Improvement of solubility and dissolution properties of clotrimazole by solid dispersions and inclusion complexes

Solid dispersions of a slightly water-soluble drug, clotrimazole, were prepared in different weight ratios using polyethyleneglycol 4000 and different molecular weight polyvinyl pyrrolidones as carriers. Moreover, binary and ternary β-cyclodextrin complexes were prepared in different molar ratios. Both solid dispersions and β-cyclodextrin complexes were prepared by solvent evaporation technique. A phase solubility method was used to evaluate the effect of the tested carriers on the aqueous solubility of clotrimazole. The dissolution of all the preparations was tested using the USP paddle method. The selected solid dispersions and inclusion complexes were characterized by differential scanning calorimetry and X-ray powder diffractometry studies, and results clarified the role of the tested carriers in decreasing the crystallinity of clotrimazole and complexing abilities. Based on physical characters and in vitro drug release pattern, polyvinylpyrrolidone solid dispersions (1:1 weight ratio) and ternary cyclodextrin complexes (clotrimazole-β-cyclodextrin complexes with either polymer, 1:1 molar ratio) were selected as ideal batches for suppositories. Suppocire AM/50 mg carbopol 940, was chosen as a suppository base and the suppositories were prepared by molding technique. The prepared suppositories were characterized for weight variation, softening time and drug content. All these properties were found to be ideal. The in vitro drug release pattern was determined in citrate buffer (pH 4.5) containing 1% sodium lauryl sulfate. The in vitro release of clotrimazole from its solid dispersions and inclusion complexes incorporated suppositories was markedly improved when compared to the intact drug incorporated suppositories. Polyvinyl pyrrolidone solid dispersions incorporated suppositories were found to possess excellent antifungal activity.     

Study of the Complexation Behaviour of Fexofenadine with β-Cyclodextrin

Fexofenadine is a selective histamine H(1) receptor antagonist, used for relief of the symptoms of allergy. However its aqueous solubility is very poor. Solid inclusion complexes of fexofenadine and β-cyclodextrin were prepared at the molar ratios of 1:1 and 1:2 by kneading, and coprecipitation methods to improve its solubility. Characterization of the complexes was performed using infrared spectroscopy, X-ray diffractometry, and in vitro dissolution studies. Fexofenadine was found to exhibit interaction with β-cyclodextrin both in solid and liquid state. Phase solubility studies indicated that fexofenadine forms a stable complex with β-cyclodextrin. Both IR spectroscopy and X-ray diffractometry studies indicated interaction of fexofenadine with β-cyclodextrin. Kneading method at 1:1 and co-precipitation method at 1:1 and 1:2 molar ratios showed significant interaction. In vitro dissolution studies confirmed the same results.     

Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-β-cyclodextrin

Abstract

The therapeutic potential of acyclovir is limited by the low oral bioavailability owing to its limited aqueous solubility and low permeability. The present study was a systematic investigation on the development and evaluation of inclusion complex using hydroxypropyl-β-cyclodextrin for the enhancement of oral bioavailability of acyclovir. The inclusion complex of acyclovir was prepared by kneading method using drug: hydroxypropyl-β-cyclodextrin (1:1 mole). The prepared inclusion complex was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, NMR spectroscopy and evaluated in vitro by dissolution studies. In vivo bioavailability of acyclovir was compared for inclusion complex and physical mixture in rat model. Phase solubility studies indicate the formation of acyclovir–hydroxypropyl-β-cyclodextrin complex with higher stability constant and linear enhancement in drug solubility with increase in hydroxypropyl-β-cyclodextrin concentration. Characterization of the prepared formulation confirms the formation of acyclovir–hydroxypropyl-β-cyclodextrin inclusion complex. Dissolution profile of inclusion complex demonstrated rapid and complete release of acyclovir in 30?min with greater dissolution efficiency (90.05?±?2.94%). In vivo pharmacokinetic data signify increased rate and extent of acyclovir absorption (relative bioavailability ～160%; p?<?0.0001) from inclusion complex, compared to physical mixture. Given the promising results in the in vivo studies, it can be concluded that the inclusion complex of acyclovir could be an effective and promising approach for successful oral therapy of acyclovir in the treatment of herpes viruses.     

