JPH11147825A - Improvement of absorption from mucous membrane and preparation for external use for mucous membrane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for improving absorption from a mucous membrane, capable of improving the absorption from the mucous membrane of glycyrrhizic acids, allowing the glycyrrhizic acids to sufficiently manifest the antiinflammatory activities and improving the promotion activities of the absorption from the mucous membrane of a medicine coexisting with the glycyrrhizic acids, and further to obtain a preparation for external use for mucous membrane, having not only improved absorption of the glycyrrhizic acids through the mucous membrane but also improved absorption of the medicine coexisting with the glycyrrhizic acids through the mucous membrane, capable of manifesting an excellent pharmacological effect and useful as an eye drop or a nasal drop. SOLUTION: The concentration of glycyrrhizic acids in the preparation for external use for mucous membrane, containing one or more kinds of the glycyrrhizic acids selected from among glycyrrhizic acid, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate and diammonium glycyrrhizinate is regulated so that the concentration thereof may be not less than the critical micelle concentration and the pH of the preparation may be 4-6 to improve the absorption of the glycyrrhizic acids from the mucous membrane in the method for improving absorption from the mucous membrane.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for improving the absorption of glycyrrhizic acids from the mucous membrane, and further to the improvement of the absorption of glycyrrhizic acids to the coexisting drug, and a method for improving the absorption of glycyrrhizic acid. The present invention relates to an external preparation for mucosa, particularly an eye drop and a nasal drop, in which the absorbability of glycyrrhizic acids and coexisting drugs from the mucous membrane is improved.

[0002]

2. Description of the Related Art Glycyrrhizin, the main component of licorice, which is a precursor of a glycyrrhizic acid derivative, is a conjugate of glycyrrhizin and two molecules of glucuronic acid, and is composed of glycyrrhizic acid, dipotassium glycyrrhizinate, Glycyrrhizinates such as tripotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, and diammonium glycyrrhizinate are used as sweeteners and are known to have anti-inflammatory effects. In addition, since it has relatively weak irritation to mucous membranes and is absorbed from mucous membranes, it is widely used as an active ingredient of external preparations for mucous membranes such as eye drops and nasal drops.

[0003] Further, when the above glycyrrhizic acids are used to prepare eye drops, nasal drops, and the like, an active ingredient other than glycyrrhizic acids is blended as a coexisting drug. In recent years, glycyrrhizic acids have been It has been discovered that the drug itself not only is absorbed transmucosally but also has an absorption-promoting effect on coexisting drugs, and its use as an external preparation for mucous membranes has attracted attention.

However, the transmucosal absorption of glycyrrhizic acids and the mucosal absorption-promoting effect on coexisting drugs still need to be studied, and there has been a demand for a technique for further improving those effects.

SUMMARY OF THE INVENTION The present invention has been made to meet the above-mentioned demands. The present invention has been made to improve the absorbability of the above-mentioned glycyrrhizic acids from the mucous membrane, to exert its anti-inflammatory effect sufficiently, and to coexist with glycyrrhizic acids. A method for improving mucosal absorption that can also enhance the mucosal absorption promoting action on a drug, and the method not only improves the transmucosal absorption of the glycyrrhizic acids, but also promotes the mucosal absorption of a coexisting drug, and is excellent. An object of the present invention is to provide a preparation for external use of mucous membrane, which can exert an excellent pharmacological effect and is particularly suitable as eye drops and nasal drops.

[0006]

Means for Solving the Problems and Embodiments of the Invention The present inventors have conducted intensive studies to achieve the above object, and as a result, the transmucosal absorbability of the glycyrrhizic acids under a specific pH environment has been improved. As a result, the pharmacological effects of these glycyrrhizic acids are improved.
Under the environment, it has been found that the absorption promoting action of glycyrrhizic acids can be further improved and the drug effect of the coexisting drug with the glycyrrhizic acids can be improved, and as a result of further intensive studies, the concentration of the glycyrrhizic acids in the formulation Was found to be more excellent in the absorbability of the above-mentioned glycyrrhizic acids themselves and the action of promoting the absorption of coexisting drugs by making the concentration equal to or higher than the critical micelle concentration, and completed the present invention.

