Chun-Woong Park

Preparation of highly porous gastroretentive metformin tablets using a sublimation method.

The present investigation is aimed to formulate floating gastroretentive tablets containing metformin using a sublimation material. In this study, the release of the drug from a matrix tablet was highly dependent on the polymer concentrations. In all formulations, initial rapid drug release was observed, possibly due to the properties of the drug and polymer. The effect of the amount of PEO on swelling and eroding of the tablets was determined. The water-uptake and erosion behavior of the gastroretentive (GR) tablets were highly dependent on the amount of PEO. The water-uptake increased with increasing PEO concentration in the tablet matrix. The weight loss from tablets decreased with increasing amounts of PEO. Camphor was used as the sublimation material to prepare GR tablets that are low-density and easily floatable. Camphor was changed to pores in the tablet during the sublimation process. SEM revealed that the GR tablets have a highly porous morphology. Floating properties of tablets and tablet density were affected by the sublimation of camphor. Prepared floating gastroretentive tablets floated for over 24 h and had no floating lag time. However, as the amount of camphor in the tablet matrix increased, the crushing strength of the tablet decreased after sublimation. Release profiles of the drug from the GR tablets were not affected by tablet density or porosity. In pharmacokinetic studies, the mean plasma concentration of the GR tablets after oral administration was greater than the concentration of glucophase XR. Also, the mean AUC(0-∞) values for the GR tablets were significantly greater than the plasma concentrations of glucophase XR.

Preparation of sildenafil citrate microcapsules and in vitro/in vivo evaluation of taste masking efficiency

The aim of the present study was to prepare the particulate taste-masking system to mask the bitter taste of sildenafil citrate (SC), a well-known phosphodiesterase-5 inhibitor used for erectile dysfunction (ED) and pulmonary artery hypertension (PAH). It was evaluated for the taste masking efficiency by the in vitro measurement using electronic tongue (e-tongue) system and the in vivo human panel sensory test. Microcapsules were prepared by microencapsulation with a gastro-soluble polymer, Eudragit(®) E100 (E100), using a spray drying technique at four different weight ratios (2:1, 1:1, 1:2, and 1:3). Characters of prepared microcapsules and the effect of polymer ratio on the taste masking were investigated. The particle morphology and the distribution of SC in microcapsules were observed by SEM-EDS and physical properties were evaluated by PXRD, Raman spectroscopy, and DSC. By drug dissolution studies at pH 1.2 buffer and DW, it was found that E100 was not able to alter the drug release in stomach. As the result of taste evaluation studies, there were a good correlation (R(2)=0.9867) between the weight ratio of polymer and the taste masking efficiency expressed in the distances on the PCA map of the e-tongue data, and a relevance of the e-tongue measurement with the result of sensory test.

Formulation and Evaluation of a Self-microemulsifying Drug Delivery System Containing Bortezomib

The purposes of the present study were to develop a self-microemulsifying drug delivery system (SMEDDS) containing bortezomib, a proteasome inhibitor. The solubility of the drug was evaluated in 15 pharmaceutical excipients. Combinations of oils, surfactants and cosurfactants were screened by drawing pseudo-ternary phase diagrams. The system exhibiting the largest region of microemulsion was considered optimal. Bortezomib SMEDDS spontaneously formed a microemulsion when diluted with an aqueous medium with a median droplet size of approximately 20-30 nm. In vitro release studies showed that the SMEDDS had higher initial release rates for the drug when compared with the raw drug material alone. Measurement of the viscosity, size, and ion conductivity indicated that a phase inversion from water in an oil system to oil in a water system occurred when the weight ratio of the water exceeded 30% of the entire microemulsion system. In a pharmacokinetics study using rats, the bortezomib microemulsion failed to improve the bioavailability of the drug. The reason was assumed to be degradation of the drug in the microemulsion in the gastrointestinal tract. However, bortezomib in Labrasol(®) solution (an aqueous solution containing 0.025% Labrasol(®)) showed significantly increased area under the curve from 0-24 h (AUC0-24 h) and maximum plasma concentration (Cmax) values compared to the drug suspension. The findings of this study imply that oral delivery of a bortezomib and colloidal system containing Labrasol(®) could be an effective strategy for the delivery of bortezomib.

Preparation and evaluation of dual-mode floating gastroretentive tablets containing itraconazole.

