Enhancement of dissolution amount and in vivo bioavailability of itraconazole by complexation with beta-cyclodextrin using supercritical carbon dioxide

The main objective of this study was to improve the inclusion formation between itraconazole and beta-cyclodextrin and thus enhance dissolution amount and bioavailability characteristics of itraconazole. Inclusion complexes between itraconazole and beta-cyclodextrin were prepared using simple physical mixing, conventional coprecipitation method, and supercritical carbon dioxide (SC CO(2)). Effects of process variables (temperature, pressure) and drug:cyclodextrin ratio on inclusion yield and thermal behavior of the solid complexes prepared by SC CO(2) were studied and compared to those obtained by physical mixing and coprecipitation methods. In addition, dissolution amounts of the products obtained by different methods were measured in gastric fluid. Finally, pharmacokinetic studies of the inclusion complexes were conducted in male Wistar rats to assess the bioavailability of the prepared complexes. Results showed that temperature, pressure and itraconazole:beta-cyclodextrin ratio had significant effects on the inclusion yield of the complex prepared by SC CO(2) method. Higher inclusion yields were obtained in the SC CO(2) method as compared to physical mixing and coprecipitation methods. In vivo drug pharmacokinetic studies showed that the itraconazole-beta-cyclodextrin product prepared using SC CO(2) gave higher bioavailability of itraconazole (in blood, liver and kidney of male Wistar rats) as compared to the products obtained by physical mixing or coprecipitation methods.     

伊曲康唑固体分散体制备及体外溶出实验

目的:运用固体分散体技术提高难溶性药物伊曲康唑的溶解度及体外溶出速率.方法:选用聚乙烯吡咯烷酮(PVPK30)为载体,采用喷雾干燥法制备伊曲康唑固体分散体,通过差热分析及X射线衍射对固体分散体进行鉴定,比较考察伊曲康唑及其物理混合物和固体分散体的溶出特性.结果:差热分析、X射线衍射图谱表明药物以无定形状态分散于载体中;体外溶出结果表明固体分散体能显著增加药物在水及人工胃液中的溶出度(45 min时1:4固体分散体体外溶出度为伊曲康唑的11.5倍.1:4固体分散体在0.1 mo1·L-1盐酸中溶解度是伊曲康唑的67倍).结论:伊曲康唑固体分散体能明显提高伊曲康唑的溶解度及体外溶出速率.     

Itraconazole nanosuspension for oral delivery: Formulation, characterization and in vitro comparison with marketed formulation

Background and the purpose of the study

Itraconazole is a poorly water soluble drug which results in its insufficient bioavailability. The purpose of the present study was to formulate Itraconazole in a nanosuspension to increase the aqueous solubility and to improve its formulation related parameters, dissolution and hence oral bioavailability.

Methods

Itraconazole nanosuspension was prepared by pearl milling technique using zirconium oxide beads as a milling media, Poloxamer 407 as a stabilizer and glycerol as a wetting agent. Effects of various process parameters like, stirring time and the ratio of the beads were optimized by keeping drug:surfactant:milling media (1:3.0:50) as a constant initially and then optimized process parameters were used to optimize formulation parameters by 32 factorial designs. The optimized nanosuspension was lyophilized using mannitol (1:1 ratio) as a cryoprotectant. Nanosuspension was characterized by particle size and size distribution, drug content, scanning electron microscopy, differential scanning colorimetry and X-ray diffraction techniques.

Results

Optimized nanosuspension showed spherical shape with surface oriented surfactant molecules and a mean particle diameter of 294 nm. There was no significant change in crystalline nature after formulation and it was found to be chemically stable with high drug content.

Conclusion

The in vitro dissolution profile of the optimized formulation compared to the pure drug and marketed formulation (Canditral Capsule) by using 0.1N Hydrochloric acid as release medium showed higher drug release.     

