JP2009256216A - Liquid amlodipine besylate formulation for internal administration stable in solution state - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a liquid amlodipine besylate formulation administrable to a patient who is difficult to take a solid formulation such as a tablet and excellent in storage stability. <P>SOLUTION: The liquid amlodipine besylate formulation for internal administration is prepared by dissolving amlodipine besylate in an aqueous solution containing propylene glycol and a sugar alcohol as essential components. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

The present invention relates to an amlodipine besylate internal-use solution that can be easily taken by elderly people or patients with dysphagia and is used in the medical field.

More specifically, the present invention relates to an amlodipine besylate internal use solution that can be easily taken by patients with reduced swallowing function that are difficult to swallow as an antihypertensive drug, amlodipine besylate, as a tablet or capsule. The present invention relates to a liquid solution for taking amlodipine besylate that can be easily administered into the digestive tract through a tube for patients who receive tube feeding due to a nasogastric tube or gastric fistula due to a disorder.

Amlodipine besilate is widely used as a hypotensive agent for hypertension. The mechanism of action is considered to be calcium antagonism, and the action is moderate among antihypertensive agents, and can be used safely even for elderly people. Until now, only solid preparations are available on the market, but some elderly people have difficulty masticating or swallowing drugs in the form of tablets as well as food due to sequelae of cerebral infarction. There are many difficult patients. In addition, there are many patients who cause dysphagia other than elderly people such as Parkinson's disease patients. In order to administer amlodipine besylate to such patients, tablets that are easily disintegrated by saliva in the oral cavity have been developed in recent years, but there are many patients with low saliva secretion in the elderly, etc., and it is not always easy to take I can't say that. Therefore, there is a demand for an amlodipine besylate preparation in a dosage form that can be easily and safely taken by patients with dysphagia.

In view of the above situation, it is considered useful to provide an amlodipine besylate solution for internal use, which is a dosage form that can be easily taken by patients with dysphagia.
However, it has been clarified that dihydropyridine compounds such as amlodipine besylate are unstable in an aqueous solution and generate various related substances (impurities) during storage. Furthermore, in addition to stability, solubility and taste are also problems in providing a liquid for internal use. Patent Document 1 shows that nilvadipine exhibits an excellent effect in improving the solubility and stability of a drug by adding polyethylene glycol and / or glycerin, and further increases the solubility of the drug by adding propylene glycol and / or glycerin. It describes that it has an excellent effect in improving and improving the taste of liquid for internal use. However, in the case of amlodipine besylate, the same dihydropyridine compound, solubility and stability are improved in propylene glycol (PG) and ethanol (EtOH) as shown in Table 4, but polyethylene glycol and glycerin. Only the improvement of the solubility of the drug is recognized, and the stability in the solution deteriorates conversely. Table 4 suggests that amlodipine besylate is stable in PG and EtOH, but amlodipine besylate solution consisting only of those solvents that do not contain moisture is highly irritating in the oral cavity and has an unpleasant taste. And is not suitable for oral administration due to irritation to the digestive tract. Therefore, it is desirable to use an aqueous solution of amlodipine besylate.
Patent Document 2 reports a liquid composition of a dihydropyridine compound, in which the use of propylene glycol as a diluent is described. However, according to the invention, as a solubilizer for dissolving the dihydropyridine compound, a surfactant such as sorbitan monolaurate or polyethylene glycol (20) -sorbitan monolaurate is added in an amount of 20 to 60% by weight. Yes. The above surfactants have a problem with respect to safety to living bodies, and it is not preferable to use a preparation containing these as essential requirements for the treatment of diseases.
Furthermore, Patent Document 3 refers to a sterile aqueous solution containing propylene glycol as one of the compositions of benzenesulfonate of amlodipine, but this invention is in a form that can be administered parenterally like an injection. It merely shows a composition that exhibits a certain solution state, and does not indicate an amlodipine besylate preparation that is stable during storage and can be used as a liquid medicine for internal use.

