Biomedical subjects

Shigeo Kojima

Publications and source records attributed to Shigeo Kojima.

15 recordsLinked to original sources

PubMed2005

Effect of polymer size and cosolutes on phase separation of poly(vinylpyrrolidone) (PVP) and dextran in frozen solutions.

The aim of this study was to elucidate the effect of the molecular weight of polymers on their miscibility in frozen solutions to model the physical properties of freeze-dried pharmaceutical formulations. Thermal analysis of frozen solutions containing poly(vinylpyrrolidone) (PVP) and dextran of various molecular weights was performed at polymer concentrations below the binodal curve at room temperature. Frozen solutions containing PVP 29,000 and dextran 10,200 showed two thermal transitions (glass transition temperature of maximally freeze-concentrated solution: Tg') representing two freeze-concentrated amorphous phases, each containing predominantly one of the polymers. A combination of smaller polymers (PVP 10,000 and dextran 1,060) was freeze-concentrated into an amorphous mixture phase across a wide range of concentration ratios. Combinations of intermediate size polymers separated into two freeze-concentrated phases only at certain concentration ratios. Addition of NaCl prevented the phase separation of PVP and dextran in the aqueous and frozen solutions. Higher concentrations of NaCl were required to retain the miscibility of larger polymer combinations in the freeze-concentrate. The molecular weights of the component polymers, polymer concentration ratio, and cosolute composition are the important factors that determine component miscibility in frozen solutions.

Calorimetry, Differential Scanning↗

PubMed2004

Effects of sodium tetraborate and boric acid on nonisothermal mannitol crystallization in frozen solutions and freeze-dried solids.

The purpose of the present study was to elucidate the effects of sodium tetraborate (borax) and boric acid on the crystallization of mannitol in frozen aqueous solutions and freeze-dried solids. Thermal analysis of frozen solutions showed that sodium tetraborate inhibits mannitol crystallization at sodium tetraborate/mannitol molar concentration ratios of approximately 0.05, which is much lower than the other co-solutes studied (boric acid, sucrose, sodium phosphate buffer). Inhibition of the mannitol crystallization in frozen solutions resulted in highly amorphous mannitol in the freeze-dried solids. Mannitol remained in an amorphous state in some of the combination freeze-dried solids, even at elevated temperatures. Changes in the thermal transition temperatures (glass transition temperature of maximally freeze-concentrated solute ( T'g) and glass transition temperature of freeze-dried solid (Tg)) suggested reduced mannitol molecular mobility with increases in the sodium tetraborate ratio. Fourier-transform infrared spectroscopy (FT-IR) analysis of the bovine serum albumin secondary structure showed apparent protein structure-stabilizing effects of the amorphous mannitol and sodium tetraborate combination during the freeze-drying process. The mannitol and sodium tetraborate combination also protected lactate dehydrogenase (LDH) from inactivation during freeze-drying. We conclude that the complex formation and the accompanying reduction in molecular mobility make sodium tetraborate an effective mannitol crystallization inhibitor in frozen solutions and freeze-dried solids.

Animals↗

PubMed2004

Molecular mobility-based estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly(vinylpyrrolidone) solid dispersions.

The overall crystallization rates and mean relaxation times of amorphous nifedipine and phenobarbital in the presence of poly(vinylpyrrolidone) (PVP) were determined at various temperatures to gain further insight into the effect of molecular mobility on the crystallization rates of amorphous drugs and the possibility of predicting stability from their molecular mobility. Nifedipine-PVP (9:1 w/w) and phenobarbital-PVP (95:5 w/w) solid dispersions were prepared by melting and rapidly cooling mixtures of each drug and PVP. The amount of amorphous nifedipine remaining in the solid dispersion was calculated from the heat of crystallization,which was obtained by differential scanning calorimetry. The amount of amorphous phenobarbital remaining in the solid dispersion was estimated from the change in the heat capacity at its glass transition temperature (T(g)). The time required for the amount of amorphous drug remaining to fall to 90% (t(90)) was calculated from the profile of time versus the amount of amorphous drug remaining. The t(90) values for the solid dispersions studied were 100-1000 times longer than those of pure amorphous drugs when compared at the same temperature. Enthalpy relaxation of the amorphous drugs in the solid dispersions was reduced compared with that in the pure amorphous drugs, indicating that the molecular mobility of the amorphous drugs is reduced in the presence of PVP. The temperature dependence of mean relaxation time (tau) for the nifedipine-PVP solid dispersion was calculated using the Adam-Gibbs-Vogel equation. Parameters D and T(0) in this equation were estimated from the heating rate dependence of T(g). Similar temperature dependence was observed for t(90) and tau values of the solid dispersion, indicating that the information on the temperature dependence of the molecular mobility, along with the crystallization data obtained at around the T(g), are useful for estimating the t(90) of overall crystallization at temperatures below T(g) in the presence of excipients.

