Biomedical subjects

Katsuhide Terada

Publications and source records attributed to Katsuhide Terada.

At least 19 recordsLinked to original sources

PubMed2006

Effect of physical properties of troglitazone crystal on the molecular interaction with PVP during heating.

This study examined the effect of physical properties of troglitazone drug substance on the molecular interaction with polyvinylpyrrolidone K30 (PVP) during preparation by a closed melting method. Milling was conducted using impact and jet mills to change the physical properties of troglitazone, such as particle size, specific surface area, surface free energy and acidic-basic parameters. Solid dispersions (SDs) prepared from milled troglitazone, irrespective of milling method, showed almost 100% dissolution when not less than 7.5% of water was added during heating. SDs prepared from unmilled troglitazone showed almost 100% dissolution when not less than 12.8% of water was added during heating. Physical mixture (PM) containing unmilled troglitazone must be heated above at least 50 degrees C higher than the glass transition temperature (T(g)) of PVP to obtain an SD showing 100% dissolution, while PMs containing milled troglitazone could be heated above only 20 degrees C higher than the T(g) of PVP to obtain an SD showing 100% dissolution. The melting points of troglitazone in PMs containing milled troglitazone, irrespective of milling method, were lower than those in PMs containing unmilled troglitazone. These results indicated that specific interaction could occur more easily during heating between milled troglitazone and PVP during preparation by a closed melting method. In addition, Fourier transform infrared study indicated that hydrogen bonding could occur between the N-H of troglitazone and the C=O of PVP.

Calorimetry, Differential Scanning↗

PubMed2006

Solid-state 13C NMR study of indomethacin polymorphism.

The purpose of this study was to analyze the difference in the molecular conformation packed in the crystal lattice between the meta-stable alpha-form and stable gamma-form of indomethacin on the basis of solid-state (13)C NMR spectral patterns. The chemical shifts of each resonance of the alpha-form were distinctly different from the gamma-form. Each carbon nucleus of the gamma-form showed a single signal with no splitting. In contrast, carbon nuclei of the alpha-form showed a complicated set of resonances for each carbon. For some carbons of the alpha-form, four signals assigned to one carbon were observed at 203 K. Two of these four signals were merged between the temperature range from 203 to 343 K without a transformation in the crystal structure. It was found that solid-state (13)C NMR can be a powerful tool to estimate the number of molecular conformations as well as configurational differences in the packing of molecules in a unit cell.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2006

Evaluation of rapidly disintegrating tablets containing glycine and carboxymethylcellulose.

A rapidly disintegration tablet in the oral cavity was prepared using a glycine as a disintegrant. Effect of disintegrant on the disintegration behavior of the tablet in the oral cavity was evaluated. Wetting time prepared from carboxymethylcellulose (NS-300) having the hardness of 4 kg was 3 s. Tablet containing NS-300 showed fastest disintegration compared to other formulations. These results suggested that NS-300 possessed excellent wetting nature and resulted in the rapid disintegration of tablet. Ethenzamide and ascorbic acid were added to the formulation, and their disintegration behavior were evaluated. Ethenzamide did not affect the disintegration property, however, ascorbic acid prolonged disintegration time. It was suggested that the tablet formulation containing NS-300 and glycine was highly applicable to water-insoluble drug, such as ethenzamide.

Ascorbic Acid↗

PubMed2006

Novel approach to DPI carrier lactose with mechanofusion process with additives and evaluation by IGC.

The effect of lactose carrier surface property on the inhalation profile of dry powder inhaler (DPI) was evaluated using a micronized drug (Compound A) by inverse gas chromatography (IGC). Mechanofusion with magnesium stearate (Mg-St) or sucrose stearate increased the fine particle fraction (FPF), considered to be due to decrease in the interaction between Compound A and the lactose carrier. The effect of Compound A concentration on FPF was smaller in mechanofusion-processed lactose compared to intact lactose, especially when processed with Mg-St. The relationship between the IGC parameters of the lactose and FPF was also investigated. FPF increased as both the dispersive component of the surface energy and acidity similarity between the lactose carriers and Compound A increased. Although further investigation is necessary, it could be suggested that acidity similarity decreases the interaction between Compound A and lactose, thus contributing to the increase in the FPF. In conclusion, (1) mechanofusion with Mg-St or sucrose stearate could be an effective method to improve FPF of a DPI drug formulation; (2) IGC would be a valuable method to investigate the interaction between a drug and the DPI carrier; and (3) a relationship between surface acidity and inhalation profile was suggested.

