Biomedical subjects

K Sugibayashi

Publications and source records attributed to K Sugibayashi.

At least 37 records · Page 2Linked to original sources

PubMed1999

Skin disposition of drugs after topical application in hairless rats.

Drug fraction transported from a topical formulation on skin to subcutaneous tissues or muscles is dependent on the physicochemical properties of the entrapped drug. Cutaneous disposition of model drugs, antipyrine (ANP), lidocaine (LC) and piroxicam (PXC) as well as flurbiprofen (FP) was thus evaluated in hairless rats in which an agar gel disc was subcutaneously inserted into the abdominal region as a drug receptor and a drug donor cell was placed above it. Time courses of plasma level and agar gel amount were measured after topical application of 50% ANP, 3% LC, 1% PXC and 1% FP in hydroxypropylcellulose gel. Percutaneous absorption clearance of unionized form, CLab* was proportional to true octanol/water distribution coefficient and the order of FP > PXC > LC > ANP, suggesting that skin permeation of the drug was determined mainly by its distribution from the formulation to the skin barrier. PXC, however, had a relatively low flux compared to the other three drugs, probably due to its high molecular weight and melting point. Migration clearance of unionized form from systemic circulation to the subcutaneous agar gel, CLg* was also influenced by the lipophilicity of drugs. On the other hand, fraction from the formulation to the systemic circulation was in the order of PXC > FP > ANP > LC. This fraction was much higher than the direct migration fraction from the formulation to the subcutaneous agar gel. Factors determining for these fractions are still unclear. A drug having a low lipophilicity and a low protein binding, however, had a tendency to have a great targeting ability to the subcutaneous agar gel. In addition, most of the drug in the agar gel was contributed by the direct flow from formulation, not from the systemic circulation. The present in situ experimental method is a useful tool to evaluate skin disposition of drugs. Detailed understanding of the skin disposition of drugs from several formulations will enable the findings of a good drug and formulation candidates.

Administration, Topical↗

PubMed1999

Optimum threshold values of 201Tl SPET in the determination of the left ventricular border and extent of myocardial infarction.

The aim of this study was to determine the optimum threshold value of the left ventricular border and the extent of myocardial infarction using quantitative 201Tl single photon emission tomography (SPET). We used the unfolded map method to determine the size of the left ventricle and the extent of myocardial infarction in 10 patients, because it has been shown to be superior to the conventional polar map method. The relative differences in the size of the left ventricle and extent of infarction between 201Tl SPET and post-mortem examination were calculated. The optimum threshold value was determined when the relative difference = 0%. There was an excellent correlation between scintigraphic and post-mortem left ventricular size at a threshold value of 53% (r = 0.91, P < 0.001); an excellent correlation was also observed between scintigraphic and post-mortem infarct size at a threshold value of 55% (r = 0.93, P < 0.03). The optimum threshold value in determining left ventricular size using 201Tl SPET is 53% and that in determining infarct size is 55%.

Adult↗

PubMed1998

Enhancing effect of N-acetyl-l-cysteine or 2-mercaptoethanol on the in vitro permeation of 5-fluorouracil or tolnaftate through the human nail plate.

The enhancing effects of various vehicles on the in vitro permeation of a hydrophilic model drug, 5-fluorouracil (5-FU), or a lipophilic model drug, tolnaftate (TN), through human nail plates were investigated using a modified side-by-side diffusion cell. Tip pieces from the 5th finger-nail, clipped from healthy volunteers, were used in this permeation study. The swelling and softening properties of the nail pieces were also measured in each vehicle. The weights and stresses of the nail pieces were dramatically changed after immersion in aqueous solvents containing N-acetyl-L-cysteine (AC) or 2-mercaptoethanol (ME). However, no significant change in the physicochemical properties of the nail pieces was found in the lipophilic vehicles. Thus, the water content in the nail plates absorbed from vehicles may relate to their physicochemical properties. Although keratin-softening agents and new skin permeation enhancers did not significantly promote 5-FU permeation compared with water alone, the flux from solvent systems containing AC or ME was substantially higher. In addition, TN permeation from solvents containing AC or ME could be measured, whereas that from other solvents was undetectable. When the AC concentration was increased, the 5-FU permeation and the nail weight increased and the stress of each nail piece decreased. It is concluded from these experimental results that AC and ME may be useful as enhancers for increasing drug permeation through the human nail plate.

