JPS61172818A - External drug composition for skin - Google Patents

Abstract

PURPOSE:To provide the titled composition having high absorbability, by compounding a base with an alkali metal salt of 1,3-bis(2-carboxychromon-5- yloxy)-2-hydroxypropane useful as an antiallergic agent and a saponin useful as a transcutaneous absorbefacient. CONSTITUTION:A base is compounded with 0.5-40wt%, preferably 1-30wt% alkali metal salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane (abbreviated as present substance) and 0.5-30wt%, preferably 1-20wt% saponin (e.g. glycyrhizin, senegenin, etc.). The present substance is a medicine effective to bronchial asthma and allergic rhinitis, etc., however, it has poor bioavailability by oral administration or inhalation. Furthermore, it has low transcutaneous absorbability because of its low transmissibility through cornal layer. The addition of saponin promotes the absorption of the present substance and gives an external dermatic drug composition capable of keeping high concentration of the drug component in blood.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a composition for external use on the skin, and more specifically to a composition containing 1,3-bis(2-carboxyl Chromone-5
The present invention relates to a skin external preparation composition containing an alkali metal salt of -yloxy)-2-hydroxypropane.

Prior art 1. The alkali metal salt of 3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane is
It is known as a substance that suppresses the release of chemical messengers from mast cells during allergic reactions, and is currently used as an inhaler, nasal spray, and eye drops to treat bronchial asthma, allergic rhinitis, and allergic conjunctivitis. [For example, History of Medicine, 130 (12), 800 (
1984) and Basic and Clinical Research, 16 (51, 2426-2
432 (1982)]. Alkali metal salts of 1.3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane have also been reported to be effective as oral agents for the treatment of food-induced ulcers. [For example, Pharmacology and Therapy, 8(1), 80-91 (1980)
reference〕.

However, in the administration method described above, 1,3-bis(2-
Although the alkali metal salt of carboxychromon-5-yloxy)-2-hydroxypropane is present in high concentration at the local site where it is administered and exerts its medicinal efficacy [e.g., Pharmacology and Treatment, 8(1), 80 ~91 (1980)
and Toxicol, Appl, Pharma-c
ol, 17.699-707 (1970)],
It is known that the administration of an alkali metal salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane by the above-mentioned known method has the following problems.

(1) The bioavailability of the administered drug is extremely low, e.g.
When administered by inhalation, only about 8% of the dose passes into the lungs, and when administered orally, only about 1% is absorbed [e.g., pharmacology and therapy,
8(1), 80-91 (1980) and J. Ph.
arm, Pharmacol, 20s 147-1
56 (1971)].

(2) Excretion from the body is rapid, with most of the absorbed drug being excreted within 4 to 6 hours after administration, resulting in short duration of drug efficacy [e.g., Pharmacology and Treatment, 8Tl), 80-91
(1980), J. Pharm, Pharmac.
ol,.

Dan, 525-531 (1971) and Toxico
l, Appl.

Pharmacol, 20.147-156 (19
71)].

(3) Nasal inhalation administration requires special equipment such as a spin spatula or nebulizer, and requires experience and skill in the administration method (see, for example, Japanese Patent Application Laid-Open No. 53-20417).

(4) In absorption administration, it may not be possible to administer to infants or patients with poor ventilation (for example, Japanese Patent Application Laid-open No. 53-20417).

On the other hand, topical skin preparations have traditionally been used to treat local skin diseases, but in recent years there has been an active development of transdermal absorption preparations with the aim of expressing precursor effects, such as nitroglycerin and scopolamine. There are reports about.

This method of administration has the advantages of being able to continuously control drug administration by combining base agents, etc., having a small first-pass effect in the liver, and having an extremely simple administration procedure. The alkali metal salt of -bis(2-carboxychromon-5-yloxy)-2-hydroxypropane is a compound that hardly penetrates the stratum corneum and is difficult to be absorbed transdermally.

Problems to be Solved by the Invention Therefore, the present invention effectively provides 1°3-bis(2-carboxychromon-5-yloxy)-2-
1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane is effective in the treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, etc. for which alkali metal salts of hydroxypropane can be administered. The purpose is to develop a skin external preparation composition containing an alkali metal salt.

Explanation of Means for Solving the Problems and Their Effects According to the present invention, 0.5% of the alkali metal salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane is added to the base. A skin external preparation composition comprising ~40M amount % and saponin 0.5-30% by weight is provided.

