Availability of NSAIDH beta-cyclodextrin inclusion complexes

The diffusion of a series of non steroidal antiinflammatory drugs through a silicone rubber membrane has been studied from suspensions both of the free and beta-cyclodextrin complexes forms at different pH values of the medium. Higher diffusion rates of the complexed forms as compared with the free ones and a rate-limiting effect of the apparent stability constant in the diffusion of the complexes were observed.     

Enantioselective stabilization of inclusion complexes of metoprolol in carboxymethylated beta-cyclodextrin.

The inclusion complexes of metoprolol (MT) and carboxymethyl-beta-cyclodextrin (CMCD) were prepared and the stability constants of the complexes were determined. Binding studies performed using high performance liquid chromatography (HPLC), UV spectrometry and capillary electrophoresis (CE) indicated that a complex with 1:1 stoichiometry is predominant in the solution. The enantiomers of MT possess relatively high affinity towards CMCD with stability constants of 288 and 262 per M for (R)- and (S)-MT, respectively. Through nuclear magnetic resonance (NMR) analysis, MT was predicted to be a bent structure with phenyl ring of MT inserted in the shielding cavity of CMCD during complex formation. The NMR data suggested that the chiral side chain and the methoxyethyl moiety of MT are aligned in the deshielding zone, above and below the CMCD torus ring.     

Study on the inclusion complex between beta-cyclodextrin and celecoxib by spectrofluorimetry and its analytical application

The supramolecular interaction of celecoxib (chemically 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzene sulfonamide) and beta-cyclodextrin (beta-CD) has been studied by spectrofluorimetry. The results showed that beta-CD reacted with celecoxib to form an inclusion complex. 1:1 stoichiometry for beta-CD-celecoxib complex was established and its association constant at different temperatures was calculated by applying a non-linear regression method to the change in the fluorescence of celecoxib that brought about by the presence of beta-CD. The thermodynamic parameters (DeltaH degrees, DeltaS degrees and DeltaG degrees) associated with the inclusion process were also determined. Based on the significant enhancement of the fluorescence intensity of celecoxib produced through complex formation, a simple, rapid and highly sensitive spectrofluorimetric method for the determination of celecoxib in aqueous solution in the presence of beta-CD was developed. The measurement of relative fluorescence intensity was carried out at 390 nm with excitation at 270 nm. A linear relationship between the fluorescence intensity and celecoxib concentration was obtained in the range of 0.1-4.0 microg ml-1, with a correlation coefficient of 0.9996. The detection limit was 7.29 ng ml-1 and the relative standard deviation was 1.28%. The method was successfully applied to the determination of celecoxib in pharmaceutical preparations.     

Nuclear magnetic resonance investigation of the stoichiometries in beta-cyclodextrin:steroid inclusion complexes.

Nuclear magnetic resonance at high field has been used to investigate the stoichiometries of pharmacologically important beta-cyclodextrin:steroid complexes. This technique provides evidence for the existence of true inclusion complexes and allows unequivocal determination of the stoichiometry for complexes obtained in the solid state, as well as in solution. The present data clarify previously published determinations of the stoichiometry of these complexes and show the influence of the nature and position of functional groups on the molecular ratio in the complex. The observed behavior can be rationalized using representative steroids and allows prediction of the strength of inclusion and the most probable stoichiometry.     

1H NMR investigations of inclusion complexes between beta-cyclodextrin and 1-hexadecanol

The inclusion complex between beta-CD and 1-hexadecanol is synthesized and identified via (1)H NMR spectrum. The possible conformation of the inclusion complex is figured out. Via MM2 calculations, the possibility of complexation is verified.     

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.     

Multidisciplinary investigation of atypical inclusion complexes of beta-cyclodextrin and a phospholipase-A2 inhibitor

BMS-188184, an anthracene derivative, has been found to form at least two complexes with beta-cyclodextrin. The association/dissociation kinetics of the two complexes were extremely slow, with one complex requiring approximately 24 h, and the other complex requiring more than 8 weeks, to reach equilibrium. The stability constants of the two complexes were estimated at approximately 11,000 and 39,000 M(-1) under nonequilibrium conditions. The slow rates of dissociation allowed the complexes and the unbound BMS-188184 to be separated using high-performance liquid chromatography. Exact mass liquid chromatography/mass spectrometry, tandem mass spectrometry, and nuclear magnetic resonance techniques were used to characterize the stoichiometry of both complexes as 1:1. Because of the ability of the complexes to survive high-performance liquid chromatography analysis, their slow reaction rates, and 1:1 stoichiometry, the complexes were tentatively characterized as [2]-rotaxanes. The available data suggest that the two complexes are conformational isomers.     

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.     

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.     

