JP2005187404A - External spray composition for mucosa, nasal drop and preparation for oral cavity/throat disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external spray composition for mucosa, a nasal drop and a preparation for oral cavity/throat diseases, each yielding good spreading adherability in a relatively low viscosity and excellent in pharmacological activity sustainability, feeling in use and irritation-mitigating effect. <P>SOLUTION: The external spray composition for mucosa comprises (A) 0.05-2 w/v% of glycyrrhizinic acid and/or its salt, (B) 0.05-10 w/v% of a cellulose derivative, (C) 0.5-10 w/v% of a polyhydric alcohol and (D) 0.005-2 w/v% of a terpenoid compound. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  TECHNICAL FIELD The present invention relates to a spray composition for external mucosa, and in particular, relates to a spray composition for external mucosa, nasal drops and an agent for oral and throat diseases, which are excellent in pharmacological action, durability and irritation mitigation effect. .

  In recent years, due to an increase in hay fever patients and the like, there is an increasing demand for nasal drops formulated with an antihistamine and administered intranasally using a nebulizer or the like. In addition, many products for the oral and throat sprays for the treatment of throat, pain, stomatitis, sterilization / disinfection for the prevention of colds, prevention of bad breath and the like are on the market. When sprayed, sprays are more susceptible to irritation than normal application, and in particular, sprays containing a large amount of lower alcohols such as ethanol to give a refreshing feeling are expected to improve the refreshing feeling, but mucous membranes There is a problem that the feeling of feeling is too strong and the feeling of use is bad. In addition, nasal sprays and oral sprays are often of the type in which aqueous solutions are sprayed by manual pressurization, but the drawbacks such as poor spreadability at the sprayed place and lack of durability, poor usability, etc. There is.

  In order to improve spreadability during spraying, there is a method to increase the viscosity of an aqueous solution using a water-soluble polymer compound that is a thickener, but the viscosity is too high at a blending amount that provides good durability. In other words, it cannot be ejected from the spray container, or a feeling of use such as stickiness may occur.

  As a solution to these problems, a gel base prepared by disrupting agar jelly with a homomixer is used as a nasal spray for spraying (Patent Document 1: Japanese Patent Laid-Open No. 5-124955), and a vasoconstrictor and an antihistamine are included. As an O / W emulsion preparation, there is a nasal preparation (Patent Document 2: Japanese Patent Laid-Open No. 7-258069) with enhanced retention in the nasal cavity, but a homomixer, an ultrasonic emulsifier, etc. A manufacturing apparatus having a strong shear force is necessary. Further, a gel-like nasal drop containing 25-35% butylene glycol, 8% or more of glycerin, a thickener and water has been proposed (Patent Document 3: Japanese Patent Laid-Open No. 2003-63957), which is in a moisturized state. Although sustainability is excellent, there is room for improvement in terms of drug retention and a refreshing feel. Therefore, there has been a demand for a spray composition for external mucosa excellent in pharmacological durability, usability and irritation mitigation effect.

Japanese Patent Laid-Open No. 5-124955 JP-A-7-258069 JP 2003-63957 A JP 2003-252800 A

  The present invention has been made in view of the above circumstances, and can be spread to the nasal cavity, oral cavity, and throat without being manufactured by a special manufacturing apparatus, and has a sustained pharmacological action, usability, and a stimulating effect. It is an object of the present invention to provide an excellent spray composition for external mucosa, nasal drops, and oral and throat diseases.

  As a result of intensive studies to achieve the above object, the present inventor has found that (A) glycyrrhizic acid and / or a salt thereof, (B) a cellulose derivative, By forming a spray composition for extramucosal use containing a specific amount of C) polyhydric alcohol and (D) terpenoid compound, a spray base that can be spread in the nasal cavity, oral cavity, and throat can be obtained. It has been found that the duration of action and effectiveness and the feeling of use are improved, and the present invention has been made.

Therefore, the present invention
[1]. (A) Glycyrrhizic acid and / or its salt 0.05-2 W / V%,
(B) Cellulose derivative 0.05 to 10 W / V%,
(C) Polyhydric alcohol 0.5 to 10 W / V%,
(D) Terpenoid compound 0.005 to 2 W / V%
A spray composition for external application to the mucosa, characterized by comprising
[2]. An external spray composition for mucous membranes according to [1], which is a nasal spray;
[3]. An external mucosal spray composition according to [1], which is an agent for oral and throat diseases.

