• Proceedings of the PSK Conference
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• 2000.04a
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• pp.70-81
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• 2000

DA-5018 is a synthetic capsaicin derivative under development as a non-narcotic a analgesic ag$\varepsilon$nt. DA-50 18 showed a potent analgesic activity against acute and chronic pain m model(Tablel, 2.), but it had a narrow margin of safety. DA-5018 did not bind to opioid(${\kappa}, {\delta}, {\mu}$), NKl, CGRP receptors in vitro and its analgesic effect was not antagonized by naloxone, a and it did not develop analgesic tolerance. In addition DA-5018 had no inhibitory effects against c cyclooxygenase and 5-lipooxygenase activities. DA-5018 significantly increased the relcase of substance P from the slices of the rat spinal cord. These results suggest that DA-50 18 is not a narcotic nor aspirin-like analgesic and the release of substance P is one of analgesic mechanism of action of DA-5018. We found that DA-5018 was almost ten times more potent and was at l least IOO-times less irritable compared to capsaicin. Accordingly development of topical formula was adopted. Topical formula was desiged and screened by flux test of DA-5018 using hairless mouse skin and several formulas were selected. With these topical formulas we a assessed the analgesic efficacy and carried out the toxicity, skin irritation and pharmacokinetic studies. In streptozotocin-induced hyperalgesic rat and 50 % galactose-fed hyperalgesic rat as diabetic pain models, DA-5018 cream increased the pain thresh이ds up to 77.0% and 24.4% respectively, while Zostrix-HP(capsaicin cream) incr$\varepsilon$as cd by 65.9% and 21.0%. DA-5018 c cream showed a good analgesic effect as welI in FCA-induced arthritic rat. DA-5018 cream did not show any toxicological signs in acute and chronic toxicity test and had little skin irritation in car swclIing and scratching t$\varepsilon$st. Pharmacokinetics of DA-50 18 were studied after topical application of ${14}^C$-Iabelled or unlabelIed DA-5018 cream. Plasma and skin concentrations c except applied skin wcre below the dctection limit and after 7-day cummulative application, plasma concentrations were also below detection limit DA-50 18 may have an advantag$\varepsilon$ ov$\varepsilon$r c capsaicin and is now being developed as a topical agent for the treatment of pains. DA-50 18 cream was approved for Korean IND and is now under a Phase II clinical study for arthritic pain a after finising Phase I study. DA-50 18 was also liscensed out to Stiefel Company in America in

• Journal of the Society of Cosmetic Scientists of Korea
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• v.40 no.1
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• pp.1-10
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• 2014

At present, there are few research papers on skin penetration of cosmeceutical ingredients. What is worse is that in vivo studies are hard to find. In this study, we measured skin epidermal penetration of cosmeceutical ingredients using in vivo Raman spectroscopy and compared with the results obtained from experiments using in vitro franz cell. Results showed that ascorbyl-2-glucoside, retinol, retinyl palmitate, and kojic acid were good for penetration ratio in measurement in vitro and retinol, vitamin C, and arbutin were good in measurement in vivo. Among them, retinol was best in skin penetration in vivo experiment using Raman spectroscopy and ascorbyl-2-glucoside was best in skin penetration in vitro experiment using Franz cell system. It is estimated that the differences were originated from the experimental procedures of two different methods; in vivo Raman experiment can be sensitive to the effect of epidermis and dermis as characteristics of matter by estimating the stratum corneum and in vitro measurement is evaluation of material to penetrate skin of hairless mouse. However, most penetration barrier is the stratum corneum, thus it is important to examine movement of material in the stratum corneum. We expect that these results provided useful information for many cosmetic related research.

• Journal of Pharmaceutical Investigation
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• v.40 no.5
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• pp.305-311
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• 2010

The present study was aimed at preparing microemulsion-based hydrogel (MBH) for the skin delivery of itraconazole. Microemulsion prepared with Transcutol as a surfactant, benzyl alcohol as an oil and the mixture of ethanol and phasphatidyl choline (3:2) as a cosurfactant were characterized by solubility, phase diagram, particle size. MBHs were prepared using 0.7 % of xanthan gum (F1-1) or carbopol 940 (F1-2) as gelling agents and characterized by viscosity studies. The in vitro permeation data obtained by using the Franz diffusion cells and hairless mouse skin showed that the optimized microemulsion (F1) consisting of itraconazole (1% w/w), benzyl alcohol (10% w/w), Transcutol (10% w/w) and the mixture of ethanol and phospahtidylcholine (3:2) (10% w/w) and water (49% w/w) showed significant difference in the flux (${\sim}1{\mu}g/cm^2/h$) with their corresponding MBHs (0.25-0.64 ${\mu}g/cm^2/h$). However, the in vitro skin drug content showed no significant difference between F1 and F1-1, while F1-2 showed significantly low skin drug content. The effect of the amount of drug loading (0.02, 1 and 1.5% w/w) on the optimized MBH (F1-2) showed that the permeation and skin drug content increased with higher drug loading (1.5%). The in vivo study of the optimized MBH (F1-2 with1.5% w/w drug loading) showed that this formulation could be used as a potential topical formulation for itraconazole.