Solubility enhancement of low soluble biologically active compounds--temperature and cosolvent dependent inclusion complexation

The solubility enhancement of biologically active compounds was analysed in dependence on temperature, amount of cosolvents and on beta-cyclodextrin as complexing agent. The analysis was performed for the systemic fungicide triflumizole (TF), a poorly water soluble compound. All parameters lead to an improvement of the solubility, the largest effect was obtained for host-guest complexation with beta-cyclodextrin. Generally, the combination of cosolvents and beta-cyclodextrin does not increase the solubility of the compound, because cosolvents destabilize the inclusion complex. At higher cosolvent concentrations the solubility of TF is mainly determined by the solubility of the free non-complexed compound in the solvent mixtures. Raising temperature enhances the solubility in any cases. It could be shown that the temperature dependence of the solubility of TF is controlled by the solubility in the solvent mixtures and not by the inclusion reaction.     

UV-vis spectral analysis of inclusion complexes between beta-cyclodextrin and aromatic/aliphatic guest molecules

beta-Cyclodextrin (beta-CD) forms a series of supramolecular complexes with aromatic or aliphatic guest molecules such as benzaldehyde, butyl acrylate, etc. Remarkable blue shifts (lambda max) of the UV-vis absorption peaks of the guest molecules are observed after the formation of inclusion complexes. The congestion lines appearing in the guest molecules are reduced in a remarkable extent accordingly. The mechanisms of the blue shifts are investigated herein.     

Solid-state characterization and dissolution profiles of the inclusion complexes of omeprazole with native and chemically modified beta-cyclodextrin.

The aim of this work was to investigate the formation of the inclusion complex between omeprazole (OME), a benzimidazolic derivative and a methylated cyclodextrin, methyl-beta-cyclodextrin (MbetaCD), with an average degree of substitution of 0.5. Inclusion complex between OME and beta-cyclodextrin (betaCD), a natural cyclodextrin, was used as reference. In aqueous media, apparent stability constants (K(s)), which describe the extent of formation of the complexes, have been determined by UV spectroscopy and 1H NMR experiments. The stoichiometry of the complexes was found to be 1:1 mol:mol OME:cyclodextrin (CD) and the value of K(s) was higher for OME:MbetaCD than for OME:betaCD inclusion complexes. Solid binary systems of OME and CDs were prepared by different techniques, namely kneading, spray-drying and freeze-drying. The formation and physicochemical characterization of solid inclusion complexes were investigated by differential scanning calorimetry (DSC), Fourier transform-infrared (FTIR), X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The results show that freeze-drying method produces true inclusion complexes between OME and both CDs. In contrast, crystalline drug was detectable in kneaded and spray-drying products. The dissolution of OME from the binary systems was studied to select the most appropriate system for the development of a buccal drug delivery formulation. It was concluded that the preparation technique played an important role in the dissolution behaviour of the drug and the inclusion complex between OME and MbetaCD obtained by spray-drying and freeze-drying allowed better performances.     

In-vitro evaluation of cinnarizine as a competing agent to beta-cyclodextrin inclusion complexes: effect of cinnarizine on the membrane permeation rate of progesterone from its beta-cyclodextrin inclusion complex

The use of competing agents is considered a powerful tool for the development of a drug-delivery system with drug/cyclodextrin inclusion complexes. However, there are very few studies examining this issue. To explain this phenomenon, it was thought that a competing agent with a sufficiently high stability constant had not yet been reported. In this study, cinnarizine (CN), which has a high stability constant with beta-cyclodextrin (beta-CD) and unique solubility characteristics, was selected, and its ability as a competing agent was examined in a membrane permeability study. The permeability study showed that the permeation rates of the drugs flurbiprofen, progesterone, and spironolactone decreased with their stability constants with the addition of beta-CD. In one of the drugs, progesterone (Pro), the decrease was restored by the addition of CN. The amount of CN added was a 1:1 molar ratio to the amount of Pro. However, no similar action was induced with the addition of DL-phenylalanine (Phe) in the permeation study at the 1:5 (Pro:Phe) molar ratio. These finding indicate that CN acts as a competing agent, and its action is much stronger than that of Phe.     

Preparation and characterization of inclusion complexes of a cationic beta-cyclodextrin polymer with butylparaben or triclosan

The preparation of a cationic β-cyclodextrin polymer (CPβCD) and its complexes with butylparaben and triclosan were reported in this paper. FT-IR and 2D ¹H–¹H gCOSY NMR spectra confirmed that the antibiotics could be included inside of the lipophilic cavities of CPβCD. The formation of complexation of CPβCD with the antibiotics significantly improved the water solubility. The solubility of the antibiotics linearly increased with the concentration of CPβCD, and the values of the association constant K_1:1 of the butylparapben/CPβCD and triclosan/CPβCD complexes were 3800 and 3082 M⁻¹, respectively. The results also suggested that it was easier for butylparaben, which had relative smaller molecular size, to form the complexes with CPβCD than triclosan. Due to the targeting effect after the complexation with CPβCD, the antimicrobial activity of butylparaben can be significantly improved. Meanwhile, this improvement effect was not obvious for triclosan.     

