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 B 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>

Novel technologies to enhance solubility of food-derived bioactive compounds: A review

Recharla, Neeraja,Riaz, Muhammad,Ko, Sanghoon,Park, Sungkwon Elsevier 2017 Journal of Functional Foods Vol.39 No.-

<P><B>Abstract</B></P> <P>Food-derived multifunctional bioactive compounds, such as carotenoids, fat soluble vitamins, phytosterols, polyunsaturated lipids, curcuminoids and flavonoid compounds provide promising therapeutic health benefits. However, the efforts in identifying their mode of action and applying them into food industry are still unsuccessful because majority of these compounds are water-insoluble and ingested are not delivered to the site of action, therefore, less bioavailable. Several strategies to enhance the water solubility have been developed over the years. There has been active research in the area during recent times. The present review will comprehensively discuss about novel technologies which have used to improve the aqueous solubility of bioactives.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Food bioactives provide health benefits beyond their nutritional functions. </LI> <LI> Low solubility is a major limitation for commercial application of bioactives. </LI> <LI> Nanotechnology approaches can improve the solubility of lipophilic bioactives. </LI> </UL> </P>

고분자/베타-사이클로덱스트린 포접 화합물로 이루어진 고분자 혼성체 필름의 물성 및 구조에 미치는 게스트 분자의 영향

배준원 ( Joonwon Bae ) 한국공업화학회 2021 공업화학 Vol.32 No.5

본 연구에서는 게스트 분자(guest molecule)의 특성이 고분자/베타-사이클로덱스트린(beta-cyclodextrin) 포접화합물(inclusion compound)로 이루어진 고분자 필름의 구조 및 물성에 미치는 영향에 대해서 고찰하고자 한다. 본 연구에서 사용된 게스트 분자는 미백 효과를 지니는 것으로 알려진 3가지로 하이드로퀴논(hydroquinone, HQ), 알부틴(arbutin, AB), 그리고 트랜액사믹 애시드(tranexamic acid, TA)이다. 먼저, 베타-사이클로덱스트린과 게스트 분자 간의 포접화합물의 성공적인 형성과 이를 포함하는 고분자 필름의 제조여부를 라만(Raman) 분광학으로 확인하였다. 포접화합물을 포함하는 고분자 필름의 구조 및 물성은 엑스선 회절법(X-ray diffraction)과 주사열용량법 및 열중량추적법 같은 열분석법으로 고찰하였다. 그 결과, 트랜액사믹 애시드의 영향이 다른 분자의 영향과 비교하여 상당히 상이하였음을 관찰할 수 있었다. 이러한 경향은 간단한 분자 시뮬레이션 기법으로 재검증하였다. 본 연구는 포접화합물을 형성하는 게스트 분자들의 상이한 영향에 대한 체계적인 접근을 통한 실험적 검증의 사례로 향후 관련 연구에 중요한 정보를 제공할 것으로 기대된다. In this study, the effect of molecular features of guest molecules on the structure, property, and formation of poly(vinyl alcohol) (PVA)/beta-cyclodextrin (bCD) inclusion compound hybrid films was investigated using three types of guest molecules such as hydroquinone (HQ), arbutin (AB), and tranexamic acid (TA). First, the successful formation of inclusion compounds between bCD and the guest molecules, and polymer/inclusion compound hybrid were proved using Raman spectroscopy. The effect of bCD-based inclusion compounds on the structure and property of PVA matrix composites containing inclusion compounds was also studied using X-ray diffraction (XRD) and thermal analyses such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). It was notable that the effect of TA to the crystalline structure of the PVA was significantly different from that of using other guest molecules including HQ and AB. It was also supported by a simple molecular simulation result. This article will be a good example for demonstrating the effect of molecular characteristics on the inclusion compound formation in polymer films, which can provide important information for relevant future research.