• Journal of Pharmaceutical Investigation
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• v.38 no.1
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• pp.31-38
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• 2008

The objective of this work is to study transdermal delivery of levodopa using iontophoresis and evaluate various factors which affect the transdermal transport. Levodopa is unstable in aqueous solution, and, in order to establish a stable condition for levodopa for the duration of experiment, we investigated the stability of levodopa in aqueous solutions of different pHs with/without the addition of dextrose or the application of current. Using stable aqueous solution, we have studied the effect of pH, polarity and penetration enhancer (ethanol) on transdermal flux and compared the results. We also investigated the iontophoretic flux from hydroxypropyl cellulose (HPC) hydrogel. In vitro flux study was performed at $33^{\circ}C$, using side-by-side diffusion cell. Full thickness hairless mouse skin and rat skin were used for this work. Current densities applied were 0.4 or $0.6mA/cm^2$ and current was off after 6 hour application. Stability study showed that levodopa solution with a pH 2.5 or 4.5 maintained the initial concentration of levodopa for 24 hours with the addition of 5% dextrose. However, at pH 9.5, levodopa was unstable and 30 to 40% of levodopa degraded within 24 hours, even with the addition of 5% dextrose. Hydrogel swollen with dextrose added levodopa solution maintained about 97% of the initial concentration of levodopa for 13 days, when stored in $4^{\circ}C$. The application of current did not affect the stability of levodopa in hydrogel. Flux study from levodopa solution with pH 2.5 showed that cathodal delivery of levodopa was higher than passive or anodal delivery. When the pH of the donor solution was 4.5, anodal delivery of levodopa was higher than passive or cathodal delivery. These results seem to indicate that electroosmosis plays more dominant role than electrorepulsion in the flux of levodopa at pH 2.5, and the reverse situation applies for pH 4.5. The passive flux was unexpectedly high for the ionized levodopa. Similar to the results from aqueous solution, cumulative amount of levodopa transported trom HPC hydrogel by cathodal delivery was significantly higher than passive or anodal delivery. The treatment of 70% ethanol cotton ball by scrubbing increased passive, anodal and cathodal flux, with the largest increase for anodal flux. These results indicate that iontophoretic delivery of zwitterion such as levodopa is much complicated than that can be expected from small ionic molecules with single charge. The results also indicate that the balance between electroosmosis and electrorepulsion plays a very important role in the transport through skin.

• Journal of Microbiology and Biotechnology
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• v.25 no.1
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• pp.74-80
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• 2015

Skin is the soft outer covering of vertebrates that provides protection from pathogenic infection, physical damage, or UV irradiation, and controls body temperature and water content. In this study, we examined the effects of oral intake of kimchi-derived Lactobacillus plantarum K8 lysates on skin moisturizing. In an in vitro study, we observed that the hyaluronic acid content increased in HaCaT cells treated with L. plantarum K8 lysates. Oral administration of L. plantarum K8 lysates effectively attenuated the horny layer formation and decreased epidermal thickening in DNCB-treated SKH-1 hairless mice skin. The damage to barrier function was reduced after 8 weeks of oral administration of L. plantarum K8 lysates as compared with that in the atopic dermatitis mice. For the test with volunteers, we manufactured experimental candy containing 2.1% L. plantarum K8 lysates, while control candy did not contain bacterial lysate. A significant increase in hydration in the experimental candy-administered group as compared with the control candy-administered group was observed on the face after 4 and 8 weeks, and on the forearm after 4 weeks. Decreases in horny layer thickness and TEWL value were observed on the face and forearm of the experimental group. Together, the in vitro cell line and in vivo mouse studies revealed that L. plantarum K8 lysates have a moisturizing effect. A clinical research study with healthy volunteers also showed an improvement in barrier repair and function when volunteers took L. plantarum K8 lysates-containing candy. Thus, our results suggest that L. plantarum K8 lysates may help to improve skin barrier function.

