Influence of Characteristics of Oily Vehicle on Skin Penetration of Ufenamate

Abstract

Skin penetration amounts of a highly lipophilic drug, ufenamate, prepared in four oily vehicles, including white petrolatum (WP), liquid paraffin (LP), isopropyl myristate (IPM), and isocetyl stearate (ICS), were compared. Ufenamate was mixed in each vehicle at 5% and applied at a rate of 2 mg/cm² to intact, stripped, and delipidized Yucatan micropig skin. The amounts of ufenamate and IPM in the stratum corneum (SC), epidermis, and dermis were determined. The skin penetration amounts of ufenamate from liquid oils were significantly higher than those from WP; the amounts of ufenamate were in the order WP<LP≤ICS<IPM, which was the same as that of the vehicle viscosities. The IPM skin penetration amount was approximately 20 times that of ufenamate. The skin penetration amounts of ufenamate from the liquid vehicles decreased after application to delipidized skin and were not significantly different among the four vehicles. The skin penetration amounts of the vehicle oils were significant and might disrupt intercellular lipid structures, especially in the strips 1–6 of the SC. In the deeper SC, there was no effect of the vehicle or skin condition. Thus, ufenamate mixed in liquid vehicles was found to be an effective dosage form.

Drugs are commonly applied to the skin using a vehicle. The drug moves in the vehicle and partitions into the skin surface, i.e., the stratum corneum (SC).¹⁾ It is well known that the activity of a drug in a vehicle affects the partitioning of the drug into the SC, which affects the overall skin penetration of the drug. A specific drug shows different skin penetrations for different vehicles.^2,3) Thus, consideration of the partition coefficient between skin and vehicle is one of the most important factors in vehicle selection for the development of dosage forms for skin applications.

There have been many reports of studies in which substances mixed in vehicles have changed the partition coefficient into the skin or the diffusion constant within the skin and, therefore, have enhanced the skin permeation of drugs.^4,5) However, there are fewer reports on the effect of commonly used oily vehicles for the treatment of skin diseases, such as white petrolatum (WP) or liquid paraffin (LP), on skin penetration of drugs.

Drugs typically suitable for skin penetration have molecular weights of <500 and logarithms of the octanol/water partition coefficient (log P) of 1–3. Many studies have attempted to improve the permeation of hydrophilic drugs, which are not suitable for skin permeation. Some studies have also tried to improve permeation of lipophilic drugs; however, log P values were not very large (approximately 4).^6–8) Many highly lipophilic drugs, such as dibucaine (log P=4.8), glycyrrhetinic acid (log P=5.5), and tocopherol acetate ester (log P=10.7), are used in clinical treatment of skin diseases.

WP is the preferred vehicle for treatment of skin diseases. LP is also a commonly used vehicle. Both WP and LP are hydrocarbon oils extracted from petroleum and have different viscosities. Isopropyl myristate (IPM) is a fatty acid ester that is also used in external applications. Isocetyl stearate (ICS) is another fatty acid ester that has a higher viscosity than that of IPM.

In this study, the effects of four oily vehicles on the skin penetration of ufenamate, a highly lipophilic (log P=6.7), non-steroidal anti-inflammatory drug,^9–13) were investigated.

MATERIALS AND METHODS

Materials

Ufenamate (Japanese Pharmaceutical Codex grade) was obtained from Shiono Finesse (Osaka, Japan). WP was obtained from Mylan Pharmaceutical (JP grade; Tokyo, Japan). LP was obtained from Wako Pure Chemical Industries, Ltd. (Wako 1st grade; Osaka, Japan). IPM was obtained from Kao (Japanese Pharmaceutical Excipients grade; EXCEPARL IPM, Tokyo, Japan). ICS was obtained from Kokyu Alcohol Kogyo (Japanese Standards of Quasi-drug Ingredients grade; ICS-R, Chiba, Japan). The other reagents used were of analytical or HPLC grade. Table 1 shows the characteristics of ufenamate and the four substances used as vehicles.