Chromatography, Gas↗

PubMed2005

Formulation design of a novel fast-disintegrating tablet.

As our society is becoming increasingly aged, the development of an appropriate dosage form for the elderly patients is mostly desirable. A novel fast-disintegrating tablet was investigated in this study as a user-friendly dosage form for the aged. Advantages of this formulation have sufficient hardness and can be manufactured by commonly used equipment. Saccharides can be divided into high- and low-compressibility categories, and an appropriate material for fast-disintegrating tablets was created by taking advantage of this fact. To improve the compressibility of low-compressibility saccharides, particle modification was conducted by coating and granulating a low-compressibility saccharide with a high one to enable the production of a fast-disintegrating tablet. Another discovery was that the high-compressibility saccharide used as a binder solution was present in an amorphous state after the granulation process. The crystal change from amorphous to crystal state intentionally by a conditioning process after compression enabled to increase tablet hardness by strengthening adhesion between particles. The conditioning process made it possible to achieve sufficient hardness while maintaining the fast disintegration time. As a result, this fast-disintegrating tablet that can be manufactured by commonly used equipment, can be used for the dosing of a wide range drugs.

Acetaminophen↗

PubMed2005

Dissolution mechanism of poorly water-soluble drug from extended release solid dispersion system with ethylcellulose and hydroxypropylmethylcellulose.

The purpose of this study is to investigate the release mechanism of poorly water-soluble drug from the extended release solid dispersion systems with water-insoluble ethylcellulose (EC) and water-soluble hydroxypropylmethylcellulose (HPMC) (1:1). Indomethacin (IND) was used as a model of poorly water-soluble drug. Two kinds of solid dispersions were prepared by the solvent evaporation methods, which consist of the same formulation but exhibit different physical performance. It appeared that the dissolution behavior of IND depended on the structures of EC-HPMC matrices, which were governed by the preparation method. In addition, the dissolution behavior showed pH dependency that the dissolution rate of IND was slower in acidic medium than that in neutral medium. The experimental results revealed that the hydrophobic interaction between IND and EC occurred under lower pH and strongly delayed the dissolution rate of IND. The relationship between this hydrophobic interaction and the dissolution rate of IND was also proposed.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2005

Effects of water content in physical mixture and heating temperature on crystallinity of troglitazone-PVP K30 solid dispersions prepared by closed melting method.

Troglitazone, which possesses two asymmetric carbons, is obtained as a mixture of four isomers present in equal amounts. Troglitazone (Lot T003) has two melting points, about 120 and 175 degrees C. To increase the bioavailability of insoluble troglitazone, troglitazone-polyvinylpyrrolidone K30 (PVP) solid dispersions (SDs) were prepared with water by a unique closed melting method. In this study, the effects of the water content in the physical mixture (PM) and the heating temperature on the apparent crystallinity of troglitazone in SDs prepared by this method were investigated. When the water content in the PM was controlled at 3%, although the apparent crystallinity of troglitazone in the SD prepared by heating at 105 degrees C did not decrease (99%), that of the SDs prepared by heating at 130 and 150 degrees C were reduced to 54 and 11%, respectively. This result indicated that the meltage of troglitazone varies depending on the heating temperature. The apparent crystallinity of troglitazone in the SDs decreased with increase in water content in the PM. In particular, SDs prepared by heating at 130 and 150 degrees C showed 0% apparent crystallinity when the water content in the PM were more than 13 and 8%, respectively. When the heating temperature used was higher than the glass transition temperature of PVP plasticized with water, troglitazone crystals were dissolved in the rubbery PVP. Therefore, even if the heating temperature is lower than the melting point of troglitazone during preparation, controlling the water content in the PM at a high level can produce a troglitazone SD with 0% apparent crystallinity.

Antineoplastic Agents↗

PubMed2005

Comparison of molecular mobility in the glassy state between amorphous indomethacin and salicin based on spin-lattice relaxation times.

