JP2000273051A - Liquid preparation whose bitter taste is masked - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a liquid preparation which contains a medicinal ingredient having a bitter taste and gives a significantly improved oral administration touch, by rapidly and continuously masking the bitter taste of the medicinal ingredient. SOLUTION: This oral liquid preparation comprises a bitter medicine, and (i) at least one of aspartame and saccharine sodium, (ii) at least one of stevia, raw sugar and caramel, and (iii) a licorice extract. The oral liquid preparation also comprises dihydrocodeine phosphate and potassium guaiacol sulfonate as medicinal ingredients, and aspartame, stevia, a licorice extract, a sugar alcohol, glycerol and raw sugar or caramel.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to improving the taste of pharmaceutical products. More specifically, the present invention relates to an oral liquid preparation which has improved discomfort due to oral administration by masking the bitterness of a drug early and continuously and which has excellent taste.

[0002]

2. Description of the Related Art It is effective to take a medicine containing an antitussive / expectorant, a bronchodilator or the like in a liquid form such as syrup in order to alleviate and improve cough and pale symptoms. However, most of these drugs have bitterness, making them extremely difficult to take in liquid form.

[0003] Therefore, as a method of masking the bitterness of a liquid preparation with bitterness, sucrose has been conventionally added to a drug. However, since a large amount of sucrose is required to mask bitterness, the sucrose becomes unnecessarily sweet, and on the contrary, there is a problem that the feeling of taking the drug is worsened and the sugar content and the calorie are increased. In this case, in order to mask the bitterness of the target drug in a range of sweetness that can be tolerated, a method of reducing the drug concentration in the liquid per administration can be considered. However, in order to reduce the drug concentration and to administer an effective amount, it is necessary to increase the dose of the liquid preparation, which results in an increased burden on the breather.

[0004] In order to improve such problems, the use of high-intensity sweeteners such as stevia in place of sucrose has been studied (JP-A-9-20654 and JP-A-9-20654).
No. 52849).

[0005] However, stevia is not always effective for masking a drug that rapidly develops bitterness in the oral cavity, because stevia has a relatively slow development of sweetness and is in a liquid form. Early (see experimental example below). Similarly, sodium saccharin, which is a sweetener having a high degree of sweetness, has a problem that, although the sweetness is expressed relatively quickly, the sweetness is heavy and the unpleasant aftertaste of the sweetness remains. Furthermore, aspartame expresses sweetness very quickly, but its disappearance is also rapid (see Experimental Examples described later).

[0006]

DISCLOSURE OF THE INVENTION The present invention relates to a liquid preparation containing a drug which originally has bitterness, wherein the bitterness is masked quickly and continuously so that the feeling of taking is significantly improved. It is intended to provide a pharmaceutical composition. Further, the present invention provides a liquid preparation excellent in flavor (taste), in particular, a liquid pharmaceutical composition containing one or more components such as an antitussive component, an expectorant component, an antihistamine component, an analgesic component, and a bronchodilator. The purpose is to:

DISCLOSURE OF THE INVENTION The present inventors have found that a liquid preparation for oral administration containing a bitter component expresses bitterness in the oral cavity immediately after administration, particularly on the basis of its liquid dosage form, and causes bitterness in the mouth. Paying attention to the fact that remains, and various studies have been repeated with the aim of improving the feeling of taking the liquid preparation, according to the sweetener composition in which various sweeteners having unique sweetness characteristics are variously combined. It has been found that sweetness develops and persists quickly, and that such sweetness properties are effective in masking the bitterness inherent in the above liquid preparations.

[0007] Further, the present inventors can mask the bitter component contained in a liquid preparation from the initial stage to a long period, and further improve the taste of the preparation by using a specific sweetener combination. It has been found that a preparation excellent in palatability and feeling of taking can be prepared. The present invention
It was developed based on such knowledge.

