Comparison of three different types of cilostazol-loaded solid dispersion: Physicochemical characterization and pharmacokinetics in rats

Mustapha, Omer,Kim, Kyung Soo,Shafique, Shumaila,Kim, Dong Shik,Jin, Sung Giu,Seo, Youn Gee,Youn, Yu Seok,Oh, Kyung Taek,Yong, Chul Soon,Kim, Jong Oh,Choi, Han-Gon Elsevier 2017 Colloids and surfaces Biointerfaces Vol.154 No.-

<P><B>Abstract</B></P> <P>The aim of this research was to compare three different types of cilostazol-loaded solid dispersion system including solvent-evaporated, solvent-wetted and surface-attached solid dispersion. The effect of polymers and surfactants on the aqueous solubility of cilostazol was investigated, leading to the selection of polyvinylpyrrolidone (PVP) and sodium lauryl sulphate (SLS). Employing a spray-drying technique, numerous surface-attached, solvent-evaporated and solvent-wetted solid dispersions were prepared with various amounts PVP and SLS using water, 90% ethanol and acetone, respectively. Their physicochemical properties, solubility, dissolution and oral bioavailability in rats were assessed compared to the drug powder. Among each solid dispersion system tested, the surface-attached, solvent-evaporated and solvent-wetted solid dispersions composed of cilostazol, PVP and SLS at weight ratios of 3.0 : 0.75 : 1.5, 3.0 : 3.0 : 1.5 and 3.0 : 3.0 : 1.5, respectively, provided the highest drug solubility and dissolution. The solvent-evaporated solid dispersion gave homogeneous and very small spherical particles, in which the drug was changed to an amorphous state. In the solvent-wetted solid dispersion, the amorphous drug was attached to the polymer surface. Conversely, in the surface-attached solid dispersion, the carriers were adhered onto the surface of the unchanged crystalline drug. The solubility, dissolution and oral bioavailability were significantly increased in the order of solvent-evaporated>solvent-wetted>surface-attached>drug powder. Thus, the type of solid dispersion considerably affected the physicochemical properties, aqueous solubility and oral bioavailability. Furthermore, the cilostazol-loaded solvent-evaporated solid dispersion with the highest oral bioavailability would be actively recommended as a practical oral pharmaceutical product.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Cilostazol-loaded three different types of cilostazol-loaded solid dispersions were prepared. </LI> <LI> They were prepared with PVP, sodium laurylsulfate and different solvents using spray-drying techniques. </LI> <LI> The solvent-evaporated solid dispersion gave higher drug solubility and bioavailability than the others. </LI> <LI> These different types affected the physicochemical properties and oral bioavailability. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Development of novel cilostazol–loaded solid SNEDDS using a SPG membrane emulsification technique: Physicochemical characterization and in vivo evaluation

Mustapha, Omer,Kim, Kyung Soo,Shafique, Shumaila,Kim, Dong Shik,Jin, Sung Giu,Seo, Youn Gee,Youn, Yu Seok,Oh, Kyung Taek,Lee, Beom-Jin,Park, Young Joon,Yong, Chul Soon,Kim, Jong Oh,Choi, Han-Gon Elsevier 2017 Colloids and surfaces Biointerfaces Vol.150 No.-

