双氢青蒿素羟丙基-β-环糊精包合物的制备与表征

采用正交设计法,以双氢青蒿素(dihydroartemisinin,DHA)和羟丙基-β-环糊精(hydroxypropyl-β-cyclodextrin,HP-β-CD)的摩尔比、包合温度和包合时间为考察因素,以包合物中DHA的包封产率和载药量为评价指标,优选包合工艺。用红外光谱法、差示扫描量热法和粉末X-射线衍射法表征制备的包合物,并采用分子模拟技术研究HP-β-CD包合DHA的可行性。结果显示,最佳包合条件:DHA与HP-β-CD的投料摩尔比为1∶5、包合温度为50℃、包合时间为1 h。红外光谱法、差示扫描量热法和粉末X-射线衍射分析均表明DHA与HP-β-CD形成了包合物,分子模拟结果揭示了DHA与HP-β-CD包合物具有较低的结合自由能和较高的溶剂可及表面积,HP-β-CD包合DHA可行,能显著提高DHA的水溶性。DHA-HP-β-CD包合工艺可行,为研究生产工艺提供了理论和实验依据。     

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.     

Structural characterization of prazosin hydrochloride and prazosin free base

The three-dimensional solid-state structures of prazosin hydrochloride, C19H22N5O4+.Cl- (A), and prazosin free base, C19H21N5O4 (B), have been determined by synchrotron X-ray powder diffraction. A and B crystallize in triclinic P-1 and monoclinic Cc space groups, respectively, with one structural unit per asymmetric part. In A and B, the prazosin molecule adopts different conformations, which do not correspond to those obtained by DFT optimizations of protonated and free prazosin.     

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.     

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.     

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.     

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.     

The physicochemical characteristics and bioavailability of indomethacin from beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, and hydroxypropyl-beta-cyclodextrin complexes

In an effort to improve the bioavailability of the insoluble drug indomethacin, three complexes were prepared with indomethacin and the soluble complexing agents β-, hydroxyethyl-β-, and hydroxypropyl-β-cyclodextrin. The indomethacin content was similar among the complexes (P≤0.05). To confirm complex formation, each complex was characterized by ultraviolet, infrared, nuclear-magnetic resonance, powder X-ray diffraction, and differential-scanning calorimetry techniques. Powder diffraction studies show the β-cyclodextrin complex was polycrystalline, and the hydroxyethyl- and hydroxypropyl-β-cyclodextrin complexes were amorphous. Phase-solubility analysis confirmed the formation of complexes and suggested the three complexes were bound similarly. Solubility studies show complexation increased indomethacin solubility, and the hydroxyethyl- and hydroxypropyl-β-cyclodextrin complexes were more soluble than the β-cyclodextrin complex in 0.1N hydrochloric acid and distilled water. Dosage forms were prepared by encapsulating the complexes without the addition of excipients. Dissolution studies show the encapsulated β- and hydroxyethyl-β-cyclodextrin complexes had superior dissolution when compared to the hydroxypropyl-β-cyclodextrin and Indocin^® (50 mg) capsules. Bioavailability studies were performed by administering the indomethacin complex or Indocin capsules to male-albino, New Zealand rabbits. Indomethacin plasma-time concentration data fit best to a compartment-independent model for all capsule formulations. Bioavailability comparisons by ANOVA show no significant difference (P≤0.10) in the peak-plasma time and peak concentration among the capsule formulations. The area-under-the-curve for the β-cyclodextrin complex capsules was found to be significantly higher (P≤0.10) than all other capsule formulations. In conclusion, the bioavailabilty of indomethacin was improved by complexation with only β-cyclodextrin. No correlations were found among the bioavailability, solubility, and dissolution results.     

Preparation and characterization of simvastatin/hydroxypropyl-beta-cyclodextrin inclusion complex using supercritical antisolvent (SAS) process.

In the present study, the practically insoluble drug, simvastatin (SV), and its inclusion complex with hydroxypropyl beta-cyclodextrin (HP-beta-CD) prepared using supercritical antisolvent (SAS) process were investigated to improve the aqueous solubility and the dissolution rate of drug, thus enhancing its bioavailability. Inclusion complexation in aqueous solution and solid state was evaluated by the phase solubility diagram, differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The phase solubility diagram with HP-beta-CD was classified as A(L)-type at all temperatures investigated, indicating the formation of 1:1 stoichiometric inclusion complex. The apparent complexation constants (K(1:1)) calculated from phase solubility diagram were 774, 846 and 924 M(-1) at 25, 37 and 45+/-0.5 degrees C, respectively. No endothermic and characteristic diffraction peaks corresponding to SV was observed for the inclusion complex in DSC and PXRD. FT-IR study demonstrated the presence of intermolecular hydrogen bonds between SV and HP-beta-CD in inclusion complex, resulting in the formation of amorphous form. Aqueous solubility and dissolution studies indicated that the dissolution rates were remarkably increased in inclusion complex, compared with the physical mixture and drug alone. Moreover, SV/HP-beta-CD inclusion complex performed better than SV in reducing total cholesterol and triglyceride levels. This could be primarily attributed to the improved solubility and dissolution associated with inclusion complex between drug and HP-beta-CD. In conclusion, SAS process could be a useful method for the preparation of the inclusion complex of drug with HP-beta-CD and its solubility, dissolution rate and hypolipidemic activity were significantly increased by complexation between SV and HP-beta-CD.     

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.     

