TW201803564A - Oral tipepidine preparation - Google Patents

Abstract

The present invention provides a novel oral composition of a single or twice daily dose type, which contains tipepidine or a pharmaceutically acceptable salt thereof, wherein the drug dissolution rate of tipepidine or the pharmaceutically acceptable salt thereof is controlled.

Description

Tipipidine oral preparation

The present invention relates to a sustained-release oral preparation containing tiperidine or a pharmaceutically acceptable salt thereof, and can be applied to the field of pharmaceuticals.

Tiperidine is a substance that has an antitussive effect equal to or higher than that of codeine phosphate, and also has an expectorant effect, and because it is non-narcotic, it has been widely used as a medical and general pharmaceutical Antitussive and expectorant or cold medicine.

In recent years, tiperidine has been known to inhibit the G protein-coupled inwardly-rectifying potassium ion channel (GIRK), in addition to its use as an antitussive, expectorant or cold medicine, as well as Some people report on central dysfunction, such as emotional disorders or mood disorders such as attention deficit hyperactivity disorder, depression, brain dysfunction due to environmental chemicals, obsessive-compulsive disorder, Parkinson's disease, schizophrenia, neurological causes Sexual pain, dysuria, dementia induced by amyloid beta protein, Alzheimer's disease, etc. (Patent Documents 1 to 9).

So far, tiperidine is an ingot with tiperidine sea benzoate as an active ingredient. In the form of oral preparations such as agents, powders, syrups, it is used as an antitussive, expectorant or cold medicine. In the case of tiperidine sea benzoate, to reach the highest plasma concentration, it takes about 1.3 hours after oral administration; and the plasma half-life is about 1.8 hours, which is only effective for a short time, so it is usually 1 day Patients were prescribed 3 oral doses.

On the other hand, among the recently discovered uses for the prevention and treatment of attention deficit hyperactivity disorder and depression, it is desirable that the effect is stable and continuous, and it can be minimized in destinations such as schools and workplaces. Oral preparations for single or double administration once a day can reduce the number of cases of forgetting to take them, and it is expected that the preventive and therapeutic effects of these applicable diseases will be fully exerted. In addition, in these applications, it is premised on taking tepididine for several months and, depending on the circumstances, up to several years, and it is required to improve the compliance of taking medication once or twice a day. Oral preparation. However, although tepididine benzoate shows good solubility in the acidic stomach, it is extremely difficult to dissolve in water. Therefore, the solubility in the lower part of the digestive tract that is neutral and less water will be greatly reduced. It is not easy to release continuously in the stomach ~ intestine.

[Prior technical literature] [Patent Literature]

[Patent Document 1] Japanese Special Re-publication Sheet 2007-37258

[Patent Document 2] Japanese Patent Laid-Open No. 2009-227631

[Patent Document 3] Japanese Special Re-publication Table 2007-139153

[Patent Document 4] Japanese Patent Application Publication No. 2012-62272

[Patent Document 5] Japanese Patent Laid-Open No. 2011-246446

[Patent Document 6] Japanese Patent Laid-Open No. 2013-63958

[Patent Document 7] Japanese Special Re-publication Table 2012-118172

[Patent Document 8] Japanese Patent Laid-Open No. 2007-204366

[Patent Document 9] Japanese Patent Laid-Open No. 2017-36242

The subject of the present invention is to provide a novel sustained-release oral preparation containing tiperidine, particularly a sustained-release oral preparation for administration once or twice a day.

The inventors of the present case made efforts to solve the aforementioned problems and found that it is possible to achieve the following: regardless of the above drug dynamics of tiperidine, the dissolution rate of tiperidine in the stomach can be controlled, and it can be stable in the stomach to the intestine and Oral sustained release formulations that release tiperidine continuously.