[0008] That is, the present invention is an oral liquid preparation described in the following (1) to (7). (1) a drug having bitterness, (i) at least one of aspartame or saccharin sodium, (ii) at least one selected from the group consisting of stevia, brown sugar and caramel,
And (iii) an oral liquid preparation containing a liquorice extract. (2) The liquid preparation according to (1), further containing at least one of sugar alcohol and glycerin. (3) An oral liquid preparation containing a bitter drug, aspartame, saccharin sodium, stevia, licorice extract, sugar alcohol, glycerin and brown sugar or caramel. (4) The oral liquid preparation according to (1) or (2), wherein the sugar alcohol is D-sorbitol. (5) The oral liquid preparation according to any one of (1) to (4), wherein the drug belongs to any of an antitussive, an expectorant, a bronchodilator, an antihistamine and an analgesic. (6) The drug is dihydrocodeine phosphate, potassium guaiacol sulfonate, dextromethorphan hydrobromide, tipepidine citrate, alloclamide hydrochloride, cloperastine hydrochloride, sodium dibnate, dl-methylephedrine hydrochloride, noscapine hydrochloride, guaifenesin, cresol sulfonic acid The oral liquid preparation according to (5), which is at least one selected from the group consisting of potassium, chlorpheniramine maleate, caffeine, caffeine anhydride, and acetylsalicylic acid. (7) The oral liquid preparation according to any one of (1) to (4), wherein the drug is at least one selected from the group consisting of dihydrocodeine phosphate, potassium guaiacol sulfonate, and dextromethorphan hydrobromide. .

Further, the present invention provides the following (8) or (9)
And a bitter masking agent for a bitter drug. (8) (i) at least one of aspartame or saccharin sodium, (ii) at least one selected from the group consisting of stevia, brown sugar and caramel,
And (iii) a bitter masking agent for a bitter drug, which contains a liquorice extract. (9) A bitter masking agent for a bitter drug, which contains aspartame, stevia, licorice extract, sorbitol, glycerin and brown sugar or caramel. The masking agent may further contain saccharin sodium.

[0010] The drugs targeted by these bitterness masking agents are not particularly limited, but include, for example, the aforementioned drugs, preferably antitussives or expectorants.

[0011] Conventionally, it has been desired to reduce the amount of a pharmaceutical solution per dose. However, according to the present invention, the bitterness of a drug is significantly masked, so that an effective drug effect can be obtained with a small dose. It is possible to provide a liquid preparation which is excellent in taking feeling to exert, especially a liquid preparation having an antitussive or expectorant action.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The oral liquid preparation of the present invention contains at least (i) at least one of aspartame or sodium saccharin, and (ii) stevia, brown sugar and It is characterized by containing at least one selected from the group consisting of caramel and (iii) liquorice extract.

Aspartame is a dipeptide (α-L-aspartyl-L-phenylalanine methyl ester) composed of aspartic acid and phenylalanine, and is used as an artificial sweetener having a high sweetness approximately 200 times that of sucrose as a food and medicine, Widely used in the field of quasi-drugs. Saccharin sodium is about 50% of sucrose, which is widely used as a food additive in the field of food and the like.
It is a high-sweetness sweetener having about 0 times the sweetness.

Stevia is Stevia Reb
audiana BERT0NI) is a high-intensity sweetener having steviol glycosides contained in the leaves as main sweeteners and having a sweetness approximately 100 to 300 times that of sucrose. Steviol glycosides include stevioside, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, zurcoside A, zurcoside B, steviol Glycosides containing steviol as aglycone, such as pioside and steviol, are included. The stevia referred to in the present invention may be any of these steviol glycosides alone, or may contain two or more of these glycosides.

Glycyrrhiza uralensis FlSCHER, leguminous liquorice (Glycyrrhiza inflata BATALlN) or leguminous liquorice (Glycyrrhiza glabra LlNNE), is mainly contained in the root or rhizome of legume family Glycyrrhiza glaen LlNNE. ,
It is a high-intensity sweetener having about 100 to 300 times the sweetness of sucrose. Examples of the sweet component mainly include glycyrrhizic acid, its sodium salt, disodium glycyrrhizinate or trisodium glycyrrhizinate, and glycyrrhizin, which is a glycoside in which gluconic acid is bound to glycyrrhizic acid. In general, licorice extract is an aqueous extract containing 4.5% or more of glycyrrhizic acid, but in the present invention, it may contain the sweet component alone or two or more thereof.

As will be apparent from the experimental examples described later, each of the above-mentioned sweet components has a characteristic sweet taste characteristic (see FIG. 1).