Japanese Unexamined Patent Publication No. 2000-247883 JP 59-167512 A JP-A-62-240660

As a result of studying the formulation and production method of a liquid medicine for oral administration of amlodipine besylate which is chemically stable to solve the above problems, the present inventors have found that amlodipine besylate in an aqueous solution containing propylene glycol and sugar alcohols. A stable formulation of amlodipine besylate for internal use that can be safely taken by dissolving it, produces less related substances even during long-term storage, and reduces the content of amlodipine besylate. The present invention was completed.
That is, the liquid medicine for oral administration of amlodipine besylate of the present invention is a pharmaceutical preparation to be administered to a patient in a liquid state, and has a water content of 5% to 60% by weight, preferably 10% to 40% by weight, propylene glycol 5 wt% or more and less than 70 wt%, preferably 10 wt% or more and less than 50 wt%, more preferably 20 wt% or more and less than 40 wt%, sugar alcohol is 10 wt% or more and less than 70 wt%, preferably 20 wt% Or more, less than 60% by weight, more preferably 30% by weight or more and less than 50% by weight. The sugar alcohol is not particularly limited as long as it does not affect the stability of amlodipine besylate in the liquid. For example, D-sorbitol, xylitol, mannitol, erythritol, maltitol, lactitol, reduced palatinose and reduction Maltose water candy etc. are mentioned, It can select and combine arbitrarily. Further, for the purpose of assisting dissolution and / or stabilization, an appropriate amount of ethanol can be added, and preferably 2 to 20% by weight can be added. Preservatives, pH adjusters, sweeteners, antioxidants, and fragrances can be added as necessary. The agent has a viscosity at 20 ° C. of 5 mPa · s to 200 mPa · s, preferably 10 mPa · s to 50 mPa · s. Because the clinical dose of amlodipine besylate is 2.5 mg to 10 mg (administered once a day) in terms of amlodipine and because it is easier for elderly people and patients with dysphagia to take a lower dose, The amlodipine besylate concentration is preferably 0.69 mg / mL (0.5 mg / mL in terms of amlodipine) to 10.4 mg / mL (7.5 mg / mL as amlodipine).

(1) Examination of the effect of pH and buffer (phosphate / citrate buffer) on the stability of amlodipine besylate in aqueous solvents not containing propylene glycol, sugar alcohol, etc. The examination result regarding the stability of amlodipine besilate in is shown. Table 1 shows the total amount of related substances produced when amlodipine besylate in various buffer solutions is heated at 90 ° C for 40 minutes at a concentration of 0.1 mg / mL, as "Total related substances (%)".
A phosphate / citrate buffer was used as the buffer. The “total related substance amount” here represents the ratio of the total peak area of all related substances detected by high performance liquid chromatography (HPLC) analysis to the total amount of all peak areas including amlodipine. Like the amlodipine residual rate described below, it was used as an index of stability. (Hereinafter the same)
As a result, when the pH in the solution was extremely acidic or alkaline, the formation of related substances was remarkable, suggesting that it was unstable. On the other hand, the production of similar substances was relatively small in the neutral range, but it was found that the amount of the related substances was small only in the aqueous solvent that did not use the buffer even in the vicinity of the same neutrality.

(2) Examination of the effect of pH and buffer (citrate buffer) on the stability of amlodipine besylate in an aqueous solvent that does not contain propylene glycol, sugar alcohol, etc. but contains 10% EtOH ), Even in the vicinity of neutrality similar to water, it was found that the amount of related substances produced was smaller when no buffer solution was used. Therefore, next, the type of buffer used was changed, and the amount of related substances produced near neutrality was compared with the case of water alone containing no buffer.
Table 2 shows the results of studies on the stability of amlodipine besylate in aqueous solutions at various pHs. Table 2 shows the total amount of related substances produced when amlodipine besylate in various buffers was heated at 121 ° C for 20 minutes at a concentration of 1.73 mg / mL. In Table 2, citrate buffer is used, and EtOH 10% is added.
As a result, as in (1), it was suggested that when a buffer solution was used even in the vicinity of the same neutrality, the amount of related substances was large compared to the case where a buffer solution was not used, and it became unstable. Therefore, it was considered that the use of a buffering agent in the amlodipine besylate solution is more stable and preferable as a preparation.

(3) Effect of antioxidants on the stability of amlodipine besylate in aqueous solutions that do not contain propylene glycol, sugar alcohol, etc. Various antioxidants were added to aqueous solutions containing only 1.73 mg / mL amlodipine besylate. Table 3 shows the amount of related substances produced after addition of 0.1 wt% and storage at 60 ° C for 2 weeks. As is apparent from Table 3, the antioxidants usually used were not effective in stabilizing amlodipine besylate in an aqueous solvent.

