Development of taste-masking microcapsules containing azithromycin by fluid bed coating for powder for suspension and in vivo evaluation.

This research aims to develop bitter taste-masking microcapsules containing azithromycin (AZI) by a simpler and familiar method, fluid-bed coating technology, in comparison with Zithromax®. Cores of microcapsules, AZI microparticles, were prepared by fluid-bed granulation, then taste-masking polymer was covered on by fluid-bed coating technique. Eudragit L100, Eudragit RL100, and ethyl cellulose in single and combined with Eudragit L100 and Eudragit E100 were used as taste-masking polymers. The obtained microcapsules were characterised by taste-masking ability, in vitro release, SEM, coating thickness, and coating efficiency. Combination of ethyl cellulose and Eudragit E100 (3:1) in coating thickness of 45.13 ± 2.12% w/w prevents AZI release from microcapsules below bitter taste threshold (1.78 ± 1.17 µg/ml). Bioavailability of powders containing AZI microcapsules and pH modulators (50 mg Na3PO4 and 35 mg Mg(OH)2) was not significantly different from the reference product (Zithromax®, Pfizer, New York, NY) in the rabbit model (p > 0.05). These results support the possibility of developing a generic product containing AZI.

Physicochemical, pharmacokinetic and pharmacodynamic evaluations of novel ternary solid dispersion of rebamipide with poloxamer 407.

This study was conducted primarily to improve the solubility of rebamipide, a poorly water-soluble anti-ulcer drug, using novel ternary solid dispersion (SD) systems and secondly to evaluate the effect of solubility enhancement on its pharmacokinetic (PK) and pharmacodynamic (PD) profile. After dissolving the three components in aqueous medium, ternary SD containing the drug, sodium hydroxide (NaOH) and PVP-VA 64 was achieved by spray drying method, which was used as primary SD. Poloxamer 407, a surfactant polymer, was incorporated in this primary SD by four different methods: co-grinding, physical mixing, melting or spray drying. SD was then characterized by dissolution test, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). The spray dried SD of poloxamer 407 together with primary SD displayed highest dissolution rate of the drug of about 70% after 2 h. DSC, PXRD and FT-IR characterized the amorphous state and molecular dispersion of the drug in the SD. PK and PD studies in Sprague-Dawley rats revealed that the bioavailability of the drug using optimal SD was about twofold higher than that of reference product, and the irritation area of stomach was significantly reduced in the ulcer-induced rat model using optimal SD as compared to the reference product.

Synergistic effect of miscible cellulose-based microparticles and pH modulators on the bioavailability of a weakly basic drug and its metabolites.

This study aimed to evaluate the miscibility of cellulose derivatives to improve the release rate and stability of microparticles containing the weakly basic drug itraconazole (ITZ). We also investigated the effect of some organic acids on the microenvironmental pH (pHm) and the release rate of ITZ from the cellulose-based microparticles. The synergistic effect of cellulose-based microparticles and pHm modulators on the bioavailability of ITZ compared with the reference product was investigated in a rabbit model. Differential scanning calorimetry and Fourier-transform infrared spectroscopy (FTIR) analysis showed that ITZ, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose phthalate were miscible at a ratio of 1.5:3:1 (w/w/w), and the stability of the microparticles was maintained for 6 months under accelerated conditions. In addition, X-ray diffraction, FTIR, and scanning electron microscopy were used to characterize the properties of the microparticles. Through the titration technique and determination of pHm, the combination of fumaric acid and maleic acid (1:2, w/w) was found to be the most effective pHm modulator for microparticles. The integration of cellulose-based microparticles and pHm modulators showed a synergistic effect on the flux and relative bioavailability of ITZ and its active metabolite OH-ITZ (182.60 % and 217.67 %, respectively) when compared with the reference product.

Integration of lornoxicam nanocrystals into hydroxypropyl methylcellulose-based sustained release matrix to form a novel biphasic release system.

The study aims to (a) enhance the solubility of a poorly soluble drug by optimization of nanocrystal formulation using the top-down approach and (b) modify the release profile of this drug, which exhibits a short elimination half-life, by the integration of a fast-release phase containing the optimized nanocrystals and a sustained-release phase in a compression-coated tablet. Nanocrystals of the model drug (lornoxicam; LNX) was prepared by simultaneous application of jet-milling and ball-milling techniques. Investigation of the precipitation inhibition capacity, thermal property, and interaction of different polymers with the drug revealed polyvinyl pyrrolidone K30 (PVP) as the most effective stabilizer for nanocrystals. The immediate-release layer containing the optimized nanocrystals (size of 279.5 ± 11.25 nm and polydispersity index of 0.204 ± 0.01) was then compressed on a zero-order sustained-release matrix core using different derivatives of hydroxypropyl methylcellulose (HPMC). Application of the Design of Experiment approach (DoE) was applied to optimize the formulation of tablet. Analysis of drug concentration in dog plasma by liquid chromatography-tandem mass spectrometry demonstrated an improvement in the release behavior of LNX from the optimal compression-coated tablet integrating a HPMC-based sustained release matrix core and a PVP-stabilized lornoxicam nanocrystals coating layer compared to the reference product.