  According to the present invention, (A) glycyrrhizic acid and / or a salt thereof, (B) a cellulose derivative, (C) a polyhydric alcohol and (D) a spray composition for external mucosa containing a specific amount of terpenoid compound, It is possible to obtain a spray composition for external mucosa, a nasal drop, and an agent for oral and throat diseases, which has good spreadability at a relatively low viscosity, and has excellent pharmacological durability, usability and irritation mitigation effect. it can.

Hereinafter, the present invention will be described in more detail.
The component (A) of the present invention is glycyrrhizic acid and / or a salt thereof. In addition to the effect as a drug, when combined with the cellulose derivative (B) of the present invention, even if the viscosity is low, the foamability of foaming spray and foam It will be better. Examples of glycyrrhizic acid and / or a salt thereof include glycyrrhizic acid, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, and diammonium glycyrrhizinate. Among these, dipotassium glycyrrhizinate can be preferably used because it is excellent in solubility in water. In addition, in this invention, herbal medicines, such as a plant containing a glycyrrhizic acid and / or its salt, for example, a licorice, a licorice extract, can also be mix | blended. These can be used individually by 1 type or in combination of 2 or more types.

  The content of (A) glycyrrhizic acid and / or a salt thereof is 0.05 to 2 W / V% (mass / volume%, the same applies hereinafter) in the spray composition for external mucosa. The lower limit of the amount is preferably 0.07 W / V% or more, more preferably 0.1 W / V% or more. The upper limit is preferably 1 W / V% or less, more preferably 0.5 W / V% or less. By setting the amount within this range, a particularly excellent pharmacological durability can be obtained, and an external preparation for mucosa having good foam feeling when sprayed in foam from a foamed container and having a good feeling in use can be obtained. In particular, 0.1 W / V% or more is preferable because, in addition to the above effects, the drug absorbability is improved and the immediate effect is excellent.

  The component (B) of the present invention is a cellulose derivative, and by blending the component (B), it is possible to improve the sustainability of the pharmacological action and the feeling of use, and to reduce irritation. Examples of the cellulose derivative include methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and hydroxyethyl methyl cellulose. These can be used individually by 1 type or in combination of 2 or more types. Of these, hydroxyethylcellulose and hydroxypropylmethylcellulose are preferred.

  (B) Content of a cellulose derivative is 0.05-10 W / V% in the spray composition for external mucosa. The lower limit of the amount is preferably 0.1 W / V% or more. The upper limit is preferably 5 W / V% or less. By setting it as this range, the usability in the nasal cavity, oral cavity and throat is good, and excellent persistence of pharmacological action can be obtained.

  The component (C) of the present invention is a polyhydric alcohol. By blending this component in combination, it is possible to further improve the persistence of the pharmacological action and the feeling of use, and to reduce irritation. Examples of the polyhydric alcohol include glycerin, concentrated glycerin, polyethylene glycol, propylene glycol, mannitol, sorbitol, xylitol and the like. Among these, glycerin and propylene glycol are preferable. These can be used individually by 1 type or in combination of 2 or more types.

  (C) Content of polyhydric alcohol is 0.5-10 W / V% in the spray composition for external mucosa. The lower limit of the amount is preferably 0.6 W / V% or more, more preferably 1.0 W / V% or more. The upper limit is preferably 5 W / V% or less. By setting it within this range, even when a composition containing a drug or terpenoid is sprayed and applied to the nose or throat, a spray composition for external mucosa with no irritation and good usability can be obtained.

  The component (D) of the present invention is a terpenoid compound. The terpenoids used in the present invention exhibit actions such as imparting a refreshing feeling, bactericidal disinfection, alleviating mucosal inflammation, calming action, and imparting a refreshing feeling. Terpenoids include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. Also, depending on the number of carbons, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes, but monoterpenes are preferably used. As the terpenoids, a purified compound may be used, or an essential oil containing terpenoids may be used. Specific examples of essential oils containing terpenoids include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, dipterocarp plant essential oil, rosmarin oil, lavender oil and the like. It is done. Specific preferred terpenoids include l-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, citral, citronellal, limonene, citronellol, cineol, geraniol, cineol, linalool, eucalyptus oil Bergamot oil, rose oil, peppermint oil, peppermint oil and the like. These terpenoids (including essential oils containing terpenoids) can be used singly or in appropriate combination of two or more.