Comparative bioavailability of furosemide from solution and 40 mg tablets with different dissolution characteristics following oral administration in normal men

Furosemide tablets, with markedly different dissolution characteristics, and solution were orally administered to 21 healthy adult males to determine the effect of in vitro dissolution rate on in vivo bioavailability profiles. Furosemide 40 mg was given as Tablet A (fast dissolution characteristics), Tablet B (slow dissolution characteristics), and an aqueous solution. Both batches of tablets had identical formulae and were produced by a common process. The dissolution rate of the slower Tablet B was probably retarded by extension of the wet granulation time. Blood was collected for 12 h postdose and urine for 24 h. Peak plasma furosemide concentrations after the solution were significantly greater than after the tablets; there was no significant difference between the tablets. The time to peak occurred significantly earlier with the solution, with no significant difference between the tablets. Relative bioavailabilities of Tablet A and B were 89 per cent and 101 per cent, respectively, as determined by AUC, and 79 per cent and 84 per cent, respectively, as determined by urine recovery. These differences are not statistically significant. These results indicate that dissolution rate profiles of furosemide tablets may not be predictive of in vivo bioavailability.     

Supersaturation,nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: Polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs

The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit® EPO and AQOAT® AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat® 603 and Kollidon® VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat® 603 > Eudragit® L-100-55 > AQOAT® AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation.     

In vitro dissolution and oral bioavailability study of fenofibrate nanomatrix system prepared by hot-melt extrusion

Solvent evaporation method for preparation of nanomatrix has the disadvantages, such as residual organic solvent, environmental pollution, explosion-proofing and so on. To overcome these shortcomings, a series of fenofibrate nanomatrix drug delivery system (NDDS) consisting of nano-porous silica Sylysia^®350 (S350) and pH sensitive material Eudragit^® L100-55 (EL100-55) were prepared using hot-melt extrusion (HME), and their in vitro dissolution and in vivo bioavailability were compared. Finally, the formulation with the highest in vivo bioavailability was selected as the optimized formulation for DSC and PXRD characterization. The results showed that the optimized NDDS showed a higher bioavailability than the reference formulation, although there was crystalline form drug remaining in NDDS. The relative bioavailability of the optimized formulation was 157.1% compared with the commercial product Lipanthyl^®. In addition, the relative bioavailability of the optimized formulation was 124.8% in comparison with the formulation prepared by solvent evaporation method, showing that the NDDS prepared by the HME method was effective in improving the bioavailability of fenofibrate. In conclusion, HME was a promising method to prepare NDDS.     

Evaluation and prediction of oral drug absorption and bioequivalence with food-druginteraction

This article reviews the impacts on the in vivo prediction of oral bioavailability (BA) and bioequivalence (BE) based on Biopharmaceutical classification systems (BCS) by the food-drug interaction (food effect) and the gastrointestinal (GI) environmental change. Various in vitro and in silico predictive methodologies have been used to expect the BA and BE of the test oral formulation. Food intake changes the GI physiology and environment, which affect oral drug absorption and its BE evaluation. Even though the pHs and bile acids in the GI tract would have significant influence on drug dissolution and, hence, oral drug absorption, those impacts largely depend on the physicochemical properties of oral medicine, active pharmaceutical ingredients (APIs). BCS class I and III drugs are high soluble drugs in the physiological pH range, food-drug interaction may not affect their BA. On the other hand, BCS class II and IV drugs have pH-dependent solubility, and the more bile acid secretion and the pH changes by food intake might affect their BA. In this report, the GI physiological changes between the fasted and fed states are described and the prediction on the oral drug absorption by food-drug interaction have been introduced.     

Influence of concomitant food intake on the oral absorption of two triazole antifungal agents,itraconazole and fluconazole

The influence of food on the pharmacokinetics of the triazole antimycotics fluconazole and itraconazole was investigated in a randomised, parallel group, single dose study in 24 healthy subjects. Each group took either a 100 mg capsule of fluconazole or a 100 mg capsule of itraconazole, pre-prandially or after a light meal or a full meal, in a three-way crossover design. Gastric and intestinal pH were measured with a co-administered radio-telemetric pH capsule, and gastric emptying time of the capsule (GET) was taken as the maximum gastric residence time of drug and food.The plasma AUC and C_max of itraconazole were significantly different under the various conditions and the mean AUC was greatest after the full meal. The bioavailability (90% confidence intervals) of itraconazole relative to that after the full meal, was 54% (41–77%) on an empty stomach and 86% (65–102%) after a light meal. The criteria for bioequivalence were not attained. In contrast, the bioavailability (90% CI) of fluconazole relative to the full meal was 110% pre-prandially (100–115%) and 102% after the light meal (88–103%), and the criteria for bioequivalence were attained.Itraconazole absorption was promoted by low stomach pH, long gastric retention time and a high fat content of the coadministered meal, whereas the pharmacokinetics of fluconazole was relatively insensitive to physiological changes in the gastrointestinal tract.     

