Preparation and characterization of inclusion complexes of prazosin hydrochloride with beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin

The slightly water-soluble drug prazosin hydrochloride (PRH) and its inclusion with either beta-cyclodextrin (betaCD) or hydroxypropyl-beta-cyclodextrin (HPbetaCD) were investigated. The phase solubility profiles of PRH with betaCD and HPbetaCD were classified as B(s)- and A(L)-types, respectively. Stability constants with 1:1 molar ratio were calculated from the phase solubility diagrams and the solubility of PRH could be enhanced by 27.6% for betaCD and 226.4% for HPbetaCD, respectively. Binary systems of PRH with betaCD or HPbetaCD prepared by various methods were characterized by differential scanning calorimetry and Fourier transformation-infrared spectroscopy. It could be concluded that PRH could form inclusion complex with either betaCD or HPbetaCD. The dissolution profiles of inclusion complexes were determined and compared with those of PRH alone and their physical mixtures. The dissolution rate of PRH was increased by betaCD and HPbetaCD inclusion complexation remarkably. Both the preparation technique and nature of the carriers played important roles in the dissolution performance of the systems. All the systems with HPbetaCD showed better performance than the corresponding ones with betaCD.     

Improvement in solubility and dissolution rate of 1, 2-dithiole-3-thiones upon complexation with beta-cyclodextrin and its hydroxypropyl and sulfobutyl ether-7 derivatives.

Inclusion complexes between beta-cyclodextrin derivatives and 1, 2-dithione-3-thiones were studied in aqueous solution and in the solid state. Phase solubility study was used to evaluate the complexation in solution, at 37 degrees C, of three cyclodextrins, i. e., beta-cyclodextrin (betaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD), sulfobutyl ether-7-beta-cyclodextrin (SBE7betaCD), and four 1,2-dithiole-3-thiones, i.e., the parent compound dithiolethione (DTT), dimethyldithiolethione (DMDTT), 5-phenyldithiolethione (5PDTT), and anetholetrithione (ATT). Stability constants of the DTT complexes with HPbetaCD and SBE7betaCD were also determined spectrophotometrically using a nonlinear least-squares methodology. Differential scanning calorimetry (DSC) and scanning electronic microscopy (SEM) were used to characterize spray-dried complexes formed between 5PDTT and SBE7betaCD, ATT and SBE7betaCD. Dissolution studies using the USP paddle method were carried out in water at 37 degrees C for both ATT and 5PDTT binary systems with HPbetaCD and SBE7betaCD. Solubility enhancements were much greater with the more lipophilic ATT and 5PDTT compared to DTT and DMDTT, whatever the cyclodextrin used, in the rank order SBE7betaCD > HPbetaCD > betaCD. Stability constants obtained (between 120 and 12800 mol(-1)) were also the highest for the more lipophilic drugs and in the same rank order SBE7betaCD > HPbetaCD > betaCD. Results obtained by UV spectrophotometry were in good agreement with those obtained by phase-solubility study. DSC thermograms of spray-dried complexes of ATT and 5PDTT with HPbetaCD and SBE7betaCD lacked the endothermal peak of pure drug peak which was found for the physical mixtures (107 degrees C and 125 degrees C for ATT and 5PDTT, respectively). Finally, dissolution profiles of spray-dried inclusion complexes studied displayed a faster dissolution rate compared to physical mixtures and pure drugs. The present study showed that complexation of 1,2-dithiole-3-thiones with beta-cyclodextrin derivatives resulted in an increase in solubility, allowing intravenous formulation for bioavailability and metabolism studies and an increase in the dissolution rate of the drugs, which should be of interest for oral absorption of these lipophilic compounds.     

Study of freeze-dried quercetin-cyclodextrin binary systems by DSC, FT-IR, X-ray diffraction and SEM analysis

The inclusion behavior of 2-hydroxypropyl beta-cyclodextrin (HPbetaCD) and beta-cyclodextrin (betaCD), in solution and solid-state was studied towards a poorly water-soluble bioflavonoid, quercetin (QURC), chemically 3,3',4',5',7-pentahydroxy flavone. Drug-cyclodextrin solid systems were prepared by freeze-drying. Phase solubility study was used to evaluate the complexation in solution, of two cyclodextrins, i.e., betaCD and HPbetaCD. The stoichiometry and stability constants of QURC-betaCD (1:1 and 402M(-1)) and QURC-HPbetaCD (1:1 and 532M(-1)) complexes were calculated by phase solubility method. The formation of inclusion complexes with betaCD and HPbetaCD in the solid-state were confirmed by infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy (SEM).     

