JP4860940B2 - Transdermal delivery of tranexamic acid by iontophoresis. - Google Patents

Description

  The present invention relates to a cosmetic method using iontophoresis and a composition for iontophoresis. More particularly, the present invention relates to a cosmetic method that enhances transdermal delivery of tranexamic acid by iontophoresis to prevent or improve whitening or rough skin, and a composition for iontophoresis containing tranexamic acid.

  In recent years, iontophoresis (ion introduction) technology has been used to promote percutaneous or mucosal absorption of active ingredients contained in pharmaceuticals and cosmetics. Iontophoresis is a technique that promotes transdermal delivery of components that are inherently difficult to penetrate the skin by applying a weak current by applying an electrode to the skin, etc., and the same kind of charge in the electric field formed by the current Electro-repulsion force and electroosmosis due to water flow from the positive electrode to the negative electrode generated when the negatively charged horny layer is attracted to the negative electrode It is believed that force due to electro-osmosis results in transdermal delivery of the components. FIG. 1 schematically illustrates the mechanism of transdermal delivery by iontophoresis.

  For example, administration by iontophoresis has been reported for a water-soluble steroid (Patent Document 1), lidocaine salt as a local anesthetic (Patent Document 2), and the like.

  In the beauty industry, iontophoresis is performed on placenta, which is an extracted component of human placenta, and vitamin C for whitening and improving skin quality. Since vitamin C (ascorbic acid or a derivative thereof) is negatively charged simply by dissolving the powder in water, transdermal delivery is enhanced by electrorepulsion by applying iontophoresis from the negative pole side.

On the other hand, tranexamic acid and its derivatives are generally used as antiplasmin agents, and even in cosmetic applications, they are blended in various external preparations and the like as having whitening action and anti-skin roughening action. It has been strongly desired to enhance the transdermal delivery of tranexamic acid in order to be hardly absorbed transdermally and to provide a higher whitening effect. However, tranexamic acid is an amphoteric compound and apparently hardly dissociates in the neutral pH range (about 7.3 to 7.8) of an aqueous solution usually used in cosmetics, etc. As shown in the figure, almost no current flowed when tranexamic acid was simply dissolved in water. Therefore, there has been no report so far on enhancing transdermal delivery of tranexamic acid by iontophoresis.
International Publication No. 96/011034 Pamphlet Japanese Patent Laid-Open No. 10-316590

  In view of the circumstances as described above, the present invention provides a cosmetic method capable of enhancing transdermal delivery of tranexamic acid by iontophoresis and providing more effective whitening and roughening prevention or improvement effects. It is the purpose.

  Another object of the present invention is to provide a tranexamic acid-containing composition for iontophoresis that enables transdermal delivery of tranexamic acid by iontophoresis.

Tranexamic acid is an amphoteric compound having a carboxyl group and an amino group, and the dissociation state varies depending on pH. The isoelectric point is about 7.5, Pka ₁ is 4.33, and pKa ₂ is 10.65. Therefore, tranexamic acid apparently hardly dissociates around pH 7, which is a pH range when tranexamic acid is dissolved in water, and tranexamic acid when pH is weakly acidic (pH 3.5 to 6.5). Is positively charged, while it is negatively charged when the pH is weakly basic (pH 8.5 to 10.5).

The following shows the pH of the composition and the dissociation state of tranexamic acid:

  The present inventor made tranexamic acid by making the pH of the composition containing tranexamic acid weakly acidic from 3.5 to 6.5, positively charging tranexamic acid, and applying iontophoresis from the positive electrode side. Transdermal delivery can be significantly enhanced, and further, iontophoresis can be performed from the negative electrode side by negatively charging tranexamic acid with a weakly basic pH of 8.5 to 10.5. The present inventors have found that transdermal delivery of tranexamic acid can be enhanced as compared with normal external application, and have completed the present invention.

  The cosmetic method for preventing or improving whitening or rough skin according to the present invention comprises bringing a composition having a pH of 3.5 to 6.5 containing tranexamic acid into contact with the skin and then applying iontophoresis from the positive electrode side to the skin. It is characterized in that cis is applied or a composition having a pH of 8.5 to 10.5 containing tranexamic acid is brought into contact with the skin and then iontophoresis is applied to the skin from the negative electrode side.

