• Journal of Pharmaceutical Investigation
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• 제36권6호
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• pp.363-369
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• 2006

Granisetron is a selective 5-HT3 receptor antagonist that is used therapeutically for the prevention of vomiting and nausea associated with emetogenic cancer chemotherapy. Although this drug is commercially available for intravenous and oral dosage, there is a need for intranasal delivery formulations in specific patient populations in which the use of these dosage forms may be unfeasible and/or inconvenient. A rapid and specific high-performance liquid chromatography method with mass spectrometric detection(LC-MS) was developed and validated for the analysis of granisetron in plasma after nasal administration in rats. This method has been validated for concentrations ranging from 5 to 1000 ng/ml with simple treatment. This technique has high level reproducibility, accuracy, and sensitivity. The method described was found to be suitable for the analysis of all samples collected during preclinical pharmacokinetic investigations of granisetron in rats after nasal administration. This study was aimed to investigate the feasibility of nasal delivery of granisetron for the elimination of vomiting. The effects of osmolarity, dosage volume at the same dose and applied dose on the nasal absorption of granisetron in rats were observed. No significant difference in the effect of osmolarity and dosage volume at the same dose was observed. As the applied dose of granisetron in nasal formulation increased, the absorption increased linearly. Based on these results it appears that only the applied dose(drug mass) determines the nasal absorption of granisetron. The bioavailability of granisetron on nasal administration of 4 mg/kg appeared to be comparable to that of intravenous administration of the same dose. These results suggest that granisetron can be efficiently delivered nasally and the development of nasal formulation will be feasible.

• Journal of Pharmaceutical Investigation
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• 제33권2호
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• pp.85-89
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• 2003

Piroxicam-arginine complex was prepared to improve the solubility and dissolution rate of poorly water-soluble piroxicam. Its formation was identified by infrared spectrophotometry, differential thermal analysis and dissolution rate. Piroxicam complex dispersible tablets, commercial $Feldene^{\circledR}$ dispersible tablets and piroxicam physical mixture hard capsules were prepared to compare dissolution rate in water. Dissolved amounts (%) after 15 mins of piroxicam complex dispersible tablets, commercial $Feldene^{\circledR}$ dispersible tablets and piroxicam physical mixture hard capsules were 98%, 48% and 10%, respectively. The solubility of complex in water was significantly higher than that of piroxicam itself. In vivo, pharmacokinetic parameters were obtained after oral administrations of piroxicam complex and physical mixture at a does of 2 mg to New Zealand White Rabbit. The $C_{max}$ of piroxicam complex was similar to that of piroxicam. However, there were much difference between the two formulations with regard to $T_{max}$ and AUC. The $T_{max}$ of piroxicam alone was 4 hours, but that of piroxicam complex was 0.8 hours. In addition, the AUC of piroxicam complex was 1.38 times greater than that of piroxicam alone.

• Journal of Pharmaceutical Investigation
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• 제38권3호
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• pp.171-176
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• 2008

Talniflumate is a nonsteroidal anti-inflammatory drug (NSAID), which has been used treat of rheumatoid diseases, is insoluble in water, therefore it has low bioavailability after oral administration. The purposes of this study were to prepare O/W or W/O microemulsions for solubilization of poorly water soluble drug, talniflumate and to formulate into other dosage form. For this purpose, we made O/W or W/O microemulsion with oil(soybean oil, IPM), surfactant (Cremophor $EL^{(R)}$, Tween 80) and water or propylene glycol and evaluated solubility of talniflumate. The microemulsion systems were very stable and showed transmittance above 95% without flocculation or aggregation. Especially, the solubility of talniflumate in the formulation B-1 containing 18% of isopropyl myristate and 71% of tween 80 was 10 times higher than that of other O/W microemulsions. The addition of propylene glycol and N-methylglutamine to the fomulation B-1 showed excellent capacity on the solubilization of talniflumate and the percentage was almost 2.0%. These results suggest that the microemulsion system may be promising for the solubility improvement of talniflumate.