• Journal of Life Science
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• v.15 no.2 s.69
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• pp.267-272
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• 2005

The objective of this study is to suggest the potentialities of nanoliposome composed of ceramide as an anti-irritant against various irritants used in cosmetics. Ceramides are major structural components of the epidermal permeability barrier, which is known to play an essential part in human physiology by not only preventing the loss of water from the body but also protecting the body from external physical, chemical, and microbial insults. According to the results, better effects on reinforcement of skin barrier function and anti-irritation were obtained with nanoliposome composed of ceramide than with dispersed ceramide. And, we performed in vitro skin penetration test using horizontal Franz diffusion cells with skin membrane prepared from hairless mouse to evaluate the influence of nanoliposome composed of ceramide on the skin penetration of lactic acid in formulations. From the results, we found that the anti-irritation effects of nanoliposome containing ceramide were due to reduced penetration rate of irritants. Conclusively, we could develop a new anti-irritation system and apply this nanoliposome composed of ceramide to the final cosmetic products successfully.

• Journal of Pharmaceutical Investigation
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• v.38 no.6
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• pp.373-380
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• 2008

In order to develop optimal formulation and iontophoresis condition for the transdermal delivery of levodopa, we have evaluated the effect of two permeation enhancers, ethanol and oleic acid in microemulsion, on transdermal delivery of levodopa. In vitro flux studies were performed at $33^{\circ}C$, using side-by-side diffusion cell and full thickness hairless mouse skin. Current density applied was $0.4\;mA/cm^2$ and current was off after 6 hours application. Levodopa was analysed by HPLC at 280 nm. The o/w microemulsions of oleic acid in buffer solution (pH 2.5 & 4.5) were prepared using oleic acid, Tween 80 and ethanol. The existence of microemulsion regions were investigated in pseudo-ternary phase diagrams. Contrary to our expectation, cumulative amount of levodopa transported from microemulsion (pH 2.5) for 10 hours was similar to that from aqueous solution in all delivery methods (passive, anodal and cathodal). When pH of the micro-emulsion was pH 4.5, cumulative amount of levodopa transported for 10 hours increased about 40% (anodal) to 50% (cathodal), when compared to that from aqueous solution. Flux from pH 4.5 microemulsion showed higher value than that from pH 2.5 in all delivery methods. These results seem to indicate that electroosmosis plays more dominant role than electrorepulsion in the flux of levodopa at pH 2.5. The effect of ethanol on iontophoretic flux was studied using pH 2.5 phosphate buffer solution containing 3% or 5% (v/v) ethanol. Flux enhancement was observed in passive and anodal delivery as the concentration of the ethanol increased. Without ethanol, cathodal delivery showed higher flux than anodal delivery. Anodal delivery increased the cumulative amount of levodopa transported 1.6 fold by 5% ethanol after 10 hours. However, in cathodal delivery, no flux enhancement of levodopa was observed during current application and only marginal increase in cumulative amount transported after 10 hours was observed by 5% ethanol. These results seem to be related to the decrease in dielectric constant of the medium and the lipid extraction of the ethanol, which decrease the electroosmotic flow, and thus decrease the flux. Overall, the results provide important insights into the role of electroosmosis and electrorepulsion in the transport of levodopa through skin, and provide some useful informations for optimal formulation for levodopa.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.30 no.3 s.47
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• pp.389-392
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• 2004

We screened several materials to stimulate IGF-1 promoter activity using luciferase reporter assay and found that Amomi Semen extract (ASE) among them is the most powerful stimulator We also studied about the anti-wrinkle effect of ethanolic extract of Amoni Semen in vitro and in vivo. Semi-quantitative RT-PCR showed that the extract elevated the presence level of IGF-1 mRNA. And $[^3H]$ proline incorporation and semi-quantitative RT-PCR showed that the extract increased the expression of type-I collagen compared with vehicle in vitro and in vivo, respectively. Significant inhibition of MMP-1 expression was determined by ELISA and Western blot. Finally, topical treatment of the extract on hairless mouse's dorsal skin expanded the volume of collagen and dermal thickness. These results suggest that Amomi Semen may be a good candidate for improving extracellular matrix through the increase of collagen expression and inhibition of MMP-1 expression. Moreover, this study enables us to guess that IGF-1 stimulated by the extract may be involved in the mechanism of anti-wrinkle effect of it.