Table 1. Characteristics of the Vehicles and Ufenamate Used in This Study

	Abbr.	Type of oil	Molecular weight	log P	Viscosity (mPa·s)	Surface tension (mN/m)
White petrolatum	WP	Hydrocarbon	—	—	3.4×108	Not determined
Liquid paraffin	LP	Hydrocarbon	—	—	67	29.6
Isocetyl stearate	ICS	Ester	508.9	16	25	30.7
Isopropyl myristate	IPM	Ester	270.4	7.3	4.5	28.3
Ufenamate	—	—	337.3	6.7	70	32.7

Surface Tension

The surface tension of various oils was measured using a Wilhelmy type surface tension meter (CBVP-Z type; Kyowa Interface Science, Saitama, Japan). Measuring plates made of platinum were used at 25°C (thermostatically controlled).

Viscosity

The viscosity of oil was determined using a controlled-stress rheometer (HAAKE RheoStress 600; Thermo Fisher Scientific, Kanagawa, Japan). Steady flow viscosity was measured using a double-cone plate sensor (diameter 60 mm, cone angle of 1°) or a serrated parallel-plate sensor (diameter 20 mm, gap 1 mm) at 25°C.

Skin Penetration Study

Yucatan micropig (YMP) skin (YMP skin set; Charles River Laboratories Japan, Kanagawa, Japan) with the adhering fat layer removed was used as intact skin.^14,15) Delipidized skin was prepared by applying 2 mL of a 1 : 1 mixture of acetone and ether to intact skin attached to a modified Franz-type diffusion cell apparatus for 40 min.¹⁶⁾ Stripped skin was stripped 50 times using adhesive tape (Scotch 313, 3M, Tokyo, Japan) to obtain complete SC removal.

Ufenamate was used as the test material and mixed at a concentration of 5% in each vehicle, and skin penetrations into the SC, epidermis, and dermis were determined after application at 2 mg/cm². A piece of skin was placed on a modified Franz-type diffusion cell apparatus (effective area, 1.1 cm²). For the receptor phase, 17 mL of pH 7.1 phosphate-buffered saline with 5% polysorbate 80 (TO-10MV; Nikko Chemicals, Tokyo, Japan) was added to improve the solubility of ufenamate to maintain sink conditions at 37°C. Test material (2 mg/cm²) was applied to the skin, and the skin was placed on the diffusion cell.

After a 4-h application, the skin surface was wiped with a laboratory wipe (KimWipes; Nippon Paper Crecia, Tokyo, Japan). The wipe was soaked in methanol. Then, intact and delipidized skin were stripped 10 times using adhesive tape to collect the SC. Although the SC of YMP skin consists of approximately 20 layers, the outer 10 layers are easily collected by stripping with adhesive tape. Furthermore, ufenamate amounts deeper than 10 SC layers were lower than the limit of quantitation obtained using HPLC. Remaining skin was then separated into epidermis and dermis using the heat separation method.¹⁷⁾ Ufenamate and IPM in stripped SC, epidermis, or dermis was extracted with methanol, and ufenamate and IPM amounts were determined by HPLC and GC, respectively. For strips 1 and 2 of the SC, the amounts of extracted substances were measured from each layer. For strips 3–10 of the SC, the amounts of extracted ufenamate and IPM were measured from four pairs of two adjacent layers combined (strips 3/4, 5/6, 7/8, and 9/10). A data recovery percentage of ufenamate and IPM >75% of the applied amount was adopted as a result.

Determination of Ufenamate

Ufenamate was determined using HPLC performed on an LC-10A_VP system (Shimadzu, Kyoto, Japan) equipped with a Wakosil-II5C18HG (length, 150 mm; inner diameter, 4.6 mm; Wako Pure Chemical Industries, Ltd.) under the following conditions: mobile phase, methanol : purified water (90 : 10); column temperature, 25°C; flow rate, 1.0 mL/min; detection wavelength, 285 nm. The components of the adhesive tape were confirmed in advance as having no effect on the determination of ufenamate.

