JPS60152410A - External preparation for skin - Google Patents

Abstract

PURPOSE:An external preparation for skin having a raised endemic absorption of active substance without causing irreversible denaturation of skin, by adding liposome to an active substance. CONSTITUTION:A liposome film-forming material (e.g., phospholipid such as soybean lecithin, phosphatidylcholine, etc.) is dissolved in an organic solvent such as chloroform, ether, methanol, etc., and the solvent is distilled away, to form a film. An aqueous solution containing an active substance is added to the film, shaked, or shaked and stirred, or water or an aqueous solution is added to the film to give a liposome solution, which is blended with the aqueous solution containing an active substance, to give the desired external preparation for skin. When the active substance is oil-soluble, the active substance is simultaneously dissolved in the film forming, and preferably water or the aqueous solution is added to the prepared film. 0.001-10pts.wt. especially 0.01-0.1pts.wt. active substance is preferably used based on 1pt.wt. liposome film-forming material.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel external preparation for skin, and provides a novel external preparation for skin in which liposomes are coexisting in order to promote absorption of an active substance when it is locally administered to the skin. be.

Generally, drugs containing active substances are administered to living organisms by oral administration or parenteral administration such as injection, but in these methods, the active substance is absorbed into the intestine and then passes through the liver. Because they tend to be easily metabolized, there is a problem that sufficient effects cannot be obtained even if the active substance is administered at the active concentration level, or that it is difficult to maintain the optimal concentration for a long period of time. .

Therefore, it is conceivable to increase the concentration of the active substance in dogs, but in this case, there is a risk that the level of toxicity may exceed the level of activity, so it is not necessarily a desirable measure.

Transdermal administration may be an alternative to the above administration method, but even in this case, the amount of drug absorbed is small due to the barrier function of the skin's stratum corneum, and sufficient medicinal efficacy cannot be expected. Can not. Therefore, attempts have been made to use various absorption enhancers, but there are problems such as irreversible denaturation of the skin and skin irritation, and no effective solution has yet been found.

As a result of intensive research aimed at solving the drawbacks of the various administration methods mentioned above, the present inventor has found that by using liposomes containing active substances as external preparations for the skin, there are no various problems and the efficacy of the active substances can be fully exerted. We succeeded in providing a skin preparation for external use.

The present invention will be explained in detail below.

In the skin external preparation of the present invention, when liposomes containing an active substance reach the skin surface, the liposomes are adsorbed or disintegrated at the skin JR interface, and the active substance contained therein is transferred to the skin surface without the liposomes themselves being absorbed transdermally. This has the effect of increasing the concentration of the active substance and increasing the amount of active substance absorbed.

The active substance-containing liposome skin preparations according to the present invention can be broadly classified into the following categories.

(1) The liposome film-forming material (lipid) is dissolved in an organic solvent, the solvent is then distilled off to form a film (lipid thin film), and an aqueous active substance solution (including an aqueous buffer solution) is added thereto and shaken.・Ribonome skin topical preparation containing active substance prepared by shaking and stirring.

(2) Nome skin pain external preparation prepared by dissolving the liposome film-forming material (lipid) and the active substance in an organic solvent, and then distilling off the solvent to form a film (lipid thin film).

(3) Dissolve the liposome film forming material (lipid) in an organic solvent, then distill off the solvent to form a film (lipid thin film), then add water or an aqueous solution (including an aqueous buffer solution) and shake.・For liposome solutions prepared by shaking and stirring.

An active substance-containing ribbon foam skin preparation for external use obtained by mixing an active substance aqueous solution (including a buffer aqueous solution).

Each of the skin dregs external preparations (1), (2), and (3) above are selected as appropriate depending on the effect of the intended active substance and the dosage form, etc., and the manufacturing methods of these external preparations can be used in combination with each other. Can be used. In addition, if the active substance is a water-soluble substance,
The methods (1) and (3) for producing a skin external preparation are advantageously used, and when the active substance is a fat-soluble substance, the method (2) for producing a skin external preparation is advantageously used. Case (3) above is particularly effective when the water-soluble active substance is a substance that is not suitable for shaking, stirring, or ultrasonication.