That is, the present invention is (1) a slow-release oral solid composition, which contains tiperidine or a pharmaceutically acceptable salt thereof as an active ingredient; (2) a single or two-time administration per day The preformed sustained-release oral solid composition contains teperidine or a pharmaceutically acceptable salt thereof as an active ingredient; (3) a composition such as (1) or (2), which is a substitute Perididin or a pharmaceutically acceptable salt thereof is an active ingredient and further contains a high water-soluble content Child base agent; (4) A composition such as (3), wherein the water-soluble polymer base is hypromellose or a carboxyvinyl polymer; (5) A composition such as (3), wherein the water-soluble polymer The base is hypromellose; (6) A composition such as (5), wherein the content of hypromellose is in the range of 5 to 90% by mass in the composition; (7) such as (4) to (6) The composition according to any one of the above, wherein hypromellose is a mixture of hypromellose having different viscosities; (8) The composition of (7), wherein the mixture of hypromellose having different viscosities is Combination of at least one type of hypromellose 50 ~ 100mPa‧s and at least one type of hypromellose 4000 ~ 100000mPa‧s; (9) A composition such as (7), wherein hypromellose with different viscosity The cellulose mixture is a combination of hypromellose 100mPa‧s and at least one of hypromellose 4000 ~ 15000mPa‧s; (10) The composition according to any one of (7) to (9), The content of the mixture of hypromellose having different viscosities is in the range of 5 to 45% by mass in the composition; (11) The composition according to any one of (7) to (9), in which hydroxypropion having different viscosities The content of methylcellulose mixture is The range of 10 to 30% by mass of the composition; (12) The composition of any one of (7) to (11), wherein the mixed mass ratio of low viscosity and high viscosity of hypromellose having different viscosities is 25: 75 ~ 90: 10 range; (13) The composition according to any one of (7) to (11), wherein the mixed mass ratio of low viscosity and high viscosity of hypromellose having different viscosities is in a range of 25:75 to 80:20; ( 14) The composition according to any one of (7) to (11), wherein the mixed mass ratio of low viscosity and high viscosity of hypromellose having different viscosities is in a range of 40:60 to 60:40; (15 ) The composition according to any one of (1) to (14), further comprising particles containing an excipient; (16) The composition according to (15), wherein the particles are formed by wet granulation or (17) The composition according to (16), wherein the solvent used in the wet granulation is a solvent with a mixed mass ratio of water and ethanol in the range of 100: 0 to 20:80; 18) The composition according to (16), wherein the solvent used in the wet granulation is a solvent having a mixed mass ratio of water and ethanol in a range of 100: 0 to 40:60; (19) such as (1) to ( 18) The composition according to any one of the above, wherein the tiperidine or a pharmaceutically acceptable salt thereof is Tipipidine hibenzate; (20) As in any one of (1) to (19) Composition, wherein the oral solid composition is selected from the group consisting of lozenges, capsules, or granules (21) The composition of any one of (1) to (20), which is cough, sputum difficulty, attention deficit hyperactivity disorder, depression (including treatment of rejection depression), bipolar disorder, mental Schizophrenia, anxiety, dementia, It is used for the prevention or treatment of obsessive-compulsive disorder (including treatment of obsessive-compulsive disorder), Parkinson's disease, dysuria, pain, dementia induced by amyloid beta protein, or Alzheimer's disease.

The oral solid composition of the present invention can control the dissolution rate of tiperidine in the stomach, and can stably and continuously release tiperidine in the stomach to the intestine. With regard to the oral solid composition of the present invention, controlled release of the rate of dissolution of teperidine or a pharmaceutically acceptable salt thereof can be confirmed, so that it is possible to provide one or two times a day to improve compliance with medication. Sub-administration formulation.

Figure 1 shows the results of the dissolution tests of Examples 1 and 2.

Fig. 2 shows the results of the dissolution tests of Examples 3 and 4.

Fig. 3 shows the results of the dissolution tests of Examples 1 and 5.

Fig. 4 shows the results of the dissolution tests of Examples 6 and 7.

Fig. 5 shows the results of the dissolution tests of Examples 8 and 9.

Fig. 6 shows the results of the dissolution tests of Examples 9 and 10.

Fig. 7 shows the results of the dissolution tests of Examples 11 and 12.

FIG. 8 shows the results of the dissolution test of Comparative Example 1. FIG.

Fig. 9 is a graph showing the results of dissolution tests of test solutions of different pHs in Example 6.

Fig. 10 is a graph showing the results of dissolution tests of test solutions of different pHs in Example 7.

Fig. 11 is a graph showing the results of dissolution tests of test solutions of different pHs in Example 13;

Fig. 12 is a graph showing the results of dissolution tests of test solutions of different pHs in Example 14.

[Form of Implementing Invention]

One aspect of the present invention is a sustained-release pharmaceutical composition using teperidine or a pharmaceutically acceptable salt thereof as an active ingredient.

Tiperidine can be used as a free body or as a pharmaceutically acceptable salt of tiperidine. Examples of the pharmaceutically acceptable salt of tiperidine include tiperidine sea benzoate, teperidine citrate, teperidine octadecyl sulfate, and the like.