Here, although the mechanism of action of the glycyrrhizic acids for promoting absorption of the coexisting drug is not clear, the glycyrrhizic acids are, for example, dipotassium glycyrrhizinate represented by the following structural formula (1). It has a hydrophilic group represented by the following structural formula (2) and a hydrophobic group represented by the following structural formula (3), and has not only an anti-inflammatory action as a pharmacological action but also a surfactant action function. Therefore, if the concentration of glycyrrhizic acids in the preparation is equal to or less than the critical micelle concentration (cmc, the same applies hereinafter), glycyrrhizic acids are present as monomolecular monomers having an action of promoting absorption of the coexisting drug from the mucosa in the preparation. However, it is considered that when the concentration becomes cmc or more, aggregate micelles incorporating the coexisting drug are formed, and the function as a carrier of the coexisting drug is exhibited.

[0008]

Embedded image

Therefore, the present invention relates to one or two kinds selected from glycyrrhizic acid, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, and diammonium glycyrrhizinate.
The concentration of the above glycyrrhizic acids in the external preparation for mucosa containing at least one kind of glycyrrhizic acids is not less than cmc of the glycyrrhizic acids, and the pH of the above preparation is 4 to
The method for improving mucosal absorption of the glycyrrhizic acids by adjusting the glycyrrhizic acids to the mucous membrane by adjusting the glycyrrhizic acids into the above-mentioned preparations. Provided is a method for improving mucosal absorbability, which enhances the action of promoting the mucosal absorption of the active ingredient by acids. Furthermore,
The glycyrrhizic acid and the active ingredient for ophthalmology and otolaryngology are blended with one or more active ingredients selected from the active ingredient for otolaryngology, and the mucosa of the glycyrrhizic acid and the active ingredient are improved by the method for improving mucosal absorption. Provided is a mucosal external preparation having improved absorbability. Here, it is more preferable that the mucosal external preparation is prepared as an eye drop or a nasal drop.

Hereinafter, the present invention will be described in more detail. The method for improving mucosal absorbability of the present invention is intended to increase the concentration of glycyrrhizic acid in an external preparation for mucosa containing glycyrrhizic acid to a level higher than its critical micelle concentration (cmc, hereinafter the same). In addition, the absorbability of glycyrrhizic acids from the mucous membrane is improved by adjusting the pH of the external preparation to 4 to 6.

Here, the external preparation of the mucosa of the present invention is not particularly limited in its form, and can be prepared as an oily preparation, an emulsion preparation or an aerosol preparation, but is preferably prepared as an aqueous preparation. For example, it is suitable to prepare as a liquid preparation applied to mucous membranes such as eye drops, nasal drops, ear drops or throat spray, and among them, it is particularly preferable to prepare them as eye drops or nasal drops.

The above-mentioned external preparation for mucosa contains glycyrrhizic acid, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, and diammonium glycyrrhizinate.
These can be used alone or in appropriate combination of two or more. Among them, dipotassium glycyrrhizinate can be used more preferably because of its excellent solubility in water.

In the method of the present invention, the amount of the above-mentioned glycyrrhizic acids in the preparation is set to not less than cmc.
Specifically, in the case of the above-mentioned glycyrrhizic acids, they are blended so that the concentration when converted to glycyrrhizic acid is 0.07% (% by weight, the same applies hereinafter), especially 0.1% or more. If the concentration is too low, the object of the present invention cannot be sufficiently achieved. In the case of the present invention, the concentration of the glycyrrhizic acid is 0.07 in terms of glycyrrhizic acid.
%, The upper limit is not particularly limited, but any glycyrrhizic acid is 3% or less, especially 0.5%, based on the whole preparation in consideration of safety and the like.
It is desirable that:

