Development of Edaravone Ionic Liquids and Their Application for the Treatment of Cerebral Ischemia/Reperfusion Injury.

Preparation of the ionic liquid (IL) form of active pharmaceutical ingredients (APIs), termed API-IL, has attracted attention because it can improve upon certain disadvantages of APIs, such as poor water solubility and low stability. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a clinically approved cerebroprotective agent against ischemic stroke and amyotrophic lateral sclerosis, while new formulations that enable improvement of its physicochemical properties and biodistribution are desired. Herein, we report a newly developed API-IL of edaravone (edaravone-IL), in which edaravone is used as an anionic molecule. We investigated the physicochemical properties of edaravone-IL and its therapeutic effect against cerebral ischemia/reperfusion (I/R) injury, a secondary injury after an ischemic stroke. Among the cationic molecules used for edaravone-IL preparation, the IL prepared with tetrabutylphosphonium cation existed as a liquid at room temperature, and significantly increased the water solubility of edaravone without decreasing its antioxidative activity. Importantly, edaravone-IL formed negatively charged nanoparticles upon suspension in water. Intravenous administration of edaravone-IL showed significantly higher blood circulation time and lower distribution in the kidney compared with edaravone solution. Moreover, edaravone-IL significantly suppressed brain cell damage and motor functional deficits in model rats of cerebral I/R injury and showed comparable cerebroprotective effect to edaravone. Taken together, these results suggest that edaravone-IL could be a new form of edaravone with superior physicochemical properties and could be useful for the treatment of cerebral I/R injury.

Preparation of Cubosomes with Improved Colloidal and Structural Stability Using a Gemini Surfactant.

Cubosomes are nanoparticles with bicontinuous cubic internal nanostructures that have been considered for use in drug delivery systems (DDS). However, their low structural stability is a crucial concern for medical applications. Herein, we investigated the use of a gemini surfactant, sodium dilauramidoglutamide lysine (DLGL), which is composed of two monomeric surfactants linked with a spacer to improve the structural stability of cubosomes prepared with phytantriol (PHY). Uniform nanosuspensions comprising a specific mixing ratio of DLGL and PHY in water prepared via ultrasonication were confirmed by using dynamic light scattering. Small-angle X-ray scattering and cryo-transmission electron microscopy revealed the formation of Pn3̅m cubosomes in a range of DLGL/PHY solid ratios between 1 and 3% w/w. By contrast, cubosome formation was not observed at DLGL/PHY solid ratios of 5% w/w or higher, suggesting that excess DLGL interfered with cubosome formation and caused them to transform into small unilamellar vesicles. The addition of phosphate-buffered saline to the nanosuspension caused aggregation when the solid ratio of DLGL/PHY was less than 5% w/w. However, Im3̅m cubosomes were obtained at solid ratios of DLGL/PHY of 6, 7.5, and 10% w/w. The lattice parameters of the Pn3̅m and Im3̅m cubosomes were approximately 7 and 11-13 nm, respectively. The lattice parameters of Im3̅m cubosomes were affected by the concentration of DLGL. Pn3̅m cubosomes were surprisingly stable for 4 weeks at both 25 and 5 °C. In conclusion, DLGL, a gemini surfactant, was found to act as a new stabilizer for PHY cubosomes at specific concentrations. Cubosomes composed of DLGL are stable under low-temperature storage conditions, such as in refrigerators, making them a viable option for heat-sensitive DDS.

Efficient Drug Loading Method for Poorly Water-Soluble Drug into Bicelles through Passive Diffusion.

The bicelle, a type of solid lipid nanoparticle, comprises phospholipids with varying alkyl chain lengths and possesses the ability to solubilize poorly water-soluble drugs. Bicelle preparation is complicated and time-consuming because conventional drug-loading methods in bicelles require multiple rounds of thermal cycling or co-grinding with drugs and lipids. In this study, we proposed a simple drug-loading method for bicelles that utilizes passive diffusion. Drug-unloaded bicelles were placed inside a dialysis device and incubated in a saturated solution of ketoconazole (KTZ), which is a model drug. KTZ was successfully loaded into bare bicelles over time with morphological changes, and the final encapsulated concentration was dependent on the lipid concentration of the bicelles. When polyethylene glycol (PEG) chains of two different lengths (PEG2K and 5K) were incorporated into bicelles, PEG2k and PEG5k bicelles mitigated the morphological changes and improved the encapsulation rate. This mitigation of morphological changes enhanced the encapsulated drug concentration. Specifically, PEG5k bicelles, which exhibited the greatest prevention of morphological changes, had a lower encapsulated concentration after 24 h than that of PEG2k bicelles, indicating that PEGylation with a longer PEG chain length improved the loading capacity but decreased the encapsulation rate owing to the presence of a hydration layer of PEG. Thus, PEG with a certain length is more suitable for passive loading. Moreover, loading factors, such as temperature and vehicles used in the encapsulation process, affected the encapsulation rate of the drug. Taken together, the passive loading method offers high throughput with minimal resources, making it a potentially valuable approach during early drug development phases.