Determination of IPM

IPM was determined by GC performed on a GC-2014 system (Shimadzu) equipped with a ZB-1HT column (length, 30 m; inner diameter, 0.25 mm; film thickness, 0.25 µm; Phenomenex, California, U.S.A.). IPM was determined under the following conditions: carrier gas, helium; column temperature, 230 from 70°C (held for 9 min); rate of heating, 30°C/min; flow rate, 1.43 mL/min; injection, 2 µL (splitless); injection temp., 230°C; detector, flame ionization detector (250°C). Components of skin and the adhesive tape were confirmed in advance as not having an effect on the determination of IPM.

Data Processing of Distance of Skin Depth Direction

The concentrations of ufenamate and IPM in the skin were calculated using assumed thicknesses of YMP skin of 1×10⁻⁴ cm (SC), 3×10⁻³ cm (epidermis), or 2×10⁻¹ cm (dermis), as determined using a micrograph. The distance from the skin surface was estimated by sum of thickness of upper layers of sample layer and half of sample layer thickness, for example, strip 1 was 0.5×10⁻⁴ cm; strip 2, 1.5×10⁻⁴ cm; strips 3/4, 3×10⁻⁴ cm and so on.

Statistical Analyses

We used ANOVA followed by Fisher’s protected least significant difference test. A p-value of <0.05 was considered to indicate statistical significance.

RESULTS

Effect of Vehicle on Skin Penetration of Ufenamate into Intact Skin

The skin penetration amounts of ufenamate from four different vehicles were examined. Figure 1 shows the amounts of ufenamate in the SC, epidermis, and dermis of intact skin 4 h after application. WP and LP are both hydrocarbon oils, but the penetration amount of ufenamate in the SC from LP was 4.0 µg/cm², which was four times higher than that from WP (1.0 µg/cm²). The amount of ufenamate in the SC from ICS was 4.4 µg/cm², which was four times higher than that from WP and similar as that from LP. The amount of ufenamate in the SC was significantly higher from IPM, which is known as an absorption enhancer, than from any other vehicle. The amount of ufenamate in the epidermis was two times higher from the liquid oils (LP: 0.9 µg/cm², ICS: 0.7 µg/cm², and IPM: 1.0 µg/cm²) than from WP (0.4 µg/cm²). In the dermis, the amount of ufenamate was significantly higher from ICS and IPM than from WP.

Fig. 1. Amount of Ufenamate in the Skin 4 h after Application in Various Vehicles

■, WP; , LP; , ICS; □, IPM. The ufenamate concentration in vehicle was fixed at 5%. Data are expressed as the mean±S.D. of 4–5 experiments. * Significantly different (p<0.05) from WP.

To assess the skin distribution of ufenamate, the amount of ufenamate was divided by the assumed volume of the SC, epidermis, and dermis and plotted versus the distance from the skin surface. Figure 2(a) shows ufenamate concentration (C) to distance from skin surface (x). The concentration gradient of the SC was not linear in all cases and did not follow Fick’s equation. In this study, the applied dose was a practical amount of 2 mg/cm², and the amount penetrated was determined at 4 h after application. Thus, it was possible that a steady state was not achieved. In the non-steady state, the concentration gradient is not linear. The distribution of ufenamate after 48-h application at the dose of 2 mL/cm² showed similar non-linear curve; thus, it achieved a steady state at least in the SC and epidermis, and there was other reason for non-linear gradient.

Fig. 2. Ufenamate Distribution in Intact Skin at 4 h after Application in Various Vehicles

Concentrations of ufenamate presented as a linear (a) and logarithmic (b) scale. ●, WP; □, LP; △, ICS; ○, IPM. Data are shown as the mean±S.D. of 4–5 experiments.

