JP2001131055A - Liquid agent, removal of white cloudiness of liquid agent and acceleration of trans-mucous membrane absorption of liquid agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a clear liquid agent having an improved safety since the addition of a nonionic surfactant becomes not necessary, and further achieving the improvement of trans-mucous membrane absorption of 1,3-bis(2- carboxychromon-5 yloxy)-2-hydroxypropane or its pharmaceutically permissible salt and a glycyrrhetinic acid salt. SOLUTION: This liquid agent contains 1,3-bis(2-carboxychromon-5-yloxy)-2- hydroxypropane or its pharmaceutically permissible salt, 0.0001-0.04 mass/vol.% quaternary ammonium cationic surfactant and the glycyrrhetinic acid salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a liquid preparation and a method for removing cloudiness of the liquid preparation, and more particularly, to 1,3-bis (2-
A solution containing carboxychromone-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, a quaternary ammonium cationic surfactant, and 1,3-bis (2-carboxychromone-5 The present invention relates to a method for removing turbidity of a liquid agent, which removes turbidity occurring in a system containing (iloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof.

[0002] The present invention further relates to a method for promoting transmucosal absorption of a liquid preparation, and more particularly to 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof. The present invention relates to a method for promoting transmucosal absorption of a liquid agent for improving transmucosal absorption of salts and glycyrrhizinates.

[0003]

2. Description of the Related Art 1, 3
-Bis (2-carboxychromone-5-yloxy)-
Disodium salt of 2-hydroxypropane (hereinafter, referred to as sodium cromoglycate) has been used as a therapeutic agent for bronchial asthma, allergic conjunctivitis, or allergic rhinitis. On the other hand, quaternary ammonium cationic surfactants such as benzalkonium chloride have a broader antibacterial spectrum than other preservatives and are very effective as preservatives that work more effectively even in small amounts. It is often used.

However, a quaternary ammonium cationic surfactant is added to a solution containing 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof. Then, a cloudy phenomenon occurs, and 1,3-bis (2-carboxychromone-5-
Iloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, such as sodium cromoglycate,
It is known that it is difficult to formulate a clear aqueous solution.

Therefore, in order to eliminate such cloudiness,
A method comprising preparing two kinds of solutions, one containing sodium cromoglycate and a chelating agent and the other containing a preservative, and mixing these two aqueous solutions over a long period of time (Japanese Patent Publication No. 54-1979).
No. 25082) and a method of adding a nonionic surfactant (Japanese Patent Publication No. 4-88452), but none of them are satisfactory.

[0006] In particular, the method described in the above-mentioned Japanese Patent Publication No. 54-25082 requires the preparation of two kinds of aqueous solutions, respectively. However, it is a very complicated manufacturing method.

The nonionic surfactant used in the method described in Japanese Patent Publication No. 4-66452 is generally a substance excellent in solubilizing ability, but has a hemolytic action,
There are concerns about side effects such as mucosal irritation. Furthermore, there is a problem that the antibacterial activity of the preservative is reduced or inactivated.

On the other hand, various means for improving the transmucosal absorbability of various drugs have been proposed, but 1,3-bis (2
-Carboxychromon-5-yloxy) -2-hydroxypropane or its pharmaceutically acceptable salt, glycyrrhizinate, still has room for improvement in its transmucosal absorption.

The present invention has been made in view of the above circumstances, and is directed to 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof and a quaternary ammonium. A liquid formulation containing a cationic cationic surfactant, which can be prepared without complicated means, and is also excellent in safety,
And the cloudiness caused by adding a quaternary ammonium cationic surfactant to 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, It is an object of the present invention to provide a method for eliminating cloudiness of a liquid agent that can be easily and without any loss of safety.

Further, the present invention improves the transmucosal absorption of 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or pharmaceutically acceptable salts thereof and glycyrrhizinates. An object of the present invention is to provide a method for promoting transmucosal absorption of a liquid preparation.

[0011]

Means for Solving the Problems and Embodiments of the Invention The present inventors have studied 1,3-bis (2-carboxychromone-
As a result of intensive studies to eliminate the clouding phenomenon that occurs in a system containing 5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof and a quaternary ammonium cationic surfactant, When glycyrrhizinates are added to the prepared system, for example, the aforementioned JP-B-54-250
No. 82, as described in Japanese Patent Publication No. 4-66452, it is only necessary to sequentially mix the components without using a complicated method. It has been found that clarification is achieved by means of excellent safety, such as no use of an agent and no side effects.