Solubilization of ibuprofen with β-cyclodextrin derivatives: energetic and structural studies

The aim of this work was to investigate the complexation of ibuprofen as model drug with various β-cyclodextrins (native β-cyclodextrin, hydroxypropyl-β-cyclodextrin with two different molar degrees of substitution, and methyl-β-cyclodextrin). Solutions of the commercially available β-cyclodextrins were prepared in phosphate buffer (73mM). The pH value was adjusted to 7.4 and the solutions were isotonized with NaCl. A solution of ibuprofen was prepared in the same way. A thermal activity monitor was used for isothermal titration calorimetry (ITC). (1)H NMR analysis was employed to investigate the structures of the complexes. ITC analysis showed that each type of β-cyclodextrin had its characteristic values of both enthalpy and mass equilibrium constant for the complexation processes with the drug molecules. (1)H NMR spectroscopy of the complexes showed through significant differences in chemical shifts that the physical interaction between the cyclodextrins and ibuprofen molecules were also different, probably due to different three-dimensional arrangements of ibuprofen in the cyclodextrin cavity, induced by the different substituents bonded to the glucose rings. These differences were connected to the thermodynamic parameters of the complexes.     

A Study on Improvement of Solubility of Rofecoxib and its effect on Permeation of Drug from Topical Formulations

Rofecoxib, a practically insoluble cox-2 selective nonsteroidal antiinflammatory agent was subjected to improvement in solubility by preparing its binary mixtures with β cyclodextrin using various methods such as physical mixing, co-grinding, kneading with aqueous methanol and co-evaporation from methanol-water mixture. Characterization of the resulting binary mixtures by differential scanning calorimetry and X-ray diffraction studies indicated partial amorphization of the drug in its binary mixtures. In vitro dissolution studies exhibited remarkable increase in rate and extent of dissolution of the drug from its complexes with β -cyclodextrin. Pure rofecoxib as well as its co-ground binary mixture were formulated as aqueous gels for topical application. In vitro skin permeation of rofecoxib from formulation containing rofecoxib-cyclodextrin complex was significantly higher (p<0.05) at 1, 2, 12, 18 and 24 hr as compared to formulation containing pure rofecoxib. This could be attributed to better solubility of binary mixture in the aqueous gel vehicle leading to greater concentration gradient between the vehicle and skin and hence higher flux of the drug.     

Meloxicam β-cyclodextrin transdermal gel: physicochemical characterization and in vitro dissolution and diffusion studies

The aim of the study was to develop a Meloxicam (ME) transdermal gel formulations based on complexation with β-cyclodextrin. ME β-Cyclodextrin gel formulations were prepared using four different gel bases with different concentrations and different permeation enhancers. The developed formulations were examined for their in vitro characteristics and their diffusion through a mouse skin. The gel formulations were prepared successfully. Physicochemical characterization of ME β-CD complex in solution state by phase solubility revealed 1:1 M complexation of ME with β-Cyclodextrin. ME release profiles from the inclusion complex were superior over ME alone. Hydroxypropyl methyl cellulose 15% w/w gel base was proven to be a suitable base for ME inclusion complex formulation as it provides a high drug release than other studied bases. ME β-CD complex gel formulations containing oleic acid (1% w/w) or (5% w/w) cineol used as permeation enhancers in (15% w/w) HPMC gel base were proven to provide a higher diffusion rate of the drug through the mouse skin. This is very promising in providing analgesic activity of meloxicam via topical route of administration.     

Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin

The objectives of the study were to investigate the effects of β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) on the solubility and dissolution rate of norfloxacin prepared using three different methods, at drug to cyclodextrin weight ratios of 1:1, 1:2, 1:4 and 1:8. All the methods increased the solubility and dissolution rate of norfloxacin via inclusion complexation with βCD and HPβCD. Norfloxacin was converted from crystalline to amorphous form through inclusion complexation. Solvent evaporation method was the most effective method in terms of norfloxacin solubilisation, while inclusion complex of HPβCD has higher solubility than βCD complex when prepared using the same procedure.     

几种非促渗剂方法对氟比洛芬凝胶经皮渗透的影响

目的考察几种非促渗剂方法对氟比洛芬凝胶经皮渗透的影响。方法采取提高氟比洛芬浓度、制备了氟比洛芬羟丙基-β-环糊精包合物、氟比洛芬单乙醇胺盐和钠盐来改善氟比洛芬的经皮渗透。结果含药质量分数在2%以下时,氟比洛芬的经皮渗透速率随含量增加而升高。随着羟丙基-β-环糊精浓度的增加,氟比洛芬的经皮渗透速率降低。氟比洛芬单乙醇胺盐经皮渗透速率略高于氟比洛芬,而氟比洛芬钠盐经皮渗透速率远低于氟比洛芬。结论增加药物含量、合成氟比洛芬单乙醇胺盐对氟比洛芬有渗透促进作用,羟丙基-β-环糊精包合以及合成氟比洛芬钠盐对氟比洛芬有渗透抑制作用。     