Increased dissolution rate and oral bioavailability of hydrophobic drug glyburide tablets produced using supercritical CO2 silica dispersion technology

The aim of this study was to design a silica-supported solid dispersion of a water-insoluble drug, glyburide, to increase its dissolution rate and oral absorption using supercritical fluid (SCF) technology. DSC and PXRD results indicated that the encapsulated drug in the optimal solid dispersion was in an amorphous state and the product was stable for 6 months. Glyburide was adsorbed onto the porous silica, as confirmed by the SEM images and BET analysis. Furthermore, FT-IR spectroscopy confirmed that there was no change in the chemical structure of glyburide after the application of SCF. The glyburide silica-based dispersion could also be compressed into tablet form. In vitro drug release analysis of the silica solid dispersion tablets demonstrated faster release of glyburide compared with the commercial micronized tablet. In an in vivo test, the AUC of the tablets composed of the new glyburide silica-based solid dispersion was 2.01 times greater than that of the commercial micronized glyburide tablets. In conclusion, SCF technology presents a promising approach to prepare silica-based solid dispersions of hydrophobic drugs because of its ability to increase their release and oral bioavailability.     

Development and evaluation of lafutidine solid dispersion via hot melt extrusion: Investigating drug-polymer miscibility with advanced characterisation

In current study, immediate release solid dispersion (SD) formulation of antiulcer drug lafutidine (LAFT) was developed using hot melt extrusion (HME) technique. Amphiphilic Soluplus^® used as a primary solubilizing agent, with different concentrations of selected surfactants like PEG 400, Lutrol F127 (LF127), Lutrol F68 (LF68) were used to investigate their influence on formulations processing via HME. Prepared amorphous glassy solid dispersion was found to be thermodynamically and physicochemically stable. On the contrary, traces of crystalline LAFT not observed in the extrudates according to differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM) and Raman spectroscopy. Raman micro spectrometry had the lowest detection limit of LAFT crystals compared with XRD and DSC. Atomic Force microscopy (AFM) studies revealed drug- polymer molecular miscibility and surface interaction at micro level. 1H–COSY NMR spectroscopy confirmed miscibility and interaction between LAFT and Soluplus^®, with chemical shift drifting and line broadening. MD simulation studies using computational modelling showed intermolecular interaction between molecules. Dissolution rate and solubility of LAFT was enhanced remarkably in developed SD systems. Optimized ratio of polymer and surfactants played crucial role in dissolution rate enhancement of LAFT SD. The obtained results suggested that developed LAFT has promising potential for oral delivery and might be an efficacious approach for enhancing the therapeutic potential of LAFT.     

Avoidance of food effect on oral absorption profile of itraconazole by self-micellizing solid dispersion approach

The present study was aimed to avoid pharmacokinetic transitions of itraconazole (ITZ) evoked by high-fat meal intake by employing a self-micellizing solid dispersion (SMSD) approach. The dissolution behavior of SMSD/ITZ was assessed in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). To evaluate the food effect on the oral absorption profile of ITZ, a pharmacokinetic study was conducted on orally-dosed ITZ samples in fasted and high-fat meal-fed rats. Crystalline ITZ showed a 9.0-fold higher dissolution amount of ITZ in fed-state SGF (FeSSGF) than in fasted-state SGF (FaSSGF), whereas there was no significant difference in the dissolution amount of ITZ in SMSD/ITZ between FeSSGF and FaSSGF. In fed- and fasted-state SIF, SMSD/ITZ exhibited reduced variation of ITZ dissolution, possibly leading to suppression of the food effect on the dissolution behavior of ITZ. After the oral administration of crystalline ITZ to high-fat meal-fed rats, the oral bioavailability of ITZ was 14-fold higher than that in fasted rats. In contrast, orally-dosed SMSD/ITZ in fed rats exhibited limited transition of pharmacokinetic behavior regardless of food intake due to the improvement in the dissolution behavior of ITZ even under fasted conditions. SMSD technology could be an efficacious dosage option for the consistent oral absorption and clinical outcomes of ITZ.     