• 한국임상약학회지
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• 제20권3호
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• pp.193-199
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• 2010

Tacrolimus, an immunosuppressant prescribed against graft-versus-host disease (GVHD) in patients with allogeneichematopoietic stem cell transplantation (HSCT), is affected to change its pharmacokinetic properties by various factors. For this reason, it is needed a close monitoring to adjust dosage amount in order to optimize the blood concentration of tacrolimus is located within the effective range. According to our in-house study, 62% of HSCT-patients were needed dosage-adjustment and it is necessary to optimize the current immunosuppressive regimen in clinical settings. A retrospective study was designed to evaluate the dosing regimen (converting ratio of IV:PO=1:4) of tacrolimus in HSCT patients (n=62). After collecting data from patient's profile and medical record, pharmacokinetic parameters were calculate and compared between the estimated and the actual values in the selected subjects (n=58). It was found that the bioavailabilty (BA) of oral tacrolimus was 40.5% very much different from that is known as 25%. It implies that the current protocol has a potent risk causes dose-related toxicities to the patients. Furthermore, analyses among factors demonstrated that there was no statistical significance between BA of tacrolimus and the variable factors. In the clinical perspectives, the current converting ratio of tacrolimus in patients with HSCT to be re-considered and an appropriate and optimal alternative regimen should be adopted to prevent GVHD and to increase the quality of life of patients.

• Biomolecules & Therapeutics
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• 제26권3호
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• pp.274-281
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• 2018

A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately $1.2{\pm}0.4h$ and $1.4{\pm}0.5h$, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of $31.5{\pm}5.7%$ was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at $46.5{\pm}3.5ng/g$ in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, $46.5{\pm}3.5ng/g$ donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.

• 대한화장품학회지
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• 제25권4호
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• pp.145-154
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• 1999

A novel retinol derivative, polyethoxylated retinamide(Medimin A) was synthesized, as an anti-aging agent. Collagen synthesis, skin permeation, stability, and toxicity of Medimin A were evaluated and compared with those of retinol and retinyl palmitate. In vitro collagen synthesis was evaluated by quantitative assay of $[^3H]-proline$ incorporation into collagenase sensitive protein in fibroblast cultures. For in vitro skin permeation experiments, Franz diffusion cells(effective diffusion area: 1,766 $cm^2$) and the excised skin of female hairless mouse aged 8 weeks were used, The stabilities of retinoids were evaluated at two different temperature($25^{\circ}C\;and\;40^{\circ}C$) and under UV in solubilized state and in O/W emulsion. To estimate the safety, acute oral toxicity, acute dermal toxicity, primary skin irritation, acute eye irritation and human patch test were performed. The effect of Medimin A on collagen synthesis was similar to that of retinol. The skin permeability of Medimin A was higher than those of retinol and retinyl palmitate. The Medimin A was more stable than retinol and retinyl palmitate. Medimin A was nontoxic in various toxicological tests. These results suggest that Medimin A would be a good anti-aging agent for enhancing bioavailability and stability.

• BMB Reports
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• 제48권7호
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• pp.419-425
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• 2015

Ginseng has been widely used for therapeutic and preventive purposes for thousands of years. However, orally administered ginseng has very low bioavailability and absorption in the intestine. Therefore, fermented ginseng was developed to enhance the beneficial effects of ginseng in the intestine. In this study, we investigated the molecular mechanisms underlying the anti-inflammatory activity of fermented wild ginseng (FWG). We found that FWG significantly alleviated the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis mouse model, and decreased expression level of pro-inflammatory cytokines in colonic tissue. Moreover, we observed that FWG suppressed the infiltration of macrophages in DSS-induced colitis. FWG also attenuated the transcriptional activity of nuclear factor-κB (NF-κB) by reducing the translocation of NF-κB into the nucleus. Our data indicate that FWG contains anti-inflammatory activity via NF-κB inactivation and could be useful for treating colitis. [BMB Reports 2015; 48(7): 419-425]

• Journal of Pharmaceutical Investigation
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• 제31권1호
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• pp.37-41
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• 2001

