JP2005068076A - External liquid preparation containing tranexamic acids and cleaning agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external liquid preparation having excellent long-term preservation stability by improving the preservation stability of an external liquid preparation containing at least tranexamic acids, a water-soluble germicide and an antiseptic; and to obtain a cleaning agent containing the preparation. <P>SOLUTION: The external liquid preparation contains 0.1-10 mass% one kind or mixture of two or more kinds selected from the group consisting of the tranexamic acid, a derivative of the tranexamic acid and a salt of the tranexamic acid, 0.0001-0.2 mass% water-soluble germicide, 0.01-1 mass% antiseptic, and 0.1-5 mass% nonionic surfactant. The cleaning agent contains the external liquid preparation. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an externally applied liquid agent excellent in storage stability and a wiping agent containing the same. More specifically, it contains tranexamic acids with high hemostatic, antiallergic and anti-inflammatory effects, water-soluble disinfectant, preservative, and nonionic surfactant to clean the area around the anus. The present invention relates to a liquid for external use and a wiping agent containing the same.

  Tranexamic acid (trans-4- (aminomethyl) cyclohexanecarboxylic acid) has anti-hemorrhage, anti-allergic, and anti-inflammatory effects due to antiplasmin action, bleeding tendency considered to be related to systemic or local fibrinolysis, eczema Symptoms such as erythema, swelling and pruritus in urticaria and urticaria; symptoms such as sore throat, redness, hyperemia and swelling in tonsillitis and pharyngopharyngitis; oral pain in stomatitis and after-mucosal mucosa after-treatment.

  However, tranexamic acid is stable when dissolved alone in water, but when mixed with other active ingredients and additives to form a liquid, stability is reduced and formulation is difficult. There was a problem.

  On the other hand, Patent Document 1 adds an edible acid such as citric acid or a salt thereof in a syrup preparation containing tranexamic acid or an oral liquid containing tranexamic acid and other active ingredients. It describes that the long-term stability of tranexamic acid can be maintained.

  By the way, tranexamic acid is applied not only to internal preparations such as syrups and oral liquids, but also to external preparations, that is, to the therapeutic area in anticipation of therapeutic effects because of its anti-bleeding action, anti-allergic action and anti-inflammatory action It is also expected to be used as an active ingredient of an external solution used for cleaning the vicinity of the affected area. For example, it is expected to be used as a liquid for external use to clean the affected area or the perianal area of a person with hemorrhoids.

  Such an external solution usually contains a bactericide to improve the cleaning effect and a preservative to improve the storage stability.

  However, according to the experiments of the present inventors, when tranexamic acid is dissolved in water together with a water-soluble disinfectant and an antiseptic, and an aqueous external preparation is prepared, it becomes cloudy at room temperature to form a precipitate, There was a problem that the storage stability was significantly reduced.

  Such a problem does not occur in the aqueous solution of tranexamic acid alone as described above, and in our experiments, an aqueous solution of tranexamic acid and a water-soluble disinfectant, an aqueous solution of tranexamic acid and an antiseptic agent, and an aqueous solution, respectively. It did not occur in aqueous solutions of bactericides and preservatives.

  By the way, in patent document 2, in addition to tranexamic acid as a compound having a protease inhibitory action as an example of a cleaning / wiping agent composition that reduces skin irritation and prevents deterioration of various symptoms such as the peripheral area of the anus, ethanol is used. An emulsifying aerosol-type wiping agent containing dimethylpolysiloxane, glycerin, 1,3-butylene glycol, preservative, nonionic surfactant, LPG, water and the like is disclosed.

Although it is separately described in Patent Document 2 that a bactericidal agent may be blended, an aspect in which tranexamic acid, a preservative, and a bactericidal agent are blended is not described. There is no description of the problem of precipitate formation. This is an emulsified composition containing an oil component in the above examples, and since it does not contain a bactericidal agent, it is considered that such a precipitate did not occur in the first place.

As a result of diligent research in view of such circumstances, the present inventors have formulated nonionic surfactants at specific concentrations together with specific concentrations of tranexamic acids, water-soluble fungicides and preservatives, The present invention has been completed by finding out that the above problems can be solved and an externally applied liquid preparation excellent in storage stability can be obtained.
JP-A-9-286726 JP-A-4-182423

  An object of the present invention is to improve the storage stability of an external liquid preparation containing at least tranexamic acids, a water-soluble disinfectant, and an antiseptic, and to provide an external liquid preparation excellent in long-term storage stability and a wiping agent containing the same. Yes.