<P><B>Abstract</B></P> <P>The objective of this study was to develop a novel solid self-nanoemulsifying drug delivery system (SNEDDS) using a membrane emulsification technique involving Shirasu porous glass (SPG) which produced very small and uniform emulsion droplets, resulting in enhanced solubility, dissolution and oral bioavailability of poorly water–soluble cilostazol. The effects of carriers on the drug solubility were assessed, and pseudo-ternary phase diagrams were plotted. Among the liquid SNEDDS formulations tested, the liquid SNEDDS composed of peceol (oil), Tween 20 (surfactant) and Labrasol (cosurfactant) at a weight ratio of 15/55/30, produced the smallest emulsion droplet size. The cilostazol–loaded liquid SNEDDS formulation was suspended in the distilled water and subjected to SPG membrane emulsification. Calcium silicate was added as a solid carrier in this liquid SNEDDS, completely suspended and spray–dried, leading to the production of a cilostazol–loaded solid SNEDDS. The emulsion droplet size, solubility and dissolution of the emulsified solid SNEDDS were assessed as compared to the solid SNEDDS prepared without emulsification. Moreover, the physicochemical characteristics and pharmacokinetics in rats were evaluated with the emulsified solid SNEDDS. The emulsified solid SNEDDS provided significantly smaller and more uniform nanoemulsions than did the non-emulsified solid SNEDDS. The emulsified solid SNEDDS showed significantly higher drug solubility and dissolution as compared to the non-emulsified solid SNEDDS. The crystalline drug in it was converted into the amorphous state. Moreover, in rats, it gave significantly higher initial plasma concentrations and AUC compared to the drug powder, suggesting its improved oral bioavailability of cilostazol. Thus, this novel solid SNEDDS developed using a membrane emulsification technique represents a potentially powerful oral delivery system for cilostazol.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Cilostazol-loaded solid SNEDDS was prepared using membrane emulsification technique. </LI> <LI> It was prepared with calcium silicate as a solid carrier. </LI> <LI> It provided smaller and more uniform nanoemulsions than the non-emulsified SNEDDS. </LI> <LI> It gave higher drug solubility and dissolution than the non-emulsified SNEDDS. </LI> <LI> This SNEDDS improved the oral bioavailability of cilostazol. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Novel electrosprayed nanospherules for enhanced aqueous solubility and oral bioavailability of poorly water-soluble fenofibrate

Yousaf, Abid Mehmood,Mustapha, Omer,Kim, Dong Wuk,Kim, Dong Shik,Kim, Kyeong Soo,Jin, Sung Giu,Yong, Chul Soon,Youn, Yu Seok,Oh, Yu-Kyoung,Kim, Jong Oh,Choi, Han-Gon Dove Medical Press 2016 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.11 No.-

<P><B>Purpose</B></P><P>The purpose of the present research was to develop a novel electrosprayed nanospherule providing the most optimized aqueous solubility and oral bioavailability for poorly water-soluble fenofibrate.</P><P><B>Methods</B></P><P>Numerous fenofibrate-loaded electrosprayed nanospherules were prepared with polyvinylpyrrolidone (PVP) and Labrafil<SUP>®</SUP> M 2125 as carriers using the electrospray technique, and the effect of the carriers on drug solubility and solvation was assessed. The solid state characterization of an optimized formulation was conducted by scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopic analyses. Oral bioavailability in rats was also evaluated for the formulation of an optimized nanospherule in comparison with free drug and a conventional fenofibrate-loaded solid dispersion.</P><P><B>Results</B></P><P>All of the electrosprayed nanospherule formulations had remarkably enhanced aqueous solubility and dissolution compared with free drug. Moreover, Labrafil M 2125, a surfactant, had a positive influence on the solubility and dissolution of the drug in the electrosprayed nanospherule. Increases were observed as the PVP/drug ratio increased to 4:1, but higher ratios gave no significant increases. In particular, an electrosprayed nanospherule composed of fenofibrate, PVP, and Labrafil M 2125 at the weight ratio of 1:4:0.5 resulted in a particle size of <200 nm with the drug present in the amorphous state. It demonstrated the highest solubility (32.51±2.41 μg/mL), an excellent dissolution (~85% in 10 minutes), and an oral bioavailability ~2.5-fold better than that of the free drug. It showed similar oral bioavailability compared to the conventional solid dispersion.</P><P><B>Conclusion</B></P><P>Electrosprayed nanospherules, which provide improved solubility and bioavailability, are promising drug delivery tools for oral administration of poorly water-soluble fenofibrate.</P>

Novel electrosprayed nanospherules for enhanced auqeous solubility and oral bioavailability of poorly water-soluble fenofibrate

( Abid Mehmood Yousaf ),( Omer Mustapha ),( Dong Wuk Kim ),( Dong Shik Kim ),( Kyeong Soo Kim ),( Sung Giu Jin ),( Chul Soon Yong ),( Yu Seok Youn ),( Yu Kyoung Oh ),( Jong Oh Kim ),( Han Gon Choi ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-