Algorithms↗

PubMed2004

Temperature- and glass transition temperature-dependence of bimolecular reaction rates in lyophilized formulations described by the Adam-Gibbs-Vogel equation.

Bimolecular reaction rates in lyophilized aspirin-sulfadiazine formulations containing poly(vinylpyrrolidone), dextran, and isomalto-oligomers of different molecular weights were determined in the presence of various water contents, and their temperature- and glass transition temperature (Tg)-dependence was compared with that of structural relaxation time (tau calculated according to the Adam-Gibbs-Vogel equation, in order to understand how chemical degradation rates of drugs in lyophilized formulations are affected by molecular mobility. The rate of acetyl transfer in poly(vinylpyrrolidone) K30 and dextran 40k formulations with a constant Tg, observed at various temperatures, exhibited a temperature dependence similar to that of tau at temperatures below Tg. Furthermore, the rates of acetyl transfer and the Maillard reaction in formulations containing alpha-glucose polymers and oligomers increased, as the Tg of formulations decreased, either associated with decreases in molecular weight of excipient or with increases in water content. The observed Tg dependence was similar to that of tau in the range of Tg higher than the experimental temperature. The results suggest a possibility that bimolecular reaction rate at temperatures below Tg can be predicted from that observed at the Tg on the basis of temperature dependence of structural relaxation time in amorphous systems, if the degradation rate is proportional to the diffusion rate of reacting compounds.

Algorithms↗

PubMed2004

Ability of polyvinylpyrrolidone and polyacrylic acid to inhibit the crystallization of amorphous acetaminophen.

The inhibition of crystallization of amorphous acetaminophen (ACTA) by polyvinylpyrrolidone (PVP) and polyacrylic acid (PAA) was studied using amorphous solid dispersions prepared by melt quenching. Co-melting with PVP and PAA decreased the average molecular mobility, as indicated by increases in glass transition temperature and enthalpy relaxation time. The ACTA/PAA dispersion exhibited much slower crystallization than the ACTA/PVP dispersion with a similar glass transition temperature value, indicating that interaction between ACTA and polymers also contributed to the stabilizing effect of these polymers. The carboxyl group of PAA may interact with the hydroxyl group of ACTA more intensely than the carbonyl group of PVP does, resulting in the stronger stabilizing effect of PAA. Dielectric relaxation spectroscopy showed that the number of water molecules tightly binding to PVP per monomer unit was larger than that to PAA. Furthermore, a small amount of absorbed water decreased the stabilizing effect of PVP, but not that of PAA. These findings suggest that the stronger stabilizing effect of PAA is due to the stronger interaction with ACTA. The ability of PAA to decrease the molecular mobility of solid dispersion was also larger than that of PVP, as indicated by the longer enthalpy relaxation time.

Acetaminophen↗

PubMed2004

Protection of protein secondary structure by saccharides of different molecular weights during freeze-drying.

The protective effects of saccharides with various molecular weights (glucose, maltose, maltotriose, maltotetraose, maltopentaose, maltoheptaose, dextran 1060, dextran 4900, and dextran 10200) against lyophilization-induced structural perturbation of model proteins (BSA, ovalbumin) were studied. Fourier transform infrared (FT-IR) analysis of the proteins in initial solutions and freeze-dried solids indicated that maltose conferred the greatest protection against secondary structure change. The structure-stabilizing effect of maltooligosaccharides decreased in increasing the number of saccharide units. Larger molecules of dextran also showed a smaller structure-stabilizing effect. Increasing the effective saccharide molecular size by a borate-saccharide complexation reduced the protein structure-stabilizing effect of all of the saccharides except glucose. The results indicate that the larger saccharide molecules, and/or the complex formation with borate ion, reduce the free and accessible hydroxyl groups to interact with and stabilize the protein structure by a water-substitution mechanism.