The content of teperidine or a pharmaceutically acceptable salt thereof is usually 10 to 50% by mass based on the entire composition.

In the present invention, the term "sustained release" refers to, for example, the second method of the dissolution test (stirring paddle method) of the Japanese Pharmacopoeia, using a 900 mL dissolution test second solution (for phosphate buffer of 1 volume of pH 6.8 When 1 volume of water is added to the liquid) as the test solution, the dissolution rate of the active ingredient at the time point of 2 hours after the start of the test is controlled to 5 to 70% when it is dissolved under the condition that the number of revolutions of the stirring paddle is 50 rpm. The dissolution rate of the active ingredient at the time point of 2 hours after the start of the test is controlled to be 5 to 60%, and it is more preferable that the dissolution rate is 6 hours after the start of the test. The dissolution rate of the active ingredient at the time point is controlled at 30 to 80%.

The sustained-release preparation of the present invention can be mixed with an inert carrier as required, and provided as granules, powders, capsules, tablets, etc. by a common method. The inert carrier in the present invention refers to a component other than a water-soluble polymer base which is contained in a preparation together with a medicinal ingredient but does not show medicinal effect. For example, excipients, lubricants, disintegrants, binders, plasticizers, antioxidants, coating agents, colorants, flavoring agents, surfactants, plasticizers, and the like are included here.

The water-soluble polymer base agent used in the present invention refers to a water-soluble polymer of a sustained-release base agent. As the water-soluble polymer, it can be mixed and selected from the group consisting of hypromellose, hydroxypropylcellulose, and phthalate. Hydroxypropyl methyl cellulose formate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, phthalate acetate Copolymerization of cellulose formate, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetal diethylaminoacetate, amine alkyl methacrylate copolymer E, amine alkyl methacrylate RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, carboxyvinyl polymer, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, One or more types of polymers of xanthan gum.

Examples of the excipient used in the preparation of the present invention include a mixture selected from lactose, crystalline cellulose, white sugar, powdered sugar, granulated sugar, glucose, mannitol, sorbitol, corn starch, starches, arabic Gum, dextrin, polytriglucose, light anhydrous silicic acid, low-substitution hydroxypropyl cellulose, sodium carboxymethyl cellulose, synthetic aluminum silicate, magnesium aluminosilicate, calcium hydrogen phosphate, and anhydrous hydrogen phosphate 1 or 2 groups of calcium on.

Examples of the lubricant used in the preparation of the present invention include a mixture selected from magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous silicic acid, colloidal silicon dioxide, and synthetic aluminum silicate. , And one or more types of magnesium aluminosilicate.

Examples of the disintegrant used in the preparation of the present invention include a mixture selected from the group consisting of crospovidone, croscarmellose sodium, carboxymethylcellulose, sodium carboxymethyl starch, and a low degree of substitution. One or more of hydroxypropyl cellulose, calcium carboxymethyl cellulose, crystalline cellulose, hydroxypropyl starch, corn starch, potato starch, and partially alpha starch.

Examples of the binder used in the preparation of the present invention include one or two or more selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, polytriglucose, and starch paste. .

In addition to the water-soluble polymer, the slow-release base of the present invention may also use a fat-soluble polymer or a combination of a water-soluble polymer and a fat-soluble polymer. More preferably, it is a water-soluble polymer.

The water-soluble polymer in the present invention is preferably hypromellose or a carboxyvinyl polymer, and more preferably hypromellose.

Hypromellose in the present invention is synonymous with hydroxypropyl methylcellulose, and is a mixed ether of cellulose methyl and hydroxypropyl. In the present invention, as the hypromellose, one having a different degree of substitution between a methoxy group and a hydroxypropoxy group can be used. As representative examples of hypromellose, there are substitution types of 1828, 2208, 2906, and 2910 (for example, refer to the 17th revised Japanese Pharmacopoeia page 1305), which can be used in the sustained-release preparation of the present invention. Moreover, hypromellose of various viscosities can be used. Here, the viscosity of hypromellose refers to the value measured in accordance with the 17th revised Japanese Pharmacopoeia (display viscosity: 2% aqueous solution viscosity at 20 ° C of the Japanese Pharmacopoeia). The preferred viscosity is 50 ~ 100000mPa‧s, more preferably 100 ~ 15000mPa‧s.