According to the method of the present invention, when an active ingredient other than the above-mentioned glycyrrhizic acids is blended as a co-existing drug, the absorbability of the co-existing drug is also improved, and such an active ingredient is absorbed from the mucous membrane. If it is, the type is not particularly limited, but in the case of the present invention, particularly an ophthalmic active ingredient, an otolaryngological active ingredient are suitably used, and as the ophthalmic active ingredient, for example, an antiviral agent, an antibiotic, Antibacterial agents, anti-inflammatory analgesics, antiallergic agents, corticosteroids, vasoconstrictors, β-blockers, miotics, biological redox balance agents, antiregulatory eyestrain, glaucoma treatment, retinopathy treatment Agents, senile cataract treatment agents, vitamins, amino acids, dark adaptation improving agents, antihistamines, parasympathetic blockers, etc. Specifically, acyclovir, idox as antiviral agents Lysine or the like, erythromycin as antibiotics, hydrochloric oxytetracycline, hydrochloric cefmenoxime, chloramphenicol, succinic acid chloramphenicol, sul penicillin sodium, Prakan mycin,
Erythromycin lactopionate, kanamycin sulfate,
Gentamicin sulfate, sisomicin sulfate, dibekacin sulfate, bekanamycin sulfate, micronomycin sulfate, colistin methanesulfonic acid, etc., as antibacterial agents such as sulfisoxazole, nofloxacin, pimaricin, sulfatomethoxazole, sulfatomethoxazole sodium,
Anti-inflammatory analgesics such as sodium sulfisomidine, ofloxacin, sodium azulene sulfonate, epsilon-aminocaproic acid, allantoin, berberine chloride, berberine sulfate, lysozyme chloride, indomethacin, diclofenac sodium, pranoprofen, etc., and antiallergic agents such as amlexanox, Sodium cromoglycate, tranilast, ketotifen fumarate, pemirolast potassium, fluorometholone, etc. as corticosteroids epinephrine, hydrocortisone acetate, prednisolone acetate, dexamethasone, prednisolone, dexamethasone sodium metasulfobenzoate, dexamethasone sodium phosphate, betamethasone phosphate Sodium and other vasoconstrictors epinephrine, epinephrine hydrochloride, ef hydrochloride Dorin, tetrahydrozoline hydrochloride (tetryzoline), naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride ephedrine, hydrobromic acid homatropine, tropicamide, etc.,
Treatment of glaucoma, such as carteol hydrochloride, dipivefrin hydrochloride, befnolol hydrochloride as a β-blocker, carbachol and the like as miotic agents, glutathione and the like as a bioredox balance agent, cyanocobalamin and meneostigmine methyl sulfate as antiregulatory eye strain agents Agents such as diclofenamide, distigmine bromide, epinephrine bitartrate, pilocarpine, timolol maleate, methazolamide, and ecothioparte iodide; calcium diiodostearate for treating retinopathy; pyrenoxine for treating senile cataract; and flavin adenine as a vitamin agent. Dinucleotide, sodium flavin adenine dinucleotide, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, bread Antihistamines, such as sodium L-aspartate, magnesium L-aspartate, magnesium / potassium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, etc .; Examples thereof include chlorpheniramine maleate and diphenhydramine hydrochloride, and parasympathetic blockers such as atropine sulfate and atropine. These can be used alone or in appropriate combination of two or more.

Here, when the external preparation for mucosa of the present invention is an eye drop, if the coexisting drug has poor water solubility, it is necessary to use a surfactant to solubilize the drug. Considering that some surfactants are poorly compatible with glycyrrhizic acids, those having a certain degree of solubility in water are preferred among the above components,
The degree is sufficient if it is "very insoluble" (solubility 0.1 to 0.01%) or more as described in the Japanese Pharmacopoeia, and specifically, sodium azulene sulfonate,
Oxytetracycline hydrochloride, carteolol hydrochloride, dipivefrin hydrochloride, cefmenoxime hydrochloride, phenylephrine hydrochloride, befnolol hydrochloride, carbachol, sodium cromoglycate, glutathione, chloramphenicol succinate, colistin methanesulfonic acid, cyanocobalamin, diclofenac sodium, distigmine bromide,
Homatropine hydrobromide, epinephrine bitartrate, naphazoline nitrate, sulpenicillin sodium, tetrahydrozoline hydrochloride, topramycin, pilocarpine, flavin adenine dinucleotide, pemirolast potassium,
Chlorpheniramine maleate, diphenhydramine hydrochloride, naphazoline hydrochloride, tetrahydrozoline hydrochloride, timolol maleate, dexamethasone sodium metasulfobenzoate, ecothiopart iodide, erythromycin lactopionate, atropine sulfate, kanamycin sulfate,
Gentamicin sulfate, sisomicin sulfate, dibekacin sulfate, bekanamycin sulfate, micronomycin sulfate, dexamethasone sodium phosphate, betamethasone sodium phosphate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, meneostigmine methyl sulfate, epsilon-aminocapron Acid, allantoin, berberine chloride, berberine sulfate, lysozyme chloride, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate, L
-Potassium aspartate, magnesium L-aspartate, magnesium potassium L-aspartate,
Aminoethylsulfonic acid, sodium chondroitin sulfate, sulfatomethoxazole, sodium sulfatomethoxazole, sodium sulfisomidine, and the like are preferable, and among these, carteolol hydrochloride, chlorpheniramine maleate, diphenhydramine hydrochloride,
Nafazoline hydrochloride, tetrahydrozoline hydrochloride, timolol maleate and the like are more preferable.