PURPOSE: The purpose of the current study was to evaluate the molecular mobility of amorphous indomethacin and salicin in the relaxed glassy state based on spin-lattice relaxation times (T(1c)) and to clarify the effects of molecular mobility on their physical stability. METHODS: Pulverized glassy amorphous indomethacin and salicin samples were completely relaxed, and the T(1c) values were investigated using solid-state (13)C-nuclear magnetic resonance (NMR) at temperatures below the glass transition temperature (T(g)). All NMR spectra were obtained using the T(1c) measurement method combined with variable-amplitude cross-polarization, the Torchia method, and total sideband suppression method. RESULTS: The T(1c) value of amorphous indomethacin indicated that 73% of carbons were in a state of monodispersive relaxation, suggesting that the amorphous state was relatively homogeneous and restricted, particularly in backbone carbons. On the other hand, 92% of carbons of amorphous salicin exhibited both fast and slow biphasic relaxation. Individual structures of the salicin molecules behaved heterogeneously, and thus the entire molecule showed relatively fast local as well as slow mobility. CONCLUSIONS: At temperatures below T(g), amorphous salicin had relatively greater molecular mobility than amorphous indomethacin. This difference in the molecular mobility of the two compounds is correlated with their crystallization behavior. Solid-state (13)C NMR provides valuable information on the physical stability of amorphous pharmaceuticals.

Benzyl Alcohols↗

PubMed2005

Application of Eudragit RS to thermo-sensitive drug delivery systems: II. Effect of temperature on drug permeability through membrane consisting of Eudragit RS/PEG 400 blend polymers.

The Eudragit RS and polyethylene glycol 400 (PEG 400) blend polymer (EPG) membranes were prepared by the solvent casting method to pioneer a novel application of Eudragit RS to a thermo-sensitive material. The EPG membranes containing 2.5-10% PEG 400 (2.5-10% EPG) showed the glass transition temperatures (Tgs) around the body temperature (32-42 degrees C). Drug permeation studies through the EPG membranes were carried out using acetaminophen (AAP) and aminopyrine (AMP) as the model drugs. The permeability of AAP and AMP through the EPG membranes has been shown to be a discontinuous function of temperature, that is, their permeability increased steeply above the Tg of the membranes. The amount of AMP permeated at 42 degrees C was nearly eight times as much as that at 36 degrees C. Arrhenius plots of the steady-state permeability coefficient (P) of AAP indicated two straight lines that intersect at the Tg of the 10% EPG membrane. In the water uptake study for the 10% EPG membrane, the degree of the swelling for the membrane tended to increase with increasing temperature above the Tg of the membrane. The thermo-sensitive permeation mechanism for the EPG membranes might be based on the structure change of the membranes caused by the glass transition, so that the membranes could absorb more water. Considering the high biological safety of Eudragit RS and PEG 400, the EPG membranes might be used to develop a novel thermo-sensitive drug delivery system.

Acrylic Resins↗

PubMed2005

Effects of sugar ester and hydroxypropyl methylcellulose on the physicochemical stability of amorphous cefditoren pivoxil in aqueous suspension.

The improvement in physicochemical stability of amorphous cefditoren pivoxil (CDTR-PI) in aqueous suspensions by addition of sugar ester (SE) and hydroxypropyl methylcellulose (HPMC) was explained by prolonging the induction period prior to crystallization and the reduction in crystal peak intensity. Furthermore, the stabilizing effect of these additives in a multiple additive system was greater than in a single additive system. To determine the mechanism, by which these additives stabilized the amorphous CDTR-PI, we evaluated the surface states of CDTR-PI in suspension by measuring Raman spectra and zeta potential. The change in Raman spectra demonstrated that SE and HPMC interacted with CDTR-PI at the same interaction sites on CDTR-PI. The zeta potential reflected the adsorption phenomena of the additives and indicated that both SE and HPMC adsorbed onto particles of CDTR-PI with no apparent competitive interaction and the response was complementary. It was considered, based on this study, that HPMC and SE would stabilize amorphous CDTR-PI by different mechanisms; HPMC would mainly inhibit crystal growth by small amount of adsorption and SE would inhibit both crystal growth and nucleation by large amount of adsorption. This was considered to result in the hybrid effect in the multiple additive system.

Carbohydrates↗

PubMed2005

Development of fast disintegrating compressed tablets using amino acid as disintegration accelerator: evaluation of wetting and disintegration of tablet on the basis of surface free energy.