Abstract The aims of the present study were to prepare new dual-mode floating gastroretentive tablets (DF-GRT) containing itraconazole (ITR) and to evaluate influence of the dosage forms on pharmacokinetic parameters of ITR. The solubility of ITR was enhanced around 200 times (from 1.54 to 248.38 µg/mL) by preparing solid dispersion (SD) with hydroxypropylmethyl cellulose. Buoyancy of DF-GRT containing ITR-SD was established by both camphor sublimation and gas generation. Camphor sublimation decreased density of DF-GRT by making pores in tablet matrix, which led to elimination of lag time for floating. Carbon dioxide generated by sodium bicarbonate and citric acid helped to maintain buoyancy of DF-GRT. Therefore DF-GRT floated on the medium without lag time until disintegrated entirely during in vitro release study. They released 89.11% of the drug at 2 h. Residual camphor was <0.5 wt% after sublimation. The pharmacokinetics of DF-GRT was evaluated in six miniature pigs and compared to immediate release tablets (IRT). Mean AUC ratio of GRT/IRT was 1.36 but there was no statistical difference between AUC values. However delayed tmax, increased MRT and equivalent Cmax of DF-GRT supposed it could be a promising tool for gastroretentive drug delivery system containing ITR.

Design and in vivo evaluation of oxycodone once-a-day controlled-release tablets

The aim of present study was to design oxycodone once-a-day controlled-release (CR) tablets and to perform in vitro/in vivo characterizations. Release profiles to achieve desired plasma concentration versus time curves were established by using simulation software and reported pharmacokinetic parameters of the drug. Hydroxypropyl methylcellulose (HPMC) 100,000 mPa·s was used as a release modifier because the polymer was found to be resistant to changes in conditions of the release study, including rotation speed of paddle and ion strength. The burst release of the drug from the CR tablets could be suppressed by applying an additional HPMC layer as a physical barrier. Finally, the oxycodone once-a-day tablet was comprised of two layers, an inert HPMC layer and a CR layer containing drug and HPMC. Commercial products, either 10 mg bis in die (bid [twice a day]) or once-a-day CR tablets (20 mg) were administered to healthy volunteers, and calculated pharmacokinetic parameters indicated bioequivalence of the two different treatments. The findings of the present study emphasize the potential of oxycodone once-a-day CR tablets for improved patient compliance, safety, and efficacy, which could help researchers to develop new CR dosage forms of oxycodone.

Formulation and in Vitro Evaluation of Self-microemulsifying Drug Delivery System Containing Fixed-Dose Combination of Atorvastatin and Ezetimibe

This paper focuses on the development and physicochemical characterization of a self-microemulsifying drug delivery system (SMEDDS) containing a fixed-dose combination of atorvastatin (ATR) and ezetimibe (EZT). The solubility of both drugs was determined in excipient screening studies. Ternary-phase diagrams were drawn for 27 systems composed of different surfactants, cosurfactants, and oils at different surfactant-to-cosurfactant (S/CoS) ratios, and the system exhibiting the largest percentage area of the self-microemulsifying region was selected. The optimum oil ratio in the SMEDDS was selected by evaluating the mean droplet size of the resultant microemulsions. The underlying mechanism of the lower ATR loading capacity compared with EZT was elucidated by measurement of the zeta potential and UV absorption analysis. The results implied that ATR was located exclusively in the surfactant-cosurfactant layer, whereas EZT was located both in the microemulsion core and the surfactant-cosurfactant layer. In vitro dissolution studies showed that the SMEDDS had higher initial dissolution rates for both drugs when compared with marketed products. More importantly, EZT had a significantly increased dissolution profile in distilled water and pH 4.0 acetate buffer, implying enhanced bioavailability.

A Comparative Study Between Spray-Drying and Fluidized Bed Coating Processes for the Preparation of Pramipexole Controlled-Release Microparticles for Orally Disintegrating Tablets

In the present study, controlled-release microparticles for orally disintegrating tablets (ODT) were prepared using two different processes, spray drying and fluidized bed coating processes. Pramipexole dihydrochloride monohydrate (PRM), an anti-Parkinsons disease agent, was selected as a model drug. The in vitro release rate and morphology of microparticles were evaluated and compared. The size of microparticles prepared by spray drying (SD microparticles) and fluidized bed coating (FC microparticles) was around 10 and 200 µm, respectively. The latter size was defined by the size of an inert core bead. The release behavior of SD microparticles was characterized by a large initial burst release prior to slow release. In the case of FC microparticles, the initial burst release was smaller than that of SD microparticles and the compression process damaged the release-controlling layer, which led to a change in release rate. The results indicated the importance of carefully considering the manufacturing process for microparticles during the design of controlled-release ODT.