Fabrication of Zero-Order Sustained-Release Floating Tablets via Fused Depositing Modeling 3D Printer.

A three-dimensional (3D) printer is a powerful tool that can be used to enhance personalized medicine. A fused deposition modeling (FDM) 3D printer can fabricate 3D objects with different internal structures that provides the opportunity to introduce one or more specific functionalities. In this study, zero-order sustained-release floating tablet was fabricated using FDM 3D printer. Filaments comprising poorly water-soluble weak base drug, itraconazole (ITZ) and polymers (hydroxypropyl cellulose and polyvinylpyrrolidone) were prepared, and tablets with a hollow structure and different outside shell thicknesses were fabricated. In the 3D printed tablets, ITZ existed as an amorphous state and its solubility improved markedly. As the outside shell thickness of the tablet increased, drug release was delayed and floating time was prolonged. In the tablets with 0.5 mm of the upper and bottom layer thickness and 1.5 mm of the side layer thickness, holes were not formed in the tablets during the dissolution test, and the tablets floated for a long period (540 min) and showed nearly zero-order drug release for 720 min. These findings may be useful for improving the bioavailability of several drugs by effective absorption from the upper small intestine, with floating gastric retention system.

Crystal Structures of Flavone C-Glycosides from Oolong Tea Leaves: Chafuroside A Dihydrate and Chafuroside B Monohydrate.

Chafuroside A and chafuroside B are flavone C-glycosides isolated from oolong tea leaves. They have a number of beneficial pharmacological activities related to antiinflammation at various concentrations. However, no crystallographic study of chafurosides has yet been reported. In the present study, the crystal structures of chafuroside A and chafuroside B were investigated using single-crystal X-ray diffraction. The asymmetric unit of the chafuroside A crystal consists of one chafuroside A and two water molecules, and that of chafuroside B contains one chafuroside B and one water molecule. The flavone moiety of chafuroside A is curved, i.e., the angle between the best-fit planes of the chromene and phenyl rings is 18.9°, whereas the chafuroside B flavone moiety is relatively flat. A comparison of the curvatures of the flavone moieties of various C-glycosides showed that the curvature of chafuroside A is significantly larger than those of the others. This structural feature might contribute to the differences between the strengths of the pharmacological activities of chafurosides A and B.

Controlled-Release Fine Particles Prepared by Melt Adsorption for Orally Disintegrating Tablets.

Melt adsorption is a manufacturing method that offers precise control of particle size distribution of granules and circumvents the disadvantages of conventional melt granulation. However, drug release from particles adsorbed with hydrophobic materials has not been fully investigated, and there are missing details as to whether particles manufactured by this technique can be applied to orally disintegrating tablets (ODT). In this report, we aimed to optimize process parameters and formulation to manufacture ODT containing melt adsorption-particles with the specific characteristic of sustained release. Melt adsorption particles containing Neusilin US2 as the adsorbent were prepared by using various waxes to determine the most suitable material for controlled release formulation. Glycerol fatty acid ester (Poem TR-FB: TR-FB) was the optimal wax examined because of its drug release pattern and tabletability. We then optimized manufacturing conditions by examining granulation time, disintegrant amount per tablet and compression force on the tablet for ODT that meet the criteria of controlled drug release, tensile strength and disintegration of the tablet. Multiple regression analysis revealed the effect of process parameters on tablet properties and drug release with increasing the granulation time affording sustained release of the drug. The analysis also showed that a high compression force crushed the granules coated by TR-FB, which impaired sustained drug release. From the regression model the optimal manufacturing conditions were determined, and the tablet prepared under these conditions concurred with the predicted values and met all criteria. This new technique should contribute to the development of ODT to improve medication adherence.

Novel Dissolution Approach for Tacrolimus-Loaded Microspheres Using a Dialysis Membrane for in Vitro-in Vivo Correlation.