A fast disintegrating compressed tablet was formulated using amino acids, such as L-lysine HCl, L-alanine, glycine and L-tyrosine as disintegration accelerator. The tablets having the hardness of about 4 kgf were prepared and the effect of amino acids on the wetting time and disintegration time in the oral cavity of tablets was examined on the basis of surface free energy of amino acids. The wetting time of the tablets increased in the order of L-lysine HCl, L-alanine, glycine and L-tyrosine, whereas the disintegration time in the oral cavity of the tablets increased in the order of L-alanine, glycine, L-lysine HCl and L-tyrosine. These behaviors were well analyzed by the introduction of surface free energy. When the polar component of amino acid was large value or the dispersion component was small value, faster wetting of tablet was observed. When the dispersion component of amino acid was large value or the dispersion component was small value, faster disintegration of tablet was observed, expect of L-tyrosine tablet. The fast disintegration of tablets was explained by the theory presented by Matsumaru.

Adult↗

PubMed2004

Uniformity and physical states of troglitazone in solid dispersions determined by electron probe microanalysis and microthermal analysis.

Solid dispersions of troglitazone with PVP K30 in a weight ratio of 1:2 were prepared by the closed melting method. Solid dispersions that exhibit different degrees of crystallinity (0 and 36%) were prepared by changing the charged amount of water, which functions as a plasticizer for PVP K30. Electron probe microanalysis (EPMA) and microthermal analysis (micro TA) of the solid dispersions were performed to investigate the uniformity and physical state of troglitazone in the solid dispersions. The EPMA study confirmed that troglitazone was dispersed homogeneously in the sample whose apparent crystallinity was 0%. However, the sample with a 36% crystallinity was heterogeneous. The micro TA study showed that the sample with a 36% crystallinity was present in two states, crystal and amorphous. EPMA and micro TA would be useful tools to confirm the uniformity and physical states, respectively, of solid dispersions.

Chemistry, Pharmaceutical↗

PubMed2004

Changes in surface properties by granulation and physicochemical stability of granulated amorphous cefditoren pivoxil with additives.

The evaluation of the physicochemical stability of granules of amorphous cefditoren pivoxil (CDTR-PI), alone or with polymers, demonstrated that granulated amorphous CDTR-PI with hydroxypropyl methylcellulose was the most stable. We measured glass transition temperature by differential scanning calorimetry (DSC). The molecular mobility of the whole granules did not change, and it was not consistent with the results of the evaluation of physicochemical stability. Peak shifts were observed in IR spectra of amorphous CDTR-PI with polymers after granulation, and the shifts were similar to those observed for spray-dried samples. Furthermore, the shifts were not observed after the granules were ground. Acid-base parameters, which were also measured by inverse gas chromatography (IGC), changed after granulation. These results suggested that on the surface of the granules, CDTR-PI and the polymers would be mixed monomolecularly, as in the spray-dried samples. The changes in the molecular state of a drug when mixed monomolecularly with a polymer on the surface of granules were successfully confirmed by IGC and IR.

Cephalosporins↗

PubMed2004

Microscopic molecular mobility of amorphous AG-041R measured by solid-state 13C NMR.

PURPOSE: AG-041R is characterized to be stable in amorphous state and difficult to crystallize at normal period of time. In order to investigate the molecular mobility in microscopically, the spin-lattice relaxation time (T1) of AG-041R was investigated by solid-state CP/MAS 13C NMR at temperature below and above glass transition temperature (Tg). METHOD: CP/MAS measurement and T1 measurement were performed by means of 13C NMR, where the measurement temperatures were 60, 70, 80, 100, and 110 degrees C. The spin-lattice relaxation time (T1) of AG-041R was calculated from the relaxation curves. RESULTS: From the analysis of T1 of amorphous AG-041R, it was clarified that all of the carbons did not start moving drastically at Tg and there were some groups of carbon in terms of temperature dependency of T1. One is a type, such as the carbons in benzene ring: their T1 was drastically changed at Tg. On the other hand, T1 of carbonyl carbons gradually decreased, and above Tg their T1 was still higher than that of the other carbons. There was no significant change of T1 in the methyl carbons around Tg. From the study of IR and 1H NMR in solution, the inter- and intramolecular hydrogen bondings between NH and C=O were found in AG-041R. Due to hydrogen bonding, the inter- and/or intramolecular interaction is considered to retain even at supercooled liquid state. CONCLUSION: The structure that contributes glass transition is the main skeleton structure, such as benzene ring, while small group, like methyl, start to move at lower temperature than Tg. On the other hand, for the carbons, such as carbonyl, their structure was restricted by inter- and/or intramolecular interaction, therefore, their molecular mobility was significantly low above Tg.

