JPS6140203B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention uses ferulic acid ester (hereinafter referred to as this substance)
This relates to an oil-solubilized skin rubbing agent that contains a high amount of FE (referred to as FE). The characteristic feature is that FE was found to be extremely well solubilized in egg yolk oil, lanolin, or lanolin derivatives (lanolin fatty acids, lanolin alcohol, etc.), and the present invention was completed based on this finding. A representative example of FE is gamma oryzanol, which is administered orally or by injection (intramuscularly) as a therapeutic agent for symptoms such as menopausal disorders, after-effects of head or neck trauma, and senility. It is. On the other hand, its application in the dermatology field is due to its pharmacological effects, such as increased local sebum secretion, sebaceous gland activation,
It has been reported that it has an effect on increasing skin temperature, and based on this fact, it is added to cosmetics such as creams, milky lotions, and hair tonics. Recently, a lubricant containing 1% FE in an ointment such as Vaseline has been tested for senile xeroderma, etc., and has been reported to be effective. However, the drawback is that when FE is used as a skin abrasion and an immediate therapeutic effect is expected, only a very small amount of FE is solubilized in various oils and fats. In other words, in oils and fats used in ointments and cosmetics, the upper limit of solubility is 1 to 1.
For example, the amount that is soluble in external pharmaceutical ointments such as Vaseline, water-absorbing ointments, and hydrophilic ointments is around 1% when heated, and less than 1% when cooled. It was hot in quantity. That is, when 1% or more of FE is added, the excess amount of FE that is not oil-solubilized becomes crystalline and insoluble in the ointment. In addition, olive oil and other liquid oils such as soybean oil and sesame oil, which are often used in cosmetics and pharmaceuticals, pork fat,
Even in beef tallow, the upper limit for solubilization was 1% or less. Therefore, the present inventors searched for a state in which FE is always stably oil-solubilized even when added in large quantities to the above-mentioned external skin lubricants and oils and fats. Alternatively, it has been found that it can be completely dissolved by mixing it in a lanolin derivative (lanolin fatty acid, lanolin alcohol, etc.). In other words, if you use this dissolved product, even in formulations using any fats and oils,
In an oil-solubilized state without using an emulsifier,
It has been found that it can be mixed arbitrarily. In other words, it has been found that in order to add FE to fats and oils, it is best to use egg yolk oil, lanolin, or a lanolin derivative as a dissolving agent for FE in advance. However, the method for dissolving FE is simple as shown in the following example. [Example] Egg yolk oil (the component composition and properties of the egg yolk oil used here is that it is a liquid oil and contains 1 to 10% of phospholipids; however, egg yolk oil that does not contain phospholipids) Alternatively, lanolin, lanolin fatty acid, or lanolin alcohol is stirred while being heated at 40 to 100°C or less, and FE is gradually added thereto and mixed. By this operation, FE is dissolved. Looking at the amount of dissolved FE and the heating conditions, the results shown in Figure 2 were obtained. That is, it is solubilized in large quantities in egg yolk oil and lanolin, and moreover, it is stably solubilized even by cooling. As mentioned above, it is well known that FE has traditionally been used in cosmetics and external skin preparations, but when it comes to FE content, the upper limit is 1%, and there have been no products containing more than that. . Moreover, no preparation was found in which the entire amount of added FE was completely solubilized. In other words, the amount that could be soluble in fats and oils was very small, so
When adding FE to a formulation, by adding an emulsifier (surfactant), etc., FE crystals are dispersed in oils and fats as creams or emulsions, and the dispersed FE is The particles were barely able to be absorbed or permeated into the skin to enhance the effect. In other words, the amount that is soluble in cosmetics and ointments is the amount that is expected to permeate through the skin epidermis and exert its original therapeutic effect. In other words, when considering transdermal absorption, the first condition is that it be oil-soluble. Furthermore, it is thought that the absorption of the drug will be improved if it is soluble in any fat or oil, but the present invention solves these drawbacks by using it in combination with egg yolk oil, lanolin, or lanolin derivatives. be. The therapeutic effect is
Although it is necessary to eliminate subjective symptoms in a short period of time, when the content of FE for this purpose is around 1%, its action is slow and lacks immediate effect. Therefore, it was unsuitable as a short-term therapeutic drug for use by physicians. However, until now, no method has been found to solubilize and use 1% or more, and the content has been insufficient. At least, a skin rub with about 5% solubilization was required to be used as a short-term treatment for FE, and the present invention has made this possible.
The egg yolk oil used in the Examples was a liquid oil that contained almost no phospholipids (lecithin, etc.). In other words, commercially available products include
Some of the so-called egg yolk oils contain high amounts of phospholipids such as lecithin, but here we will focus on the oil obtained by removing lecithin during the process of extracting it from egg yolks.
FE dissolves even in liquid oils that do not contain phospholipids. Therefore, the phospholipid itself contained in egg yolk oil shows this. This is slightly different from the case in which FE was dissolved due to the dispersibility and emulsification aid effect brought about by amphoteric surfactant action, and egg yolk oil and FE have
It seemed that there was a special relationship. Of course, in egg yolk oil containing phospholipids such as lecithin,
FE further improves solubility. Now, using the method shown in Examples, an attempt was made to apply a composition prepared by containing 20% FE in egg yolk oil to treat blistering skin inflammation. This symptom is a cluster of small blisters, small impotence, and scaling between the toes, forming a clearly defined border, and may be accompanied by eczema or a disease accompanied by skin infiltration, thickening, and itching. be. The results are shown in Table 1.

