JP2015189677A - Pharmaceutical composition comprising solifenacin amorphous body - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition comprising a stable solifenacin amorphous body.SOLUTION: A pharmaceutical composition comprises an amorphous body of solifenacin or pharmaceutically acceptable salt thereof, and at least one selected from malic acid or pharmaceutically acceptable salt thereof and meglumine or pharmaceutically acceptable salt thereof.

Description

  The present invention relates to a pharmaceutical composition containing a stable solifenacin amorphous form.

  Solifenacin or a pharmaceutically acceptable salt thereof is known as a pharmaceutical active ingredient useful as a therapeutic and / or prophylactic agent for urological diseases such as frequent urination and urinary incontinence. Solifenacin has the following formula:

The chemical name is (R) -quinuclidin-3-yl (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate. Solifenacin is also known as the free base form and the succinate form (lysofenacin succinate).

  Solifenacin succinate is a bladder spasm that functions as a selective antagonist for the muscarinic M3 receptor and is a symptom of overactive bladder (eg, urgency, urination frequency that may occur in patients with overactive bladder syndrome (OAB)) It is used as a therapeutic agent. In addition, it is reported to be useful as a preventive and therapeutic agent for gastrointestinal diseases such as chronic obstructive pulmonary disease, chronic bronchitis, respiratory diseases such as asthma and rhinitis, irritable bowel syndrome, spastic colitis and diverticulitis. (Patent Document 1). In particular, the present compound has a higher selectivity for M3 receptors present in smooth muscle, glandular tissues and the like compared to M2 receptors present in the heart and the like, and as an M3 receptor antagonist with few side effects on the heart and the like. It is particularly useful as a preventive or therapeutic agent for urinary incontinence, frequent urination, chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis. Solifenacin is currently sold in Japan as a treatment for urgency, frequent urination and urge urinary incontinence in overactive bladder, as Vesicare®, VESIcare® in the US, and Vesicare® in Europe Has been.

  Thus far, attempts have been made to obtain a stable pharmaceutical composition / pharmaceutical formulation for solifenacin succinate, which is a useful pharmaceutical ingredient.

  So far, solifenacin is a non-soliphenacin by adding a stabilizer such as citric acid or a technology for ensuring stability by limiting the proportion of amorphous solifenacin as an active ingredient. A technique (Patent Document 3) that ensures stabilization even in a crystalline state has been reported.

International Publication No. WO96 / 20144 Pamphlet International Publication No. WO2005 / 092889 Pamphlet International Publication No. WO2010 / 113840 Pamphlet

  However, first, the invention described in Patent Document 2 is not a technique that stabilizes the amorphous form of solifenacin itself, and the invention described in Patent Document 3 uses an amorphous form of solifenacin by using citric acid. However, citric acid is not suitable for use in compression molded formulations.

  Therefore, in order to provide a stable pharmaceutical composition containing an amorphous form of solifenacin, further improvement has been demanded at present.

  The present invention has been made in view of the above points, and an object thereof is to provide a more stable pharmaceutical composition containing an amorphous form of solifenacin.

  A pharmaceutical composition according to one embodiment of the present invention includes an amorphous form of solifenacin or a pharmaceutically acceptable salt thereof, malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutically acceptable salt thereof. And at least one solifenacin amorphous amorphous maintenance agent selected from acceptable salts.

  In the above pharmaceutical composition, it is preferable that the amorphous body maintenance agent is contained in a ratio of 1: 1 or more with respect to the amount of solifenacin or an amorphous body of a pharmaceutically acceptable salt thereof.

  Moreover, in the said pharmaceutical composition, it is preferable that content of the said amorphous body maintenance agent in a pharmaceutical composition is 1 mass%-50 mass%.

  Furthermore, it is preferable that the pharmaceutical composition contains an adsorbent.

  In the pharmaceutical composition, the adsorbent is preferably at least one selected from the group consisting of mannitol, partially pregelatinized starch, magnesium aluminate metasilicate, crystalline cellulose, calcium silicate, and the like.

  Furthermore, it is preferable that the pharmaceutical composition contains a binder.

  In the pharmaceutical composition, the binder is preferably at least one selected from the group consisting of polyvinylpyrrolidone, hypromellose, pullulan, methylcellulose, and the like.

  The pharmaceutical composition is preferably an intraoral quick disintegrating tablet.