To describe in detail a specific example of the method for producing the skin external preparation of the present invention, for example, liposome film-forming material (lipid) alone or together with a desired fat-soluble active substance are dissolved in an organic solvent, and an eggplant-shaped After the solvent is distilled off to form a film (lipid thin film) by drying under reduced pressure in a flask, water or an aqueous solution or an aqueous buffer solution or an aqueous solution or an aqueous buffer solution containing a desired water-soluble active substance is added. Add
A liposome solution or an active substance-containing liposome is obtained by shaking or stirring at a temperature above the phase transition temperature. At this time, ultrasonic treatment may be performed at a temperature higher than the phase transition temperature, if necessary. In this way, particles of approximately 02 to 10 microns are obtained as liposomes. At this time, when the ultrasonic treatment is carried out for about 60 seconds to 10 minutes, multilamellar formation tends to occur, and when the ultrasonication is carried out for about 60 minutes to 120 minutes, unilamellar formation tends to occur. The final active substance-containing liposome is then obtained by mixing the liposome solution or the active substance-containing liposome solution with a water-bathable active substance aqueous solution or a buffer water bath solution. As the organic solvent used in the production method, a solvent that can dissolve the liposome film forming material (lipid) is used. Examples include chloroporum, ether, methanol, and benzene. The buffer used in the buffer water bath may also be a customary buffer, such as phosphorus, the active substance-containing ribbon obtained as described above.

The liposome film forming material (lipid) used in the present invention includes phospholipids such as egg yolk lecithin, soybean lecithin,
Phosphatidylcholine, phosphaticylinositol, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, L-β-oleoyl-γ-noglumitoyl-α-renotin, cyhalumitoyllentin, dimyristoyllentin, etc. These can be used singly or in combination of two or more. In addition to these phospholipids, other liposomal film-forming materials (lipids) such as evacholesterol, ergosterol, triglycerides, cholesterol esters, antioxidants (e.g. alpha-tocopherol), mixtures of sugars, dicetyl phosphate, stearylamine etc. may be mixed.

The active substance applied to the external skin preparation of the present invention may be any substance that can be used as an external skin preparation, regardless of whether it is water-soluble or fat-soluble. For example, anti-inflammatory agents, antihistamines, psoriasis treatment agents, healing agents, melanin production inhibitors,
Examples include ultraviolet absorbers, prurigo treatment agents, and skin irritation prevention agents. In the liposome of the skin external preparation of the present invention, the active substance of these drugs is located in the outermost layer of the lamellae, between the lamellae, or in the central core.
The oil-soluble substance is located in the hydrophobic part of the lamella. In addition, in the active substance-containing liposome skin external preparation of the present invention, the preferred composition ratio of the ponome film-forming material (lipid) to the active substance is 1 part of the liposome film-forming material (lipid).
0001 to 10 parts by weight (most preferably 001 to 01 parts by weight) of active substance.

In order to confirm the effect of transdermal absorption of active substance-containing liposomes applied to the present invention, the behavior of 14C-labeled liposomes after transdermal administration was investigated using whole-body autoradiography. It was as follows.

(1) Sample preparation Egg yolk lecithin 127.7 mg and cholesterol 31.2 mg
mg and dicetyl phosphate 21.9 #l! ? 14 as a marker in the noposome film-forming material consisting of 14
C-dipalmitoylphosnoatine lucholine 50 μC1
(Curie) and mix this with butylnoξlaben 11
01I1 was dissolved in 5 ml of chloroform in a 251 nl eggplant-shaped flask and dried under reduced pressure to remove the chloroform and form a lipid thin film.
was added, and after shaking and stirring at a temperature higher than the phase transition temperature, ultrasonication was performed for 25 minutes to prepare liposomes. This 11 is L
Set to ip 1. A liposome prepared in the same manner with the addition of 100 μCi of 140-butylparaben instead of 14C-dinoS lumitoyl phosphatidylcholine as a marker is referred to as Lip II. The behavior of lecithin can be monitored using Lip I, and the behavior of active substances in liposome solutions can be monitored using Lip n.