Enhanced Bioavailability of Poorly Water-Soluble Clotrimazole by Inclusion with ${\beta}$-Cyclodextrin

Prabagar, Balakrishnan,Yoo, Bong-Kyu,Woo, Jong-Soo,Kim, Jung-Ae,Rhee, Jong-Dal,Piao, Ming Guan,Choi, Han-Gon,Yong, Chul-Soon 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.2

Clotrimazole, a poorly water-soluble antimycotic agent, is a promising agent for various diseases including cancer and sickle cell anemia. To improve the oral bioavailability of clotrimazole, the inclusion compound of clotrimazole with ${\beta}$-cyclodextrin was prepared by spray-drying method and characterized by phase solubility, differential scanning calorimetry and dissolution. Furthermore, the pharmacokinetics after oral administration in rats was then performed compared with clotrimazole powder. The solubility of clotrimazole increased linearly as a function of ${\beta}$-cyclodextrin concentration, resulting in A$_L$ type Phase solubility diagram Which revealed a formation of inclusion compound in a molar ratio of 1:2, with the apparent association constant of 230.2 M$^{-1}$. The dissolution rate of clotrimazole in the inclusion compound increased greatly compared to clotrimazole powder in pH 7.4 phosphate buffer solution. The inclusion compound gave significantly higher initial plasma concentrations, Cmax and AUC of clotrimazole than did clotrimazole powder when they were administered as suspension form, indicating that the drug from inclusion compound could be more orally absorbed in rats. Thus, the oral bioavailability of clotrimazole could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.

Enhanced Bioavailability of Poorly Water-Soluble Clotrimazole by Inclusion with β-Cyclodextrin

Balakrishnan Prabagar,Bong-Kyu Yoo,우종수,Jung-Ae Kim,이종달,Ming Guan Piao,최한곤,용철순 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.2

Clotrimazole, a poorly water-soluble antimycotic agent, is a promising agent for various diseases including cancer and sickle cell anemia. To improve the oral bioavailability of clotrimazole, the inclusion compound of clotrimazole with β-cyclodextrin was prepared by spray-drying method and characterized by phase solubility, differential scanning calorimetry and dissolution. Furthermore, the pharmacokinetics after oral administration in rats was then performed compared with clotrimazole powder. The solubility of clotrimazole increased linearly as a function of β-cyclodextrin concentration, resulting in AL type phase solubility diagram which revealed a formation of inclusion compound in a molar ratio of 1:2, with the apparent association constant of 230.2 M-1. The dissolution rate of clotrimazole in the inclusion compound increased greatly compared to clotrimazole powder in pH 7.4 phosphate buffer solution. The inclusion compound gave significantly higher initial plasma concentrations, Cmax and AUC of clotrimazole than did clotrimazole powder when they were administered as suspension form, indicating that the drug from inclusion compound could be more orally absorbed in rats. Thus, the oral bioavailability of clotrimazole could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.

NMR Study of the Orientational Phase Transition in the Monohalogen-substituted Cyclohexane/Thiourea Inclusion Compounds C6H11X/SC(NH2)2 (X=Cl, Br)

Toku Ishibashi 한국물리학회 2009 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.55 No.2