Various characteristics of polyethylene oxide (PEO) are useful for drug delivery systems. In this study, PEO was used as a sustained release matrix system containing cefatrizine propyleneglycol (Cefa-PG) which is a new semi-synthetic broad-spectrum and orally active cephalosporin. Five kinds of sustained release matrix tablets were formulated with various content of PEO and other ingredients. And three types of matrix tablets were formulated of which compositions were the same but the hardness was different. It was found that PEO content influenced drug release rate. Increasing PEO content, the drug release rate from matrix tablets was decreased. In addition, Avicel, one of the ingredients of matrix components, changed the drug release from the sustained release PEO matrix tablets. With increasing Avicel content, the rate of drug release was increased. For the effect of hardness of matrix tablets, the rate of drug release is decreased with increasing hardness. In comparison of bioavailability parameters after oral administration of Cefa-PG PEO matrix tablets and general Cefa-PG capsule in beagle dog, the sustained release PEO matrix tablets is more useful than a general dosage form. $AUC^{0-12}$ of the sustained release PEO matrix tablet and the general dosage form was 1.16 and 0.644 respectively.

• Biomolecules & Therapeutics
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• 제5권4호
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• pp.419-425
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• 1997

The pharmacokinetics of DWP20364 (1-cyclopropyl -5-amino-6,8-difluoro-7-(2,7-diazabiclo [3,3,0] oct-4-ene-7-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid), a novel fluoroquinolone containing C7-bicyc-talc structure, were compared with those of ciprofloxacin (CPFX) after single intravenous (i.v.) and oral (p.o.) administration to rats using microbiological assay (bioassay). After i.v. administration to rats, the plasma concentrations of the two drugs declined biexponentially. The terminal half-lives (t$_{1}$2$\beta$/) of DWP20364 were 110$\pm$ 13.2 min and 117$\pm$3.09 min after i.v. and p.o. administration, respectively, and they were significantly higher than those of CPFX (45.5$\pm$9.52 min and 48.3$\pm$ 12.1 min, respectively). Similar results were also obtained from plasma concentrations and area under the plasma concentration-time curves. The total body clearance of DWP20364, 7.82$\pm$0.37 ml/min/kg was significantly slower than that of CPFX, 27.3 $\pm$ 11.1 m1/ min/kg. Above data suggested that the antimicrobial activity of DWP20364 could be longer than that of CPFX. The urinary recovery after i.v. and p.o. administration of DWP20364 was significantly lower than those of CPFX suggesting that the effect of DWP20364 on urinary tract infection could be lower than that of CPFX. The serum protein binding values of DWP20364 at 2$\mu$g/ml were apparently 91.5~93.1% in rats and human. DWP20364 was distributed by the order of liver, lung, kidney, sf)leon, heart, muscle and brain collected at 30 min after orally administered.

• Archives of Pharmacal Research
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• 제18권4호
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• pp.219-223
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• 1995

Rectal absorption of opeprazole, a proton pump inhibitor, from suppositories was studied in rabbits. The suppositories were prepared by the conventional melting method with two types of bases, water-soluble polyethylene glycol (PEG) 4000 and oil-soluble Witepsol H15 bases, and administered intractally (ir) to rabbits at a dose of 10 mg omeprazole/kg. The plasma omeprazole concentration-time profiles of the two suppositories were compared with those following intravenous 9iv) administration of the same dose. There were no significant differences between the two suppositories in bioabailabilities and peak plasma concentrations $(C_{max})$. Bioavaiabilities and $C_{max}$ of PEG- and Witpsol suppositories were 30.3 and 33.9%, and 7.0 and $5.6\mug/ml$, resepectively. However, PEG suppository showed significantly (p<0.05) shorter time to reach peak plasma concentration $(T_{max})$ mean absorption time (MAT) and mean residence time in the plasma (MRT) than Witepsol suppository. The $T_{max}$ MRT nad MAT were 25.0, 83.0 and 38.5 min for PEG syppository, but were 90.0, 122.5 and 78.0 min for Wiepsol supposiotory, respectively. These differences between thw two suppositories could be explanined by the difference in the in vitro dissolution rates between the suppositories. The dissolution of omeprazole form PEG suppository was reportedly much faster than that from Witepsol suppository. It suggests that plasma profiles of omeprazole, especially $C_{max}$ MAT and MRT, could be controlled by modifying the in vitro dissolution rate of the drug from the suppositories. Above results suggest that rectal suppository is worth developing as an alternative dosage form of omeprazole to the conventional oral preparations which need sophisticated treatments, such as enterix coating, to prevent acid degradation of the drug in the stomach fluid.