• Biomolecules & Therapeutics
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• v.7 no.3
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• pp.263-270
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• 1999

The in vitro permeation of thyrotropin-releasing hormone (TRH) through rabbit nasal, rectal and duodenal mucosae was studied in the absence and presence of an enzyme inhibitor and permeation enhancer. TRH in the donor and receptor solutions was assayed by HPLC. When thimerosal (TM, 0.5 mM) was added to the donor cell as an inhibitor, the permeation rate of TRH (200 $\mu\textrm{g}$/ml) increased linearly as a function of time. Fluxes of TRH through the nasal, rectal and duodenal mucosae were found to be 33.3$\pm$5.9, 11.8$\pm$1.9 and 9.6$\pm$0.7 $\mu\textrm{g}$/$\textrm{Cm}^2$/hr, respectively. The addition of sodium glycocholate, glycyrrhizic acid ammonium salt, sodium taurodihydrofusidate or L-$\alpha$-lysophosphatidylcholine to the donor solution containing TM did not result in the significant increase of permeation flux except for the duodenal mucosa, comparing with that in the presence of TM alone. Consequently, it was suggested that the nasal route was advantageous for systemic delivery of TRH, and the addition of TM and/or an enhancer was necessary to maximize the transmucosal permeation of TRH.

• Journal of Pharmaceutical Investigation
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• v.31 no.1
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• pp.27-35
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• 2001

To evaluate the site-specific permeation of aspalatone (acetylsalicylic acid maltol ester, AM) through gastrointestinal tract, the enzymatic degradation and permeation studies were carried out using gastric, duodenal and jejunal mucosae of rabbits. It was found that $15.2{\pm}11.4%$, $11.6{\pm}5.2$ and $0.8{\pm}0.6%$ of the donor dose of AM, salicylmaltol (SM) and aspirin (ASA) permeated through the upper gastric mucosa after 8 hr of permeation, respectively. After 8 hr of AM permeation, SM and ASA were measured to be $15.0{\pm}1.7$ and $2.6{\pm}0.8%$ of the dose in the donor solutions, respectively, and salicylic acid (SA) was not detected even after 6 hr, suggesting a very low gastric damage. For the gastric mucosa, the increase of donor dose from 100 to $1,000\;{\mu}g/ml$ increased the permeation flux dose-dependently (r=0.9905). For the duodenal and jejunal mucosae, however, AM was fully degraded into SM and SA due to the esterase activities within 30 min. AM and ASA were not detected in the receptor solution. This result indicates that AM is not a prodrug of ASA. Addition of potassium fluoride (0.5%) into the donor solution delayed the degradation of AM, but did not allow the permeation through duodenal mucosa even by the inhibition of esterase activity. The addition of $dimethyl-{\beta}-cyclodextrin$ and $2-hydroxypropyl-{\beta}-cyclodextrin$ (5%) into the donor solutions also did not show favorable effects on the permeation of AM through various mucosae. In comparison of permeation rates of AM and ASA through the upper gastric mucosa, the flux of ASA was 4.2 times faster than AM based on the molar concentration. ASA also was fully degraded in the donor solutions faced with duodenal and jejunal mucosae within 2 hr, and was not detected in the receptor solution, suggesting a slower metabolism compared with AM.

• Journal of Pharmaceutical Investigation
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• v.39 no.2
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• pp.97-106
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• 2009