Further, the present inventors have proposed 1,3-bis (2-
As a result of intensive studies to improve the transmucosal absorbability of (carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof and glycyrrhizinates, glycyrrhizates in a specific pH environment By controlling the concentration of the glycyrrhizinate in the preparation, the transmucosal absorption of glycyrrhizinates is increased, and as a result, the pharmacological effects of the glycyrrhizinates are improved, and the coexisting drug 1,3-bis (2-carboxylate) is used. It has been found that transmucosal absorption of chromone-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, for example, sodium cromoglycate, can be improved, and the medicinal effect can be improved. .

That is, the present invention relates to (1) 1,3-bis (2
-Carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, and 0.0
(2) 1,3-bis (2) a liquid agent comprising a quaternary ammonium cationic surfactant in an amount of from 0.01 to 0.04 mass / volume% and glycyrrhizinates.
-Carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, and 0.0
A method for removing turbidity of a liquid preparation, which comprises adding glycyrrhizinates to a system containing from 0.01 to 0.04 mass / volume% of a quaternary ammonium cationic surfactant;
And (3) 1,3-bis (2-carboxychromone-5)
-Yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, 0.001 to 0.04% by mass / volume
PH of a liquid formulation containing a quaternary ammonium cationic surfactant and glycyrrhizinates
6, and adjusting the concentration of the glycyrrhizinates to be equal to or higher than the critical micelle concentration,
-Bis (2-carboxychromone-5-yloxy)-
It is intended to provide a method for promoting transmucosal absorption of a liquid preparation, characterized by improving transmucosal absorption of 2-hydroxypropane or a pharmaceutically acceptable salt thereof and the glycyrrhizinates.

Now, the present invention will be described in detail. The present invention relates to 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, quaternary. An ammonium cationic surfactant and glycyrrhizinates are used.

In the present invention, 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof (hereinafter referred to as cromoglycic acid) includes, for example, disodium salt, Examples thereof include dipotassium salts, and these can be used alone or in an appropriate combination of two or more. In the case of the present invention, among these, a disodium salt (sodium cromoglycate) is particularly preferable.

The concentration of the above cromoglycic acids in the liquid preparation of the present invention is not particularly limited, but is usually 0.1%.
05 to 10% by mass / volume (hereinafter, w / v%), preferably 0.1 to 5% w / v, more preferably 0.5 to 3% w / v.
v%. If the concentration is too low, sufficient drug efficacy may not be obtained, and if the concentration is too high, it may be difficult to sufficiently eliminate cloudiness.

As the quaternary ammonium cationic surfactant used in the present invention, for example, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride and the like can be used, and these can be used alone or in combination of two or more. Can be used in appropriate combination. In the case of the present invention, these quaternary ammonium cationic surfactants may be added to other pharmaceutically acceptable preservatives, for example, parabens such as methyl, ethyl, propyl or butyl paraben, chlorhexidine gluconate, chlorobenzene and the like. Butanol, phenylethyl alcohol, benzyl alcohol,
Sodium dehydroacetate, sorbic acid, potassium sorbate, sodium sorbate and the like can be used in combination.

In the solution of the present invention, the amount of the quaternary ammonium cationic surfactant is 0.001 to 0.04 w / v%, preferably 0.001%, based on the total amount of the solution.
2 to 0.02 w / v%, more preferably 0.002 to
0.01 w / v%. When the amount of the quaternary ammonium cationic surfactant is less than 0.001 w / v%, the preservative power is reduced. On the other hand, when the amount is more than 0.04 w / v%, side effects such as mucous membrane irritation and skin irritation are caused. Is generated.

As the glycyrrhizinates, for example, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, diammonium glycyrrhizinate and the like can be used. Species can be used alone or in appropriate combination of two or more kinds. Among them, dipotassium glycyrrhizinate is particularly preferable because of its excellent solubility in water.

The amount of the above-mentioned glycyrrhizinates in the liquid preparation of the present invention is not particularly limited, but is usually 0.05 w / v% or more based on the total amount of the liquid preparation when the purpose is only to eliminate cloudiness. Is preferred. 0.05w
If it is lower than / v%, it may not be possible to sufficiently eliminate the cloudiness of the liquid preparation, which is the object of the present invention.

On the other hand, in order to promote transmucosal absorption as well as to eliminate opacity, the concentration of the glycyrrhizinates must be equal to or higher than the critical micelle concentration. 0.07w
/ V% or more, especially 0.1 w / v% or more. If it is lower than 0.07 w / v%, the transmucosal absorption of glycyrrhizinates and the above cromoglycates cannot be sufficiently achieved.