When the logarithm of skin concentration was used, a straight line was obtained from strips 1 to 6 of the SC [Fig. 2(b)]. Thus, the skin concentration near the skin surface could be represented by the following Eq. 1:   

(1)

where C₀ is the ufenamate concentration at the skin surface (x=0), and k is the concentration gradient constant. C₀ and k calculated from the intercept and slope of semi-logarithmic plots and the correlation coefficient R are shown in Table 2. High correlation (|R|>0.9) was observed in all cases. The concentration gradient depended on the concentration of ufenamate, which could not be explained by Fick’s law. The skin surface concentration (C₀) from the use of the liquid oils (LP, ICS, and IPM) was significantly higher than that from WP. Comparing the liquid oils showed that the C₀ was significantly higher using IPM than using the other liquid oils. There was no significant difference in k among WP and the liquid oils of LP and ICS, in contrast to the C₀ results; specifically, the order of C₀ values was WP<LP=ICS<IPM. However, k was significantly higher for IPM than for WP and the other liquid oils (LP, ICS). The order of the k values was WP≒LP≒ICS<IPM.

Table 2. Skin Surface Concentration (C₀) and Concentration Gradient Constant (k) Calculated from Strips 1–6 of the SC According to Eq. 1

	Intact skin			Delipidized skin
	C0 (mg/cm3)	k (×103cm−1)	R	C0 (mg/cm3)	k (×103cm−1)	R
WP	5.1±2.0	4.2±1.6	−0.95	4.4±2.0	4.4±0.6	−0.92
LP	16.8±4.6a)	4.4±0.8	−0.95	17.9±5.2a)	6.7±0.8a) b)	−0.99
	(17.7±5.1)	(3.9±0.8)	(−0.95)
ICS	17.9±6.7a)	4.2±0.4	−0.97	13.4±3.4a)	8.0±1.1a) b)	−0.98
IPM	66.1±13.1a)	7.8±0.7a)	−0.99	13.6±3.0a) b)	6.8±0.6a)	−0.91

Data are expressed as the mean±S.D. of 3–5 experiments. Significantly different (p<0.05) from a) WP, b) intact skin. Data in parentheses are from 48 h after application of 2 mL/cm². R (correlation coefficient) is calculated from the average concentration.

In the deeper region of the SC (strip 7 to the epidermis), the concentration gradient seemed to obey Fick’s low.   

(2)

Where k′ is the concentration gradient (slope) and C₀′ is the surface (x=0) concentration extrapolated from the concentration of strip 7 of the SC to the epidermis.

C₀′ after application with liquid oil was approximately two times that of WP, and there were no significant differences among the three liquid oils. The ufenamate concentration gradient (k′) depended on C₀. Thus, diffusion through the SC near the skin surface appeared to be different in the deeper region, which could be explained generally with Fick’s law.

Effect of Vehicle on Skin Penetration of Ufenamate under Different Skin Conditions

We also studied the penetration of ufenamate into stripped and delipidized skin because ufenamate is used for skin damaged by disease. Figure 3 shows the amounts of ufenamate mixed in the four vehicles that penetrated into intact, stripped, and delipidized skin. The amount of ufenamate in the epidermis was significantly higher in stripped skin than in intact skin for all vehicles. When the SC, which is a barrier to skin penetration, was removed, the penetration into the epidermis increased. However, the amount of ufenamate that penetrated into the dermis did not increase except in the case of LP, which suggests that a highly lipophilic drug, such as ufenamate, could not penetrate into the dermis easily.

Fig. 3. Effect of Skin Conditions on Penetration of Ufenamate from Various Vehicles

(a) WP, (b) LP, (c) ICS, (d) IPM. ■, intact skin; , delipidized skin; □, stripped skin. Data are expressed as the mean±S.D. of 3–5 experiments. * Significantly different (p<0.05) from intact skin with the same vehicle.

The skin penetration amounts of ufenamate from WP were not significantly different between intact skin and delipidized skin. The skin penetration amounts of ufenamate from LP in delipidized skin tended to be low but were not significantly different from those in intact skin. From ICS and IPM, the amounts of ufenamate in skin were significantly reduced in delipidized skin.