Controlled release of nifedipine from mucoadhesive tablets of its inclusion complexes with beta-cyclodextrin

Mucoadhesive tablets formulated with nifedipine (N) alone and its inclusion complexes with beta-cyclodextrin (betaCD) and the mucoadhesive polymers sodium carboxy methylcellulose and carbopol were investigated with a view to the design of oral controlled release tablets of nifedipine. As nifedipine is practically insoluble in water and aqueous fluids, its complexation with betaCD was investigated to improve its solubility and dissolution rate. Complexation of nifedipine with betaCD has markedly enhanced the solubility and dissolution rate of nifedipine. The phase solubility studies indicated the formation of a N-betaCD inclusion complex with a stability constant of 121.9 M(-1). A 20.6 fold increase in the dissolution rate of nifedipine was observed with N-betaCD (1:2) solid inclusion complex. Mucoadhesive tablets formulated employing nifedipine alone gave very low dissolution, whereas those formulated employing its betaCD inclusion complexes gave slow, controlled and complete release spread over a period of 12 h. Drug release from these tablets followed zero order kinetics up to 85-90% release and the release was diffusion controlled. Good controlled release two layered tablet formulations of nifedipine, satisfying the theoretical sustained release requirements based on its pharmacokinetics, were developed using its inclusion complexes with betaCD.     

Melarsoprol-cyclodextrins inclusion complexes

Melarsoprol, a water-insoluble drug, is mainly used in the treatment of trypanosomiasis and has demonstrated an in vitro activity on myeloid and lymphoid leukemia derived cell lines. It is marketed as a very poorly tolerated non-aqueous solution (Arsobal). The aim of our work was to develop melarsoprol-cyclodextrin complexes in order to improve the tolerability and the bioavailability of melarsoprol. Phase-solubility analysis showed A(L)-type diagrams with beta-cyclodextrin (betaCD), randomly methylated beta-cyclodextrin (RAMEbetaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD), which suggested the formation of 1:1 inclusion complexes. The solubility enhancement factor of melarsoprol (solubility in 250 mM of cyclodextrin/solubility in water) was about 7.2x10(3) with both beta-cyclodextrin derivatives. The 1:1 stoichiometry was confirmed in the aqueous solutions by the UV spectrophotometer using Job's plot method. The apparent stability constants K(1:1), calculated from mole-ratio titration plots, were 57 143+/-4 425M(-1) for RAMEbetaCD and 50 761+/-5 070 M(-1) for HPbetaCD. Data from 1H-NMR and ROESY experiments provided a clear evidence of inclusion complexation of melarsoprol with its dithiaarsane extremity inserted into the wide rim of the cyclodextrin torus. Moreover, RAMEbetaCD had a pronounced effect on the drug hydrolysis and the dissolution rate of melarsoprol. However, the cytotoxic properties of melarsoprol on K562 and U937 human leukemia cell lines was not modified by complexation.     

Solubility enhancement of celecoxib using beta-cyclodextrin inclusion complexes.

Celecoxib has very low water solubility. It forms a complex with beta-cyclodextrin (betaCD) both in aqueous and in solid state. It was observed that due to formation of the inclusion complex, the solubility and dissolution rate of celecoxib were enhanced. The formation of 1:1 complex with betaCD in solution was confirmed by phase solubility and spectral shift studies. The apparent stability constants calculated by these techniques were 881.5 and 341.5 M(-1), respectively. The solid inclusion complexes of celecoxib and betaCD were prepared by the kneading method using different molar proportions of betaCD, and formation of solid inclusion complexes of celecoxib and betaCD at different molar ratios were confirmed by differential scanning calorimetry. Enhancement of dissolution rates with increasing quantity of betaCD in the complex was observed. It was also observed that the complexes exhibit higher dissolution rates than the pure drug and physical mixture.     

Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds.

Inclusion complexation between nicardipine hydrochloride (NC), a calcium-channel antagonist, and beta-cyclodextrin (beta-CD) or hydroxypropyl-beta-cyclodextrin (HPbetaCD) was evaluated in aqueous environment and in solid state. The phase solubility profiles with both cyclodextrins (CDs) were classified as A(L)-type, indicating the formation of 1:1 stoichiometric inclusion complexes. Stability constants (Ks) were calculated from the phase solubility diagrams and were found to be pH dependent. More stable NC:CDs complexes were formed in alkaline medium in which the drug is in its non-ionized form. Binary systems of NC with CDs, prepared experimentally by different techniques (kneading, evaporation, freeze-drying and spray-drying), were investigated by differential scanning calorimetry, Fourier transformation-infrared spectroscopy, X-ray diffractometry and scanning electron microscopy. From this analysis, evaporation, freeze-drying and spray-drying were found to produce inclusion complexes. In contrast, crystalline drug was still clearly detectable in the kneaded products. The dissolution profiles of the obtained powders were studied in order to define the most appropriate CD and preparation method to originate inclusion complexes, which will be used in the development of a new controlled release formulation of NC. Both the preparation and nature of carrier played an important role in the dissolution performance of the system. However, independently of the preparation technique, all the combinations with HPbetaCD were more effective in achieving the enhancement of the NC dissolution rate, yielding better performances than the corresponding ones with betaCD.     

Preparation & characterization of solid inclusion complex of cefpodoxime proxetil with beta-cyclodextrin

Cefpodoxime proxetil (CPDX-PR) is an oral cephalosporin antibiotic with poor aqueous solubility and bioavailability. Effect of beta-cyclodextrin on aqueous solubility and dissolution rate of cefpodoxime proxetil was evaluated by the formation of solid inclusion complexes in 1:2 molar ratio of drug: cyclodextrin. Phase solubility study was carried out whereby a typical B's type curve was obtained thus, indicating a 1:2 stoichiometric ratio for optimum complex formation. Solid inclusion complexes in 1:2 molar ratios were prepared by using methods such as physical mixture, solvent evaporation and freeze drying. Prepared complexes were characterized by fourier transform infrared spectroscopy (FT-IR) differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD) and scanning electron microscopy (SEM). Results of in vitro studies appraised of an increased solubility and dissolution rate of cefpodoxime proxetil on complexation with beta- cyclodextrin (P < 0.05) as compared to CPDX-PR alone. Amongst the complexes prepared by different methods, the complex prepared by freeze drying showed the highest dissolution rate (P< 0.01). The in vitro antimicrobial activity of cefpodoxime proxetil and its freeze dried complex (1:2) was studied against both antibiotic-susceptible and antibiotic-resistant clinical isolates of Neisseria gonorrhoeae. The freeze dried complex (1:2) inhibited all penicillin-susceptible strains and penicillinase-producing strains at 0.015 microg/ml concentration. Chromosomally resistant strains which were not responsive to penicillin were inhibited by the complex at 0.125 microg/ml concentration. The study revealed that complexation of cefpodoxime proxetil with beta-cyclodextrin effectively enhanced the aqueous solubility and in vitro antibacterial activity.     

Encapsulation of methyl and ethyl salicylates by beta-cyclodextrin HPLC, UV-vis and molecular modeling studies