Study on dissolution and absorption of four dosage forms of isosorbide mononitrate: Level A in vitro–in vivo correlation

The objective of the present study was to develop a novel in vitro system to simulate the process of dissolution and permeation of oral solid dosage forms in vivo, and to establish a correlation between in vitro permeation and in vivo absorption that could predict the bioavailability (BA) and bioequivalence (BE) of congeneric products. The in vitro dissolution and absorption kinetics of four dosage forms of isosorbide mononitrate (ISMN) were evaluated by the USP basket/paddle system and drug dissolution/absorption simulating system (DDASS). The corresponding pharmacokinetic study was performed in beagle dogs. A comparative study was carried out between the classical and the novel method to estimate the effectiveness of the modified DDASS in simulating the course of dissolution and absorption in vivo. Indeed, the correlation coefficients of in vitro dissolution and in vivo absorption obtained from DDASS and dogs were higher. Moreover, a higher level A in vitro–in vivo correlation (IVIVC) between DDASS permeation and dog absorption was established, with correlation coefficients of 0.9968, 0.9872, 0.9921, and 0.9728. The DDASS method was more accurate at modeling the process of dissolution and absorption in vivo for both immediate-release (IR) and sustained-release (SR) dosage forms of ISMN.     

Improvement of dissolution and oral absorption of ER-34122, a poorly water-soluble dual 5-lipoxygenase/cyclooxygenase inhibitor with anti-inflammatory activity by preparing solid dispersion.

Several formulation approaches were attempted to improve the dissolution and the oral absorption of ER-34122, which is a novel dual 5-lipoxygenase/cyclooxygenase inhibitor with potent anti-inflammatory activity. The solid dispersion of ER-34122 with hydroxypropylmethylcellulose (TC-5RW), which is an inert solid carrier, resulted in a significant improvement in the dissolution rate of ER-34122. The solid dispersion was prepared by a solvent evaporation method using ethanol and water. The solid-state characteristics of the solid dispersion, the corresponding physical mixture, and ER-34122 alone were investigated by X-ray powder diffraction, Fourier transform infrared spectroscopy (FTIR), and an automated controlled-atmosphere microbalance. The X-ray powder diffraction patterns suggest that the solid dispersion exists in a totally amorphous state and the others exist in a crystalline state. The FTIR spectra results suggest that ER-34122 can interact with TC-5RW through intermolecular hydrogen bonding in the solid dispersion. This interaction may cause a stabilization of ER-34122 in the higher-energy, faster-dissolving amorphous state. The dissolution rate of ER-34122 from the solid dispersion was significantly greater than that from the physical mixture or the pure drug. Furthermore, when orally administrated to beagle dogs, ER-34122 showed about a 100-fold increase in both maximum concentration (C(max)) and area under the curve of concentration versus time (AUC) compared with the pure drug. Consequently, it was determined that the solid dispersion technique with TC-5RW provides a promising way to increase the dissolution rate and the oral absorption of poorly water-soluble drugs such as ER-34122.     

