JP4084329B2 - Liquid composition and method for producing the same - Google Patents

Description

  The present invention provides a novel liquid composition having improved pharmaceutical stability, effectively removing discomfort and pain caused by pharyngeal diseases, and providing a refreshing refreshing feeling in the oral cavity, and a method for producing the same About.

  Pain in the pharynx, redness, swelling, and symptoms such as that and voice are not only very uncomfortable, but sometimes cause unbearable pain. The causes of such symptoms are mainly virus infections and bacterial infections, particularly respiratory virus infections, and it is known that the frequency of such symptoms is high. As a countermeasure to be taken when such a symptom is recognized, the actual situation is that it relies on a causal therapy that reduces or eliminates a viral infection or bacterial infection that causes such discomfort or pain.

  Currently, bactericidal disinfectants represented by iodine preparations containing iodine as an active ingredient are known to have a high effect on the sterilization and disinfection of causative viruses and bacteria. Disinfectants are often used. However, after all, these disinfectants only disinfect the causative virus and the causative bacteria, and do not act directly on the above-mentioned series of symptoms to quickly eliminate discomfort and pain. Absent.

  For the purpose of directly eliminating these symptoms, oral bactericides in the form of external preparations containing local anesthetics and vasoconstrictors, such as iodine-based bactericides, local anesthetics and polyhydric alcohols have been included. A composition for pharyngeal diseases (for example, see Patent Document 1), a medicinal composition (for example, see Patent Document 2) containing an iodine-based disinfectant containing a local anesthetic and a vasoconstrictor, and an iodine system A composition for pharyngeal diseases comprising a bactericide and a local anesthetic (for example, see Patent Document 3) has been proposed.

  However, the compositions described in these prior arts are used, although the pharmacological action of the local anesthetics and vasoconstrictors formulated therein can be used to alleviate discomfort and pain that appear in the pharynx. As a result, side effects such as nausea and drowsiness may be exhibited, and the problems related to safety in use have not been solved yet.

In addition, for the purpose of improving the palatability based on a viewpoint different from the composition using the above-mentioned local anesthetics or vasoconstrictors, it is used for the oral cavity using the refreshing action and flavoring effect of menthol. Compositions have also been proposed so far. For example, a liquid mouth refreshing agent (for example, see Patent Document 4) containing 0.5 to 2% by weight of menthol, 15 to 40% by weight of ethanol, and 1 to 20% by weight of xylitol; A composition for pharyngeal diseases that contains an organic acid-containing pH buffer and optionally contains menthol has been proposed (for example, see Patent Document 5). However, all of these compositions require a large amount of an organic solvent and a surfactant in order to stably solubilize menthol in the preparation. Therefore, unpleasant irritation and taste caused by these organic solvents and surfactants used to promote dissolution of menthol cannot be avoided, and eventually, the refreshing action and flavoring action exhibited by menthol is inhibited. However, the improvement of the palatability is still unsatisfactory, for example, the palatability of the whole preparation is impaired.
JP 09-151127 A JP 11-228387 A German Patent No. 3234350 JP 2000-178152 A JP 2000-229863 A

  The present invention quickly eliminates discomfort and pain in the pharynx without causing side effects such as nausea and drowsiness recognized in the above-mentioned prior art, and also has palatability and formulation stability. It is an object to provide an improved liquid composition.

  That is, the gist of the present invention is a liquid composition containing a multi-component liquid agent composed of terpene alcohol, polyhydric alcohol and lower alcohol, in particular, pharmaceutical stability that does not allow precipitation of terpene alcohol, particularly menthol. In the liquid composition.

  According to another aspect of the present invention, (1) a terpene alcohol and at least one alcohol solvent are mixed to prepare a liquid mixture, and (2) the liquid mixture and at least one alcohol solvent. Alternatively, there is provided a method for producing a liquid composition comprising a step of mixing a liquid solvent containing the alcohol solvent to prepare a multi-component liquid agent, and (3) mixing the multi-component liquid agent and an aqueous medium. .