Preparation and characterization of mosapride citrate inclusion complexes with natural and synthetic cyclodextrins

The aim of this work was to investigate the inclusion complexes between mosapride citrate and SBE₇β-CD in comparison with the natural β-CD to enhance its bioavailability by improving the solubility and dissolution rate. The complexation efficiency value of SBE₇β-CD was higher than that for β-CD. Solid binary systems of mosapride citrate with CDs were prepared by physical mixing, kneading and freeze-drying techniques at molar ratio of 1:1(drug:CD). Physicochemical characterization of the prepared systems was studied using X-ray diffractometry, differential scanning calorimetry, Fourier-transform infrared spectroscopy and scanning electron microscopy (SEM). Amorphous drug was detectable to large extent in inclusion complexes prepared using the freeze-drying technique. From the dissolution study of different inclusion complexes in simulated saliva solution (pH 6.8), we could concluded that irrespective of the preparation technique, the systems prepared using SBE₇β-CD showed better performance than the corresponding ones prepared using β-CD. In addition, the freeze-drying technique showed superior dissolution enhancement than other methods especially when combined with the SBE₇β-CD     

卡马西平β-环糊精包合物的制备及其包合作用的考察

目的为提高卡马西平的溶解性,采用饱和水溶液法制备卡马西平β-环糊精包合物并对其工艺和包合作用进行研究。方法以包封率、收率、载药量为指标,采用综合评分法,通过正交设计优选最佳包合工艺。采用连续递变浓度法测定包合比,绘制不同温度下的相溶解度曲线,测定包合常数和热力学参数。结果最佳包合工艺为包合温度80℃,卡马西平与β-环糊精物质的量比为1∶1,包合时间为1 h。所测定的包合物的包封率为93%,收率为98.6%,载药量为16%。相溶解度曲线为AL型,于25、35、45和55℃下包合常数分别为499.8、673.2、916.9和1 240.8 L·mol-1,吉布斯自由能(ΔG)分别为-15.4、-16.7、-18.0和-19.4 k J·mol-1,焓变(ΔH)为24.7 k J·mol-1,熵变(ΔS)为134.3 J·mol-1·K-1。结论所制备的卡马西平β-环糊精包合物,溶解性显著提高,包合过程是自发进行的熵驱动下的吸热反应。     

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.     

Preparation and study the 1:2 inclusion complex of carvedilol with beta-cyclodextrin

An inclusion complex of beta-cyclodextrin with carvedilol was prepared by using a convenient new method of microwave irradiation. Phase-solubility studies demonstrated the ability of beta-cyclodextrins to complex with carvedilol and increase drug solubility. The structure of inclusion complex was determined by fluorescence spectroscopy and 1H NMR, 13C NMR measurements in solution. The solid inclusion was characterised by infrared spectroscopy, differential scanning calorimetry (DSC) and element analysis. These experimental results confirmed the existence of 1:2 inclusion complex of carvedilol with beta-cyclodextrin, the formation constant of complex was determined by the fluorescence method. Molecular modeling predicted the energy-minimized structure of the complex.     

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.     

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.     

Preparation, characterization and in vivo evaluation of formulation of baicalein with hydroxypropyl-beta-cyclodextrin

The interaction of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and a poorly water-soluble flavonoid, baicalein (Ba), chemically 5,6,7-trihydroxy flavone in solution and solid-state was studied. Ba/HP-beta-CD solid systems were prepared by freeze-drying method. The formation of Ba/HP-beta-CD complex in aqueous solution was demonstrated by UV spectroscopy, while Ba/HP-beta-CD co-lyophilized product was characterized by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Through complexation with HP-beta-CD, the solubility of Ba in neutral aqueous solution was improved significantly. The phase-solubility profile was AP-type, indicating the formation of higher-order complexes or complex aggregates. Ba/HP-beta-CD solid powders were amorphous and show a significantly improved dissolution rate in comparison with free Ba. Comparison of the pharmacokinetics between Ba/HP-beta-CD co-lyophilized product and free Ba was also performed in rats. The concentration of Ba and its mainly conjugated metabolite, 7-O-glucuronide of baicalein (BG) in rat plasma was determined by HPLC method. The in vivo results show that Ba/HP-beta-CD co-lyophilized product exhibits the similar pharmacokinetics as that of free Ba after intravenous administration. Ba/HP-beta-CD co-lyophilized product displays earlier tmax and higher Cmax of BG than free Ba after oral dosing. By comparing the AUC0-infinity of BG between oral dosing, the relative bioavailability of Ba/HP-beta-CD co-lyophilized product to free Ba was 165.0%, which highlighted the evidence of significantly improved bioavailability of formulation of Ba with HP-beta-CD.     

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.     

Preparation, characterization and pharmacokinetics of liposomes-encapsulated cyclodextrins inclusion complexes for hydrophobic drugs

Liposomes-encapsulated indomethacin/cyclodextrins (IMC/ CD) inclusion complexes were prepared. The characteristics and pharmacokinetics of the combined system were investigated. The high drug entrapment values of 2.38 +/- 0.16 microg/mg and 2.48 +/- 0.12 microg/mg for liposomes-encapsulated IMC/ beta-CD and IMC/HP-beta-CD inclusion complexes were achieved, as only 1.60 +/- 0.09 microg/mg for conventional liposomes. Encapsulating IMC/CD inclusion complexes into liposomes resulted in a slow release of drug. Following intravenous administration, both liposomes-encapsulated inclusion complexes showed significantly improved AUC(0 - infinity) compared with that of conventional liposomes (p < 0.05). After intramuscular administration, C(max) has been increased to 5.21 +/- 1.14 microg x ml(-1) and 6.02 +/- 1.22 microg x ml(- 1) for liposomes-encapsulated IMC/ beta -CD and IMC/HP-beta -CD inclusion complexes, respectively, whereas only 2.43 +/- 0.69 microg x ml(- 1) for liposomes-encapsulated free drug (p < 0.01).