Although lovastatin (LS) is widely used in the treatment of hypercholesterolemia, its bioavailability is known to be around 5%. This study was aimed to increase the solubility and dissolution-permeation rates of LS using solid dispersions (SDs) with bile salts. The solubilities of LS in water, aqueous bile salt solutions and non-aqueous vehicles were determined, and effects of bile salts on the cellulose or duodenal permeation of LS from SDs were evaluated using a horizontal permeation system. SDs were prepared at various ratios of LS to carriers, such as sodium deoxycholate (SDC), sodium glycocholate (SGC) and/or 2-hydroxypropyl-$\beta$-cyclodextrin (HPCD). The addition of bile salts (25 mM) in water increased markedly the solubility of LS by the micellar solubilization. Some non-aqueous vehicles were effective in solubilizing LS. From differential scanning calorimetric studies, it was found that the crystallinity of LS in SDs disappeared, indicating a formation of amorphous state. The SDs showed markedly enhanced dissolution compared with those of their physical mixtures (PMs) and drug alone. In the dissolution-permeation studies using a cellulose membrane, the donor and receptor solutions were maintained as a sink condition using pH 7.0 phosphate buffer containing 0.05% sodium lauryl sulfate (SLS). The flux of LS alone was nearly same as that of LS-SDC-HPCD (1:3:6) PM. However, the flux of LS-SDC-HPCD (1:3:6) SD slightly increased compared with drug alone and PM, suggesting that entrapment of LS in micelles does not significantly hinder the permeation across cellulose membrane. In the dissolution-duodenal permeation studies using a LS-HPCD-SDC (1:3:6) SD, the addition of various bile salts in donor solutions (25 mM) enhanced the permeation of LS markedly, and the fluxes were found to be $0.69{\pm}0.41$, $0.87{\pm}0.51$, $0.84{\pm}0.46$, $0.47{\pm}0.17$ and $0.68{\pm}0.32{\mu}g/cm^2/hr$ for sodium cholate (SC), SDC, SGC, sodium taurodeoxycholate (STDC) and sodium taurocholate (STC), respectively. The stepwise increase of donor SGC concentration increased the flux dose-dependently. From the relationship of donor SGC concentration and flux, the concentration of SGC initiating the permeation across the duodenal mucosa was calculated to be 11.1 mM, which is nearly same as the critical micelle concentration (CMC, 11.6 mM) of SGC. However, with no addition of bile salts and below CMC, the permeation was very limited and irratic, indicating that LS itself is very poor permeable. Higher protions of bile salt in SD such as LS-SDC or LS-SGC (1 : 49 and 1 : 69) showed highly promoted fluxes. In conclusion, SD systems with bile salts, which may form their micelles in intestinal fluids, might be a promising means for providing enhanced dissolution and intestinal permeation of practically insoluble and non-absorbable LS.

• YAKHAK HOEJI
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• v.42 no.1
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• pp.59-69
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• 1998

To increase the solubility of quercetin, which is a practically insoluble flavonoid of Ginkgo biloba leaf, the effects of nonaqueous vehicles. Their cosolvents, water-sol uble polymers and modified cyclodextrins (CDs) were observed. Polyethylene glycols, diethyleneglycol monoethyl ether, and their cosolvents with water showed a good solvency toward quercetin. Also the aqueous solutions of povidone, copolyvidone and Cremophor RH 40 was effective in solubilizing quercetin. Complex formation of quercetin with ${\beta}$-cyclodextrin (${\beta}$-CD), dimethyl-${\beta}$-cyclodextiin (DMCD), 2-hydroxypropyl-${\beta}$-cyclodextrin (HPCD) and ${\beta}$-cyclodextrin sulfobutyl ether (SBCD) in water was investigated by solubility method at $37^{\circ}C$. The addition of CDs in water markedly increased the solubility of quercetin with increasing the concentration. AL type phase solubility diagrams were obtained with CDs studied. Solubilizaton efficiency by CDs was in the order of SBCD >> DMCD > HPCD > ${\beta}$-CD. The dissolution rates of quercetin from solid dispersions with copolyvidone, povidone and HPCD were much faster than those of drug alone and corresponding physical mixtures, and exceeded the equilibrium solubility (3.03${\pm}1.72{\mu}$g/ml). The permeation of quercetin through duodenal mucosa did not occur even in the presence of enhancers such as bile salts, but the permeation was observed when the mucus layer was scraped off. This was due to the fact that quercetin had a strong binding to mucin ($58.5{\mu}$g/mg mucin). However rutin was permeable to the duodenal mucosa. The addition of enhancer significantly increased the permeation of rutin in the order of sodium glycocholate.

• Journal of Pharmaceutical Investigation
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• v.30 no.2
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• pp.119-125
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• 2000

In an attempt to develop a non-aqueous liquid formulation of practically insoluble biphenyl dimethyl dicarboxylate (DDB), dissolution and permeation studies were performed. Various non-aqueous DDB solutions were formulated and filled into empty hard capsules. Dissolution rates of a new formulation were compared with those of commercially available DDB preparations using one and eight dose units. Dissolution rates after 2 hr of DDB tablets (DDB 25 mg), hard capsules (DDB 7.5 mg) and soft capsules (DDB 7.5 mg) on market and new formulation (DDB 7.5 mg) were 6.3, 15.0, 84.5 and 98.0%, respectively. Higher doses (8 units) resulted in a supersaturation within one hr of dissolution, and dissolved amounts were reduced markedly. Due to the saturation and precipitation, a directly proportional dose-dissolution relationship was not observed. The addition of copolyvidone and/or glycyrrhizic acid ammonium salt to DDB solution in polyethylene glycol 300 and 400 inhibited the formation of precipitates during dissolution and markedly enhanced the rabbit duodenal permeation of DDB. From the site-specific gastrointestinal permeation studies, it was found that permeation rates of DDB after mixing of non-aqueous DDB solutions with aqueous buffered solutions were faster in the order of $rectal\;<\;colonic\;{\risingdotseq}\;ileal\;{\risingdotseq}\;duodenal\;<\;jejunal\;<\;gastric$.