The active ingredients for otolaryngology include, for example, vasoconstrictors, antihistamines, bactericides, local anesthetics, anti-inflammatory agents, nasal depressants, corticosteroids, allergic agents, antibiotics and the like. Specific examples thereof include epinephrine, ephedrine hydrochloride, tetrahydrozoline hydrochloride, tramazoline hydrochloride, nafazoline hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, iproheptin hydrochloride, diphenhydramine hydrochloride, and diphenhydramine hydrochloride as anti-histamines. , Chlorpheniramine maleate, etc., bactericides such as acrinol, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, ofloxacin, etc., and local anesthetics lidocaine hydrochloride, lidocaine, etc. Methyl salicylate as an anti-inflammatory agent, ipratropium bromide as a nasal depressant, flunisolide, prednisolone, beclomethasone propionate, dexamethasone sodium phosphate, betamethasone sodium phosphate as adrenocortical agents, and amlexanox, sodium cromoglycate as allergic agents. Cefmenoxime hydrochloride, kanamycin sulfate and the like can be mentioned as antibiotics, such as ketotifen fumarate and pemilorous potassium, and these can be used alone or in combination of two or more.

When the topical mucosal preparation of the present invention is a nasal drop, for the same reasons as the above eye drops, among them, epinephrine, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, nitric acid Tetrahydrozoline, naphazoline nitrate, iproheptin hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate, acrinol, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, lidocaine hydrochloride, sodium cromoglicate, dimilolas potassium, kanamycin sulfate, dexamethasone sodium phosphate , Betamethasone sodium phosphate and the like are preferred, especially tetrahydrozoline hydrochloride, naphazoline hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate There is more preferable.

The amount of the above-mentioned active ingredient in the external preparation for mucosa of the present invention is not particularly limited, and can be appropriately selected depending on the kind and dosage form of the active ingredient. On the other hand, 0.0006 to 5%, particularly 0.003 to 2% is suitable, and in the case of nasal drops, 0.01 to 1%, particularly 0.05 to 0.5%, based on the whole preparation.
Is preferred. If the amount of the active ingredient is too small, it may be difficult to sufficiently obtain the effect of the active ingredient, and if the amount is too large, not only is the formulation restricted, but also the glycyrrhizic acid sufficiently enhances the absorption promoting action. May not be possible. In addition, the compounding amount is more preferably a normal dose when each active ingredient is appropriately prepared in a dosage form, for example, it is more preferable that each active ingredient is a compounding amount permitted by the pharmaceutical production guidelines, for example, chloro maleate. If pheniramine is to be incorporated into eye drops, its concentration should be 0.006 to 0.0
3%, 0.01 to 0.5 if formulated in nasal drops
%, If diphenhydramine hydrochloride is to be incorporated into eye drops, the concentration is 0.01-0.05%, if it is to be incorporated into nasal drops, 0.04-0.2%. If blended, the concentration should be 0.000
6 to 0.003%, 0.0 if used in nasal drops
If 25 to 0.05% of tetrahydrozoline hydrochloride is added to the eye drops, the concentration is 0.01 to 0.05.
%, If it is to be incorporated into nasal drops, the content is preferably 0.05 to 0.1%.

The mixing ratio of the above-mentioned active ingredient to the above-mentioned glycyrrhizic acids is not particularly limited, but usually, the active ingredient: glycyrrhizic acids (weight ratio) = 1: 1.
0.001-1: 5000, preferably 1: 0.01-
1: 1000, more preferably 1: 0.1 to 1: 100
It is preferable that If the compounding ratio of the active ingredient is too small, it may be difficult to sufficiently obtain the effect of the compounding of the active ingredient, and if it is too large, the glycyrrhizic acids may not be able to sufficiently obtain the absorption promoting action.