Calorimetry, Differential Scanning↗

PubMed2003

Prediction of glass transition temperature of freeze-dried formulations by molecular dynamics simulation.

PURPOSE: To examine whether the glass transition temperature (Tg) of freeze-dried formulations containing polymer excipients can be accurately predicted by molecular dynamics simulation using software currently available on the market. Molecular dynamics simulations were carried out for isomaltodecaose, a fragment of dextran, and alpha-glucose, the repeated unit of dextran. in the presence or absence of water molecules. Estimated values of Tg were compared with experimental values obtained by differential scanning calorimetry (DSC). METHODS: Isothermal-isobaric molecular dynamics simulations (NPTMD) and isothermal molecular dynamics simulations at a constant volume (NVTMD) were carried out using the software package DISCOVER (Material Studio) with the Polymer Consortium Force Field. Mean-squared displacement and radial distribution function were calculated. RESULTS: NVTMD using the values of density obtained by NPTMD provided the diffusivity of glucose-ring oxygen and water oxygen in amorphous alpha-glucose and isomaltodecaose, which exhibited a discontinuity in temperature dependence due to glass transition. Tg was estimated to be approximately 400K and 500K for pure amorphous a-glucose and isomaltodecaose, respectively, and in the presence of one water molecule per glucose unit, Tg was 340K and 360K, respectively. Estimated Tg values were higher than experimentally determined values because of the very fast cooling rates in the simulations. However, decreases in Tg on hydration and increases in Tg associated with larger fragment size could be demonstrated. CONCLUSION: The results indicate that molecular dynamics simulation is a useful method for investigating the effects of hydration and molecular weight on the Tg of lyophilized formulations containing polymer excipients. although the relationship between cooling rates and Tg must first be elucidated to predict Tg vales observed by DSC measurement. January 16.

Calorimetry, Differential Scanning↗

PubMed2003

Inactivation and aggregation of beta-galactosidase in lyophilized formulation described by Kohlrausch-Williams-Watts stretched exponential function.

PURPOSE: To examine whether the empirical Kohlrausch-Williams-Watts (KWW) equation is applicable not only to protein aggregation but also to protein denaturation in lyophilized formulations. Lyophilized beta-galactosidase (beta-GA) formulations containing polyvinylalcohol and methylcellulose were used as model formulations. The possibility of predicting storage stability based on the temperature dependence of the estimated parameters of inactivation/aggregation--time constant (tau) and its distribution (beta) is discussed. METHODS: Protein aggregation in lyophilized beta-GA formulations at 10-70 degrees C and 6-43% relative humidity was determined as a function of time by size exclusion chromatography. Enzyme activity was also determined using 2-nitrophenyl-beta-D-galactopyranoside as a substrate. RESULTS: Inactivation and aggregation of beta-GA were describable with the empirical KWW equation, regardless of whether the temperature was above or below the NMR relaxation-based critical mobility temperature (Tmc) or whether protein molecules with different degrees of deformation resulting from stresses during lyophilization exist in formulation. The estimated beta parameter for protein aggregation creased rapidly as temperature increased beyond Tmc becausethe mobility of polymer molecules increased in the initial stages of glass transition. The time required for 10% enzyme to aggregate (t90) calculated from the tau and beta parameters exhibited a change in temperature dependence gradient near Tmc. In contrast, t90 for protein inactivation exhibited temperature dependence patterns varying withthe excipients. CONCLUSIONS: The t90 calculated from the estimated tau and beta parameters was found to be a useful parameter for evaluating the stability of lyophilized beta-GA formulations. The prediction of t90 by extrapolation was possible in the temperature range in which beta did not rapidly vary with temperature.

Chemistry, Pharmaceutical↗

PubMed2003

Abnormal dissolutions of chlorpromazine hydrochloride tablets in water by paddle method under a high agitation condition.