Carbon Radioisotopes↗

PubMed2004

Quantitative determination of amorphous nicardipine hydrochloride in long acting formula (NIC-LA) using light anhydrous silicic acid.

We investigated a method to quantitatively determine amorphous nicardipine hydrochloride (NIC) in the NIC-long acting formula (LA) model formulas prepared using NIC, light anhydrous silicic acid (LASA) and carboxymethylethylcellulose (CMEC). Consequently, since the quantity of total NIC in the formula can be determined by means of HPLC and crystal NIC can be determined by the differential scanning calorimetry (DSC) method because the heat of fusion (85.08 J/g) of NIC is constant and unaffected by excipients, we developed the HPLC-DSC method by which the quantity of amorphous NIC is calculated as the difference between the quantity of total NIC determined by HPLC and the quantity of crystal NIC determined by DSC. This practical HPLC-DSC method was confirmed to have good accuracy and reproducibility.

Calcium Channel Blockers↗

PubMed2003

Factors affecting the apparent solubility of ursodeoxycholic acid in the grinding process.

Ursodeoxycholic acid (UDCA) was ground by a vibrating mill. Apparent solubility of the ground sample was determined by Coulter counter method. The samples were characterized by pore size distribution measurement, powder X-ray diffraction (PXRD) measurement, near infra-red (NIR) spectroscopy and contact angle measurement. The dispersive and polar components of surface free energy were calculated from the contact angle data determined by a contact angle analyzer. Surface polarity was calculated from the surface free energy components. The apparent solubility of UDCA was increased by the grinding with vibrating mill, however, the particle size of ground sample was not decreased. An amorphization was observed in the PXRD pattern of the ground sample, and the crystallinity of sample was decreased with increasing the grinding time. During the initial grinding, the dispersive component of surface free energy was decreased, whereas the polar part of surface free energy was increased. The surface polarity of the sample was increased in the same manner. Relationship between the solubility and the factors changing in the grinding process was evaluated. There was a significant correlation between the apparent solubility and the surface polarity and crystallinity of the sample. The NIR spectra confirmed the appearance of [bond]OH group on the sample surface. The apparent solubility increase of the ground sample was closely related to the improvement of the surface polarity and the destruction of crystalline structure.

Crystallization↗

PubMed2002

Prediction of passive intestinal absorption using bio-mimetic artificial membrane permeation assay and the paracellular pathway model.

The purpose of this study was to construct and examine the prediction model for total passive permeation through the intestinal membrane. The paracellular pathway prediction model based on Renkin function (PP-RF) was combined with a bio-mimetic artificial membrane permeation assay (BAMPA), which is an in vitro method to predict transcellular pathway permeation, to construct the prediction model (BAMPA-PP-RF model). The parameters of the BAMPA-PP-RF model, e.g. apparent pore radius and potential drop of the paracellular pathway, were calculated from BAMPA permeability, the dissociation constant, the molecular radius and the fraction of a dose absorbed in humans consisting of 80 structurally diverse compounds. The apparent pore radius and the apparent potential drop obtained in this study were 5.61-5.65 A and 75-86 mV, respectively, and these were in accordance with the previously reported values. The mean square root error of the BAMPA-PP-RF model was 13-14%. The BAMPA-PP-RF model was shown to be able to predict the total passive permeability more adequately than BAMPA alone.

Humans↗

PubMed2002

Estimation of initial dissolution rate of drug substance by thermal analysis: application for carbamazepine hydrate.

We have proposed a theory indicating the correlation between the dissolution rate and the heat of solution of drug substances. The initial dissolution rates of the drug substances containing amorphous were predicted accurately from their heats of solution. In this report, the possibility for the theory to estimate the dissolution rates of hydrate and polymorphs was examined using thermal analysis. The initial dissolution rates of carbamazepine dihydrate and polymorphs (forms I, II, and III) were measured by the rotating disk method. The heats of solution and the heats of fusion of samples were measured by microcalorimetry and Differential Scanning Calorimetry (DSC), respectively. The logarithm of the initial dissolution rate of the sample was correlated linearly with the heat of fusion as well as the heat of solution. The obtained correlation would be applicable for the quality control of the drug substances the contained hydrate and/or polymorphic forms.

Calorimetry, Differential Scanning↗