JP5211677B2 - Oral solution - Google Patents

Description

  The present invention relates to a low-calorie, low-cariogenic diphenhydramine-containing sleep-improving sleep fluid that has excellent antiseptic power against various fungi and fungi, has high stability of diphenhydramine, and has good taste and flavor. Specifically, the present invention relates to a sleep improving oral solution containing diphenhydramine and / or a salt thereof, benzoic acid and / or a salt thereof, and erythritol and having a pH of 3.8 to 4.2.

Diphenhydramine is a highly safe drug that has been widely used as a histamine H1 receptor antagonist (antihistamine) regardless of whether it is used internally or externally. Moreover, since it suppresses the action of histamine involved in maintaining arousal, it is known to exhibit hypnotic sedation. Diphenhydramine has a particularly strong hypnotic sedative effect among antihistamines and is also used as an OTC drug for the purpose of introducing sleep in Europe and the United States.
In recent years, in Japan, over-the-counter drugs that do not require a doctor's prescription are widely used as various medicinal properties and various dosage forms, such as sleep-improving drugs, motion sickness (antipruritic drugs), and skin itching prevention Patent Documents 1 to 3).

The sleep-improving agent is usually taken before going to bed because of its use, but in order to simplify the medication and expect immediate effects, the development of a liquid for internal use has been desired.
However, diphenhydramine salts represented by diphenhydramine and diphenhydramine hydrochloride are drugs that have specific bitterness and a specific taste that paralyzes the tongue, and are not very suitable for taking unless the bitterness and taste are masked.
In the case of tablets, the bitterness of these tablets and the specific taste that paralyzes the tongue are masked by adding structural ingenuity such as sugar-coated tablets, film-coated tablets, and chewable tablets (see Patent Document 1).
However, when this drug is used as a liquid for internal use, it is necessary to consider the balance with other ingredients, and masking is very difficult.

In general, a drug having such a bitter taste is usually masked with a large amount of sugars in order to make it easier to take. For example, it is difficult for children to take capsules, tablets, powders and other dosage forms, so pediatric syrups are widely used to improve compliance, but large amounts of sugar are added to make them easier to drink. (See Non-Patent Document 4).
However, if a masking method using a sweetener such as sugar is used, a high-calorie beverage is taken before going to bed. In recent years, emphasis has been placed on prevention of metabolic syndrome in which visceral fat accumulates due to overeating and lack of exercise, and is associated with multiple lifestyle-related diseases such as hypertension, hyperlipidemia, and diabetes. Therefore, even if it has an effect as a sleep improving agent, it is not desirable to be anxious about obesity and metabolic syndrome. Furthermore, if you take it before going to bed and go to bed as it is, you will also have a problem of caries, and you will need to brush your teeth again after taking to prevent tooth decay.

In addition, it is known that the internal solution of diphenhydramine hydrochloride progresses particularly in the acidic region of low pH, and it is necessary to raise the pH to some extent, but in the liquid, bacteria can propagate compared to other drug types. It is necessary to provide antiseptic power. Therefore, parabens that exhibit stable antiseptic power even in a high pH range are widely used (see Patent Document 2).
However, since parabens have a peculiar taste, there is a drawback that the flavor of the liquid agent becomes worse. In particular, in the diphenhydramine solution, the taste is further significantly reduced in combination with the bitter taste of diphenhydramine itself.
In addition, ethyl paraoxybenzoate, butyl paraoxybenzoate, and propyl paraoxybenzoate, which are widely used in oral liquid preparations, are suspected of being environmental hormone substances (endocrine disrupting chemical substances). It has been suggested that environmental hormones, when they enter the human body, can be linked to the hormones in the body and disrupt the normal hormonal balance. In experiments with rats, it has been reported that this paraben has an effect of reducing sperm (Non-patent Document 5).