Absorption↗

PubMed1998

Effect of several hydrophilic polymers on the permeation of morphine and salicylic acid through excised hairless rat skin.

Several hydrophilic polymers changed the cumulative amount of morphine (MOR) permeated through excised hairless rat skin from 1% MOR hydrochloride solution containing ethanol and l-menthol at concentrations of 40% and 5%, respectively, as permeation enhancers. Anionic polymers (carboxyvinylpolymer and methylvinylether-maleic anhydride copolymer) in the test solutions decreased the skin permeation of MOR, whereas cationic polymers (polyethyleneimine and chitosan) increased it, compared with that without polymers. Little change, however, was observed by the addition of nonionic polymers (hydroxypropylcellulose and polyethyleneoxide). On the other hand, the cationic and anionic polymers in the test solutions decreased and increased, respectively, the skin permeation of salicylic acid (SA) from the same enhancing system containing sodium salicylate. These opposite results were probably caused by the change in escaping tendency of the drugs from the vehicles, which was due to the drug-polymer interaction. (The escaping tendency has a great effect on the drug partition from the polymer solution to the skin barrier). The effect of hydrophilic polymers on the partition was then evaluated by Donnan membrane theory. The partition of MOR was increased and decreased by the presence of polymers having identical and opposite charge to MOR. The low partition of the drugs to skin may also be caused by low diffusion of the drugs in the polymer solutions. The drug release from the hydrophilic polymer solutions was then measured, and the release rate was found to have decreased in the presence of polymers having opposite charge to MOR and SA. It is suggested that these drug-polymer interactions changed the drug partition to skin thus changing the skin permeation of the drug.

Analgesics, Opioid↗

PubMed1998

[Transdermal therapeutic systems].

Advances in transdermal therapeutic systems (TTS) and the technology involved have been rapid because of the sophistications of physiology and biology on skin, enhancing methodology for the skin penetration of drugs, and material and polymer sciences on the pharmaceutical additives. In this review paper, such progress was introduced and the future on the TTS was augured.

Administration, Cutaneous↗

PubMed1997

Evaluation of skin permeability of drugs by newly prepared polymer membranes.

Four polymeric membranes were prepared consisting of various ratios of 2-hydroxyethyl-methacrylate/polydimethylsiloxane-methacrylate copolymer. These membranes had both lipophilic and hydrophilic domains in their copolymer networks like skin barrier. From permeation studies of the aqueous solutions or suspensions of various lipophilic and hydrophilic drugs using these membranes, a membrane having a similar drug permeability to hairless rat and human skins was selected. Permeation of indomethacin through the selected polymer membrane from simple ointment, gel and a marketed cream were then measured. About 10(2) times higher permeability was found in the polymer membrane than through excised hairless rat skin, but the rank order of the permeability through the polymer membrane among the formulations was the same through the skin membranes. These higher permeations of indomethacin were probably related to physical and chemical properties of pharmaceutical additives in the topical formulations. It is concluded that these synthetic polymer membranes may be utilized as an alternative tool to predict human or rat skin permeability of various (hydrophilic or lipophilic) drugs as well as to screen drug candidates for transdermal drug delivery.

Administration, Cutaneous↗

PubMed1996

Analysis of simultaneous transport and metabolism of ethyl nicotinate in hairless rat skin.

