Thermo-reversible flurbiprofen liquid suppository with HP-β-CD as a solubility enhancer: improvement of rectal bioavailability

The purpose of this work was to develop a thermo-reversible flurbiprofen liquid suppository base composed of poloxamer and sodium alginate for the improvement of rectal bioavailability of flurbiprofen. Cyclodextrin derivatives such as α-, β-, γ-cyclodextrin and hydroxypropyl-β-cyclodextrin (HP-β-CD) were used to enhance the aqueous solubility of flurbiprofen. The effects of HP-β-CD and flurbiprofen on the physicochemical properties of liquid suppository were then investigated. Pharmacokinetic studies were performed after rectal administration of flurbiprofen liquid suppositories with and without HP-β-CD or after intravenous administration of commercial Lipfen^® (flurbiprofen axetil-loaded emulsion) to rats, and their pharmcokinetic parameters were compared. HP-β-CD decreased the gelation temperature and reinforced the gel strength and bioadhesive force of liquid suppository, while flurbiprofen was opposed to HP-β-CD. Thermo-reversible flurbiprofen liquid suppository showed the physicochemical properties suitable for rectal administration. The flurbiprofen liquid suppository with HP-β-CD showed significantly higher plasma levels, AUC and C_max of flurbiprofen than those of the liquid suppository without HP-β-CD, indicating that flurbiprofen could be well absorbed due to the enhanced solubility by formation of inclusion complex. Moreover, the flurbiprofen liquid suppository with HP-β-CD showed an excellent bioavailability in that the AUC of flurbiprofen after its rectal administration was not significantly different from that after intravenous administration of commercial Lipfen^®. It is concluded that HP-β-CD could be a preferable solubility enhancer for the development of liquid suppository containing poorly water-soluble drugs.     

Complexation of ebastine with β-cyclodextrin derivatives

Complexation of ebastine (EB) with hydroxypropyl and methyl-β-cyclodextrin (HP-β-CD and Me-β-CD) was studied in aqueous solutions and in the solid state. The formation of inclusion complexes in aqueous solutions was analysed by the solubility method. The assays were designed using low CD concentrations compared with the solubility of these derivatives in order to avoid non-inclusion phenomena and to obtain a linear increase in EB solubility as a function of CD concentration. The values of complexation efficiency for HP-β-CD and Me-β-CD were 1.9 × 10^?2 and 2.1 × 10^?2, respectively. It seems that the non polar character of the methyl moiety slightly favoured complexation. In relation to solid state complexation, 1:1 EB:CD systems were prepared by kneading, and by heating a drug-CD mixture at 90 ºC. They were analysed using X ray diffraction analysis by comparison with their respective physical mixtures. A complex with a characteristic diffraction pattern similar to that of the channel structure of β-CD was formed with Me-β-CD in 1:1 melted and 1:2 EB:CD kneaded systems. Complexation with HP-β-CD was not clearly evidenced because only a slight reduction of drug crystallinity was detected. Finally, the loading of EB in two β-CD polymers cross-linked with epichlorohydrin yielded 7.3 and 7.7 mg of EB/g polymer respectively.     

Enantiomeric separation of (R, S)-naproxen by recycling high speed counter-current chromatography with hydroxypropyl-β-cyclodextrin as chiral selector

Recycling high speed counter-current chromatography (HSCCC) was successfully applied to resolution of (R, S)-naproxen (NAP) using hydroxypropyl-β-cyclodextrin (HP-β-CD) as chiral selector. The two-phase solvent system composed of n-hexane-ethyl acetate-0.1 mol L(-1) phosphate buffer solution with pH=2.67 (8:2:10, v/v/v) was selected. Influence factors for the chiral separation process were investigated, including concentration of HP-β-CD, equilibrium temperature and pH of aqueous phase. Suitable elution mode was selected for HSCCC enantioseparation of (R, S)-NAP. Under optimum separation conditions, 29 mg of (R, S)-NAP was separated using preparative recycling HSCCC with the molar ratio HP-β-CD/NAP racemate 83:1. Technical details for recycling elution mode were discussed as for chiral HSCCC separation. The purities of both (S)-NAP and (R)-NAP were over 99.5% as determined by HPLC. Enantiomeric excess of (S)-NAP and (R)-NAP reached 99.4%. Recovery for NAP enantiomers from HSCCC fractions was 82-89%, yielding 13 mg of (S)-NAP and 12 mg of (R)-NAP.     