For this reason, in order to take it more safely as a drug, it has sufficient antiseptic power without using parabens while ensuring the stability of diphenhydramine, and on top of that, the bitter taste of diphenhydramine and the tongue There has been a demand for a sleep-improving agent that is masked for numbness and that can be easily taken immediately before going to bed.
JP 2002-138034 A JP 2003-095933 A "Driel package insert" SS Pharmaceutical Co., Ltd. "Travelmin attached document" Eisai Co., Ltd. “Lanakane S package insert” Kobayashi Pharmaceutical Co., Ltd. Fifteenth revision Japanese Pharmacopoeia Manual General Formulation Syrup "Abstracts of the 3rd meeting of the Environmental Hormone Society"("Effects of Paraben on the male rat gonadal system" Toxicology Department, Tokyo Metropolitan Institute of Health

An object of the present invention is to provide a diphenhydramine-containing sleep-improving oral liquid composition that is excellent in antiseptic power against various fungi and molds, has high stability of diphenhydramine, and has good taste and flavor. Specifically, the present invention relates to a sleep improving oral solution containing diphenhydramine and / or a salt thereof, benzoic acid and / or a salt thereof, and erythritol and having a pH of 3.8 to 4.2.
It is another object of the present invention to provide a sleep-improving oral solution with improved compliance from the viewpoint of low calorie and caries, considering taking before bedtime.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have improved sleep at pH 3.8 to 4.2 containing diphenhydramine and / or its salts, benzoic acid and / or its salts and erythritol. It has been found that by using an internal solution, an internal solution having excellent antiseptic power against various fungi and fungi, high stability of diphenhydramine, and good taste and flavor can be obtained.
Moreover, by setting the content of erythritol to 5 to 20 W / V%, an internal liquid preparation masking the bitter taste of diphenhydramine and / or a salt thereof can be obtained without causing low calorie and caries problems. As a result, the present invention has been completed.

That is, this invention is an internal use liquid agent hung up to the following [1]-[5].
[1] An agent for improving sleep of pH 3.8 to 4.2 containing diphenhydramine and / or a salt thereof, benzoic acid and / or a salt thereof, and erythritol
[2] The sleep improving oral solution according to [1], wherein the content of erythritol is 5 to 20 W / V%.
[3] The liquid for improving sleep according to [1] or [2], which does not contain parabens.
[4] The sleep improving liquid preparation according to [1], [2] or [3], further comprising at least one selected from sucralose and / or acesulfame potassium.
[5] The sleep improving oral solution according to [1], [2], [3] or [4], wherein energy per 100 mL is 20 kcal or less.

  The internal liquid preparation in the present invention is not particularly limited, for example, a drink prepared by the same method as a vitamin-containing health medicine classified as a commonly used pharmaceutical product, a newly designated quasi-drug, etc. Point to.

  The diphenhydramine and / or salts thereof used in the present invention may be those used in ordinary pharmaceuticals. For example, diphenhydramine hydrochloride listed in the 15th revised Japanese pharmacopoeia can be used. The concentration of diphenhydramine and / or a salt thereof is preferably in the range of 0.01 to 1.0 W / V%, particularly preferably 0.08 to 0.5 W / V%. When the concentration of diphenhydramine and / or its salt is less than 0.01 W / V%, the sleep-improving effect cannot be sufficiently exerted. On the other hand, when the concentration of diphenhydramine and / or its salt is more than 1.0 W / V%, This is not preferable because the taste is impaired.

  The benzoic acid and / or salt thereof used in the present invention may be any benzoic acid and / or salt thereof as long as it is used in ordinary pharmaceuticals. For example, sodium benzoate listed in the 15th revised Japanese pharmacy law can be used.

