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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
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Journal of Pharmaceutical Investigation
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Journal DOI :
The Korean Society of Pharmaceutical Sciences and Technology
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Volume & Issues
Volume 23, Issue 4 - Dec 1993
Volume 23, Issue 3 - Sep 1993
Volume 23, Issue 3 - Sep 1993
Volume 23, Issue 2 - Jun 1993
Volume 23, Issue 1 - Mar 1993
Selecting the target year
Use of the Stratum Corneum Reservoir for the Prediction of Skin Penetration
Cholee, Ae-Ri ; Tojo, Kakuji ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 1~8
A simple and quick method based on the transient diffusion theory for predicting the steady state rate of penetration of a drug after transdermal drug administration was proposed. The amount of drug entering the stratum corneum was determined by 20 strippings with an adhesive tape. From the profile of the amount of drug as a function of the number of strippings, the quantity of drug on the surface of stratum corneum was extrapolated. Based on the amounts of drug entering the stratum corneum during two time intervals
within 1 hour after the application, the diffusion and partition coefficient were determined. Once the diffusion coefficient of the drug in the stratum corneum and the partition coefficient (stratum corneum/vehicle) were determined from the present approach, the steady-state flux of penetration across the stratum corneum was calculated. The steady-state rates of penetration of ascorbic acid and estradiol across hairless mouse skin were evaluated from this approach and compared with those obtained from ill vitro penetration experiment using excised hairless mouse skin. The data confirmed that the proposed method can predict the steady-state rate of penetration of these drugs across the stratum corneum.
Development and Evaluation of an Oral Controlled Release Delivery System for Melatonin
Lee, Beom-Jin ; Parrott, Keith A. ; Sack, Robert L. ; Ayres, James W. ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 9~18
Sugar spheres loaded with melatonin (MT) were coated with
to control the release rate of MT over 8 hours. A zero-order release pattern over 8 hours was obtained with 20% coating on 8-10 mesh beads in USP basket dissolution studies. MT in 20% coated beads was quite stable at room temperature with less than 5% MT degraded during 6 months' storage. Dissolution profiles were also unchanged after 6 months. An oral preparation containing MT-loaded uncoated beads for immediate release and 20% coated beads with
for controlled release over 8 hours was evaluated in six human subjects. When total 0.5 mg MT as low dose (immediate release portion of MT, 0.1 mg) was administered to four subjects, average peak plasma MT concentration was reached at about 600 pg/ml and maintained at about 10 pg/ml over 8 hours. Plasma MT concentration-time profiles were similar in shape to computer-simulated profiles. However, maximal plasma MT concentrations were three times greater compared to computer simulated curve. These results suggest that MT dose, ratio of immediate and controlled release MT, and pharmacokinetic parameters selected are adjusted to mimic endogenous MT concentration-time curve. In another study, 0.2 mg MT having 10% of immediate release portion and 80% controlled release portion produced plasma MT concentration-time curve which is more similar to endogenous profiles. A low bioavailability (<20%) may result from extensive first pass metabolism and remaining amounts of MT from controlled beads. A good correlation between plasma MT concentration and urinary excretion rate of 6-sulphatoxymelatonin (6-STMT), a major metabolite of MT was observed. As plasma MT concentration increased, urinary excretion rate of 6-STMT increased concomitantly. The linear relation between plasma MT and urinary excretion rate of 6-STMT was statistically significant. This result suggests that urinary 6-STMT may be used as an index of circadian rhythms of MT in humans.
Lymphatic Delivery of Oral Anticancer Tegafur by Emulsion Formulations
Lee, Yong-Bok ; Koh, Ik-Bae ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 19~30
The influence of emulsion type of tegafur, an oral anticancer agent, on lymphatic transport was studied in rats. The water-in-oil-type of emulsion and the oil-in-water-type emulsion of tegafur each in 50 mg, calculated in terms of tegafur, were prepared by adding tegafur aqueous solution to sesame oil containing hydrogenated castor oil following ultrasonic treatment, and then the prepared emulsions and aqueous solution as a comparative formulation were administered orally to rats (50 mg/5 ml/kg). The concentration levels of tegafur in plasma of femoral artery and lymph from thoracic duct cannula were measured simultaneously along a time course after administration and the pharmacokinetic parameters were investigated. At the same time, we examined the above described factors of 5-FU which is known as an active metabolite of tegafur. In comparison with tegafur solution, AUC and mean residence time of plasma tegafur were significantly increased in w/o-emulsion but significantly decreased in o/w-emulsion. Lymph flow rates were similar in both solution and w/o-emulsion but half in o/w-emulsion. Ratios between area under the lymph and plasma concentration time curves were always less than 1 reflecting the passive lymphatic delivery after oral administration of the prepared tegafur emulsions, but those to the 5-FU in the case of w/o-emulsion were more than 1. These results suggested that lymphatic delivery of tegafur by w/o-emulsion was more effective than that by o/w-emulsion due to its differences of formation ability of chylomicrons.