The mixing amount of hypromellose in the present invention is preferably 3 to 90% by mass, more preferably 5 to 60% by mass, and particularly preferably 5 to 45% by mass in the oral composition. The mixing amount of hypromellose may also change depending on the viscosity of hypromellose. For example, when the viscosity of hypromellose is 50-100 mPa‧s, the preferred blending amount is 15-90 mass%, the more preferred blending amount is 35-90 mass%, and the more preferred blending amount is 35. ~ 60% by mass. When the viscosity is 4000 to 100,000 mPa‧s, such as 4000, 15000, 100,000 mPa‧s, the preferred blending amount is 5 to 40% by mass, and the more preferred blending amount is 10 to 30% by mass.

Furthermore, in order to provide more stable sustained-release properties of the active ingredients, hypromellose having different viscosities is preferably used. Hypromellose with different viscosity is, for example, a low-viscosity hypromellose such as 50 ~ 100mPa‧s and a high-viscosity hypromellose such as 4000 ~ 100000mPa‧s are preferably used in combination. The mixing mass ratio of hypromellose and high viscosity hypromellose is in the range of 25: 75 ~ 90: 10, more preferably 25: 75 ~ 80: 20, and even more preferably 40: 60 ~ 60: 40. Particularly good is 50:50. By using low-viscosity hypromellose and high-viscosity hypromellose in the above specific mixing ratio, extremely stable sustained-release properties of the active ingredients can be achieved.

The viscosity of the carboxyethylene polymer refers to the viscosity of a 0.5% by mass aqueous solution (pH 7.5), and preferably from 4000 to 39400 mPa · s. In the present invention The blending amount of the carboxyethylene polymer in the oral composition is preferably 15 to 90% by mass.

Teperidine or a pharmaceutically acceptable salt thereof can be used in a granulated state or an ungranulated state together with an excipient. In addition, hypromellose can be mixed with teperidine or a pharmaceutically acceptable salt thereof and used in a granulated state or an ungranulated state. For example, sufficient sustained release can be seen regardless of the manufacturing method. More preferably, hypromellose is preferably an oral preparation prepared by mixing tiperidine or a pharmaceutically acceptable salt thereof, granulating, and tabletting.

The mixed mass ratio of water and ethanol used as a solvent in the wet granulation may be in a range of 100: 0 to 0: 100. It is more preferably in the range of 100: 0 to 20:80, and even more preferably in the range of 100: 0 to 40:60.

In order to prevent or treat cough, sputum difficulty, etc., the sustained-release pharmaceutical composition of the present invention is used as an antitussive, expectorant or cold medicine, and teperidine can also inhibit G protein coupled inward rectifying potassium (GIRK) Channel, it can be used for the following purposes.

Can also be used as attention deficit hyperactivity disorder, depression (e.g., treatment of rejection depression), bipolar disorder, schizophrenia (positive symptoms, negative symptoms, cognitive impairment), anxiety, dementia (Alzheimer's type , Lewy body type), obsessive-compulsive disorder (for example, treatment of rejection obsessive-compulsive disorder), Parkinson's disease, dysuria, pain, etc.

[Example]

Hereinafter, the present invention will be described in more detail with reference to examples, but these examples are not intended to limit the present invention and can be used without departing from the present invention. The scope of the invention is changed.

Examples 1 and 2

Ingredients 1 to 4 described in Table 1 were mixed, granulated with water, and dried to prepare granulated particles. The granulated granules were mixed with the ingredients 5 to 7 described in Table 1, and tableted to obtain a tablet.

Examples 3 and 4

The components 1 to 5 described in Table 2 were mixed and tableted to obtain a tablet.

Example 5

Ingredients 1 to 4 described in Table 3 were mixed, granulated with water, and dried to prepare granulated particles. The granulated granules were mixed with the ingredients 5 to 6 described in Table 3, and tableted to obtain a tablet.

Examples 6 and 7

The components 1 to 4 described in Table 4 were mixed, and a water / ethanol (mass ratio: 50:50) mixed solution was used for granulation and then dried to prepare granulated particles. The granulated granules were mixed with the ingredients 5 to 7 described in Table 4 and tableted to obtain a tablet.