以羟丙基-β-环糊精为增溶剂和促渗剂制备的辣椒碱凝胶的研究

目的：考察羟丙基-β-环糊精（HP-β-CD）在辣椒碱凝胶剂中作为增溶剂和促渗剂的作用。方法：以相溶解度法考察辣椒碱与HP-β-CD的相互作用。制备含HP-β-CD的辣椒碱凝胶剂和含月桂氮酮、乙醇的凝胶剂,并以上市辣椒碱软膏Zostrix为阳性对照,分别比较其经皮渗透率、镇痛作用、抗炎作用以及对皮肤的刺激性。结果：辣椒碱与HP-β-CD包合的表观稳定性常数为1 061.7 L/mol;与Zostrix软膏和含月桂氮酮、乙醇的凝胶相比,HP-β-CD使辣椒碱的透皮吸收显著提高（P〈0.01）;抗炎、镇痛的效果依次为含HP-β-CD凝胶≈Zostrix软膏〉月桂氮酮乙醇凝胶。皮肤刺激性实验结果为月桂氮酮乙醇凝胶〉HP-β-CD凝胶≈Zostrix软膏。结论：HP-β-CD能与辣椒碱发生较强相互作用,在辣椒碱凝胶中作为增溶剂和促渗剂,可以显著促进辣椒碱的皮肤渗透性,提高辣椒碱的抗炎、镇痛效果,且不会对家兔的完整皮肤产生刺激性。     

维生素D3-羟丙基-β-环糊精包合物的制备及性质考察

摘要：目的 提高维生素D3在制剂中的稳定性与体外溶出度。方法 采用冷冻干燥法制备维生素D3-羟丙基-β-环糊精包合物;通过差示扫描量热法验证包合物的形成;采用加热和光照实验考察包合物的稳定性;采用《中华人民共和国药典》溶出度测定法考察包合物的体外溶出度。结果 同维生素D3相比,维生素D3-羟丙基-β-环糊精包合物对光、热的稳定性显著提高,在高温或强光条件下存放10 d,包合物中维生素D3的含量下降均在6 %以内;体外溶出度在60 min内达到97 %以上,是包合前的5倍。结论 维生素D3经羟丙基-β-环糊精包合后能显著提高其稳定性和体外溶出度。     

Mucoadhesive microspheres for nasal administration of cyclodextrins

The aim of this study was to examine the in vitro capacity of cyclodextrins to interfere on the β-amyloid fibril formation; then, mucoadhesive microspheres containing cyclodextrins were prepared and characterised as nasal delivery system for brain targeting. Eight batches of microspheres containing chitosan or alginate loaded with β-cyclodextrin or hydroxypropyl-β-cyclodextrin in two different cyclodextrin to polymer ratios were produced by spray drying. The results show that none of the tested CDs has direct cellular toxicity and they protect the cell viability from β-peptide. The microspheres prepared are characterised by small particle sizes, ability to absorb water and to delay the in vitro dissolution rate of the CDs; good ex vivo mucoadhesive properties of the formulations are assessed. The microsphere properties are influenced by the kind of polymer, of cyclodextrin and by cyclodextrin to polymer ratio used. In particular, the alginate formulation containing the higher cyclodextrin content shows the best performance.     

卡维地洛羟丙基-β-环糊精包合物的制备与评价

目的制备卡维地洛羟丙基-β-环糊精包合物,对包合物进行物性研究。方法采用超声法制备包合物,通过相溶解度研究包合类型,以差示扫描热分析法(DSC)和X-射线衍射法验证卡维地洛羟丙基-β-环糊精包合物的形成,并测定包合物的溶解度和溶出度。结果相溶解度曲线呈AL型,表明卡维地洛能够与羟丙基-β-环糊精形成1∶1的包合物。DSC和X-射线衍射结果显示药物峰消失,证明包合物的形成。包合物的溶解度比原药提高5倍,溶出速度明显加快。结论超声法制备的卡维地洛羟丙基-β-环糊精包合物能显著提高原药的溶解度和溶出速度。     

Preparation,characterization, dissolution,and permeation of flibanserin − 2-HP-β-cyclodextrin inclusion complexes