The complexation of methyl salicylate (MS) and ethyl salicylate (ES), non-steroidal analgesic, anti-inflammatory and antirrheumatic drugs with beta-cyclodextrin (betaCD) has been studied from thermodynamic and structural points of view. The complexation with betaCD has been investigated using reversed-phase liquid chromatography. Retention behavior has been analyzed on a reverse-phase column Luna 18(2) 5 microm. The mobile-phase was methanol:water in different ratios (55:45 to 70:30) in which betaCD (1-9 mM) was incorporated as a mobile-phase additive. The decrease in retention times with increasing concentrations of betaCD enables the determination of the apparent stability constant of the complexes. Values at 30 degrees C with 55% methanol were K(MS:betaCD): 15.84 M(-1) and K(ES:betaCD): 12.73 M(-1) for MS and ES, respectively. The apparent stability constants decrease as the polarity of the solvent decreases. The low solubility of MS and ES in aqueous solution has been improved by complexation with betaCD (1-9 mM). The stability constants of the complexes obtained from the phase-solubility diagrams using a UV-vis spectrophotometric method were K(MS:betaCD): 229 M(-1) and K(ES:betaCD): 166 M(-1). In addition, semi-empirical quantum mechanics calculations using AM1 and PM3 methods in vacuum were performed. The energetically favorable inclusion structures were identified and the most favorable orientation for the inclusion process was found to be the head-down orientation for both complexes. Enthalpy for encapsulation processes was found to be favorable (DeltaH degrees <0), while entropy (DeltaS degrees <0) and Gibbs free energy were unfavorable (DeltaG degrees >0). By means of HPLC and UV-vis measurements and quantum mechanics calculations, it was found that MS and ES form a 1:1 inclusion complex with betaCD. The theoretical results are in agreement with the experimental parameters associated with the encapsulation process.     

Physicochemical characteristics and bioavailability of a novel intestinal metabolite of ginseng saponin (IH901) complexed with beta-cyclodextrin

In an effort to improve the bioavailability (BA) of the insoluble compound 20-O-(beta-d-glucopyranosyl)-20(S)-protopanaxadiol (IH901), we prepared beta-cyclodextrin (betaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) inclusion complexes containing IH901. IH901 is a major metabolite formed by intestinal bacteria from protopanaxadiol ginseng saponins. We developed and validated an HPLC-based method to measure IH901 levels from samples prepared in vitro. The phase solubility profiles with both cyclodextrins (CDs) were classified as AL-type, indicating the formation of a 1:1 stoichiometric inclusion complex. Stability constants (Ks) calculated from the phase solubility diagrams showed that the betaCD complex was more stable than the HPbetaCD complex. Consequently, complexes of IH901 and betaCD were prepared by a freeze-drying method and were analyzed by fourier transformation-infrared spectroscopy (FT-IR), X-ray diffraction, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). From these physicochemical characterizations, we confirmed the presence of a new solid phase in the freeze-dried samples. The IH901 released from the complex in a pH 1.2 solution, the pH range of gastric fluids, was considerably lower than the amount released in the other solutions. The IH901 released from the complex in pH 6.8 solution, the range of intestinal fluids, was 9.0-fold greater than pure IH901 powder. However, the amount of IH901 released from the complex in pH 4.0-8.0 was less than 20%. After oral administration of the IH901-betaCD inclusion complex (30 mg/kg IH901) into rats, plasma concentrations were determined by LC/MS/MS. The peak concentration (Cmax) for the inclusion complex was 2.8-fold higher than that for pure IH901 powder. The BA, calculated from the ratio of the AUCoral to the AUCi.v., for the pure IH901 powder, the IH901-betaCD physical mixture, and the inclusion complex was 3.52, 4.34, and 6.57%, respectively. These results indicate that the BA for the inclusion complex was 1.9-fold higher than that for the pure IH901 powder.     

Physicochemical characterization and dissolution enhancement of aceclofenac-hydroxypropyl beta-cyclodextrin binary systems

The aim of this study is to prepare and characterize binary systems of aceclofenac (AC) with hydroxypropyl beta-cyclodextrin (HPbetaCD) in equimolar ratio. Solid binary systems of aceclofenac with HPbetaCD were prepared using cogrinding, kneading, and coevaporating methods, and a physical mixture was prepared for comparison. The binary systems were characterized by differential scanning calorimetry, thermogravimetric analysis, mass spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy, and in vitro dissolution studies. 1H NMR studies showed that AC partially fits into the HPbetaCD torus cavity with a preferential inclusion of the phenyl ring of the drug. All the binary systems showed superior dissolution and lower dose:solubility ratio (D:S ratio) as compared to pure AC, but the kneaded product exhibited the best dissolution, with complete drug release within 10 min and a D:S ratio of 5 mL. Hence, it was suggested that complexation of aceclofenac with HPbetaCD may be used as an approach to change the drug from Biopharmaceutics Classification System BCS Class II to BCS Class I without changing its intrinsic permeability.     