  According to yet another aspect of the present invention, there is also provided an oropharyngeal drug comprising the above-described liquid composition of the present invention.

  According to the present invention, there is provided a liquid composition having an effect of promptly eliminating discomfort or pain generated in the pharynx without relying on a desired pharmacological component that causes side effects such as nausea and sleepiness. It is realized.

  In addition, the liquid composition of the present invention uses a combination of a polyhydric alcohol and a lower alcohol, thereby realizing a reduction in the use amount of an organic solvent, in particular, a lower alcohol that exhibits unpleasant irritation and taste. At the same time, the formulation stability at low temperatures is also improved.

  Furthermore, when the liquid composition of the present invention is applied to the pharynx, terpene alcohol, typically menthol, diffuses into the oral cavity, giving a good refreshing feeling.

  Thus, the liquid composition of the present invention synergistically exhibits many excellent effects in terms of not only medicinal efficacy but also palatability and formulation stability.

  The configuration of the liquid composition of the present invention will be described in detail below.

  According to one aspect of the present invention, there is provided a liquid composition comprising a multicomponent liquid agent comprising terpene alcohol, polyhydric alcohol and lower alcohol.

  Unless otherwise specified, the unit expressing the amount of the component of the liquid composition of the present invention such as terpene alcohol, polyhydric alcohol, lower alcohol, etc. is w / v% (weight / volume%) in the present specification. ).

  First, the terpene alcohol contained in the liquid composition of the present invention has an effect of reducing the discomfort and pain generated at the application site and applying a refreshing refreshing feeling when applied to the skin and mucous membranes. It is. In the liquid composition of the present invention, terpene alcohol generally used in oral products such as mouthwash, dentifrice, mouth freshener, gum, and candy, for example, menthol that can be mass-produced industrially , Linalool, borneol and the like can be suitably used as the terpene alcohol. Among these terpene alcohols, menthol or a derivative thereof is most preferable from the viewpoint that a refreshing feeling can be efficiently imparted to the pharynx.

  When the blending amount of the terpene alcohol in the liquid composition of the present invention increases, the refreshing feeling increased accordingly, while the irritation and bitterness exhibited by the terpene alcohol itself increase. In view of impairing the palatability of the liquid composition, it is usually about 0.01 to about 10.0 w / v%, preferably about 0.5 to about 3.0 w / v%, more preferably, with respect to the total liquid amount of the liquid composition. Is prepared in the range of about 1.0 to about 1.7 w / v%.

  The polyhydric alcohol used in the liquid composition of the present invention essentially refers to a chemical substance that functions as a solvent in the liquid composition of the present invention. In addition, this polyhydric alcohol is involved in maintaining the formulation stability of the liquid composition of the present invention, such as prevention of precipitation of terpene alcohol, and also contributes to the removal of discomfort and pain generated in the pharynx.

  Examples of such polyhydric alcohols include ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycerin, and diglycerin. It is not limited to these, Only any one of these can be used, or two or more can be used in combination. Among these polyhydric alcohols, propylene glycol, glycerin and a combination of both can be preferably used in the liquid composition of the present invention.

  By the way, the blending ratio of the polyhydric alcohol in the liquid composition of the present invention is usually the concentration of the liquid composition from the viewpoint of imparting good pharmaceutical stability to the liquid composition of the present invention. Of about 5.0 to about 120 w / v%, preferably about 35.0 to about 110 w / v% of the total liquid amount.

  Similarly, the lower alcohol used in the liquid composition of the present invention is also a chemical substance that functions as a solvent in the liquid composition of the present invention, and these are stable substances of the liquid composition of the present invention. Contribute to maintenance. As such a lower alcohol, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, and isopentanol can be used in the present invention. However, the present invention is not limited to these, and any of these can be used. Only one type can be used, or two or more types can be used in combination. Among these lower alcohols, ethanol can be suitably used in the liquid composition of the present invention.