PURPOSE: Simultaneous skin transport and metabolism of ethyl nicotinate (EN), a model drug, were measured and theoretically analyzed. METHODS: Several permeation studies of EN or its metabolite nicotinic acid (NA) were done on full-thickness skin or stripped skin with and without an esterase inhibitor. Permeation parameters such as partition coefficient of EN from the donor solution to the stratum corneum and diffusion coefficients of EN and NA in the stratum corneum and the viable epidermis and dermis were determined by these studies. Enzymatic parameters (Michaelis constant Km and maximum metabolism rate Vmax) were obtained from the production rate of NA from different concentrations of EN in the skin homogenate. Obtained permeation data were then analyzed by numerical method based on differential equations showing Fick's second law of diffusion in the stratum corneum and the law with Michaelis-Menten metabolism in the viable epidermis and dermis. RESULTS: Fairly good steady-state fluxes of EN and NA through the skin were obtained after a short lag time for all the concentrations of EN applied. These steady-state fluxes were not proportional to the initial donor concentration of EN: EN and NA curves were concave and convex, respectively, which suggests that metabolic saturation from EN to NA takes place in the viable skin at higher EN application. The steady-state fluxes of EN and NA calculated by the differential equations with resulting permeation and enzymatic parameters were very close to the obtained data. CONCLUSIONS: The present method is a useful tool to analyze simultaneous transport and metabolism of many drugs and prodrugs, especially those showing Michaelis-Menten type-metabolic saturation in skin.

Animals↗

PubMed1996

In vitro/in vivo difference in enhanced skin permeation of nicardipine hydrochloride by the 1-menthol-ethanol system.

The in vitro/in vivo difference in enhanced skin permeation of nicardipine hydrochloride (NC) by simultaneous use of 1-menthol and ethanol (MEW system, 1-menthol:ethanol:water = 5:40:55) was investigated in hairless rats. First, the cutaneous blood flow clearance (clearance from skin to blood flow) of NC per unit area of skin (CLCB/A), which was comparable to the permeability coefficient across skin (PC), was calculated from intracutaneous and intravenous injection data using the deconvolution method; the value was 1.67 microliters/h/cm2. Two formulations containing NC and the MEW system, solution (SOL) and 15% hydroxypropyl cellulose gel (GEL), were used for in vitro and in vivo permeation experiments. The in vitro PC of NC via excised skin from SOL (23.3 microliters/h/cm2) was significantly higher than CLCB/A, and that from GEL (1.48 microliters/h/cm2) was similar to CLCB/A. Consequently, the steady-state concentration of NC in skin during in vivo application of SOL was 6.6 times higher than corresponding in vitro data. In vivo PCs from SOL and GEL were however significantly lower than CLCB/A. These results may be explained by the findings, using a laser Doppler flowmeter, that cutaneous blood flow was decreased by the application of MEW.

Animals↗

PubMed1996

Analysis of in vitro iontophoretic skin permeation of sodium benzoate by transport numbers of drug and additives.

Effect of species and concentrations of pharmaceutical additives on the iontophoretic transport of benzoate anion through excised hairless rat skin was investigated using a 2-chamber iontophoretic diffusion cell equipped with platinum electrodes at 0 mA for 4h (control) followed by a constant direct current of 0.5 mA for another 4h. One cell facing the stratum corneum was filled with sodium benzoate solution, and the other cell facing the dermis with lithium chloride (LiCl), potassium chloride (KCl) or tetraethylammonium bromide (TEA-Br) solution. Iontophoretic delivery rate of benzoate anion that permeated through skin increased with an increase in the sodium benzoate concentration while maintaining a constant KCl concentration. In contrast, a flux of benzoate anion decreased with an increase in KCl concentration and a constant concentration of sodium benzoate. When KCl was replaced by LiCl or TEA-Br, the flux of benzoate anion was almost the same. These phenomena were evaluated by a concept of transport numbers: theoretical values of benzoate anion flux were very close to the observed data. Potential difference between the skin during the permeation study was also measured between two salt bridges which were connected via calomel electrodes to a potentiometer. It gradually decreased to a certain level in each case, but increased again in some cases. This gradual decrease and increase in the potential difference, in spite of a constant current, were theoretically explained by a gradual increase of ion concentration in the skin membrane and depletion of the cation in the receiver cell, respectively. Analysis of ionic mobility and concentration of penetrants gave a great deal of information on iontophoretic drug permeation through skin.