(4) Stability of amlodipine besylate in various solvents Study in non-aqueous solvent system (stability and solubility)
The amlodipine besylate salt, which is unstable in water, was examined in a non-aqueous solvent system. Japanese pharmacopoeia propylene glycol (hereinafter referred to as PG), Japanese pharmacopoeia ethanol (hereinafter referred to as EtOH), polyethylene glycol 400 (hereinafter referred to as PEG400), Japanese Pharmacopoeia concentrated glycerin (hereinafter referred to as concentrated glycerin), which are organic solvents Table 4 shows the results of examining the stability of each solvent in which amlodipine besylate was dissolved at 60 ° C. for 14 days. Also in Table 4, the total amount of related substances produced was used as an indicator of stability.
In Table 4, the concentration of amlodipine besylate indicates mg / mL, and the value of each solvent indicates wt%. The column for 14 days at 60 ° C. shows the total amount of related substances (%).

In Table 4, it was found that PG or EtOH not only showed no precipitation of the active ingredient and no coloration of the liquid agent, but also suppressed the formation of related substances and improved the stability of amlodipine besylate. Above all, it was suggested that PG contributes more to stabilization. On the other hand, PEG400 and concentrated glycerin, which are the same non-aqueous solvent, turn yellow and precipitates are observed, and the amount of related substances tends to increase extremely more than the aqueous solvent (Comparative Example 1). No stabilizing action was observed.
However, 100% solvents such as PG and EtOH are not good as a base for liquid medicines for internal use because they not only have bad smell, taste and texture but also irritate the oral cavity and gastrointestinal mucosa when taken orally. Is appropriate.
Therefore, it was considered necessary to add a highly safe solvent such as water to PG and EtOH to reduce their adverse effects.

2. Examination of thickeners for aqueous solutions When patients with dysphagia swallow liquid foods and drinks, it is known that liquids with low viscosity, such as water, are easy to immerse, and are intended for such patients to take It is considered that it is desirable that the liquid medicine for internal use described above has fluidity and has a higher viscosity than water. In particular, liquid medicines having a viscosity of about 10 to 50 mPa · s (20 ° C.) set by many liquid nutritional foods for those who have difficulty swallowing are considered to be easy for those patients to take.
Therefore, the effect of various thickeners was examined. That is, a thickener was dissolved in water to prepare a 0.2 w / v% solution, and 173 mg of amlodipine besylate was added to 100 mL of this solution, and the appearance was observed. However, since xanthan gum did not dissolve at 0.2 w / v%, it was examined at 0.05 w / v%. The results are shown in Table 5. As for all of carrageenan, guar gum, gellan gum, and xanthan gum, formation of precipitates and water separation were observed, and they were not stable and uniform for a long period of time.

3. Relationship between PG solution and viscosity On the other hand, since PG has a relatively high viscosity, in order to investigate the possibility of using PG aqueous solution with water added to PG as a solvent for amlodipine besylate, PG aqueous solution of various concentrations The viscosity was measured using a rotational viscometer.
The results are shown in Table 6, but 60% or more of PG is required to obtain the same level of viscosity as liquid food without using a thickener, and even if amlodipine besylate is dissolved in PG solution, it is significant in viscosity. No significant change was observed.

(5) Study on composition of amlodipine besylate solution that can be administered to human body and is stable. In Table 4, it was found that amlodipine besylate in a solution state was stably maintained by using PG and EtOH as solvents, but as described above, a solution composed only of them is preferable for the human body. It is desirable to contain water, not a thing. EtOH has various physiological effects such as vasodilatation and low flash point, and there is a risk of fire during production, etc., so PG aqueous solution is more suitable as a base for liquid medicine for internal use. it was thought.
Table 7 shows the total amount of related substances when amlodipine besylate was dissolved in PG solutions of various concentrations at a concentration of 1.73 mg / mL and stored at 60 ° C. for 14 days under shading. From Table 7, it became clear that the stabilizing effect of PG is proportional to the concentration.