That is, (i) aspartame expresses sweetness quickly in the oral cavity after ingestion, and saccharin sodium also expresses sweetness relatively quickly, although the rise is not as fast as aspartame. Aspartame exhibits the strongest sweetness from the early to late stage of the initial dose, and saccharin sodium loses the sweetness relatively quickly without the persistence of the middle to late sweetness of the initial dose.
(Ii) Stevia and brown sugar do not develop sweetness earlier than aspartame or the like, but have a characteristic that sweetness is developed slowly and persists for a relatively middle period.
Stevia and brown sugar develop sweetness relatively slowly, but exhibit the strongest sweetness in the middle and late doses, and brown sugar relatively retains sweetness in the latter half of the description. Although not shown in FIG. 1, caramel also has sweetness characteristics similar to brown sugar. (Iii) Licorice extract develops sweetness extremely slowly, but gradually develops sweetness from the latter half of administration, and exhibits the strongest sweetness from the latter half to the latter half.

[0018] Based on such sweetness properties, (i) at least one of aspartame or sodium saccharin which rapidly develops a strong sweetness after ingestion, (ii) stevia which develops a strong sweetness in the early to late middle period after ingestion, A liquid formulation is prepared by combining at least one of brown sugar or caramel and (iii) a composition containing a liquorice extract that expresses a strong sweetness in the latter half to the latter half of the dose with a drug having bitterness. Based on the liquid dosage form, the bitterness of the drug that spreads quickly and persists in the mouth can be masked significantly well.

Preferred combinations of sweetening ingredients include combinations of aspartame, sodium saccharin, brown sugar and liquorice extract; combinations of aspartame, sodium saccharin, stevia and licorice extract; combinations of aspartame, stevia, brown sugar and liquorice extract; and aspartame, Combinations of saccharin sodium, stevia, brown sugar and liquorice extract; combinations of aspartame, brown sugar and liquorice extract; combinations of aspartame, stevia and liquorice extract. In the above, caramel can be used instead of or in combination with brown sugar.

Particularly preferably, a combination of aspartame, sodium saccharin, stevia, licorice extract and brown sugar or caramel, or aspartame,
It is a combination of stevia, licorice extract and brown sugar or caramel.

[0021] In addition to these sweet components, at least one of sugar alcohols or glycerin, which retains a weak sweetness over a long period of time after ingestion, can be blended, whereby the bitterness of the drug can be further masked from the initial stage over a long period of time. , And a liquid preparation having good taste (preference) can be prepared. In this sense, although different depending on the type of bitter drug to be incorporated and the composition thereof, more preferable examples of the combination of sweetening ingredients include aspartame, sodium saccharin, stevia, licorice extract, sugar alcohol, glycerin and brown sugar or caramel, or aspartame. , Stevia, liquorice extract, sugar alcohols, glycerin and brown sugar or caramel.

The sugar alcohol is not particularly limited.
D-sorbitol, D-mannitol, xylose, xylitol, erythritol, maltitol, lactitol and the like can be exemplified. Preferred are D-sorbitol, D-mannitol, maltitol and lactitol, and more preferred is D-sorbitol.

The drug targeted by the present invention is not particularly limited as long as it has bitterness. Preferably, an antitussive,
Drugs belonging to expectorants, bronchodilators, antihistamines and analgesics can be exemplified.

Examples of antitussives include codeine phosphate,
Examples thereof include dihydrocodeine phosphate, dextromethorphan hydrobromide, noscapine, noscapine hydrochloride, tipepidine citrate, cloperastine hydrochloride, alloclamide hydrochloride, sodium dibnate and the like. Preferably,
Dihydrocodeine phosphate, codeine phosphate and dextromethorphan hydrobromide.

Examples of expectorants include potassium guaiacol sulfonate, guaifenesin, ambroxol hydrochloride, potassium cresol sulfonate, lysozyme chloride, ethyl cysteine hydrochloride and the like. Preferred are potassium guaiacol sulfonate, guaifenesin and lysozyme chloride.

Examples of the bronchodilator include methylephedrine hydrochloride, trimethoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride and the like. Preferred is methylephedrine hydrochloride.