• YAKHAK HOEJI
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• v.56 no.3
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• pp.164-172
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• 2012

This study was aimed to increase the solubility, dissolution and permeation rates of atorvastatin calcium (ATC) using bile salt and/or 2-hydroxypropyl-${\beta}$-cyclodextrin ($HP{\beta}CD$). From solubility studies, sodium deoxycholate (SDC) among bile salts studied was found to have the highest solubilizing effect on ATC ($4.4{\pm}0.4$ mg/ml), and the order of increasing solubility was SDC>sod. cholate>sod. glycocholate>sod. taurodeoxycholate>sod. taurocholate>conjugated bile acid. ATC solid dispersions were prepared at various ratios of drug to SDC and/or $HP{\beta}CD$, and evaluated by differential scanning calorimetry (DSC), dissolution studies and dissolution-permeation studies. DSC curves showed amorphous state of ATC in the physical mixture and solid dispersion. Dissolution rates of ATC-SDC solid dispersions and physical mixture were markedly increased at pH 6.8, but decreased at pH 1.2 with greater proportions of SDC due to the precipitation of SDC, compared with that of drug alone. On the other hand, dissolution rates of ATC-$HP{\beta}CD$ solid dispersion and physical mixture at pH 1.2 were varied with the ratio of drug to carriers. From duodenal permeation studies, it was found that fluxes of ATC (donor dose: 0.5 mg/3.5 ml) in the presence of 25 mM sodium glycocholate, SDC, sod. cholate and sod. taurocholate $(5.7{\pm}0.9$, $5.6{\pm}0.9$, $4.8{\pm}0.7$ and $4.6{\pm}0.9\;{\mu}g/cm^2/hr$, respectively) were enhanced, compared with drug alone ($3.4{\pm}0.9\;{\mu}g/cm^2/hr$). In the dissolution-permeation studies, 1 : 9 : 10 (w/w) ATC-SDC-$HP{\beta}CD$ solid dispersion increased the flux 2.2 times, compared with 1 : 5 : 4 (w/w) ATC-lactose-corn starch mixture as control. In conclusion, solid dispersions with bile salt and $HP{\beta}CD$ were found to be an effective means for increasing the dissolution and permeation rates of ATC.

• Journal of Pharmaceutical Investigation
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• v.24 no.2
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• pp.57-65
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• 1994

To increase the dissolution rate of practically insoluble biphenyl dimethyl dicarboxylate (DDB), various solid dispersions were prepared with water soluble carriers, such as povidone (PVP K-30), poloxamer 407, sodium deoxycholate (SDC) and polyethylene glycol (PEG) 6000, at drug to carrier ratios of 1:3, 1:5 and 1:10 (w/w) by solvent or fusion method. Dissolution test was performed by the paddle method. The dissolution rate of DDB tablets (25 mg) on market was found to be very low (11.44, 9.02 and 6.42% at pH 1.2, 4.0 and 6.5 after 120 min, respectively). However, dissolution rates of DDB from various solid dispersions were very fast and reached supersaturation within 10 min. DDB-PEG 6000 solid dispersion appeared to be better in enhancing the in vitro dissolution rate than others. Furthermore, the incorporation of DDB and phosphatidylcholine (PC) into ${\beta}-cyclodextrin$ at ratios of 1:2:20, 1:5:20 and 1:10:20 resulted in a 4.9-, 11.2- and 19.6-fold increase in DDB dissolution after 120 min as compared with the pure drug, respectively. This might be attributed to the formation of lipid vesicles which entrapped a certain concentration of DDB during dissolution. On the other hand, the permeation of DDB through rabbit duodenal mucosa was examined using some enhancers such as SDC, sod. glycocholate (SGC) and glycyrrhizic acid ammonium salt (GAA). Only trace amounts of DDB were found to permeate through deuodenal mucosa in the absence of enhancer. SDC was found to markedly decrease the permeation flux of DDB, however, SGC and GAA (5 mM) enhanced the flux of DDB 1.6 and 2.4 times higher as compared with no additive, respectively.