Phase solubility and inclusion complex of itraconazole with beta-cyclodextrin using supercritical carbon dioxide

Phase-solubility techniques were used to assess the formation of inclusion complex between itraconazole and beta-cyclodextrin. The stability constant and free energies of transfer of itraconazole from aqueous solution to the cavity of beta-cyclodextrin were calculated. Itraconazole solubility in supercritical carbon dioxide (SC CO(2)) was measured at different temperatures and pressures. Drug formulations of itraconazole were prepared by complexation of the drug into beta-cyclodextrin using SC CO(2). Effects of temperature and pressure on inclusion yield of the prepared complexes were studied. The solvent-free inclusion complexes obtained from this method were characterized by UV spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy and compared to those obtained from physical mixing and coprecipitation methods. Results showed that beta-cyclodextrin significantly improved solubility of itraconazole in aqueous solutions. The free energies of transfer of itraconazole from aqueous solution to the cavity of beta-cyclodextrin increased negatively with increasing beta-cyclodextrin concentration. Higher inclusion yields were obtained in the SC CO(2) method compared to physical mixing and coprecipitation methods. Both temperature and pressure had significant effects on itraconazole solubility in SC CO(2) and the inclusion yield of the complex prepared by SC CO(2) method.     

Molecular modeling of beta-cyclodextrin complexes with nootropic drugs.

The geometry and structural features of the inclusion complexes of beta-cyclodextrin (beta-CD) with the chiral antiamnesic drugs (+/-)-1-benzyl-4-hydroxymethylpyrrolidin-2-one (WEB-1868). (+/-)-1-benzenesulfonyl-5-ethoxypyrrolidin-2-one (RU-35929), and (+/-)-1-(3-pyridinlysulfonyl)-5-ethoxypyrrolidin-2-one (RU-47010) were studied by the molecular modeling method (MacroModel interactive computer program). Docking procedures yielded the most stable complexes, which showed the aromatic ring of the guests inside the cavity and the pyrrolidinone ring out from the side of the beta-CD secondary hydroxyl groups. The binding energies were essentially due to hydrogen-bonded structures involving the C=O group of the guests. Selective interactions allowed chiral discrimination, and accordingly, separate beta-CD complexes of the R and S enantiomers of each guest compound were studied. The almost round beta-CD structure, in all the cases, assumed an elliptic shape on passing from the isolated molecule to the docked complex. The optimized structures and conformations of beta-CD and its inclusion compounds showed acceptable general agreement with information from proton nuclear magnetic resonance studies.     

Preparation and properties of valdecoxib-hydroxypropyl beta-cyclodextrin inclusion complex

Valdecoxib is a non-steroidal anti-inflammatory drug used in the treatment of rheumatoid and osteoarthritis. It is practically insoluble in water. Incidence of adverse events such as nausea has been reported in some trials. Therefore, an attempt was made to improve the aqueous solubility of the drug by making an inclusion complex using hydroxypropyl beta-cyclodextrin (HPbeta-CD). The complexes were prepared by physical mixture and freeze-drying methods. The different methods employed for evaluation--including differential scanning calorimetry, Fourier transform infrared spectral analysis, and scanning electron microscopy studies--indicated complete formation of the complex by the freeze-drying method in a molar ratio of 1:1. The prepared complexes showed an improved in vitro dissolution profile and better anti-inflammatory activity as compared to the pure drug.     

氟脲嘧啶和呋氟脲嘧啶的β-环糊精包合物的组成和稳定常数的核磁共振研究

利用氟脲嘧啶(5-Fu)和呋氟脲嘧啶(FT-207)与β-环糊精(β-CD)形成主—客包合物后¹⁹F化学位移的变化研究了这些包合物的组成和稳定常数。5-Fu和FT-207均与β-CD形成1:1包合物,包合物的稳定常数在40℃分别为17.0±1.7mol^-1·L和9.0±0.1mol^-1·L。研究结果还表明,与β-CD形成包合物后,5-Fu和FT-207的¹⁹F化学位移的变化有较明显的差异,提示了它们分子中的氟脲嘧啶环在β-CD疏水性内腔中的位置是不同的。     

Suppositories containing beta-cyclodextrin complexes. Part 1: Stability studies

Application of beta-cyclodextrin complexes of volatile substances in suppositories improves the mechanical properties and stability of suppositories. The incompatibility between the volatile components and suppository bases can be eliminated.