The role of lactose carrier on the powder behavior and aerodynamic performance of bosentan microparticles for dry powder inhalation

&NA; In this study, we prepared carrier‐based formulations for dry powder inhalers by mixing bosentan microparticles with carrier, prepared in three separate types of lactose. Spray‐dried, milled and sieved lactose resulted in formulations with various shapes, surface morphology and particle size distributions. In the spray‐dried lactose, the micronized bosentan particles were trapped and strongly interlocked in the rugged surface of spray‐dried lactose, whereas in the milled and sieved lactose they exhibited lower binding affinity onto the smooth surface of carrier. In all of the carrier‐based formulations, the flow properties were improved compared with bosentan microparticles alone, in the following order spray‐dried, sieved and milled lactose. The aerodynamic characteristics of each were evaluated by particle image velocimetry and Andersen cascade impactor™. Depending on the lactose carrier type, particle dispersion showed different flow characteristics. In the spray‐dried lactose, the formulation was dispersed fast in the only frontal direction, while the milled and sieved lactose formulations formed a relatively slower S‐shaped and fountain‐shaped flow stream, respectively. In addition, milled and sieved lactose formulations showed that the drug particles were readily liberated from the lactose carrier, and demonstrated significantly higher aerosol performance than spray‐dried lactose. Graphical abstract Figure. No caption available.

Preparation and in vivo evaluation of lecithin-based microparticles for topical delivery of minoxidil

Minoxidil is widely used for treatment of androgenic alopecia. Commercial products containing minoxidil are usually in solution form. Repeated applications of minoxidil solution can lead to adverse effects such as skin irritation and horniness. The aims of this study were to prepare lecithin-based microparticle in minoxidil solution for enhancement of minoxidil topical delivery and skin protection and evaluate the ability of lecithin on in vitro delivery, in vivo hair growth, and skin trouble improvement compared to commercial minoxidil solution. In in vitro skin permeation study, minoxidil solution containing lecithin microparticle showed higher skin penetration rate and higher retention of drug inside the skin compared to minoxidil solution without lecithin. After topical application of minoxidil solutions with or without lecithin to C57BL/6 mice, minoxidil 5% solution containing lecithin microparticle showed hair re-growth as efficient as commercial product of minoxidil 5% solution. It also significantly improved skin troubles while commercial product presented horny substance and crust formation. Therefore, the lecithin-based microparticle in minoxidil 5% solution has good ability to promote hair growth without adverse effects.

Preparation and physicochemical characterization of spray-dried and jet-milled microparticles containing bosentan hydrate for dry powder inhalation aerosols.

The objectives of this study were to prepare bosentan hydrate (BST) microparticles as dry powder inhalations (DPIs) via spray drying and jet milling under various parameters, to comprehensively characterize the physicochemical properties of the BST hydrate microparticles, and to evaluate the aerosol dispersion performance and dissolution behavior as DPIs. The BST microparticles were successfully prepared for DPIs by spray drying from feeding solution concentrations of 1%, 3%, and 5% (w/v) and by jet milling at grinding pressures of 2, 3, and 4 MPa. The physicochemical properties of the spray-dried (SD) and jet-milled (JM) microparticles were determined via scanning electron microscopy, atomic force microscopy, dynamic light scattering particle size analysis, Karl Fischer titration, surface analysis, pycnometry, differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy. The in vitro aerosol dispersion performance and drug dissolution behavior were evaluated using an Anderson cascade impactor and a Franz diffusion cell, respectively. The JM microparticles exhibited an irregular corrugated surface and a crystalline solid state, while the SD microparticles were spherical with a smooth surface and an amorphous solid state. Thus, the in vitro aerosol dispersion performance and dissolution behavior as DPIs were considerably different due to the differences in the physicochemical properties of the SD and JM microparticles. In particular, the highest grinding pressures under jet milling exhibited excellent aerosol dispersion performance with statistically higher values of 56.8%±2.0% of respirable fraction and 33.8%±2.3% of fine particle fraction and lower mass median aerodynamic diameter of 5.0±0.3 μm than the others (P<0.05, analysis of variance/Tukey). The drug dissolution mechanism was also affected by the physicochemical properties that determine the dissolution kinetics of the SD and JM microparticles, which were well fitted into the Higuchi and zero-order models, respectively.