  The lower alcohol used in the liquid composition of the present invention is inferior to propylene glycol and glycerin in terms of safety in a base having solubility in menthol, and is also observed when an excessive amount is taken. If the influence on a person etc. is considered, the mixture ratio of the lower alcohol used for a liquid composition should be as small as possible. In addition, generally, when the amount of the lower alcohol is increased, unpleasant irritation is exhibited in the mouth, and the bitterness is increased and the palatability is impaired. Under such circumstances, the concentration of the lower alcohol in the liquid composition is usually about 0.3 to about 75 w / v%, preferably about 3.0 to about 15.0 w / v%, based on the total liquid amount of the liquid composition. And most preferably from about 5.0 to about 10.0 w / v%.

  In addition, a bactericidal disinfectant that kills viruses and / or bacteria in the oral cavity can be added to the liquid composition of the present invention and used as an oropharyngeal drug. The term disinfectant used in the present specification refers to a chemical substance blended as a bactericidal component of an oropharyngeal drug or a mouthwash, such as iodine, potassium iodide, povidone iodine, cetylpyridinium chloride, decalinium chloride, Benzethonium chloride, benzalkonium chloride, chlorhexidine chloride, chlorhexidine gluconate, isopropylmethylphenol, triclosan, hinokitiol, phenol, thymol, creosote and the like can be used in the present invention, but are not limited to these. Any one of these may be used, or two or more may be used in combination. Among these disinfectants, iodine, potassium iodide and a combination of both can be suitably used in the liquid composition of the present invention.

  The blending ratio of these disinfectants in the liquid composition of the present invention is the same as in the case of lower alcohols. The disinfectant disinfectant also exhibits an unpleasant irritation in the mouth and increases the bitter taste as the blending amount increases. The concentration is usually adjusted in the range of about 0.01 to about 10.0 w / v%, preferably about 0.1 to about 5.0 w / v%, based on the total liquid volume of the liquid composition. .

  By the way, the terpene alcohol which is a component of the liquid composition of the present invention has already been sufficiently solubilized by the mixed polyhydric alcohol and lower alcohol, and the stability of the liquid composition has also been realized. Yes. However, a surfactant can optionally be added to further improve such solubilization and stability. For example, surfactants such as polyoxyethylene hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene polyoxypropylene copolymer, polysorbates, sodium lauryl sulfate and sucrose fatty acid ester Can be used in the present invention, but is not limited thereto, and any one of them can be used, or two or more can be used in combination.

  When the surfactant is used in the liquid composition of the present invention, the blending ratio is preferably a small amount as much as possible, and even if the amount is increased, when the blending amount is increased, unpleasant irritation is exhibited in the mouth. Since bitterness is also increased and palatability is impaired, the concentration is usually about 0.01 to about 30.0 w / v%, preferably about 0.01 to about 10.0 w / v, based on the total liquid volume of the liquid composition. Prepare in the range of v%.

  And unless it inhibits the effect of the liquid composition of the present invention, other components generally used in oral compositions, such as buffers, preservatives, fragrances, sweeteners, antioxidants , Pigments, enzymes, etc. can be optionally added to the multi-component solution.

  As the buffering agent, organic acids such as citric acid, malic acid, tartaric acid, fumaric acid, gluconic acid, and succinic acid, and salts thereof can be used in the present invention, but are not limited to these. Any one of these may be used, or two or more may be used in combination.

  Examples of preservatives include benzoic acids, salicylic acids, sorbic acids, parabens, cetylpyridinium chloride, decalinium chloride, benzethonium chloride, benzalkonium chloride, chlorhexidine chloride, chlorhexidine gluconate, isopropylmethylphenol, triclosan, hinokitiol, and phenol. Although it can utilize in this invention, it is not limited to these, Any one of these can be used, or 2 or more types can also be used together.