  Further, according to another embodiment of the present invention, a method for producing a pharmaceutical composition containing an amorphous form of solifenacin or a pharmaceutically acceptable salt thereof includes malic acid or a pharmaceutically acceptable salt thereof. And at least one selected from meglumine or a pharmaceutically acceptable salt thereof is sprayed with a solution in which solifenacin or a pharmaceutically acceptable salt thereof is dissolved in a solvent to make the solifenacin amorphous. Including a process.

  According to still another aspect of the present invention, a method for stabilizing an amorphous form of solifenacin or a pharmaceutically acceptable salt thereof comprises malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutical thereof. Stabilization is carried out by adding at least one amorphous solifenacin amorphous maintenance agent selected from pharmaceutically acceptable salts.

  According to the present invention, it is possible to provide a pharmaceutical composition containing a stable amorphous form of solifenacin which is superior to conventional ones. That is, the amorphous solifenacin succinate contained in the pharmaceutical composition of the present invention can maintain a stable amorphous state over time.

  As used herein, “amorphous” or “amorphous form” of solifenacin or a pharmaceutically acceptable salt thereof means that solifenacin or a pharmaceutically acceptable salt thereof is crystallographically amorphous. It means having the structure.

  The method for evaluating the crystal state of solifenacin or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is a method capable of identifying the crystal structure. For example, powder X-ray diffraction (XRD), DSC measurement, Examples of the method include measurement by NMR measurement or near infrared spectroscopy. For example, when the evaluation is performed using the XRD method, it should not be interpreted strictly because it varies somewhat depending on the measurement conditions, but a specific peak derived from a solifenacin crystalline substance seen in the vicinity of 2θ = 10 ° C. is seen. If not, it can be determined to be amorphous.

  Hereinafter, although the embodiment concerning the present invention is described, the present invention is not limited to these.

  The pharmaceutical composition of the present embodiment is characterized by containing an amorphous form of solifenacin or a pharmaceutically acceptable salt thereof and an amorphous form maintenance agent.

  First, “solifenacin or a pharmaceutically acceptable salt thereof” or “a salt of solifenacin” used in the present embodiment means solifenacin or a pharmaceutically acceptable salt thereof, specifically For example, succinic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, Examples include acid addition salts and quaternary ammonium salts with organic acids such as glutamic acid, and mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid (Patent Document 1). ). Among them, succinate of solifenacin is preferable in providing as a pharmaceutical product.

  “Solifenacin or a pharmaceutically acceptable salt thereof” used in the present embodiment can be produced by a known method, specifically, for example, by the method described in Patent Document 1 or It can be easily obtained by a production method according to it.

  In the present embodiment, the method for obtaining “amorphous form of solifenacin or a pharmaceutically acceptable salt thereof” from “solifenacin or a pharmaceutically acceptable salt thereof” is not particularly limited as long as it is a general method. Is not to be done. Specifically, a method of mixing “solifenacin or a pharmaceutically acceptable salt thereof” with any additive or subsequent grinding, “solifenacin or a pharmaceutically acceptable salt thereof” such as freeze drying or spray drying. The `` Salt '' is dissolved in some solvent and dried again, and the `` Solifenacin or its pharmaceutically acceptable salt '' dissolved in some form is adsorbed on some carrier. It is not limited to.

  The blending amount of solifenacin or an amorphous form of the salt thereof in the pharmaceutical composition of the present embodiment is usually appropriately selected depending on the pharmaceutical use (indication), and is therapeutically or prophylactically effective in the pharmaceutical use. The amount is not particularly limited as long as it is an appropriate amount. As such a compounding quantity, it is 0.1 mass% or more normally with respect to the whole pharmaceutical composition, Preferably, it is 0.5 mass% or more, More preferably, it is 1 mass% or more. Moreover, it is 50 mass% or less normally, Preferably it is 40 mass% or less, More preferably, it is 30 mass% or less.

  Further, the amount of solifenacin in the preparation is usually 0.1 mg or more, preferably 0.5 mg or more, more preferably 1 mg or more. Moreover, it is 100 mg or less normally, Preferably it is 30 mg or less, More preferably, it is 20 mg or less.

  Next, the pharmaceutical composition of this embodiment contains at least one selected from malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutically acceptable salt thereof as an essential component. . In this embodiment, at least one selected from malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutically acceptable salt thereof is “solifenacin or a pharmaceutically acceptable salt thereof. It has a role as an amorphous body maintaining agent for maintaining the amorphous state of the “amorphous body”. Hereinafter, in the present specification, at least one selected from malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutically acceptable salt thereof is simply referred to as an amorphous body maintenance agent. There is also.