(2) Experimental method■ Guinea pig dorsal skin with prickly hairs ('4.5 x 6.
5 cm ) of the above liposome solution Lip l or Li
p n 1rnI! After administration and occlusion for a certain period of time (6 hours ~
48 hours).

■ After a certain period of time, the animal is anesthetized with ether,
Freeze the guinea pig with dry ice-acetone and place it in an autocryodome at 50μ? Whole body thin sections of guinea pigs were prepared.

(2) The thin sections were then dried, brought into contact with X-ray film, and stored in a cool, dark place.

(2) After a certain period of time (1 week to 2 months), the X-win film was developed, and the areas exposed to β-rays from +4C were identified, and knowledge about the behavior of 14C was obtained.

(6) Results After administration, 14C-butylparaben migrated into the body through the skin, and high radioactivity was found in Boukola already within 6 hours. Radioactivity has also been found in some parts of the small intestine, and this suggests that 14C-butylparaben has two routes: after percutaneous absorption, it is excreted in the urine via the kidneys, then through the bowels, and also through the liver, bile, small intestine, and feces. It has become clear that there is a route for excretion.

Regarding 14C-ampalmitoylphosphatidylcholine, even 48 hours after administering the can, 14
Only 0 activity was observed, and no movement into the body was detected.

From these experimental results, it was confirmed that the liposomes according to the present invention are not absorbed transdermally, but the active substances they contain are absorbed and transferred into the body.

Separately, it was confirmed that even in the case of liposomes using water-soluble substances, no absorption of 14C-dinolumitoylphosphatidylcholine was observed.

A particularly important feature of the skin external preparation of the present invention is that when a negatively charged lipid is used in addition to phospholipids as the liposome film-forming material, the resulting liposomes are particularly adsorbed to the skin. Such negatively charged lipids are incorporated into liposomes as components of the lipid bilayer membrane, and specifically include, in addition to the above-mentioned shitacyl phosphate, for example, phosphatidine, distearyl phosphate, etc. It is preferable to use seven or more of these, or a mixture thereof. The molar ratio of phospholipids and negatively charged lipids is
The optimum range is 2:/ to SO:/.

When the amount of negatively charged lipids is less than these values, the amount of adsorption decreases or aggregation of liposomes tends to occur, so there is a tendency that there is no point in using it. Furthermore, if the number of negatively charged lipids exceeds the above value, it becomes difficult to produce liposomes.

The effect of charge state on the adsorption of liposomes to the skin was investigated using the method of liposome solution-keratin, e-Uder distribution experiment, and it was found that liposomes using negatively charged lipids were significantly adsorbed to the skin. Served. Due to this adsorption, the active substance-containing liposomes therefore function as carriers for transporting the active substance to the skin surface. The above liposome solution-keratin powder distribution experiment was conducted as follows.

(1) Preparation of sample (g) Preparation of liposome solution (10-) 2. As a marker to the liposome film forming material shown in Table 1 below.
Add 3H-dipalmitoylphosphatidylcholine of 5 x I D' tt C1/me, and mix this with 10 mg of butylparaben at 25rnI! It was dissolved in chloroform 5- in an eggplant-shaped flask and dried under reduced pressure to distill off the chloroform to form a lipid thin film.
After adding rnl and stirring at a temperature above the phase transition temperature, ultrasonication was performed for 25 minutes to form three types of liposomes.
were prepared respectively.

Table 1 (B) Preparation of keratin flea The stratum corneum of keratinized skin was collected from the palms and soles of people, and after drying, 100 to 200 mesh fractions were used as a powder in experiments.