  As perfumes, spearmint oil, anise oil, eucalyptus oil, winter green oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, mint oil, cardamom oil, coriander oil, mandarin oil, lime oil, Natural fragrances such as lavender oil, rosemary oil, laurel oil, camomile oil, caraway oil, marjoram oil, bay oil, lemongrass oil, orina gum oil, pine needle oil; carvone, anethole, cineol, methyl salicylate, cinnamic aldehyde , Eugenol, thymol, linalool, linalyl acetate, limonene, menthone, menthyl acetate, pinene, octylaldehyde, citral, pulegone, carbyl acetate, anisaldehyde, etc .; A blended fragrance obtained by mixing a fragrance arbitrarily selected from a fragrance and / or a non-natural fragrance can be used in the present invention, but is not limited thereto, and only one of these is used. Or two or more types can be used in combination.

  As the sweetener, saccharin sodium, stevioside, aspartame, sucrose, fructose and the like can be used in the present invention. However, the present invention is not limited to these, and only one of these may be used or two of them may be used. The above can also be used together.

  As the antioxidant, vitamin C, vitamin E, sorbic acid (salt) and the like can be used in the present invention. However, the antioxidant is not limited to these, and only one of these may be used. Two or more types can be used in combination.

  Next, the manufacturing procedure of the liquid composition of the present invention will be described.

  The liquid composition of the present invention can be produced according to the following series of procedures.

  First, each of terpene alcohol, polyhydric alcohol, and lower alcohol is weighed. When using arbitrary components such as a disinfectant and a surfactant, they are also weighed in predetermined amounts.

  The liquid mixture is prepared by mixing the terpene alcohol after weighing and the whole or a part of the polyhydric alcohol and / or the lower alcohol. Next, an aqueous medium is added to the multi-component liquid obtained by mixing the obtained liquid mixture and another alcohol solvent, and the volume is adjusted to a quantitative value.

  By the way, this aqueous medium is mainly used for adjusting the volume of the liquid composition, but is used for preparing a bactericidal disinfecting component such as an aqueous solution of iodine or potassium iodide or an aqueous solution of an active component. It can also be used as a solvent. And as an aqueous medium, Preferably, water with little impurity content, for example, purified water, deionized water, distilled water etc., can be used suitably.

  Through this series of steps, the liquid composition of the present invention is prepared.

  In the case of using a disinfectant or a surfactant in the liquid composition of the present invention, the time point at which they are added to the preparation system is not particularly limited, taking into consideration the manufacturing conditions and properties to be given to the final product. Can be determined arbitrarily.

  By passing through these manufacturing procedures, a liquid composition is provided that is excellent in stability and that effectively removes discomfort and pain due to pharyngeal diseases, and gives a refreshing refreshing sensation in the oral cavity.

  The present invention will be described below with reference to examples thereof, but it is needless to say that the present invention should not be construed in a limited manner based on the disclosure of the examples.

A: Production of liquid composition Iodine, potassium iodide, propylene glycol, glycerin, l-menthol and ethanol were prepared, and each of these was weighed according to the amounts shown in Table 1 below. The liquid composition of 1-7 and the comparative example 1 was manufactured.

はじめに、ｌ−メントールとエタノールとを混合して液状混合物を調製した。 これとは別に、ヨウ素、ヨウ化カリウムおよび精製水（約１ml）を混合して殺菌消毒剤を調製した。 次に、得られた液状混合物と殺菌消毒剤とを合わせて得た混合物に、プロピレングリコールとグリセリンとを混合して多成分液剤を調製した。 そして、こうして得られた多成分液剤に精製水を加えて、100mlの定量値にまで体積調製し、これを混合して得られたものを液状組成物とした。

First, l-menthol and ethanol were mixed to prepare a liquid mixture. Separately, iodine, potassium iodide and purified water (about 1 ml) were mixed to prepare a disinfectant. Next, propylene glycol and glycerin were mixed into the mixture obtained by combining the obtained liquid mixture and the disinfectant, thereby preparing a multi-component liquid agent. Then, purified water was added to the multi-component liquid thus obtained to adjust the volume to a quantitative value of 100 ml, and this was mixed to obtain a liquid composition.

B: Examination of blending amount of terpene alcohol With respect to each of the liquid compositions of Examples 1 to 7 and Comparative Example 1 prepared in A above, each item of analgesic effect, mouth irritation, feeling of use and refreshing feeling according to the following assay method Was evaluated.