The Design of Experiment Approach, Rheology for Optimization of a Topical Anti-inflammatory and Analgesic Cream.

BACKGROUND: A capsaicin cream was formulated by optimizing the rheological stability, the release behavior of the drug, and the pharmacological effect. OBJECTIVES: This study aimed to: (a) apply the Design of Experiment approach to study the rheological stability and release behaviors of a drug (capsaicin) from a formulated oil-in-water cream and (b) investigate the skin irritation and anti-inflammatory and analgesic effects of the optimized cream. METHODS: The cream prepared by the emulsification method was optimized using the central composite design, and then the pharmacological effect in experimental animals was determined using Complete Freund's adjuvant (CFA). RESULTS: The effects of a permeation enhancer (X1), Vaseline (X2), and surfactants (X3) on the fluctuation of the ratio of the viscous modulus (G ') to elastic modulus (G') (tan δ) after three cycles of cooling-heating (10-40°C), flux, and skin deposition of capsaicin after 8 h on mouse skin were statistically analyzed and optimized. The final obtained CAP-cream did not cause irritation in the rabbit model and produced comparable anti-inflammatory and analgesic effects to the reference product (Voltaren® emulgel). CONCLUSION: This study successfully integrated the DoE approach, rheological science, and pharmacological studies to develop a stable and highly effective semi-solid product containing capsaicin.

Effect of surfactant on the in vitro dissolution and the oral bioavailability of a weakly basic drug from an amorphous solid dispersion.

This study aimed to investigate the effect of a surfactant on the liquid-liquid phase separation, dissolution, diffusion, and the oral bioavailability of a weakly basic drug (l-tetrahydropalmatine; l-THP) from an amorphous solid dispersion (ASD). The carrier used in the ASD was optimized by the application of casting film, solvent shift, and pH shift methods. The interaction between the optimized carrier (HPMCP) and l-THP was then evaluated by Fourier transform-infrared spectroscopy and powder X-ray diffraction. The impact of the surfactant on ASD prepared by the spray-drying method was evaluated by both in vitro and in vivo studies. The results of in vitro studies, including liquid-liquid phase separation, drug diffusion, and pH-shift dissolution, indicated that the addition of a surfactant at a certain concentration below critical micelle concentration to ASD caused the precipitation of and a reduction in the membrane diffusion of l-THP in pH 6.8. This observation was confirmed in an in vivo study in which the drug concentration of l-THP in rabbit plasma was determined by the LC-MS/MS analysis method. Then the absolute and relative bioavailability of l-THP was calculated from the obtained pharmacokinetic parameters. Specifically, the addition of 1.5% surfactant (Poloxamer 188) to the binary ASD decreased the relative bioavailability of l-THP by approximately 2.4 times compared with the original binary ASD. Besides, the study proved that l-THP had low absolute bioavailability (around 1.24%), and the application of binary ASD was meaningful in enhancing the oral bioavailability of l-THP by around 334.77% compared to the raw material. The study is expected to provide a better understanding of how different dosage forms influence the bioavailability of l-THP, thereby allowing the selection of the optimal approach for this weakly basic drug.

DoE-based development, physicochemical characterization, and pharmacological evaluation of a topical hydrogel containing betamethasone dipropionate microemulsion.

This study was performed to achieve two primary goals: First, a microemulsion containing betamethasone dipropionate was optimized using the quality by design approach. Second, a hydrogel-containing microemulsion was developed using cellulose derivatives, and its anti-inflammatory and skin irritation effects were evaluated. Face-centered central composite design was used to investigate the impacts of two independent variables (oleic acid and ratio of surfactant to cosolvent, S/CoS) on three dependent variables (skin deposition, flux of BMD, and microemulsion droplet size). The microemulsion including oleic acid at a low level (coded with -1) and S/CoS at a high level (coded with +1) was considered optimal since it was the most effective in terms of skin deposition and flux of BMD. Different cellulose derivatives (HPMC E6, HEC, NaCMC, and CMC) were screened to prepare a hydrogel-containing microemulsion based on four properties: flux and skin deposition of BMD, hydration of stratum corneum, and rheological properties of hydrogel-containing microemulsion (ME-hydrogel). The anti-inflammatory effect and flux of BMD from optimal ME-hydrogel with carboxymethyl cellulose as the hydrogel-forming agent were then compared to those of the hydrogel-containing solid lipid nanoparticles (SLN-hydrogel) and nanostructure lipid carriers (NLC-hydrogel). The percentage of edema inhibition declined proportionally with flux of BMD in the following order: ME-hydrogel (44.56 ±â€¯8.08%) > NLC-hydrogel (35.93 ±â€¯7.22%) > SLN-hydrogel (25.68 ±â€¯9.05%).