[Table] Effective, - means no effect)
For the symptoms shown in Table 1 above, the administration method was to apply it directly to the area between the toes, and then apply it on a lint cloth and place it tightly on the area, and administer once a day.
The administration period is 1 to 2 weeks, and during that period,
No other drugs were used, and the treatment was performed alone. As a result, the itching disappears in about 20-30 minutes after rubbing. Further, the infiltrated thickened area peels off in about 2 to 3 days, and an epidermis is formed in about 1 week. It is also extremely effective against eczema. In addition, it is highly effective for symptoms such as tinea hidraformis when used in combination with oral gluceofulvin. Next, a feature of a skin application preparation made of this FE solubilized composition is that it exhibits a tyrosinase activity inhibiting effect. In other words, the crystal powder of FE itself, egg yolk oil, lecithin, lanolin, or lanolin derivatives have no inhibitory effect on tyrosinase activity, whereas the solubilized composition of FE has been tested using the following test method. Although it is slightly weaker than vitamin C, it does not have the inhibitory effect that rapidly decreases after being dissolved like vitamin C, and has a long-lasting inhibitory effect on tyrosinase activity. Therefore, it was estimated that it suppresses melanin pigment production in the skin and is effective as a controller for skin pigmentation disorders. In addition, the inhibitory effect of the FE solubilized composition is 0.3
% or more, but clinically it seems necessary to contain at least 1% or more.