Animals↗

PubMed1996

Difference in the enhancing effects of ultrasound on the skin permeation of polar and non-polar drugs.

The effect of ultrasound (150 kHz, 111 mW/cm2) on the permeability of isosorbide dinitrate (ISDN) and antipyrine (ANP) through excised hairless rat skin was evaluated using an Arrhenius plot. The permeability coefficients of ISDN across skin (at various temperatures) in the presence and absence of ultrasound were virtually isolinear on the Arrhenius plot. It has been suggested that the temporal increase in the ISDN flux, which was observed when ultrasound was applied in our previous study, was only a result of the thermal effect of ultrasound, i.e., an increase in the temperature of the donor solution. On the other hand, ultrasound influenced the Arrhenius plot of ANP, suggesting that the enhancement effect for ANP permeation could be not explained only by the thermal effect of ultrasound. In addition, the effective diffusion (D) and partition coefficients (K) of ISDN and ANP were estimated using their skin permeation profiles across the ultrasonic pretreated skin. The coefficients of ISDN with ultrasonic pretreatment were comparable to those without pretreatment. On the other hand, the D value of ANP with ultrasonic pretreatment was increased about 4 times by ultrasonic pretreatment, in spite of an insignificant change in the K value. These results suggest that the ultrasound used in the present study increased the effective diffusivity across the aqueous region in the stratum corneum to enhance the skin permeation of the polar compound, ANP.

Animals↗

PubMed1995

[Feasibility assessment of skin permeation for the local anesthetic lidocaine].

In this paper, the feasibility of skin permeation for lidocaine and pressure sensitive adhesive (PSA) tape formulation containing lidocaine for skin local anesthetic were assessed. Firstly, in vitro skin permeation of the molecular and ionic forms of lidocaine from water and silicone fluid suspensions was measured using a side-by-side two diffusion cells and excised hairless rat skin. Secondly, PSA tape containing lidocaine was prepared by a general casting method using styrene-isoprene-styrene block copolymer. The in vitro release and skin permeation were evaluated and compared with that of Japan marketed xylocaine jelly. The effect of lidocaine concentration on the steady-state flux of skin permeation from 10% to 60% lidocaine PSA tapes was also evaluated.

Anesthetics, Local↗

PubMed1994

The effect of different routes of administration on the metabolism of morphine: the disposition of morphine and its metabolites after topical application.

The disposition of morphine (MOR) and its metabolites in the rabbit was measured after topical administration of its hydrochloride salt (MOR.HCl), and their time course was compared with those after intravenous and oral administration. The area under the plasma concentration-time curve (AUC) ratio of metabolites/MOR after the topical application of MOR.HCl was similar to that after intravenous injection, but differed from that after oral administration. Pharmacokinetic parameters of the disposition of MOR and its metabolites were obtained by a general curve fitting of the time course of plasma concentrations of these compounds after intravenous injection of MOR.HCl and its metabolites, respectively. On the other hand, the time courses of plasma concentrations of the metabolites after intravenous, oral, and topical administration of MOR.HCl were simulated using a simple compartment model without consideration of enterohepatic circulation and the pharmacokinetic parameters obtained as above. The resulting curves of the metabolites agreed well with the observed values except for those after oral administration. These results suggest that no first-pass metabolism of MOR.HCl occurs after percutaneous administration, and that topical administration of this salt is more advantageous than oral administration in terms of bioavailability.