Thiourea host molecules form inclusion compounds with monohalogen-substituted cyclohexane guest molecules. C6H11X / SC(NH2)2 (X=Cl, Br) undergoes a phase transition from a hightemperature phase (HT phase), where the guest molecules reorient rapidly, to a low-temperature phase (LT phase). To study the guest motion in a thiourea host lattice, we measured the spin lattice relaxation time T1 of carbon nuclei. In the HT phase, log(T1) of both nuclei in guest molecules was linearly related to the inverse temperature. The relaxation was affected by the sufficiently isotropic motion of the guest molecule. In the LT phase, the temperature dependences showed a single-mode behavior. The mode can either be a three-fold reorientation (C3 reorientation) in the channel direction or two-fold reorientations (C2 reorientations) in the directions perpendicular to the channel. The observed mode was found to be a C3 reorientation for both samples. Thus, C3 reorientation shows a T1 minimum and freezes at a higher temperature than the C2 reorientations. Thiourea host molecules form inclusion compounds with monohalogen-substituted cyclohexane guest molecules. C6H11X / SC(NH2)2 (X=Cl, Br) undergoes a phase transition from a hightemperature phase (HT phase), where the guest molecules reorient rapidly, to a low-temperature phase (LT phase). To study the guest motion in a thiourea host lattice, we measured the spin lattice relaxation time T1 of carbon nuclei. In the HT phase, log(T1) of both nuclei in guest molecules was linearly related to the inverse temperature. The relaxation was affected by the sufficiently isotropic motion of the guest molecule. In the LT phase, the temperature dependences showed a single-mode behavior. The mode can either be a three-fold reorientation (C3 reorientation) in the channel direction or two-fold reorientations (C2 reorientations) in the directions perpendicular to the channel. The observed mode was found to be a C3 reorientation for both samples. Thus, C3 reorientation shows a T1 minimum and freezes at a higher temperature than the C2 reorientations.

Inclusion Complex of Analgesic and antiinflammatory Agents with Cyclodextrins (II) : Effect of $2-Hydroxypropyl-{\beta}-cyclodextrin$ on the Release of Ibuprofen Suppository

오인준,이미영,이용복,신상철,Oh, In-Joon,Lee, Mi-Young,Lee, Yong-Bok,Shin, Sang-Chul 한국약제학회 1997 Journal of Pharmaceutical Investigation Vol.27 No.3

Ibuprofen, a nonsteroidal antiinflammatory, analgesic and antipyretic drug, has several limitations in clinical application because of low solubility in water and gastrointestinal irritation. Effect of ibuprofen/$2-Hydroxypropyl-{\beta}-cyclodextrin\;(HP{\beta}CD)$ inclusion compound on release of suppository was investigated. Complex formation was confirmed by $^{1}H-\;and\;^{13}C-NMR$ spectroscopy. The release of ibuprofen from suppository base in vitro was significantly increased by the complexation with $HP{\beta}CD$. The release of ibuprofen from hydrophilic base was faster than that from hydrophobic base. In vivo studies, the release rate of ibuprofen from suppository was accelerated after rectal administration in complex form. This results suggested that ibuprofen/$HP{\beta}CD$ complex can be practically used for suppository to have faster effect of ibuprofen with reduced side effect.

Synthesis and Aqueous Colloidal Solutions of RE₂(OH)₅NO₃·nH₂O (RE = Nd and La)

Lee, Kyung-Hee,Byeon, Song-Ho WILEY-VCH Verlag 2009 European journal of inorganic chemistry Vol.2009 No.31

<P>A new, simple route leading to layered rare-earth hydroxy nitrates was developed. The pH-independent procedure uses ethanol containing alkali-metal hydroxide (KOH, RbOH, or CsOH) as a solvothermal medium. Two new, layered rare-earth hydroxy nitrates (LRHs), Nd<SUB>2</SUB>(OH)<SUB>5</SUB>NO<SUB>3</SUB>·nH<SUB>2</SUB>O and La<SUB>2</SUB>(OH)<SUB>5</SUB>NO<SUB>3</SUB>·nH<SUB>2</SUB>O, were prepared by this nonaqueous solvothermal reaction. Because the RE = Nd and La members have not yet been synthesized in an aqueous system, the successful synthesis of these compounds implies the completion of the RE<SUB>2</SUB>(OH)<SUB>5</SUB>NO<SUB>3</SUB>·nH<SUB>2</SUB>O (RE = rare earths) series. The typical properties of a layered structure was demonstrated by ready ion-exchange reactions between NO<SUB>3</SUB><SUP>–</SUP> and some organic anions such as decanoate, decanesulfonate, and decyl sulfate. In particular, the as-synthesized hydroxide from solvothermal reaction, where the alkali-metal nitrates are partially intercalated in the interlayer gallery, form an aqueous colloidal solution under ultrasonic treatment. Hydration of the LRHs intercalated with alkali-metal salts results in the formation of colloidal LRH suspensions in water. The colloidal character of the LRH solutions is supported by the Tyndall effect, TEM, and AFM images.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)</P> <B>Graphic Abstract</B> <P>A new, simple route was developed to synthesize the complete rare-earth series of the RE<SUB>2</SUB>(OH)<SUB>5</SUB>NO<SUB>3</SUB>·nH<SUB>2</SUB>O family. The hydration of La<SUB>2</SUB>(OH)<SUB>5</SUB>NO<SUB>3</SUB>·nH<SUB>2</SUB>O and Nd<SUB>2</SUB>(OH)<SUB>5</SUB>NO<SUB>3</SUB>·nH<SUB>2</SUB>O synthesized by this nonaqueous solvothermal method yielded transparent aqueous colloidal solutions. <img src='wiley_img/14341948-2009-2009-31-EJIC200900635-fig000.gif' alt='wiley_img/14341948-2009-2009-31-EJIC200900635-fig000'> </P>