  The liquid preparation for external use according to the present invention contains 0.1 to 10% by mass of one or more mixtures selected from the group consisting of tranexamic acid, tranexamic acid derivatives and salts of tranexamic acid (hereinafter also referred to as tranexamic acids). It contains 0.0001 to 0.2% by mass of a water-soluble disinfectant, 0.01 to 1% by mass of a preservative, and 0.1 to 5% by mass of a nonionic surfactant. Yes.

  In the present invention, the water-soluble disinfectant is preferably a quaternary ammonium salt and / or chlorhexidine gluconate.

  The preservative is preferably at least one selected from the group consisting of alkyl paraoxybenzoate, sodium edetate, sorbic acid, and benzoic acid.

  In the present invention, as the nonionic surfactant, known nonionic surfactants can be widely used. Among them, those having a polyoxyethylene group are preferable.

  Further, the nonionic surfactant comprises polyoxyethylene hydrogenated castor oil, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether. Particularly preferred is at least one selected from the group.

  Moreover, in this invention, it is preferable that the mass ratio of the contained water-soluble disinfectant and tranexamic acids exists in the range of 1: 0.5-1: 100000.

  In addition, in this invention, it is preferable that it is an aqueous | water-based external solution which contains water as the remainder in the said external solution.

  Furthermore, it is desirable that the external preparation of the present invention does not substantially contain a lower alcohol having 1 to 4 carbon atoms.

The wiping agent according to the present invention is characterized in that it contains the external liquid agent. Specifically, the wiping agent is an impregnated sheet obtained by impregnating the external liquid agent into paper, cotton, woven fabric, or non-woven fabric. It is preferable.

  According to the external use liquid preparation of the present invention, the generation of precipitates can be prevented and long-term storage stability can be ensured even in an external use liquid preparation containing at least tranexamic acids, a water-soluble disinfectant, and a preservative. Thereby, it becomes possible to ensure the effectiveness of the external solution for a long period of time.

  Moreover, since the wiping agent of this invention contains the said external preparation, there is no precipitation of a component and it can be used stably over a long period of time.

  Hereinafter, the present invention will be specifically described.

  The liquid preparation for external use according to the present invention contains 0.1 to 10% by mass of one or more mixtures selected from the group consisting of tranexamic acid, tranexamic acid derivatives and salts of tranexamic acid (hereinafter also referred to as tranexamic acids). It contains 0.0001 to 0.2% by mass of a water-soluble disinfectant, 0.01 to 1% by mass of a preservative, and 0.1 to 5% by mass of a nonionic surfactant. Yes. Generation | occurrence | production of a precipitate can be prevented effectively by mix | blending each component with the quantity in the said range, respectively.

  Examples of the tranexamic acids used in the external preparation of the present invention include one or a mixture of two or more selected from the group consisting of tranexamic acid, tranexamic acid derivatives, and salts of tranexamic acid.

  Examples of the tranexamic acid derivative include dimers of tranexamic acid, esters, vitamin esters, alkylamides, phenyl esters, N, N-maleoylminotranexamic acid, and the like. Specific examples of the ester of tranexamic acid include phenyl esters which may be substituted with alkyl esters having 1 to 30 carbon atoms, alkyl groups having 1 to 30 carbon atoms, halogen atoms, carboxyl groups and the like. It is done. Specific examples of the alkylamide of tranexamic acid include methylamide and ethylamide of tranexamic acid.

  In addition, tranexamic acid salts include inorganic acid salts such as hydrochloride, nitrate, and sulfate; organic salts such as acetate, lactate, maleate, fumarate, tartrate, citrate, and methanesulfonate. Acid salts: Organic amine salts such as monoethanolamine salts, diethanolamine salts, triethanolamine salts; ammonium salts; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and the like.

  These may be used alone or in combination of two or more.

  Among these, tranexamic acid or a salt thereof is preferable, and tranexamic acid is more preferable from the viewpoint of hemostasis, antiallergy and anti-inflammatory effects.

  The tranexamic acids are usually contained in an amount of 0.1 to 10% by mass, preferably 1 to 10% by mass, more preferably 2 to 10% by mass in 100% by mass of the external liquid preparation of the present invention. When tranexamic acids are contained in such an amount in an external solution, hemostatic, antiallergic and anti-inflammatory effects can be expected.

Examples of the water-soluble disinfectant used in the external liquid preparation of the present invention include quaternary ammonium salts and chlorhexidine gluconate. These may be used alone or in a combination of two or more.