  The composition for iontophoresis from the positive electrode side according to the present invention contains tranexamic acid and has a pH of 3.5 to 6.5, and is used for iontophoresis from the negative electrode side. The composition is characterized by containing tranexamic acid and having a pH of 8.5 to 10.5.

  In the present specification, “iontophoresis from the positive electrode side” means that the positive electrode is applied to the skin contacted with the composition (that is, the positive electrode is used as an introduction electrode: Anodal IP) to introduce ions. To do. Further, “iontophoresis from the negative electrode side” means that ions are introduced by applying a negative electrode to the skin contacted with the composition (that is, using the negative electrode as an introduction electrode: Cathodal IP).

  When iontophoresis is performed from the positive electrode side, the composition for iontophoresis preferably contains 0.1 to 0.5% by mass of citric acid. The tranexamic acid aqueous solution has a pH of about 7 when it is not adjusted, and can be adjusted to a desired pH using an arbitrary acid such as an organic acid such as citric acid, lactic acid and acetic acid, and an inorganic acid such as HCl. From the viewpoint of stability, safety, and iontophoresis effect, it is preferable to use citric acid as a pH adjuster.

  In the iontophoresis composition of the present invention, the amount of salt is preferably 0.5% by mass or less. When ions from the salt become competing ions for tranexamic acid and the amount of the salt exceeds 0.5% by mass, transdermal delivery of tranexamic acid tends to decrease.

  The cosmetic method of the present invention can be applied to the skin after chemical peeling treatment, for example. Drying, inflammation, and rough skin due to chemical peeling can be effectively reduced, and a synergistic whitening and skin-beautifying effect can be brought about.

  In the present invention, the tranexamic acid-containing composition has a slightly acidic pH of 3.5 to 6.5 and is subjected to iontophoresis from the positive electrode side, or the tranexamic acid-containing composition has a pH of 8.5. By applying iontophoresis from the negative pole side with weak alkalinity of 10.5, the transdermal delivery of tranexamic acid can be remarkably enhanced, and the effect of preventing or improving skin whitening and rough skin efficiently in a short period of time. Can bring.

  The composition used in the cosmetic method of the present invention or the iontophoretic composition of the present invention contains tranexamic acid.

  The compounding amount of tranexamic acid is not particularly limited, but is preferably 0.1% by mass to 10.0% by mass, more preferably 0.5% by mass to 5% by mass with respect to the total amount of the composition. More preferably, it is 1% by mass to 3% by mass. If the blending amount is less than 0.1% by mass, sufficient whitening or anti-skin roughening effect may not be achieved. Even if the blending amount exceeds 10.0% by mass, the blending amount increases. It is not preferable because the corresponding effect is not enhanced.

  When iontophoresis is applied from the positive electrode side, the pH of the composition in the present invention is slightly acidic from pH 3.5 to 6.5. When the pH is lower than 3.5, the irritation is too strong when the skin is contacted, and when the pH is higher than 6.5, tranexamic acid is not sufficiently dissociated. More preferably, the pH is 4.5 to 5.5, and most preferably about pH 5.

  In addition, when iontophoresis is applied from the negative pole side, the pH of the composition in the present invention is weakly alkaline from pH 8.5 to 10.5. If the pH is higher than 10.5, the irritation is too strong when contacting the skin, and if the pH is lower than 8.5, tranexamic acid is not sufficiently dissociated. More preferably, the pH is 8.5 to 9.5, and most preferably about pH 9.

  When iontophoresis is performed from the positive electrode side, for example, an organic acid such as citric acid, lactic acid, and acetic acid, and / or an inorganic acid such as hydrochloric acid, and the like can be used alone or in combination of two or more. The pH of the composition of the present invention can be adjusted to the desired pH as described above. From the viewpoint of pH stability, safety, and iontophoresis effect, it is preferable to use an organic acid such as citric acid, lactic acid, and acetic acid as a pH adjuster, and citric acid is most preferable. The amount of acid is an amount that can achieve the desired pH, and is not limited depending on the type of acid used and the amount of tranexamic acid used. For example, when citric acid is used with respect to 2.0% by mass of tranexamic acid. The amount is usually 0.1 to 0.5% by mass, more preferably 0.3 to 0.5% by mass. When the blending amount of an organic acid such as citric acid exceeds 0.5% by mass, the transdermal delivery of tranexamic acid tends to decrease, and when it is less than 0.1% by mass, the pH stability is poor. There is.

