Characterization of β-lapachone and methylated β-cyclodextrin solid-state systems

The purpose of this research was to explore the utility of β cyclodextrin (βCD) and β cyclodextrin derivatives (hydroxypropyl-β-cyclodextrin [HPβCD], sulfobutylether-β-CD [SB\CD], and a randomly methylated-β-CD [RMβCD]) to form inclusion complexes with the antitumoral drug, β-lapachone (βLAP), in order to overcome the problem of its poor water solubility. RMβCD presented the highest efficiency for βLAP solubilization and was selected to develop solid-state binary systems. Differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared (FTIR) and optical and scanning electron microscopy results suggest the formation of inclusion complexes by both freeze-drying and kneading techniques with a dramatic improvement in drug dissolution efficiency at 20-minute dissolution efficiency (DE_20-minute 67.15% and 88.22%, respectively) against the drug (DE_20-minute 27.11%) or the βCD/drug physical mixture (DE_20-minute 27.22%). However, the kneading method gives a highly crystalline material that together with the adequate drug dissolution profile make it the best procedure in obtaining inclusion complexes of RMβCD/βLAP convenient for different applications of βLAP. Published: July 27, 2007     

Preformulation Study of the Inclusion Complex Irbesartan-β-Cyclodextrin

The aim of the present work was to improve the solubility and dissolution profile of Irbesartan (IRB), a poorly water-soluble drug by formation of inclusion complex with β-cyclodextrin (βCD). Phase solubility studies revealed increase in solubility of the drug upon cyclodextrin addition, showing A_L—type of graph with slope less than one indicating formation of 1:1 stoichiometry inclusion complex. The stability constant (K _s) was found to be 104.39 M⁻¹. IRB–βCD binary systems were prepared by cogrinding, kneading using alcohol, kneading using aqueous alcohol, and coevaporation methods. Characterization of the binary systems were carried out by differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and proton nuclear magnetic resonance. The dissolution profiles of inclusion complexes were determined and compared with those of IRB alone and physical mixture. Among the various methods, coevaporation was the best in which the solubility was increased and dissolution rate of the drug was the highest. The study indicated the usefulness of cyclodextrin technology to overcome the solubility problem of IRB.     

Influence of hydrophilic polymers on celecoxib complexation with hydroxypropyl beta-cyclodextrin

Complexation of celecoxib with hydroxypropyl beta-cyclodextrin (HPbetaCD) in the presence and absence of 3 hydrophilic polymers-polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG)-was investigated with an objective of evaluating the effect of hydrophilic polymers on the complexation and solubilizing efficiencies of HPbetaCD and on the dissolution rate of celecoxib from the HPbetaCD complexes. The phase solubility studies indicated the formation of celecoxib-HPbetaCD inclusion complexes at a 1:1M ratio in solution in both the presence and the absence of hydrophilic polymers. The complexes formed were quite stable. Addition of hydrophilic polymers markedly enhanced the complexation and solubilizing efficiencies of HPbetaCD. Solid inclusion complexes of celecoxib-HPbetaCD were prepared in 1:1 and 1:2 ratios by the kneading method, with and without the addition of hydrophilic polymers. The solubility and dissolution rate of celecoxib were significantly improved by complexation with HPbetaCD. The celecoxib-HPbetaCD (1:2) inclusion complex yielded a 36.57-fold increase in the dissolution rate of celecoxib. The addition of hydrophilic polymers also markedly enhanced the dissolution rate of celecoxib from HPbetaCD complexes: a 72.60-, 61.25-, and 39.15-fold increase was observed with PVP, HPMC, and PEG, respectively. Differential scanning calorimetry and X-ray diffractometry indicated stronger drug amorphization and entrapment in HPbetaCD because of the combined action of HPbetaCD and the hydrophilic polymers.     