Complexation of tyrosol with cyclodextrins

Tyrosol (TY), 4-(2-hydroxyethyl)phenol, is an olive oil biophenol with antioxidant activity and positive effects on human health. This study has investigated the interactions of TY with cyclodextrins (CD) and a CD polymer. Complexation of TY with β-CD, hydroxypropyl-β-CD (HP-β-CD), and methyl-β-CD (Me-β-CD) has been evaluated both in aqueous solution and in the solid state. The techniques employed in solution to determine the apparent stability constants of the respective complexes were fluorescence and UV–visible spectroscopies. Complexation with β-CD and its derivatives involved an increase of both the UV absorbance and the intrinsic fluorescence of TY; a bathochromic shift of the UV spectrum was detected as well. The apparent stability constants obtained with native β-CD, Me-β-CD and HP-β-CD presented similar values. Complexes in the solid state were obtained by coevaporation and kneading. They were characterised by X-ray diffraction analysis and differential thermal analysis. The interaction of TY with β-CD led to a crystalline complex; the same diffraction pattern was obtained by coevaporation and kneading. The complexes obtained with methyl- and HP-β-CD were amorphous irrespective of the preparation method. In addition, the retention of TY in an insoluble polymer of CD crosslinked with epichlorohydrin has been quantified. In approximately 20 min, 1 mg of TY per gram of polymer was retained.     

Effect of hydroxypropyl-β-cyclodextrin complexation on the aqueous solubility, structure, thermal stability, antioxidant activity, and tyrosinase inhibition of paeonol

The objective of this paper is to study the effect of hydroxypropyl-β-cyclodextrin (HP-β-CD) complexation on the aqueous solubility, structure, thermal stability, antioxidant activity, and tyrosinase inhibition of paeonol (PAE). The inclusion complex (PAE-HP-β-CD complex) of HP-β-CD and PAE was prepared by a freeze-drying method. Phase solubility tests showed that the stability constant of the inclusion complex was about 33.8?M^?1 at 25?°C. The experimental results of proton nuclear magnetic resonance (H-NMR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) suggested that PAE was included by HP-β-CD to form the PAE-HP-β-CD complex. Furthermore, the thermogravimetric analysis (TGA) results showed that the thermal stability of PAE was improved when it was complexed with HP-β-CD. Comparing the antioxidant activity of PAE with that of the PAE-HP-β-CD complex at the same concentration revealed that the complex of PAE with HP-β-CD was better able to eliminate radical. Furthermore, the experimental results revealed that the formation of a complex with HP-β-CD increased the water solubility of PAE, improving its apparent inhibitive activity of tyrosinase.     

The effect of cyclodextrin mixtures on aqueous solubility of beclomethasone dipropionate

The aim of present study was to evaluate the effect of natural, synthetic cyclodextrins (CDs) and CD mixtures on aqueous solubility of beclomethasone dipropionate (BDP). The phase solubility studies were done in the presence of 6 CDs. Furthermore, aqueous solubility of BDP was tested in the presence of CD mixtures. The solubility of BDP in water was increased by 30, 77, 155 and 30 folds in the solution containing 20%?w/v α-CD, hydroxylpropyl β-CD (HP-β-CD), hydroxypropyl γ-CD (HP-γ-CD) and sulphobutylether β-CD (SBE-β-CD), respectively. CD mixtures had remarkable effect on the aqueous solubility of BDP so that solubility in water increased between 200 and 1,500 times in the presence of different CD mixtures. Further addition of sodium acetate to the solubilisation medium reduced the aqueous solubility. In conclusion, CD complexation was able to improve the aqueous solubility of BDP. The synergistic effect of cyclodextrin mixture was observed.     