According to the method of the present invention, the concentration of the glycyrrhizic acids in the external preparation for mucosa is set to not less than its cmc, and the pH of the preparation is adjusted to 4 to 6 when the preparation is made to coexist with the active ingredient as required. By adjusting, the absorption of glycyrrhizic acids from the mucosa is improved, and the absorption promoting action of the glycyrrhizic acids on the coexisting drug is further improved, so that the absorption of the coexisting drug from the mucosa is also improved. Is more preferably adjusted to 4 to 5.5, more preferably 4 to 5.3, and still more preferably 4 to 5.0. If the pH is too high, the effect of improving absorption of glycyrrhizic acids from mucous membranes and the effect of promoting absorption of coexisting drugs cannot be sufficiently obtained. In addition,
Although the effects of the present invention can be obtained even when the preparation pH is less than 4, the mucosal irritation may occur if the preparation pH is too low.
It is desirable that the number be 4 or more. The pH of the external preparation for mucosa of the present invention is determined by the general test method described in Japanese Pharmacopoeia. It can be measured according to the pH measurement method.

The type of the pH buffer for adjusting the external preparation for mucosa of the present invention to the above-mentioned pH range is not particularly limited as long as it is pharmaceutically acceptable. Specifically, for example, if it is an eye drop,
For nasal preparations such as boric acid, borax, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, sodium acetate, citric acid, sodium citrate, and taurine, ascorbic acid, sodium chloride, citric acid, citric acid Sodium phosphate, chlorobutanol, trisodium phosphate, sodium dihydrogen phosphate, sodium acetate, boric acid, borax,
Sodium hydrogen phosphate, dipotassium phosphate and the like can be mentioned, and a normal dose which can be adjusted to the above-mentioned pH range can be used.

The external preparation for mucosa of the present invention contains, in addition to the above-mentioned components, a surfactant, an isotonic agent, a saccharide, a solubilizing agent, a chelating agent, which are usually added in the preparation unless the effects of the present invention are hindered. And additives such as preservatives, fresheners, thickeners and the like. Specifically, in the case of eye drops, polyoxyethylene hydrogenated castor oil 60 and polyoxymonooleate are used as surfactants. Sorbitan (20EO), etc.
Potassium chloride, sodium chloride, propylene glycol, polyethylene glycol, glycerin and the like as tonicity agents, mannitol and the like as sugars, β- as a solubilizing agent
Cyclodextrins such as cyclodextrin, propylene glycol, etc .; sodium edetate, etc. as a chelating agent; benzalkonium chloride, cetylpyridinium chloride, sorbic acid, parabens, etc. as preservatives; l-menthol, etc. as a refreshing agent The amount can be blended.
In the case of nasal drops, in addition to the above-mentioned components, further, polysorbate 80 or the like as a surfactant, citric acid or sodium citrate as a tonicity agent, mint water as a refreshing agent,
It can be prepared using mint oil or the like. In the case of the external preparation for mucosa of the present invention, the glycyrrhizic acids and other active ingredients used in combination are improved in the mucosal absorbability. It is also possible to reduce it.

As described above, the external preparation for mucosa of the present invention
Eye drops, nasal drops and the like can be prepared, and the preparation method is not particularly limited, and can be prepared by a conventional method of each preparation. Specifically, if it is an eye drop, for example, the above-mentioned glycyrrhizic acids , A co-existing drug, other optional components and the above-mentioned pH buffer are sequentially added to and dissolved in sterilized purified water, and each component is adjusted to a desired concentration by further adding sterilized purified water to the obtained solution, and the pH buffer is added. After the final adjustment of the formulation pH with the agent, a method of obtaining an eye drop by sterile filtration can be mentioned, and a nasal drop can also be obtained by a method according to the eye drop.

The amount and usage of the external preparation for mucosa of the present invention are not particularly limited. For example, in the case of eye drops prepared as a general marketed drug, it is 3 to 6 times a day, 1 to 1 time.
It is preferable to instill three drops, and in the case of nasal drops prepared as a general over-the-counter drug, for adults (15 years old or older), spray once or twice at a time, or drop 1-2 drops And
It is preferable to use it within 6 hours a day at intervals of 3 hours or more.

According to the method for improving mucosal absorbability of the present invention,
Not only can the absorption of glycyrrhizic acids from the mucous membrane be improved, but also the absorption promoting effect of glycyrrhizic acids on coexisting drugs can be improved.According to the external preparation for mucosa of the present invention, glycyrrhizic acids can be improved by the above-described method. Also, since the absorption of the coexisting drug from the mucous membrane is improved, it is particularly suitable as eye drops and nasal drops.