Anticryptosporidial activity of furan derivative G1 and its inclusion complex with beta-cyclodextrin

The capacity of beta-cyclodextrin (betaCD) to form a complex with a new furanic derivative, G1, was investigated. Interactions of the drug and betaCD in solution and in the solid state were studied using phase solubility techniques, thermal methods, X-ray, and IR spectroscopy. Preparation of a kneaded mix of G1/betaCD increased both the aqueous solubility and the dissolution rate of the furan derivative. The anticryptosporidial efficacies of the drug and of the inclusion complex were evaluated using a suckling murine model. Oral administration of G1 considerably decreased the intensity of the infection, but betaCD showed similar anticryptosporidial activity to that of the betaCD-G1 complex and higher activity than G1 alone.     

Enhanced solubility and dissolution rate of lamotrigine by inclusion complexation and solid dispersion technique

The solid-state properties and dissolution behaviour of lamotrigine in its inclusion complex with beta-cyclodextrin (betaCD) and solid dispersions with polyvinylpyrrolidone K30 (PVP K30) and polyethyleneglycol 6000 were investigated. The phase solubility profile of lamotrigine with betaCD was classified as AL-type, indicating formation of a 1:1 stoichiometry inclusion complex, with a stability constant of 369.96+/-2.26 M(-1). Solvent evaporation and kneading methods were used to prepare solid dispersions and inclusion complexes, respectively. The interaction of lamotrigine with these hydrophilic carriers was evaluated by powder X-ray diffractometry, Fourier transform infrared spectroscopy and differential scanning calorimetry. These studies revealed that the drug was no longer present in crystalline state but was converted to an amorphous form. Among the binary systems tested, PVP K30 (1:5) showed greatest enhancement of the solubility and dissolution of lamotrigine.     

Solid-state characterization and dissolution properties of bicalutamide-beta-cyclodextrin inclusion complex

The solid-state properties and dissolution profile of bicalutamide beta-cyclodextrin (betaCD) inclusion complex were investigated. The phase solubility profile of bicalutamide with beta-cyclodextrin was classified as A(L)-type. Stability constant with 1:1 molar ratio was calculated from the phase solubility diagram and the aqueous solubility of bicalutamide was found to be enhanced by 86% for beta-cyclodextrin. Binary systems of bicalutamide with betaCD were prepared by the kneading method. The solid-state properties of the complex were characterized by differential scanning calorimetry, Fourier transformation-infrared spectroscopy and X-ray powder diffractometry. It could be concluded that bicalutamide could form an inclusion complex with beta-cyclodextrin. The dissolution profile of the inclusion complex was determined and compared with those of bicalutamide alone and its physical mixture. The dissolution rate of bicalutamide was significantly increased bycomplexation with betaCD, as compared with pure drug and physical mixture.     

Elucidation of solution state complexation in wet-granulated oven-dried ibuprofen and beta-cyclodextrin: FT-IR and 1H-NMR studies

The effect of oven-dried wet granulation on the complexation of beta-cyclodextrin with ibuprofen (IBU) in solution was investigated using Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (1H NMR), and molecular modeling. Granulation was carried out using 5 mL of three different granulating solvents; water, ethanol (95% v/v), and isopropanol and the granules were oven-dried at 60 degrees C for 2 h. The granules were compared to oven-dried physical mixture and conventionally prepared complex. Phase solubility study was performed to investigate the stability of the granulation-formed complexes in solution. FT-IR was used to examine the complexation in the granules while 1H NMR, and molecular modeling studies were carried out to determine the mechanism of complexation in the water-prepared granules. The solubility studies suggested a 1:1 complex between IBU and betaCD. It also showed that the stability of the complex in solution was in the following order with respect to the granulating solvents: ethanol > water > isopropanol. The FT-IR study revealed a shift in the carboxylic acid stretching band and decrease in the intensities of the C-H bending bands of the isopropyl group and the out-of-plane aromatic ring, of IBU, in granules compared to the oven-dried physical mixture. This indicated that granules might have some extent of solid state complexation that could further enhance dissolution and the IBU-betaCD solution state complexation. 1H NMR showed that water prepared oven-dried granules had a different 1H NMR spectrum compared to similarly made oven-dried physical mixture, indicative of complexation in the former. The 1H NMR and the molecular modeling studies together revealed that solution state complexation from the granules occurred by inclusion of the isopropyl group together with part of the aromatic ring of IBU into the betaCD cavity probably through its wider side. These results indicate that granulation process induced faster complexation in solution which enhances the solubility and the dissolution rate of poorly soluble drugs. The extent of complexation in the granules was dependent on the type of solvent used.     