The erythritol used by this invention should just be used for a normal pharmaceutical, for example, a pharmaceutical additive specification listed product can be used. The concentration of erythritol is preferably in the range of 5 to 20 W / V%, particularly preferably in the range of 7 to 15 W / V%.
If the concentration of erythritol is less than 5 W / V%, the effect of suppressing the bitter taste of diphenhydramine and the specific taste that numb the tongue is reduced. Furthermore, the antiseptic effect of the internal use liquid preparation of the said invention also falls. On the other hand, if the concentration of erythritol is higher than 20 W / V%, a problem arises in terms of solubility, and the production method becomes complicated, which is not preferable.

  In the present invention, a high sweetener can be added as necessary. For example, sucralose, acesulfame potassium, thaumatin, rahan fruit, stevia, saccharin and the like can be used. Among these, sucralose has a particularly improved flavor, and acesulfame potassium or a combination of these two types also improves the flavor.

  When sucralose is used, it may be used as long as it is used for ordinary pharmaceuticals, and for example, a pharmaceutical additive standard listed product can be used. The concentration of sucralose is preferably in the range of 0.03 to 0.3 W / V%, particularly preferably 0.05 to 0.2 W / V%. When the sucralose concentration is 0.03 W / V%, the effect of suppressing the bitter taste of diphenhydramine and the specific taste that paralyzes the tongue is poor, and when the sucralose concentration is higher than 0.3 W / V%, the sweetness is too strong. It is not preferable.

  When acesulfame potassium is used, it may be used as long as it is used for ordinary pharmaceuticals. The concentration of acesulfame potassium is desirably in the range of 0.03 to 0.6 W / V%, particularly preferably 0.06 to 0.4 W / V%. If the concentration of acesulfame potassium is less than 0.03 W / V%, it is difficult to suppress the bitter taste of diphenhydramine and the specific taste that paralyzes the tongue, and the concentration of acesulfame potassium is more than 0.6 W / V%. And the sweetness is too strong, and the flavor of the oral solution is impaired.

  Parabens in the present invention are alkyl esters of paraoxybenzoic acid, and the alkyl ester has 2 to 4, for example, ethyl paraoxybenzoate, propyl paraoxybenzoate or paraoxybenzoic acid listed in the 15th revised Japanese Pharmacopoeia. Examples include butyl.

  The low calorie in the present invention means “energy” of nutritional component labeling defined by the nutrition labeling standard based on Article 31 of the Health Promotion Act, and is the same as the standard in the case of emphasizing that the nutritional component is scarce. That is, the energy per 100 mL is 20 kcal or less. In the present invention, “energy” is preferably 10 kcal or less, more preferably less than 7 kcal.

  In addition to sweeteners, additives as shown below can be added to the internal liquid preparation of the present invention as necessary in order to improve the taste and flavor as needed. That is, examples include sour agents such as citric acid, tartaric acid, malic acid, and lactic acid, flavoring agents, stabilizers, solubilizers, pH adjusters, thickeners, thickeners, and fragrances. These may be used alone or in combination of two or more. These components are desirably blended appropriately in amounts used in conventional oral solutions.

  The thus obtained sleep-improving oral solution containing diphenhydramine and / or a salt thereof of the present invention satisfies both antiseptic power and stability, and is a liquid agent, so it has high compliance, and is low in calories and low. Because it is tactile, it is very suitable for taking before bedtime.

(Method for preparing oral solution)
The method for preparing the internal liquid preparation of the present invention is not particularly limited, and various components necessary for preparing a normal internal liquid preparation can be appropriately selected and blended and prepared by a conventional method.
Usually, each component and a part of purified water are mixed and dissolved. If necessary, dissolve by heating to obtain the optimum pH of the preparation. After the adjustment, it may be filtered as necessary to remove insoluble matters.

  Next, although an Example and a comparative example are given and this invention is demonstrated concretely, this invention is not limited to these Examples.