The aim of this study was to establish a novel approach to in vitro dissolution evaluation using a combination of the paddle method and a dialysis membrane, both to predict the overall in vivo performance of tacrolimus microspheres and also to identify a suitable dissolution test method to describe the in vivo initial burst phenomenon. This new dissolution method for evaluating the release of tacrolimus from microspheres consisted of rotating a customized paddle inside a dialysis membrane using a conventional paddle apparatus. Findings were compared with a method in which the paddle was rotated outside the dialysis membrane, the conventional paddle method, and the flow-through cell method. We concluded that the paddle method with a dialysis membrane and internal agitation, which was designed to mimic in vivo conditions, predicted the overall pharmacokinetic (PK) profile of tacrolimus microspheres whereas the conventional paddle method described the initial burst. These findings suggest that it may not be possible to predict both the PK profile and initial burst using a single analysis method. We therefore recommend that evaluation of the initial burst be performed separately. In conclusion, we propose that combination of the paddle method with a dialysis membrane and internal agitation to evaluate the overall PK profile, together with the paddle method to describe the in vivo initial burst, represents a novel approach to in vitro dissolution evaluation for microsphere formulations.

Use of Mixer Torque Rheometer to Clarify the Relationship between the Kneading States of Wet Mass and the Dissolution of Final Product in High Shear Granulation.

The properties of wet mass, which indicate the progress of high shear granulation processes, usually have an effect on final product properties, such as tablet dissolution. The mixer torque rheometer (MTR) is a useful tool for quantitatively measuring the 'kneading state' of wet mass and detecting differences in granules. However, there have been no studies of the relationship between the MTR torque and the final product properties to date. In this study, we measured the MTR torque of wet granules at different kneading states, which were prepared by changing the granulation conditions. We then evaluated the relationship between the MTR torque and the dissolution rate of the final product properties. The amperage of the high shear granulator is usually monitored during granulation, but we could not detect a difference in the kneading state through the amperage. However, using MTR torque we were able to quantify the difference of the wet mass. Moreover, MTR torque showed a high correlation with dissolution, compared with the correlations with other intermediate properties, such as granules particle size and tablet hardness. These other properties are affected by following processes and are not properties that directly relate to the kneading state. Thus, MTR torque is a property of wet mass after granulation, and it can be used to directly evaluate differences of the kneading state, and as a result, dissolution. These results indicate the importance of controlling the kneading state, i.e., the progress of granulation, and the utility of MTR for detecting differences in wet mass.

A Scale-up Approach for Film Coating Process Based on Surface Roughness as the Critical Quality Attribute.

Scale-up approaches for film coating process have been established for each type of film coating equipment from thermodynamic and mechanical analyses for several decades. The objective of the present study was to establish a versatile scale-up approach for film coating process applicable to commercial production that is based on critical quality attribute (CQA) using the Quality by Design (QbD) approach and is independent of the equipment used. Experiments on a pilot scale using the Design of Experiment (DoE) approach were performed to find a suitable CQA from surface roughness, contact angle, color difference, and coating film properties by terahertz spectroscopy. Surface roughness was determined to be a suitable CQA from a quantitative appearance evaluation. When surface roughness was fixed as the CQA, the water content of the film-coated tablets was determined to be the critical material attribute (CMA), a parameter that does not depend on scale or equipment. Finally, to verify the scale-up approach determined from the pilot scale, experiments on a commercial scale were performed. The good correlation between the surface roughness (CQA) and the water content (CMA) identified at the pilot scale was also retained at the commercial scale, indicating that our proposed method should be useful as a scale-up approach for film coating process.

Mutants and molecular dockings reveal that the primary L-thyroxine binding site in human serum albumin is not the one which can cause familial dysalbuminemic hyperthyroxinemia.