Antipyretic, analgesic and anti-inflammatory activities of ketoprofen beta-cyclodextrin inclusion complexes in animals

Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID) orally effective in treating fever, pain, and inflammation but gastrointestinal side effects were observed. Preparation of ketoprofen beta-cyclodextrin inclusion complexes was to increase the solubility and reduce the irritation. The complexes were prepared and preliminarily confirmed using X-ray diffraction and dissolution test. Antipyretic, analgesic and anti-inflammatory models were induced by 10% yeast using rabbits, 0.8% acetic acid using mice and 1% carrageenin using rats, respectively. Results showed that the dissolution rate of ketoprofen was significantly improved by complexation. X-Ray diffraction pattern of the complexes exhibited a diffuse pattern that differed from that of physical mixture of ketoprofen and beta-cyclodextrin. Ketoprofen markedly inhibited the fever reactions at a single dose of 2 mg/kg as follows: 64.53% (inhibition rate %) at 1 h for ketoprofen, 73.04% at 1 h for ketoprofen beta-cyclodextrin inclusion complexes, respectively. Alleviating pain reaction rates following a single dose of 8 mg/kg at 20 min were 39.25% for the inclusion complexes and 26.72% for ketoprofen, respectively. Inhibition rates to rat edema following a single dose of 5 mg/kg at 1 h were 39.47% for the inclusion complexes and 23.86% for ketoprofen. Results for antipyretic, analgesic and anti-inflammatory activities showed that the rapid and stronger effects were found in the treatment group of ketoprofen beta-cyclodextrin inclusion complexes in comparison with those of free ketoprofen.     

Physicochemical investigation of the effects of water-soluble polymers on vinpocetine complexation with beta-cyclodextrin and its sulfobutyl ether derivative in solution and solid state.

The studies reported in this work aimed to elucidate the inclusion complex formation of vinpocetine (VP), a poorly water-soluble base type drug, with beta-cyclodextrin (betaCD) and its sulfobutyl ether derivative (sulfobutyl ether beta-cyclodextrin (SBEbetaCD)), with or without water-soluble polymers (PVP and HPMC), by thoroughly investigating their interactions in solution and solid state. Phase solubility studies were carried out to evaluate the solubilizing power of both cyclodextrins (CDs), in association with water-soluble polymers, towards VP and to determine the apparent stability constants (Kc) of the complexes. SBEbetaCD showed higher solubilizing efficacy toward VP than the parent betaCD due to its greater solubility and complexing abilities, what was reflected in higher Kc values. Improvement in Kc values for ternary complexes clearly proves the benefit on the addition of water-soluble polymers to promote higher complexation efficiency. VP-CDs (1:1) binary and ternary systems were prepared by physical mixing, kneading, co-evaporation, and lyophilization methods. In the solid state, drug-carrier interactions were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier-transform infrared spectroscopy. The results of these analysis suggested the formation of new solid phases, some of them in amorphous state, allowing to the conclusion of strong evidences of binary and ternary inclusion complex formation between VP, CD and water-soluble polymers, particularly for co-evaporated and lyophilized binary and ternary products.     

Improvement of gliquidone hypoglycaemic effect in rats by cyclodextrin formulations.