[Table] (Test method) The test was carried out using tyrosinase extracted and purified from potatoes at a constant enzyme titer, and a 0.2% solution of L-ascorbic acid as a standard substance (inhibitor). In advance, put a solution of 2% agar and 0.1% L-tyrosine in a 8 cm diameter shear dish, add the FE solubilizer (inhibitor) to this, cool and solidify it, pour 0.5% tyrosinase solution over it, The sample was left in a constant temperature bath at 37°C for 48 hours, and the degree of blackening of the agar surface in this shearlay was observed to determine the presence or absence of an inhibitory effect and its sustainability. A consideration based on the results in (2) above shows that FE solubilized products. The inhibitory effect on tyrosinase activity is
It is thought that it inhibits the production of melanin pigment by competing with the substrate tyrosine, and is presumed to be due to the structural similarity between tyrosine and FE due to the substrate specificity of tyrosinase. The tyrosinase activity inhibitory effect of vitamin C inhibits the oxidation of tyrosine through its reducing power, but this mechanism of action is different and is weaker than that of vitamin C. However, the effect is sustained for a long period of time, and a highly durable therapeutic agent for hyperpigmentation is required, and the present invention has advantageous conditions in this respect. Next, prescription examples are shown in %. (Formulation example 1) Egg yolk oil (Etsugu oil)...80% Ferulic acid ester (Oryza gamma V)
...20 *Produced by gradually adding ferulic acid ester while stirring egg yolk oil under heating at 70-80℃. (Prescription Example 2) Mix 20% of the dissolved composition prepared in Prescription Example 1 in an ointment listed in the Japanese Pharmacopoeia, such as petrolatum, hydrophilic ointment, or water-absorbing ointment, such that the total amount is 100%. The temperature is 50-60°C while stirring. (Formulation Example 3) Lanolin (Japanese Pharmacopoeia) or Fullline SP (purified liquid lanolin) or Acelan J (acetylated lanolin) or Proteclan SK88 (water-soluble lipoid lanolin) or Super Heartlan (lanolin alcohol) or Crestaran AB (isopropylene) Lanolin ester)...60 Ferulic acid ester...20 *Produced by gradually adding fernic acid ester to lanolin or its derivatives while stirring at 45-50°C. In addition, it is also soluble in a substance made by adding ethien oxide to lanolin. (Formulation Example 4) Mix 30% of the dissolved composition prepared in Formulation Example 3 with petrolatum, hydrophilic ointment, absorbent ointment, etc. so that the total amount is 100%. The temperature is 50-60°C while stirring. (Formulation example 5) Egg yolk oil...80 Lanolin...5 Ferulic acid ester...15 *While heating egg yolk oil at 70-80℃, add lanolin and mix, then gradually add ferulic acid ester. Make by stirring. In addition, when using lanolin or its derivatives,
Adding a small amount of egg yolk lecithin or soybean lecithin tends to suppress skin inflammation,
Soothes itching. Also, soy lecithin,
Egg yolk oil with a phospholipid content of about 25% to 55% seems to have a higher anti-inflammatory effect than highly purified egg yolk lecithin, so in some cases, anti-inflammatory effects may be higher. From the standpoint of an allergy agent, it is considered more advantageous to use egg yolk oil. However, egg yolk oil, which does not contain lecithin (phospholipids), is particularly effective in suppressing itching.
This is noticeable when ferulic acid ester is dissolved in this, and as mentioned in the previous table [Table 1], this is because the ferulic acid ester itself is solubilized. Therefore, it is presumed that an anti-allergic effect or an anti-itch effect is expressed. In any case, the combination of egg yolk oil and ferulic acid ester is due to the synergistic effect of both substances.
It is advantageous as a skin rub.

[Brief explanation of the drawing]

FIG. 1 shows the peaks of ferulic acid ester obtained by liquid chromatography. a is ferulic acid ester. Measurement conditions were: column: LS410, eluent: methanol, flow rate 1.0 ml/min, chart speed: 0.5 cm/min, column temperature: 40°C, detection wavelength: UV 254 nm, sensitivity: 124 AUFS. Figure 2 shows
Graph showing the relationship between temperature and the amount of ferulic acid ester dissolved in lanolin in egg yolk oil (which does not contain phospholipids). 1 in egg yolk oil, 2 in lanolin, and 3 in petrolatum.

Claims (1)

[Claims] 1. General formula (In the formula, R represents a steroid group) [1] using ferulic acid ester as the main drug substance,
The solubilizing base consists of egg yolk oil, lanolin, or lanolin derivatives, and the total phospholipid content of the egg yolk oil as the base is zero or 1.
The content is within ~10%, and the lanolin derivative is at least one of lanolin fatty acids, lanolin alcohol, isoprolanolin ester, and acetylated lanolin as a base;
An oil-solubilized skin rubbing agent characterized in that at least 5% or more of the main substance is dissolved in these bases.