• Journal of Pharmaceutical Investigation
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• 제22권2호
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• pp.77-96
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• 1992

In recent years intranasal administration of drugs has received great attention as a convenient and efficent method of drug delivery because of its potential to improve the systemic effect of substances with a poor oral bioavailability. In addition to offering advantages such as rapid absorption, fast onset of action and avoiding the first -pass effect, it provides for delivery of drugs from very lipophilic drugs such as steroids to polar and hydrophilic drugs such as peptides and proteins. However, little is still known about the nature of various barriers existing in the nasal mucosae as well as mechanism by which these molecules are absorbed. This review article therefore intends to discuss nasal physiology, experimental methods and evaluation of absorption from the nasal cavity, factors influencing nasal absorption, mechanism of nasal absorption, approaches to improve the residence time and to obtain the sustained-release effect of intranasally administered drugs, promoters and mechanism for the enhancement of nasal absorption, Several examples for intranasal delivery of various systemically effective drugs will be reviewed and illustrated. Drug metabolism in the nasal mucosae and problems associated with intranasal administration of drugs will be also discussed.

• 약학회지
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• 제38권2호
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• pp.114-122
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• 1994

A study on the absorption mechanism of cefixime(CF), an oral ${\alpha}-amino$ group deficient cephalosporin antibiotic, has been undertaken through the rat jejunum and nasal cavity using an in situ simultaneous perfusion technique developed in our laboratory. CF was well absorbed in the jejunum and nasal cavity of rats at pH 5.0, but not at pH 7.0. CF absorption was studied over four orders of magnitude in concentration to determine saturability. Disappearance of CF in the perfusate followed first-order kinetics at all tested concentrations. The apparent first-order absorption rate constant was found to be dependent on the concentration over the range of $0.1\;mM{\sim}3\;mM$ in the jejunum and nasal cavity of rats. Inhibitors were added to determine the competitive inhibition of CF absorption. The presence of L-tyrosine, L-phenylalanine, alanine-alanine, glycine-glycine and cefadroxil produced the significant inhibition of CF absorption in the nasal cavity and jejunum. However, there was no evidence of the inhibition in the presence of cefazolin. In addition, The CF absorption in the nasal cavity and jejunum was inhibited significantly by ouabain and 2,4-dinitrophenol(DNP). This study suggested that CF is absorbed across the rat nasal cavity and jejunum by carrier-mediated transport mechanism and energy consuming system.

• Journal of Pharmaceutical Investigation
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• 제25권4호
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• pp.353-363
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• 1995

The purpose of this study was to investigate the intestinal and nasal absorption enhancement of cefotaxime (CTX) by ion-pairing with counterions and to design an effective oral and intranasal drug delivery system for antibiotics. Counterions for absorption promotion were cationic surfactants [cetylpyridinium chloride (CP), cetrimide (CT) and benzalkonium chloride (BA)]. In the presence of counterions, the apparent partition coefficient of cefotaxime was increased depending on the molar concentration of the counterions. Anion interference was observed for ion-pairing of cefotaxime with counterions because of the counterbalance between an anion and counterions. The present study employed the in situ simultaneous nasal and intestinal perfusion technique in rats. The apparent permeabilities $(P_{app})$ of cefotaxime were $1.43{\pm}0.04{\times}10^{-5}\;cm/sec(mean{\pm}S.E)$ in the nasal cavity and 0 in the jejunum, respectively, which indicated that the intrinsic absorptivity of cefotaxime was greater in the nasal cavity than in the jejunum. When ionupairing formers were used, the decreasing order of apparent cefotaxime permeability $(P_{app},\;10^{-5}\;cm/sec)$, corrected for surface area of absorption, was as followings: $BA\;(7.50{\pm}0.36)\;>\;CT\;(4.92{\pm}0.24)\;>\;CP\;(3.01{\pm}0.17)$ in the jejunum and $BA\;(22.31{\pm}1.36)\;>\;CP\;(18.24{\pm}0.81)\;>\;CT \;(16.22{\pm}1.87)$ in the nasal cavity. The increase in permeability of cefotaxime was about 13-fold in the rat nasal cavity and was marked in the rat jejunum for ion-pairing with counterions as compared to those without ion-pairing. The damages of jejunal and nasal mucosal membrane by counterions were observed within approximately 2hrs after removal of ion-pair of cefotaxime with counterions from the nasal cavity and jejunum. These results suggest that CP can be used as an ion-pairing former in the jejunum and CP and CT can be used as ion-pairing formers in the nasal cavity for cefotaxime, as well as for poorly absorbed drugs with a negative charge due to ionization.