Examples of antihistamines include chlorpheniramine maleate, mequitazine, clemastine fumarate, carbinoxamine maleate, astemizole,
Diphenhydramine hydrochloride and the like can be mentioned. Preferred are chlorpheniramine maleate and diphenhydramine hydrochloride.

Examples of the analgesic include antipyretic analgesics such as aspirin, aspirin aluminum, acetaminophen, etensamide and lactylphenetidine, and analgesics (headaches) such as caffeine and anhydrous caffeine. Preferably it is acetaminophen.

These drugs are contained in the liquid preparation of the present invention.
In combination with the above-mentioned sweetness components, one kind may be used alone, or two or more kinds may be used in combination.

Among these drugs, those belonging to an antitussive or expectorant are preferred. Particularly, antitussives include dihydrocodeine phosphate or dextromethorphan hydrobromide, and expectorants include potassium guaiacolsulfonate. Can be.

The amounts of these drugs to be added to the liquid preparation of the present invention can be in accordance with a conventional method depending on the use of the drug. For example, as a drug amount to be blended per 100 ml of liquid preparation, about 600 mg of acetaminophen,
About 5 mg of chlorpheniramine maleate, about 25 mg of dextromethorphan hydrobromide, about 50 mg of diphenhydramine hydrochloride, about 280 mg of potassium guaiacol sulfonate, and about 30 mg of dihydrocodeine phosphate.

In the liquid preparation of the present invention, each group (i) to
The sweetness component belonging to (iii) varies depending on the type and the amount of the target drug, but is usually (i) :( ii) :( iii) = 0.01 to 1: per 100 parts by weight of the liquid preparation.
0.1 to 20: 0.02 to 2 parts by weight, preferably 0.0
2 to 0.4: 0.5 to 12: 0.1 to 1 part by weight, more preferably 0.1 to 0.2: 2 to 8: 0.2 to 0.4 part by weight. it can.

The mixing ratio of various sweetening ingredients to be mixed per 100 parts by weight of the liquid preparation is, for example, 0.01 to 0.15 parts by weight, preferably 0.075 to 0.095 parts by weight for sodium saccharin; 0.
01 to 0.15 parts by weight, preferably 0.075 to 0.0
95 parts by weight; stevia is 0.05 to 0.5 parts by weight, preferably 0.12 to 0.25 parts by weight; brown sugar or caramel is 1 to 10 parts by weight, preferably 4 to 8 parts by weight; 0.1 to 1 part by weight, preferably 0.2 to 0.4
Parts by weight; sugar alcohol: 0.5 to 10 parts by weight, preferably 1.5 to 3.5 parts by weight; glycerin: 0.5 to 15 parts by weight, preferably 1 to 6 parts by weight. it can.

The liquid preparation of the present invention may be any liquid preparation which can be orally administered, and examples thereof include liquid preparations, suspensions, emulsions and syrups. Note that the syrups include dry syrups that are dissolved or suspended at the time of use.

Depending on the form of the preparation, the liquid preparation of the present invention may contain a preservative, a stabilizing agent, a suspending agent, an emulsifying agent, a thickener, and the like in a conventional manner, as long as the effects of the present invention are not impaired. Coloring agents, fragrances and the like can also be blended.

[0036]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples and experimental examples, but the present invention is not limited to these examples. EXPERIMENTAL EXAMPLE Sweetness test of sweetness components (1) Characteristics of sweetness (swift development and persistence of sweetness) for seven kinds of sweetness components, aspartame, sodium saccharin, stevia, brown sugar, licorice extract, sugar alcohol and glycerin The following experiment was performed in order to examine sex). <Method> Aspartame 100 mg, saccharin sodium 50 mg, stevia (steviol vs. saccharide (stevioside, rebaudioside A, rebaudioside C, zurcoside A, lugsoside) as a total of 80
%), Brown sugar 600 mg, liquorice extract (containing 6% glycyrrhizic acid) 100 mg, D-sorbitol 7 g, glycerin 10 g, and sucrose 10 g as a control sweetener, each dissolved in water to make a total amount of 100 g.
To obtain eight kinds of sweet component-containing solutions.

