Shin-ichiro Kimura

Effect of granule properties on rough mouth feel and palatability of orally disintegrating tablets

In this study, we evaluated the palatability of orally disintegrating tablets (ODTs) containing core granules with different particle sizes, coating, and types of materials using visual analog scales (VAS). Tableting the core granules into ODTs reduced rough mouth feel and improved overall palatability compared to the ingestion of core granules alone. Moreover, the evaluation performed immediately after spitting out ODTs demonstrated differences in rough mouth feel between ODTs containing placebo and core granules. Rough mouth feel was found to be significantly more intense with core granules with particle sizes ≥ 200 μm. Since ODTs may contain taste-masked particles, palatability of ODTs containing coated core granules was also evaluated. Although coating with polymers impairs palatability, it was improved by coating the outer layer with d-mannitol. The effects on palatability of materials constituting core granules were also evaluated, with reduced rough mouth feel observed with core granules composed of water-soluble additives. Based on these data, receiver operating characteristic analysis was performed to determine the threshold VAS scores at which the subjects felt roughness and discomfort. In addition, the threshold particle size of the core granule contained within the ODT required for feeling roughness was determined to be 244 μm. This study elucidated the effect of the properties of masking particles on the rough mouth feel and palatability of ODTs.

Mathematical model to analyze the dissolution behavior of metastable crystals or amorphous drug accompanied with a solid-liquid interface reaction

Metastable crystals and the amorphous state of poorly water-soluble drugs in solid dispersions (SDs), are subject to a solid-liquid interface reaction upon exposure to a solvent. The dissolution behavior during the solid-liquid interface reaction often shows that the concentration of drugs is supersaturated, with a high initial drug concentration compared with the solubility of stable crystals but finally approaching the latter solubility with time. However, a method for measuring the precipitation rate of stable crystals and/or the potential solubility of metastable crystals or amorphous drugs has not been established. In this study, a novel mathematical model that can represent the dissolution behavior of the solid-liquid interface reaction for metastable crystals or amorphous drug was developed and its validity was evaluated. The theory for this model was based on the Noyes-Whitney equation and assumes that the precipitation of stable crystals at the solid-liquid interface occurs through a first-order reaction. Moreover, two models were developed, one assuming that the surface area of the drug remains constant because of the presence of excess drug in the bulk and the other that the surface area changes in time-dependency because of agglomeration of the drug. SDs of Ibuprofen (IB)/polyvinylpyrrolidone (PVP) were prepared and their dissolution behaviors under non-sink conditions were fitted by the models to evaluate improvements in solubility. The model assuming time-dependent surface area showed good agreement with experimental values. Furthermore, by applying the model to the dissolution profile, parameters such as the precipitation rate and the potential solubility of the amorphous drug were successfully calculated. In addition, it was shown that the improvement in solubility with supersaturation was able to be evaluated quantitatively using this model. Therefore, this mathematical model would be a useful tool to quantitatively determine the supersaturation concentration of a metastable drug from solid dispersions.

Investigation of Physicochemical Drug Properties to Prepare Fine Globular Granules Composed of Only Drug Substance in Fluidized Bed Rotor Granulation

The effect of some drug properties (wettability and particle size distribution) on granule properties (mean particle size, particle size distribution, sphericity, and granule strength) were investigated in a high (>97%) drug-loading formulation using fluidized bed rotor granulation. Three drugs: acetaminophen (APAP); ibuprofen (IBU); and ethenzamide (ETZ) were used as model drugs based on their differences in wettability and particle size distribution. Granules with mean particle sizes of 100-200 µm and a narrow particle size distribution (PSD) could be prepared regardless of the drug used. IBU and ETZ granules showed a higher sphericity than APAP granules, while APAP and ETZ granules exhibited higher granule strength than IBU. The relationship between drug and granule properties suggested that the wettability and the PSD of the drugs were critical parameters affecting sphericity and granule strength, respectively. Furthermore, the dissolution profiles of granules prepared with poorly water-soluble drugs (IBU and ETZ) showed a rapid release (80% release in 20 min) because of the improved wettability with granulation. The present study demonstrated for the first time that fluidized bed rotor granulation can prepare high drug-loaded (>97%) globular granules with a mean particle size of less than 200 µm and the relationship between physicochemical drug properties and the properties of the granules obtained could be readily determined, indicating the potential for further application of this methodology to various drugs.

Optimal conditions to prepare fine globular granules with a multi-functional rotor processor.

