Biomedical subjects

H Sunada

Publications and source records attributed to H Sunada.

At least 19 recordsLinked to original sources

PubMed2001

A nifedipine coground mixture with sodium deoxycholate. I. Colloidal particle formation and solid-state analysis.

Sodium deoxycholate (DCNa) is a bile salt that forms multimolecular inclusion compounds with a variety of organic substances. In this study, complex formulation of DCNa with nifedipine, a poorly water soluble drug, by grinding was investigated. The coground mixture was prepared with a vibration rod mill, and its solid state was characterized using powder X-ray diffraction, differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) spectroscopy. A laser diffraction particle size analyzer was also used to determine the particle size distribution curve in solution. When a nifedipine-DCNa (1:2 w/w) mixture coground for 30 min was dispersed into water and a pH 6.8 buffer solution, a semitransparent colloidal solution occurred immediately; 90% of the total particles formed in solution had a diameter less than 600 nm. Both powder X-ray diffraction peaks and DSC endothermic peak of nifedipine crystals were not found for the coground mixture, whereas a new exothermic peak was observed on DSC thermograms. The magnitude of this exothermic peak depended on the weight fraction of DCNa and the grinding time, indicating that nifedipine crystals changed into an amorphous state by complex formation with DCNa during the grinding process. In the FTIR spectrum of the coground mixture, the peaks of aromatic CH out-of-plane bend and dihydropyridine NH stretch of nifedipine were considerably weakened, suggesting that van der Waals interaction may be present between the drug and DCNa molecules. From these results, it is clear that the cogrinding method with DCNa is very useful for the formation of amorphous nifedipine in the solid state and the production of colloidal particles of the drug in solution.

Buffers↗

PubMed2001

A nifedipine coground mixture with sodium deoxycholate. II. Dissolution characteristics and stability.

Nifedipine is a poorly water soluble drug that demonstrates low bioavailability. In a previous study, a coground mixture of nifedipine with sodium deoxycholate (DCNa), a bile salt, immediately produced colloidal particles when dispersed in water. In this study, the effect of the weight fraction of DCNa, grinding time, dissolution media, and storage conditions on colloidal particle formation in solution was investigated. The coground mixture was prepared with a vibration rod mill, and its solid state was characterized using powder X-ray diffraction. A laser diffraction particle size analyzer was used to determine the particle size distribution curve in water. The size of particles formed in solution decreased with an increase in the weight fraction of DCNa and grinding time. A nifedipine-DCNa (1:2 w/w) mixture coground for 30 min was used in the experiments. Colloidal particle formation from the coground mixture was also observed in dissolution media of water and a pH 6.8 buffer solution at 37 degrees C. Most precipitates passed through a filter with a pore size of 0.8 microm, but the particle size distribution in water was different from that in the pH 6.8 buffer solution. DCNa exhibited not only micellar solubilization for drug crystals, but also a retarding effect on drug crystal growth in a supersaturated solution. The latter effect could serve to form colloidal particles in solution. When stored under 75% relative humidity at 40 degrees C for 1 month, the amorphous coground mixture crystallized, and the particle size in water markedly increased. Therefore, the weight fraction of DCNa, grinding time, dissolution media, and humidity during storage influence the dissolution characteristics of nifedipine from a coground mixture.

Chromatography, High Pressure Liquid↗

PubMed2001

Release from or through a wax matrix system. I. Basic release properties of the wax matrix system.

Release properties from a wax matrix tablet was examined. To obtain basic release properties, the wax matrix tablet was prepared from a physical mixture of drug and wax powder (hydrogenated caster oil) at a fixed mixing ratio. Properties of release from the single flat-faced surface or curved side surface of the wax matrix tablet were examined. The applicability of the square-root time law and of Higuchi equations was confirmed. The release rate constant obtained as g/min(1/2) changed with the release direction. However, the release rate constant obtained as g/cm2 x min(1/2) was almost the same. Hence it was suggested that the release property was almost the same and the wax matrix structure was uniform independent of release surface or direction at a fixed mixing ratio. However, these equations could not explain the entire release process. The applicability of a semilogarithmic equation was not as good compared with the square-root time law or Higuchi equation. However, it was revealed that the semilogarithmic equation was available to simulate the entire release process, even though the fit was somewhat poor. Hence it was suggested that the semilogarithmic equation was sufficient to describe the release process. The release rate constant was varied with release direction. However, these release rate constants were expressed by a function of the effective surface area and initial amount, independent of the release direction.