[0026]

According to the present invention, the absorption of glycyrrhizic acids from the mucous membrane is improved, and the effect of glycyrrhizic acids on the absorption of coexisting drugs is also improved. Further, by coexisting a drug other than glycyrrhizic acids, the medicinal effect of the coexisting drug is sufficiently exhibited. Therefore, the external preparation for mucosa of the present invention is useful as a therapeutic agent for mucosal inflammation and the like, and particularly useful as eye drops and nasal drops.

[0027]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Experimental Examples, Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[Experimental Example 1] It is generally known that as the lipid solubility (hydrophobicity) of a drug increases, its permeability to cell membranes (penetration into living tissues and absorption) increases. The relationship between lipophilicity and cell membrane permeability has not been confirmed, and it has not been confirmed how the lipophilicity is affected by changes in pH, so the lipophilicity of glycyrrhizic acids and cell membrane permeability In order to clarify the relationship between the lipophilicity and the pH change, the pH of a solution containing dipotassium glycyrrhizinate as glycyrrhizic acids was changed to obtain a solution of dipotassium glycyrrhizinate in water-1-octanol at each pH. Is determined by the following method, and the distribution rate is used as an index of the fat solubility of dipotassium glycyrrhizinate at that pH. . The results are shown in FIG. <Measurement of Partition Ratio> pH 4.0 and pH 4.0 with 0.05 M citric acid-0.1 M disodium phosphate buffer, respectively.
4.5, pH 4.9, pH 5.2, pH 5.4, pH
0.3 mM adjusted to 5.7, pH 5.9, pH 6.5, and pH 7.4 (calculated as glycyrrhizic acid: 0.25%
(% By weight, hereinafter the same)), 5 ml of each liquid was dispensed into a test tube with a stopper, 5 ml of 1-octanol was added, and then 12 ml at 37 ° C. using an incubator. Shake for time, then 300
After centrifugation at 0 rpm for 10 minutes, the amount of dipotassium glycyrrhizinate in the obtained lower layer solution (aqueous layer) is measured by a conventional method of high performance liquid chromatography, and dipotassium glycyrrhizinate is obtained by using the following formula. 1 from the water layer
-The transfer rate (partition rate) to the octanol layer was calculated.

[0029]

(Equation 1)

[Experimental Example 2] Glycyrrhizic acids contain dipotassium glycyrrhizinate at a concentration of at least cmc (0.07%) based on the fact that glycyrrhizic acids have an anti-inflammatory effect and suppress edema caused by various inflammatory substances. Eye drops
By changing H, the edema inhibition rate of dipotassium glycyrrhizinate at each pH was determined by the following method and used as an index of the anti-inflammatory action of dipotassium glycyrrhizinate. Table 1 shows the results. <Measurement of edema inhibition rate> pH 5.0, p, respectively with 0.05M citric acid-0.1M disodium phosphate buffer
A 0.125% dipotassium glycyrrhizinate solution adjusted to H5.3, pH 5.5, pH 5.8, and pH 6.0 was prepared as an eye drop for the experiment.

Next, under anesthesia, 20 μl of a 1% carrageenan solution as an inflammation substance was injected under the upper eyelid conjunctiva of the rat, and immediately thereafter, 30 μl of each of the above eye drops or physiological saline (control) was instilled. Each of the above eye drops or physiological saline was brought into contact with the surface of the eye for 2 minutes in a state in which the eye drops were raised by surface tension. Five hours after carrageenin injection, the rat was killed, the upper eyelid was excised, the weight of the edema formed at the injection site was measured, and the inhibition rate of each eye drop was determined by the following formula.