Formulation and biopharmaceutical evaluation of supersaturatable self-nanoemulsifying drug delivery systems containing silymarin.

The first objective of this study was to optimize a supersaturatable self-nanoemulsifying drug delivery system (S-SNEDDS) containing silymarin through the investigation of the single and synergistic effect of either SNEDDS or a precipitation inhibitor on dissolution efficiency (DE) of silymarin. The bioavailability and hepatoprotective activity of S-SNEDDS were then compared to those of a branded product (Legalon®, Meda). SNEDDS containing silymarin was developed by titration technique, and Poloxamer 407 was selected as the optimal precipitation inhibitor by using casting film and solvent-shift method. The interaction of silybin (the major active constituent of silymarin) and the polymer was then determined by differential scanning calorimetry, powder X-ray diffractometry (PXRD), Fourier transforms infrared spectroscopy and 1H NMR analysis. The combination of two techniques including SNEDDS and addition of 10% of Poloxamer 407 remarkably increased DE4h (88.28%) compared to the reference product (6.41%). The relative bioavailability of S-SNEDDS versus Legalon® was about 760%. The hepatoprotective activity of S-SNEDDS in CCl4-induced mice was also superior to the commercial product in declining both the levels of serum transaminases (ALT, AST) and lipid peroxidation as well as glutathione and superoxide dismutase (SOD) activities under tested doses calculated as silybin (10, 25 and 50 mg/kg). These biopharmaceutical and pharmacological advantages of S-SNEDDS indicated prospects in the development of a novel product that offers lower strength of silymarin while enhancing therapeutic outcomes.

Formulation and biopharmaceutical evaluation of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets.

The objective of this study was to prepare and evaluate some physiochemical and biopharmaceutical properties of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets. In the first stage of the study, the bitter taste masking microparticles were prepared by solvent evaporation and spray drying method. When compared to the bitter threshold (32.43µg/ml) of azithromycin (AZI), the microparticles using AZI:Eudragit L100=1:4 and having a size distribution of 45-212µm did significantly mask the bitter taste of AZI. Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance spectroscopy (1H NMR) proved that the taste masking of microparticles resulted from the intermolecular interaction of the amine group in AZI and the carbonyl group in Eudragit L100. Differential scanning calorimeter (DSC) analysis was used to display the amorphous state of AZI in microparticles. Images obtaining from optical microscopy and scanning electron microscopy (SEM) indicated the existence of microparticles in regular cube shape with many layers. In the second stage, dispersible tablets containing microparticles (DTs-MP) were prepared by direct compression technique. Stability study was conducted to screen pH modulators for DTs-MP, and a combination of alkali agents (CaCO3:NaH2PO4, 2:1) was added into DTs-MP to create microenvironment pH of 5.0-6.0 for the tablets. The disintegration time of optimum DTs-MP was 53±5.29s and strongly depended on the kinds of lubricant and diluent. The pharmacokinetic study in the rabbit model using liquid chromatography tandem mass spectrometry showed that the mean relative bioavailability (AUC) and mean maximum concentration (Cmax) of DTs-MP were improved by 2.19 and 2.02 times, respectively, compared to the reference product (Zithromax®, Pfizer).

Development of solidified self-microemulsifying drug delivery systems containing l-tetrahydropalmatine: Design of experiment approach and bioavailability comparison.

The study first aimed to apply a design of experiment (DoE) approach to investigate the influences of excipients on the properties of liquid self-microemulsifying drug delivery system (SMEDDS) and SMEDDS loaded in the pellet (pellet-SMEDDS) containing l-tetrahydropalmatine (l-THP). Another aim of the study was to compare the bioavailability of l-THP suspension, liquid SMEDDS and pellet-SMEDDS in the rabbit model. By using Central Composite Face design (CCF), the optimum ratio of Capryol 90, and Smix `(Cremophor RH 40: Transcutol HP) in the formulation of SMEDDS was determined. This optimum SMEDDS was absorbed on the solid carrier (Avicel or Aerosil) for the preparation of pellet-SMEDDS by extrusion and spheronization method. The ANOVA table indicated that Avicel was more effective than Aerosil, the traditional solid carrier, in both terms of preservation of dissolution rate of l-THP from the original SMEDDS and pelletization yield. Results obtained from scanning electron microscopy (SEM) indicated that the existence of liquid SMEDDS droplets on the surface of pellet-SMEDDS was due to the absorption on Avicel. The powder X-ray diffractometry proved the amorphous state of l-THP in pellet-SMEDDS. Pharmacokinetic study in the rabbit model using liquid chromatography tandem mass spectrometry showed that the SMEDDS improved the oral bioavailability of l-THP by 198.63% compared to l-THP suspension. Besides, pharmacokinetics study also proved that the mean relative bioavailability (AUC) and mean maximum concentration (Cmax) of pellet-SMEDDS were not significantly different from the original liquid SMEDDS (p > 0.05).