  (D) Content of a terpenoid compound is 0.005 to 2 W / V% in the spray composition for external mucosa. The lower limit of the amount is preferably 0.006 W / V% or more, more preferably 0.01 W / V% or more. The upper limit is preferably 1 W / V% or less, more preferably 0.5 W / V% or less. By setting it within this range, an external preparation for mucosa with no irritation and good usability can be obtained.

  In the external preparation for mucosa of the present invention, in addition to the above essential components, various components to be added to external preparations for mucosa such as nasal drops, oral cavity and throat preparation can be blended within a range not impairing the effects of the present invention. Examples of these components include various drugs, buffers, solubilizers, tonicity agents, stabilizers, chelating agents, pH adjusters, preservatives, humectants, and flavoring agents. In addition, these components can be conveniently used with normal usage-amount.

  Examples of various drugs include decongestants, anti-inflammatory agents, astringents, antihistamines, vitamins, amino acids, bactericides, and local anesthetics. These can be used individually by 1 type or in combination of 2 or more types.

  Examples of the decongestant include naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, and naphazoline nitrate.

  Examples of anti-inflammatory and astringent agents include neostigmine methyl sulfate, ε-aminocaproic acid, allantoin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, lysozyme chloride, bromelain, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, salicylic acid Examples include methyl, tranexamic acid, sodium azulene sulfonate, chamomile, and cromoglycic acid sodium.

  Examples of the antihistamine include iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipentyl hydrochloride, chlorpheniramine maleate and the like.

  Examples of vitamins include flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, vitamins A (for example, retinol acetate, retinol palmitate), vitamins E (for example, tocopherol acetate (for example, d-α-tocopherol acetate). Examples of amino acids include potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, and the like.

  Bactericides include cetylpyridinium chloride, chlorhexidine gluconate, decalinium chloride, benzalkonium chloride, benzethonium chloride, iodine, potassium iodide, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, Examples include sodium sulfisomidine, isopropylmethylphenol, and hinokitiol. Examples of the local anesthetic include lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, chlorobutanol and the like.

  Examples of the buffer include citric acid or a salt thereof (such as sodium citrate), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate, etc.), 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), carbonic acid or a salt thereof (such as sodium bicarbonate), trometamol, various amino acids (epsilon- Aminocaproic acid, potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate, etc.). These buffering agents can be used singly or in appropriate combination of two or more.

  Examples of the solubilizer include polyoxyethylene (p = 60) hardened castor oil and other polyoxyethylene higher fatty acid esters, polyoxyethylene (p = 20) sorbitan monooleate and other polyoxyethylene sorbitan higher fatty acid esters, Examples thereof include propylene glycol and polyethylene glycol (commercially available products such as Magrogol 400 and 4000 manufactured by Goodrich Chemical Co., Ltd.). These solubilizers can be used singly or in appropriate combination of two or more.

  Examples of the isotonic agent include sodium chloride, potassium chloride, glycerin and the like. These tonicity agents can be used singly or in appropriate combination of two or more.

  Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, citric acid or a salt thereof, dibutylhydroxytoluene, ascorbic acid and the like. These stabilizers can be used singly or in appropriate combination of two or more.

  Examples of chelating agents include sodium edetate and sodium citrate. These chelating agents can be used individually by 1 type or in combination of 2 or more types.

  Examples of the pH adjuster include sodium hydroxide, potassium hydroxide, hydrochloric acid and the like. These pH adjusters can be used singly or in appropriate combination of two or more.

  Preservatives include paraoxybenzoates such as methyl paraben, ethyl paraben, propyl paraben, and butyl paraben, alcohol derivatives such as phenyl ethyl alcohol, benzyl alcohol, phenol, and acrinol, sorbic acid and its salts (such as potassium sorbate), Benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyridinium chloride, alkylpolyaminoethylglycine and the like can be mentioned. These preservatives can be used singly or in appropriate combination of two or more.

  Examples of the humectant include glycerin, concentrated glycerin, sugar alcohols (sorbitol, xylitol, etc.) and the like. These humectants can be used singly or in appropriate combination of two or more.

  Examples of the corrigent include aspartame, xylitol, and saccharin sodium. These flavoring agents can be used alone or in combination of two or more.

  The pH of the spray composition for external mucosa of the present invention is preferably 4 to 9, more preferably 5 to 8.5. The viscosity at 20 ° C. (measured with a rotational viscometer (E-type viscometer) based on the viscosity measurement method of the 14th revised Japanese pharmacopoeia) of the spray composition for external mucosa of the present invention is preferably 1 to 500 mPa · s. ˜200 mPa · s is more preferable. When the viscosity exceeds 500 mPa · s, the contents may not be ejected or the usability may be deteriorated.