¹⁾以90：10的比率組合使用黏度100mPa‧s與4000mPa‧s之羥丙甲纖維素(比率係指質量比；以下同) ²⁾以50：50的比率組合使用黏度100mPa‧s與4000mPa‧s之羥丙甲纖維素

¹⁾ Use hypromellose with a viscosity of 100mPa‧s and 4000mPa‧s in a ratio of 90:10 (the ratio refers to the mass ratio; the same applies hereinafter) ²⁾ Use a viscosity of 100mPa‧s and 4000mPa in a ratio of 50:50 ‧S Hypromellose

Examples 8 and 9

The components 1 to 7 described in Table 5 were mixed in Example 8 and tableted to obtain a tablet. The components 1 to 4 described in Table 9 in Example 9 were mixed, granulated with water, and dried to prepare granulated particles. The granulated granules were mixed with the ingredients 5 to 7 described in Table 5 and tableted.

Example 10

The components 1 to 4 described in Table 6 were mixed, granulated using a water / ethanol (mass ratio: 20:80) mixed solution, and dried to prepare granulated particles. The granulated granules were mixed with component 5 described in Table 6 and tableted to obtain a tablet.

Examples 11 and 12

In Example 11, the components 1 to 4 described in Table 7 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and dried to prepare granulated particles. The granulated granules were mixed with the ingredients 5 to 7 described in Table 7 and tableted to obtain a tablet. Example 12 was obtained by applying the dispersing component 8 to the tablet of Example 11 to obtain a tablet.

Examples 13 and 14

The components 1 to 4 described in Table 8 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and dried to prepare granulated particles. The granulated granules were mixed with the ingredients 5 to 7 described in Table 8 and tableted to obtain a tablet.

³⁾以80：20的比率組合使用黏度100mPa‧s與4000mPa‧s之羥丙甲纖維素 ⁴⁾以40：60的比率組合使用黏度100mPa‧s與4000mPa‧s之羥丙甲纖維素

³⁾ Use hypromellose with a viscosity of 100mPa‧s and 4000mPa‧s at a ratio of 80:20 ⁴⁾ Use hypromellose with a viscosity of 100mPa‧s and 4000mPa‧s at a ratio of 40:60

Test example 1: Dissolution test

About the obtained Examples 1-12 and Comparative Example 1, the dissolution property was confirmed. Using Examples 1 to 12 and Comparative Example 1, following the dissolution test method (stirring paddle method) of the general test method of the Japanese Pharmacopoeia, the second solution of the 900 mL dissolution test was used as the test solution, and automatic sampling was performed at a rotation number of 50 rpm. Perform a dissolution test. From the obtained measured values, the dissolution rate at each sampling time was determined.

The results of Examples 1 and 2 are shown in Fig. 1. As can be seen from Fig. 1, Example 1 containing hypromellose and Example 2 containing a carboxyvinyl polymer showed excellent sustained-release properties.

The results of Examples 3 and 4 are shown in FIG. 2. As can be seen from FIG. 2, by changing the content of hypromellose, the dissolution rate of tepididine can be controlled.

The results of Examples 1 and 5 are shown in FIG. 3. As can be seen from Fig. 3, by changing the viscosity of hypromellose, the dissolution rate of tepididine can be controlled.

The results of Examples 6 and 7 are shown in FIG. 4. As can be seen from FIG. 4, the dissolution rate of tiperidine can be controlled by using hypromellose having different viscosities in combination.

The results of Examples 8 and 9 are shown in FIG. 5. It can be seen from FIG. 5 that Example 8 manufactured by the direct tabletting method and Example 9 manufactured by the wet granulation method show excellent sustained-release properties of tiperidine.

The results of Examples 9 and 10 are shown in FIG. 6. It can be seen from FIG. 6 that Example 9 using water and Example 10 using a water / ethanol mixed solution for the granulating solvent show excellent sustained-release properties of teperidine.

The results of Examples 11 and 12 are shown in FIG. 7. It can be seen from FIG. 7 that Examples 11 and 12 show excellent sustained-release properties of tiperidine, with or without coating.

The results of Comparative Example 1 are shown in FIG. 8. In Comparative Example 1, a commercially available aspirin tablet 20 was used.

Test example 2: Dissolution test of test solution with different pH

Using Examples 6, 7, 13, and 14, following the dissolution test method (stirring paddle method) of the general test method of the Japanese Pharmacopoeia, a 900 mL dissolution test solution (pH 1.2; 2.0 g of sodium chloride was dissolved in the test solution) 7.0 mL of hydrochloric acid and water to make 1000 mL) and 900 mL of the second solution for dissolution test, automatic sampling was performed at a number of rotations of 50 rpm, and the dissolution test was performed based on automatic absorbance measurement. From the obtained measured values, the dissolution rate at each sampling time was determined.