The skin external preparation composition according to the present invention has, as a drug component,
Contains an alkali metal salt of 1.3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane. As mentioned above, the alkali metal salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane is known as a compound that suppresses the release of chemical messengers from mast cells during type I allergic reactions. It is an effective compound for the treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, etc. As the alkali metal salt of 1.3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane, for example, a disodium salt and a dipotassium salt are common, and a disodium salt is particularly preferred. The concentration of the alkali metal salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane in the skin external preparation composition according to the present invention is 0.5 to 40% by weight, preferably It is 1 to 30% by weight. If this concentration is too low, the amount of absorption will be insufficient, and if it is too high, the compound will be difficult to dissolve or disperse in the base, which is not preferred.

The saponin blended into the skin external preparation composition according to the present invention has the effect of promoting transdermal absorption of the alkali metal salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane. The content thereof is 0.5 to 30% by weight, preferably 1 to 20% by weight. If this amount is too small, the desired absorption promoting effect cannot be obtained, and if it is too large, the viscosity of the composition becomes too high, making projection preparation difficult and giving a poor feeling of use, which is not preferable in the present invention. Saponins used in are classified into steroid saponins and triterpenoid saponins, and their sugars include glucose, galactose, pentose,
Methylpentose, etc.

More specifically, glycyrrhizin, cenegenin, tenuigenin, saikosaponin, smilax saponin, digitonin, gitonin, tigonin, timosaponin, etc. can be mentioned.

The base used in the skin external preparation composition according to the present invention is:
When used in the manufacture of general skin preparations such as ointments, aerosols, lotions, poultices, and tapes, they are substances that do not exhibit medicinal effects in themselves; for example, oily bases such as vegetable oil, lard, and petrolatum , hydrophilic petrolatum, purified lanolin,
Water-absorbing bases such as water-absorbing ointment and hydrated lanolin, hydrophilic bases such as hydrophilic ointment, water-soluble bases such as macrogol ointment,
Examples include natural water-soluble polymers such as starch, pullulan, gelatin, and water-soluble cellulose derivatives, and synthetic water-soluble polymers such as carboxyvinyl polymers, sodium polyacrylate, and polyvinyl alcohol.

In the case of external preparation compositions such as tapes and plasters, natural water-soluble polymers and synthetic water-soluble polymers can be suitably used among the above-mentioned bases.

Natural water-soluble polymers that can be used in the present invention include plant-based water-soluble polymers such as gum arabic, gum tragacanth, guar gum, gum karaya, and quince seed starch; seaweed-based water-soluble polymers such as alginic acid and carrageenan; Animal-based water-soluble polymers such as gelatin, microbial-based water-soluble polymers such as dextran, methylcellulose
MC>, carboxymethyl cellulose and its salts (CM
C), hydroxyethylcellulose (HEC), hydroxypropylcellulose (RPC), and other cellulose-based water-soluble polymers, preferably cellulose-based water-soluble polymers, particularly preferably hydroxypropylcellulose. be.

The natural water-soluble polymer preferably has a 2% aqueous solution having a viscosity of 6 to 400 cps at 20°C.

If the viscosity of the natural water-soluble polymer exceeds 400 cps, bubbles tend to form during base preparation, making it difficult to create a uniform film, and if the viscosity is less than 6 cps, it tends to be difficult to obtain a sufficient film thickness. It is not desirable because it is in

Further, as the synthetic water-soluble polymer that can be used in the present invention, any synthetic water-soluble polymer such as carboxyvinyl polymer, polyvinyl alcohol, polyethylene oxide, etc. can be used, and in particular, a synthetic water-soluble polymer mainly composed of acrylic acid can be used. Polyacrylic acid and its sodium salts, such as HIVIS-waKo' manufactured by Wako Pure Chemical Industries and VISCOMATE ■ manufactured by Showa Denko, etc., can be suitably used. .

The addition ratio of the water-soluble cellulose derivative and the synthetic water-soluble polymer is preferably 8:2 to 2:8, more preferably 6:4.
~4:6.

The skin external preparation composition according to the present invention may further include emulsifiers such as gum arabic, stearic acid, and lecithin, as necessary.
Suspending agents and other conventional additives can be added.