Flibanserin (FLB), an antiserotonin drug, is used to treat women with hypoactive sexual appetite disorder. FLB shows low bioavailability (~33%) probably due to its low water solubility. The current study investigated the impact of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium lauryl sulfate (SLS) on the dissolution and permeation of FLB. HP-β-CD–FLB inclusion complexes were prepared using physical mixing and kneading at 1:1 and 1:2 M ratios and characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. The dissolution and permeation of the complexes through a cellophane membrane were performed in, 0.1, 0.3 and 0.5% SLS in phosphate buffer (pH 6.8).Derived from the slope of the linear phase solubility diagram, the apparent stability constant (K_1:1) was 372.54 M⁻¹. Kneading changed the crystalline form of FLB to an amorphous appearance characterized by minimal crystalline peaks, indicating successful inclusion complex formation. In addition, the HP-β-CD–FLB inclusion complexes showed twofold increased dissolution efficiency at 6 h. The cumulative FLB amount permeated at 6 h increased from 14.1% to 21.88% and 34.56% in the presence of 0.1% and 0.3% of SLS, respectively. However, increasing SLS to 0.5% did not show an increase in FLB permeation. Therefore, the HP-β-CD–FLB inclusion complex has an improved dissolution rate compared to FLB alone. The presence of SLS in the dissolution medium increases the dissolution rate of pure FLB and its complex with HP-β-CD. kneaded 1:1 complex was formulated bioadhesive buccal tablets and showed enhanced drug release.     

羟丙基-β-环糊精对他克莫司的增溶作用

目的:制备他克莫司/羟丙基-β-环糊精包合物,考察羟丙基-β-环糊精对药物的增溶作用。方法:采用搅拌法制备他克莫司/羟丙基-β-环糊精包合物,相溶解度法考察羟丙基-β-环糊精对药物的增溶作用,并用差式扫描量热法和X-射线衍射法对包合物进行鉴定。结果:羟丙基-β- 环糊精可显著增加他克莫司在水中的溶解度,并且随着羟丙基-β-环糊精质量浓度和试验温度的增加,他克莫司的溶解度明显增加,在25 ℃及羟丙基-β-环糊精浓度为0.50g.mL-1条件下,他克莫司的溶解度从2.07μg.mL-1增加到167.74μg.mL-1;差式扫描量热法和X-射线衍射法确证包合物已形成。结论:羟丙基-β-环糊精对他克莫司有显著的增溶作用。     

Preparation,characterization, dissolution,and permeation of flibanserin − 2-HP-β-cyclodextrin inclusion complexes

Flibanserin (FLB), an antiserotonin drug, is used to treat women with hypoactive sexual appetite disorder. FLB shows low bioavailability (~33%) probably due to its low water solubility. The current study investigated the impact of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium lauryl sulfate (SLS) on the dissolution and permeation of FLB. HP-β-CD–FLB inclusion complexes were prepared using physical mixing and kneading at 1:1 and 1:2 M ratios and characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. The dissolution and permeation of the complexes through a cellophane membrane were performed in, 0.1, 0.3 and 0.5% SLS in phosphate buffer (pH 6.8).Derived from the slope of the linear phase solubility diagram, the apparent stability constant (K_1:1) was 372.54 M⁻¹. Kneading changed the crystalline form of FLB to an amorphous appearance characterized by minimal crystalline peaks, indicating successful inclusion complex formation. In addition, the HP-β-CD–FLB inclusion complexes showed twofold increased dissolution efficiency at 6 h. The cumulative FLB amount permeated at 6 h increased from 14.1% to 21.88% and 34.56% in the presence of 0.1% and 0.3% of SLS, respectively. However, increasing SLS to 0.5% did not show an increase in FLB permeation. Therefore, the HP-β-CD–FLB inclusion complex has an improved dissolution rate compared to FLB alone. The presence of SLS in the dissolution medium increases the dissolution rate of pure FLB and its complex with HP-β-CD. kneaded 1:1 complex was formulated bioadhesive buccal tablets and showed enhanced drug release.     