  Regarding the analgesic effect, 6 panelists applied about 0.3 ml of each liquid composition to the oropharyngeal head within 1 minute, with an analgesic effect (5 points), with a slight analgesic effect (4 points), and an analgesic effect. However, the evaluation was made according to the scoring criteria of vague and unclear (3 points), no analgesic effect (2 points), and no analgesic effect (1 point). The liquid composition having an average value of 1 point to less than 2.5 points is marked with x, the liquid composition having a score of 2.5 points to less than 3.5 points is marked with △, and 3.5 points. About the above-mentioned 5 points | pieces of liquid composition, (circle) was marked and graded.

  Regarding mouth irritation, 6 panelists applied about 0.3 ml of each liquid composition to the oropharyngeal head, and immediately thereafter, there was no unpleasant irritation to the oral mucosa (5 points), and no unpleasant irritation (4 The evaluation was performed according to the scoring criteria of a point), a feeling of irritation was vague and unclear (3 points), a little unpleasant stimulus (2 points), and an unpleasant stimulus (1 point). The average value of the liquid composition having a score of 1 to less than 2.5 points is indicated by X, the liquid composition having a value of 2.5 points to less than 3.5 points is indicated by Δ, and 3.5 points. About the above-mentioned 5 points | pieces of liquid composition, (circle) was marked and graded.

  Regarding the feeling of use, 6 panelists applied about 0.3 ml of each liquid composition to the oropharyngeal head, and the feeling of feeling immediately after that was good (5 points), slightly good (4 points), normal ( Evaluation was performed according to the scoring standards of 3 points), slightly bad (2 points), and bad (1 point). The average value of the liquid composition having a score of 1 to less than 2.5 points is indicated by X, the liquid composition having a value of 2.5 points to less than 3.5 points is indicated by Δ, and 3.5 points. About the above-mentioned 5 points | pieces of liquid composition, (circle) was marked and graded.

  Regarding the refreshing feeling, 6 panelists applied about 0.3 ml of each liquid composition to the oral and pharyngeal head, and immediately after that, the refreshing feeling that diffused in the oral cavity was too strong (5 points) and slightly strong (4 Evaluation was performed according to the scoring standards of (point), refreshing (3 points), slightly weak (2 points), and weak (1 point). And about the liquid composition whose average value is 1 point-less than 1.5 point x mark, 1.5 mark or more about the liquid composition less than 2.5 point | point, 2.5 mark or more- For a liquid composition of less than 3.5 points, a circle mark, for a liquid composition of 3.5 points or more to less than 4.5 points, a triangle mark, and for a liquid composition of 4.5 points or more to 5 points Grading was performed with a cross.

  The evaluation results are summarized in Table 2 below.

表２に記載の結果から、比較例１の液状組成物にあっては効果的な鎮痛効果や清涼感が認められず、その使用感も満足のゆくものでもなかった。 これに対して、実施例１〜７に記載の液状組成物は使用感に優れ、しかも咽頭部に生じた不快感が効果的に解消されており、良好な鎮痛効果を発現することが明らかとなった。 とりわけ、実施例１〜４に記載の液状組成物にあっては、前述の良好な鎮痛効果や使用感以外にも、口内刺激が穏やかで、しかも、口腔内に清涼感が効果的に付与されていることが明らかとなった。

From the results shown in Table 2, in the liquid composition of Comparative Example 1, an effective analgesic effect and a refreshing feeling were not recognized, and the feeling of use was not satisfactory. On the other hand, it is clear that the liquid compositions described in Examples 1 to 7 are excellent in feeling of use, and the discomfort generated in the pharynx is effectively eliminated and a good analgesic effect is expressed. became. In particular, in the liquid compositions described in Examples 1 to 4, in addition to the above-described good analgesic effect and feeling of use, the mouth irritation is mild and a refreshing feeling is effectively imparted to the oral cavity. It became clear that.