Molecule-based electrorheological material with luminescence property

Ming-Xing Chen,Fu-Hui Liao,Yan-Li Shang,Yun-Ling Jia,Jun-Ran Li 한국유변학회 2013 Korea-Australia rheology journal Vol.25 No.1

Molecule-based electrorheological (ER) materials with luminescence property, based on β-cyclodextrin [(C6O5H10)7, β-CD] inclusion compounds between β-CD (host) and the rare earth (RE) (RE=Tb, Eu) complex (guest), have been synthesized as a novel type of ER materials using β-CD, Tb(NO3)3, Eu(NO3)3, sulphosalicylic acid (C7H6O6S·2H2O, SSA) and m-phthalic acid (C8H6O4, MPA) as original materials. The composition, ER performance, luminescence property and dielectric property of the materials have been studied. The results show that the rare earth complex in the cavity of β-CD may enhance the ER performance of β-CD, and the complex (Tb-SSA) of Tb3+ can improve more effectively the ER activity of β-CD than that (Eu-MPA) of Eu3+ among both of the complexes. The composition and structure are the dominant factors in improving the ER effect. The fluorescence intensity, fluorescence lifetime and emission quantum yield of the particle materials and their suspensions in silicone oil have been tested, and fine luminescence performance has been detected. The material with ER activity and luminescence performance is a novel multifunctional material which would have wide application prospect.

Molecule-based electrorheological material with luminescence property

Chen, Ming-Xing,Liao, Fu-Hui,Shang, Yan-Li,Jia, Yun-Ling,Li, Jun-Ran 한국유변학회 2013 Korea-Australia rheology journal Vol.25 No.1

Molecule-based electrorheological (ER) materials with luminescence property, based on ${\beta}$-cyclodextrin [($C_6O_5H_{10})_7$, ${\beta}$-CD] inclusion compounds between ${\beta}$-CD (host) and the rare earth (RE) (RE=Tb, Eu) complex (guest), have been synthesized as a novel type of ER materials using ${\beta}$-CD, $Tb(NO_3)_3$, $Eu(NO_3)_3$, sulphosalicylic acid ($C_7H_6O_6S{\cdot}2H_2O$, SSA) and m-phthalic acid ($C_8H_6O_4$, MPA) as original materials. The composition, ER performance, luminescence property and dielectric property of the materials have been studied. The results show that the rare earth complex in the cavity of ${\beta}$-CD may enhance the ER performance of ${\beta}$-CD, and the complex (Tb-SSA) of $Tb^{3+}$ can improve more effectively the ER activity of ${\beta}$-CD than that (Eu-MPA) of $Eu^{3+}$ among both of the complexes. The composition and structure are the dominant factors in improving the ER effect. The fluorescence intensity, fluorescence lifetime and emission quantum yield of the particle materials and their suspensions in silicone oil have been tested, and fine luminescence performance has been detected. The material with ER activity and luminescence performance is a novel multifunctional material which would have wide application prospect.