The skin distribution curve of ufenamate in delipidized skin was similar to that in intact skin, so the skin surface concentration (C₀) and concentration gradient coefficient (k) were calculated from strips 1 to 6 according to Eq. 1, and the results are shown in Table 2. In the case of delipidized skin, the C₀ and k values of the liquid vehicles were significantly higher (with no differences among them) than those of WP. The C₀ of IPM of delipidized skin was significantly lower than that of intact skin, and the k value was significantly higher in delipidized skin in the case of LP and ICS and were similar to that of IPM. In the deeper region (Table 3), there were no differences in the C₀′ and k′ values of WP and LP between intact and delipidized skin and tended to be low in the case of ICS and lower in the case of IPM. These changes seemed to depend on the upper SC concentration. Thus, the effect of vehicle on the skin distribution of ufenamate in delipidized skin was different from that of intact skin, especially in the upper SC.

Table 3. Skin Surface Concentration (C₀′) and Concentration Gradient (k′) Calculated from the Strip 7 of the SC to the Epidermis According to Eq. 2

	Intact skin			Delipidized skin
	C0′ (mg/cm3)	k′ (×103 mg/cm3/cm)	R	C0′ (mg/cm3)	k′ (×103 mg/cm3/cm)	R
WP	0.7±0.1	0.19±0.05	−0.93	0.73±0.35	0.22±0.13	−0.92
LP	1.5±0.8	0.37±0.28	−0.98	1.17±0.53	0.38±0.17	−0.98
ICS	1.7±0.7a)	0.48±0.26	−0.96	0.58±0.29	0.21±0.12	−0.87
IPM	1.8±0.7a)	0.47±0.28	−0.99	0.46±0.12b)	0.14±0.05	−0.99

Data are expressed as the mean±S.D. of 3–5 experiments. Significantly different (p<0.05) from a) WP, b) intact skin. R (correlation coefficient) is calculated from the average concentration.

Skin Penetration of IPM

The skin penetration amounts of IPM applied under various skin conditions were determined. Figure 4(a) shows the amount of IPM in skin after application under various skin conditions. IPM penetrated into skin at extremely high levels. The penetration amount of IPM in the SC was 184 µg/cm², which was approximately 20 times that of ufenamate. IPM has a molecular weight of 270.45 and log P=7.3, so it is reasonable that the skin penetration correlated with IPM concentration. The IPM amount in the SC of delipidized skin was 63 µg/cm², which was approximately one-third that of intact skin. The reduction rate was consistent with the decrease in the skin penetration amount of ufenamate.

Fig. 4. Effect of Skin Conditions on the Penetration Amount of IPM (a) and Distribution in Skin (b)

■, intact skin; , delipidized skin; □, stripped skin. Data are expressed as the mean±S.D. of 3–5 experiments. * Significantly different (p<0.05) from intact skin with the same vehicle.

The IPM distribution was fitted according to Eq. 1 in the upper SC in a manner same as that of ufenamate distribution [Fig. 4(b)]. The distribution also depended on its concentration in skin. The C₀ values of intact and delipidized skin were 1055±231 and 357±18 mg/cm³, respectively. The k values of intact and delipidized skin were 6.0±0.5 and 6.5±0.7×10³ cm⁻¹, respectively, and were not significantly different. These phenomena were similar to those for the case of ufenamate applied with IPM.

DISCUSSION

It is well known that vehicles have an influence on drug penetration in skin. One of the most important related factors is drug activity in vehicles.¹⁸⁾ Previously, we found that the skin penetration of ufenamate, which is a highly lipophilic drug, is superior from aqueous vehicle than from LP.¹⁹⁾ However, oily vehicles are often used in treating skin diseases because of their low irritation. Therefore, we investigated the skin penetration of ufenamate prepared in four oily vehicles. Studies about the effects of characteristics of oily vehicles on penetration of lipophilic drugs would provide information for design of effective dosage forms. In addition to LP, we investigate 3 other oily vehicles, WP, ICS, and IPM.