Release kinetics of highly porous floating tablets containing cilostazol.

This study focuses on developing a highly porous floating tablet containing cilostazol. The underlying release mechanism of cilostazol from porous and floating tablets in dissolution media containing surfactants was investigated. The tablets were prepared by compressing granules and excipients with a sublimating agent, followed by sublimation under vacuum. The volatile material for the sublimating agent was chosen based on its flow properties using conventional methods as well as the twisted blade method. Resultant tablets could float immediately and had significantly higher tensile strengths than conventional tablets of similar porosities, holding a promising potential for increasing gastroretentive properties. Fitting the release profiles to the Korsmeyer-Peppas equation indicated Super Case II, Case II and non-Fickian kinetics, which implied that the release was affected by both floating behavior and matrix erosion. Abrupt changes in release kinetic parameters and erosional behaviors were found between the tablets containing different amounts of HPMC, indicating the existence of an excipient percolation threshold. Neither the surfactant in the media nor the porosity affected the dominant release mechanism, which was matrix erosion. Understanding the dominant release mechanism and percolation threshold allows for tuning the formulation to obtain various release profiles.

Pharmacokinetic analysis of levo-tetrahydropalmatine in rabbit plasma by rapid sample preparation and liquid chromatography-tandem mass spectrometry.

A rapid extraction method was developed and validated for levo-tetrahydropalmatine (l-THP) determination in rabbit plasma by liquid chromatography tandem-mass spectrometry (LC-MS/MS). The sample preparation included a single-step acetonitrile extraction and salting out liquid-liquid partitioning from the water in plasma with MgSO4. Berberine was used as internal standard. The mass spectrometry source was negative electrospray ionization. The method showed good performance in the concentration range from 5 to 200ngmL(-1). The limit of quantification (LOQ) was 1ngmL(-1). The method was successfully applied to a pharmacokinetic study in rabbit comparing the two drug formulation of l-THP including the raw material and the self-microemulsifying drug delivery system pellet.

Topical delivery of dexamethasone acetate from hydrogel containing nanostructured liquid carriers and the drug.

The potential of hydrogel containing nanostructured lipid carriers (NLC) to enhance the skin permeation rate and skin deposition of dexamethasone acetate (DEA) was investigated. The particle size of obtained NLCs was around 224.4 nm. NLCs had core-shell structure and DEA existed in amorphous state in NLCs. The permeation rate of DEA through excised mouse skins from hydrogel containing DEA-NLC (DEA-NLC-hydrogel) was 7.3 times higher than DEA-ointment. The skin deposition of DEA from DEA-NLC-hydrogel increased 3.8 folds compared to that from solution of DEA in hydrogel (DEA-hydrogel).

Formulation of solid dispersion of rebamipide evaluated in a rat model for improved bioavailability and efficacy.

OBJECTIVES: Rebamipide, a novel anti-ulcer agent, is listed in biopharmaceutics classification class IV because of its low aqueous solubility and permeability. Consequently, the bioavailability of rebamipide is under 10% in humans. The aim of this study was to increase the solubility and determine the effect of solubility enhancement on the bioavailability and efficacy of rebamipide (RBM). METHODS: After taking into account the physiochemical properties of RBM (solubility, melting point, dosage etc.), solid dispersion was chosen as the solubility enhancement method. A rebamipide solid dispersion system containing the drug, l-lysine, PVP-VA 64 and poloxamer 407 was obtained from a spray-drying method. Solubility enhancement of RBM from the solid dispersion was determined by a dissolution test in 900 ml at pH 1.2. The bioavailability and efficacy of RBM solid dispersion were evaluated in a rat model. KEY FINDINGS: The aqueous solubility of RBM was improved 62.17 times by solid dispersion. The oral bioavailability of the drug was also increased 1.74-fold from solid dispersion compared with the reference product in a rat model. With regard to the anti-ulcer effect, the percentage inhibition of the solid dispersion was 2.71 times higher than that of the reference product in the ulcer-induced rat model. CONCLUSIONS: A solid dispersion of rebamipide was successfully formulated using the spray-drying method. Bioavailability and efficacy of rebamipide were increased significantly by solubility enhancement of the drug.