JP6039849B1 - Aripiprazole-containing internal preparation - Google Patents

Abstract

A solution for internal use of aripiprazole, which is stable even when stored for a long period of time and in which the formation of related substances over time is suppressed, is provided. An internal solution containing aripiprazole, hydrochloric acid and malic acid. The internal solution is excellent in storage stability because generation of related substances is suppressed even when stored for a long period of time. [Selection figure] None

Description

  The present invention relates to a liquid preparation for internal use comprising aripiprazole as an active ingredient. Specifically, the present invention relates to an internal solution containing aripiprazole, hydrochloric acid, and malic acid.

Aripiprazole which is an active ingredient in the present invention, that is, 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] -butoxy} -3,4-dihydrocarbostyril (7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] -butoxy} -3,4-dihydro-2 (1H) -quinolinone) is an effective antipsychotic agent for the treatment of schizophrenia, It is a D ₂ and serotonin 5-HT _1A receptor agonist and an antagonist of serotonin 5-HT _2A receptor. Aripiprazole is widely used as a drug for the treatment of schizophrenia and other psychiatric and central nervous system disorders.

  Since it can be easily administered to children, elderly patients and the like who are difficult to swallow solid oral preparations, an internal solution for aripiprazole can be said to be a dosage form suitable for administration to these patients.

  Regarding an internal solution containing aripiprazole, Patent Document 1 discloses a medically suitable solvent comprising one or more agents selected from the group consisting of aripiprazole, water, a surfactant, a water-miscible solvent, and a solubilizing agent, A medical solution containing one or more flavor improving / masking agents and one or more compounds selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid, and having a pH of 2.5 to 4.5 and suitable for oral administration Is disclosed. Patent Document 2 relates to an aripiprazole pharmaceutical preparation containing an antioxidant, and Examples and Examples describe tablets and suspensions using various acids as acidifying agents. Patent Document 3 discloses a technique of adding a specific organic acid such as malic acid when preparing an internal solution of aripiprazole for the purpose of improving the solubility of aripiprazole in an aqueous solvent.

Japanese Patent No. 4401777 Special table 2014-522820 gazette JP 2015-164907 A

  The present inventors have a problem that when aripiprazole is used as a solution, aripiprazole generates a related substance by decomposition or the like, and when stored for a long period of time, the related substance increases over time. Recognized for the first time. There is no report on this problem at the time of the priority date of the present application, and the above-mentioned Patent Documents 1 and 2 have no suggestion or teaching about this problem and means for solving it. In addition, although the said patent document 3 has described the increase of the related substance in a liquid agent, this patent document is not what was published at the time of the priority date of this application.

  Accordingly, an object of the present invention is to provide an aripiprazole internal solution in which the production of related substances is suppressed during long-term storage.

  As a result of various studies to solve the above problems, the present inventors have suppressed the generation of related substances over time in an internal solution containing aripiprazole, hydrochloric acid and malic acid, The present invention was completed by discovering that it is a stable internal solution during storage.

That is, the following internal solution is provided by the present invention.
(1) An internal solution containing aripiprazole, hydrochloric acid, and malic acid.
(2) The internal solution according to (1) above, wherein the weight ratio of hydrochloric acid to malic acid [hydrochloric acid / malic acid] is in the range of 0.1 to 3.0.
(3) The internal solution according to (1) or (2) above, which contains one or more additives selected from the group consisting of glycerin, propylene glycol, and sodium hydroxide.

  The internal use liquid preparation of the present invention is an internal use liquid preparation in which the generation of aripiprazole-related substances is suppressed and is stable even when stored for a long period of time.

Hereinafter, the present invention will be described in detail.
The content of aripiprazole in 100% by weight of the internal solution of the present invention is not particularly limited, but is generally 0.005 to 10% by weight, preferably 0.01 to 0.5% by weight. %, More preferably 0.05 to 0.25% by weight.

