JPS61260026A - External dermatic agent having improved transcutaneous absorbability - Google Patents

Abstract

PURPOSE:To provide the titled external agent containing an anionic water-soluble drug, by using an anionic water-soluble drug and a basic oil-soluble substance or its salt as active components. CONSTITUTION:A dermatic external agent having improved transcutaneous absorbability of an anionic water-soluble drug can be produced by compounding (A) an anionic water-soluble drug (which is solid at normal temperature and has a pKa of <=4.5: e.g. an antiepileptic agent such as valproate sodium) and (B) a basic oil-soluble substance or its salt (having one or more dissociable basic groups in the molecule and soluble in oil: e.g. alkanolamine, its salt, quaternary ammonium, its salt, alkyldiamine, its salt, etc.) at a weight ratio of 1:0.05-100, preferably 1:0.1-80. The external agent can be applied in an arbitrary form contacting with skin for a moderate period (e.g. ointment, aerosol, lotion, poultice, tape, etc.).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a skin preparation for external use that has enhanced transdermal absorption of anionic water-soluble drugs, and more specifically, contains a basic oil-soluble substance in the base. and/or by containing a salt thereof,
This invention relates to a skin preparation for external use that has enhanced transdermal absorption of anionic water-soluble drugs.

BACKGROUND OF THE INVENTION Conventionally, there is a large amount of knowledge regarding external preparations for skin for the purpose of treating diseases locally on the skin. In addition, in recent years, the development of products aimed at exerting systemic effects has become active, and the usefulness of external preparations for the skin has been highly evaluated. However, most of these involve drugs that are naturally easily absorbed through the skin, are fat-soluble, and are neutral. (For example, rug Dev,
Ind. Pharm., 9 (4) 671 (1983
)reference).

On the other hand, many of the drugs that are currently highly evaluated for their usefulness in clinical practice are water-soluble drugs.It is possible to develop their medicinal effects systemically through transdermal absorption without chemical modification such as prodrugs. can achieve sustained drug efficacy, reduce side effects, reduce the amount and frequency of administration, simplify treatment, and prevent drug avoidance, and are extremely useful in clinical treatment (e.g. Drug Dev, I
nd, Pharm, 9(4), 725 (19
83)).

However, when trying to absorb water-soluble drugs transdermally, it is said that the stratum corneum of the skin acts as a strong barrier and blocks absorption (for example, DrugDev, Ind., P.
hars+, 9 (4), 627 (1983)
As far as the present inventors know, only a small number of findings have been obtained regarding transdermal absorption of water-soluble drugs. For example, a method of preparing a film by dissolving a water and/or alcohol solution of a water-soluble drug in a solution of an adhesive polymer substance containing methacrylic acid alkyl ester as the main component (JP-A-5
9-164715) and a skin external preparation containing a water-soluble antiallergic agent, isothibenzyl hydrochloride, and a water-soluble basic substance or a nonionic surfactant (Japanese Patent Application Laid-open No. 1986-
Publication No. 51212.

(Refer to Japanese Patent Application Laid-open No. 59-98014), hydrophilic drug and organic acid or organic acid gold 1i'! Tape containing (MgSCaSZn or AI) salt (JP-A-59-164714
There have been reports of skin external preparations containing sodium polyacrylate, aluminum hydroxide, and drugs that can be absorbed transdermally (see Japanese Patent Laid-Open No. 59-25320).

However, all of these are aimed at improving the stability and solubility of the active ingredient in the formulation, the release of the active ingredient from the formulation, or the complexity of manufacturing, and they are aimed at improving the stability and solubility of the active ingredient in the formulation, or the complexity of manufacturing. No sufficient explanation has been given regarding the effect of promoting skin absorption or the effect of improving the expression of drug efficacy.