2. Examination of stabilizers Furthermore, when PG is included in the mouth, bitterness is felt. Although there are individual differences, at 30% by weight or less, a weak bitter taste is felt, but as the concentration increases, bitterness increases. In particular, PG aqueous solution with a high concentration of 70% by weight or more not only feels bitter and uncomfortable when contained in the oral cavity, but also leaves a strong bitter taste on the tongue after vomiting or swallowing. In addition, according to the Pharmaceutical Additives Dictionary (Pharmaceutical Daily Inc .; 2006), the upper limit of PG use for oral administration is 2.08 g per day, and ADI (allowable daily intake) is 25 mg per kg body weight Therefore, it was considered that a smaller amount of PG included in the liquid medicine for internal use is desirable from the viewpoint of safety.
Therefore, the present inventors stabilized the amlodipine besilate by adding a stabilizer based on an aqueous solution containing 40% by weight or less of PG, and at the same time have an appropriate viscosity so that it can be easily swallowed by people with dysphagia. In order to obtain a liquid medicine for internal use, a stabilizer was investigated.
As a stabilizer having both a stabilizing action and a thickening action, a sugar alcohol that is highly safe, dissolves well in water, and exhibits viscosity was investigated.
PG was 30% by weight, and D-sorbitol was selected as the sugar alcohol. Table 8 shows the amount of impurities produced when samples with a D-sorbitol concentration changed from 0 to 60% by weight (containing 1.73 mg / mL amlodipine besylate) at 40 ° C for 6 months are stored. Table 8 shows that D-sorbitol alone does not provide a stabilizing effect, but a stabilizing effect can be obtained when used in combination with 30% by weight of PG. In particular, when the amount of D-sorbitol was 30% by weight or more, the amount of the related substance was small, and the stabilizing effect was most remarkable when the amount was 50% by weight. However, a high-concentration D-sorbitol solution is not preferable in terms of appearance because it easily precipitates as a white powder when the water evaporates when left unsealed. Furthermore, D-sorbitol is said to be involved in the development of diabetic neuropathy. Therefore, it is preferable that D-sorbitol is as low as possible.

In order to reduce the concentration of D-sorbitol, we tried to use EtOH, which had a stabilizing effect in the previous study results. The results are shown in Table 9. Table 9 shows the effect of ethanol addition on specimens stored in glass vials at 40 ° C for 6 months when the amlodipine besylate concentration is 1.73 mg / mL. The total amount of related substances was examined as an indicator of the stabilizing effect. In Table 9, when 30% by weight of PG and 40% by weight of D-sorbitol were added, it was suggested that amlodipine besylate is further stabilized by adding 5% by weight of EtOH. In Table 9, the numerical value of each compounding component indicates% by weight.
In order to examine the stabilization effect by adding ethanol in more detail, specimens with various ethanol concentrations were prepared with a constant PG concentration, and the total amount of related substances and amlodipine besylate residual rate were measured when stored at 60 ° C for 14 days. Table 10 shows. (In Table 10, amlodipine besilate is expressed in mg / mL, and the others are expressed in weight%) From Table 10, a decrease in the amount of related substances and an improvement in the residual ratio of amlodipine besilate were observed with the increase in ethanol concentration. Therefore, it was revealed that amlodipine besylate is stabilized depending on the ethanol concentration. However, ethanol has strong physiological activity as already described, and it is preferable that the blending amount is as small as possible. On the other hand, in the preparations containing 30% PG by weight, 5% by weight EtOH, and 40% by weight D-sorbitol, a high residual rate was observed in both cases of 1.73 mg / mL and 3.46 mg / mL, and related substances Was found to be a stable formulation with relatively little. None of the liquid medicines for internal use consisting of these compositions had a strong bitter taste when taking 4 mL of them orally, but by adding sucralose and fragrance as sweeteners, We were able to.

3. Examination of stabilization effect by combination of stabilizers In order to clarify the stabilization effect by the combined use of propylene glycol, sorbitol and ethanol, samples shown in Table 11 were prepared and compared. Table 11 shows the total amount of related substances and the remaining amount of amlodipine besylate when stored at 60 ° C for 14 days. In Table 11, amlodipine besylate is mg / mL, and the values of the other ingredients are% by weight. Table 11 shows that the combination of propylene glycol and sorbitol has an effect that exceeds the stabilization effect of propylene glycol alone. Furthermore, Table 11 shows that the stabilization effect is further enhanced by adding D-sorbitol to the combination of propylene glycol and ethanol.

4). Examination of stability by using other organic solvents in combination with D-sorbitol Solvents that were not stable when used alone, concentrated glycerin and PEG400 were used in combination with D-sorbitol in the same manner as propylene glycol, at 90 ° C, 40 The stabilization effect when heated to a minute was investigated. The results are shown in Table 12. In Table 12, amlodipine besylate is mg / mL, and the numerical values of the other ingredients are% by weight.
From Table 12, it can be seen that concentrated glycerin and PEG400, which have become less stable by themselves, may not have a stabilizing effect similar to the combined use of PG and D-sorbitol even when used in combination with D-sorbitol. Recognize.