(2) Experimental method ■ 2 ml of each liposome prepared according to (A) above! Collect 20mg of keratin powder into 7 ear pins,
After mixing at 67°C, let stand.

(2) After a certain period of time had elapsed, the solution in the vial was sampled, and the 3H count of the solution was measured, as well as the 3H adsorbed to the keratin powder.

■ The distribution coefficient was calculated as follows.

■ Figure 1 shows the distribution coefficients of the six types of liposomes that were tested.

(6) Results O From FIG. 1, even after 20 hours, in the case of liposome (■) using positively charged lipids, almost no adsorption to keratin was observed. In addition, in the case of liposome (3), which does not use a charged substance, only slight adsorption was observed.

On the other hand, in contrast to these, it was observed that the use of negatively charged lipids and those of Bonome ■ were significantly adsorbed to keratin.

In addition, significant adsorption of negatively charged lipids to the skin was also confirmed for liposomes produced by a different method using the same marker and using glucose as a water-soluble substance instead of butylparaben.

Next, examples of liposome skin external preparations containing active substances of the present invention will be described.

Example 2 1 Egg yolk lecithin 127.7 m9, cholesterol 31
．． 2 mg, 21.9 my of dicetyl phosphate 5
10rnl of chloroform in a 0ml eggplant flask
The solution was dissolved in H and dried under reduced pressure to remove chloroform and form a lipid thin film. To this was added 10 f of an aqueous solution containing 5 mg of hydrocortiscin, and after shaking and stirring at room temperature,
Hydrococcin-containing liposomes with particles of about 0.2 to 10 μm were prepared by ultrasonication for 2 minutes at 10.19 °C.
F was obtained and used as a skin external preparation.

Example 2 Dinoξ lumitoyl phosphatidylcholine 1277rn
g and 5 my of triamcinolone acetonide were dissolved in 10-chloroform in a 25-sized eggplant-shaped flask and dried under reduced pressure to distill off the chloroform to form a lipid thin film. To this, buffer (Tris-HCl) pH 6.5 aqueous solution 1
After shaking and stirring at 45°C, the ultrasonic treatment was continued for 2 minutes to obtain about 10.13 r of posomes containing triamcinolone acetonide in particles of about 0.2 to 10 µm, which were used as a skin external preparation. did.

Example 5 Soybean lecithin 255.4ml? was dissolved in 10-chloroform in an eggplant-shaped flask and dried under reduced pressure to remove chloroform and form a lipid thin film.

Purified water 10- was added to this and the liposome solution was obtained by shaking and stirring at room temperature, followed by sonication at 0°C for 2 minutes, and then an aqueous solution containing 081% hydrocortiscin 10-
were mixed to obtain about 2062 hydrocortiscin-containing liposomes with particles of about 02 to 10 microns, which was used as a skin external preparation.

[Brief explanation of the drawing]

Figure 1 shows the results of the aforementioned liposome solution-keratin powder distribution experiment, where ■ indicates liposomes using positively charged lipids, ■ indicates liposomes without charged lipids, and ■ indicates negatively charged liposomes. It is a liposome made using lipids. Patent applicant: POLA CHEMICAL INDUSTRIES, INC.

Claims (1)

[Claims] 1. An active substance-containing material prepared by dissolving a liposome film-forming material in an organic solvent, then distilling off the solvent to form a film, and then adding an aqueous solution containing an active substance thereto and shaking it. Ribonorm skin topical preparation. 2. Active substance-containing ribonome for external use on the skin prepared by dissolving the liposome film-forming material and the active substance in an organic solvent, then distilling off the solvent to form a film, and then adding water or an aqueous solution and shaking. agent. 6. Dissolve the liposome film-forming material in an organic solvent, then distill off the solvent to form a film, add water or an aqueous solution and shake, and mix the active substance aqueous solution with the liposome solution prepared. The obtained active substance-containing liposome skin preparation for external use.