Algorithms↗

PubMed2000

Measurement of the adhesive force of fine particles on tablet surfaces and method of their removal.

The adhesion force of fine particles on the surface of tablets was measured by a centrifugal force and impact separation method. A Finededuster (FDD) was employed to remove fine particles from the tablet surface. The centrifugal force and impact separation method was suggested to be effective for measuring the adhesive forces between particles and the tablet surface, and effective disjoining force in the FDD could be estimated by comparison of the results obtained using these two methods. The FDD showed high removal efficiency regardless of how many tablets were processed at the same time. In either of these methods, critical particle size was about 10-20 microns, and larger particles were removed more efficiently. This critical particle size was similar to that observed for other mechanical properties of powders, such as angle of repose and flowability. We simulated particle residual percentage under various operation conditions by ANN (artificial neural network) analysis and multiple regression analysis. This simulation enabled us to predict how the efficiency of particle removal is affected by the interaction of the experimental and material factors.

Administration, Oral↗

PubMed2000

Influence of granulating method on physical and mechanical properties, compression behavior, and compactibility of lactose and microcrystalline cellulose granules.

The physical and mechanical properties of lactose (LC) and microcrystalline cellulose (MCC) granules prepared by various granulating methods were determined, and their effects on the compression and strength of the tablets were examined. From the force-displacement curve obtained in a crushing test on a single granule, all LC granules appeared brittle, and MCC granules were somewhat plastically deformable. Inter-granular porosity epsilon inter clearly decreased with greater spherical granule shape for both materials. Decrease in intragranular porosity epsilon intra enhanced the crushing force of a single granule Fg. Agitating granulation brought about the most compactness and hardness of granules. In granule compression tests, the initial slope of Heckel plots K1 appeared closely related to ease of filling voids in a granule bed by the slippage or rolling of granules. The reciprocal of the slope in the succeeding step 1/K2 in compression of MCC granules indicated positive correlation to Fg, while in LC granules, no such obvious relation was evident. 1/K2 differed only slightly among granulating methods. Tensile strength of tablets Tt obtained by compression of various LC granules was low as a whole and was little influenced by granulating method. For MCC granules, which are plastically deformable, tablet strength greatly depended on granulation. Granules prepared by extruding or dry granulation gave strong tablets. Tablets prepared from granules made by the agitating method showed particularly low Tt. From stereomicroscopic observation, the contact area between granule particles in a tablet appeared smaller; this would explain the decrease in inter-granular bond formation.

Cellulose↗

PubMed2000

Granulation of acetaminophen by a rotating fluidized-bed granulator.

The purpose of this research was to evaluate the use of a rotating fluidized-bed granulator to produce acetaminophen granules with sufficient binding force between particles and good plasticity in tablets. Ethenzamide and ascorbic acid were used to compare the relationship between granulation and the sample wetness. It was revealed that a blade rotation rate of 300 rpm, inlet air flow rate of 42 m3/hr, and spraying pressure of 1.5 kg/cm3 produced tablets with the best properties. The granule and tablet properties of ethenzamide and ascorbic acid were compared to those of acetaminophen. These compounds showed different wetting behaviors with water and different compression behaviors. With an increase in medicament content, tablet hardness increased except for the ascorbic acid formulation. Capping and sticking were observed in acetaminophen and in ascorbic acid, respectively, and acetaminophen and ethenzamide showed prolonged disintegration time.

Acetaminophen↗

PubMed1999

Rapidly disintegrating tablets prepared by the wet compression method: mechanism and optimization.

To make rapidly disintegrating tablets with sufficient mechanical integrity, tablets were prepared by compressing wet granules under low compression force and then drying the resulting wet mass in a circulating-air oven (wet compression method). Lactose with various particle sizes was used as the excipient, and water was used as a wetting agent. The effect of drying time, compression force, size of lactose particles, and moisture content of wet granules on tablet properties indicated that the formation and disintegration time of tablets were related to the effect of the formation of solid bridges between lactose particles. By optimizing compression force, size of lactose particles, and moisture content of the granules, tablets meeting tensile strength greater than 0.5 MPa and disintegration time shorter than 15 s were obtained by the wet compression method.

Calorimetry, Differential Scanning↗

PubMed1999

In vivo performance of wax matrix granules prepared by a twin-screw compounding extruder.