5. Examination of other sugar alcohols In addition, sugar alcohols other than D-sorbitol, xylitol, mannitol, erythritol, maltitol, lactitol, reduced palatinose and reduced maltose water candy were also used in combination with PG to examine the stabilizing effect. . As a result, because erythritol, mannitol, and reduced palatinose have low solubility, 30 g each was weighed into a 100 mL volumetric flask, PG 30 g and EtOH 5 g were added, and when purified water was added to make 100 mL, it did not dissolve, A good formulation could not be obtained. On the other hand, maltitol, xylitol, lactitol and reduced maltose water candy could be obtained as a uniform and clear composition when the same operation was performed. Furthermore, when they were stored at 60 ° C for 7 days, a stabilizing effect was observed as with D-sorbitol. The results are shown in Table 13.
In Table 13, amlodipine besylate is mg / mL, and the numerical values of the other ingredients are% by weight.

  Table 13 shows that the monosaccharide alcohols xylitol and D-sorbitol show better results in terms of total affinity and residual rate than the disaccharide alcohols lactitol, maltitol, and reduced maltose starch syrup. (From the hydration characteristics of sugars that contribute to the stabilization of amlodipine besylate, sugar alcohols have OH specific to each sugar in one molecule, and form stable hydrogen bonds with surrounding water molecules in aqueous solution. Therefore, the amount of water that is hydrated and bound to sugar is related to the steric conformation of sugar, which suggests that the difference between monosaccharide alcohols and disaccharide alcohols affects the degree of stabilization effect. In amlodipine besylate, it is most preferable to use monosaccharide alcohols among sugar alcohols.)

(6) Viscosity of Stable Amlodipine Besylate Solution Composition Table 14 shows the results of examining the viscosity of the stable amlodipine besylate solution composition obtained by the present invention. In Table 14, it was suggested that the amlodipine besylate solution having any composition exhibits a viscosity that is considered to be easily taken by people with dysphagia. In Table 14, amlodipine besylate is mg / mL, and the other components are% by weight.

Examples are provided below to explain the effects of the present invention in more detail.

Example 1
-Formulation study with D-sorbitol (amlodipine besylate 1.73mg / mL)-
An amlodipine besylate composition was prepared by the following method and filled into a stick-shaped bag container (width 17 mm length 140 mm) made of polyethylene film laminated with aluminum every 4 mL.

Preparation method 1. Weigh 95.2 mg of methylparaben and 31.7 mg of ethylparaben and dissolve in 10 mL of EtOH.
2. Weigh out 173 mg of amlodipine besylate and dissolve in 30 g of PG.
3. Weigh 100 mg of sucralose and weigh 61.54 g of 65% D-sorbitol solution and mix.
4.2. 3 to the mixed liquid. 1 of the mixture is mixed. Mix ethanol solution of methylparaben and ethylparaben with 6.3mL.
5. Add 10 μL of fragrance to the above preparation and add purified water to make 100 mL.

The composition of this composition is shown in Table 15. The composition was stored at room temperature for 1 year. As a result, the amount of amlodipine besylate remaining relative to the amount of total related substances produced and the beginning of storage was 0.44% and 99.1%, respectively.
In addition, no deposits were observed when opened one year later. The results showed that the amlodipine besylate formulation shown in Table 15 was stable for one year. Moreover, the taste of this composition was a pharmaceutically acceptable taste.

The viscosity at 20 ° C. of the amlodipine besylate preparation shown in Table 15 was 21.5 mPa · s.

Example 2
-A formulation consisting of D-sorbitol but with amlodipine besylate concentration of 3.46 mg / mL-
Amlodipine besylate preparations having the compositions listed in Table 16 were obtained in the same manner as in Example 1. However, only amlodipine besylate weighed 346 mg.
2 ml of this amlodipine besylate solution was filled into a stick-shaped bag (width 17 mm, length 120 mm) made of aluminum laminated polyethylene film. This was stored at room temperature for 1 year. As a result, the remaining amount of amlodipine besylate was 0.41% and 99.4%, respectively.
Therefore, the amlodipine besylate formulation shown in Table 16 was shown to be stable for one year. It was the same as in Example 1 that no precipitate was observed when opened one year later, and the taste was the same as in Example 1.

