• Journal of Pharmaceutical Investigation
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• v.34 no.4
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• pp.269-274
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• 2004

To enhance the solubility and stability of lansoprazole (LAN), new proton pump inhibitor, we were prepared various molar ratio of inclusion complex with $2-hydroxypropyl-{\beta}-cyclodextrin$ (HPCD) and organic alkali agent, meglumine (MEG). Inclusion complex formation of LAN with HPCD was investigated by Differential Scanning Calorimetry and X-ray diffractometry. The aqueous solubilities of inclusion complexes, and the stabilities of 1:4 and 1:5 inclusion complexes in aqueous solutions containing different concentrations of MEG were examined. The stability of 1:5 LAN-HPCD inclusion complex containing MEG, which was equaled to amount of LAN, was performed in 0.9% NaCl and 5% dextrose solution. The formation of inclusion complex of LAN with HPCD was $A_L$ type and the molar ratio of complex was 1:1. The stability constant was $41.557\;M^{-1}$. As molar ratio of LAN to HPCD was increased, solubility of inclusion complex was increased. 1:5 LAN-HPCD inclusion complex was more stable than 1:4 LAN-HPCD inclusion complex. And as contained MEG amount in LAN solution was increased, stability of 1:4 and 1:5 LAN-HPCD inclusion complexes was improved. Also stability of 1:5 LAN-HPCD-MEG inclusion complex in 0.9% NaCl solution and 5% dextrose solution was similar to it in water at room temperature, but it was unstable at $40^{\circ}C$.

• Archives of Pharmacal Research
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• v.18 no.1
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• pp.22-26
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• 1995

The solubility and dissolution rate of naproxen (NPX) complexed with 2-hydroxypropyl-.betha.-cyc-lodextrin (2-HP.betha.CD) using coprecipitation, evaporation, freeze-drying and kneading method were investigated. Solubility of NPX linearly increased (correlation cefficient, 0.995) as $2-HP\betaCD$ concentraction increased, resutling in $A_l$ type phase solubility curve. Inclusion complexes prepared by four different methods were compared by different methods were compared by dfferential scanning calorimetry(DSC). The NPX showed sharp endothemic peak around $156^{\circ}C$ but inclusion complexes by evaporation, freeze-drying and kneading method showed very broad peak without distinct phase transtion temperature. In contrast, inclusion complex prepared by coprecipitation method resulted in detectable peak around $156^{\circ}C$ which is similar to NPX, suggesting incoplete formation of indusion co plex. Dissolution rate of inclusion complexes prepared by evaporation, frezz-drying and kneding except coprecipitation method was largely enhanced in the simultaed gastric and intestinal fluid when compared to NPX powder and commercial $NA-XEN^\registered$tablet. However, about 65% of NPX in gstric fluid. in case of inclusion complex prepared by coprecipitation method, formation of inclusion complex appeared to be incoplete, resulting in no marked enhancement of dissolution rate. From these findings, inclusion complexes of poorly water-soluble NPX with $2-HP\betaCD$ were useful to increase soubility and dissolution rate, resting in enhancement of bioavailability and minimization of gastrointestinal toxicity of drug upon oral administration of inclusion complex.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1997.04a
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• pp.116-116
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• 1997