[Example 1]
In 400 mL of heated purified water, 90 g of erythritol was stirred and dissolved. 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, and sucralose 6 g, caramel 0.75 g and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 3.8, and the total volume is adjusted to 900 mL with purified water. This apparatus was filtered using a device with a filter paper as a filter layer, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Example 2]
In 400 mL of heated purified water, 90 g of erythritol was stirred and dissolved. 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, and sucralose 6 g, caramel 0.75 g and a fragrance are sequentially added while stirring, and after confirming dissolution, the pH is adjusted to 4.0, and the total volume is adjusted to 900 mL with purified water. This apparatus was filtered using a device with a filter paper as a filter layer, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Example 3]
In 400 mL of heated purified water, 90 g of erythritol was stirred and dissolved. 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, and sucralose 6 g, 0.75 g of caramel and a fragrance are sequentially added with stirring. After confirming dissolution, the pH is adjusted to 4.2, and the total volume is adjusted to 900 mL with purified water. This apparatus was filtered using a device with a filter paper as a filter layer, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Example 4]
In 400 mL of warm purified water, 45 g of erythritol was stirred and dissolved. 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, and sucralose 6 g, caramel 0.75 g and a fragrance are sequentially added while stirring, and after confirming dissolution, the pH is adjusted to 4.0, and the total volume is adjusted to 900 mL with purified water. This apparatus was filtered using a device with a filter paper as a filter layer, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Example 5]
In 400 mL of heated purified water, 180 g of erythritol was stirred and dissolved, and 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, and 0.1% of sucralose. 6 g, caramel 0.75 g and a fragrance are sequentially added while stirring, and after confirming dissolution, the pH is adjusted to 4.0, and the total volume is adjusted to 900 mL with purified water. This apparatus was filtered using a device with a filter paper as a filter layer, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Example 6]
In 400 mL of heated purified water, 90 g of erythritol was dissolved with stirring. 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, acesulfame potassium 1 .2 g, caramel 0.75 g and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 4.0, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Example 7]
In 400 mL of heated purified water, 90 g of erythritol was stirred and dissolved, and 0.63 g of sodium benzoate, 4.5 g of sodium citrate, 2.85 g of citric acid, 3.6 g of malic acid, 0.45 g of diphenhydramine hydrochloride, and 0.4% of sucralose. 27 g, acesulfame potassium 0.27 g, caramel 0.75 g and a fragrance were sequentially added with stirring, and after confirming dissolution, the pH was adjusted to 4.0, and the total volume was adjusted to 900 mL with purified water. This apparatus was filtered using a device with a filter paper as a filter layer, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Example 8]
In 400 mL of heated purified water, 135 g of erythritol was stirred and dissolved. 0.63 g of sodium benzoate, 11.4 g of sodium citrate, 5.7 g of citric acid, 8.4 g of malic acid, 6 g of diphenhydramine hydrochloride, 1.5 g of sucralose, 2.4 g of acesulfame potassium, 0.9 g of caramel and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 4.0, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

  The following table summarizes the above examples.