All sugar-coated tablets of chlorpromazine hydrochloride except for those produced by one manufacture showed concave dissolution profiles in water by paddle method at 100 rpm but not at 50 rpm. The study was undertaken to clarify the agitation-dependent abnormal dissolutions. The strange dissolutions were also observed in water at different ionic strengths but not in buffer solutions of pH 1.2, 4.0 and 6.8. When monitored, the pH's of water in dissolution vessels for the abnormal tablets increased with time at 100 rpm and some of them exceeded pH 8 but did not at 50 rpm. The solubility of chlorpromazine hydrochloride decreased with the increase of pH which was too low to dissolve the whole amount of drug contained in a tablet at pH 8. The elevation of pH seemed to be mainly brought about by dissolution of calcium carbonate popularly used for sugar-coated tablets, because larger amount of calcium ion was dissolved out from the abnormal tablets at 100 rpm than from a normal tablet and from them at 50 rpm. These findings indicate that the concave dissolution profiles should be caused by the decrease of drug solubility with increase in pH of water, probably because of dissolution of calcium carbonate. We should pay attention to the change in pH of water which may differ depending on the agitation speed of dissolution tests.

Antipsychotic Agents↗

PubMed2003

Molecular mobility of lyophilized poly(vinylpyrrolidone) and methylcellulose as determined by the laboratory and rotating frame spin-lattice relaxation times of 1H and 13C.

Laboratory- and rotating- frame spin-lattice relaxation times (T(1) and T(1rho)) of (1)H and (13)C in lyophilized poly(vinylpyrrolidone) (PVP) and methylcellulose (MC) are determined to examine feasibility of using T(1) and T(1rho) as a measure of molecular motions on large time scales related to the storage stability of lyophilized formulations. The T(1rho) of proton and carbon was found to reflect the mobility of PVP and MC backbones, indicating that it is useful as a measure of large-time-scale molecular motions. In contrast to the T(1rho), the T(1) of proton measured in the same temperature range reflected the mobility of PVP and MC side chains. The T(1) of proton may be useful as a measure of local molecular motions on a smaller-time-scale, although the measurement is interfered by moisture under some conditions. The temperature dependence of T(1) and T(1rho) indicated that methylene in the MC molecule had much higher mobility than that in the dextran molecule, also indicated that methylene in the PVP side chain had a higher mobility than that in the MC side chain.

Calorimetry, Differential Scanning↗

PubMed2003

Effect of sodium tetraborate (borax) on the thermal properties of frozen aqueous sugar and polyol solutions.

The effect of sodium tetraborate (Na(2)B(4)O(7), borax) on the thermal property of frozen aqueous sugar and polyol solutions was studied through thermal analysis. Addition of borax raised the thermal transition temperature (glass transition temperature of maximally freeze-concentrated solutes; T(g)') of frozen sucrose solutions depending on the borax/sucrose concentration ratios. Changes in the T(g)' of frozen mono- and disaccharide solutions suggested various forms of complexes, including those of a borate ion and two saccharide molecules. Borax exerted the maximum effect to raise the oligosaccharide and dextran T(g)'s at borax/saccharide molar ratios of approximately 1-2 (maltose and maltooligosaccharides), 2 (dextran 1060), 5 (dextran 4900), and 10 (dextran 10200). Further addition of borax lowered T(g)'s of the saccharide solutions. Borax also raised T(g) and T(g)' temperatures of frozen aqueous glycerol solutions. The decreased solute mobility in frozen solutions by the borate-polyol complexes suggested higher collapse temperature in the freeze-drying process and improved stability of biological systems in frozen solutions.

Borates↗

PubMed2002

Different molecular motions in lyophilized protein formulations as determined by laboratory and rotating frame spin-lattice relaxation times.

The spin-lattice relaxation times in the laboratory and rotating frame (T(1) and T(1rho)) of protons and carbons in lyophilized bovine serum gamma-globulin formulation containing dextran were determined by (1)H solid-state pulsed nuclear magnetic resonance (NMR) and high-resolution (13)C solid-state NMR. The temperature dependence of T(1) and T(1rho) of dextran protons in the lyophilized formulation suggests that the correlation time, tau(c), of the methylene protons in dextran is approximately 10(-6) s at -100 degrees C and 60% relative humidity, and decreases to 10(-7) s at 0 degrees C. When temperature is increased from 0 degrees C, the increased motion of the methylene groups is reflected in T(1), but is too fast to be observed by changes in T(1rho). Thus, the motion of the methine groups rather than the methylene groups begins to be reflected in T(1rho). The correlation time of the methine protons as determined by T(1rho) was of the same order as that of the methine carbons as determined by T(1rho). As the temperature is increased past the glass/rubber transition temperature, both the methylene and methine motions are greatly enhanced, resulting in much shorter T(1) and T(1rho) relaxation times.