Complex formation of practically insoluble dexamethasone dipropionate (DDP) with ${\beta}$-cyclodextrin (${\beta}$-CD), dimethyl-${\beta}$-cyclodextrin (DMCD), trimethyl-${\beta}$-cyclodextrin (TMCD), 2-hydroxypropyl-${\beta}$-cyclodextrin (HPCD) and sulfobutyl ether ${\beta}$-cyclodextrin (SBCD) in water was investigated by solubility method at various temperatures. Water solubility of DDP was found to be 1.78 $\mu\textrm{g}$/$m\ell$ at 37$^{\circ}C$. Propylene glycol (PG)-water cosolvent increased the solubility of DDP, but the solubilization was not sufficient (8.93 $\mu\textrm{g}$/$m\ell$ in 20% PG). The addition of CD markedly increased the solubility of DDP in water, and A$\sub$L/ type phase solubility diagrams were obtained with ${\beta}$-CD, TMCD, HPCD and SBCD, where the apparent stability constants of the soluble complexes at 25$^{\circ}C$ were determined to be 1388, 216, 1054, and 1992 M$\^$-1/, respectively. However, DMCD remarkably increased the solubility of DDP, and showed an A$\sub$P/ type diagram, suggesting that DMCD forms a soluble complex of high order with DDP. The stability constant for the DDP-DMCD complex at 25$^{\circ}C$ was determined to be 19132 M$\^$-1/. The thermodynamic parameters were calculated for the inclusion complex formation in aqueous solution. CD (1${\times}$10$\^$-2/M) remarkably decreased the partition coefficients of DDP between isopropyl myristate/water in the order of TMCD < ${\beta}$-CD < HPCD < SBCD < DMCD, and in squalane/water system in the order of HPCD < TMCD < ${\beta}$-CD < DMCD < DMCD $\leq$ SBCD. This finding represents that, in a o/w type cream, cyclodextrin complexation with DDP may result in high concentration of DDP in aqueous phase. The permeation of DDP through a cellophane membrane was highly suppressed by the addition of CD, and the degree of suppression was different among CDs, indicating that CD may control the skin permeation of DDP. The dissolution rates of solid dispersions with CDs were much faster than those of drugs alone and corresponding physical mixtures. All DDP-CD solid dispersions exceeded the equilibrium solubility. Consequently these results suggest that complex formation of DDP with CDs may provide useful means to markedly enhance the solubility, and CDs are useful in the semi-solid preparations such as creams and gels for topical application.

• Journal of the Korean Chemical Society
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• v.39 no.2
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• pp.94-102
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• 1995

S-Hydroxypropyl(PH) ${\beta}$-cyclodextrin(hydrophilic), dialkyl(DA)-cyclodextrin(hydrophobic), trifluoroacetyl(TA) ${\gamma}$-cyclodextrin(intermediate) stationary phases were used for gas chromatographic separation of racemic alcohols and their derivatives. All the alcohols used for this experiment were derivatived by using trifluoro acetic anhydride, acetic anhydride, or trichloro acetic anhydride. It is apparent that the enantioselectivity of the enantiomeric pairs was very dependent on the type of acylation reagent. The best experimental condition of optical resolution of the alcohols and their derivatives was different on the polarity of the solute molecules. The chiral separation was also studied depending on temperature, polarity of the column, and hydrogen bonding ability and steric effect between the alchols and CD stationary phase. The chiral recognition mechanism is dependent not upon the kinds of the chiral stationay phases but upon the derivatization of the racemic alchols.

• 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.25 no.1
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• pp.31-36
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• 1995

Solid dispersions and inclusion complex were prepared for the enhancement of solubility and dissolution rate of poorly water-soluble ibuprofen(IPF) as a model drug. Polyethylene glycol 4000(PEG4000) and polyvinylpyrrolidone(PVP) were used for the preparation of solid dispersion. $2-Hydroxypropyl-{\beta}-cyclodextrin(2-HP{\beta}CD)$ was also used for the preparation of inclusion complex. The solubility of IPF increased as the concentration of PEG4000, PVP and $2-HP{\beta}CD$ increased. Solubilization capacity of $2-HP{\beta}CD$ was increased about 10 times when compared to PEG 4000 and PVP. The dissolution rate of drug from solid dispersions and inclusion complex in the simulated gastric fluid was enhanced when compared to pure IPF and commercial $BR4^{\circledR}$ tablet as a result of improvement of solubility. In case of solid dispersions, dissolution rate of drug was proportional to polymer concentration in the formulation. The marked enhancement of dissolution rate of drug by inclusion complexation with $2-HP{\beta}CD$ was noted. However, dissolution rate of drug from solid dispersions and inclusion complex in the simulated intestinal fluid was not significant because IPF was readily soluble in that condition. From these findings, water-soluble polymers and cyclodextrin were useful to improve solubility and dissolution rate of poorly water-soluble drugs. However, easiness and reliability of preparation method, scale-up and cost of raw materials must be considered for the practical application of solid dispersion and inclusion complex in pharmaceutical industry.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.48 no.1
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• pp.77-85
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• 2022

