• 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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• 제22권3호spc1호
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• pp.1-15
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• 1992

• 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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• 제22권2호
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• pp.97-104
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• 1992

The purpose of this study was (i) to determine whether protease inhibition by medium chain fatty acids such as sodium caprate, sodium caprylate and sodium laurate led to suppression of insulin proteolysis over a range of insulin concentrations and (ii) elucidate preventing effect of the enhancers on molecular self-association of insulin in pH 7.4 phosphate buffer isotonic solution. To this end, the rate of insulin proteolysis in nasal tissue supernatants of the albino rabbits was determined in the presence of $0.1{\sim}2%$ sodium caprylate, sodium caprate and sodium laurate at insulin concentrations ranging from $5\;to\;100\;{\mu}M$. At fatty acid salts concentration lower than 0.5%, insulin proteolysis was accelerated but the enhancers of high concentration (>1%) reduced the rate of insulin proteolysis. These effects were dependent upon insulin concentration and chain length of fatty acid salts. Circular dichroism spectra of insulin solutions were then determined. Monomer fraction of insulin was increased with increasing sodium caprate. Therefore, half-life decrease of insulin at low concentrations of the enhancers was attributed to deaggregation of insulin by the enhancers, increasing the proportion of monomers available for nasal proteolysis. And the increase of half-life at high concentration of the enhancers was attributed to inhibitory effect on protease rather than the effect of monomer fraction.

• 약학회지
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• 제38권4호
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• pp.440-450
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• 1994

Due to the limited bioavailability of $[D-Ala^6]$LHRH from nonparenteral transmucosal sites of administration, enhancement of mucosal permeability by coadministration of several protease inhibitors and/or penetration enhancers were studied in rabbit mucosa. As a reliable bioassay method for $[D-Ala^6]$LHRH, ovulation-inducing effect were measured after vaginal administration in the rat. The permeation of $[D-Ala^6]$LHRH through the mucosal membrane of rabbit mounted on George-Grass diffusion cells were examined in the presence of polyoxyethylene 9-lauryl ether (POE), ${\beta}$-cyclodextrin$({\beta}-CyD)$ or ethylene diamine tetra acetate disodium salt(EDTA). The vaginal membrane showed higher permeability of $[D-Ala^6]$LHRH than the rectal and nasal membrane. POE and ${\beta}-CyD$ showed a small promoting effect on the membrane permeation of $[D-Ala^6]$LHRH, but EDTA showed significant enhancement. Ovaluation was enhanced by the coadministration of sodium laurate(0.5%), a protease inhibitor but was not enhanced by EDTA, a penetration enhancer. On the other hands, coadministration of sodium tauro 24,25 dihydrofusidate(1%) and EDTA(2%) enhanced the ovulation inducing-effect 2.8 times. These results suggest that the vaginal administration of $[D-Ala^6]$LHRH with STDHF or sodium laurate as a protease inhibitor, and EDTA as a penetration enhancer, may become an elective method for transmucosal delivery of $[D-Ala^6]$ LHRH.