Administration, Oral↗

PubMed1994

Effect of sodium taurodihydrofusidate on nasal drug delivery: differences in its concentration and penetrant molecular weight.

The effect of sodium taurodihydrofusidate (STDHF) on drug permeation across nasal mucosa was studied in vitro using Ussing type diffusion chamber. Disodium cromoglicate (DSCG, M.W. 512.3) and fluorescein isothiocyanate-dextran (FD) of different molecular weights (M.W. 4400-71200) were used as model drugs. Permeation profiles of DSCG and FDs showed a typical pseudo steady-state curve with short lag time. The permeability coefficient of FD (M.W. 9400) sigmodially increased with increasing STDHF concentration. It also enhanced the DSCG permeation. Interestingly the enhancement efficacy was independent of molecular weight of penetrants.

Adjuvants, Pharmaceutic↗

PubMed1994

Interaction between drugs and pressure-sensitive adhesives in transdermal therapeutic systems.

Release experiments with four drugs using representative pressure-sensitive adhesive (PSA) matrices were performed at 37 degrees C, and drug-PSA polymer interaction was determined by the Williams, Landel, and Ferry (WLF) equation. Two acrylic-type [2-ethylhexylacrylate and acrylic acid copolymer (2EHA/AA) or acrylamide copolymer (2EHA/AAm)], one rubber-type (a mixture of high and low molecular weight polyisobutylene), and one silicone-type PSA were used, and dipropylphthalate (PP), aminopyrine (AMP), ketoprofen (KP), and lidocaine (LC) were selected as model drugs because of their molecular size and functional groups. PSA containing acrylic acid (2EHA/AA) strongly interacted with the amide LC, with the tertiary amine AMP, and with the carboxylic acid KP; PSA-containing acrylamide (2EHA/AAm), however, did not interact with LC or AMP, although it markedly interacted with KP. The rubber-type and silicone-type PSAs, composed of no or only a few polar functional groups, did not interact with any of the drugs used in this experiment. Therefore, the diffusion coefficient of the drugs through PSA was influenced by the drug-PSA polymer interaction, and the extent of this interaction can be estimated by the relationship between the drug concentrations in the PSA and their diffusion coefficients.

Acrylates↗

PubMed1994

An application of the hydrodynamic pore theory to percutaneous absorption of drugs.

Skin permeability of drugs was evaluated based on the hydrodynamic pore theory. Four polar solutes were used, with differing molecular sizes--ethylene glycol, 1,3-butylene glycol, antipyrine and sucrose--and isosorbide dinitrate was also selected as a lipophilic drug. The skin permeations of solvent (D2O) and one of these drugs were measured simultaneously under various osmotic pressures to calculate the reflection coefficient. The clearance of isosorbide dinitrate was independent of the solvent flux, whereas a linear relationship was obtained between the solvent flux and the clearance of each hydrophilic drug except for sucrose. The reflection coefficient of the hydrophilic drugs increased with increasing molecular radius. These results suggest that the convective flow contributes significantly to the total skin permeability of hydrophilic drugs and that the extent of contribution decreases with increasing molecular size of the drugs. The pore radius of the skin barrier could be estimated from the reflection coefficient of the hydrophilic drugs and the resulting value was compared with that for the other absorption sites, jejunum, rectum, and nose. The apparent water influx was also compared to assess the volume occupied by the pores. The pore radius and apparent influx of skin were lower than those for the other absorption sites, which is apparently one reason for low skin permeability of drugs, especially hydrophilic drugs.

Animals↗

PubMed1994

Analysis of the combined effect of 1-menthol and ethanol as skin permeation enhancers based on a two-layer skin model.