Retinaldehyde (RA), vitamin A derivative, is an intermediate between retinol and retinoic acid and has an excellent wrinkle improving effect. In this study, Drug-in-cyclodextrin-in-liposome (DCL) was used to enhance the stability and skin penetration of RA. The complex of RA and hydroxypropyl-beta-cyclodextrin (HP-β-CD) was prepared by the freeze-drying method, and the presence or absence of inclusion of retinal was confirmed by UV-Vis spectrometer, FT-IR and SEM images. RA was captured in HP-β-CD about 95.6% on 1 : 15 (w/w). The retinal-HP-β-CD complex was encapsulated in liposomes using a homomixer and microfluidizer, with an average particle size of 215 ± 4.2 nm and a zeta potential of -31.2 ± 0.5 mv. In the evaluation of the degradation stability of RA, degradation rate of RA-HP-β-CD-liposomes in water was 1.8% higher than RA-liposome (5.8%), RA-HP-β-CD complex (9.7%) and RA alone (37.6%). RA cream (0.05% RA) including RA-HP-β-CD-liposomes was prepared for clinical test with wrinkle-improving efficacy and skin dermis denseness evaluated for 2 or 4 weeks. RA cream showed a significant wrinkle improving effect without skin irritation. In conclusion, it was confirmed that the double stabilization technology using the DCL system contribu tes to the effect of improving skin wrinkles by increasing the stabilization of retinal.

• 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.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1997.04a
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• pp.118-118
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• 1997

Solid dispersions were used to increase the dissolution rate of biphenyl dimethyl dicarboxylate (DDB) in water, with the ultimate goal of optimizing its bioavailability when incoporated into pharmaceuticals. Carriers used were Kollidon 30, Kollidon VA 64, 2-hydroxypropyl-${\beta}$-cyclodextrin (HPCD), sodium salicylate or sodium benzoate. DDB solid dispersions were prepared at drug to carrier proportions ranging from 1 : 5 to 1 : 20 (w/w) by solvent evaporation method. DDB tablets (7.5 mg) were prepared by compressing the powder mixture composed of solid dispersions, lactose, corn starch, crospovidone and magnesium stearate using a single-punch press. DDB capsules (7.5 mg) were prepared by filing the mixture into empty hard gelatin capsules (size #1). Dissolution studies of DDB from powdered solid dispersions, tablets and capsules were performed in 900 $m\ell$ of water at 100 rpm and 37$^{\circ}C$ by the paddle method. The dissolved amount was assayed by HPLC and expressed as the mean(%)of three determinations.

• KSBB Journal
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• v.21 no.2
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• pp.157-163
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• 2006

A supercritical fluid process, called aerosol solvent extraction system(ASES), is especially suitable to the pharmaceutical, cosmetic and food industries due to its environmentally-friendly, non-toxic and residual solvent-free properties. In particular, the application of the ASES process to the processing of thermo-labile bioactive compounds has received attention of many scientists and engineers because of its low-temperature operating conditions. Unstable substances such as Vitamin-C and Vitamin-A can be effectively protected from degradation during the preparation process, because the ASES process is free from oxygen and moisture. In this study, Vitamin-C was formulated with 2-hydroxypropyl-${\beta}$-cyclodextrin (HP-${\beta$-CD) for enhancement of Vitamin-C stability and bioavailability using the ASES process. To investigate the influence of the preparation process on the stability of Vitamin-C, Vitamin-C/HP-${\beta}$-CD inclusion complexes were prepared using both conventional solvent evaporation method and ASES process, and stored in a 50 mM phosphate buffer solution of pH 7.0 at $25^{\circ}C$ for 24 hours. From the experimental results, the stability of the Vitamin-C/HP-${\beta}$-CD inclusion complex prepared from the ASES process was found to be much higher than that of pure Vitamin-C and the Vitamin-C/HP-${\beta}$-CD inclusion complex prepared by the solvent evaporation method. The stability of Vitamin-C was observed to increase with the decrease of temperature at a constant pressure or with the increase of pressure at a constant temperature.