Any malic acid used in the present invention can be used as long as it is used for pharmaceuticals, and salts thereof such as sodium, zinc, calcium, magnesium and the like may be used. The amount of malic acid added is not particularly limited. For example, in 100% by weight of the internal solution, 0.001 to 5% by weight is preferable, more preferably 0.01 to 1% by weight, and still more preferably. Is 0.01 to 0.2% by weight.
In addition, in this specification, the weight of the salt of malic acid is the weight converted into malic acid.

Any hydrochloric acid can be used as long as it is used for pharmaceutical use. Although the addition amount of hydrochloric acid used in the present invention is not particularly limited, for example, 0.001 to 5% by weight is preferable in 100% by weight of an internal solution, and more preferably 0.01 to 1% by weight. Yes, and more preferably 0.05 to 0.2% by weight.
In the present specification, the amount of hydrochloric acid is a net amount as hydrogen chloride.

  According to the present invention, by adding hydrochloric acid and malic acid to an internal solution containing aripiprazole as an active ingredient, generation of aripiprazole-related substances over time in the internal solution can be suppressed. When only one of hydrochloric acid or malic acid is blended, the above inhibitory effect cannot be obtained sufficiently.

  The weight ratio of hydrochloric acid to malic acid [hydrochloric acid / malic acid] is not particularly limited, but is preferably 0.1 to 3.0, more preferably 0.2 to 2.0, 0.3 to 1.2 is more preferable, and 0.5 to 1.0 is particularly preferable. If it is in the said range, the time-dependent production | generation of related substances can be suppressed more efficiently.

  Although the total addition amount of hydrochloric acid and malic acid is not specifically limited, For example, 100-500 weight part is preferable with respect to 100 weight part of aripiprazole, and 150-300 weight part is more preferable. If it is in the said range, the time-dependent production | generation of related substances can be suppressed more efficiently.

  The internal use liquid preparation of the present invention preferably adjusts the pH to a certain range. The pH of the internal solution of the present invention may be usually about 2 to 4, but is preferably adjusted to a range of 2.7 to 3.5 from the viewpoint of long-term stability. By adjusting the pH within this preferable range, it is possible to efficiently suppress the production of related substances and provide an internal liquid preparation having high stability.

  The internal use liquid preparation of this invention can contain a sweetening agent in order to improve ingestion property. Although the kind of sweetener is not specifically limited, For example, a high sweetness degree sweetener can be used. Examples of the high-intensity sweetener include sucralose, thaumatin, acesulfame potassium, saccharin sodium, and aspartame, preferably sucralose and / or thaumatin. Two or more of these sweeteners may be used in combination.

  The liquid preparation for internal use of the present invention may contain a fragrance and / or a preservative. Although the kind of fragrance | flavor is not specifically limited, For example, strawberry, pineapple, orange, apple, grapefruit, mint, menthol, etc. can be used. Two or more of these may be used in combination.

  The kind of the preservative is not particularly limited. For example, benzoic acid, sodium benzoate, hydroxypropyl benzoate, sodium propylhydroxybenzoate, methyl hydroxybenzoate, or sodium methylhydroxybenzoate may be used. it can. Two or more of these may be used in combination.

  Further, the liquid preparation for internal use of the present invention includes, for example, sodium alginate, carboxyvinyl polymer, carmellose sodium, xanthan gum, crystalline cellulose, carmellose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose as other pharmacologically acceptable additives. , Hydroxypropylmethylcellulose, polyvinyl alcohol, glycerin, concentrated glycerin, propylene glycol, polyethylene glycol, trehalose, sucrose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, or the like. Two or more of these may be used in combination.

  The present inventors have confirmed that when the internal preparation of the present invention contains one or more of glycerin, propylene glycol, and sodium hydroxide, the production of aripiprazole-related substances over time can be more efficiently suppressed. ing. Therefore, it is more preferable to add at least one of glycerin, propylene glycol, and sodium hydroxide to the internal use liquid preparation of the present invention.

  The internal use liquid agent of this invention can be manufactured by melt | dissolving aripiprazole, hydrochloric acid, malic acid, and 1 or more types of additives as needed in water, such as ion-exchange water and distilled water. In addition, when dissolving aripiprazole among the above components, and when adding one or more of the other components to aripiprazole and dissolving in water, heat dissolution treatment is performed in the range of 70 to 90 ° C. Thus, it is possible to obtain a liquid for internal use in which aripiprazole hardly precipitates even when stored in a cold place.

