Kazunori KATAYAMA

Toyama Medical and Pharmaceutical University, Тояма, Toyama, Japan

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Publications (71)87.3 Total impact

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    ABSTRACT: The age-related changes in the electrical and physiological properties of the skin were examined in rats at the ages of 5, 10, 21, 90, and 180 d. The resistance of the stratum corneum, the resistance of the viable skin (epidermis and dermis), and the capacitance of the stratum corneum were analyzed from skin impedance data using an equivalent circuit. With development and aging, the resistance of the stratum corneum and the viable skin increased, whereas the capacitance of the stratum corneum decreased. Physiological characteristics such as the thickness of skin strata and the content of lipid and water in the stratum corneum were also measured. The lipid content in the stratum corneum was constant at all ages. The water content in the stratum corneum decreased, and the thickness of skin strata increased with age. Comparison between electrical data and physiological properties suggested that the increase in the resistance of the stratum corneum with aging is primarily caused by the decrease in the water content and that the capacitance of the stratum corneum and the resistance of the viable skin depend on age-related increases in the thickness of skin strata. In conclusion, the age dependency of cutaneous electrical properties may affect the permeation profile of drugs through the skin, and impedance analysis can be used to estimate age-related changes in transdermal drug delivery.
    Full-text · Article · Oct 2002 · Biological & Pharmaceutical Bulletin
  • Kazunori Katayama · Rakan Matsui · Tomomi Hatanaka · Tamotsu Koizumi
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    ABSTRACT: The effect of pH on the skin permeation enhancement of three acidic drugs by the l-menthol-ethanol system was investigated. The total flux of acidic drugs from the system remarkably varied over the pH range 3.0-8.0, and the permeation enhancement factor depended on the system pH and drug. A skin permeation model, which consists of two permeant (unionized and ionized) species, two system (oily and aqueous) phases, and two permeation (lipid and pore) pathways, was developed. The assumptions were made that only the unionized species can distribute to the oily phase and transport via the lipid pathway. The model explained the relationship between the concentration of drug in the aqueous phase and system pH. The skin permeability data were also described by the model and permeability coefficients corresponding to the physicochemical properties of permeant were calculated for the lipid and pore pathways. The model simulation showed that the permeation of acidic drugs occurred from the aqueous phase and the oily phase acted as a reservoir. Whether the total flux increased with increase of pH was dependent on the lipophilicity of drug. These results suggest that the pH of l-menthol-ethanol system should be given attention to elicit the maximum permeation enhancement.
    No preview · Article · Oct 2001 · International Journal of Pharmaceutics
  • T Hatanaka · K Ihara · M Kodera · K Katayama · T Koizumi
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    ABSTRACT: Plasma concentration and vasodilating effect after i.v. bolus injection of stereoisomeric organic nitrates were evaluated. Pharmacokinetics of mononitrates was analyzed with a linear one-compartment model. The apparent volumes of distribution were almost identical, but systemic clearances were different among stereoisomers. The concentration data after dinitrate administration could be described based on a two-compartment model with elimination only from the central compartment via metabolism to mononitrate, and then mononitrate-dependent metabolic clearance was estimated. In the vasodilation by mononitrate administered intravenously, the maximum effect was not observed. The reduction of mean arterial pressure from baseline level was related to plasma concentration with a log-linear model. The pharmacological effect following dinitrate dosing was analyzed by a sigmoidal Emax model assuming a simple additive effect of dinitrate and mononitrate. Although almost the same Hill's constant and maximum effect (Emax) values were estimated, the concentrations required to produce 50% of Emax (EC50) differed among stereoisomers. The clearance and EC50 values of stereoisomers with nitrate group at the exo position were generally higher than those with the same group at the endo position. This suggests that the stereostructure of organic nitrates controls the vasodilator potency and duration of action.