FUNCTIONAL EXPRESSION OF A PEPTIDE TRANSPORTER IN XENOPUS OOCYTES
Oh, Doo-Man ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 31~40
It is essential to clone the peptide transporter in order to obtain better understanding of its molecular structure, regulation, and substrate specificity. Characteristics of an endogenous peptide transporter in oocytes were studied along with expression of an exogenous proton/peptide cotransporter from rabbit intestine. And further efforts toward cloning the transporter were performed. The presence of an endogenous peptide transporter was detected in Xenopus laevis oocytes by measuring the uptake of
(Gly-Sar) at pH 5.5 with or without inhibitors. Uptake of Gly-Sar in oocytes was significantly inhibited by 25 mM Ala-Ala, Gly-Gly, and Gly-Sar (p<0.05), but not by 2.5 mM of Glu-Glu, Ala-Ala, Gly-Gly, Gly-Sar and 25 mM glycine and sarcosine. This result suggests that a selective transporter is involved in the endogenous uptake of dipeptides. Collagenase treatment of oocytes used to strip oocytes from ovarian follicles did not affect the Gly-Sar uptake. Changing pH from 5.5 to 7.5 did not affect the Gly-Sar uptake significantly, suggesting no dependence of the endogenous transporter on a transmembrane proton gradient. An exogenous
cotransporter was expressed after microinjection of polyadenylated messenger ribonucleic acid
obtained from rabbit small intestine. The Gly-Sar uptake in mRNA-injected oocytes was 9 times higher than that in water-injected oocytes. Thus, frog oocytes can be utilized for expression cloning of the genes encoding intestinal
cotransporters. Using the technique size fractionation of mRNA was sucessfully obtained.
The Role of Excipients in Iontophoretic Drug Delivery: In vitro Iontophoresis of Isopropamide and Pyridostigmine through Rat Skin and Effect of Ion-pair Formation with Organic Anions
Shim, Chang-Koo ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 41~50
The iontophoretic delivery across rat skin of quaternary ammonium salts (isopropamide: ISP, pyridostigmine: PS), which are positively charged over a wide pH range, was measured ill vitro. The study showed that: (a) iontophoresis significantly enhanced delivery of ISP and PS compared to respective passive transport; (b) delivery of ISP and PS was directly proportional to the applied continuous direct current density over the range of
(c) delivery of ISP and PS was also proportional to the drug concentration in the donor compartment over the range of
(d) sodium ion in the donor compartment inhibited the drug transport possibly due to decreasing the electric transference number of the drug; (e) delivery of ISP and PS increased as the pH of the donor solution increased over the pH range 2-7 suggesting permselective nature of the epidermis, and inhibition of the transference number of the drugs by hydronium ion; (f) some organic anions such as taurodeoxycholate, salicylate and benzoate which form lipophilic ion-pair complexes with ISP inhibited the delivery of ISP. The degree of inhibition by the organic anions was linearly proportional to the extraction coefficient
of ISP from the partition system with each counteranion between phosphate buffer (pH 7.4) and n-octanol. For PS, however, taurodeoxycholate, but not salicylate and benzoate inhibited the iontophoretic delivery. It suggests that not only sodium ion and hydronium ion but also the counteranions which form lipophilic ion-pairs with quaternary ammonium drugs are not favorable components in formulating the donor solution of the drugs to achieve an effective iontophoretic delivery.
Formulation Strategies for Proteins and Peptides
Deluca, Patrick P. ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 51~60
The Effect of Physicochemical Properties of Salicylate Analogs on Binding to Bovine Serum Albumin
Yong, Chul-Soon ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 119~125
The protein binding of salicylate analogs has been investigated by equilibrium dialysis. A series of binding experiments were performed in order to elucidate the effects of physicochemical properties of salicylate analogs on the binding with bovine serum albumin. Attempts to correlate affinity constants with capacity factor, steric factor and Hammett
values suggested hydrophobic forces to be involved in the binding of salicylate analogs. Steric factor contributes to binding process partly, whereas electronic interaction appears to be insignificant.