  On the other hand, when iontophoresis is performed from the negative electrode side, for example, organic amines such as KOH, triethanolamine, 2-amino-2-methyl-1,3 propanediol, 2-amino-2-methyl-1-propanol Any basic substance such as a basic amino acid such as arginine can be blended alone or in combination of two or more to adjust the pH of the composition of the present invention to the desired pH as described above. The blending amount of these basic substances is an amount that can achieve a desired pH, and varies depending on the type of basic substance used, the blending amount of tranexamic acid, etc., and is not limited.

The composition of the present invention may contain a salt, but when tranexamic acid is used at pH 7.5 or lower, cations such as Na ⁺ and K ⁺ are used, and when used at pH 7.5 or higher. Since an anion such as Cl ⁻ becomes a competing ion for tranexamic acid, the amount of salt such as NaCl is preferably 0.5% by mass or less, more preferably 0.1% by mass or less. .

  Although the composition in the present invention is not limited, for example, an aqueous solution, a gel aqueous solution, a water-containing molded gel, a gel ointment, a sheet-form preparation carrying a water-containing molded gel, or an oil component such as squalane or ester oil. It is provided in the form of an O / W emulsion or the like.

  Furthermore, in the composition of the present invention, in addition to the above-described constituent components, other optional components usually used in the intended dosage form such as an aqueous solution, a gel or an emulsion are appropriately blended as necessary. Can do. Such components are not particularly limited, and examples thereof include humectants, thickeners, and organic solvents such as alcohol.

  Examples of the humectant include glycerin, diglycerin, 1,3-butylene glycol, propylene glycol, dipropylene glycol, sorbitol, fructose, mannose, erythritol, trehalose, xylitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, and caronic acid. Is mentioned.

  As thickeners, gum arabic, carrageenan, caraya gum, gum tragacanth, carob gum, quince seed (malmello), casein, dextrin, gelatin, sodium pectate, sodium alginate, methylcellulose, ethylcellulose, CMC, hydroxyethylcellulose, hydroxypropylcellulose , PVA, PVM, PVP, sodium polyacrylate, carboxyvinyl polymer, locust bean gum, guar gum, tamarint gum, cellulose dialkyldimethylammonium sulfate, xanthan gum, agar, bentonite, hectorite, AlMg silicate (beegum), laponite, etc. It is done.

  Examples of the organic solvent include alcohols such as ethanol and isopropanol.

  Further, for example, preservatives such as phenoxyethanol and paraben, antioxidants such as butylhydroxytoluene, tocopherol, and phytin, and, if necessary, buffers or pH adjusters other than the above-mentioned acids or basic substances. However, it is preferable not to contain preservatives or antioxidants from the viewpoint of safety.

  In the cosmetic method of the present invention, any method may be employed as the method of bringing the composition into contact with the skin, as long as tranexamic acid in the composition can be delivered transdermally. For example, an aqueous solution, a gel preparation or an O / W emulsion may be applied directly to the skin, or the composition may be impregnated with gauze or the like and applied to the skin. Moreover, you may affix a sheet-like composition directly on skin. Or you may make a chemical | medical agent storage part integrated with the electrode structure of an iontophoresis apparatus contain a composition, and may make it contact with skin through a pad, an ion exchange membrane, etc. The application site is not particularly limited, and may be any skin of the body such as the face, arms, back, legs, and chest.

  Iontophoresis is performed by applying a positive electrode or a negative electrode to the skin contacted with the composition. As the iontophoresis method, apparatus, voltage application conditions, and the like, any commonly used one can be used.

  For example, a platinum, carbon, silver, silver chloride electrode or the like can be used as the electrode, and the energization method may be any method such as a direct type, a pulse type, or a pulse depolarization type.

The current density is not limited, but is preferably 0.001 to 0.5 mA / cm ² , more preferably 0.01 to 0.4 mA / cm ² , and still more preferably 0.05 to 0.3 mA / cm ^2. cm ² . May 0.001 mA / cm ² less than a is a transdermal delivery of tranexamic acid is not sufficient, when it exceeds 0.5 mA / cm ² may exhibit skin irritation.

