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      Soluplus ®/TPGS-based solid dispersions prepared by hot-melt extrusion equipped with twin-screw systems for enhancing oral bioavailability of valsartan

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          Soluplus ® (SP) and D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS)–based solid dispersion (SD) formulations were developed by hot-melt extrusion (HME) to improve oral bioavailability of valsartan (VST).


          HME process with twin-screw configuration for generating a high shear stress was used to prepare VST SD formulations. The thermodynamic state of the drug and its dispersion in the polymers were evaluated by solid-state studies, including Fourier-transform infrared, X-ray diffraction, and differential scanning calorimetry. Drug release from the SD formulations was assessed at pH values of 1.2, 4.0, and 6.8. Pharmacokinetic study was performed in rats to estimate the oral absorption of VST.


          HME with a high shear rate produced by the twin-screw system was successfully applied to prepare VST-loaded SD formulations. Drug amorphization and its molecular dispersion in the polymer matrix were verified by several solid-state studies. Drug release from SD formulations was improved, compared to the pure drug, particularly at pH 6.8. Oral absorption of drug in rats was also enhanced in SP and TPGS-based SD groups compared to that in the pure drug group.


          SP and TPGS-based SDs, prepared by the HME process, could be used to improve aqueous solubility, dissolution, and oral absorption of poorly water-soluble drugs.

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          Most cited references 39

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          Improving drug solubility for oral delivery using solid dispersions.

           C Leuner (2000)
          The solubility behaviour of drugs remains one of the most challenging aspects in formulation development. With the advent of combinatorial chemistry and high throughput screening, the number of poorly water soluble compounds has dramatically increased. Although solid solutions have tremendous potential for improving drug solubility, 40 years of research have resulted in only a few marketed products using this approach. With the introduction of new manufacturing technologies such as hot melt extrusion, it should be possible to overcome problems in scale-up and for this reason solid solutions are enjoying a renaissance. This article begins with an overview of the historical background and definitions of the various systems including eutectic mixtures, solid dispersions and solid solutions. The remainder of the article is devoted to the production, the different carriers and the methods used for the characterization of solid dispersions.
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            The importance of amorphous pharmaceutical solids lies in their useful properties, common occurrence, and physicochemical instability relative to corresponding crystals. Some pharmaceuticals and excipients have a tendency to exist as amorphous solids, while others require deliberate prevention of crystallization to enter and remain in the amorphous state. Amorphous solids can be produced by common pharmaceutical processes, including melt quenching, freeze- and spray-drying, milling, wet granulation, and drying of solvated crystals. The characterization of amorphous solids reveals their structures, thermodynamic properties, and changes (crystallization and structural relaxation) in single- and multi-component systems. Current research in the stabilization of amorphous solids focuses on: (i) the stabilization of labile substances (e.g., proteins and peptides) during processing and storage using additives, (ii) the prevention of crystallization of the excipients that must remain amorphous for their intended functions, and (iii) the selection of appropriate storage conditions under which amorphous solids are stable.
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              The applications of Vitamin E TPGS in drug delivery.

              D-α-Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E TPGS) is formed by the esterification of Vitamin E succinate with polyethylene glycol 1000. As novel nonionic surfactant, it exhibits amphipathic properties and can form stable micelles in aqueous vehicles at concentration as low as 0.02 wt%. It has been widely investigated for its emulsifying, dispersing, gelling, and solubilizing effects on poorly water-soluble drugs. It can also act as a P-glycoprotein (P-gp) inhibitor and has been served as an excipient for overcoming multidrug resistance (MDR) and for increasing the oral bioavailability of many anticancer drugs. Since TPGS has been approved by FDA as a safe pharmaceutic adjuvant, many TPGS-based drug delivery systems (DDS) have been developed. In this review, we discuss TPGS properties as a P-gp inhibitor, solubilizer/absorption and permeation enhancer in drug delivery and TPGS-related formulations such as nanocrystals, nanosuspensions, tablets/solid dispersions, adjuvant in vaccine systems, nutrition supplement, plasticizer of film, anticancer reagent and so on. This review will greatly impact and bring out new insights in the use of TPGS in DDS. Copyright © 2013 Elsevier B.V. All rights reserved.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                22 May 2015
                : 9
                : 2745-2756
                [1 ]College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
                [2 ]School of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Republic of Korea
                [3 ]College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
                [4 ]College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea
                Author notes
                Correspondence: Dae-Duk Kim, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea, Tel +82 2 880 7870, Fax +82 2 873 9177, Email ddkim@ 123456snu.ac.kr
                Hyun-Jong Cho, College of Pharmacy, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon 200-701, Republic of Korea, Tel +82 33 250 6916, Fax +82 33 259 5631, Email hjcho@ 123456kangwon.ac.kr

                These authors contributed equally to this work

                © 2015 Lee et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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