The results of Example 6 are shown in FIG. 9. It can be seen from FIG. 9 that the tablet of Example 6 using hypromellose having different viscosities showed a certain rate of dissolution of tepididine regardless of the test solution (pH).

The results of Example 7 are shown in FIG. 10. It can be seen from FIG. 10 that the tablets of Example 7 using hypromellose having different viscosities showed a certain rate of dissolution of tepididine regardless of the test solution (pH).

The results of Example 13 are shown in FIG. 11. It can be seen from FIG. 11 that the tablets of Example 13 using hypromellose having different viscosities showed a certain rate of dissolution of tepididine regardless of the test solution (pH).

The results of Example 14 are shown in FIG. 12. It can be seen from FIG. 12 that the tablet of Example 14 using hypromellose having different viscosities was used, regardless of the test solution. (pH) showed a certain rate of dissolution of teperidine.

[Industrial availability]

According to the present invention, the dissolution rate of tiperidine in the stomach can be controlled, and the tiperidine can be released stably and continuously from the stomach to the intestine. The tiperidine or a pharmaceutically acceptable salt thereof can be administered orally. It is provided with a sustained-release preparation.

Claims (21)

A sustained-release oral solid composition containing teperidine or a pharmaceutically acceptable salt thereof as an active ingredient. A sustained-release oral solid composition of the type for once or twice daily administration, which comprises tiperidine or a pharmaceutically acceptable salt thereof as an active ingredient. For example, the composition of claim 1 or 2 uses teperidine or a pharmaceutically acceptable salt thereof as an active ingredient, and further contains a water-soluble polymer base. The composition of claim 3, wherein the water-soluble polymer base is hypromellose or a carboxyvinyl polymer. The composition of claim 3, wherein the water-soluble polymer base is hypromellose. The composition according to claim 5, wherein the content of hypromellose is in the range of 5 to 90% by mass of the composition. The composition according to any one of claims 4 to 6, wherein hypromellose is a mixture of hypromellose having different viscosities. For example, the composition of claim 7, wherein the mixture of hypromellose having different viscosities is at least one of hypromellose 50 to 100 mPa‧s and at least one of hypromellose 4000 to 100,000 mPa‧s. combination. For example, the composition of claim 7, wherein the mixture of hypromellose having different viscosities is a combination of at least one of hypromellose 100 mPa‧s and hypromellose 4000-15000 mPa · s. The composition according to any one of claims 7 to 9, wherein the content of the mixture of hypromellose having different viscosities is in the range of 5 to 45% by mass in the composition. The composition according to any one of claims 7 to 9, wherein the content of the mixture of hypromellose having different viscosities is in the range of 10 to 30% by mass of the composition. For example, the composition of any one of claims 7 to 11, wherein the mixed mass ratio of low viscosity and high viscosity of hypromellose having different viscosities is in a range of 25:75 to 90:10. For example, the composition of any one of claims 7 to 11, wherein the mixed mass ratio of low viscosity and high viscosity of hypromellose having different viscosities is in a range of 25:75 to 80:20. For example, the composition of any one of claims 7 to 11, wherein the mixed mass ratio of low viscosity and high viscosity of hypromellose having different viscosities is in a range of 40:60 to 60:40. The composition according to any one of claims 1 to 14, further comprising particles containing an excipient. The composition according to claim 15, wherein the granules are made by wet granulation or dry granulation. For example, the composition of claim 16, wherein the solvent used in the wet granulation is a solvent having a mixed mass ratio of water and ethanol in a range of 100: 0 to 20:80. For example, the composition of claim 16, wherein the solvent used in the wet granulation is a solvent having a mixed mass ratio of water and ethanol in a range of 100: 0 to 40:60. For example, the composition according to any one of claims 1 to 18, wherein tepididine or a pharmaceutically acceptable salt thereof is tipipidine hibenzate. The composition according to any one of claims 1 to 19, wherein the oral solid composition is selected from the group consisting of a tablet, a capsule or a granule. If the composition of any one of claims 1 to 20, it is cough, sputum difficulty, hyperactivity disorder, depression (including the treatment of rejection depression), bipolar disorder, schizophrenia, anxiety, loss Prevention or treatment of mental illness, obsessive-compulsive disorder (including the treatment of rejection obsessive-compulsive disorder), Parkinson's disease, dysuria, pain, dementia induced by amyloid beta protein or Alzheimer's disease