In the present invention, the upper limit is not particularly limited as long as the concentration of the glycyrrhizinates is equal to or higher than the concentration described above. In consideration of properties and the like, it is desirable that the content be 3 w / v% or less, particularly 2 w / v% or less, based on the total amount of the liquid preparation.

In the present invention, the pH of the preparation is not particularly limited as long as it is a pharmaceutically acceptable range when the purpose is only to eliminate cloudiness, and usually pH 3 to 9 is desirable.

On the other hand, in the present invention, in order not only to eliminate cloudiness but also to promote transmucosal absorption, the pH of the preparation must be 4 or less.
By adjusting the value to 吸収 6, the absorption of glycyrrhizinates from the mucous membrane is improved, and the improvement of the coexistence of the coexisting cromoglycic acids such as sodium cromoglycate is also achieved. Therefore, the solution of the present invention has a formulation pH of 4 to
6, and more preferably 4 to 5.
Adjust to 5.

The use of the liquid preparation of the present invention is not particularly limited. For example, an external preparation applied to mucous membranes such as eye drops, nasal drops, ear drops, and throat spray, or other liquids such as injections. It can be used as an external solution in a dosage form. Among these, it is particularly preferable to prepare them as eye drops or nasal drops.

In the present invention, as long as the effects of the present invention are not impaired, in addition to the above-mentioned essential components, all buffers, solubilizing agents, isotonic agents, stabilizers and the like usually used for the preparation of the above-mentioned preparations are used. In addition, various additives such as a thickener, a chelating agent, a pH adjuster, and a cooling agent, and other pharmaceutically active ingredients can be blended in a usual amount.

Examples of the buffer include boric acid or a salt thereof (borax or the like), citric acid or a salt thereof (sodium citrate or the like), phosphoric acid or a salt thereof (sodium monohydrogen phosphate or the like), tartaric acid or a salt thereof (Such as sodium tartrate), gluconic acid or a salt thereof (such as sodium gluconate), acetic acid or a salt thereof (such as sodium acetate), various amino acids, and a combination thereof.

Examples of the solubilizing agent include polyethylene glycol, propylene glycol and the like. Examples of the tonicity agent include sodium chloride, potassium chloride, mannitol, propylene glycol and the like.

Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, citric acid and salts thereof. Examples of the thickener include polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, and chondroitin sodium sulfate.

Examples of the chelating agent include sodium edetate, sodium citrate and the like. Examples of the pH adjuster include hydrochloric acid, citric acid or a salt thereof, boric acid or a salt thereof, phosphoric acid or a salt thereof, acetic acid or a salt thereof, tartaric acid or a salt thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, and carbonic acid Sodium hydrogen and the like. Examples of the cooling agent include menthol, borneol, camphor, geraniol, limonene, eugenol, peppermint oil, eucalyptus oil and the like.

Examples of other pharmaceutically active ingredients include decongestants (naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, etc.), anti-inflammatory and astringents (neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride, zinc sulfate, zinc sulfate, Lysozyme chloride, etc.), antihistamines (diphenhydramine hydrochloride, isotipendyl hydrochloride, chlorpheniramine maleate, etc.), vitamins [vitamin A and its esters (eg acetate, palmitate)], active vitamin B ₂ , vitamin B ₆ , vitamin B ₁₂ , vitamin E and its esters (for example, acetate), etc.], amino acids (potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, etc.) , A sulfa drug, a bactericide (eg, sulfur, isopropylmethylphenol, hinokitiol), a local anesthetic (eg, lidocaine, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride) and the like.

In the present invention, the method for producing a liquid preparation is not particularly limited, and it can be prepared according to a conventional method for each dosage form. Usually, each of the above components is purified water (if necessary, sterilized purified water). It is prepared by dissolving in At this time, there is no particular limitation on the mixing order of the glycyrrhizinates, and after the glycyrrhizates are dissolved in advance,
A cromoglycic acid and a quaternary ammonium cationic surfactant may be blended, and after the solution becomes cloudy with the cromoglycic acid and the quaternary ammonium cationic surfactant, glycyrrhizinate is added. Can also clear the solution.

Further, in the case of the method for promoting transmucosal absorption of the present invention, the amount of the above-mentioned glutyl litate in the liquid preparation is controlled within the above range, and the pH of the preparation of the liquid preparation is controlled by the above-mentioned various pH adjusters or the above buffer. Adjust to ~ 6.

When the solution of the present invention is applied to eye drops, the prepared solution is sterilized (for example, by aseptic filtration).

The method of using the liquid preparation of the present invention is not particularly limited, and the use of the above-mentioned cromoglycic acids and glycyrrhizinates can be exerted by using a normal dose of the intended use and dosage form in a conventional manner. You.