Host–guest complexation of a nitroheterocyclic compound with cyclodextrins: a spectrofluorimetric and molecular modeling study

Nitroheterocyclic compounds (NC) were candidate drugs proposed for Chagas disease chemotherapy. In this study, we investigated the complexation of hydroxymethylnitrofurazone (NFOH), a potential antichagasic compound, with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), Hydroxypropyl-β-cyclodextrin (HP-β-CD), Dimethyl-β-cyclodextrin (DM-β-CD) and γ-cyclodextrin (γ-CD) by fluorescence spectroscopy and molecular modeling studies. Hildebrand–Benesi equation was used to calculate the formation constants of NFOH with cyclodextrins based on the fluorescence differences in the CDs solution. The complexing capacity of NFOH with different CDs was compared through the results of association constant according to the following order: DM-β-CD > β-CD > α-CD > HP-β-CD > γ-CD. Molecular modeling studies give support for the experimental assignments, in favor of the formation of an inclusion complex between cyclodextrins with NFOH. This is an important study to investigate the effects of different kinds of cyclodextrins on the inclusion complex formation with NFOH and to better characterize a potential formulations to be used as therapeutic options for the oral treatment of Chagas disease.     

Minoxidil–2-hydroxypropyl-β-cyclodextrin inclusion complexes: characterization and in vivo evaluation of an aqueous solution for hair growth in rats

Minoxidil dissolved in organic solvents is commonly used in the treatment of androgenic alopecia because it is hydrophobic and poorly soluble in water. The aim of this investigation was to develop an aqueous minoxidil solution without addition of organic solvents. To this end, minoxidil was encapsulated in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) to form a minoxidil–HP-β-CD inclusion complex with aqueous solubility higher than that of pure minoxidil. Minoxidil–HP-β-CD inclusion complexes were prepared using a freeze-drying method from minoxidil and HP-β-CD at a molar ratio of 1:1. Complex formation was confirmed by nuclear magnetic resonance, thermogravimetric analysis, and thin layer chromatography. The structure of the complex was determined using two-dimensional rotating frame overhauser effect spectroscopy. Minoxidil–HP-β-CD inclusion complexes were dissolved in water to form a homogeneous aqueous solution, and its effect on the hair cycle of mice was evaluated in vivo. The results support the feasibility of using HP-β-CD to prepare an aqueous minoxidil solution to replace organic solvent-based solutions.     

Complexation of Ketoconazole by Native and Modified Cyclodextrins

Complexation of ketoconazole (KET), a broad-spectrum antifungal drug, with β- and γ-cyclodextrins (CDs), heptakis (2,6-di-O-methyl)-β-CD (2,6-DM-β-CD), heptakis (2,3,6-tri-O-methyl)-β-CD (TM-β-CD), 2-hydroxypropyl-β-CD (2HP-β-CD) and carboxymethyl-β-CD (CM-β-CD) was studied. The stability constants were determined by the solubility method at pH = 6 and for 2,6-DM-β-CD and CM-β-CD at pH = 5. At pH = 6, the stability constants increased in the order: TM-β-D < γ-CD < 2HP-β-CD < β-CD < CM-β-CD < 2,6-DM-β-CD. At pH = 5, due to the increased ionization of KET, the stability constant with CM-β-CD increased and with 2,6-DM-β-CD decreased. For complexes of KET with 2HP-β-CD and 2,6-DM-β-CD, the thermodynamic parameters of complexation were determined from the temperature dependence of the corresponding stability constants. For β–γ and TM-β-CD complexes, calculations using HyperChem 6 software by the Amber force field were carried out to gain some insight into the host–guest geometry.     