• Journal of Pharmaceutical Investigation
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• 제23권2호
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• pp.71-80
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• 1993

The purpose of this study was to compare the intrinsic absorptivity of piperacillin in the jejunum and the nasal cavity, to investigate the effect of bile salts, fatty acids and their mixed micelles on the intestinal and nasal absorption of piperacilIin, to examine the reversibiIity of bile salt-fatty acid mixed micelles absorption promoting action and to design an effective intranasal drug delivery system for antibiotics. And absorption promoters used were bile salts [sodium cholate (NaC), sodium glycocholate (NaGC)], unsaturated fatty acids [oleic acid (OA), linoleic acid (LA)] and their mixed micelles (NaC-LA). The present study employed the in situ nasal and intestinal perfusion technique in rats. The apparent permeabilities $(P_{app})$ of piperacillin were $0.40{\pm}0.04{\times}10^{-5}cm/sec(mean{\pm}S.E)$ in the jejunum and $1.32{\pm}0.08{\times}10^{-5}\;cm/sec$ in the nasal cavity, which indicated that intrinsic absorptivity of piperacillin was greater in the nasal cavity than in the jejunum. When absorption promoters were used in the rat nasal cavity, the decreasing order of apparent piperacillin permeability $(P_{app},\;10^{-5}\;cm/sec)$, corrected for surface area of absorption, was NaC-LA $(4.62{\pm}0.16)$> NaC $(4.36{\pm}0.32)$>LA$(2.24{\pm}0.26)$ NaGC $(2.17{\pm}0.21)$>OA $(1.53{\pm}0.16)$. The increase in permeability of piperacillin was 3.5-fold in the rat nasal cavity and 1.5-fold in the rat jejunum for formulations containing NaC-LA mixed micelles as compared to those without absorption enhancer. The effect of NaC-LA mixed micellar solutions was synergistic and was greater than that with single adjuvant. The reversibility of nasal mucosal permeability was observed within approximately 2 hr after removal of NaCLA mixed micelles from the nasal cavity. These results suggest that NaC-LA mixed micelles can be used as nasal mucosal absorption promoters of poorly absorbed drugs.

• Journal of Pharmaceutical Investigation
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• 제24권2호
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• pp.95-104
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• 1994

Inclusion complexes of ketoconazole(KT) with ${\alpha}^_$, ${\beta}^_$cyclodextrin(CD) and $dimethy1-{\beta}-cyclodextrin$ (CD) and $dimethy1-{\beta}-cyclodextrin(DM{\beta}CD)$ as nasal absorption enhancer were prepared in 1: 2 molar ratios by freeze-drying and solvent evaporation methods. In order to compare with the intrinsic absorptivity of KT in the jejunum(J) and the nasal cavity(N), the in situ simultaneous perfusion method was employed. The in situ recirculation study revealed that KT-CD inclusion complexes with the greater stability constant and the faster dissolution rate proportionally increased the absorption of KT in the J and N of rats. The rank order of apparent KT permeability$(P_{app}\;:\;cm/sec\;{\time}\;1O^{-5}{\pm}S.E.)$, corrected by surface area of absorption, was $5.10{\pm}0.3(N,\; KT-DM{\beta}CD)$ )> $4.13{\pm}0.4(N,\;KT-{\beta}-CD)$ )> $3.52{\pm}0.2(N,\;KT-{\alpha}-CD)$ )> $2.76{\pm}0.3(J,\; KT-DM{\beta}CD)$ )> $2.61{\pm}0.5(J,\;KT-{\beta}-CD)$ )> $2.42{\pm}0.4(J,\;KT-{\alpha}-CD)$ at pH 4.0. The in crease in permeability of $KT-DM{\beta}CD$ inclusion complex was 2.6 folds in the J and 4.5 folds in the N when the perfusing solution was changed from the buffer(pH 4.0) to saline. The absorption rate of $KT-DM{\beta}CD$ inclusion complex after nasal administration was more rapid than those of ketoconazole alone and $KT-DM{\beta}CD$ inclusion complex after oral administration to rats. In comparision with an oral administration of ketoconazole suspension in corn oil, the relative bioavailability was calculated 137.3% for the oral and 195.0% for nasal $KT-DM{\beta}CD$ inclusion complex in rats. The present results suggest that $KT-DM{\beta}CD$ inclusion complex may serve as a potential nasal absorption enhancer for the nasal delivery of ketoconazole.

• 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.