The penetration amounts of ufenamate varied among the vehicles and skin conditions. The skin penetration amounts of ufenamate from the liquid vehicles were higher than that from WP, regardless of skin condition, but the enhancement of penetration by the liquid vehicle was small in the case of delipidized skin.

The concentration of ufenamate plotted versus the distance from the skin surface shows two phases (Fig. 2). The concentration gradient depended on the concentration of ufenamate in the first phase, strips 1–6 of the SC, as described by Eq. 1. The second phase, strip 7 of the SC to the epidermis, showed a linear concentration–distance plot that followed Eq. 2 according to Fick’s diffusion law. In the second phase, the slope (k′) correlated with C₀′ (Fig. 5). The k′ values only depended on C₀′, regardless of vehicle or skin condition. Kubo et al. reported that the function of the SC is different in the upper, middle, and deeper regions.²⁰⁾ They suggested that the structure of the upper part of the SC has some porosity, which is easily penetrated by low molecular weight compounds. C₀′ correlated with the concentration of the boundary face of the second phase, so it is important to clarify why the skin penetration of ufenamate in strips 1–6 of the SC was enhanced when ufenamate was applied with liquid vehicles.

Fig. 5. Relationship between C₀′ and k′ in Intact and Delipidized Skin

Data are expressed as the mean±S.D. of 3–5 experiments. Intact skin: ●, WP; ■, LP; ▲, ICS; ◆, IPM. Delipidized skin: , WP; , LP; , ICS; , IPM.

It is reasonable that a liquid oil itself would penetrate skin because of the typical molecular weights and log P values. In fact, IPM penetrated the skin in this study [Fig. 4(a)], and its concentration was extremely high and could be calculated according to Eqs. 1 and 2. The C₀ calculated using Eq. 1 was 1055±231 mg/cm³, and the determined concentrations in strips 1 and 2 were 907±137 and 420±100 mg/cm³ [Fig. 4(b)]. One of the reasons that the concentration–distance plot did not show a linear relationship is that the assumption of a 1-µm thickness of the SC was incorrect because of the high penetration of IPM in strips 1 and 2 of the SC. Intercellular lipids in the SC account for approximately 10% of the SC volume,²¹⁾ which is ca. 100 mg/cm³. The IPM concentration in strips 3–6 of the SC was equal to that of the lipid. It has been reported that the diffusion of water in polymer film depends on the water concentration.²²⁾ A similar phenomenon occurred in the SC. The first-order concentration gradient of ufenamate or IPM is due to the high concentration of liquid oil, which should weaken the structure of intercellular lipid and enhance the diffusion.

The ratios of ufenamate/IPM were 0.055 and 0.048 in strips 1 and 2 of the SC, respectively, and were similar to the ratio in the dosage form, 0.05. The ratios became low and were 0.039 and 0.030 in strips 3 and 4 of the SC, respectively. These results indicate that ufenamate penetrated the first and second layers of the SC with vehicle.

In a preliminary study, ICS also penetrated the SC, but the amount was lower than that of IPM. The amount of LP in the SC could not be determined; the effect on the SC concentration of ufenamate was similar to that of ICS. The vehicle viscosity has some effect on the penetration in the first and second layers of SC.

The penetrations into delipidized skin and intact skin were compared. The amounts (Fig. 3) and distributions (C₀ and k in Table 2) of ufenamate applied with WP were not significantly different between intact and delipidized skin; however, there were some differences when applied with liquid vehicles. When applied with LP or ICS, the C₀ values were not different between intact and delipidized skin, but the k values were significantly higher and the amounts in the SC were lower. When ufenamate was applied to delipidized skin with IPM, the amount and C₀ were significantly decreased and k was not different from that of intact skin. The amounts in the SC were not different between LP or ICS.