[0032]

(Equation 2)

[0033]

[Table 1]

[Experimental Example 3] The concentration of dipotassium glycyrrhizinate was adjusted to 0.02 lower than its cmc (0.07%).
The pH dependence of the partition ratio of the coexisting drug between water-1-octanol when the coexisting drug is set to 0.125% which is 5% or more and the cmc or more and the pH dependence of the partition ratio in the case of the coexisting drug alone are determined by the following methods. The distribution rate was used as an index of the mucosal absorbability of the coexisting drug. The results are shown in FIGS. <Measurement of Partitioning Ratio of Coexisting Drug> The concentration of dipotassium glycyrrhizinate in the preparation is 0.025% or 0.125%, and chlorpheniramine maleate, tetrahydrozoline hydrochloride, diphenhydramine hydrochloride, naphazoline nitrate are used as coexisting drugs of dipotassium glycyrrhizinate. Is 0.3m each
M and each drug is dissolved in purified water, and 0.05M is adjusted so that the formulation pH is 4 to 7.4, respectively.
After preparing solutions by adjusting with citric acid-0.1 M disodium phosphate buffer, 5 ml of each solution was dispensed into a test tube with a stopper, and 5 ml of 1-octanol was added. At 120 ° C. for 12 hours, and then centrifuged at 3000 rpm for 10 minutes, and the amount of dipotassium glycyrrhizinate in the obtained lower layer solution (aqueous layer) was measured by a conventional method of high performance liquid chromatography. The transfer rate (partition rate) of each coexisting drug from the aqueous layer to the 1-octanol layer was calculated by using the equation. For comparison, the partition ratio was similarly determined for the solution containing only the coexisting drug.

[0035]

(Equation 3)

According to the graphs of FIGS. 2 to 5, dipotassium glycyrrhizinate has the effect of improving the fat solubility of any of chlorpheniramine maleate, tetrahydrozoline hydrochloride, diphenhydramine hydrochloride and naphazoline nitrate which coexist at pH 6 or less. Is observed, and especially, the concentration of dipotassium glycyrrhizinate in the cmc
If it is above, chlorpheniramine maleate and diphenhydramine hydrochloride which show high fat solubility in a pH range higher than pH 6 when used alone (without dipotassium glycyrrhizinate) have almost the same fat solubility even in a pH range of pH 6 or lower. On the other hand, tetrahydrozoline hydrochloride and naphazoline nitrate, which have almost no pH dependence of fat solubility in the pH range of pH 7.4 or less alone, significantly reduce the fat solubility of these coexisting drugs in the pH range of pH 6 or less. It is recognized that the concentration of dipotassium glycyrrhizinate in the preparation is at least cmc and the pH of the preparation is at most 6, especially p
By adjusting the value to H5.5 or less, it is expected that the effect of dipotassium glycyrrhizinate to promote the penetration of coexisting drugs into living tissues will be improved.

[Example 1 and Comparative Examples 1 to 5] Eye drops having the compositions shown in Table 2 were prepared, and the antihistamine effect of chlorpheniramine maleate of each eye drop was evaluated by the following method. It was used as an index of the effect of potassium on the promotion of mucosal absorption of chlorpheniramine maleate.
The results are also shown in Table 2. <Evaluation method of antihistamine action> Histamine involved in the expression of immediate edema in the early stage of the inflammatory reaction was used as a proinflammatory substance. That is, under anesthesia, 20 μl of a 0.1% histamine physiological saline solution was injected under the upper eyelid conjunctiva of a rat, and immediately after that, each eye drop or physiological saline (control) 3 was injected.
0 μl was instilled, and the above eye drops or physiological saline was brought into contact with the surface of the eye for 5 minutes in a state of being raised by the surface tension of eye drops or the like. One hour after histamine injection, the rat was killed, the upper eyelid was excised, the weight of the edema formed at the injection site was measured, and the edema inhibition rate of each eye drop was calculated from the average weight of each eye drop and control as follows: The antihistamine effect of each eye drop was evaluated according to the following criteria.

[0038]

(Equation 4) Evaluation criteria Edema suppression rate is 0% or less No antihistamine effect Edema suppression rate exceeds 0% and 5% or less Antihistamine action is weak Edema suppression rate exceeds 5% and 10% or less Slightly strong antihistamine action Edema Suppression rate exceeds 10%, 15% or less Strong antihistamine action Strong edema suppression rate exceeds 15% Very strong antihistamine action

[0039]

[Table 2]

Comparing the results of Table 2 with Example 1 and Comparative Examples 1 and 2 containing dipotassium glycyrrhizinate alone, it was found that the antihistamine action was the action of chlorpheniramine maleate. Example 1
And the case where the preparation pH was 5.0 without adding dipotassium glycyrrhizinate (Comparative Example 3),
Is 5.0, the antihistamine effect of chlorpheniramine maleate is less than that of dipotassium glycyrrhizinate.
It is recognized that the content is significantly improved by the concentration of c or more. On the other hand, if the pH of the preparation is 7.4, the cmc can be obtained even without dipotassium glycyrrhizinate (Comparative Example 4).
Even with the above concentration combination (Comparative Example 5), a strong antihistamine action is exhibited, but it is recognized that dipotassium glycyrrhizinate cannot enhance the antihistamine action of chlorpheniramine maleate. Therefore, according to the eye drops of the present invention in which dipotassium glycyrrhizinate is added at a concentration of at least cmc and the pH of the preparation is adjusted to 6 or less, the pharmacological effect of the coexisting drug chlorpheniramine maleate is significantly enhanced. Is allowed.