The optimal manufacturing conditions to obtain fine globular granules with a narrow size of particle distribution were investigated for a multi-functional rotor processor. A fractional factorial design analysis was undertaken to find out the significant operational conditions influencing the following physical characteristics of the obtained granules: size distribution, roundness and water content. Operational conditions tested were binder flow rate, atomization pressure, slit air flow rate, rotating speed and temperature of inlet air. It was observed that: the proportion of fine particles (106-212 microm) was positively affected by the atomization pressure, while negatively affected by the slit air flow rate; and roundness and water content were positively affected by the binder flow rate. Furthermore, the multiple regression analysis enabled the identification of an optimal operating window for production of fine globular granules. Therefore, the present study demonstrated that the combination of experimental design and multiple regression analysis allows a better understanding of complicated granulating process of multi-functional rotor processor to obtain fine globular granules.

Formulation of a poorly water-soluble drug in sustained-release hollow granules with a high viscosity water-soluble polymer using a fluidized bed rotor granulator

Water-soluble polymers with high viscosity are frequently used in the design of sustained-release formulations of poorly water-soluble drugs to enable complete release of the drug in the gastrointestinal tract. Tablets containing matrix granules with a water-soluble polymer are preferred because tablets are easier to handle and the multiple drug-release units of the matrix granules decreases the influences of the physiological environment on the drug. However, matrix granules with a particle size of over 800 μm sometimes cause a content uniformity problem in the tableting process because of the large particle size. An effective method of manufacturing controlled-release matrix granules with a smaller particle size is desired. The aim of this study was to develop tablets containing matrix granules with a smaller size and good controlled-release properties, using phenytoin as a model poorly water-soluble drug. We adapted the recently developed hollow spherical granule granulation technology, using water-soluble polymers with different viscosities. The prepared granules had an average particle size of 300 μm and sharp particle size distribution (relative width: 0.52-0.64). The values for the particle strength of the granules were 1.86-1.97 N/mm2, and the dissolution profiles of the granules were not affected by the tableting process. The dissolution profiles and the blood concentration levels of drug released from the granules depended on the viscosity of the polymer contained in the granules. We succeeded in developing the desired controlled-release granules, and this study should be valuable in the development of sustained-release formulations of poorly water-soluble drugs.

Effects of tablet formulation and subsequent film coating on the supersaturated dissolution behavior of amorphous solid dispersions

The effects of tablet preparation and subsequent film coating with amorphous solid dispersion (ASD) particles that were composed of a drug with poor water solubility and hydrophilic polymers were investigated. ASD particles were prepared with a drug and vinylpyrrolidone-vinyl acetate copolymer (PVPVA) or polyvinylpyrrolidone (PVP) at a weight ratio of 1:1 or 1:2 using a melt extrusion technique. Tablets were prepared by conventional direct compression followed by pan coating. A mathematical model based on the Noyes-Whitney equation assuming that stable crystals precipitated at the changeable surface area of the solid-liquid interface used to estimate drug dissolution kinetics in a non-sink dissolution condition. All the ASD particles showed a maximum dissolution concentration approximately ten times higher than that of the crystalline drug. The ASD particles with PVPVA showed higher precipitation rate with lower polymer ratio, while PVP did not precipitate within 960 min regardless of the polymer ratio, suggesting the ASD particles of 1:1 drug:PVPVA (ASD-1) were the most unstable among the ASD particles considered. The dissolution of a core tablet with ASD-1 showed less supersaturation and a much higher precipitation rate than those of ASD-1 particles. However, a film-coated tablet or core tablet with a trace amount of hydroxypropylmethylcellulose (HPMC) showed a similar dissolution profile to that of the ASD-1 particles, indicating HPMC had a remarkable precipitation inhibition effect. Overall, these results suggest that tablet preparation with ASD may adversely affect the maintenance of supersaturation; however, this effect can be mitigated by adding an appropriate precipitation inhibitor to the formulation.

Inflamed site-specific drug delivery system based on the interaction of human serum albumin nanoparticles with myeloperoxidase in a murine model of experimental colitis