  From this, in the liquid composition of the present invention, the blending amount of 1-menthol (terpene alcohol) is 0.50 to 3.00 w / v%, preferably 0.50 to 1.70 w of the liquid composition. It has been found that it is preferred to prepare in the range of / v%, most preferably in the range of 1.00 to 1.70 w / v%.

C: Examination of blending amount of lower alcohol Iodine, potassium iodide, propylene glycol, glycerin, l-menthol (0.50 w / v% fixed concentration), ethanol (concentration from 3.00 w / v% to 15.00 w / v%) And purified water was prepared. And each of these was weighed according to the amount described in Table 3 below, and the analgesic effect according to the method described in A above for the liquid compositions of Examples 8 to 12 obtained according to the method described in A above. Each item of mouth irritation, feeling of use and refreshing feeling was evaluated. Moreover, about the liquid composition of Examples 8-12, it evaluated also about the formulation stability according to the following test methods.

  About formulation stability, about 20g was put into each of three glass containers (glass container with a lid) about each liquid composition. Next, these glass containers were put in a refrigerator set at 4 ° C. and allowed to stand there for 48 hours. Regarding l-menthol in a glass container that had been allowed to stand for 48 hours, precipitation of l-menthol was observed in one or two containers for liquid compositions in which all three containers were observed. The liquid composition was graded with a Δ mark and the liquid composition that was not recognized in any container with a circle mark. The evaluation results for each of these items are also summarized in Table 3 below.

表３に記載の結果から、嗜好性を損なわずに、咽頭部に生じた不快感を解消せしめ、しかも製剤的安定性に優れた液状組成物を得る上で、低級アルコールの配合量としては、液状組成物の３.０〜15.０w/v％の範囲の濃度が好適に利用できることが判明した。

From the results shown in Table 3, in order to eliminate the discomfort generated in the pharynx without impairing palatability, and to obtain a liquid composition excellent in pharmaceutical stability, It has been found that concentrations in the range of 3.0 to 15.0 w / v% of the liquid composition can be suitably used.

D: Examination of blending amount of polyhydric alcohol From the results of Tables 1 to 3 above, a liquid composition excellent in pharmaceutical stability that can eliminate discomfort generated in the pharynx without impairing palatability It was found that the amount of polyhydric alcohol (mixed system of propylene glycol and glycerin) is preferably adjusted to a concentration in the range of 80.0 to 30.40 w / v% of the liquid composition. This is nothing but an indication that the desired effect can be obtained even when the polyhydric alcohol is added to the liquid composition of the present invention at a high concentration of about 110 w / v%.

  Based on the test results, iodine, potassium iodide, propylene glycol, glycerin, l-menthol (fixed concentration of 0.50 w / v%), ethanol and purified water were prepared. With respect to the liquid compositions of Examples 13 to 16 and Comparative Examples 2 to 3 obtained according to the method described in A above, the pharmaceutical stability was evaluated according to the method described in C above. Went. The evaluation results are also summarized in Table 4 below.

表４の結果から、液状組成物の製剤的安定性を好適に維持する上で、多価アルコールの配合量としては、少なくとも液状組成物の35.00w/v％の濃度に調製することが好ましいことが判明した。

From the results of Table 4, it is preferable that the blending amount of the polyhydric alcohol is preferably adjusted to a concentration of at least 35.00 w / v% of the liquid composition in order to suitably maintain the pharmaceutical stability of the liquid composition. There was found.

  The liquid composition of the present invention is useful as a means for quickly removing discomfort or pain perceived by the pharynx and easily imparting a refreshing refreshing feeling to the oral cavity.

Claims (2)

Contains no local anesthetic and vasoconstrictor, water , 1.0-2.5 w / v% menthol, 5.0-50 w / v% propylene glycol, 5.0-90 w / An oropharyngeal drug comprising v% glycerin, 3.0-15.0 w / v% ethanol and 0.01-10.0 w / v% iodine and / or potassium iodide. The oropharyngeal drug according to claim 1, wherein the blending amount of ethanol is 3.0 to 5.0 w / v% with respect to the total liquid volume.