吲哚美辛β-环糊精包合物的制备

制备吲哚美辛β-环糊精包合物考察其有关性质。方法：采用共沉淀法制备吲哚美辛β-环糊精包合物．结果：采用显微镜法和红外光谱法进行鉴定,表明吲哚美辛与β-环糊精确已形成包合物,含量测定证明包合物主、客分子比为1：1．结论：吲哚美辛β-环糊精包合成功,明显提高吲哚美辛的溶解度、溶出速度。     

Inclusion complexes of tadalafil with natural and chemically modified β-cyclodextrins. I: Preparation and in-vitro evaluation

The aim of this work was to investigate the inclusion complexation between tadalafil, a practically insoluble selective phosphodiesterase-5 inhibitor (PDE5), and two chemically modified β-cyclodextrins: hydroxypropyl-β-cyclodextrin (HP-β-CD) and heptakis-[2,6-di-O-methyl]-β-cyclodextrin (DM-β-CD), in comparison with the natural β-cyclodextrin (β-CD) in order to improve the solubility and the dissolution rate of the drug in an attempt to enhance its bioavailability. Inclusion complexation was investigated in both the solution and the solid state. The UV spectral shift method indicated guest–host complex formation between tadalafil and the three cyclodextrins (CDs). The phase solubility profiles with all the used CDs were classified as A_p-type, indicating the formation of higher order complexes. The complexation efficiency values (CE), which reflect the solubilizing power of the CDs towards the drug, could be arranged in the following order: DM-β-CD > HP-β-CD > β-CD. Solid binary systems of tadalafil with CDs were prepared by kneading and freeze-drying techniques at molar ratios of 1:1, 1:3 and 1:5 (drug to CD). Physical mixtures were prepared in the same molar ratios for comparison. Physicochemical characterization of the prepared systems at molar ratio of 1:5 was studied using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and Fourier-transform infrared spectroscopy (FTIR). The results showed the formation of true inclusion complexes between the drug and both HP-β-CD and DM-β-CD using the freeze-drying method at molar ratio of 1:5. In contrast, crystalline drug was detectable in all other products. The dissolution of tadalafil from all the prepared binary systems was carried out to determine the most appropriate CD type, molar ratio, and preparation technique to prepare inclusion complexes to be used in the development of tablet formulation for oral delivery of tadalafil. The dissolution enhancement was increased on increasing the CD proportion in all the prepared systems. Both the CD type and the preparation technique played an important role in the performance of the system. Irrespective of the preparation technique, the systems prepared using HP-β-CD and DM-β-CD yielded 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 β-CD derivatives.     

环糊精衍生物对吲达帕胺的增溶作用考察

目的考察不同分子质量水溶性β-环糊精聚合物(β-cyclodextrin polymer,β-CDP)、β-环糊精(β-cy-clodextrin,β-CD)及羟丙基-β-环糊精(hydroxypropy-β-cyclodextrin,HP-β-CD)对吲达帕胺的包合增溶作用。方法运用相溶解度法进行实验,采用紫外分光光度法测定吲达帕胺在溶液中的浓度。结果确定了不同浓度范围及不同pH条件下包合物的相溶解度图,并计算了表观稳定常数。结论5种环糊精衍生物对吲达帕胺都有一定的增溶作用,且都能形成质量比为1∶1的包合物,β-CDP的增溶作用明显优于β-CD、HP-β-CD,β-CDP增溶作用随着聚合物分子质量的增大而增大。     

不同种类环糊精对穿心莲内酯的增溶效应研究

目的用相溶解度法考察β-环糊精（β-CD）、羟丙基-β-环糊精（HP-β-CD）和磺丁基醚-β-环糊精（SBE-β-CD）对穿心莲内酯（AND）的增溶作用。方法通过测定AND在不同浓度β-CD,HP-β-CD,SBE-β-CD溶液中的溶解度,绘制出AND的相溶解度曲线,计算各稳定常数。结果β-CD,HP-β-CD,SBE-β-CD均与AND形成摩尔比为1∶1的包合物,包合类型分别为BS型、AL型和AL型。在50 mmol/L的HP-β-CD溶液中,AND的溶解度比在水中的溶解度增加了60倍;在50mmol/L SBE-β-CD溶液中,AND的溶解度比在水中的溶解度增加了55.5倍。结论在3种环糊精中,增溶效果由强到弱依次为HP-β-CD,SBE-β-CD,β-CD。     

Modification of the Dissolution Behaviour of a Water-insoluble Drug,Naftazone, for Zero-order Release Matrix Preparation*

Abstract— The preparation of hydrophilic matrix tablets able to release naftazone, a water-insoluble drug, into an aqueous medium at a constant rate (zero-order dissolution) is described. Enhancement of dissolution rate of the drug was achieved using cross-linked carmellose sodium, β-cyclodextrin or hydroxypropyl-β-cyclodextrin. Hypromellose was used as a water-gelling polymer. Tablets could be prepared that released naftazone at a constant rate over 16 h.