This study was carried out with the aim to optimize the pharmacological profile of gliquidone (GLI)--a poorly bioavailable hypoglycaemic agent sparingly soluble in water--through complexation with cyclodextrins. In order to increase the apparent solubility of GLI, two cyclodextrins, namely beta-cyclodextrin (betaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD), were tested. The effect of cyclodextrin addition on the aqueous solubility of GLI was evaluated by the phase solubility method at different pH values. The amount of GLI in solution increased upon CD addition according to A type plots. The aqueous solubility of GLI was enhanced more at higher pH values and using HPbetaCD. On the basis of its performance, HPbetaCD was selected as host to prepare GLI oral formulations. GLI/HPbetaCD solid systems were prepared at 1:2 molar ratio by co-grinding, spray-drying and freeze-drying and characterized by DSC, FTIR and X-ray powder diffractometry. Powders were amorphous and showed an improved dissolution rate in comparison with GLI. GLI/HPbetaCD co-ground and freeze-dried products were the most interesting systems, since they dissolved 62 and 94% of total drug after 15 min, respectively. The hypoglycaemic effect of the most rapidly dissolving binary systems was evaluated after oral administration in fasted rats by measuring plasma glucose level in the time interval 0.5-36 h and compared to free GLI. Our findings indicate that cyclodextrin-containing formulations not only provide an onset of hypoglycaemic effect faster than GLI, but also enhance significantly the pharmacological effect due to improved biopharmaceutics. The association GLI/HPbetaCD allows a reduction of the oral dose and is expected to provide a better control over drug side effects, contributing to improve safety and efficacy of GLI.     

Effect of cyclodextrins on the complexation and nasal permeation of melatonin

The inclusion complexation of melatonin (MT) with modified cyclodextrins (CDs) was studied with an objective of improving the solubility and nasal absorption of MT. The formation of inclusion complex of MT with Hydroxypropyl beta CD (HPbeta CD) and randomly methylated beta CD (RMbeta CD) was characterized in solution and solid states by phase solubility and differential scanning calorimetry analyses. The phase solubility data indicate a linear increase in the solubility of MT with CDs demonstrating Higuchi's A(L)-type phase solubility profiles. The effect of CDs on the permeation of MT across EpiAirway(TM)-100 cultures was studied using a modified nonstatic diffusion setup. CDs were employed at different concentrations with 1% w/v micronized MT suspension in hydroxypropyl methyl cellulose (HPMC) vehicle. At low CD concentrations (1% w/v), the permeation of MT from HPMC formulation was significantly increased (125%,p < .001). However, the permeation was significantly reduced when CDs were used at relatively high concentrations (5 to 10% w/v concentration for HPbetaCD and 10% w/v concentration for RMbetaCD,p < .001). All the tissues were viable with good tissue integrity at the end of permeation experiments, as measured by methylthiazoletetrazolium assay and transepithelial electrical resistance measurements. In conclusion, formation of inclusion complex of MT with HPbetaCD and RMbetaCD was demonstrated in solution and solid state. Both HPbetaCD and RM betaCD at 1% w/v concentration were found to improve the nasal permeability of MT from HPMC gel formulations.     

Cyclodextrin solubilization of the antibacterial agents triclosan and triclocarban: formation of aggregates and higher-order complexes

It is well known that water-soluble cyclodextrins form inclusion complexes with many lipophilic water-insoluble drugs and that such complexation frequently enhances the aqueous solubility of drugs. It is also well known that various excipients, such as water-soluble polymers, organic acids and bases and metal ions can enhance the solubilizing effects of cyclodextrins. However, it is not clear how these excipients enhance the effects. The effects of cyclodextrins, 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and randomly methylated beta-cyclodextrin (RMbetaCD) on the aqueous solubility of triclosan and triclocarban were investigated. The phase-solubility profiles were all of type A(P) indicating formation of higher-order complexes or complex aggregates. Addition of lysine and other excipients enhanced the RMbetaCD solubilization of triclocarban. NMR spectroscopic studies, including 2D ROESY and 1D gROESY techniques, indicated that HPbetaCD and RMbetaCD, as well as their complexes, form aggregates of two to three cyclodextrin molecules. The critical concentration for the aggregate formation was determined to be 5.4% (w/v). Lysine, polyvinylpyrrolidone and magnesium ions formed non-inclusion complexes resulting in formation of multiple-component cyclodextrin complexes in aqueous solutions with triclocarban.