  The iontophoresis treatment time is also not particularly limited, but is usually 0.5 to 30 minutes, and more preferably 1 to 20 minutes. Further, the number of treatments and the interval may be arbitrary.

  The cosmetic method of the present invention may be any one that can provide whitening or roughening prevention or improvement by transdermal delivery of tranexamic acid using iontophoresis, and may be performed alone or any other cosmetics. You may combine with a method.

  For example, by applying the cosmetic method of the present invention to the skin after chemical peeling treatment, it is possible to effectively reduce dryness, inflammation, rough skin, etc. due to chemical peeling, and to provide a synergistic whitening and skin-beautifying effect. Can do. In the present specification, “chemical peeling” is a method in which a chemical substance such as α-hydroxy acid, trichloroacetic acid, salicylic acid, or phenol is applied to the skin, and the surface layer portion is peeled off at a certain depth by its action. Means.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited to the following Example.

1. Examination of pH and Introduced Electrode of Tranexamic Acid-Containing Composition Tranexamic acid-containing compositions at pH 5, 7, and 9 were prepared according to the formulations shown in Table 1. All compounding amounts are expressed in mass% with respect to the total amount of the composition. Tranexamic acid was positively charged at pH 5, apparently had no charge at pH 7, and negatively charged at pH 9.

  A Franz cell was used as an iontophoresis experiment device, and a function generator (FG273; manufactured by KENWOOD) was used as a power source. Further, an Ag electrode was used as the positive electrode, and an AgCl electrode was used as the negative electrode. Each composition was used as a donor solution, and phosphate buffered saline (pH 7.4) was used as a receiver solution. FIG. 2 shows an outline of the in vitro iontophoresis experiment.

Hairless mouse skin was sandwiched between cells kept at 37 ° C., and 7.5 ml of the receiver solution was added to the cell on the dermis layer side, and 3 ml of the donor solution was added to the cell on the stratum corneum side. When the positive electrode is used as the introduction electrode (Anodal IP), an Ag electrode is used on the donor liquid side and the AgCl electrode is used on the receiver liquid side. Conversely, when the negative electrode is used as the introduction electrode (Cathal IP), Using an AgCl electrode and an Ag electrode on the receiver liquid side, a current was passed for 30 minutes under the conditions of 0.28 mA / cm ² , 10 kHz, 50% duty. As a control, the same experiment was conducted for each composition without applying current (no IP). The concentration of tranexamic acid (TA) in the receiver solution was measured using a micro-quantitative method by LC-MS, and the accumulated permeation amount was determined. Cumulative permeation is defined as the skin permeation of drug per area (μg / cm ² ). Further, the intradermal concentration (corneal epidermal concentration) of tranexamic acid (TA) in the hairless mouse skin sandwiched between cells was determined. FIG. 3A shows the cumulative amount of tranexamic acid permeated after 30 minutes, and FIGS. 3 (B) and 3 (C) were introduced from the positive electrode side at pH 5 and from the negative electrode side at pH 9, respectively. Shows the intradermal concentration (stratum corneum) of tranexamic acid (TA). All are shown as mean ± SD (n = 3).

  As shown in FIG. 3 (A), when the pH of the composition is 5 and ions are introduced from the positive electrode side, the cumulative amount of tranexamic acid is the highest, and transdermal delivery of tranexamic acid can be significantly enhanced. It was. In addition, when the pH of the composition is 9 and ions are introduced from the minus side, the effect is lower than when ions are introduced from the plus side at pH 5, but the transdermal delivery of tranexamic acid is significantly greater than when ions are not introduced. I was able to increase it. As described above, transdermal delivery by iontophoresis is based on the negative polarity due to the force due to the electric repulsion of the same kind of charge in the electric field formed by the current and the cation adsorbed on the negatively charged stratum corneum. It is thought that this is caused by the force generated by electroosmotic flow caused by the flow of water from the positive pole to the negative pole when it is pulled by (Fig. 1). Accordingly, when ions are introduced into the positively charged tranexamic acid at pH 5 from the positive electrode, both the electric repulsive force and the force generated by the electroosmotic flow act positively, and it is considered that the cumulative amount of tranexamic acid permeated is the highest. On the other hand, it is considered that the transdermal delivery promoting effect of tranexamic acid when ions are introduced from the negative electrode at pH 9 is due only to the electric repulsive force.