[0036]

According to the present invention, it is not necessary to add a nonionic surfactant, so that it is possible to provide a clear liquid preparation with improved safety. Improved transmucosal absorption of 2-carboxychromon-5-yloxy) -2-hydroxypropane or its pharmaceutically acceptable salts and glycyrrhizinates has been achieved.

[0037]

The present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to the following examples.

Examples 1 to 10 and Comparative Examples 1 to 5
Sodium cromoglycate as a 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof in purified water, quaternary ammonium cation interface Benzalkonium chloride was added as an activator, and dipotassium glycyrrhizinate was added at various concentrations as glycyrrhizinates to prepare solutions. Table 1 also shows the results of visual observation of the appearance of each solution.

[0039]

[Table 1]

[Examples 11 to 18 and Comparative Examples 6 to 9] According to the composition shown in Table 2, 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutical thereof was added to purified water. To this solution, sodium cromoglycate as an acceptable salt, benzethonium chloride as a quaternary ammonium cationic surfactant, and dipotassium glycyrrhizinate as glycyrrhizinates were added at various concentrations to prepare solutions. The appearance of each solution was visually observed. The results are also shown in Table 2.

[0041]

[Table 2]

[Examples 19 and 20 and Comparative Examples 10 and 1
1] Each component was dissolved in purified water by a conventional method so as to have the composition shown in Table 3, to prepare an eye drop, and the appearance was visually observed. The results are also shown in Table 3.

[0043]

[Table 3]

Example 21 and Comparative Example 12 In accordance with the composition shown in Table 4, eye drops were prepared by a conventional method, and 100 μl was applied to both eyes of Japanese white rabbits (body weight: about 3 kg, n = 5) by instillation into the lower eyelid. After a certain period of time, the aqueous humor was collected, and the amount of sodium cromoglycate and dipotassium glycyrrhizinate transferred into the aqueous humor of the rabbit was measured by high performance liquid chromatography. The results are also shown in Table 4.

[0045]

[Table 4]

[Examples 22 to 49] In accordance with the compositions shown in Tables 5 to 9, ophthalmic solutions, nasal drops and throat sprays were prepared by a conventional method, and the appearance was visually observed. The transfer amount of sodium cromoglycate and dipotassium glycyrrhizinate in rabbit aqueous humor was measured in the same manner as in Example 21, and evaluated based on the following evaluation criteria. The results are shown in Tables 5-9
It is described together.

Evaluation criteria ◎: The amounts of sodium cromoglycate and dipotassium glycyrrhizinate in the aqueous humor are each 0.1 μg / ml or more. The amounts of sodium cromoglycate and dipotassium glycyrrhizinate in the aqueous humor are each 0.05 μg / ml. Not more than 0.1 μg / ml Δ: sodium cromoglycate and dipotassium glycyrrhizinate in the aqueous humor are respectively 0.01 μg / ml or more and less than 0.05 μg / ml ×: sodium cromoglycate and dipotassium glycyrrhizinate in the aqueous humor Less than 0.01μg / ml each

[0048]

[Table 5]

[0049]

[Table 6]

[0050]

[Table 7]

[0051]

[Table 8]

[0052]

[Table 9]

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA11 BB21 CC03 CC10 CC15 DD19F DD69 FF15 FF34 FF36 FF67 4C086 AA01 AA02 BA08 DA11 MA03 MA05 MA16 MA56 NA02 NA11 ZA33 ZA34 ZB13

Claims (3)

[Claims] 1. A method according to claim 1, wherein 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof is used in an amount of 0.001 to 0.04% by mass.
A volume% of a quaternary ammonium cationic surfactant;
A liquid preparation comprising glycyrrhizinates. 2. A composition comprising 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, and 0.001-0.04 mass /
A method for eliminating turbidity of a liquid preparation, comprising adding a glycyrrhizinate to a system containing a volume% of a quaternary ammonium cationic surfactant. 3. A mixture of 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof, and 0.001 to 0.04 mass /
A volume% of a quaternary ammonium cationic surfactant;
In a liquid formulation containing glycyrrhizinates, pH
Is adjusted to 4 to 6 and the concentration of the glycyrrhizinates is equal to or higher than the critical micelle concentration, whereby the 1,3-bis (2-carboxychromone-5-yloxy) -2-hydroxypropane or a pharmaceutical thereof is prepared. A method for promoting transmucosal absorption of a liquid preparation, which comprises improving the transmucosal absorbability of a pharmaceutically acceptable salt and the glycyrrhizinate.