Damage of Omeprazole Suppository on Rectal Mucosa of Rats
Kim, Hyun-Ji ; Han, Yong-Hae ; Shim, Chang-Koo ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 127~132
The effect of omeprazole (OPZ) suppository on rat rectal mucosa was investigated microscopically. The suppository was prepared with Witepsol H15 base by molding method. Rectal irritation was evaluated according to defined pathological features. The suppository produced a slight damage to the rectal mucosa at 1 hr after the interectal administration, which was almost completely recovered within 24 hr. The damage was not due to OPZ but due to suppository base, Witepsol H15, itself, since Witepsol H15 suppository without OPZ produced the same damage. Therefore, it was concluded that OPZ itself has no rectal mucosa-irritating effect and thus can be developed as a suppository dosage form without any further toxicity problems.
High Performance Liquid Chromatographic Assay of Acebutolol and its Acetyl Metabolite in Plasma
Baek, Chai-Sun ; Lin, Emil T. ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 133~137
A high-performance liquid chromatographic assay using ion-pair reverse-phase system was developed for the separation of acebutolol and acebutolol acetyl metabolite in plasma. A ion-pair reversephase system consisting of an ODS-bonded silica column and a mixture of 20%
, 0.035 M heptanesulfonic acid and 0.005 M tetrabutylammonium hydrogen sulfate as the mobile phase were used. Triamterene was employed as an internal standard. Based on 0.2 ml of plasma, the detection limits were 10.4 ng/ml for acebutolol and 10.3 ng/ml of acebutolol acetyl metabolite at the signal-to-noise ratio of 3:1.
Biological Evaluation of Acyclovir Microcapsule Suspension Prepared by Carbopol-Gelatin Coacervation
Cho, Jin-Ho ; Hahn, Yang-Hee ; Yi, Jung-Woo ; Choi, Young-Wook ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 139~144
Microencapsulation of acyclovir, an effective antiviral agent which acts as a specific inhibitor of herpes DNA polymerase, by carbopol-gelatin complex coacervation has been carried out to develop an oral controlled release preparation, which could improve the absorption characteristics in GI tract. After dissolving carbopol and gelatin separately in distilled water at
, gelatin solution was mixed with carbopol solution while stirring at the same temperature. The pH of the mixture was lowered gradually by dropwise addition of 10% HCI with continuous stirring, and then, at pH 3.5, positively charged gelatin molecules were attracted to negatively charged carbopol. These coacervation processes were observed by optical microscopy during preparation. Plasma concentrations of acyclovir in rats after an oral administration of microcapsule suspension were assayed by HPLC, and pharmacokinetic parameters were calculated based on the model-independent analyses. Two standard formulations, oral solution and intravenous bolus injection, were used as references to compare the bioavailability. It has been revealed that
, and MRT of microcapsule suspension were greater than those of oral solution, which results in about two-fold increases in bioavailability. Therefore, in conclusion, the carbopol-gelatin microcapsule of acyclovir might be evaluated as an effective oral controlled release preparation which could increase the bioavailability of acyclovir.
Albumin-Crosslinked PVP Hydrogel as a Gastric Retention Platform
Shim, Chang-Koo ; Yeo, So-Hyeon ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 145~153
Retaining a drug in the stomach by some means is sometimes necessary to extend the G1 absorption time of the drug more than 6-8 hrs. Hydrogel has often been examined for its feasibility as a dosage form, so called platform, that could be retained in the stomach due to its excellent swelling properties in the gastric fluid. In this study, polyvinylpyrrolidone (PVP) hydrogel crosslinked by albumin or acrylated albumin was synthesized in a tablet form and evaluated for its possibility as the platform. The synthesis of the hydrogel was performed by
irradiation of N-vinyl-2-pyrrolidone (monomer) in the presence of a crosslinking agent: aqueous solution of albumin or acrylated albumin. Synthetic conditions such as radiation dose, dose rate and concentration of crosslinking agent were varied in order to optimize the swelling and mechanical properties of the hydrogels. Degree of swelling of albumin-crosslinked PVP (Al-PVP) was highly dependent on radiation dose, dose rate and albumin concentration: it was decreased as they increased. On the other hand, that of acrylated albumin-crosslinked PVP (Acryl-PVP) was almost independent on them except dose rate: it was decreased as the radiation dose rate increased. The compressive strength of the two hydrogels was decreased as the dose rate increased. Digestion of both PVP in artificial gastric fluid containing pepsin was delayed by the
irradiation. In conclusion, Al-PVP and Acry-PVP with diverse swelling and mechanical properties could be obtained by controlling synthetic conditions, mainly the irradiation dose rate.