Determination of mequitazine in human plasma by gas-chromatography/mass spectrometry with ion-trap detector and its pharmacokinetics after oral administration to volunteers

The objective of this study was to develop an assay for mequitazine (MQZ) for the study of the bioavailability of the drug in human subjects. Using one mL of human plasma, the pH of the sample was adjusted and MQZ in the aqueous phase extracted with hexane; the organic layer was then evaporated to dryness, reconstituted and an aliquot introduced to a gas chromatograph/mass spectrometer (GC/MS) system with ion-trap detector. Inter- and intra-day precision of the assay were less than 15.1 and 17.7%, respectively; Inter- and intra-day accuracy were less than 8.91 and 18.6 %, respectively. The limit of quantification for the current assay was set at 1 ng/mL. To determine whether the current assay is applicable in a pharmacokinetic study for MQZ in human, oral formulation containing 10 mg MQZ was administered to healthy male subjects and blood samples collected. The current assay was able to quantify MQZ levels in most of the samples. The maximum concentration (Cmax) was 8.5 ng/mL, which was obtained at 10.1 h, with mean half-life of approximately 45.5 h. Under the current sampling protocol, the ratio of AUCt-->last to AUCt-->infinity was 93.4%, indicating that the blood collection time of 216 h is reasonable for MQZ. Therefore, these observations indicate that an assay for MQZ in human plasma is developed by using GC/MS with ion-trap detector and validated for the study of pharmacokinetics of single oral dose of 10 mg MQZ, and that the current study design for the bioavailability study is adequate for the drug.     

Predicting the oral absorption of a poorly soluble,poorly permeable weak base using biorelevant dissolution and transfer model tests coupled with a physiologically based pharmacokinetic model

通过构建瑞舒伐他汀空腹状态下的生理药动学(physiologically based pharmacokinetic model,PBPK)模型,预测其餐后状态下的吸收,并探究其可能的食物效应机制,为服用他汀类药物的高脂血症患者提出合理的饮食建议,提高BCSⅢ类他汀类药物的药物吸收。

根据文献和已有研究获得瑞舒伐他汀建模的理化参数、生物药剂学参数以及药动学参数,利用GastroPlus^TM软件建立瑞舒伐他汀餐后给药的PBPK预测模型,并结合实测的血药浓度数据验证模型,判断是否可以准确预测出瑞舒伐他汀餐后的药物吸收结果,并进行参数敏感性分析。

通过构建瑞舒伐他汀PBPK模型预测其餐后吸收,计算得到模型预测数据与实测数据的平均折叠误差和绝对平均折叠误差<2,结合模型验证的拟合相关系数表明拟合效果较好,同时参数敏感性分析提示高热量饮食、药物的油水分配系数(LogD)和渗透性对瑞舒伐他汀的吸收影响较大。

所建立的模型能够较好地预测瑞舒伐他汀餐后状态下的吸收,基于参数敏感性分析结果,为服用BCSⅢ类他汀类药物的高脂血症患者提出合理的饮食建议,包括适当增加饮食中蛋白质的比重、减少脂肪和水溶性膳食纤维的占比等,可提高BCSⅢ类他汀类药物的肠道吸收。

     

Aqueous Dissolution and Dispersion Behavior of Polyvinylpyrrolidone Vinyl Acetate-based Amorphous Solid Dispersion of Ritonavir Prepared by Hot-Melt Extrusion with and without Added Surfactants

In this study, the lack of complete drug release from amorphous solid dispersions (ASDs), as observed in most published reports, was investigated. ASDs with 20% ritonavir were prepared by HME using polyvinylpyrrolidone vinyl acetate (PVPVA) alone and in combination with 10% poloxamer 407 or Span 20 as carriers. It was established by the film casting technique that ritonavir was molecularly dispersed in formulations, and accelerated stability testing confirmed that extrudates were physically stable. Dissolution of ASDs (100-mg ritonavir equivalent) was performed in 250 mL 0.01 N HCl (pH 2), pH 6.8 phosphate buffer and FeSSIF-V2. Drug concentrations were measured by filtration through 0.45-μm pores and in unfiltered media; the latter gave total amounts of drug present in dissolution media, both as solution and dispersion. Because of low solubility, ritonavir did not dissolve completely in aqueous media. Rather, it formed supersaturated solutions, and the excess drug dispersed in the oily amorphous form with low particle sizes that could crystallize with time. Due to higher drug solubility, the dissolved drug in FeSSIF-V2 was much higher than that in the phosphate buffer. Complete drug release could be observed by accounting for drug both in solution and as phase-separated dispersion. Thus, the present study provides a complete picture of in vitro drug dissolution and dispersion from ASDs.