  The time for the heat treatment is not particularly limited, but is preferably 5 minutes or longer, more preferably 10 minutes or longer, and even more preferably 20 minutes or longer from the viewpoint of sufficiently obtaining the effect of the heat treatment. Moreover, since sufficient effect is acquired in 1 hour, it is preferable that heating time shall be 1 hour or less. The above heat treatment needs to be performed on a solution in which at least aripiprazole is dissolved, and is preferably performed on a solution in which aripiprazole, hydrochloric acid and / or malic acid is dissolved, and aripiprazole, hydrochloric acid and apple It is more preferable to carry out with respect to the solution in which the acid is dissolved.

  The liquid preparation for internal use of the present invention can be used as an oral preparation, and the liquid preparation for internal use of the present invention can be directly administered to a patient without dilution at the time of use. The container for filling the internal liquid preparation of the present invention is not particularly limited. For example, if it is a pharmaceutically acceptable container that can be filled with the internal liquid preparation and can be sealed, Any container can be suitably used. The material of the container is not particularly limited, and any pharmaceutically acceptable one can be used. For example, examples of the material include glass, plastic, or aluminum laminate film.

  In the liquid preparation for internal use provided by the present invention, generation of aripiprazole-related substances is suppressed even during long-term storage. The related substances of aripiprazole include, for example, the United States Pharmacopeia (USP) and “Abilify (registered trademark) 3 mg, 6 mg, 12 mg, 3 mg, 3 mg, 6 mg, 6 mg, 12 mg, OD The following seven substances can be mentioned as described in "Tablet 24 mg, Dosan 1%, Internal Solution 0.1% Pharmaceutical Interview Form (IF) June 2013 (Revised 15th Edition)". However, it is not limited to these. The above 7 types of related substances can be purchased as reagents. For example, by using these as internal standards in the purity test using high performance liquid chromatography in the following examples, a conventional aripiprazole internal solution , It can be confirmed that a peak derived from a related substance occurs at a position different from the peak of aripiprazole. In a normal case, the generation of a plurality of related substances can be confirmed, but only one kind of related substances may be generated. Moreover, the production | generation ratio of each related substance can be easily determined by measuring the peak area of aripiprazole and the peak area derived from each related substance by an automatic integration method. In this specification, the term “suppression of the production of related substances” is a concept that includes the suppression of the total amount of one or more related substances to be generated, as well as the control of the production of one or more specific related substances. It is. Preferably, the production of related compound G, which is considered to be mainly produced by oxidation from aripiprazole, is confirmed, so that generation of related substances from aripiprazole in the internal solution of the present invention compared to the internal solution containing no malic acid and hydrochloric acid It can be confirmed that is significantly suppressed.

  EXAMPLES Hereinafter, although an Example, a comparative example, and a test example demonstrate this invention further more concretely, these examples do not limit the scope of the present invention.

[Example 1]
According to the formulation of Table 2, the aripiprazole internal preparation of Example 1 was obtained. Specifically, first, acid, aripiprazole and glycerin were dissolved in purified water, dissolution was confirmed, and then an aqueous sodium hydroxide solution was added to adjust the pH to the values shown in Table 2. Thereafter, the solution was stirred at 80 ° C. for 30 minutes, and then propylene glycol and sucralose were sequentially added and stirred. After confirming dissolution, the solution was filtered to obtain an aripiprazole internal solution.
About the obtained aripiprazole internal use liquid agent, the purity test of the following test example was done.