    No preview · Article · Aug 2001 · Journal of Pharmacology and Experimental Therapeutics
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    ABSTRACT: The absorption, distribution and excretion of butylidenephthalide after dermal application to hairless mouse have been examined with [8-14C]butylidenephthalide. By the investigation of the whole body autoradiogram and liquid scintillation analysis, it was indicated that the transdermally applied butylidenephthalide quickly permeate into peripheral circulation system without accumulation in the skin and then distribute into lung, liver, bile and kidney. The total radioactivity, however, was decreased due to excretion into urine, and in the case of i.v.-administration, 80% of the administered butylidenephthalide was excreted into urine within 24 h, while only 5% was excreted into feces within 24 h. Then, the metabolite in urine was determined to be a cysteine conjugate by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method. Thus, it has been concluded that after dermal application butylidenephthalide quickly permeates through skin into peripheral circulation system; distributes to lung, liver, bile and kidney; and then excreted into urine as a cysteine adduct.
    No preview · Article · Sep 2000 · Journal of Ethnopharmacology
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    ABSTRACT: A physiological pharmacokinetic model describing the absorption and disposition of topically applied drugs was proposed, and the effect of various pharmacokinetic and physiological parameters on the drug delivery into the targeted muscle was simulated. The proposed model consists of vehicle, and stratum corneum, viable epidermis and muscle below the application and reference sites, and plasma, each joined with transfer clearance and plasma flow. Indomethacin concentrations in tissues and plasma after topical application to rats could be explained by the model. Most indomethacin delivered into the underlying muscle was via direct penetration. The model simulation showed that the increase in plasma clearance and clearance between viable skin and muscle, and the decrease in application area and plasma flow rate into viable skin and muscle would promote the targeting efficacy of topically applied drugs to the underlying muscle.
    No preview · Article · Aug 2000 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: The ion pair skin transport of cephalexin was investigated using various counter ions and solvents. The permeability of cephalexin was enhanced by 1-alkylsulfonates (ASs) at pH 3.0 and by tetraalkylammoniums (AAs) at pH 7.0; the enhancing ratio increased with the number of carbon atoms in their alkyl chains. The corresponding effects of these additives were observed on the partitioning of cephalexin. Most of the additives did not affect the skin transport of D-mannitol and cortisone. These results suggest that the enhanced transport of cephalexin results from the ion pair formation with additives. Although ASs increased the partitioning of cephalexin above that of AAs, the transport enhancement effect of ASs was lower than AAs having the same number of carbon atoms in their alkyl chains, indicating higher diffusivity of the ion pairs with AAs in skin. Moreover, the transport enhancement by AAs increased even more when ethanol-buffer solutions were used as solvents. The conductivity measurement of dissolving solutes in donor solvents showed that the further enhancement might be caused by the increasing ion pair formation in solvents with low dielectric constants. To obtain the maximum enhancement of skin transport of zwitterionic drugs via ion pair concept, one should select a counter ion having high lipophilicity and small volume, and a solvent with suitable pH and low dielectric constant.
    No preview · Article · Jun 2000 · Journal of Controlled Release
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    ABSTRACT: Plasma concentration and vasodilating effect after i.v. bolus injection of stereoisomeric organic nitrates were evaluated. Pharmacokinetics of mononitrates were analyzed with a linear 1-compartment model. The distribution volumes were identical but systemic clearances were different among stereoisomers. The concentration data after dinitrate administration could be described based on a 2-compartment model for dinitrate distribution, with elimination only from central compartment via metabolism to mononitrate, and then mononitrate-dependent metabolic clearance was estimated. In the vasodilation by mononitrate administered intravenously, the maximum effect was not observed. The difference from baseline level of mean arterial pressure (ΔMAP) was related to plasma concentration with a log-linear model, and an identical slope and different intercepts among isomeric mononitrates were obtained. The pharmacological effect following dinitrate dosing were analyzed a sigmoidal Emax model assuming additive effect of dinitrate and mononitrate. Although almost the same Hill's constant and maximum effect values were estimated, EC50 values were different among stereoisomers. The clearance and EC50 values of stereoisomers with nitrate group at the exo position were generally higher than those at the endo position. It suggests that stereostructure of organic nitrates controls the vasodilator potency and duration of action.