Effects of the Preparation Method on the Formation of True Nimodipine SBE-β-CD/HP-β-CD Inclusion Complexes and Their Dissolution Rates Enhancement

The aims of this study were to enhance the solubility and dissolution rate of nimodipine (ND) by preparing the inclusion complexes of ND with sulfobutylether-b-cyclodextrin (SBE-β-CD) and 2-hydroxypropyl-b-cyclodextrin (HP-β-CD) and to study the effect of the preparation method on the in vitro dissolution profile in different media (0.1 N HCl pH 1.2, phosphate buffer pH 7.4, and distilled water). Thus, the inclusion complexes were prepared by kneading, coprecipitation, and freeze-drying methods. Phase solubility studies were conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were investigated with differential scanning calorimetry (DSC), X-ray diffractometry (X-RD), and Fourier transform infrared spectroscopy (FT-IR). Stable complexes of ND/SBE-β-CD and ND/HP-β-CD were formed in distilled water in a 1:1 stoichiometric inclusion complex as indicated by an A_L-type diagram. The apparent stability constants (Ks) were 1334.4 and 464.1 M⁻¹ for ND/SBE-β-CD and ND/HP-β-CD, respectively. The water-solubility of ND was significantly increased in an average of 22- and 8-fold for SBE-β-CD and HP-β-CD, respectively. DSC results showed the formation of true inclusion complexes between the drug and both SBE-β-CD and HP-β-CD prepared by the kneading method. In contrast, crystalline drug was detectable in all other products. The dissolution studies showed that all the products exhibited higher dissolution rate than those of the physical mixtures and ND alone, in all mediums. However, the kneading complexes displayed the maximum dissolution rate in comparison with drug and other complexes, confirming the influence of the preparation method on the physicochemical properties of the products.     

Crystal structure of the inclusion complex of the antibacterial agent triclosan with cyclomaltoheptaose and NMR study of its molecular encapsulation in positively and negatively charged cyclomaltoheptaose derivatives

The inclusion complexes of triclosan with native cyclomaltoheptaose (beta-cyclodextrin, betaCD) as well as with negatively and positively charged derivatives are studied. The structure of the inclusion complex betaCD/triclosan in the crystalline state [P1, a=15.189(5), b=15.230(6), c=16.293(6), alpha=91.07(4), beta=91.05(3) gamma=100.71(3)] comprises two crystallographically independent host macrocycles A and B. The packing results in betaCD dimers that align head-to-head and form infinite channels along the c-axis. Only one guest molecule statistically disordered over two positions, (the dichlorophenyl ring in the cavities of either A or B) corresponds to each dimer (a 2:1 host/guest complex). The enclosed dichlorophenyl ring enters the dimer through the primary side, whereas the hydrophilic chlorophenol ring extends in the space between dimers. Water molecules in five positions are also enclosed in the intradimer region, arranged on a plane perpendicular to the sevenfold axis of betaCD. The NMR spectroscopic studies in aqueous solution show the presence of both 1:1 and 2:1 betaCD/triclosan complexes. In the first case, two different 1:1 complexes are simultaneously present, each with either ring entering the narrow primary side of one betaCD molecule. In the 2:1 complex both rings of triclosan are included in two independent betaCD hosts, a precursor to the supramolecular arrangement found in the crystalline form. In the case of the negatively charged sodium heptakis[6-deoxy-6-(3-thiopropionate)]-betaCD, the NMR studies at pH 7.9 show a complete inclusion of triclosan inside the host in two orientations, one for the non-ionized (phenol) and reverse for the ionized (phenolate) form. Finally, for the positively charged heptakis(6-aminoethylamino-6-deoxy)-betaCD, inclusion of triclosan is possible only when the pH is raised to 10 and it is concluded that both aromatic rings are alternatively inside the cavity. However in that case also, inclusion of the entire guest in the elongated cavity is suggested.     

Physicochemical Properties and Dissolution Studies of Dexamethasone Acetate-β-Cyclodextrin Inclusion Complexes Produced by Different Methods

Inclusion complexes between dexamethasone acetate (DMA), a poorly water soluble drug, and β-cyclodextrin (βCD) were obtained to improve the solubility and dissolution rate of this drug. Phase-solubility profile indicated that the solubility of DMA was significantly increased in the presence of βCD (33-fold) and was classified as A_L-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by different methods (kneading, coevaporation, freeze drying) and physical mixture were characterized by differential scanning calorimetry, thermogravimetry, infrared absorption and optical microscopy. Preparation methods influenced the physicochemical properties of the products. The dissolution profiles of solid complexes were determined and compared with those DMA alone and their physical mixture, in three different mediums: simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 7.4) and distilled water. The dissolution studies showed that in all mediums DMA presented an incomplete dissolution even in four hours. In contrast, the complexes formed presented a higher dissolution rate in simulated gastric fluid (SGF pH 1.2), which indicate that these have different ionization characteristics. According to the results, the freeze–dried and kneaded products exhibited higher dissolution rates than the drug alone, in all the mediums.     