  As quaternary ammonium salts, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, decalinium chloride, cetyltrimethylammonium chloride, lauryltrimethylammonium chloride, alkyltrimethylammonium chloride, distearyldimethylammonium chloride, alkylisoquinolium bromide And alkyltrimethylammonium bromide. These may be used singly or in combination of two or more, and among them, benzalkonium chloride is preferable.

  The water-soluble disinfectant is 0.0001 to 0.2% by mass, preferably 0.001 to 0.15% by mass, more preferably 0.01 to 0.1% by mass in 100% by mass of the external preparation of the present invention. Contained in an amount of%. When the water-soluble disinfectant is contained in such an amount in the liquid for external use, the disinfecting action can be effectively exhibited.

  Further, in relation to the tranexamic acids, the mass ratio of the water-soluble disinfectant and tranexamic acids contained in the external solution is usually 1: 0.5 to 1: 100000, preferably 1: 6 to 1: 10000. More preferably, it is desirable to be in the range of 1:20 to 1: 1000.

  Examples of the preservative used in the external liquid preparation of the present invention include paraoxybenzoic acid alkyl ester, sodium edetate, sorbic acid, and benzoic acid. These may be used singly or in combination of two or more, but in order to further improve the antifungal and antiseptic effects, it is preferable to use two combinations. Specific examples include a combination of paraoxybenzoic acid alkyl ester and sodium edetate, paraoxybenzoic acid alkyl ester and sorbic acid, paraoxybenzoic acid alkyl ester and benzoic acid, and the like. Moreover, the combination of the paraoxybenzoic acid alkylesters mentioned later may be sufficient.

  Specific examples of the paraoxybenzoic acid alkyl ester include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.

  The preservative is 0.01 to 1% by mass, preferably 0.05 to 0.5% by mass, more preferably 0.1 to 0.2% by mass, in 100% by mass of the external preparation of the present invention. Included. When antiseptic | preservative is contained in the liquid for external use in such quantity, an antifungal and antiseptic | preservative effect can be show | played effectively. In addition, when using 2 or more types of antiseptic | preservatives as mentioned above, the total amount should just be in the said range.

  As the nonionic surfactant used in the external liquid preparation of the present invention, known nonionic surfactants can be widely used. Among them, those having a polyoxyethylene group are preferred. Specifically, polyoxyethylene hydrogenated castor oil, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene lauryl ether, and polyoxyethylene cetyl ether are more preferable. These may be used alone or in combination of two or more.

  The nonionic surfactant is 0.1 to 5% by mass, preferably 0.2 to 2.5% by mass, more preferably 0.25 to 1% by mass in 100% by mass of the external liquid preparation of the present invention. Is included in the amount.

  When the nonionic surfactant is contained in such an amount in the external liquid preparation, when it is blended with the tranexamic acids, the water-soluble disinfectant and the preservative, the generation of precipitates can be prevented. As described above, an aqueous solution of tranexamic acid, an aqueous solution of tranexamic acid and a water-soluble disinfectant, and an aqueous solution of tranexamic acid and a preservative have good storage stability, and no generation of precipitates is observed. In an aqueous solution of tranexamic acid, a water-soluble disinfectant, and a preservative, white turbidity occurs at room temperature, and precipitates are formed. In this invention, generation | occurrence | production of such a precipitate can be suppressed by mix | blending nonionic surfactant with said amount with tranexamic acid, water-soluble disinfectant, and antiseptic | preservative.

  Furthermore, in addition to the above-described components, components (pharmaceutically acceptable components) that can be used in the liquid can be usually added to the external liquid preparation of the present invention. For example, 1 selected from the group consisting of corticosteroids, local anesthetics, antipyretic analgesics and anti-inflammatory agents, anti-inflammatory analgesics / wound healing agents, vitamins, sulfa drugs, vasoconstrictors, antihistamines, peripheral vasodilators, intestinals and antidiarrheals. It is possible to formulate seeds or two or more drugs.

  In addition to the above drugs, absorption accelerators, pH adjusters, preservatives, dispersants, dispersion aids (for example, gum arabic, methylcellulose, carboxymethylcellulose, dextrin, etc.), antioxidants, etc. Preservatives can be blended.

  Furthermore, the external liquid preparation of the present invention usually contains water as a solvent in addition to the above-mentioned components, and preferably includes purified water, deionized water, distilled water and the like. The amount of water contained in the external liquid preparation is usually the balance obtained by subtracting the total amount of each component described above from 100% by mass.