Purpose: The purpose of the present research was to develop a novel electrosprayed nanospherule providing the most optimized aqueous solubility and oral bioavailability for poorly water-soluble fenofibrate. Methods: Numerous fenofibrate-loaded electrosprayed nanospherules were prepared with polyvinylpyrrolidone (PVP) and Labrafil® M 2125 as carriers using the electrospray technique, and the effect of the carriers on drug solubility and solvation was assessed, The solid state characterization of an optimized formulation was conducted by scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopic analyses. Oral bioavailability in rats was also evaluated for the formulation of an optimized nanospherule in comparison with free drug and a conventional fenofibrate-loaded solid dispersion. Results: All of the electrosprayed nanospherule formulations had remarkably enhanced aqueous solubility and dissolution compared with free drug, Moreover, Labrafil M 2125, a surfactant, had a positive influence on the solubility and dissolution of the drug in the elcctrospraycd nanospherulc. Increases were observed as the PVP/drug ratio increased to 4: I, but higher ratios gave no significant increases. In particular, an electrosprayed nanospherule composed of fenofibrate, PVP, and Labrafil M 2125 at the weight ratio of I :4:0,5 resulted in a particle size of <200 nm with the drug present in the amorphous state, It demonstrated the highest solubility (32,51±2.41μg/ml.), an excellent dissolution (-85% in 10 minutes), and an oral bioavailability -2,5-fold better than that ofthe free drug, It showed similar oral bioavailability compared to the conventional solid dispersion, Conclusion: Electrosprayed nanospherules, which provide improved solubility and bioavailability, are promising drug delivery tools for oral administration of poorly water-soluble fenofibrate.

Comparison of a revaprazan-loaded solid dispersion, solid SNEDDS and inclusion compound: Physicochemical characterisation and pharmacokinetics

Park, Jong Hyuck,Kim, Dong Shik,Mustapha, Omer,Yousaf, Abid Mehmood,Kim, Jung Suk,Kim, Dong Wuk,Yong, Chul Soon,Youn, Yu Seok,Oh, Kyung Taek,Lim, Soo-Jeong,Kim, Jong Oh,Choi, Han-Gon Elsevier 2018 Colloids and surfaces Biointerfaces Vol.162 No.-

<P><B>Abstract</B></P> <P>The aim of this research was to compare three strategies for enhancing the solubility of poorly water-soluble revaprazan hydrochloride: solid dispersion, solid SNEDDS and inclusion compound. The influence of polymers, surfactants and oils on the drug solubility was assessed, and via the chosen carriers, the three types of formulations were prepared utilising spray drying technique. Their physicochemical properties, solubility, dissolution and pharmacokinetics in rats were performed compared with revaprazan powder. Among the liquid SNEDDS formulations assessed, the compositions of revaprazan, peceol, Tween 80 and Labrasol (10:15:55:30, weight ratio) provided the smallest emulsion size. Moreover, this liquid SNEDDS and dextran were suspended/dissolved in distilled water, and spray-dried, producing an optimal revaprazan-loaded solid SNEDDS. The appropriate solid dispersion and inclusion compound were composed of revaprazan, hydroxypropylmethylcellulose and cremophor A25 (5:1.4:5.6) and drug and hydroxyl-β-cyclodextrin (2.5:8.77), respectively. The crystalline drug was converted to an amorphous state in all formulations. In the solid dispersion, the drug was attached to the hydrophilic carrier. The solid SNEDDS and inclusion compound contained aggregate microspheres and separate microspheres, respectively. All formulations significantly increased the drug solubility, dissolution, plasma concentration and AUC compared with revaprazan powder. These properties were ranked in the order solid dispersion ≥ solid SNEDDS > inclusion compound. Particularly, the solid dispersion improved about 9500-fold drug solubility and 10-fold oral bioavailability. Thus, the improved properties were considerably dependent upon these techniques, although all of the techniques employed similar mechanisms. Among the strategies checked, the solid dispersion system would be recommended as an oral revaprazan-loaded pharmaceutical product.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Revaprazan-loaded solid dispersion, solid SNEDDS and inclusion compound were compared. </LI> <LI> Solid dispersion was prepared with hydroxypropylmethylcellulose and cremophor A25. </LI> <LI> Inclusion compound were composed of revaprazan and hydroxyl-β-cyclodextrin. </LI> <LI> Solid SNEDDS was prepared with peceol, Tween 80, Labrasol and dextran. </LI> <LI> Improved solubility and bioavailability were considerably dependent upon these techniques. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe

Rashid, Rehmana,Kim, Dong Wuk,Yousaf, Abid Mehmood,Mustapha, Omer,Din, Fakhar ud,Park, Jong Hyuck,Yong, Chul Soon,Oh, Yu-Kyoung,Youn, Yu Seok,Kim, Jong Oh,Choi, Han-Gon Dove Medical Press 2015 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.10 No.-