  Further, as shown in FIGS. 3 (B) and (C), the tranexamic acid concentration in the stratum corneum is also supplied with current when ion is introduced from the positive electrode at pH 5 and when ion is introduced from the negative electrode at pH 9. Significantly increased compared to the absence.

2. Examination of salt concentration Next, in order to investigate the influence of the concentration of competing ions, NaCl was added to the composition of pH 5 in Table 1 above at the concentrations shown in Table 2 below, and tranexamic acid containing salts at various concentrations. A containing composition (both having a pH of about 5) was prepared. Using a Franz cell as an iontophoresis experiment apparatus, ions were introduced from the positive electrode side according to the method described above, and the cumulative amount of tranexamic acid permeated and the stratum corneum skin concentration after 30 minutes were measured. As a control, a sample containing 0.5% by mass of NaCl was measured in the same manner without passing an electric current. An average value (n = 3) is obtained for each sample, and the accumulated permeation amount and intradermal concentration (corneal layer skin concentration) are shown in Table 2.

  In both cases, the cumulative amount of tranexamic acid permeated increased compared to the case where no current was passed. However, when the salt concentration exceeded 0.5% by mass, the permeation promoting effect of tranexamic acid by iontophoresis tended to decrease. It was.

3. Examination of the in vivo percutaneous absorption promoting effect Using the tranexamic acid-containing composition (pH 4.89 and pH 10.0) prepared by the formulation shown in Table 3, in vivo transdermal administration of tranexamic acid by iontophoresis according to the following method. The absorption promotion effect was examined. For the case where no current was passed, the formulation of pH 4.89 was used.

Experimental method After removing the hair of the back of the heart guinea pig with a shaver, 1 ml of the composition of pH 4.89 or pH 10.0 shown in Table 3 was applied, and the positive electrode side (Anodal IP) was used using Vitalion II (Indiva Japan). ) Or from the negative electrode side (Cathodal IP) for 5 minutes. As a control, the same composition was applied to the skin and left for 5 minutes without current (no IP). 30 minutes after the administration, the skin was washed with tap water, and the skin at the administration site was collected. The skin was divided into two layers, the horny layer epidermis and the dermis, and the tranexamic acid (TA) concentration in the horny layer epidermis was measured by LC-MS. The results are shown in FIG. 4 as mean values ± SD (n = 3).

  Based on the method of the present invention, a tranexamic acid-containing composition having a pH of about 5 is applied to the skin and iontophoresis is applied from the positive electrode side, or a tranexamic acid-containing composition having a pH of about 10 is applied to the skin and the negative electrode side is applied. By applying iontophoresis, it was possible to significantly promote in vivo transdermal absorption of tranexamic acid, and the effect was higher at pH 5.

4). Examination of in vivo whitening effect Using the tranexamic acid-containing composition (pH 4.89) prepared with the formulation shown in Table 3 above, the in vivo whitening effect was examined by the following method.

Experimental Method Using 8-methoxypsoralen-treated phototoxic pigmented Wiser Maple guinea pig, 1 ml of tranexamic acid-containing composition was applied to the skin on the back of the hair, and Vitalion II (manufactured by Indiva Japan) Was used for iontophoresis from the positive electrode side for 5 minutes (Anodal IP). As a control, the same composition was applied to the skin and left for 5 minutes without current (no IP). The same treatment was performed every day for 7 weeks, and the decolorization effect was evaluated every week according to the following evaluation criteria:
Evaluation criteria Based on the evaluation criteria, an average evaluation score of 5 animals after 7 weeks was determined.

Depigmentation effect of pigmentation (evaluation point 1.0): Pigmentation became almost inconspicuous (evaluation point 0.5): Pigmentation became very faint (evaluation point 0.25): Pigmentation became faint (Evaluation point 0): Pigmentation enhancement effect without change (side effects)
(Evaluation point 0): No change (Evaluation point -0.25): Pigmentation became slightly darker (Evaluation point -0.5): Pigmentation became darker (Evaluation point -1.0): Pigmentation The result is shown in the graph of FIG. In addition, a photograph of the skin after 7 weeks is shown in FIG. 5B.