The in vivo performance of wax matrix granules (WMGs) prepared by a twin-screw compounding extruder was evaluated in fasted beagle dogs. In vitro dissolution behavior of the model drug, diclofenac sodium (DS), from WMGs was strongly influenced by pH in a dissolution medium due to its solubility (DS is soluble in pH 6.8 and insoluble in pH 1.2 and 4.0) and was independent of paddle rotation rate (50, 100, and 200 rpm) of the dissolution apparatus. Pharmacokinetics parameters such as mean residence time (MRT) showed a sustained action of WMGs in beagle dogs; however, the transit time of WMGs in the small intestine is found to control total drug absorption. Furthermore, the values of the area under the curve (AUC) of the plasma concentration-time curve and the maximum concentration Cmax significantly decreased with decreases in hydroxypropylcellulose (HPC) content in WMGs. Good correlation between one in vitro dissolution parameter (mean dissolution time, MDT) and two in vivo parameters (AUC12 and MRT) suggested that it would be possible to design WMGs with a desired in vivo performance by controlling HPC content.

Animals↗

PubMed1999

Evaluation of rapidly disintegrating tablets prepared by a direct compression method.

To make rapidly disintegrating tablets with sufficient mechanical integrity as well as a pleasant taste, microcrystalline cellulose (MCC), Tablettose (TT), and crosslinked sodium carboxymethyl cellulose (Ac-di-sol) or erythritol (ET) were formulated. Tablets were made by a direct compression method (I). Tablet properties such as porosity, tensile strength, and disintegration time were determined. The tensile strength and disintegration time were selected as response variables, tablet porosity and parameters representing the characteristics of formulation were selected as controlling factors, and their relation was determined by the polynomial regression method. Response surface plots and contour plots of tablet tensile strength and disintegration time were also constructed. The optimum combination of tablet porosity and formulation was obtained by superimposing the contour diagrams of tablet tensile strength and disintegration time. Rapidly disintegrating tablets with durable structure and desirable taste could be prepared within the obtained optimum region.

Cellulose↗

PubMed1999

Pharmaceutical evaluation of multipurpose excipients for direct compressed tablet manufacture: comparisons of the capabilities of multipurpose excipients with those in general use.

Recently, a novel type of multipurpose excipient (MPE) with high binding characteristics and high fluidity has been developed. In this study, the capabilities of MPEs (Ludipress and Microcelac) were compared with those of excipients in general use. Also, the effects on powder and tableting characteristics of the physical properties and contents of active ingredients were examined in tablets prepared with these MPEs by the direct compression method. Multipurpose excipients mixed with adjuvants such as fillers, binders, lubricants, disintegrants, and the like show superior fluidity and compressibility. Tablets containing very small amounts of highly active ingredients with little dispersion were prepared. However, with increases in active ingredient content, each of the physical properties was affected strongly by the properties of the active ingredient. Tablets with appropriate hardness and disintegration characteristics could be prepared by mixing of different types of MPEs.

Chemistry, Pharmaceutical↗

PubMed1998

Mechanistic studies on hydrotropic solubilization of nifedipine in nicotinamide solution.

Nicotinamide is a hydrotropic agent that has been demonstrated to solubilize a wide variety of drugs through complexation. Past investigations on the potential interaction of nicotinamide with a solubilized drug have inadequately focused on aliphatic hydrotropes. This study examined the mechanism for the hydrotropic solubilization of nifedipine, a poorly water-soluble drug, in the aqueous solution of nicotinamide using not only nicotinamide analogues but also urea analogues as aliphatic hydrotropes. The values of stability constants, K1:2, at different temperatures in nicotinamide solution were determined by the phase solubility technique, and were utilized to estimate the thermodynamic parameters of complex formation between nifedipine and nicotinamide. The enthalpy change values suggested the participation of intermolecular forces other than hydrogen bonding in complexion. The aqueous solubility of nifedipine was measured in the presence of nicotinamide, urea and their analogues: N-methylnicotinamide, N,N-diethylnicotinamide, nipecotamide, methylurea, ethylurea and butylurea. The drug solubility increased in proportion to the amount of alkyl substituent on the amide nitrogen, and the solubilizing effect of butylurea was as high as that of nicotinamide. Furthermore, the relationship between the logarithmic drug solubilities in 1.0 M aqueous solutions of nicotinamide or urea analogues versus the logarithmic octanol-water partition coefficient values of ligands as an indication of hydrophobicity was found to be linear. The significant contributor to the hydrotropic solubilization of nifedipine with nicotinamide was therefore the ligand hydrophobicity rather than the aromaticity of the pyridine ring.

Drug Stability↗

PubMed1998

Influence of water-soluble polymers on the dissolution of nifedipine solid dispersions with combined carriers.