  In general, for the purpose of solubilization with an aqueous liquid, a method may be employed in which a lower alcohol such as ethanol is added as a solvent to increase the solubility to obtain a uniform preparation. Although the present invention does not exclude such an embodiment, when a liquid preparation containing a lower alcohol is applied to the skin as a preparation for external use or impregnated into a base material and used as a wiping agent on the skin, It is easy to cause troubles due to skin irritation such as degreasing and soaking in wounds. In particular, when the external liquid or wiping agent to be used is intended for application to an anal disease site, these stimuli are not preferable for the patient.

  In addition, since tranexamic acids are included as an active ingredient in the present invention, it is desirable that the liquid preparation for external use of the present invention substantially does not contain such a lower alcohol from the viewpoint of solubility. Here, “substantially free” means that it may be contained in an amount of lower alcohol that does not cause skin irritation when an external solution is applied to the anal disease part. It means that the amount is less than 0.1% by mass, but it is more preferable not to include it. Examples of the lower alcohol include those having 1 to 4 carbon atoms, specifically, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and the like.

  The external liquid preparation of the present invention can be produced using a conventional method, and the method is not particularly limited. Usually, the above components and a part of a solvent such as water are mixed and dissolved to obtain a solution. It can be prepared by adjusting the amount of the solution by adding the remaining solvent to the solution.

  The pH of the external preparation is preferably in the range of pH 2 to 8, more preferably in the range of pH 4 to 7, from the viewpoint of stability.

The external liquid preparation of the present invention can be used in a liquid state, but it can also be used as an impregnated sheet-like wiping agent by impregnating a base material such as paper, cotton, woven fabric or non-woven fabric. Further, a propellant such as liquefied petroleum gas (LPG) can be added to the above-mentioned external liquid agent and used as an aerosol-type wiping agent, or used as a pump (pressurized) spray-type wiping agent.

[Example]
EXAMPLES Hereinafter, although this invention is demonstrated further more concretely based on an Example, this invention is not limited to these Examples.

  In accordance with the composition shown in Table 1 below, each component was mixed and dissolved to prepare a solution 1 for external use.

[Examples 2 to 9]
According to the composition shown in Table 1 below, the respective components were mixed and dissolved to produce external preparations 2-9.

[Comparative Examples 1-3]
According to the composition shown in Table 1-2 below, each component was mixed and dissolved to produce externally applied solutions C1 to C3.

[Test example]
The external preparations produced in the above examples and comparative examples are stored for 1 month (4 weeks) under normal pressure in a 5 ° C, 25 ° C, 40 ° C, 50 ° C, 60 ° C incubator, and every week. The appearance was observed. The appearance was visually observed according to the following evaluation criteria.

Appearance Observation Evaluation Criteria ◯: No generation of precipitates Δ: Some generation of precipitates is observed ×: Significant generation of precipitates is shown in Table 2.

Claims (10)

  0.1 to 10% by mass of one or a mixture of two or more selected from the group consisting of tranexamic acid, a tranexamic acid derivative and a salt of tranexamic acid (hereinafter also referred to as tranexamic acids), and a water-soluble disinfectant of 0.1%. An external liquid preparation comprising 0001 to 0.2% by mass, an antiseptic in an amount of 0.01 to 1% by mass, and a nonionic surfactant in an amount of 0.1 to 5% by mass.   The external solution according to claim 1, wherein the water-soluble disinfectant is a quaternary ammonium salt and / or chlorhexidine gluconate.   The external preparation according to claim 1 or 2, wherein the preservative is at least one selected from the group consisting of alkyl paraoxybenzoate, sodium edetate, sorbic acid, and benzoic acid.   The external solution according to any one of claims 1 to 3, wherein the nonionic surfactant has a polyoxyethylene group.   The nonionic surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether The external preparation according to any one of claims 1 to 4, which is at least one selected.   The external liquid preparation according to any one of claims 1 to 5, wherein the mass ratio of the water-soluble disinfectant and tranexamic acids contained is in the range of 1: 0.5 to 1: 100000.   The external solution according to any one of claims 1 to 6, comprising water as a balance.   The liquid preparation for external use according to any one of claims 1 to 7, which is substantially free of a lower alcohol having 1 to 4 carbon atoms.   A wiping agent comprising the external liquid preparation according to claim 1.   The wiping agent according to claim 9, which is an impregnated sheet obtained by impregnating the liquid for external use into paper, cotton, woven fabric, or non-woven fabric.