On the other hand, for the purpose of improving transdermal absorption, external skin preparations containing anionic and/or amphoteric surfactants with pi (4 to 8) in an aqueous solvent (Japanese Patent Laid-Open No. 51-32724
(see Japanese Patent Application Laid-Open No. 52-83914). However, in reality, these publications only explain the promotion of transdermal absorption of extremely poorly water-soluble drugs, and do not mention water-soluble drugs at all. It has also been reported that dimethyl sulfoxide (DMSO) reduces the barrier function of the stratum corneum against scopolamine and increases transdermal absorption (Drug Dev, Ind., Pharm.
, 9(4), 627 (1983)), this is said to be because DMSO partially destroys the stratum corneum and increases the permeability of scopolamine to the stratum corneum.

Such methods cannot be used for diseases requiring long-term treatment due to skin irritation.

Furthermore, it has been reported that long-chain amines promote the permeability of sodium salicylate through isopropyl myristate membranes in vitro (J. Pharm, Pharmaco.
l.

36 (Supp, Dec, ), P 22 (1
(984)) However, although this suggests an improvement in drug transfer to skin lipids, it does not support the effect of promoting transdermal absorption in living bodies.

As described above, the current state of the art is that a technology for transdermally absorbing a sufficient amount of water-soluble drugs to exert their useful medicinal effects has not yet been established.

Problems that water-soluble drugs are trying to solve As mentioned above, water-soluble drugs have difficulty penetrating the stratum corneum, so it has been difficult to administer them through transdermal absorption. It is an object of the present invention to develop a composition for external use on the skin that can be absorbed transdermally.

Means for Solving the Problems and Their Effects As a result of various research into methods for effectively transdermally absorbing water-soluble drugs, the present inventors found that a basic oil-soluble substance and/or its salt was added to the base. It has been found that transdermal absorption of anionic water-soluble drugs can be effectively promoted by including the anionic water-soluble drug.

The present invention has been completed based on such knowledge, and according to the present invention, an anionic water-soluble drug is added to the skin external preparation.
By incorporating a basic oil-soluble substance and/or its salt, the transdermal absorption of an anionic water-soluble drug can be effectively enhanced.

Although the mechanism of action of the absorption promoting effect in the present invention is unknown, for example, by adding a substance that can act as a counter ion to a drug that is thought to exist mainly in ionic form at the pH of the skin surface. It is presumed that interactions such as the formation of ion pairs occur, which increases the lipid solubility of the drug and makes it easier to penetrate the skin.

Although the mechanism of action of promoting percutaneous absorption according to the present invention is estimated as described above, the mechanism of action is still in the realm of speculation.
It goes without saying that the present invention is not limited to this mechanism of action.

The basic hydrophilic substance and/or its salt used in the present invention has one or more basic dissociative groups in its molecule and is oil-soluble; examples of such substances include: Examples include alkanolamines and salts thereof, quaternary ammoniums and salts thereof, alkyldiamines and salts thereof, and the like.

The above-mentioned alkanolamines and their salts include monoethanolamine, jetanolamine, triethanolamine, diisopropanolamine and their salts (
Examples include hydrochloride, phosphate, lauryl sulfate, etc. Jetanolamine, triethanolamine, and salts thereof can be particularly preferably used.

Moreover, as the above-mentioned quaternary ammonium and its salt,
1 of 01 to C18 alkyl groups or benzyl groups
Quaternary ammonium and its salts having more than one species (e.g.
Cl-1Br-1-salt, etc.)
In particular, tetraalkylammonium salts having an alkyl group of 01 to C7, benzalkonium chloride, benzethonium chloride, stearyldimethylammonium chloride, stearyltrimethylammonium chloride, and dimethylbenzylammonium chloride can be suitably used.

Furthermore, examples of the alkyldiamine mentioned above include those having an alkyl group of 02 to C4, and ethylenediamine and propylenediamine can be particularly preferably used.