The combined effects of 1-menthol and ethanol as a skin permeation enhancer were evaluated with two equations describing the permeability coefficient through full-thickness skin (PFT) and the full-thickness skin/vehicle concentration ratio (CFT/CV) of drugs as a function of their octanol/vehicle partition coefficient (KOV). A two-layer model was applied for skin, which consists of a stratum corneum (SC) with lipid and porous pathways and a viable epidermis and dermis (ED). The two equations contain one variable (KOV) and nine coefficients, six of which (three diffusion coefficients, the porosity of the SC, and two terms of the linear free energy relationship) were considered different, dependent on the drug vehicle. In vitro permeation of four drugs (morphine hydrochloride, atenolol, nifedipine, and vinpocetine) was determined using excised hairless rat skin and four aqueous vehicles (water, 5% 1-menthol, 40% ethanol, and 5% 1-menthol-40% ethanol) to measure each PFT. Drug concentrations in full-thickness skin were also measured to obtain CFT/CV. A nonlinear least-squares method was employed to determine six coefficients using the two equations and experimentally obtained PFT and CFT/CV. The addition of 1-menthol to water and 40% ethanol increased the diffusion coefficient of drugs in lipid and pore pathways of SC, whereas the addition of ethanol to water and 5% 1-menthol increased the drug solubility in the vehicle, decreased the skin polarity, and increased the contribution of the pore pathway to whole-skin permeation.

Animals↗

PubMed1994

Effect of skin surface lipid on the skin permeation of lidocaine from pressure sensitive adhesives.

Pressure sensitive adhesives (PSA) tapes containing different concentrations of lidocaine were prepared by a general casting method using styrene-isoprene-styrene block copolymer, and the in vitro skin permeation of lidocaine from each tape was evaluated using diffusion cell and excised hairless rat skin. The skin permeation was proportionally increased by up to 40% lidocaine in the PSA tape and did not change after this concentration. Although the bending point of the steady-state flux via skin concentration curve was found at 40%, saturated concentration or solubility of lidocaine in the tape was estimated to be about 20% by differential scanning calorimetry (DSC) measurement. In addition, the steady-state flux of lidocaine through skin from water or silicone fluid suspension (92 or 120 micrograms/cm2.h, respectively) was very similar to those of 40, 50 and 60% tapes (105, 101 and 112 micrograms/cm2.h, respectively). Decrease in the concentration in tapes during the permeation experiment explained only part of these phenomena. To analyze them further, the drug free PSA tape with or without (control) skin surface lipid was affixed to 50% lidocaine PSA tape for 48 h, and the amount of lidocaine crystal in the layered tapes was measured by DSC. The amount was found to be lower in the lipid-containing tape than in the lipid-free tape, suggesting that skin surface lipid can dissolve lidocaine crystal or solid in PSA tape to decrease its thermodynamic activity. Thus it is important to follow the concentration and thermodynamic activity of lidocaine in PSA tape, skin and the interface between the two layers to exactly assess its skin permeation flux.

Adhesives↗

PubMed1994

Evaluation of enhancers to increase nasal absorption using Ussing chamber technique.

The effects of eight prospective absorption enhancers on the nasal mucosa in rabbit have been assessed using an in vitro Ussing chamber technique. Sodium taurodihydrofusidate (STDHF), sodium deoxycholate (DC), polyoxyethylene-9-lauryl ether (BL-9), lysophosphatidylcholine (LPC) and sodium dodecyl sulfate (SDS) were found to possess relatively high protein leaching activity, while sodium glycocholate (GC), sodium taurocholate (TC) and EDTA had relatively low activity. The permeation of fluorescein isothiocyanate-labeled dextran (FD, M.W. 9400) as a model drug across the nasal mucosa was found to be greater in the presence of these enhancers. Their enhancement ratio was found to be in the order of BL-9 > STDHF > SDS > LPC > DC > EDTA > GC > TC, which correlated with the protein leaching activity. The differences in protein leaching and enhancement ratio dependent on the magnitude of change of membrane resistance (delta Rm), indicating that these enhancers damaged the membrane and increased FD permeation. delta Rm thus appears to be a useful indicator by which one can estimate nasal mucosa damage by the enhancers.

Absorption↗