BACKGROUND: Natural mutations of R218 in human serum albumin (HSA) result in an increased affinity for L-thyroxine and lead to the autosomal dominant condition of familial dysalbuminemic hyperthyroxinemia. METHODS: Binding was studied by equilibrium dialysis and computer modeling. RESULTS: Ten of 32 other isoforms tested had modified high-affinity hormone binding. L-thyroxine has been reported to bind to four sites (Tr) in HSA; Tr1 and Tr4 are placed in the N-terminal and C-terminal part of the protein, respectively. Site-directed mutagenesis gave new information about all the sites. CONCLUSIONS: It is widely assumed that Tr1 is the primary hormone site, and that this site, on a modified form, is responsible for the above syndrome, but the binding experiments with the genetic variants and displacement studies with marker ligands indicated that the primary site is Tr4. This new assignment of the high-affinity site was strongly supported by results of MM-PBSA analyses and by molecular docking performed on relaxed protein structure. However, dockings also revealed that mutating R218 for a smaller amino acid increases the affinity of Tr1 to such an extent that it can become the high-affinity site. GENERAL SIGNIFICANCE: Placing the high-affinity binding site (Tr4) and the one which can result in familial dysalbuminemic hyperthyroxinemia (Tr1) in two very different parts of HSA is not trivial, because in this way persons with and without the syndrome can have different types of interactions, and thereby complications, when given albumin-bound drugs. The molecular information is also useful when designing drugs based on L-thyroxine analogues.

Anti-stress Effect of Green Tea with Lowered Caffeine on Humans: A Pilot Study.

Theanine, an amino acid in tea, has significant anti-stress effects on animals and humans. However, the effect of theanine was blocked by caffeine and gallate-type catechins, which are the main components in tea. We examined the anti-stress effect of green tea with lowered caffeine, low-caffeine green tea, on humans. The study design was a single-blind group comparison and participants (n=20) were randomly assigned to low-caffeine or placebo tea groups. These teas (≥500 mL/d), which were eluted with room temperature water, were taken from 1 week prior to pharmacy practice and continued for 10 d in the practice period. The participants ingested theanine (ca. 15 mg/d) in low-caffeine green tea. To assess the anxiety of participants, the state-trait anxiety inventory test was used before pharmacy practice. The subjective stress of students was significantly lower in the low-caffeine-group than in the placebo-group during pharmacy practice. The level of salivary α-amylase activity, a stress marker, increased significantly after daily pharmacy practice in the placebo-group but not in the low-caffeine-group. These results suggested that the ingestion of low-caffeine green tea suppressed the excessive stress response of students. This study was registered at the University Hospital Medical Information Network (ID No. UMIN14942).

Recombinant Human Serum Albumin Containing 3 Copies of Domain I, Has Significant in Vitro Antioxidative Capacity Compared to the Wild-Type.

Human serum albumin (HSA), the most abundant protein in serum, functions as carrier of drugs and contributes to maintaining serum colloid osmotic pressure. We report herein on the preparation of a genetic recombinant HSA, in which domains II and III were changed to domain I (triple domain I; TDI). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) results indicated that the purity of the TDI was equivalent to that of the wild type (WT). Both far- and near-UV circular dichroism (CD) spectra of the TDI showed that its structural characteristics were similar to the WT. Ligand binding capacity was examined by an ultrafiltration method using 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) and ketoprofen as markers for site I and site II, respectively. The binding capacity of TDI for both ligands was lower than that for the wild type. TDI significantly suppressed the oxidation of dihydrorhodamine 123 (DRD) by H2O2 compared to the WT. Our current results suggest that TDI has great potential for further development as HSA a product having antioxidative functions.

Evaluation of the Thermosensitive Release Properties of Microspheres Containing an Agrochemical Compound.

The purpose of this study was to develop a deeper understanding of the key physicochemical parameters involved in the release profiles of microsphere-encapsulated agrochemicals at different temperatures. Microspheres consisting of different polyurethanes (PUs) were prepared using our previously reported solventless microencapsulation technique. Notably, these microspheres exhibited considerable differences in their thermodynamic characteristics, including their glass transition temperature (Tg), extrapolated onset temperature (To) and extrapolated end temperature (Te). At test temperatures below the To of the PU, only 5-10% of the agrochemical was rapidly released from the microspheres within 1 d, and none was released thereafter. However, at test temperatures above the To of the PU, the rate of agrochemical release gradually increased with increasing temperatures, and the rate of release from the microspheres was dependent on the composition of the PU. Taken together, these results show that the release profiles of the microspheres were dependent on their thermodynamic characteristics and changes in their PU composition.

Melt Adsorption as a Manufacturing Method for Fine Particles of Wax Matrices without Any Agglomerates.