Example 3
-Examination of prescription consisting of xylitol (amlodipine besylate 1.73mg / mL)-
Amlodipine besylate preparations having the compositions listed in Table 17 were obtained in the same manner as in Example 1 except that only D-sorbitol was replaced with xylitol.
4 ml of this amlodipine besylate solution was filled in a brown glass ampule and stored at room temperature for 3 months. The total amount of related substances and the remaining amount of amlodipine besylate after 3 months were 0.15% and 99.89%, respectively, indicating that the amlodipine besylate preparation shown in Table 17 was stable for 3 months. It was the same as in Example 1 that no precipitate was observed when opened 3 months later, and the taste was the same as in Example 1.

Example 4
-Formulation of D-sorbitol but not containing EtOH, 50% D-sorbitol (amlodipine besylate 1.73mg / mL)-
An amlodipine besylate preparation composition comprising 30% by weight of PG and 50% by weight of D-sorbitol was prepared by the following preparation method.

Preparation method 1. Weigh out 173 mg of amlodipine besylate and dissolve in 30 g of propylene glycol.
2.1. 71.4 g of 70% D-sorbitol solution is weighed and mixed.
3. Add purified water to the above prepared solution to make 100 mL.

80 mL of this amlodipine besylate solution was filled into a 100 mL brown glass bottle and stored at room temperature for 6 months. As a result, there was no change in appearance, the amount of total related substances produced and the residual ratio of amlodipine besylate were 0.18% and 99.57%, respectively, and the above-mentioned amlodipine besylate preparation was stable for 6 months It was shown that.

Example 5
-Prescription of current active ingredient concentration (Amlodipine besylate 3.46mg / mL) consisting of maltitol-
An amlodipine besylate preparation composition (amlodipine besylate 0.346% by weight) comprising PG 30% by weight, maltitol 30% by weight, and ethanol 5% by weight was prepared by the following preparation method.

Preparation method 1. Weigh 30 g of D-maltitol, add 20 g of purified water, and dissolve by heating.
2. Weigh out 346 mg of amlodipine besylate and add 6.3 mL of ethanol and 30 g of propylene glycol to dissolve.
3.1. 2 to the mixed liquid. Mix the mixture.
4). Add purified water to the above prepared solution to make 100 mL.

This amlodipine besylate solution was filled into a brown glass ampule every 2 mL.
As a result of storage at room temperature for 4 months, no change was observed in the appearance and properties, the total amount of related substances produced and the residual rate at the start of storage were 0.19% and 98.84%, respectively, and the above amlodipine besylate preparation was It was shown to be stable for 4 months.

[The invention's effect]
The liquid pharmaceutical preparation for oral administration of amlodipine besylate of the present invention is a stable preparation with little change in properties and generation of related substances even when stored at room temperature in a brown glass bottle, ampoule or stick packaging for 3 months to 1 year. In addition, these preparations have moderate viscosity that is easy to be taken orally even for persons with dysphagia, and are practical and stable liquid medicine for oral administration of amlodipine besylate.

Claims (10)

An amlodipine besylate oral solution obtained by dissolving amlodipine besylate in an aqueous solution containing propylene glycol and sugar alcohols as essential components. The liquid for internal use of amlodipine besylate according to claim 1, which contains substantially no surfactant and / or polyethylene glycol and / or glycerin. The liquid medicine for internal use of amlodipine besylate according to claim 1 or 2, wherein the sugar alcohol is one or more selected from the group consisting of D-sorbitol, xylitol, maltitol, reduced maltose water candy, and lactitol. The liquid for internal use of amlodipine besylate according to any one of claims 1 to 3, comprising 2 to 20% by weight of ethanol. 5. The amlodipine besilate concentration according to any one of claims 1 to 4, wherein the amlodipine besylate concentration is 0.69 mg / mL (0.5 mg / mL as amlodipine) to 10.4 mg / mL (7.5 mg / mL as amlodipine). Liquid for internal use. The liquid for internal use of amlodipine besylate according to any one of claims 1 to 5, wherein the water content is 10 wt% or more and 60 wt% or less. The liquid for internal use of amlodipine besylate according to any one of claims 1 to 6, wherein the propylene glycol content is 10% by weight or more and less than 70% by weight. The liquid for oral administration of amlodipine besylate according to any one of claims 1 to 7, wherein the sugar alcohol is 10% by weight or more and less than 70% by weight. 9. The amlodipine besylate internal use liquid preparation according to any one of claims 1 to 8, which does not contain a pH buffer. 10. The liquid for internal use of amlodipine besylate according to claim 1, wherein the viscosity at 20 ° C. is 5 mPa · s to 200 mPa · s.