[Comparative Example 1]
After adding 0.063 g of butyl paraoxybenzoate to 400 mL of purified water and dissolving with heating and stirring, 90 g of erythritol, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, 0.6 g of sucralose, 0.75 g of caramel and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 4.0, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 2]
After adding 0.126 g of butyl paraoxybenzoate to 400 mL of purified water and dissolving with heating and stirring, 90 g of erythritol, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, 0.6 g of sucralose, 0.75 g of caramel and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 4.0, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 3]
To 400 mL of purified water, 0.18 g of butyl paraoxybenzoate was added and dissolved by stirring with heating. Then, 90 g of erythritol, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, 0.6 g of sucralose, 0.75 g of caramel and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 5.0, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 4]
In 400 mL of heated purified water, 90 g of erythritol was stirred and dissolved. 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, and sucralose 6 g, caramel 0.75 g and a fragrance are sequentially added while stirring, and after confirming dissolution, the pH is adjusted to 3.6, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 5]
In 400 mL of heated purified water, 90 g of erythritol was stirred and dissolved. 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, and sucralose 6 g, caramel 0.75 g and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 4.3, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 6]
In 400 mL of heated purified water, 90 g of erythritol was stirred and dissolved. 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, and sucralose 6 g, 0.75 g of caramel and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 4.6, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 7]
To 400 mL of heated purified water, 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, 0.6 g of sucralose, 0.75 g of caramel, After adding the fragrance | flavor sequentially, stirring, after confirming melt | dissolution, after adjusting pH to 4.0, it is made up to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 8]
In 400 mL of heated purified water, 90 g of D-sorbitol was stirred and dissolved, and 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, 0.6 g of sucralose, 0. 75 g and a fragrance are sequentially added while stirring, and after confirming dissolution, the pH is adjusted to 3.5, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 9]
In 400 mL of heated purified water, 240 g of D-sorbitol was dissolved with stirring, 240 g of amalty syrup, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, 1.5 g of diphenhydramine hydrochloride, 0. 75 g and a fragrance are sequentially added while stirring, and after confirming dissolution, the pH is adjusted to 4.0, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 10]
After adding 0.063 g of butyl paraoxybenzoate to 400 mL of purified water and dissolving with heating and stirring, erythritol 30 g, sodium citrate 7.2 g, citric acid 3.45 g, malic acid 4.5 g, diphenhydramine hydrochloride 1.5 g, 0.6 g of sucralose, 0.75 g of caramel and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 4.4, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

[Comparative Example 11]
After adding 300 g of white sugar to 400 mL of purified water and dissolving with heating and stirring, 30 g of amalty syrup, 0.63 g of sodium benzoate, 7.2 g of sodium citrate, 3.45 g of citric acid, 4.5 g of malic acid, diphenhydramine hydrochloride 1.5 g, sucralose 0.15 g, caramel 0.75 g and a fragrance are sequentially added with stirring, and after confirming dissolution, the pH is adjusted to 4.0, and the total volume is adjusted to 900 mL with purified water. The preparation was filtered using a filter paper filter device, filled in a 30 mL brown bottle, capped, and sterilized at 85 ° C. for 15 minutes.

  The table shown below is a table summarizing the above comparative examples.

[Test Example 1] Stability test (residual rate)
The oral liquids obtained in Examples 1 to 8 and Comparative Examples 1 to 10 were stored at 40 ° C. for 2, 4 and 6 months, and then the content of diphenhydramine hydrochloride was measured. In addition, diphenhydramine hydrochloride was quantified by a reverse phase partition high performance liquid chromatography method. .

After the measurement, the residual ratio of diphenhydramine hydrochloride was calculated by the following formula.
Residual rate (%) = Ws / Wo × 100
Ws: Diphenhydramine hydrochloride content after 40 ° C, 2, 4 and 6 months Wo: Diphenhydramine hydrochloride content immediately after production

The results of the above stability test are shown in Table 3 below.
As is apparent from the results in Table 3, in Comparative Examples 4 and 8 in the pH range lower than pH 3.8, the temporal stability of diphenhydramine hydrochloride was deteriorated and a decrease in the content was observed.

[Test Example 2] Preservative Efficacy Test Concerning the internal use liquids of the prescriptions of Examples 1 to 8 and Comparative Examples 1 to 10, the preservative efficacy test was conducted according to the Fifteenth Amendment Japanese Pharmacopoeia Reference Information Carried out. In the case of this test, bacteria of Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeru), Staphylococcus aureus (S. aureu) and Aspergillus niger (A. b. Al. The number of viable bacteria and the number of viable bacteria on the 14th day were counted and the reduction rate was calculated.

The results of the above preservation efficacy test are shown in Table 4 below.
As is clear from the results in Table 4, in Comparative Example 5 and Comparative Example 6 in a pH range higher than pH 4.2, the storage efficacy against a given bacterium was reduced.
Moreover, in the comparative example 7 which does not mix | blend erythritol, an effect becomes a little weak. In Comparative Example 8 and Comparative Example 9 in which no preservative such as sodium benzoate or parabens was blended, no preservative effect was observed.