Nanosuspensions Containing Oridonin/HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability

Chemotherapy via oral route of anticancer drugs offers much convenience and compliance to patients. However, oral chemotherapy has been challenged by limited absorption due to poor drug solubility and intestinal efflux. In this study, we aimed to develop a nanosuspension formulation of oridonin (Odn) using its cyclodextrin inclusion complexes to enhance oral bioavailability. Nanosuspensions containing Odn/2 hydroxypropyl-β-cyclodextrin inclusion complexes (Odn-CICs) were prepared by a solvent evaporation followed by wet media milling technique. The nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and dissolution. The resulting nanosuspensions were approximately 313.8 nm in particle size and presented a microcrystal morphology. Nanosuspensions loading Odn-CICs dramatically enhanced the dissolution of Odn. Further, the intestinal effective permeability of Odn was markedly enhanced in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and poloxamer. Bioavailability studies showed that nanosuspensions with Odn-CICs can significantly promote the oral absorption of Odn with a relative bioavailability of 213.99% (Odn suspensions as reference). Odn itself possesses a moderate permeability and marginal intestinal metabolism. Thus, the enhanced bioavailability for Odn-CIC nanosuspensions can be attributed to improved dissolution and permeability by interaction with absorptive epithelia and anti-drug efflux. Nanosuspensions prepared from inclusion complexes may be a promising approach for the oral delivery of anticancer agents.     

Formulation and In Vivo Evaluation of Orally Disintegrating Tablets of Clozapine/Hydroxypropyl-β-cyclodextrin Inclusion Complexes

The aim of this study was to improve the solubility and oral bioavailability of clozapine (CLZ), a poorly water-soluble drug subjected to substantial first-pass metabolism, employing cyclodextrin complexation technique. The inclusion complexes were prepared by an evaporation method. Phase solubility studies, differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy were used to evaluate the complexation of CLZ with hydroxypropyl-β-cyclodextrin (HP-β-CD) and the formation of true inclusion complexes. Characterization and dissolution studies were carried out to evaluate the orally disintegrating tablets (ODTs) containing CLZ/HP-β-CD complexes prepared by direct compression. Finally, the bioavailability studies of the prepared ODTs were performed by oral administration to rabbits. The ODTs showed a higher in vitro dissolution rate and bioavailability compared with the commercial tablets. It is evident from the results herein that the developed ODTs provide a promising drug delivery system in drug development, owing to their excellent performance of a rapid onset of action, improved bioavailability, and good patient compliance.     

Physico-Chemical Characterization and In Vitro Dissolution Assessment of Clonazepam—Cyclodextrins Inclusion Compounds

The objectives of this research were to prepare and characterize inclusion complexes of clonazepam with β-cyclodextrin and hydroxypropyl-β-cyclodextrin and to study the effect of complexation on the dissolution rate of clonazepam, a water-insoluble lipid-lowering drug. The phase-solubility profiles with both cyclodextrins were classified as A_P-type, indicating the formation of 2:1 stoichiometric inclusion complexes. Gibbs free energy ( DG_tr^o ) \left( {\Delta {G_{tr}}^o} \right) values were all negative, indicating the spontaneous nature of clonazepam solubilization, and they decreased with increase in the cyclodextrins concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrins increased. Complexes of clonazepam were prepared with cyclodextrins by various methods such as kneading, coevaporation, and physical mixing. The complexes were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry studies. These studies indicated that complex prepared kneading and coevaporation methods showed successful inclusion of the clonazepam molecule into the cyclodextrins cavity. The complexation resulted in a marked improvement in the solubility and wettability of clonazepam. Among all the samples, complex prepared with hydroxypropyl-β-cyclodextrin by kneading method showed highest improvement in in vitro dissolution rate of clonazepam. Mean dissolution time of clonazepam decreased significantly after preparation of complexes and physical mixture of clonazepam with cyclodextrins. Similarity factor indicated significant difference between the release profiles of clonazepam from complexes and physical mixture and from plain clonazepam. Tablets containing complexes prepared with cyclodextrins showed significant improvement in the release profile of clonazepam as compared to tablet containing clonazepam without cyclodextrins.     