Graphical abstract Figure. No caption available. ABSTRACT To develop a new strategy for inflamed site‐specific drug delivery in the colon for the treatment of ulcerative colitis (UC), we leveraged on the interaction between myeloperoxidase (MPO) and human serum albumin (HSA) and prepared nanoparticles (HSA NPs) conjugated with 5‐aminosalicylic acid (5‐ASA). The 5‐ASA‐HSA NPs (nine molecules of 5‐ASA per HSA molecule) were uniform particles with an average particle size of 190 nm, a zeta potential of ‐−11.8 mV, and a polydispersity index of 0.35. This was considered a suitable particle characteristic to pass through the mucus layer and accumulate into the mucosa. The specific interaction between the 5‐ASA‐HSA NPs and MPO was observed using quartz crystal microbalance analysis in vitro. In addition, the 5‐ASA‐HSA NPs group containing one thousandth of the dose of the 5‐ASA (75 &mgr;g/kg) showed significantly lower disease activity index values and colon weight/length ratios in UC model mice as similar to large amount of neat 5‐ASA group (75 mg/kg), indicating that the therapeutic effect of the 5‐ASA‐HSA NP formulation was confirmed in vivo. Microscopic images of tissue sections of colon extracted from UC model mice demonstrated that HSA NPs and MPO were both localized in the colon, and this specific interaction between HSA NPs and MPO would be involved the in the therapeutic effect in vivo. Furthermore, in the 5‐ASA and 5‐ASA‐HSA NPs groups, some inflammatory damage was observed in the colon, but the degree of damage was mild compared with the control and HSA NPs groups, suggesting mucosal repair and replacement with fibrous granulation tissue had occurred. Therefore, these data demonstrated that an HSA NP formulation has the potential to specifically deliver 5‐ASA to an inflamed site where MPO is highly expressed.

Stabilization Mechanism of Roxithromycin Tablets Under Gastric pH Conditions

Macrolide antibiotics are widely used at clinical sites. Clarithromycin (CAM), a 14-membered macrolide antibiotic, was reported to gelate under acidic conditions. Gelation allows oral administration of acid-sensitive CAM without enteric coating by hindering the penetration of gastric fluid into CAM tablets. However, it is unknown whether this phenomenon occurs in other macrolide antibiotics. In this study, we examined the gelation ability of 3 widely used macrolide antibiotics, roxithromycin (RXM), erythromycin A, and azithromycin. The results indicated that not only CAM but also RXM gelated under acidic conditions. Erythromycin A and azithromycin did not gelate under the same conditions. Gelation of RXM delayed the disintegration of the tablet and release of RXM from the tablet. Disintegration and release were also delayed in commercial RXM tablets containing disintegrants. This study showed that 2 of the 4 macrolides gelated, which affects tablet disintegration and dissolution and suggests that this phenomenon might also occur in other macrolides.

New scale-down methodology from commercial to lab scale to optimize plant-derived soft gel capsule formulations on a commercial scale

A new scale-down methodology from commercial rotary die scale to laboratory scale was developed to optimize a plant-derived soft gel capsule formulation and eventually manufacture superior soft gel capsules on a commercial scale, in order to reduce the time and cost for formulation development. Animal-derived and plant-derived soft gel film sheets were prepared using an applicator on a laboratory scale and their physicochemical properties, such as tensile strength, Youngs modulus, and adhesive strength, were evaluated. The tensile strength of the animal-derived and plant-derived soft gel film sheets was 11.7 MPa and 4.41 MPa, respectively. The Youngs modulus of the animal-derived and plant-derived soft gel film sheets was 169 MPa and 17.8 MPa, respectively, and both sheets showed a similar adhesion strength of approximately 4.5-10 MPa. Using a D-optimal mixture design, plant-derived soft gel film sheets were prepared and optimized by varying their composition, including variations in the mass of κ-carrageenan, ι-carrageenan, oxidized starch and heat-treated starch. The physicochemical properties of the sheets were evaluated to determine the optimal formulation. Finally, plant-derived soft gel capsules were manufactured using the rotary die method and the prepared soft gel capsules showed equivalent or superior physical properties compared with pre-existing soft gel capsules. Therefore, we successfully developed a new scale-down methodology to optimize the formulation of plant-derived soft gel capsules on a commercial scale.

Mechanism of the formation of hollow spherical granules using a high shear granulator

&NA; Recently, we have developed a novel granulation technology to manufacture hollow spherical granules (HSGs) for controlled‐release formulations; however, the mechanism of the granulation is still unclear. The aim of this study is to determine the mechanism of the formation of the HSGs using a high shear granulator. Samples of granulated material were collected at various times during granulation and were investigated using scanning electron microscope and X‐ray computed tomography. It was observed that the granulation proceeded by drug layering to the polymer, followed by formation of a hollow in the granule. In addition, it was also found that generation of a crack in the adhered drug layer and air flow into the granules might be involved in forming the hollow in the structure. Observation of the granulation of formulations with different types of drugs and polymers indicated that negative pressure in the granules occurred and the granules caved in when the hollow was formed. The hollow‐forming speed and the shell density of the hollow granules depended on the particular drug and polymer. Taken together, the granulation mechanism of HSGs was determined and this information will be valuable for HSGs technology development. Graphical abstract Figure. No caption available. Abbreviations: HSGs: hollow spherical granules; CR: controlled‐released; PSD: particle size distribution; SEM: scanning electron microscope; X‐ray CT: X‐ray computed tomography.