According to the above results, by blending dipotassium glycyrrhizinate at a concentration of not less than its cmc and adjusting the pH of the preparation to 6 or less, particularly to 5.5 or less,
It is recognized that the permeability of dipotassium glycyrrhizinate into the living body through the mucous membrane is enhanced, the anti-inflammatory effect of dipotassium glycyrrhizinate is enhanced, and the pharmacological effect of the coexisting drug is also significantly enhanced. The enhancement of the pharmacological effect of such a coexisting drug is achieved by improving the drug carrier function of dipotassium glycyrrhizinate in the pH range of pH 6 or less, particularly pH 5.5 or less. It is considered that the permeability into the living body is increased.

[Examples 2 to 5] Eye drops having the compositions shown in Table 3 were prepared, and the antihistamine action of each eye drop on the upper eyelid of the rat was determined by the above method for evaluating the antihistamine action. The edema inhibition rate of each ophthalmic solution was determined in the same manner as described above except that the time was 5 minutes or 5 minutes, and its antihistamine action was evaluated. The results are shown in FIG.

[0043]

[Table 3]

According to the above results, anti-edema action (anti-histamine action) was observed in any of the eye drops, and a remarkably high action was observed particularly at pH 5.3 or less.

[Examples 6 to 16] Eye drops, nasal drops and throat sprays having the compositions shown in Tables 4 and 5 were prepared, and the antihistamine action of each preparation was measured using the upper eyelid of rats using physiological saline as a control. Was evaluated by the above evaluation method. The results are shown in Tables 4 and 5.

[0046]

[Table 4]

[0047]

[Table 5]

[Brief description of the drawings]

FIG. 1 Distribution and pH of dipotassium glycyrrhizinate in 1-octanol layer between water-1-octanol
6 is a graph showing a relationship with the graph.

FIG. 2: Partition ratio of chlorpheniramine maleate between water-1-octanol to the 1-octanol layer and p
9 is a graph showing a relationship with H.

FIG. 3 is a graph showing the relationship between the partition ratio of tetrahydrozoline hydrochloride between water-1-octanol to a 1-octanol layer and pH.

FIG. 4 is a graph showing the relationship between the distribution ratio of diphenhydramine hydrochloride between water-1-octanol to a 1-octanol layer and pH.

FIG. 5 is a graph showing the relationship between the partition ratio of naphazoline nitrate between water-1-octanol to a 1-octanol layer and pH.

FIG. 6 is a graph showing the relationship between the edema suppression rate and pH by the eye drops of Examples 2 to 5 of the present invention.

Claims (5)

[Claims] 1. One or more glycyrrhizic acids selected from glycyrrhizic acid, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, and diammonium glycyrrhizinate, The concentration of the glycyrrhizic acids in the external preparation for mucosa containing is not less than the critical micelle concentration of the glycyrrhizic acids, and the pH of the preparation is adjusted to 4 to 6 to improve the absorbability of the glycyrrhizic acids from the mucous membrane. A method for improving mucosal absorbability, characterized in that: 2. The method for improving mucosal absorbability according to claim 1, further comprising adding an active ingredient other than the glycyrrhizic acids to the preparation to improve the mucosal absorption promoting action of the active ingredient by the glycyrrhizic acids. 3. The method for improving mucosal absorbability according to claim 2, wherein the glycyrrhizic acid is mixed with one or more active ingredients selected from ophthalmic active ingredients and otolaryngological active ingredients. An external mucosal preparation having improved absorption of the glycyrrhizic acids and the active ingredient from the mucous membrane. 4. The external preparation for mucosa according to claim 3, which is prepared as an eye drop. 5. The external preparation for mucosa according to claim 3, which is prepared as a nasal drop.