We have focused on melt adsorption as manufacture method of wax matrices to control particles size of granules more easily than melt granulation. The purpose of present study was to investigate the possibility of identifying a hydrophobic material with a low melting point, currently used as a meltable binder of melt granulation, to apply as a novel carrier in melt adsorption. Glyceryl monostearate (GM) and stearic acid (SA) were selected as candidate hydrophobic materials with low melting points. Neusilin US2 (US2), with a particle diameter of around 100 µm was selected as a surface adsorbent, while dibasic calcium phosphate dihydrate (DCPD), was used as a non-adsorbent control to prepare melting granules as a standard for comparison. We prepared granules containing ibuprofen (IBU) by melt adsorption or melt granulation and evaluated the particle size, physical properties and crystallinity of granules. Compared with melt granulation using DCPD, melt adsorption can be performed over a wide range of 14 to 70% for the ratio of molten components. Moreover, the particle size; d50 of obtained granules was 100-200 µm, and these physical properties showed good flowability and roundness. The process of melt adsorption did not affect the crystalline form of IBU. Therefore, the present study has demonstrated for the first time that melt adsorption using a hydrophobic material, GM or SA, has the potential capability to control the particle size of granules and offers the possibility of application as a novel controlled release technique.

Effect of the External Lubrication Method for a Rotary Tablet Press on the Adhesion of the Film Coating Layer.

External lubrication is a useful method which reduces the adhesion of powder to punches and dies by spraying lubricants during the tableting process. However, no information is available on whether the tablets prepared using an external lubrication system can be applicable for a film coating process. In this study, we evaluated the adhesion force of the film coating layer to the surface of tablets prepared using an external lubrication method, compared with those prepared using internal lubrication method. We also evaluated wettability, roughness and lubricant distribution state on the tablet surface before film coating, and investigated the relationship between peeling of the film coating layer and these tablet surface properties. Increasing lubrication through the external lubrication method decreased wettability of the tablet surface. However, no change was observed in the adhesion force of the film coating layer. On the other hand, increasing lubrication through the internal lubrication method, decreased both wettability of the tablet surface and the adhesion force of the film coating layer. The magnesium stearate distribution state on the tablet surface was assessed using an X-ray fluorescent analyzer and lubricant agglomerates were observed in the case of the internal lubrication method. However, the lubricant was uniformly dispersed in the external lubrication samples. These results indicate that the distribution state of the lubricant affects the adhesion force of the film coating layer, and external lubrication maintained sufficient lubricity and adhesion force of the film coating layer with a small amount of lubricant.

Enhancing the Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs Using Monoolein Cubosomes.

Monoolein cubosomes containing either spironolactone (SPI) or nifedipine (NI) were prepared using a high-pressure homogenization technique and characterized in terms of their solubility and oral bioavailability. The mean particle size, polydispersity index (PDI), zeta potential, solubility and encapsulation efficiency (EE) values of the SPI- and NI-loaded cubosomes were determined to be 90.4 nm, 0.187, -13.4 mV, 163 µg/mL and 90.2%, and 91.3 nm, 0.168, -12.8 mV, 189 µg/mL and 93.0%, respectively, which were almost identical to those of the blank cubosome. Small-angle X-ray scattering analyses confirmed that the SPI-loaded, NI-loaded and blank cubosomes existed in the cubic space group Im3̄m. The lattice parameters of the SPI- and NI-loaded cubosomes were 147.6 and 151.6 Å, respectively, making them almost identical to that of blank cubosome (151.0 Å). The in vitro release profiles of the SPI- and NI-loaded cubosomes showed that they released less than 5% of the drugs into various media over 12-48 h, indicating that most of the drug remained encapsulated within the cubic phase of their lipid bilayer. Furthermore, the in vivo pharmacokinetic results suggested that these cubosomes led to a considerable increase in the systemic oral bioavailability of the drugs compared with pure dispersions of the same materials. Notably, the stability results indicated that the mean particle size and PDI values of these cubosomes were stable for at least 4 weeks. Taken together, these results demonstrate that monoolein cubosomes represent promising drug carriers for enhancing the solubility and oral bioavailability of poorly water-soluble drugs.

Evaluation of Maltose-Induced Chemical Degradation at the Interface of Bilayer Tablets.

Fixed dose combination tablets consisting of mirabegron (MB) and solifenacin succinate (SS) were developed and formulated into bilayer tablets in the current study. The results of a chemical stability study showed that the original formulation for the tablets led to a significant increase of unknown degradants in the SS layer. Two compatibility studies were conducted to simulate the interface between the MB and SS layers, and the results revealed that the degradants only formed in the presence of both active pharmaceutical ingredients (APIs), and that the presence of maltose in the SS layer was critical to inducing degradation. High resolution mass spectroscopy coupled with high performance liquid chromatography was used to determine the chemical structures of the degradants, which were identified to MB derivatives bearing one or two sugar units. These findings therefore suggested that the degradation of the API could be attributed to the addition of sugar units from maltose to MB under the acidic conditions caused by SS. With this in mind, we developed a new formulation by replacing maltose with hydroxypropyl cellulose as a polymer-type binder. The results showed that this formulation suppressed the formation of the degradants. The results of this study have shown that chemical degradation can occur at the interface of bilayer tablets and that an alternative strategy is available to formulate more stable MB/SS bilayer tablets.