  By applying a tranexamic acid-containing composition of about pH 5 to the skin and applying iontophoresis from the positive electrode side, it was possible to provide a significantly higher whitening effect than simply applying the composition to the skin. .

  Hereinafter, formulation examples of the composition for iontophoresis of the present invention will be shown as examples. In addition, all compounding quantities are represented by the mass% with respect to the composition whole quantity.

Example 1
Composition for iontophoresis from the positive electrode side (1)
Compounding ingredients Compounding amount (% by mass)
Ion exchange water 97.6
Tranexamic acid 2.0
Citric acid (food) 0.4
pH 4.9

Example 2
Composition for iontophoresis from the positive electrode side (2)
Compounding ingredients Compounding amount (% by mass)
Ion exchange water 87.1
Tranexamic acid 2.0
Citric acid (food) 0.4
Alkylene oxide derivative 10.0
Phenoxyethanol 0.5
pH 5.1

Example 3
Composition for iontophoresis from the positive electrode side (3)
Compounding ingredients Compounding amount (% by mass)
Ion exchange water 87.1
Tranexamic acid 2.0
Citric acid (food) 0.4
Glycerin 10.0
Phenoxyethanol 0.5
pH 5.0

Example 4
Composition for iontophoresis from the positive electrode side (4)
Compounding ingredients Compounding amount (% by mass)
Ion exchange water 87.1
Tranexamic acid 2.0
Citric acid (food) 0.4
1,3-butylene glycol 10.0
Phenoxyethanol 0.5
pH 5.1

Example 5
Composition for iontophoresis from the positive electrode side (5)
Compounding ingredients Compounding amount (% by mass)
Ion exchange water 87.1
Tranexamic acid 2.0
Citric acid (food) 0.4
Ethanol 10.0
Phenoxyethanol 0.5
pH 5.2

Example 6
Composition for iontophoresis from the negative electrode side (1)
Compounding ingredients Compounding amount (% by mass)
Ion exchange water 87.495
Tranexamic acid 2.0
Glycerin 10.0
NaOH (reagent) 0.005
Phenoxyethanol 0.5
pH 9.0

Example 7
Composition for iontophoresis from the negative electrode side (2)
Compounding ingredients Compounding amount (% by mass)
Ion exchange water 87.46
Alkylene oxide derivatives 5.0
Tranexamic acid 2.0
Ethanol 5.0
NaOH (reagent) 0.040
Phenoxyethanol 0.5
pH 10.2

  The tranexamic acid-containing compositions of these examples all have high whitening due to iontophoresis from the positive pole side (Examples 1 to 5) or iontophoresis from the negative pole side (Examples 6 to 7). It showed the effect of improving or preventing rough skin.

Schematic diagram of the mechanism of transdermal delivery by iontophoresis Schematic diagram of in vitro iontophoresis experiments Graph showing the effects of pH and lead electrode Graph showing the in vivo percutaneous absorption enhancement effect of tranexamic acid by iontophoresis Graph showing in vivo whitening effect (A) and photograph of skin (B)

Claims (6)

Contact the skin with a composition having a pH of 3.5 to 6.5 containing 1 to 3% by mass of tranexamic acid and citric acid and / or hydrochloric acid and having a salt content of 0.5% by mass or less. Then, the skin is subjected to iontophoresis from the positive electrode side, and then a cosmetic method for whitening or preventing or improving rough skin ( excluding medical practice ). The cosmetic method according to claim 1, wherein the composition contains 0.1 to 0.5% by mass of citric acid. After contacting the skin with a composition of pH 8.5 to 10.5 containing 1 to 3% by mass of tranexamic acid and sodium hydroxide and having a salt content of 0.5% by mass or less in the composition A cosmetic method ( excluding medical practice ) for preventing or improving whitening or roughening of the skin, characterized in that iontophoresis is applied to the skin from the negative electrode side. 1 to 3% by mass of tranexamic acid, citric acid and / or hydrochloric acid , the salt content in the composition is 0.5% by mass or less , and the pH is 3.5 to 6.5. A composition for iontophoresis from the pole side. 5. The composition for iontophoresis according to claim 4, comprising 0.1 to 0.5% by mass of citric acid. 1 to 3% by mass of tranexamic acid and sodium hydroxide , the salt content in the composition is 0.5% by mass or less , and the pH is 8.5 to 10.5. Composition for iontophoresis of