C₀ of IPM was also decreased from 1054±231 to 357±18 mg/cm³, and there was no difference in k (6.0±0.5, 6.5±0.7×10³cm⁻¹). The ratio of ufenamate/IPM in strip 1 of the SC was 0.048, which was not different from that in intact skin. However, in strip 2, the ratio was low (0.032) in delipidized skin.

It has been suggested that the vehicle itself penetrates the SC and transports ufenamate along with it in the case of intact skin. In the case of delipidized skin, a cornified envelope, which connects with keratinocyte via covalent bonds, confers lipophilic characteristics to the SC. The pore pass way becomes large so that hydrophilic drugs can penetrate easily,²³⁾ but the penetrations of lipophilic drugs have shown no differences.²⁴⁾ The penetration of ufenamate applied in WP did not change with delipidization of skin, but fewer lipids in the SC caused low retention of oily vehicles so that the penetration of ufenamate was also reduced.

The skin penetration behaviors of ufenamate from each vehicle are shown in a schematic diagram in Fig. 6. The skin penetration behavior of ufenamate in WP was the same regardless of skin condition [Fig. 6(a)]. However, the skin penetration behavior in liquid oils varied greatly, particularly in the strips 1–6 of the SC (Fig. 6, 1st phase). The skin surface concentration (C₀) of the liquid oil vehicles was higher than that of the WP vehicle. The concentration gradient constant (k) was changed by the skin condition when using LP, but it did not change when using IPM [Figs. 6(b), (c)]. In the case of highly lipophilic drugs, such as ufenamate, a liquid oil vehicle should be superior to a semi-solid vehicle for high penetration of drugs for topical disease areas. The concentration in the epidermis and dermis is important clinically; thus, the 3 liquid vehicles used in this study appeared to be equally useful, although IPM showed the highest enhancement effect on the SC concentration of ufenamate near the surface.

Fig. 6. Schematic of Skin Penetration Behavior of WP (a) and LP, ICS (b) and IPM (c)

—— Intact skin. … Delipidized skin.

CONCLUSION

The penetration of a highly lipophilic drug, ufenamate, into skin varied depending on the characteristics of the semi-solid and liquid vehicles studied. The one semi-solid vehicle, WP, may itself be retained on the skin surface and ufenamate would partition into the SC. The three liquid oil vehicles, LP, ICS, and IPM enabled delivery of high SC concentrations because of the skin penetration of the liquid oils, especially into the upper part of the SC. However, in the case of delipidized skin, the penetrations of the liquid vehicles were reduced, which led to no differences in the skin penetration amounts of ufenamate in WP.

Partitioning of drug from vehicle to skin is the first step of skin penetration; however, liquid oil vehicles penetrate by themselves and transport a mixed drug, so the penetration of drug in the SC is enhanced. Thus, not only the solubility of the drug but also the physicochemical characteristics of the vehicle are important considerations when selecting an appropriate dosage form.

Conflict of Interest

The authors declare no conflict of interest.