Guest–Host Interactions between Crown-Containing 2-Styrylbenzothiazole and HP-β-CD

The inclusion complexes of the trans-isomer of2-[2-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecen-2-yl)-vinyl]-benzothiazole(CSB) with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) were investigatedby electronic absorption and fluorescence spectroscopies in aqueous solution. Theaddition of HP-β-CD has very little effect on the absorption spectra of CSB.A 17-nm blue shift and pronounced fluorescence enhancements in the emissionspectrum of CSB were observed. 1:1 and 1:2 stoichiometries were found forcomplexes of CSB with HP-β-CD, and formation constants of the complexesand other thermodynamic parameters were estimated from fluorescence measurements.In the case of the 1:1 CSB: HP-β-CD complex, the formation constant was equalto 3,802 at 293 K, the complexation reaction was exothermic (Δ H⁰ = -9.2 ±1.1 kJ mol^-1) and presented a positive entropy value (Δ S⁰ = 37.3 ± 3.8 Jmol^-1 K^-1). A molecular structure was proposed for the CSB:HP-beta;-CDinclusion complex.     

Investigation of monoterpenes complexation with hydroxypropyl-β-cyclodextrin

In this study, we investigated the inclusion complexation of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and eight monoterpenes (eucalyptol, geraniol, limonene, linalool, α-pinene, β-pinene, pulegone, and thymol) in aqueous solution and solid state. The formation constants (K _f) of inclusion complexes were determined using fluorescence spectroscopy and static headspace gas chromatography. The results indicated the formation of 1:1 inclusion complexes between HP-β-CD and all studied guests. A linear relationship was found between K _f values and the hydrophobic character of the monoterpenes expressed as logP. Solid complexes were prepared by the freeze-drying method in a 1:1 (HP-β-CD:monoterpene) molar ratio. Physicochemical characterization of solid inclusion complexes was carried out using Fourier transform infrared spectroscopy and differential scanning calorimetry. Finally, the encapsulation efficiency (EE%) of HP-β-CD was determined using HPLC analysis. Noticeable difference in the EE% was observed between monoterpene hydrocarbons and oxygenated monoterpenes. These results suggested that complexation with HP-β-CD could be a promising strategy to enlarge the application of monoterpenes in cosmetic, pharmaceutical and food industries.     

β-环糊精衍生物与吡罗昔康的包合特性

采用荧光光谱、差热扫描和核磁共振法,研究了不同酸度下吡罗昔康（PX）与β-环糊精（β-CD）、羟丙基-β-环糊精（HP-β-CD）和磺丁醚-β-环糊精（SBE-β-CD）的包合特性。 结果表明,吡罗昔康与3种环糊精均形成了1∶2.5的包合物。 以包合常数为包合能力的量度,中性条件下,包合平衡常数分别为1.2×106、1.8×106、2.0×106,3种环糊精的包合能力为SBE-β-CD＞HP-β-CD＞β-CD。     

毛细管区带电泳对手性药物盐酸美西律和盐酸异博定的对映体分离

应用环糊精-毛细管区带电泳体系对手性药物盐酸美西律和盐酸异博定的对映体分离进行了研究。结果表明, 在所研究的手性选择剂α-环糊精, β-环糊精, 二甲基-β-环糊精, 羟丙基β-环糊精和γ-环糊精中, 羟丙基β-环糊精对所研究的手性药物分离效果较好。对盐酸美西律和盐酸异博定的最佳羟丙基-β-环糊精浓度分别为30mmol/L和9mmol/L, 最佳缓冲溶液浓度为100mmol/L Tris-H3PO4(pH2.3)。向缓冲溶液中加入0.05%羟丙基纤维素(HPLC)可改善分离。盐酸美西律获得了接近基线的手性分离, 而盐酸异博定亦获得了较好的分离。     

Naproxen: Hydroxypropyl-β-Cyclodextrin:Polyvinylpyrrolidone Ternary Complex Formation