<Test example>
(Purity test)
The aripiprazole internal preparation of Example 1 was placed in a thermostatic bath and stored in an environment of 60 ° C. for 1 week and 2 weeks. Purity tests were conducted by the following method for each internal solution after storage and internal solution before storage (initial).
First, a volume corresponding to 2 mg of aripiprazole is taken based on the formulation in Table 2, and this is added to a diluent (solution of water: acetonitrile: methanol: acetic acid = 60: 30: 10: 1 (volume ratio)). 20 mL was used as a sample solution. 1 mL of the sample solution was accurately weighed, and the diluent was added to make exactly 100 mL, which was used as a standard solution. Then, the sample solution and the standard solution were quantitatively analyzed by high performance liquid chromatography under the following conditions, and the peak area derived from aripiprazole and the peak area derived from each related substance were measured by an automatic integration method. The results are shown in Table 2. In addition, the total amount of related substances described in Table 2 represents (the sum of the peak areas derived from the related substances in the sample solution / the peak area derived from aripiprazole in the standard solution) × 0.01 × 100 (%).
The standard solution was analyzed for the purpose of confirming the suitability of the analysis system.

(Measurement conditions for high performance liquid chromatography)
Detector: UV absorption photometer (measurement wavelength: 254 nm).
Column: A column filled with octadecylsilylated silica gel for liquid chromatography 3 μm in a stainless steel tube having an inner diameter of 4.6 mm and a length of 10 cm.
Column temperature: constant temperature around 30 ° C.
Mobile phase A: a solution comprising 90% by volume of an aqueous solution obtained by adding water to 1 mL of trifluoroacetic acid to make 2000 mL, and 10% by volume of acetonitrile.
Mobile phase B: A solution comprising 10% by volume of an aqueous solution obtained by adding water to 1 mL of trifluoroacetic acid to give 2000 mL, and 90% by volume of acetonitrile.
Mobile phase feeding: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 3 below.

流量：毎分１．２ｍＬ

Flow rate: 1.2 mL per minute

[Example 2, Comparative Examples 1-3]
Except having changed into the prescription of Table 2, the aripiprazole internal solution of each case was obtained by the same method as Example 1. In the example where sodium edetate hydrate was added, the liquid was stirred at 80 ° C. for 30 minutes, and then sodium edetate hydrate was added between the addition of propylene glycol and the addition of sucralose.
About the obtained aripiprazole internal use liquid agent, the purity test was done by the method similar to Example 1. FIG. The results are shown in Table 2.
In addition, since aripiprazole will precipitate when pH is adjusted to about 3 when phosphoric acid is used, in Comparative Example 1 using phosphoric acid, it adjusted so that pH might become lower than another example.

[Example 3]
According to the formulation of Table 2, the aripiprazole internal preparation of Example 3 was obtained. Specifically, first, acid, aripiprazole, glycerin, and a part of propylene glycol (amount of 20% of propylene glycol shown in the table) are dissolved in purified water, dissolution is confirmed, and then an aqueous sodium hydroxide solution Was added to adjust the pH to the values listed in Table 2. Then, the following separately prepared paraben solution and sodium edetate hydrate prepared separately were added to the solution and stirred at 80 ° C. for 30 minutes. By filtration, an aripiprazole internal solution was obtained.
The paraben solution was prepared by dissolving methyl hydroxybenzoate and propyl hydroxybenzoate in a part of propylene glycol (an amount of 80% of propylene glycol shown in the table).
About the obtained aripiprazole internal use liquid agent, the purity test was done by the method similar to Example 1. FIG. The results are shown in Table 2.

As shown in Table 2, in the internal use liquid preparations of Examples 1 to 3 in which hydrochloric acid and malic acid were used in combination, generation of aripiprazole analogs over time was suppressed.
In addition, when the aripiprazole internal preparation of each Example was separately preserve | saved at 5 degreeC for 2 weeks, and the presence or absence of crystal precipitation was observed, crystal precipitation was not confirmed in any Example.

  The aripiprazole internal use liquid preparation of the present invention suppresses the generation of aripiprazole analogues over time, and is stable even when stored for a long time.

Claims (3)

Aripiprazole, hydrochloric, and contains malic acid, liquid for internal use, wherein the Rukoto generation over time in related substances are suppressed. The internal solution according to claim 1, wherein the weight ratio of hydrochloric acid to malic acid [hydrochloric acid / malic acid] is in the range of 0.1 to 3.0. The internal use liquid agent of Claim 1 or 2 containing the 1 or more types of additive chosen from the group which consists of glycerin, propylene glycol, and sodium hydroxide.