[0037] These solutions were taken by 20 healthy adults in their twenties and fifties, and the time from drinking until the sweetness was felt and its persistence, as well as the intensity of the sweetness and the quality of the sweetness I got an answer. The experiment was performed such that the subject did not know the name of the sweetener contained in each solution other than sugar. Regarding the sweetness intensity, the sweetness was determined to be 1 based on the sucrose solution as a control sweetener.
The degree of sweetness of each solution when it was set to 00 was answered. <Results> The results obtained by averaging the responses of 20 subjects are shown in Table 1 and FIG. In addition, the total time (average result) of the time from when the sweet solution is drunk until the sweetness is felt in the mouth and the duration thereof are defined as "initial" for 0 to 3 minutes after drinking, and "3 to 5 minutes for""Midterm", 5 to 10 minutes are set as "Late term", and each term is displayed in three categories of "First half", "Middle half" and "Late half".

[0038]

[Table 1]

From these results, it was found that saccharin sodium, aspartame, D-sorbitol, and stevia were sweet components that developed sweetness from a relatively early to middle stage. Above all, aspartame rapidly developed a strong sweetness, saccharin sodium developed a strong sweetness in the middle and early middle stages, and stevia developed a strong sweetness in the middle stage. On the other hand, the sweetness of these sweet components quickly disappeared from the latter half of the middle stage to the latter stage. On the other hand, it was found that brown sugar and licorice extract are sweet components that express sweetness from the middle stage to the late stage.
In addition, it was found that glycerin had a weak sweetness, but the sweetness lasted for a relatively long period from the early stage to the late stage (see FIG. 1). A similar experiment was conducted using caramel (600 mg), and it was found that the caramel had the same sweetness characteristics as brown sugar.

From these results, it is found that at least one of aspartame which expresses strong sweetness relatively quickly after ingestion or saccharin sodium which expresses strong sweetness relatively quickly after ingestion to the first half of the middle period; It was found that a long-lasting sweetness composition can be prepared by combining at least one of stevia, brown sugar, and caramel that expresses a strong sweetness during the period; . (2) Based on this finding, as a drug having actual bitterness, an antitussive expectorant containing dihydrocodeine phosphate and potassium guaiacolsulfonate was used, and aspartame, stevia, licorice extract and brown sugar or caramel were added thereto. When a liquid preparation was prepared and taken, the bitterness derived from these drugs was masked well, and no bitterness was felt from the early stage to the late stage (taste). Examples 1 to 3 and Comparative Examples 1 to 3 Each component was mixed based on the formulation shown in Table 2 to prepare a liquid formulation of the present invention (formulation of the present invention: Examples 1 to 3).
In addition, liquid preparations with some of the sweet components removed (comparative preparations:
Comparative Examples 1 to 3 were prepared and compared with the preparation of the present invention for the bitterness index, degree of bitterness, sweetness index, sweetness degree, palatability of taste, good aftertaste, comprehensive evaluation of taste, and medicinal sensation (efficacy). .

[0041]

[Table 2]

These liquid preparations were taken by 10 adults suffering from a cold accompanied by cough and sputum in their twenties to fifties, and were evaluated for bitterness index, bitterness, sweetness index, sweetness, palatability and aftertaste. They were asked about the overall evaluation of goodness, taste, and medicinal properties (efficacy). The bitter index or sweetness index means the degree of bitterness or sweetness, and is 0 to
The score was ranked by a continuous scale method of 100, and the score was converted into a Z value (deviation value) and evaluated (Z value of sucrose =
1). Also, the degree of bitterness or sweetness indicates whether the bitterness or sweetness is good, good, slightly good,
They were asked to respond in a five-point scale (SD method) such as neither, slightly bad, or bad, and the results obtained by the SD method were converted to a scale of 0 to 100 points and evaluated. The palatability of taste, good aftertaste, comprehensive evaluation of taste, and medicinal effect (efficacy) were also evaluated based on the SD method. Dosing of each liquid preparation was performed with a double blind, and the dosing order was random for each subject. <Results> The results of Example 1 and Comparative Example 1, Example 2 and Comparative Example 2, and Example 3 and Comparative Example 3 are shown in FIGS. 2, 3 and 4, respectively.

From these results, it can be seen that the liquid preparation of the present invention has a moderately suppressed sweetness, bitterness is significantly suppressed, and has a good taste.