The anionic water-soluble drug to be used for enhancing transdermal absorption in the skin external preparation according to the present invention is solid at room temperature, has a pKa of 4.5 or less, and dissolves 1 g at 25°C. For example, antiepileptic drugs such as sodium palproate, psychiatric drugs such as calcium hopanthenate and dipotassium clorazepate, and antiallergic drugs such as sodium cromoglycate. and antibiotics such as cephaloscin sodium, ceftizoxime sodium, and carbenicillin sodium.

The basic oil-soluble substance and/or its salt contained in the skin external preparation according to the present invention is a substance that has the effect of promoting transdermal absorption of an anionic water-soluble drug, which is a medicinal ingredient. 1:0.05-1 for anionic water-soluble drugs
00 (weight ratio), preferably 1:0.1 to 80 (weight ratio).

If this blending ratio is too small, the desired absorption promoting effect cannot be obtained. In addition, in order for medicinal ingredients to exert systemic effects through transdermal absorption, a certain amount of drug is required, and therefore, if the compounding ratio is too high, it may be difficult to prepare the projections or the feeling of use may be poor. Therefore, it is not desirable.

The base used in the external skin preparation according to the present invention is a substance that itself does not exhibit medicinal efficacy when used in the manufacture of external skin preparations such as ointments, aerosols, lotions, poultices, and tapes. For example, oily bases such as vegetable oil, lard, petrolatum, hydrophilic petrolatum, purified lanolin, water-absorbing ointment, water-absorbing bases such as hydrated lanolin, hydrophilic bases such as hydrophilic ointment, and water-soluble bases such as macrogol ointment. base, starch,
Examples include natural water-soluble polymers such as 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 preparations for projection such as tapes and poultices, natural water-soluble polymers and/or 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), carboxymethylcellulose and its salts (C), hydroxyethylcellulose (IIEc), hydroxypropylcellulose (HPC), etc. Examples include cellulose-based water-soluble polymers, preferably cellulose-based water-soluble polymers, and particularly preferably hydroxypropyl cellulose.

On the other hand, examples of synthetic water-soluble polymers that can be suitably used as a base for the external skin preparation according to the present invention include:
Any synthetic water-soluble polymers such as carboxyvinyl polymers, polyvinyl alcohol, polyethylene oxide, and crosslinked products thereof can be used, especially those that meet the standards for cosmetic raw materials whose main constituent monomer is acrylic acid or vinyl alcohol, e.g. , polyacrylic acid and its sodium salt, or polyvinyl alcohol and crosslinked products thereof can be suitably used.

The external preparation for skin according to the present invention may further contain emulsifiers such as gum arabic, lecithin, glycerin, propylene glycol, etc., suspending agents, humectants, and other commonly used additives.

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

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

For example, in the case of a tape preparation, the base material, preferably a water-soluble cellulose derivative and/or a synthetic water-soluble polymer, is suspended in a solution of a basic oil-soluble substance or its salt and an anionic water-soluble drug. A sol is formed, and a desired tape preparation can then be manufactured according to a known manufacturing method. Further, an aerosol can be prepared by adding a basic oil-soluble substance and its salt and an anionic water-soluble drug to an emulsified base, and then following a known manufacturing method. In addition, ointments, lotions,
For the bump agent, a basic oil-soluble substance or its salt and an anionic water-soluble drug are mixed, this is ground with a small amount of base, and then kneaded with the remaining base, and then prepared according to a known manufacturing method. can do.

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) 0.5 g of sodium cromoglycate and 0.1 g of trietatoluamine were heated to 30 V/V ethanol water 50-
Melt it at room temperature and add 0.6g of polyvinyl alcohol to it.
and 0.6 g of glycerin were gradually added and dissolved at room temperature while stirring to form a sol.

This sol was placed on a glass plate (dimensions: 20CII
20cm square) and then dried at a temperature of 50°C to create a film, which was then transferred to an adhesive tape made of porous nonwoven fabric coated with an adhesive on one side to create a tape-like skin. A topical preparation was manufactured.

Example 2 (Example) Example 1 except that 0.1 g of triethanolamine lauryl sulfate was used in place of triethanolamine in Example 1.
A tape-shaped skin preparation for external use was obtained in the same manner as above.

