2010 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                March 2017
                23 January 2017
                : 38
                : 3
                : 424-433
                Affiliations
                [1 ]Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
                Author notes
                Article
                aps2016126
                10.1038/aps.2016.126
                5342662
                28112183
                29f5ecb2-2e54-431c-930c-229e812a28e5
                Copyright © 2017 CPS and SIMM
                History
                : 19 August 2016
                : 12 October 2016
                Categories
                Original Article

                Pharmacology & Pharmaceutical medicine
                scopoletin,soluplus,micelles,oral bioavailability,pharmacokinetics,tissue distribution,hyperuricemic mice

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