    No preview · Article · Jan 2000
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    Tomomi HATANAKA · Theera RITTIROD · Kazunori KATAYAMA · Tamotsu KOIZUMI
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    ABSTRACT: A physical modeling and theoretical simulation aspect for the simultaneous transport and metabolism of prodrug in viable skin were described to understand the influence of enzyme distribution and diffusion. The physical model was formulated assuming that the viable epidermis and dermis have distinct diffusional and metabolic characteristics and that the metabolic reaction in each layer follows a first-order kinetics. The differential equations were analytically solved, and the steady-state flux of prodrug into receiver and that of metabolite into receiver and donor and the total flux in forward (epidermis to dermis) and backward (dermis to epidermis) directions were derived. The flux of prodrug in the forward direction always equals that in the backward direction. The metabolite flux into receiver became transport direction-dependent when the diffusional characteristic of epidermis was different from that of dermis regardless of enzyme distribution. The metabolite flux into donor in the backward direction relative to that in the forward direction increased with increase of dermis/epidermis ratio of any parameters among metabolic rate constant, partition coefficient and diffusion coefficient of prodrug and metabolite. The difference of total flux between the 2 transport directions was caused by the difference in metabolic rate constant, partition coefficient and diffusion coefficient of prodrug between epidermis and dermis. The higher any parameters were for dermis, the higher was total flux in the backward direction.
    Full-text · Article · Jul 1999 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: The purpose of this work was to investigate the disposition characteristics and pharmacodynamics of a benzodiazepine, oxazepam, in renal dysfunction rats. For the in vivo experiment, normal and renal dysfunction rats were given 40 mg/kg of oxazepam as the bolus dose. A quantitative electroencephalographic (EEG) method was used as the surrogate measure of the pharmacological response. The oxazepam concentration in plasma and cerebrospinal fluid (CSF) was assayed by the HPLC method. The steady-state volume of distribution and clearance based on total and unbound plasma did not change in renal dysfunction rats. Amplitude changes in the EEG induced by oxazepam in normal and renal dysfunction rats were characterized by a log-concentration response model or sigmoidal Emax model. The pharmacodynamic parameters from these models were not altered in renal dysfunction. In in vitro binding studies for gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex, the oxazepam-induced effect was not potentiated by the plasma dialysate from renal dysfunction rats. Thus, it was suggested that the brain sensitivity to benzodiazepines was not altered in renal insufficiency.
    No preview · Article · Jul 1999 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: In vitro simultaneous transport and metabolism of three ester prodrugs of nicotinic acid (NA), methyl nicotinate (MN), ethyl nicotinate (EN) and butyl nicotinate (BN) were studied using excised skin from hairless mouse. Hydrolysis studies of these esters with and without skin homogenate were also done at 37 degrees C. Both the ester and NA were detected in all receiver solutions in permeation studies, and no chemical hydrolysis of the esters was found, indicating that the esters were hydrolyzed during the skin permeation process. The total (ester+NA) flux from a saturated solution of ester prodrugs was higher than that of NA and was highest for MN, followed by EN and BN, whereas the total permeability coefficient of ester prodrugs increased from MN to BN. A difference in the NA/total flux ratio was found among these prodrugs; thus, esterase activity was also dependent on the alkyl chain length of the esters. The total flux from each ester solution increased linearly with the donor concentration. NA flux from MN and EN solutions increased with an increase in the donor concentration and reached a plateau at the high concentration range, suggesting that metabolic saturation occurred. NA fluxes at the plateau were similar among ester prodrugs and corresponded to the Vmax estimated from the hydrolysis experiment. The order of donor concentration at which NA reached a plateau also corresponded to the order of Km. It was confirmed that a difference in alkyl chain length of the ester prodrugs affected not only permeability but also metabolism in the skin permeation process.
    Full-text · Article · Apr 1999 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: We have previously reported that brain sensitivity to thiopental with respect to electroencephalogram (EEG) is enhanced in uranyl acetate pretreated renal dysfunction rats. The results were attributed to pharmacodynamic factors. In this study, in vivo EEG and in vitro binding studies for gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex were performed to investigate the mechanism of the enhanced effect of thiopental. The receptor binding properties in the brain membrane from normal and renal dysfunction rats were examined using [3H]tertbutylbicycloorthobenzoate (TBOB), [3H]flunitrazepam and [3H]muscimol. The effect of plasma dialysate from normal (ND) and renal dysfunction rats (RDD) on the thiopental induced EEG and receptor binding were also examined to confirm the role of endogenous compounds. The intrinsic receptor binding characteristics of various sites and their allosteric interaction with thiopental was similar in membrane preparations from normal and renal dysfunction rats. However, RDD, when compared to ND, enhanced the EEG induced by thiopental. At the receptor level, RDD significantly enhanced the thiopental induced inhibition of TBOB. No difference was found between the influence of ND and RDD on the interaction between thiopental and flunitrazepam or muscimol binding. These results showed that the thiopental induced allosteric inhibition of TBOB binding was potentiated by some endogenous compounds in RDD and suggests that this action might be the mechanism, at least in part, for the increased sensitivity of thiopental in renal dysfunction rats.