The aim of the present study was to investigate the effect of the presence of thewater-soluble polymer polyvinylpyrrolidone (PVP) MW = 24000 g/mol, on thecomplexation of the phototoxic anti-inflammatory drug naproxen, in its sodiumsalt form, with hydroxypropil-β-cyclodextrin (HP-β-CD). The datashown that the polymer interacts with the free naproxen and with thenaproxen:HP-β-CD inclusion complex. The presence of different proportions of PVP, in the 0–1%(w/w) rangesystematically increased the K_app of the naproxen:HP-β-CD inclusioncomplex formation. The cause of this increase is that the polymer interactswith the HP-β-CD with a binding constant of K₂ = 29000 ± 53 M^-1; and with the naproxen:HP-β-CD inclusion complex, to givea ternary complex naproxen:HP-β-CD:PVP. The binding constant of thisprocess was K₃ = 5350 ± 1 M^-1. NMR data revealed that in the ternary system, PVP is outside of the cyclodextrin, and therefore must be wholly or partially recovering the naproxen:HP-β-CD inclusion complex.     

Inclusion complexes of cyclodextrins with 4-amino-1,8-naphthalimides (part 2)

Fluorescence spectroscopy was used to characterize inclusion compounds between 4-amino-1,8-naphthalimides (ANI) derivatives and different cyclodextrins (CDs). The ANI derivatives employed were N-(12-aminododecyl)-4-amino-1,8-naphthalimide (mono-C₁₂ANI) and N,N′-(1,12-dodecanediyl)bis-4-amino-1,8-naphthalimide (bis-C₁₂ANI). The CDs used here were α-CD, β-CD, γ-CD, HP-α-CD, HP-β-CD and HP-γ-CD. The presence of CDs resulted in pronounced blue-shifts in the emission spectra of the ANI derivatives, with increases in emission intensity. This behavior was parallel to that observed for the dyes in apolar solvents, indicating that inclusion complexes were formed between the ANI and the CDs. Mono-C₁₂ANI formed inclusion complexes of 1:1 stoichiometry with all the CDs studied. Complexes with the larger CDs (HP-β-CD, HP-γ-CD and γ-CD) were formed by inclusion of the chromophoric ANI ring system, whereas the smaller CDs (α-CD, HP-α-CD and β-CD) formed complexes with mono-C₁₂ANI by inclusion of the dodecyl chain. Bis-C₁₂ANI formed inclusion complexes of 1:2 stoichiometry with HP-β-CD, HP-γ-CD and γ-CD, but did not form inclusion complexes with α-CD, HP-α-CD and β-CD. The data were treated in the case of the large CDs using a Benesi-Hildebrand like equation, giving the following equilibrium constants: mono-C₁₂ANI:HP-β-CD (K ₁₁ = 50 M^?1), mono-C₁₂ANI:HP-γ-CD (K ₁₁ = 180 M^?1), bis-C₁₂ANI:HP-β-CD (K ₁₂ = 146 M^?2), bis-C₁₂ANI:HP-γ-CD (K ₁₂ = 280 M^?2).     

羟丙基-β-环糊精对华法林的荧光增强作用及其分析应用

研究了羟丙基-β-环糊精(HP-β-CD)对抗凝药物华法林的荧光增强作用,探讨了华法林与HP-β-CD的包合特性.并与β-环糊精(β-CD)对华法林的荧光增强作用和包合特性进行了比较,结果表明,HP-β-CD的荧光增强作用强于β-CD.基于HP-β-CD的荧光增强作用,研究建立了一种荧光光谱测定华法林的新方法.华法林在10.3～2266μg/L范围内与荧光强度呈良好的线性关系,检出限为2.92μg/L.此法已应用于华法林钠药物的测定.     

Kinetic study on reactive extraction for chiral separation of phenylsuccinic acid enantiomers

The kinetics of the extraction of phenylsuccinic acid (PSA) enantiomers by hydroxypropyl-β-cyclodextrin (HP-β-CD) in a modified Lewis cell was studied, in which HP-β-CD dissolved in 0.1 mol L^?1 NaH₂PO₄/H₃PO₄ buffer solution (pH = 2.5) was selected as the chiral extractant. PSA enantiomers were extracted from organic phase to aqueous phase in the extraction module. The theory of extraction accompanied by a chemical reaction has been used to obtain the intrinsic kinetics of this extraction module. The different parameters affecting the extraction rate such as agitation speed, interfacial area, initial concentration of PSA enantiomers in organic phase as well as HP-β-CD concentration in aqueous phase were separately studied. The experimental results demonstrate that the extraction reactions are fast. The reactions were found to be first order with respect to PSA and second order with respect to HP-β-CD with forward rate constants of 3.4 × 10^?2 m⁶ mol^?2 s^?1 for R-PSA and 9.96 × 10^?3 m⁶ mol^?2 s^?1 for S-PSA. These data will be useful in the design of extraction processes.     