  The spray composition for external mucosa of the present invention is not particularly limited in its dosage form, but it is preferably prepared as an aqueous preparation, and is an oral spray such as nasal drops and oral and throat diseases, and throat spray. It is preferable to prepare it as a liquid applied to an agent.

  The preparation method for the external preparation for mucosa of the present invention is not particularly limited, and can be prepared according to the usual method of the dosage form and form. For example, if it is a nasal drop, first (B) The cellulose derivative is dispersed in hot water and dissolved by cooling with stirring. Next, glycyrrhizic acid and / or a salt thereof, a drug and other components are added to prepare a composition by adjusting the pH, and the resulting composition can be prepared by filling a nasal container made of polyethylene. it can.

  The container may have any shape as long as the spray composition for external mucosa filled therein is made into a mist, a fine droplet, or a foam and sprayed to the mucous membrane. Examples of the container include a hand pump type in which liquid is sprayed by a hand pump without using compressed gas, and an aerosol type container in which the liquid in the container is injected by the pressure of liquefied gas or compressed gas. Examples of the container having a foaming mechanism include a container in which a discharge device such as a trigger spray or a pump spray is attached to the mouth of the container body. In the present invention, the sprayed composition for external application to the mucous membrane becomes foam and stays in the affected part of the nasal cavity, oral cavity and throat for a long time, more pharmacological persistence can be obtained, and it can be stably released to the mucous membrane. It is preferable to fill the spray container having a foaming mechanism with the composition because it can be used satisfactorily without any problems.

  The method for using the external mucosal spray composition of the present invention is to spray and apply the external mucosal spray composition into the nasal cavity, oral cavity, and throat, and use an appropriate amount about 1 to 6 times a day. .

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Example 1 and Comparative Examples 1 to 4]
According to the composition shown in Table 1 (blending amount: g / 100 mL), liquid nasal drops were prepared by a conventional method. The obtained liquid nasal drops were evaluated as follows. The results are also shown in Table 1.

[Method for evaluating the persistence, usability and irritation of pharmacological effects]
The obtained liquid nasal drops are filled into a 15 mL polyethylene spray container and sprayed directly into the nasal passages of 5 panelists with nasal inflammation, and the sustainability and usability of the effect of reducing discomfort such as nasal congestion (Stickiness, dripping, etc.) and irritation were evaluated according to the following criteria. The results are shown in Table 1. In addition, the result of the persistence of the pharmacological action effect shows the average score of the evaluation of five panelists. Usability and irritation ratings are the most common.

<Evaluation criteria for the persistence of pharmacological effects on discomfort symptoms such as nasal congestion>
5: Reducing discomfort such as nasal congestion for a very long time (60 minutes or more)
4: Feeling a long time to reduce discomfort such as stuffy nose (more than 30 minutes and less than 60 minutes)
3: Feels somewhat less annoying symptoms such as stuffy nose (from 10 minutes to less than 30 minutes)
2: Feeling of reduced discomfort such as stuffy nose (less than 10 minutes)
1: No reduction in discomfort such as stuffy nose

<Evaluation criteria for usability>
A: Usability is very good (no stickiness or dripping)
○: Good usability (no stickiness or dripping)
△: Slightly poor usability (slight stickiness, slightly dripping)
×: Poor usability (there is stickiness and dripping)

<Irritation criteria>
◎: No irritation ○: Almost no irritation △: Slight irritation ×: Irritation

  The viscosity was measured at 20 ° C. using a rotational viscometer (E-type viscometer) based on the viscosity measurement method of the 14th revised Japanese Pharmacopoeia.

[Examples 2 to 9]
Nasal drops were prepared by a conventional method according to the composition shown in Table 2 (blending amount: g / 100 mL).

[Examples 10 to 17]
According to the composition shown in Table 3 (blending amount: g / 100 mL), an oral and throat disease preparation was prepared by a conventional method.

Claims (3)

(A) Glycyrrhizic acid and / or its salt 0.05-2 W / V%,
(B) Cellulose derivative 0.05 to 10 W / V%,
(C) Polyhydric alcohol 0.5 to 10 W / V%,
(D) Terpenoid compound 0.005 to 2 W / V%
A spray composition for external mucosa, comprising:   The spray composition for external mucosa according to claim 1, which is a nasal drop. The spray composition for external mucosa according to claim 1, which is an agent for oral cavity and throat disease.