<P><B>Background</B></P><P>The objective of this study was to compare the physicochemical characteristics, solubility, dissolution, and oral bioavailability of an ezetimibe-loaded solid self-nanoemulsifying drug delivery system (SNEDDS), surface modified solid dispersion (SMSD), and solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability.</P><P><B>Methods</B></P><P>For the liquid SNEDDS formulation, Capryol 90, Cremophor EL, and Tween 80 were selected as the oil, surfactant, and cosurfactant, respectively. The nanoemulsion-forming region was sketched using a pseudoternary phase diagram on the basis of reduced emulsion size. The optimized liquid SNEDDS was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray drying technique with various amounts of hydroxypropylcellulose and Tween 80, optimized on the basis of their drug solubility. The SESD formulation was prepared with the same composition of optimized SMSD. The aqueous solubility, dissolution, physicochemical properties, and pharmacokinetics of all of the formulations were investigated and compared with the drug powder.</P><P><B>Results</B></P><P>The drug existed in the crystalline form in SMSD, but was changed into an amorphous form in SNEDDS and SESD, giving particle sizes of approximately 24, 6, and 11 µm, respectively. All of these formulations significantly improved the aqueous solubility and dissolution in the order of solid SNEDDS ≥ SESD > SMSD, and showed a total higher plasma concentration than did the drug powder. Moreover, SESD gave a higher area under the drug concentration time curve from zero to infinity than did SNEDDS and SMSD, even if they were not significantly different, suggesting more improved oral bioavailability.</P><P><B>Conclusion</B></P><P>Among the various formulations tested in this study, the SESD system would be strongly recommended as a drug delivery system for the oral administration of ezetimibe with poor water solubility.</P>

Irinotecan-encapsulated double-reverse thermosensitive nanocarrier system for rectal administration

Din, Fakhar ud,Choi, Ju Yeon,Kim, Dong Wuk,Mustapha, Omer,Kim, Dong Shik,Thapa, Raj Kumar,Ku, Sae Kwang,Youn, Yu Seok,Oh, Kyung Taek,Yong, Chul Soon,Kim, Jong Oh,Choi, Han-Gon Informa UK (TaylorFrancis) 2017 DRUG DELIVERY Vol. No.

Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe

( Rehmana Rashid ),( Dong Wuk Kim ),( Abid Mehmood Yousaf ),( Omer Mustapha ),( Fakhar Ud Din ),( Jong Hyuck Park ),( Chul Soon Yong ),( Yu Kyoung Oh ),( Yu Seok Youn ),( Jong Oh Kim ),( Han Gon Choi 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-

Background: The objective of this study was to compare the physicochemical characteristics, solubility, dissolution, and oral bioavailability of an ezetimibe-Ioaded solid self-nanoemulsifying drug delivery system (SNEDDS), surface modified solid dispersion (SMSD), and solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability. Methods: For the liquid SNEDDS formulation, Capryol 90, Cremophor EL, and Tween 80 were selected as the oil, surfactant, and cosurfactant, respectively. The nanoemulsion-forming region was sketched using a pscudotemary phase diagram on the basis of reduced emulsion size. The optimized liquid SNEDDS was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray drying technique with various amounts of hydroxypropylcellulose and Tween 80, optimized on the basis of their drug solubility. The SESD formulation was prepared with the same composition of optimized SMSD. The aqueous solubility, dissolution, physicochemical properties, and pharmacokinetics of all of the formulations were investigated and compared with the drug powder. Results: The drug existed in the crystalline form in SMSD, but was changed into an amor-phous form in SNEDDS and SESD, giving particle sizes of approximately 24, 6, and 11 urn, respectively. All of these formulations significantly improved the aqueous solubility and dis-solution in the order of solid SNEDDS "``: SESD > SMSD, and showed a total higher plasma concentration than did the drug powder. Moreover, SESD gave a higher area under the drug concentration time curve from zero to infinity than did SNEDDS and SMSD, even if they were not significantly different, suggesting more improved oral bioavailability. Conclusion: Among the various formulations tested in this study, the SESD system would be strongly recommended as a drug delivery system for the oral administration of ezetimibe with poor water solubility.