• Journal of Pharmaceutical Investigation
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• v.29 no.3
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• pp.217-225
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• 1999

These studies were designed to determine the effect of hydroalcoholic gel system (lower alkanol concentration: 40-60%) compared to general hydrogel system (lower alkanol concentration: 10-35%) on transdermal delivery of piroxicam and its anti-inflammatory activity. Piroxicam was incorporated into a hydroalcoholic gel and a hydrogel containing polymers, solvents, and cosolvents. The pH of gel was about 6.3-7.3 and the solvent mixtures were composed of water and various concentrations of ethanol (35, 40, 50, and 60%). For the in vitro study, the skin permeation of piroxicam from the gel formulations was investigated using Franz modified diffusion cells fitted with hairless mouse skin. For the in vivo study, the anti-inflammatory activity of hydroalcoholic gel was compared to other commercial products (piroxicam hydrogel and ketoprofen hydrogel) in rat and human. The anti-inflammatory activity was determined using carrageenan induced foot edema model in rat. For the clinical study, it was evaluated from determining efficacy and acceptability with 98 patients suffering from musculoskeletal pain. A novel piroxicam hydroalcoholic gel was successfully formulated in the range of 40-50% of ethanol as solvent, more than 10% of propylene glycol, 5% of $Transcutol^{\circledR}$ and 1 % of benzyl alcohol. The skin permeation of piroxicam using hydroalcoholic gel system was greater than that of general hydrogel system $(flux\;:\;139.1-148.2\;{\mu}g/cm^2/hr\;vs.43.0-84.5 {\mu}g/cm^2/hr)$ in vitro. In carrageenan-induced edema model, the anti-inflammatory activity of hydroalcoholic gel was better than that of piroxicam hydrogel for edema inhibition (75.1 % vs. 62.9%, p

• Journal of the Society of Cosmetic Scientists of Korea
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• v.30 no.2
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• pp.263-278
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• 2004

Ursolic acid (UA) and Oleanolic acid (ONA), known as urson, micromerol and malol, are pentacyclic triterpenoid compounds which naturally occur in a large number of vegetarian foods, medicinal herbs, and plants. They may occur in their free acid form or as aglycones for triterpenoid saponins, which are comprised of a triterpenoid aglycone, linked to one or more sugar moieties. Therefore UA and ONA are similar in pharmacological activity. Lately scientific research, which led to the identification of UA and ONA, revealed that several pharmacological effects, such as antitumor, hepato-protective, anti-inflammatory, anticarcinogenic, antimicrobial, and anti-hyperlipidemic could be attributed to UA and ONA. Here, we introduced the effect of UA and ONA on acutely barrier disrupted and normal hairless mouse skin. To evaluate the effects of UA and ONA on epidermal permeability barrier recovery, both flanks of 8-12 week-old hairless mice were topically treated with either 0.01-0.1mg/mL UA or 0.1-1mg/mL ONA after tape stripping, and TEWL (transepidermal water loss) was measured. The recovery rate increased in those UA or ONA treated groups (0.1mg/mL UA and 0.5mg/mL ONA) at 6h more than 20% compared to vehicle treated group (p < 0.05). Here, we introduced the effects of UA and ONA on acute barrier disruption and normal epidermal permeability barrier function. For verifying the effects of UA and ONA on normal epidermal barrier, hydration and TEWL were measured for 1 and 3 weeks after UA and ONA applications (2mg/mL per day). We also investigated the features of epidermis and dermis using electron microscopy (EM) and light microscopy (LM). Both samples increased hydration compared to vehicle group from 1 week without TEWL alteration (p < 0.005). EM examination using RuO4 and OsO4 fixation revealed that secretion and numbers of lamellar bodies and complete formation of lipid bilayers were most prominent (ONA=UA > vehicle). LM finding showed that thickness of stratum corneum (SC) was slightly increased and especially epidermal thickening and flattening was observed (UA > ONA > vehicle). We also observed that UA and ONA stimulate epidermal keratinocyte differentiation via PPAR Protein expression of involucrin, loricrin, and filaggrin increased at least 2 and 3 fold in HaCaT cells treated with either ONA (10${\mu}$M) or UA (10${\mu}$M) for 24 h respectively. This result suggested that the UA and ONA can improve epidermal permeability barrier function and induce the epidermal keratinocyte differentiation via PPAR Using Masson-trichrome and elastic fiber staining, we observed collagen thickening and elastic fiber elongation by UA and ONA treatments. In vitro results of collagen and elastin synthesis and elastase inhibitory activity measurements were also confirmed in vivo findings. These data suggested that the effects of UA and ONA related to not only epidermal permeability barrier functions but also dermal collagen and elastic fiber synthesis. Taken together, UA and ONA can be relevant candidates to improve epidermal and dermal functions and pertinent agents for cosmeseutical applications.