REFERENCES

• 1) Shimizu H. Epidermis. Textbook of modern dermatology, 2nd Edition. Nakayama Shoten, Japan, pp. 3–5 (2014).
• 2) Smith EW, Surber C, Tassopoulos T, Maibach HI. Topical dermatological vehicles. Topical absorption of dermatological products. (Bronaugh RL, Maibach HI eds.) Taylor & Francis, U.K., pp. 457–464 (2002).
• 3) Surber C, Smith EW. The mystical effects of dermatological vehicles. Dermatology, 210, 157–168 (2005).
• 4) Nakamura H, Hayashi T, Sugibayashi K, Morimoto Y. Skin penetration-enhancing effect and its mechanism of lactic acid–ethanol–isopropyl myristate system. Drug Metab. Pharmacokinet., 8 (Supplement), 695–698 (1993).
• 5) Fujii M, Yamanouchi S, Nagakura K, Takeda Y, Matsumoto M. Enhancement effect of menthoxypropandiol and menthol on the penetration of indomethacin through Yucatan micropig skin in vitro. Drug Deliv. Syst., 12, 127–131 (1997).
• 6) Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp. Dermatol., 9, 165–169 (2000).
• 7) Zhang Q, Grice JE, Li P, Jepps OG, Wang GE, Roberts MS. Skin solubility determines maximum transepidermal flux for similar size molecules. Pharm. Res., 26, 1974–1985 (2009).
• 8) Surber C, Wilhelm K, Maibach H. In vitro and in vivo percutaneous absorption of structurally related phenol and steroid analogs. Eur. J. Pharm. Biopharm., 39, 244–248 (1993).
• 9) Kubo H, Ohkuma N, Ohkawara A. Clinical effect of HF-264 ointment on atopic dermatitis. Nishinihon J. Dermatol., 43, 261–263 (1981).
• 10) Kazama T, Ishibashi Y, Satomi I, Iwai M. Clinical evaluation of HF-264 ointment. Nishinihon J. Dermatol., 43, 264–267 (1981).
• 11) Uchiyama M, Murakami J. Clinical experience of HF-264 ointment. Nishinihon J. Dermatol., 43, 268–273 (1981).
• 12) Iju M, Takashima I, Kubota K. Clinical effect of HF-264 ointment on atopic dermatitis and napkin dermatitis. Nishinihon J. Dermatol., 43, 256–260 (1981).
• 13) Sasaki R, Nakajima M, Takeuchi J. Clinical study of efficacy and safety of 5% ufenamate ointment and cream for eczematous skin changes (Miliaria and diaper rash) in infants and children. J. Pediat. Dermatol., 16, 47–52 (1997).
• 14) Lavker RM, Dong G, Zheng PS, Murphy GF. Hairless micropig skin. A novel model for studies of cutaneous biology. Am. J. Pathol., 138, 687–697 (1991).
• 15) Fujii M, Yamanouchi S, Hori N, Iwanaga N, Kawaguchi N, Matsumoto M. Evaluation of Yucatan micropig skin for use as an in vitro model for skin permeation study. Biol. Pharm. Bull., 20, 249–254 (1997).
• 16) Imokawa G, Akasaki S, Hattori M, Yoshizuka N. Selective recovery of deranged water-holding properties by stratum corneum lipids. J. Invest. Dermatol., 87, 758–761 (1986).
• 17) Kligman AM, Christophers E. Preparation of isolated sheets of human stratum corneum. Arch. Dermatol., 88, 702–705 (1963).
• 18) Higuchi T. Physical chemical analysis of percutaneous absorption process from creams and ointments. J. Soc. Cosmet. Chem., 11, 85–97 (1960).
• 19) Iino H, Fujii M, Fujino M, Koizumi N, Watanabe Y. Penetration of ufenamate into intact, stripped, or delipidized skin using different vehicles. Biol. Pharm. Bull., 38, 1645–1648 (2015).
• 20) Kubo A, Ishizaki I, Kubo A, Kawasaki H, Nagao K, Ohashi Y, Amagai M. The stratum corneum comprises three layers with distinct metal–ion barrier properties. Sci. Rep., 3, 1731 (2013).
• 21) Johnson ME, Blankschtein D, Langer R. Evaluation of solute permeation through the stratum corneum: lateral bilayer diffusion as the primary transport mechanism. J. Pharm. Sci., 86, 1162–1172 (1997).
• 22) Yamamoto S. Diffusion coefficients as mass transfer properties and water ad/desorption (drying). Japan J. Food Eng., 11, 73–83 (2010).
• 23) Rastogi SK, Singh J. Lipid extraction and transport of hydrophilic solutes through porcine epidermis. Int. J. Pharm., 225, 75–82 (2001).
• 24) Yan YD, Sung JH, Lee DW, Kim JS, Jeon EM, Kim DD, Kim DW, Kim JO, Piao MG, Li DX, Yong CS, Choi HG. Evaluation of physicochemical properties, skin permeation and accumulation profiles of salicylic acid amide prodrugs as sunscreen agent. Int. J. Pharm., 419, 154–160 (2011).