Multiple complexation of cyclodextrin with soy isoflavones present in an enriched fraction

In the present study we evaluated the complexation of daidzein/genistein/glycitein, present in an isoflavone enriched fraction (IEF), with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin (HPβCD). Based on the increased solubility and higher complexation efficiency, IEF and HPβCD solid complexes were prepared by kneading, freeze-drying, co-evaporation, spray-drying and microwave. The solid complexes were characterized using Fourier transformed-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, and nuclear magnetic resonance spectroscopy, and the isoflavone content and solubility were determined by liquid chromatography. The results suggest that the isoflavones daidzein, genistein and glycitein may be externally associated to HPβCD as well as that isoflavones/HPβCD inclusion complexes are formed through the insertion of B-ring into the cyclodextrin cavity. Except for the freeze-dried IEF/HPβCD solid complex, all complexes showed similar content and solubility. In conclusion, the three isoflavones showed to be able to simultaneously complex with HPβCD.     

Influence of hydrophilic polymers on celecoxib complexation with hydroxypropyl β-cyclodextrin

Complexation of celecoxib with hydroxypropyl β-cyclodextrin (HPβCD) in the presence and absence of 3 hydrophilic polymers—polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG)—was investigated with an objective of evaluating the effect of hydrophilic polymers on the complexation and solubilizing efficiencies of HPβCD and on the dissolution rate of celecoxib from the HPβCD complexes. The phase solubility studies indicated the formation of celecoxib-HPβCD inclusion complexes at a 1∶1M ratio in solution in both the presence and the absence of hydrophilic polymers. The complexes formed were quite stable. Addition of hydrophilic polymers markedly enhanced the complexation and solubilizing efficiencies of HPβCD. Solid inclusion complexes of celecoxib-HPβCD were prepared in 1∶1 and 1∶2 ratios by the kneading method, with and without the addition of hydrophilic polymers. The solubility and dissolution rate of celecoxib were significantly improved by complexation with HPβCD. The celecoxib-HPβCD (1∶2) inclusion complex yielded a 36.57-fold increase in the dissolution rate of celecoxib. The addition of hydrophilic polymers also markedly enhanced the dissolution rate of celecoxib from HPβCD complexes: a 72.60-, 61.25-, and 39.15-fold increase was observed with PVP, HPMC, and PEG, respectively. Differential scanning calorimetry and X-ray diffractometry indicated stronger drug amorphization and entrapment in HPβCD because of the combined action of HPβCD and the hydrophilic polymers. Published: September 29, 2006     

Interaction of sulfadiazine with cyclodextrins in aqueous solution and solid state

The main objective of this work was to increase the solubility of sulfadiazine by formation of inclusion complexes with β-cyclodextrin, and methyl-β-cyclodextrin. The apparent stability constants have been determined by phase solubility studies in water and buffer solutions of pH values of 2 and 8. The stoichiometry of all complexes was found to be 1:1 but different relative affinities were found for each cyclodextrin. It was possible to obtain a greater overall solubility by using a combined approach of pH adjustment and complexation with cyclodextrins. Guest-host interactions have been investigated using nuclear magnetic resonance. Complexes were prepared in solid state by different methods and were characterized using differential scanning calorimetry, thermogravimetric analysis, Fourier-transform infrared spectroscopy, X-ray diffractometry and scanning electron microscopy. The dissolution rate of the drug from the inclusion complex made by freeze-dried was much faster than this of the pure drug.     