Nuclear Magnetic Resonance Spectroscopic Study on Inclusion Complexation of Paracyclophane with Naphthalene Derivatives in Aqueous Solution
Chun, In-Koo ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 155~163
Inclusion complexation of 1,7,21,27-tetraaza[126.96.36.199]paracyclophane (CPM 55) with 2,7-dihydroxynaphthalene (2,7-DHN) or 1,3-dihydroxynaphthalene (1,3-DHN) in pD 1.17
solution was investigated by
nuclear magnetic resonance spectroscopy (NMR) using 4,4'-dimethylaminodiphenylmethane (ACM 11) as an acyclic analog of CPM 55. In CPM 55-naphthalene derivative complex, alkyl protons located in the cavity of CPM 55 were shown to be subjected to anisotropic shielding and protons of naphthalene moiety shifted remarkably to upfield. However, in ACM 11-naphthalene derivative systems, chemical shifts for protons of both DHN compounds were not significant. The remarkable chemical shift changes suggested that the naphthalene moiety of 2,7-DHN or 1,3-DHN was included in the hydrophobic cavity of CPM 55 in aqueous solution. From the continuous variation plots of induced chemical shifts of 2,7-DHN, it was found that 2,7-DHN was included in the cavity of CPM 55 at 1:1 molar stoichiometry. Both computer simulation of a inclusion complex and strong upfield chemical shift changes of 2,7-DHN protons supported the conformation of pseudoaxial inclusion as the presumed geometry of the host-guest complex.
Relationship between Plasma Concentrations of Haloperidol and Its Metabolite, Reduced Haloperidol, and Clinical Response in Schizophrenia
Park, Kyung-Ho ; Kim, Mu-Jin ; Lee, Myung-Gul ; Shim, Chang-Koo ; Lee, Min-Hwa ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 165~177
The relationship between the plasma haloperidol (HP) concentration and clinical response, and the effects of its active metabolite, reduced haloperidol (RH) on clinical response of HP were investigated in schizophrenic patients. In clinical study I, with 17 schizophrenic patients (male 8, fermale 9) who were administered with three different fixed doses of HP (15, 30 and 50 mg/day) for 3 weeks, the concentrations of HP and RH in plasma and blood and clinical response had been checked before and every week during the study. The clinical response was evaluated by the method of brief psychiatric rating scale (BPRS), and relative improvement of clinical response based on baseline BPRS (before drug treatment) was calculated. The concentrations of HP and RH in plasma and blood were assayed by HPLC. In clinical study II, the plasma RH/HP concentration ratios were checked in 11 patients who were administered with high doses of HP, over 60 mg a day, because of the poor clinical response at usual doses of HP. Plasma HP concentration and relative improvement of BPRS at 3 week in schizophrenic patients showed a 'curvilinear' relationship, and the clinical response was improved relatively over 50% based on the baseline BPRS in the range of
of HP in plasma. Also, the plasma RH concentrations were increased nonlinearly as the plasma HP concentration increased, and in high plasma HP concentration, over 30 ng/mI, clinical response gradually decreased, while the plasma RH/HP concentration ratio increased nonlinearly. Blood partition coefficients of HP and RH were not changed according to daily HP dose and duration of drug therapy. From these results, it is noted that the higher plasma RH/HP concentration ratio, resulted from the accumulation of RH as HP concentration increased, might explain the 'curvilinear' decrease of HP clinical response.
Pharmacokinetic Evaluation of Flurbiprofen Sustained Release Capsule
Park, Kyoung-Ho ; Lee, Min-Hwa ; Yang, Min-Yeol ; Lee, Chong-Won ;
Journal of Pharmaceutical Investigation, volume 23, issue 3, 1993, Pages 179~186
In vitro dissolution test and pharmacokinetic study in human volunteers were conducted to evaluate the pharmacokinetic characteristics of 150 mg furbiprofen sustained-release capsule (FPSR-150). As a reference product, 50 mg flurbiprofen conventional-release capsule (FPCR-50) was used. Dissolution tests of two products were run using the paddle method in 450 : 540 (v/v %) mixture of simulated gastric and intestinal fluids (K.P. VI) by adjusting medium pH according to time. FPCR-50 was dissolved very rapidly, and it took about 1.5 hr for FPCR-50 to be dissolved over 90%, whereas 15 hr for FPSR-150. Also, in pharmacokinetic study, ten healthy male volunteers were administered one capsule of FPSR-150 or two capsules of FPCR-50 (FPCR-l00) with randomized two period cross-over study. Significant differences between FPCR-l00 and FPSR-150 were found in mean times to reach peak concentration, mean resident times and mean terminal phase halflives, while not in AUC/Dose (Student's t-test). In ANOVA for AUC/Dose to compare the bioavailabilities of two FP products, there was no significant difference. From the comparison of the simulated steady-state plasma concentration-time curves following multiple medications of FPCR-50 (3 capsules a day, dosing interval=8 hrs) and FPSR-150 (1 capsule a day) based on the above results obtained from single doses of two FP products, it was noted that the medication of FPSR-150 is more useful in clinical application rather than FPCR-50.