The skin external preparation composition according to the present invention can be used as any projection that comes into contact with the skin for a sufficient period of time, and can be in the form of, for example, an ointment, an aerosol, a lotion, a poultice, a tape, etc.

The skin external preparation composition according to the present invention can be made into a desired projection by various conventionally known methods.

For example, in the case of a tape preparation, a base is suspended in a solution of an alkali metal salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and saponin to form a sol. It can be prepared according to known manufacturing methods. In addition, in aerosol formulations, 1.
3-bis(2-carboxychromon-5-yloxy)
It can be prepared by adding an alkali metal salt of -2-hydroxypropane and saponin, and then following a known manufacturing method. Furthermore, for ointments, lotions, poultices, etc., an alkali metal salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and saponin are mixed, and this is mixed with a small amount of base. It can be kneaded with the remaining base material and then cleaved according to a known manufacturing method.

EXAMPLES Hereinafter, the present invention will be further explained according to Examples, but it goes without saying that the technical scope of the present invention is not limited to the following Examples.

Example 1 (Example) 1. Disodium salt powder of 3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane1.
0g and 0.26g of saponin were dissolved in 90ml of purified water at room temperature, and 1.5g of hydroxypropylcellulose and 1.5g of polyacrylic acid were gradually added to this at room temperature while stirring to make a suspension. was formed.

This sol was placed on a glass plate (dimensions: 20 cm x 2
0 cm square) and dried at a temperature of 50°C to create a film, which was then transferred to an adhesive tape made of porous non-woven fabric coated with an adhesive on one side to create a tape-shaped skin preparation for external use. was manufactured.

Example 2 (Comparative Example) A tape-shaped skin preparation for external use was obtained in the same manner as in Example 1 except that saponin was not used.

Example 3 (Evaluation example) Sample of the skin external preparation manufactured in Example 1 and Example 2 (7 cm
A Japanese white male rabbit (3 kg in weight) was used as the animal, the abdomen was removed the previous day, and it was pasted on the hair-removed area on the day of the test.

After application, blood was collected from the ear vein over time, and the plasma obtained by a conventional method was analyzed by high performance liquid chromatography to measure the concentration of the compound in the plasma.

The results were as shown in Figure 1. As is clear from the results in FIG. 1, when the base containing saponin according to the present invention was used, the blood concentration was extremely high compared to the base containing no saponin, and 1.3-bis( By administering an alkali metal salt of 2-carboxychromon-5-yloxy)-2-hydroxypropane in a base containing saponin, it is rapidly absorbed into the body and provides a sustained high blood concentration. was confirmed.

Example 4 (Example) 5 g of disodium salt powder of 1.3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane
and 1 g of saponin were weighed in a mortar and mixed. Add a small amount of water-soluble ointment base to this and mix well, then add water-soluble ointment base and knead thoroughly to bring the total amount to 50%.
g, and an ointment-like skin preparation for external use was produced.

Example 5 (Example) 5 g of hydrophilic ointment was heated and dissolved at 70°C, purified water heated to 70°C was gradually added to the solution to give a concentration of 100°C, and the mixture was thoroughly mixed while cooling. After cooling to room temperature, 1,3-
Bis(2-carboxychromon-5-yloxy)-2
- 10 g of disodium salt powder of hydroxypropane and 5 g of saponin were added and shaken to produce a lotion-like skin preparation.

2 g of gelatin was dissolved in 30°C of warm water at 60°C, and 2 g of kaolin (sterile) was added and kneaded. To this, 30% of disodium salt powder of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane was added.
g and 5 g of saponin and 0.5 g of peppermint oil and knead.

Next, add polyacrylic [6] to 20 g of concentrated glycerin in advance.
After adding and kneading a mixture of 4.5 g of hydroxypropyl cellulose and 4.5 g of hydroxypropyl cellulose,
A poultice-shaped skin preparation for external use was prepared by spreading the mixture on a 9 cm x 9 cm square surface.

[Brief explanation of drawings]

FIG. 1 is a graph showing the transdermal absorption effect of the external skin preparations produced in Example 1 (Example) and Example 2 (Comparative Example). Time after pasting (hr)

Claims (1)

[Claims] 1. 1,3-bis(2-carboxychromone-5
A skin external preparation composition comprising 0.5 to 40% by weight of an alkali metal salt of -yloxy)-2-hydroxypropane and 0.5 to 30% by weight of saponin.