    No preview · Article · Apr 1999 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: The objective of this research was to compare the characteristics of skin permeation and metabolism of ethyl nicotinate (EN) among humans and several animal models. In vitro simultaneous skin permeation and metabolism experiment of EN was done in side by side diffusion cells at 37 degrees C. An EN hydrolysis experiment was carried out using skin homogenate and kinetic parameters (Vmax and K(m)) were estimated by computer data-fitting to Michaelis-Menten equation. Both EN and a metabolite, nicotinic acid (NA), were detected in all receiver solutions in permeation studies and no significant chemical hydrolysis was found, indicating that enzymatic hydrolysis of EN occurred during the skin permeation process. Difference in total (EN + NA) flux, from EN-saturated solution, was less than double among various species. The ratio of NA flux to total flux was highest for rat (0.94) followed by hairless rat, mouse, human and hairless mouse (0.76, 0.23, 0.19 and 0.13), and thus a great species difference was found in skin esterase activity. Total flux increased linearly with increase in donor concentration for all species. For hairless rat, mouse and hairless mouse, NA fluxes increased with increase in EN donor concentration and reached a plateau, suggesting that metabolic saturation occurred in skin. Species difference in NA fluxes and EN donor concentration in which the NA flux reached a plateau were also found. In rats, kinetic parameters for EN hydrolysis using skin homogenate were significantly higher than those in mice. These results suggest that species difference in permeation profiles of EN might primarily reflect the difference in esterase activity. To predict skin permeability in human using an animal model, the species difference in skin metabolism should be taken into consideration.
    Full-text · Article · Mar 1999 · International Journal of Pharmaceutics
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    ABSTRACT: The purpose of this work was to investigate the disposition characteristics and pharmacodynamics of a barbiturate, thiopental, in renal dysfunction rats. Normal and renal dysfunction rats were infused with 40 and 20 mg/kg of thiopental, respectively. The quantitative electroencephalographic (EEG) method was used as the surrogate measure of pharmacological response. Signals from two electrodes fitted on the skull of rats were continuously measured, recorded and subjected to off-line analysis. Total amplitude (0.5-29.9Hz) from aperiodic analysis was taken as the EEG parameter. Thiopental concentration in plasma and cerebrospinal fluid (CSF) was assayed by an HPLC method. Steady-state volume of distribution was increased in renal dysfunction rats due to decreased plasma protein binding, while no change in clearance or volume of distribution based on the plasma unbound concentration was observed. Amplitude changes induced by thiopental in both normal and renal dysfunction rats were characterized by the sigmoidal Emax model. The unbound plasma concentration at half maximal effect was lowered by 30% in renal dysfunction rats as compared to the normal rats. In addition to considerable alteration in the pharmacokinetics of thiopental, it was also evident that renal impairment is associated with an increase in apparent pharmacological sensitivity, which is related to affinity.
    No preview · Article · Jan 1999 · Biological & Pharmaceutical Bulletin
  • T Hatanaka · S Honda · S Sasaki · K Katayama · T Koizumi
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    ABSTRACT: The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after i.v. bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.
    No preview · Article · Jul 1998 · Journal of Pharmacokinetics and Biopharmaceutics
  • T. Hatanaka · R. Suzuki · K. Katayama · T. Koizumi
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    ABSTRACT: The effect of the stereochemistry of organic nitrates on rat skin permeability was investigated. Skin permeabilities significantly differed between dinitrates and mononitrates, and also among their diastereomers. The maximum flux and permeability coefficient of dinitrate diastereomers from water were dependent on the solubility in octanol and the octanol/water partition coefficient, respectively. On the other hand, the key parameters determining the maximum flux and permeability coefficient of mononitrate isomers were the aqueous solubility and diffusivity. These results suggest that dinitrate diastereomers permeate across skin via the lipid domain of the stratum corneum according to a partitioning mechanism, and that skin permeation of mononitrate isomers occurs via an aqueous domain by a porous mechanism. Factors raising stereoselectivity in skin permeation of organic nitrates were closely related with stereostructure, especially the functional groups at the exo position, of diastereomers. The interaction between the functional groups and surrounding molecules thus causes the differences in physicochemical properties and skin permeability of stereoisomers.