Example 3 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that 0.1 g of tetrabutylammonium bromide was used in place of triethanolamine.

Example 4 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that 0.1 g of tetraheptyl ammonium bromide was used in place of triethanolamine.

Example 5 (Example) Except that 0.1 g of stearyltrimethylammonium chloride was used in place of triethanolamine in Example 1,
A tape-shaped skin preparation for external use was obtained in the same manner as in Example 1.

Example 6 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that 0.1 g of ethylenediamine was used in place of triethanolamine.

Example 7 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that triethanolamine was not used in Example 1.

Example 8 (Evaluation example) Samples of external skin preparations manufactured in Examples 1 to 7 (7cva
A Japanese white male domestic rabbit (3 kg in weight) was used as the animal, the abdomen was removed the previous day, and the hair 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 FIGS. 1 to 3.

As is clear from the results shown in Figures 1 to 3, the cases of φ containing the basic oil-soluble substance and its salt according to the present invention (Examples 1 to 6) were compared with the cases of not containing it (91J7>). By containing basic oil-soluble substances and their salts in the base, sodium cromoglycate, an anionic water-soluble drug, is rapidly absorbed into the body, resulting in extremely high blood concentrations. It was confirmed that the concentration was continuously provided.

Example 9 (Example) 5 g of sodium cromolycate and 1 g of triethanolamine were weighed in a mortar and mixed. A small amount of a water-soluble ointment base was added thereto and thoroughly kneaded, and then a water-soluble ointment base was further added and thoroughly kneaded to give a total amount of 50 g to produce an ointment-like skin preparation for external use.

Example 10 (Example) 5 g of hydrophilic ointment was heated and dissolved at 70°C, and purified water heated to 70°C was gradually added thereto to make 100 Wd2, and thoroughly mixed while cooling. After cooling to room temperature, 10 g of sodium cromoglycate and 5 g of triethanolamine were added.
g was added and shaken to produce a lotion-like skin preparation for external use.

Example 11 (Example) 2 g of gelatin was added and dissolved in 60° C. warm water, and 2 g of kaolin (sterile) was added and kneaded. To this were added 30 g of sodium cromolycate, 5 g of aliethanolamine, and 0.5 g of peppermint oil and kneaded.

Next, add polyacrylic M6 to 20g of concentrated glycerin in advance.
After adding and kneading a mixed solution in which g and 4.5 g of hydroxypropyl cellulose were dispersed,
A poultice-shaped skin preparation for external use was prepared by spreading the mixture on a 1×9c11 square surface.

Example 12 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that 1.0 g of sodium palproate was used in place of sodium cromoglycate.

Example 13 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that 1.0 g of calcium hopanthenate was used in place of sodium cromoglycate.

Example 14 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that 1.0 g of ceftizoxime sodium was used in place of sodium cromoglycate.

[Brief explanation of the drawing]

Figures 1 to 3 compare the percutaneous absorption effects of the external skin preparations produced in Examples 1 to 6 (Example) with the percutaneous absorption effects of the external skin preparation of Example 7 (Comparative Example). FIG. Figure 1

Claims (1)

[Scope of Claims] 1. An external preparation for skin, which is composed of an anionic water-soluble drug and a basic oil-soluble substance or its salt, and has enhanced percutaneous absorption of the anionic water-soluble drug. 2. The skin external preparation according to claim 1, wherein the mixing ratio (weight ratio) of the basic oil-soluble substance or its salt to the anionic water-soluble drug is 0.05 to 100. 3. The skin external preparation according to claim 1, wherein the basic oil-soluble substance or its salt is an alkanolamine or its salt. 4. The skin external preparation according to claim 1, wherein the basic oil-soluble substance or its salt is quaternary ammonium or its salt. 5. The skin external preparation according to claim 1, wherein the basic oil-soluble substance or its salt is an alkyldiamine or its salt.