The objective of this investigation was to clarify the influence of water-soluble polymers on the dissolution behavior of nifedipine from solid dispersions with combined carriers. All the solid dispersions of nifedipine were prepared by the fusion method using nicotinamide and 4 different water-soluble polymers, hydroxypropylmethyl-cellulose (HPMC), polyvinylpyrrolidone (PVP), partially hydrolyzed polyvinyl alcohol (PVA) and pullulan. HPMC, PVP or PVA dissolved in the fused liquid of nicotinamide and operated efficiently on the amorphous formation of nifedipine in solid dispersions. In dissolution studies, the drug concentration for these dispersions increased to more than twice intrinsic drug solubility. The rank order of the drug concentration was HPMC > PVP > PVA. However, since pullulan did not dissolve in the fused nicotinamide, nifedipine was present as a crystalline state in the solid dispersion; the supersaturation behavior of the drug was scarcely observed. The compatibility, namely, the solubility and miscibility, between nicotinamide or nifedipine and the polymers, was determined by differential scanning calorimetry using the mixtures treated with fusing and subsequent rapid cooling. Both HPMC and PVP exhibited high compatibility not only with nicotinamide but also with nifedipine. The crystallization behavior of nifedipine from a supersaturated solution containing nicotinamide or the polymers was studied. The inhibitory effect of HPMC or PVP for drug crystallization was evident, which would be related not to the solubilizing effect but to the adhesive force of the polymer for the drug. Therefore, it was understood that the use of a polymer with high compatibility and adhesion with nifedipine provides a high supersaturation level of the drug in dissolution. Further, the solubility parameter was found to be useful for selecting a suitable polymer as a component of combined carriers.

Calcium Channel Blockers↗

PubMed1998

Study of standard tablet formulation based on fluidized-bed granulation.

In this study, acetaminophen, ascorbic acid, and ethenzamide were selected as model drugs for tableting granules. Agitation and fluidized-bed granulation were carried out at three drug contents of 30, 50, and 70%. Compared with agitation granulation, granules made by fluidized-bed granulation showed superior compressibility with wide formulation allowance for drug type and amount. Fluidized-bed granulation resulted in less granule hardness and greater plastic deformability. The granules had considerable compactness and for tablets containing 70% ethenzamide, prolonged disintegration and dissolution times were noted. These are typical features of granules produced by fluidized-bed granulation.

Acetaminophen↗

PubMed1997

Dissolution mechanism of diclofenac sodium from wax matrix granules.

Dissolution behavior of diclofenac sodium (DS) from wax matrix granules (WMGs) prepared using a twin-screw compounding extruder is closely related to swelling ability and solubility of the rate-controlling agent employed. A swellable and soluble (hydroxypropyl)-cellulose (HPC-SL) generates both an expansion of pores inside WMGs and a structural change observed as cracking on the surface of WMGs. These changes are confirmed by mercury porosimetry. Release of DS was increased with an increase in the amount of HPC-SL in WMGs, but only 35% of DS was released from WMGs containing 73% (w/w) NaCl at the 24 h point of the dissolution. Further, no cracking was observed on the surface of NaCl-containing WMGs. A linear relationship between mean dissolution time (MDT) of DS for WMGs containing different types of HPC (HPC-SL, -M, and -H) and swelling abilities suggests that release of DS could be directly controlled by swelling of HPCs. In addition to this result, an application of the exponential model (Mt/M infinity = kt(n)) introduced by Ritger and Peppas (J. Controlled Release 1987, 5, 23-36) to DS release indicates that case II release plays a critical role in HPC-SL-containing WMGs and Fickian release is predominant in NaCl-containing WMGs since the values of n of WMGs containing 73% (w/w) NaCl and 40% (w/w) HPC-SL are 0.41 and 0.71, respectively. These results suggest that proper selection of rate-controlling agents based on their physicochemical properties (such as swelling ability and solubility) is important in designing WMGs with desired dissolution profiles.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1997

Comparison of nicotinamide, ethylurea and polyethylene glycol as carriers for nifedipine solid dispersion systems.