Similar results could be obtained when maltitol, D-mannitol or lactitol sugar alcohol was used instead of D-sorbitol in Examples 1 to 3. Example 4 <Formulation Example> Dihydrocodeine phosphate 280 mg Potassium guaiacol sulfonate 2500 mg Aspartame 1800 mg Glycerin 16 g Brown sugar powder 650 mg Licorice extract (containing 6% by weight of glycyrrhizic acid) 330 mg Stevia (containing 80% by weight of steviol glycoside) 30 mg Sodium benzoate 140 mg perfumes 150mg purified water Balance Total 100g the above components were dissolved in purified water to prepare an oral antitussive疾剤liquid. Example 5 Dihydrocodeine phosphate 280 mg Potassium guaiacol sulfonate 2500 mg Aspartame 1800 mg Glycerin 16 g Caramel 650 mg Licorice extract (containing 6% by weight glycyrrhizic acid) 330 mg Stevia (containing 80% by weight steviol glycoside) 30 mg D-sorbitol 200 mg Sodium benzoate the 150mg purified water Balance Total 100g the above components were dissolved in purified water to prepare an oral antitussive疾剤liquid.

[Brief description of the drawings]

FIG. 1 is a diagram showing the state of expression of the degree of sweetness of each sweet substance (Experimental Example 1 (1)). In the figures, the broken line is saccharin sodium, the solid line is brown sugar, □ is aspartame, and ● is D
-Sorbitol, は indicates licorice extract, X indicates stevia and Δ indicates glycerin sweetness. The vertical axis in the figure is
The sweetness degree (intensity) based on the value obtained by converting the human sensory evaluation result into a Z value, and the horizontal axis represents the time after drinking the initial (before, middle,
Later), middle (before, middle, and back) and late (before, middle, and back).

FIG. 2 In Example 1 (●) and Comparative Example 1 (△),
It is a figure which shows the result of having evaluated the bitterness index, bitterness degree, sweetness index, sweetness degree, palatability of taste, good aftertaste, comprehensive evaluation of taste, and medicinal sensation (efficacy) of each sweetness composition.

FIG. 3 In Example 2 (●) and Comparative Example 2 (比較),
It is a figure which shows the result of having evaluated the bitterness index, bitterness degree, sweetness index, sweetness degree, palatability of taste, good aftertaste, comprehensive evaluation of taste, and medicinal sensation (efficacy) of each sweetness composition.

FIG. 4 shows the results in Example 3 (●) and Comparative Example 3 (△).
It is a figure which shows the result of having evaluated the bitterness index, bitterness degree, sweetness index, sweetness degree, palatability of taste, good aftertaste, comprehensive evaluation of taste, and medicinal sensation (efficacy) of each sweetness composition.

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Claims (7)

[Claims] 1. A drug having bitterness, and (i) at least one of aspartame or saccharin sodium, (ii) at least one selected from the group consisting of stevia, brown sugar and caramel, and (iii) liquorice extract A liquid preparation for oral use, characterized by containing: 2. The oral liquid preparation according to claim 1, further comprising at least one of sugar alcohol and glycerin. 3. An oral liquid preparation containing a drug having bitterness, aspartame, stevia, licorice extract, sugar alcohol, glycerin and brown sugar or caramel. 4. The oral liquid preparation according to claim 2, wherein the sugar alcohol is D-sorbitol. 5. The method according to claim 1, wherein the drug is an antitussive, expectorant, bronchodilator,
The oral liquid preparation according to any one of claims 1 to 4, which belongs to one of an antihistamine and an analgesic. 6. A drug, wherein the drug is dihydrocodeine phosphate, potassium guaiacol sulfonate, dextromethorphan hydrobromide, tipepidine citrate, alloclamide hydrochloride, cloperastine hydrochloride, sodium dibnate, dl-methylephedrine hydrochloride, noscapine hydrochloride, guaifenesin,
The oral liquid preparation according to claim 5, which is at least one selected from the group consisting of potassium cresol sulfonate, chlorpheniramine maleate, caffeine, caffeine anhydride, and acetylsalicylic acid. 7. The oral liquid preparation according to any one of claims 1 to 4, wherein the drug is at least one selected from the group consisting of dihydrocodeine phosphate, potassium guaiacol sulfonate, and dextromethorphan hydrobromide. .