Animals↗

PubMed2002

Excipient crystallinity and its protein-structure-stabilizing effect during freeze-drying.

The relationship between mannitol crystallization during freeze-drying and its effects on stabilizing protein structures was studied using lysozyme, bovine serum albumin, ovalbumin, beta-lactoglobulin and lactate dehydrogenase as model proteins. FT-IR analysis of the protein secondary structure indicated perturbation of both alpha-helix and beta-sheet regions in freeze-drying without cosolutes, whereas the proteins retained most of their native structure in co-lyophilization with sucrose. Mannitol protected the protein structure to different degrees depending on the crystallinity. The combination of mannitol with potassium phosphate buffer reduced the mannitol crystallinity and the structural changes occurring during freeze-drying, whereas mannitol by itself showed little stabilizing effect. Heat-treatment of the frozen solutions at -10 degrees C resulted in a higher mannitol crystallinity and a smaller stabilizing effect in freeze-drying. The secondary structure perturbation was mostly reversible in rehydrated solutions. The varied structure-stabilizing effects of mannitol paralleled its effects on maintaining lower concentrations of enzyme activity during freeze-drying. These results confirm the contribution of molecular interactions between amorphous excipients and proteins (e.g. hydrogen bonding) to structure stabilization during freeze-drying.

Crystallization↗

PubMed2002

Mass variation tests for coating tablets and hard capsules: rational application of mass variation tests.

The mass variation test is a simplified alternative test version of the content uniformity test. In the case of coating tablets and capsules, the mass variation test is principally applied to test the inner cores or fillings containing the active ingredient. However, some exceptions exist in pharmacopoeias. The effects of tablet coating and capsule shell on the results of the mass variation test were studied. The mass variation of outer crusts (coatings, capsule shells) and inner cores (core tablets, fillings) was measured separately in several products. The effects of coating on weight variability were very large for sugar-coated tablets. Relative standard deviation (RSD) of the formulation weight (RSD(W)) of sugar-coated tablets (2.73%) was larger than that of plain tablets (0.77%). The cause of the large RSD(W) is the large variation the weight of sugar-coating accounting for 44% of formulation weight. In the case of film-coated tablets, the effect of coating weight on the mass variation test was very small because the rate of coating in comparison to the whole weight was small. In the case of hard capsules, the usage of whole formulation weight resulted in underestimation of variations of filling weight. The differences between dosage forms in the applicability of the mass variation test are caused by differing weight proportions and variability of the outer coatings or shells. To avoid the underestimation of mass variation for hard capsules, a corrected acceptance value is useful. For all the dosage units, the mass variation test can principally be applied to determine which mass is expected to be proportional to the content of the active ingredient. However, some modification of acceptance values enables application of the mass variation tests to inapplicable cases, such as when the RSD of drug concentration (RSD(C)) is larger than 2%.

Algorithms↗

PubMed2002

A comparison of the analysis of covariance (ANCOVA) and range-based approaches for assessing batch-to-batch variability of the stability of pharmaceutical products.

Stability data were generated by the Monte Carlo method, and batch-to-batch variability was evaluated by analysis of differences in slope and intercept according to the analysis of covariance (ANCOVA) approach recommended in the FDA Guidance. Using the same generated data, batch-to-batch variability was also evaluated by assessing the equivalence of shelf lives estimated for individual batches based on the range (Range-based approach) in order to compare the ability of the two approaches to detect stability differences among batches. The results of the study indicated that the Range-based approach can detect a 30% difference in the slope of degradation curves among batches with a similar beta error as the ANCOVA approach, provided that degradation data are obtained with assay errors below 0.5. The range-based approach appears to be useful as an alternative method to ANCOVA, if it is modified such that the variance of estimates is taken into account.

Analysis of Variance↗