The most prevalent means for producing solid dispersions of nifedipine, a poorly water-soluble drug, are the solvent based processes that bring problems of environmental and health. We have investigated the preparation of solid dispersions of nifedipine (mp 173 degrees C) by the fusion method, using nicotinamide, ethylurea, polyethylene glycol (PEG) 6000 and hydroxypropylmethylcellulose (HPMC) as carriers. All these solid dispersions were obtained by cooling at room temperature after heating at 140 degrees C for 15 min. As a single carrier, nicotinamide, ethylurea and PEG were used because nifedipine dissolved in their fused liquids. Compared with the physical mixtures, the solid dispersions with ethylurea or PEG led to a higher dissolution rate of the drug, whereas the difference in drug release between the physical mixtures and the solid dispersions with nicotinamide was not clear. This peculiarity might be due to the high solubilizing effect of nicotinamide for the drug. The fused mixtures of nicotinamide-, ethylurea- or PEG-HPMC were utilized as combined carriers. HPMC dissolved in the fused liquids of nicotinamide or ethylurea, which was effective in forming the amorphous nifedipine in solid dispersions. This resulted in not only the enhanced dissolution rate but also the supersaturation behavior of nifedipine. Further, for the nicotinamide-HPMC system, the supersaturation level of nifedipine increased with an increase in the HPMC content of solid dispersions. Nicotinamide was more applicable than ethylurea and PEG for preparation of the fused dispersions of nifedipine.

Calcium Channel Blockers↗

PubMed1996

Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity.

In order to make a compressed tablet which can rapidly disintegrate in the oral cavity, microcrystalline cellulose and low-substituted hydroxypropylcellulose were used as disintegrants, and ethenzamide and ascorbic acid were chosen as poorly and easily water soluble model drugs, respectively. The mixture of microcrystalline cellulose and low-substituted hydroxypropylcellulose was compressed at 100--500 kgf in the absence of an active ingredient. The properties of these tablets, such as hardness, porosity, the time required for complete wetting of a tested tablet (wetting time), water uptake and disintegration time determined by a new disintegration apparatus, were investigated to elucidate the wetting and disintegration characteristics of these tablets, When the MCC/L-HPC ratio was in the range of 8:2 to 9:1, the shortest disintegration time was observed. The disintegration of tablets containing ethenzamide or ascorbic acid was examined next. Tablet disintegration time in the oral cavity was also tested, and good correlation between the disintegration behaviors in vitro and in the oral cavity was recognized.

Ascorbic Acid↗

PubMed1995

Influence of formulation change on drug release kinetics from hydroxypropylmethylcellulose matrix tablets.

Examination was made of the release of indomethacin from hydroxypropylmethylcellulose (HPMC) matrices and the results were found to usually follow first order release kinetics. The release mechanism changed with formulation. HPMC content was the predominant controlling factor. As the HPMC content increased, drug release rate decreased, and the release mechanism gradually changed from Higuchi diffusion release to case II transport. Additives increased the release rate and enhanced Fickian diffusion. As drug content increased, release rate calculated from percent release data decreased while that calculated from mg release data increased. When indomethacin content was lower, drug release was diffusion controlled and when higher, non-Fickian transport or case II transport was apparent. Additive effects were also examined. Starch was found to most effectively maintain case II release. Complex additives containing starch were superior to any additive by itself. A multiple regression model was used to determine the relationship between response (release rate) and factors (content of HPMC and diluents), and on the basis of this model a formulation was established and found valid by agreement with data from the regression model.

Chemical Phenomena↗

PubMed1993

Preservation of differentiated phenotypes in cultured aortic endothelial cells by malotilate and phosphoascorbic acid.

Confluent bovine aortic endothelial cells (BAECs) formed a cobblestone-shaped cell monolayer when cultured on a collagen gel in a 1:1 mixture of Dulbecco's modified Eagle's medium and Ham's-F12 supplemented with 5% newborn calf serum. Within a few days, however, they lost cell-cell attachment and became fibroblastic. When BAECs were cultured in the same culture medium but further supplemented with either 10 micrograms/ml malotilate or 1 mM phosphoascorbic acid, the monolayer organization and the cobblestone-like cell morphology were maintained for more than 2 weeks although many sprout cells were observed underneath the monolayer. In contrast, if both malotilate and phosphoascorbic acid were present in the culture medium, a tight monolayer without underlying sprout cells was maintained for at least 4 months and the cells expressed factor VIII-related antigens and massively internalized acetylated low density lipoprotein. By electron microscopy, we observed well-developed gap and adherence junctions, Golgi apparatuses and vesicles many of which were open to the outside by fusing with either the apical or the basal surface, indicating high metabolic activity of the cells cultured for weeks in the same dish. Although malotilate-treated BAEC monolayers secreted increased levels of prostacyclin (PGI2), the drug did not appear to directly affect the PGI2 production pathway since the similarly increased PGI2 production was noted in tight monolayers formed without the use of malotilate. Our results indicate that malotilate and phosphoascorbic acid together preserve differentiated phenotypes in cultured endothelial cells.

Animals↗