• Journal of Pharmaceutical Investigation
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• v.29 no.3
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• pp.227-234
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• 1999

Solid dispersions were prepared to increase the dissolution rate of biphenyl dimethyl dicarboxylate (DDB) using water-soluble carriers such as povidone, copolyvidone, $2-hydroxypropyl-{\beta}-cyclodextrin (HPCD)$, sodium salicylate or sodium benzoate by solvent evaporation method. Solid dispersions were characterized by infrared spectrometry, differential scanning calorimetry (DSC) and powder X-ray diffractometry, dissolution and permeation studies. DDB tablets (7.5 mg) were prepared by compressing the powder mixtures composed of solid dispersions, lactose, com starch, crospovidone and magnesium stearate using a single-punch press. DDB capsules (7.5 mg) were also prepared by filling the mixtures in empty hard gelatin capsules (size No.1). From the DSC and powder x-ray diffractometric studies, it was found that DDB was amorphous in the HPCD or copolyvidone solid dispersions. Dissolution rates after 10 min of DDB alone and solid dispersions (1 : 10) in sodium benzoate, sodium salicylate and copolyvidone were 11.8, 23.5, 22.8 and 82.5%, respectively. Dissolution rates of DDB after 30 min from 1 : 10 and 1 : 20 copolyvidone solid dispersions were 80.5 and 95.0%, respectively. For the DDB tablets prepared using solid dispersions (1 : 20), the initial dissolution rate was dependent on carrier material, and was ranked in order, $Kollidon\;30\;{\ll}$ copolyvidone < HPCD. For the HPCD solid dispersion tablets, dissolution rate reached 97.4% after 15 min, but thereafter slowly decreased to 80.7% after 2 hr due to the precipitation of DDB. However, in the case of copolyvidone solid dispersion tablets, dissolution increased linearly and reached 93.4% after 2 hr. Reducing the volume of test medium from 900 to 300 ml markedly decreased the dissolution rate of the tablets containing 1 : 20 HPCD solid dispersions and 1 : 10 copolyvidone solid dispersion. For 1 : 20 copolyvidone solid dispersion tablets, there was no significant change in dissolution rate up to 1 hr with different volumes of test medium. Preparation of the copolyvidone solid dispersion (1 : 20) in capsules markedly delayed the dissolution (31.2 % after 2hr) due to the limited diffusion within capsules. The permeation rate $(13.4\;g/cm^2\;after\;8\;hr)$ of DDB through rabbit duodenal mucosa from copolyvidone solid dispersion (1 : 10) was markedly enhanced, when compared with drug alone or physical mixtures. From overall findings, DDB formulations containing copolyvidone solid dispersions (1 : 20) could be used to remarkably improve the dissolution rate in dosage form of powders and tablets.

• Biomolecules & Therapeutics
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• v.4 no.4
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• pp.419-427
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• 1996

To solubilize practically insoluble biphenyl dimethyl dicarboxylate (DDB), which has been used for the treatment of chronic hepatitis as tablets or hard capsules, the solubilities of DDB in various hydrophilic, oily and hydrocarbon vehicles, and aqueous surfactant solutions were measured by high performance liquid chromatography. It was found that, among the vehicles studied, polyethylene glycol (PEG) 300 revealed the best solvency, and the solubility reached 17.6 mg/ml at 37$^{\circ}C$. The addition of glycyrrhizic acid ammonium salt (GAA) to DDB-PEG 300 solution (5-20 mg/g) inhibited the formation of precipitates, and at the concentration of 10 mg/g, any precipitaction was not observed even after 2 years at 4$^{\circ}C$. Furthermore, GAA markedly enhanced the permeation of DDB through the rabbit duodenal mucosa in a concentration dependent manner. The addition of copolyvidone (ca. 1.0%) to DDB-GAA-PEG 300 system (1 : 0.5 97.5 w/w) was most effective in preventing the considerable precipitation of DDB-PEG 300 solution (7.5 mg/750 mg) when mixed with water of 300-900 ml at 37$^{\circ}C$. GAA showed a synergistic effect in the prevention of precipitate formation. This finding suggests that this DDB formulation may form less precipitation when DDB soft capsules disintegrate and diffuse into the gastrointestinal fluid, resulting in improving the bioavailability Dissolution rate of DDB (7.5 mg) from sort elastic capsules of DDB-GAA-PEG 300 system was rapid. The supersaturation state was maintained for 2 hr at the concentration of 7.35$\pm$3.3 mg in 900 ml of water without precipitation. The total amount of DDB dissolved from this new formulation was 5.3 and 6.1 times higher, when compared to marketed DDB tablets (25 mg) and capsules (7.5 mg), respectively.