不同取代度的羟丙基-β-环糊精与大豆苷元的包合作用

采用溶液搅拌法制备了6种不同取代度（DS）的羟丙基-β-环糊精（HP-β-CD）与大豆苷元的包合物,并通过红外光谱法（IR）,X射线衍射法（XRD）,紫外光谱法（UV）等对其进行了包合鉴定.又采用相溶解度法计算了其中4种HP-β-CD/大豆苷元包合物的表观平衡常数（Kc）,研究了不同取代度的羟丙基-β-环糊精与大豆苷元的包合作用.结果表明,不同取代度的HP-β-CD对大豆苷元均产生了包合作用,且DS=7.8的HP-β-CD/大豆苷元包合物的表观平衡常数最大（Kc=2.162 7×10^-2）,达到了最佳的包合效果.     

Thermodynamic study of inclusion complexes of zaleplon with natural and modified cyclodextrins

The thermodynamics and stoichiometry of zaleplon (ZAL) complexation with different cyclodextrin derivatives [β-CD, hydroxypropyl-β-cyclodextrin (HP-β-CD), randomly methylated-β-cyclodextrin (RAMEB), sulphobutylether-β-cyclodextrin (SBE-β-CD)] in aqueous solution was studied by spectrofluorimetry and ¹H NMR spectroscopy in order to obtain a more general understanding of the driving forces behind the inclusion phenomena. Job’s plot derived from the NMR spectral data and statistical analysis of spectrofluorimetric titration data confirmed the formation of equimolar complexes in all systems tested, excluding the possibility of higher order complex formation. Furthermore, thermodynamic parameters obtained by both techniques gave similar and negative values of ΔG° for all complexes, indicating spontaneous inclusion of drug into CDs. From a thermodynamic point of view, two types of inclusions were determined. One is enthalpy driven ZAL complexation with β-CD, HP-β-CD and RAMEB, while the other is entropy driven complexation observed in the case of SBE-β-CD. The mechanisms behind each type of inclusion were discussed in detail.     

Enantioselective Extraction System Containing Binary Chiral Selectors and Chromatographic Enantioseparation Method for Determination of the Absolute Configuration of Enantiomers of Cyclopentolate

The distribution coefficients and enantioseparation of cyclopentolate were studied in an extraction system containing d-tartaric acid ditertbutyl ester in organic phase and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous phase. Various parameters involved in the enantioseparation such as the type and the concentration of chiral selectors, pH value and a wide range of organic solvents were investigated. The maximum enantioselectivity (α = 2.13) and optimum distribution coefficients (K _R = 0.85, K _S = 0.40) were obtained under the following conditions: 0.10 mol/L HP-β-CD in aqueous phase and 0.20 mol/L d-tartaric acid ditertbutyl ester in decanol as organic phase. Cyclopentolate is present as a racemic mixture to the aqueous phase. The potentially different biological activities of cyclopentolate enantiomers have not been examined yet. Two chiral liquid chromatography methods have been developed for the direct separation of the enantiomers of cyclopentolate. First method was used for the quantification analysis of cyclopentolate enantiomers in aqueous phase. Second method used two chiroptical detectors: electronic circular dichroism (ECD) and optical rotation (OR) for the identification of individual cyclopentolate enantiomers from the organic phase enriched with (R)-enantiomer. The absolute stereochemistry was determined by means of the comparison of the experimental and computed ECD spectra and signs of OR. The ECD spectra of chiral analytes were measured on-line using HPLC-ECD technique.