• Archives of Pharmacal Research
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• 제24권3호
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• pp.219-223
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• 2001

Nasal absorption of procyclidine, a synthetic anticholinergic compound, was investigated in Wistar rats and Beagle dogs. The dosing solution was prepared by dissolving$^{14}C$-procyclidme in 50% ethanolic saline. The dosing solution was administered intravenously and intranasally to rats at a dose of 0.6 mg/kg (i.e., $60{\mu}$l/kg in the form of a 1% w/v solution), and intravenously, orally and intranasally to doss at a dose of 0.3 mg/kg(i.e., $6{mu}$l/kg in the form of a 5% w/v solution). Blood samples were taken from an artery of the animals through the catheter for periods of 1200 (for rats) and 1440 min (for dogs), and the radioactivity in the samples was determined by liquid scintillation counting. The nasal bioavailability of Procyclidine in rats and dogs, based on the radioactivity was calculated to be 81.1 and 98.6% respectively. In both rats and dogs, the plasma profiles of procyclidine following nasal administration were very close to those following intravenous administration, leading to nearly superimposable profiles between the two protocols. In dogs, nasal administration resulted in significantly higher plasma concentrations during the first 30 min period compared to oral administration, suggesting the superiority of the nasal route over the oral route in terms of a prompt expression of the pharmacological effect of the drug. The results obtained in this study indicate that procyclidine is rapidly and nearly completely absorbed via the nasal route. In conclusion, nasal administration represents a viable alternative to intravenous administration in the case of procyclidine.

• Journal of Pharmaceutical Investigation
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• 제24권3호spc1호
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• pp.59-66
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• 1994

The objective of this study was to determine the influence of drug lipophilicity on the extent of ocular and systemic absorption following topical solution instillation in the pigmented rabbit. ${\beta}-Blockers$ of various lipophilicity were chosen as model drugs, $25\;{\mu}l$ of a 15 mM drug solution in isotonic pH 7.4 buffer was instilled, and ocular tissue and plasma drug concentrations were monitored. Ocular absorption was apparently increased in all eye tissues, but non-corneal absorption ratio was decreased by increasing of drug lipophilicity. Systemic bioavailability was ranged from 61% for atenolol to 100% for timolol, and at least 50% of the systemically absorbed drug reached the blood stream from the nasal mucosa. Occluding the nasolacrimal duct for 5 min reduced the extent of systemic absorption of timolol and levobunolol, but did not do so for atenolol and betaxolol. Taken together, the ocular absorption of topically applied ophthalmic drugs would be modest for lipophilic drugs. By contrast, the systemic bioavailability would be modest for drugs at the extremes of lipophilicity, and the nasal contribution to systemically absorbed drug diminished with increasing of drug lipophilicity.

• Journal of Pharmaceutical Investigation
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• 제40권6호
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• pp.321-332
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• 2010

Growing interest in the nasal route as a drug delivery system calls for a reliable in vitro model which is crucial for efficiently evaluating drug transport through the nasal cells. Various in vitro cell culture systems has thus been developed to displace the ex vivo excised nasal tissue and in vivo animal models. Due to species difference, results from animal studies are not sufficient for estimating the drug absorption kinetics in humans. However, the difficulty in obtaining reliable human tissue source limits the use of primary culture of human nasal epithelial cells. This shortage of human nasal tissue has therefore prompted studies on the "passage" culture of nasal epithelial cells. A serially passaged primary human nasal epithelial cell monolayer system developed by the air-liquid interface (ALI) culture is known to promote the differentiation of cilia and mucin gene and maintain high TEER values. Recent studies on the in vitro nasal cell culture systems for drug transport studies are reviewed in this article.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1998년도 Proceedings of UNESCO-internetwork Cooperative Regional Seminar and Workshop on Bioassay Guided Isolation of Bioactive Substances from Natural Products and Microbial Products
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• pp.137-137
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• 1998

Stability, efficacy, absorption and toxicity of a new nasal spray formulation including salmon calcitonin were studied in the laboratory animals. After the effects of many excipients on the stability of salmon calcitonin were evaluated using HPLC system, we selected taurine. Our experimental composition of salmon calcitonin contains taurine as a stabilizer and HPMC (hydroxypropylmethyl cellulose) as an adhesive polymer. After intranasal administration of salmon calcitonin formulations, Mia$\^$(R)/, Men$\^$(R)/ and experimental composition, 22 IU to rats, the reduction percentages of calcium concentration in plasma (ΔD%) were 16.3%, 12.9% and 20.8%, respectively. After intranasal administration of Mia$\^$(R)/, Men$\^$(R)/ and experimental composition to rats, C$\sub$MAX/ (205${\pm}$161, 244${\pm}$117, and 330${\pm}$202 pg/$m\ell$, respectively) and AUC (41585${\pm}$22070, 41191${\pm}$19125, and 63357${\pm}$43126 pg. min/$m\ell$, respectively) were calculated. The permeation coefficients 10$\^$-7/,cm/sec) of salmon calcitonin in Mia$\^$(R)/, Men$\^$(R)/ and experimental composition using Ussing chamber with rabbit nasal mucosa were 4.7${\pm}$1.5, 0.75${\pm}$0.4 and 5.3${\pm}$1.1, respectively. The experimental composition with taurine and HPMC was proved to be excellent because it improved the stability of salmon calcitonin and inhanced the absorption of salmon calcitonin and was not irritative to the nasal mucosa.