Enhanced Dissolution and Stability of Lansoprazole by Cyclodextrin Inclusion Complexation: Preparation, Characterization, and Molecular Modeling

In this study, lansoprazole (LSP)/cyclodextrin (CD) inclusion complexes were prepared using a fluid bed coating technique, with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HPCD) as the host molecules, respectively, to simultaneously improve the dissolution and stability of LSP. The dissolution rate and stability of LSP was dramatically enhanced by inclusion complexation regardless of CD type. LSP/HPCD inclusion complex was more stable under illumination than LSP/β-CD inclusion complex. Differential scanning calorimetry and powder X-ray diffractometry proved the absence of crystallinity in both LSP/CD inclusion complexes. Fourier transform infrared spectroscopy together with molecular modeling indicated that the benzimidazole of LSP was included in the cavity of both CDs, while LSP was more deeply included in HPCD than β-CD. The enhanced photostability was due to the inclusion of the sulfinyl moiety into the HPCD cavity. CD inclusion complexation could improve the dissolution and stability of LSP.KEY WORDS: cyclodextrin, dissolution, inclusion complex, lansoprazole, molecular modeling, stability     

Enhancement of Oral Bioavailability of Cilostazol by Forming its Inclusion Complexes

The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like β-CD, γ-CD, and the hydrophilic β-CD derivatives, DM-β-CD and HP-β-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The dissolution rate of cilostazol was markedly augmented by the complexation with DM-β-CD. DSC and XRD curves showed sharp endothermic peaks indicating the reduction in the microcrystallinity of cilostazol. Selected inclusion complex was also stable at ambient temperature up to 6 months. The in vivo study revealed that DM-β-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol–cyclodextrins complexes, cilostazol–DM-β-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.     

Spray-dried voriconazole–cyclodextrin complexes: Solubility,dissolution rate and chemical stability

The present work investigates the effect of complexation with hydroxypropyl-beta-cyclodextrin (HPBCD) and 2-O-methyl-beta-cyclodextrin (2-O-MBCD), on voriconazole solubility, dissolution rate and chemical stability. Drug–cyclodextrin complexes were prepared as aqueous solutions, which were spray-dried, and their properties were compared to wet ground samples and physical mixtures. DSC analysis revealed absence of crystalline voriconazole from spray-dried complexes. FTIR spectroscopy indicated changes in the H-bonding network of the hydroxyl groups of cyclodextrin following drug inclusion. Dissolution rate of voriconazole was significantly higher from spray-dried complexes with either cyclodextrin in comparison with free drug, physical mixtures, or wet ground mixtures. However, two degradation impurities were found in aged samples, with slightly higher impurity level with HPBCD. Performed solubility studies suggested that 2-O-MBCD is more efficient solubilizer. Molecular docking simulations showed a difference in the 1:1 binding affinities and sites, with HPBCD surprisingly forming complexes of much lower energy, thus suggesting a multiple rather than a 1:1 complexation.     

Kneading Technique for Preparation of Binary Solid Dispersion of Meloxicam with Poloxamer 188

The aim of the present study was to enhance the dissolution rate of meloxicam (MLX), a practically water-insoluble drug by preparation of solid dispersion using a hydrophilic polymer, poloxamer 188 (PXM). The kneading technique was used to prepare solid dispersions. A 3² full factorial design approach was used for optimization wherein the drug, polymer ratio (X ₁), and the kneading time (X ₂) were selected as independent variables and the dissolution efficiency at 60 min (%DE₆₀) and yield percent were selected as the dependent variable. Multiple linear regression analysis revealed that for obtaining higher dissolution of MLX from PXM solid dispersions, a high level of X ₁ and a high level of X ₂ were suitable. The use of a factorial design approach helped in optimization of the preparation and formulation of solid dispersion. The optimized formula was characterized by solubility studies, angle of repose, and contact angle; Fourier transform infrared spectroscopy, differential scanning calorimetry, x-ray diffraction studies, and scanning electron microscopy demonstrated that enhanced dissolution of MLX from solid dispersion might be due to a decrease in the crystallinity of MLX and PXM. Analysis of dissolution data of optimized formula indicated the best fitting with Korsemeyer–Peppas model and the drug release kinetics as Fickian diffusion. In conclusion, dissolution enhancement of MLX was obtained by preparing its solid dispersion with PXM using kneading technique.     