[Test Example 3] Flavor Test Evaluations were made on the “flavor” and “sweetness / acidity balance” of each composition of Examples 1 to 8 and Comparative Examples 1 to 10 by 20 evaluation panels. Evaluation of “flavor” and “sweetness / acidity balance” was carried out after each sample was put in the mouth, after confirming the flavor, and then exhaling in a sink.

The results of the above flavor test are shown in Table 5 below.
As is clear from the results in Table 5, in Examples 1 to 8, 12 or more (60% or more) as the reference responded that both flavor and sweetness / acidity balance were good. Comparative Examples 1 to 3, butyl paraben blended, erythritol or sucralose, or Comparative Examples 7 to 9 blended with neither butyl paraben In Comparative Example 10 blended with butyl paraben and containing less erythritol than the present invention, flavor, sweetness -The evaluation of the balance of sourness was less than 60%.

Comprehensive evaluation was performed based on the above Test Examples 1 to 3. Each test example was evaluated according to the following evaluation criteria.

[Evaluation criteria of Test Example 1]
○: Diphenhydramine residual rate after storage at 40 ° C. for 6 months is 95% or more Δ: Diphenhydramine residual rate after storage at 40 ° C. for 6 months is 90% or more and less than 95% ×: After storage at 40 ° C. for 6 months Diphenhydramine residual rate is less than 90%

[Evaluation criteria of Test Example 2]
○: The ratio of the number of bacteria after 2 weeks of culture for each ingested bacteria is 1% or less,
Or the ratio of the number of bacteria after 2 weeks of culture for each fungus is 1% or less
Δ: The ratio of the number of bacteria after culturing for 2 weeks to each ingested bacteria is 10% or less,
Or the ratio of the number of bacteria after 2 weeks of culture for each fungus is below the level of the number of ingested bacteria
X: The ratio of the number of bacteria after 2 weeks of culture for each ingested bacteria exceeds 10%,
Or the ratio of the number of bacteria after 2 weeks culture | cultivation with respect to each fungus exceeds the level of the number of ingested bacteria.

[Evaluation criteria of Test Example 3]
A: More than 14 out of 20 panelists answered that both the flavor and sweetness / acidity balance factors were good.
○: Among 20 people, 12 or more panels were evaluated as good.
X: When the panel evaluated as favorable among 20 persons is 11 persons or less.

  Table 6 below summarizes the results of the comprehensive evaluation described above. Those that met all of the evaluation criteria were evaluated as comprehensive evaluation ○. Moreover, since even one that does not meet the evaluation criteria cannot be used as the pharmaceutical product of the present invention, the overall evaluation is x.

Test Example 4 Measurement and Evaluation of Blood Glucose Levels of Example 2 and Comparative Example 11 1.5 mL of Comparative Example 11 using the low-calorie liquid of Example 2 and sucrose in mice after 12-hour fasting (6 mice per group) / Kg equivalent was administered, and changes in blood glucose level up to 120 minutes after administration were measured every 30 minutes. It was confirmed that the increase in blood glucose level in Example 2 was extremely low as compared with the administration group of Comparative Example 11.

上記の測定値をグラフ化したものを下記の図１に示す。
［図１］

The measured values are shown in Table 7 below.

A graph of the above measured values is shown in FIG.
[Figure 1]

Claims (4)

A sleep improving oral solution having a pH of 3.8 to 4.2 , which contains diphenhydramine and / or a salt thereof, benzoic acid and / or a salt thereof, and erythritol and does not contain a paraben .   The sleep-improving oral solution according to claim 1, wherein the content of erythritol is 5 to 20 W / V%. Furthermore, the internal use liquid for sleep improvement of Claim 1 or 2 containing 1 or more types chosen from sucralose and / or acesulfame potassium. The sleep improvement internal use liquid agent in any one of Claims 1-3 whose energy per 100 mL is 20 kcal or less.