    No preview · Article · Jun 1998 · International Journal of Pharmaceutics
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    ABSTRACT: The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after iv bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.
    No preview · Article · May 1998 · Journal of Pharmacokinetics and Pharmacodynamics
  • Kouji SEKIYA · S Kadota · Kazunori KATAYAMA · Tamotsu KOIZUMI · Tsuneo NAMBA
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    ABSTRACT: To investigate the permeability of natural compounds through hairless mouse skin, compounds having a range of lipophilicity, i.e., ginsenoside-Re (1), baicalein (2), glycyrrhizin (3), baicalein (4), wogonin (5), honokiol (6), magnolol (7), bergapten (8), shikonin (9) and sinomenine (10) were used. These compounds permeated through the skin a little, however, they were generally accumulated into the skin. The uptake amount into the skin of each compound related to their lipophilicities in the in vitro experiment. Furthermore, Ligustici Chuanxiong Rhizoma (Senkyu) ether extract (SEE) enhanced their permeability into the skin; especially, it exhibited an effect on the skin permeability of moderately lipophilic compounds such as 4, 8. The effect of SEE in vivo was similar to that obtained in the in vitro experiment. From these results, it was clarified that natural compounds having high lipophilicity sufficiently permeated into the hairless mouse skin owing to their accumulative property, and SEE enhanced the permeability of the moderately lipophilic compounds into the skin.
    No preview · Article · Oct 1997 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: Skin permeation of amino acids through excised rat skin was measured at various pH values. The permeabilities varied with the donor pH and amino acid, indicating that each ionic species of amino acid may have a different permeability. The permeability coefficient of each ion was estimated from the permeability-pH profiles using the dissociation constants. The estimated values for mono-cation and uncharged zwitterion were not dependent on the lipophilicity but on the size of the amino acid, suggesting a porous mechanism of transport. The permeability coefficient was highest for di-cation, followed by mono-cation, positively charged, uncharged and negatively charged zwitterions. The electrical potential difference across the skin was too small to affect the permeation of ions. The permselective property of skin thus seems to be determined by the difference of diffusivity in aqueous pores of skin due to the hydration of ions and other factors.
    No preview · Article · Aug 1996 · Journal of Pharmacy and Pharmacology
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    ABSTRACT: The swelling properties of hydrophilic cellulose matrices were studied using three drugs having different water solubility: indomethacin, theophylline, and mannitol. Two swelling parameters: maximum swelling index (V) and the apparent diffusion coefficient of water in the matrix (D(w)), were calculated from the swelling data and were used to describe structures and properties of the swollen matrices. The V value indicates the swelling extent as well as the capacity of maintaining the matrix shape, whereas D(w) represents the swelling rate that also reflects the structural resistance of the polymer network against the movement of water molecules. The results show that both polymers and incorporated drugs influence the swelling properties of the matrices. Polymers that contain more hydroxypropoxyl group produce matrices with high integrity, even in the presence of drugs. V values indicated that the capacity of the matrices to maintain their shape depends on polymer (i.e., the swelling part). The effect of drug solubility can be seen from D(w) values. For a highly water-soluble drug, the structural resistance of the swollen matrices is mainly governed by the drug. In contrast, this is primarily influenced by the polymer in the case of drugs that are slightly or poorly water soluble.
    No preview · Article · May 1996 · CHEMICAL & PHARMACEUTICAL BULLETIN
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    ABSTRACT: A model for swelling time course of compressed cellulose matrix is presented. The model incorporates the two most important features: water penetration by diffusion and volume change due to swelling. Approximations of the model for small t values and for large t values are also derived, which are utilized in a handy routine for estimation of swelling parameters. The observed time courses of thickness change with compressed matrices of methyl cellulose and hydroxypropyl cellulose agree well with the calculated values of the proposed model. The proposed model is compatible with the observed swelling kinetics.
    No preview · Article · Mar 1996 · Pharmaceutical Research