Evaluation of the antiulcerogenic activity of violacein and its modulation by the inclusion complexation with beta-cyclodextrin

The effects of beta-cyclodextrin (betaCD) inclusion complexation on the ability of violacein to prevent gastric ulceration in mice were studied. Violacein-betaCD inclusion complexes were prepared in 1:1 and 1:2 molar ratios and analysed by differential scanning calorimetry and powder X-ray diffractometry. Violacein previously administered orally at 10 mg/kg significantly reduced indomethacin-induced gastric lesions, as well as 100 mg/kg of cimetidine (positive control). However, betaCD complexation in both molar ratios significantly potentiated the protective action of violacein. In the HCl--ethanol-induced gastric ulcer model, violacein and the 1:2 inclusion complex (10 mg/kg, p.o.) inhibited gastric damage by almost 85%, whereas a 63% reduction was observed for the positive control, lansoprazole, at 30 mg/kg. In contrast, treatment with the 1:1 inclusion complex resulted in almost total disappearance of the antiulcer activity in this model. No significant changes in stress-induced gastric injury were found. In addition, the 1:2 inclusion complex improved the antilipoperoxidant activity of violacein in rat liver cells exposed to t-butyl hydroperoxide, whereas the 1:1 complex was less active than violacein. In summary, the 1:2 betaCD inclusion complex has gastroprotective properties similar to or higher than that of violacein. An increase in mucosal defensive mechanisms and protection against peroxidative damage might be involved.     

The self-association of the drug acemetacin and its interactions and stabilization with beta-cyclodextrin in aqueous solution as inferred from NMR spectroscopy and HPLC studies

Strongly concentration dependent, (1)H NMR chemical shifts of the non-steroidal anti-inflammatory drug acemetacin sodium salt (sodium [[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetoxy]acetate), were observed in aqueous solution. Self-titration and nOe experiments, point to a self-association model where stacking takes place via the indole portion of the drug. In addition, conformational isomerism (atropisomerism) of the anti to syn form was confirmed. Further increase of the concentration eventually led to stable chemical shifts and nearly simultaneous appearance of microcrystals. In the presence of betaCD, 1:1 inclusion complexation occurred through the p-chlorobenzoyl part of the drug, whereas with excess betaCD the indole part seemed to participate to a minor degree. The anti isomer is suggested to be involved in the inclusion process. In addition, aggregation of acemetacin was also evident, as competing with the conformational and inclusion equilibria. The present case demonstrates that many competitive processes are simultaneously active in a seemingly simple system. The measurements were strongly dependent upon the pH and use of buffered solutions was mandatory. Finally, for the quantitative analysis of acemetacin in the presence of betaCD, a special HPLC method was developed. The stability of the drug, studied by the identification of the degradation products and the pseudo-first order rate of hydrolysis, was found to be unaffected by the presence of betaCD.     

Effect of Cyclodextrin Complexation of Curcumin on its Solubility and Antiangiogenic and Anti-inflammatory Activity in Rat Colitis Model

The purpose of the study was to prepare and evaluate the anti-inflammatory activity of cyclodextrin (CD) complex of curcumin for the treatment of inflammatory bowel disease (IBD) in colitis-induced rat model. Inclusion complexes of curcumin were prepared by common solvent and kneading methods. These complexes were further evaluated for increase in solubility of poorly soluble curcumin. The inclusion complexes were characterized for enhancement in solubility, in vitro dissolution, surface morphology, infrared, differential scanning calorimetry, and X-ray studies. Solubility, phase solubility, and in vitro dissolution studies showed that curcumin has higher affinity for hydroxypropyl-β-CD (HPβCD) than other CDs. HPβCD complex of curcumin was further investigated for its antiangiogenic and anti-inflammatory activity using chick embryo and rat colitis model. HPβCD complex of curcumin proved to be a potent angioinhibitory compound, as demonstrated by inhibition of angiogenesis in chorioallantoic membrane assay. Curcumin- and HPβCD-treated rats showed a faster weight gain compared to dextran sulfate solution (DSS) controls. Whole colon length appeared to be significantly longer in HPβCD-treated rats than pure curcumin and DSS controls. An additional finding in the DSS-treated rats was the predominance of eosinophils in the chronic cell infiltrate. Decreased mast cell numbers in the mucosa of the colon of CD of curcumin- and pure-curcumin-treated rats was observed. This study concluded that the degree of colitis caused by administration of DSS was significantly attenuated by CD of curcumin. Being a nontoxic natural dietary product, curcumin could be useful in the therapeutic strategy for IBD patients.