Quantitative Appearance Inspection for Film Coated Tablets.

The decision criteria for the physical appearance of pharmaceutical products are subjective and qualitative means of evaluation that are based entirely on human interpretation. In this study, we have developed a comprehensive method for the quantitative analysis of the physical appearance of film coated tablets. Three different kinds of film coated tablets with considerable differences in their physical appearances were manufactured as models, and their surface roughness, contact angle, color measurements and physicochemical properties were investigated as potential characteristics for the quantitative analysis of their physical appearance. All of these characteristics were useful for the quantitative evaluation of the physical appearances of the tablets, and could potentially be used to establish decision criteria to assess the quality of tablets. In particular, the analysis of the surface roughness and film coating properties of the tablets by terahertz spectroscopy allowed for an effective evaluation of the tablets' properties. These results indicated the possibility of inspecting the appearance of tablets during the film coating process.

Preparation and Characterization of SN-38-Encapsulated Phytantriol Cubosomes Containing α-Monoglyceride Additives.

SN-38 is a potent active metabolite of irinotecan that has been considered as an anticancer candidate. However, the clinical development of this compound has been hampered by its poor aqueous solubility and chemical instability. In this study, we developed SN-38-encapsulated cubosomes to resolve these problems. Six α-monoglyceride additives, comprising monocaprylin, monocaprin, monolaurin, monomyristin, monopalmitin, and monostearin, were used to prepare phytantriol (PHYT) cubosomes by probe sonication. The mean particle size, polydispersity index, and zeta potential values of these systems were around 190-230 nm, 0.19-0.25 and -17 to -22 mV, respectively. Small-angle X-ray scattering analyses confirmed that the SN-38-encapsulated cubosomes existed in the Pn̄3m space group both with and without the additives. The monoglyceride additives led to around a two-fold increase in the solubility of SN-38 compared with the PHYT cubosome. The drug entrapment efficiency of PHYT cubosomes with additives was greater than 97%. The results of a stability study at 25°C showed no dramatic changes in the particle size or polydispersity index characteristics, with at least 85% of the SN-38 existing in its active lactone form after 10 d, demonstrating the high stability of the cubosome nanoparticles. Furthermore, approximately 55% of SN-38 was slowly released from the cubosomes with additives over 96 h in vitro under physiological conditions. Taken together, these results show that the SN-38-encapsulated PHYT cubosome particles are promising drug carriers that should be considered for further in vivo experiments, including drug delivery to tumor cells using the enhanced permeability and retention effect.

Preparation of Orally Disintegrating Tablets Containing Powdered Tea Leaves with Enriched Levels of Bioactive Compounds by Means of Microwave Irradiation Technique.

In the present study, a microwave treatment process has been applied to prepare orally disintegrating tablets (ODTs) containing powdered tea leaves with enriched levels of the anti-inflammatory compounds such as chafuroside A (CFA) and chafuroside B (CFB). The use of distilled water as the adsorbed and granulation solvents in this preparation process afforded tablets with a long disintegration time (more than 120 s). The CFA and CFB contents of these tablets did not also change after 4 min of microwave irradiation due to the tablet temperature, which only increased to 100°C. In contrast, the tablet temperature increased up to 140°C after 3 min of microwave irradiation when a 1.68 M Na2HPO4 solution instead of distilled water. Notably, the disintegration time of these tablets was considerably improved (less than 20 s) compared with the microwave-untreated tablets, and there were 7- and 11-fold increases in their CFA and CFB contents. In addition, the operational conditions for the preparation of the tablets were optimized by face-centered composite design based on the following criteria: tablet hardness greater than 13 N, disintegration time less than 30 s and friability less than 0.5%. The requirements translated into X1 (the amount of granulation solvent), X2 (tableting pressure) and X3 (content of the powdered tea leaves) values of 45%, 0.43 kN and 32%, respectively, and the ODTs containing powdered tea leaves prepared under these optimized conditions were found to show excellent tablet properties and contain enriched levels of CFA and CFB.