  Malic acid is not particularly limited in either L-form or D-form. The pharmaceutically acceptable salt thereof is not particularly limited, and specific examples include malic acid, sodium malate, disodium malate, calcium malate and the like. Further, a derivative of malic acid can be used as long as the effects of the present invention are not impaired.

  Although it does not restrict | limit especially as a meglumine or its pharmaceutically acceptable salt, For example, a meglumine, meglumine hydrochloride, etc. are mentioned.

  In addition, the said amorphous body maintenance agent may be used independently, or may be used in combination of 2 or more type.

  As a mixing ratio of the amorphous body maintenance agent blended in the pharmaceutical composition of the present embodiment, the above-mentioned “amorphous body of solifenacin or a pharmaceutically acceptable salt thereof” can be maintained in a stable state. If it is a range, it will not restrict | limit in particular, Usually, it is preferable that it is a ratio of about 1 mass% or more with respect to the amorphous body amount of solifenacin or its pharmaceutically acceptable salt. Furthermore, it is preferably 10% by mass or more, more preferably 50% by mass or more. A highly stable solifenacin is obtained by including an amorphous body maintenance agent in a ratio of 100% by mass or more with respect to the amorphous body amount of the active ingredient solifenacin or a pharmaceutically acceptable salt thereof. Alternatively, a pharmaceutical composition containing an amorphous form of a pharmaceutically acceptable salt thereof can be obtained.

  More preferably, from the viewpoint of maintaining “an amorphous form of solifenacin or a pharmaceutically acceptable salt thereof” over time, an amorphous form relative to solifenacin or a pharmaceutically acceptable salt thereof. It is desirable to contain the maintenance agent at a ratio of 1: 1 or more.

  Moreover, the compounding quantity of the amorphous body maintenance agent in a pharmaceutical composition is 0.1 mass% or more, for example, Preferably, it is 0.5 mass% or more, More preferably, it is 1 mass% or more. . Moreover, it is 90 mass% or less normally, Preferably it is 80 mass% or less, More preferably, it is 50 mass% or less.

  In order to maintain the amorphous body in the composition and ensure higher stability, the pharmaceutical composition of the present embodiment may further contain an adsorbent.

  By containing the adsorbent, the amorphous body and the amorphous body maintaining agent can be efficiently contacted, and as a result, the stability is further improved and the productivity is improved.

  Specific examples of the adsorbent include calcium silicate, mannitol, partially pregelatinized starch, crystalline cellulose, soft anhydrous silicic acid, magnesium metasilicate aluminate, and the like. May be used in combination.

  More preferred adsorbents include mannitol, partially pregelatinized starch, crystalline cellulose, magnesium aluminate metasilicate, calcium silicate and the like.

  When these adsorbents are used, it is usually preferable that the ratio be about 1% by mass or more with respect to the amount of solifenacin or the pharmaceutically acceptable salt thereof. Furthermore, the ratio is more preferably about 50% by mass or more, and the best ratio is 100% by mass. The blending ratio in the pharmaceutical composition is not particularly limited as long as the effect of the present invention is not hindered. However, the blending amount is, for example, usually 0.1% by mass or more with respect to the entire pharmaceutical composition. The amount is preferably 0.5% by mass or more, and more preferably 1% by mass or more. Moreover, it is 90 mass% or less normally, Preferably it is 80 mass% or less, More preferably, it is 50 mass% or less.

  Furthermore, in order to ensure higher stability of the active ingredient, the pharmaceutical composition of the present embodiment may contain a binder.

  By containing the binder, the contact between the amorphous body and the amorphous body maintaining agent can be maintained. As a result, the solifenacin can be made amorphous over time. Any additive capable of obtaining such an effect can be used as the binder of the present invention.

  Specific binders include, for example, water-soluble substances such as polyvinylpyrrolidone, hypromellose, pullulan, methylcellulose, hydroxypropylcellulose, ethylcellulose, macrogol, polyvinyl alcohol, methacrylic acid copolymer, pregelatinized starch, starches and agar. Examples include macromolecules, sugars, sugar alcohols such as mannitol. More preferable binders include polyvinyl pyrrolidone, hypromellose, pullulan, methylcellulose and the like. These may be used alone or in combination of two or more.

  Furthermore, when the amorphous body maintenance agent is malic acid or a salt thereof, a preferred binder is hypromellose, and when the amorphous body maintenance agent is meglumine or a salt thereof, a preferred binder. Is polyvinylpyrrolidone, pullulan or methylcellulose, and the most preferred binder is methylcellulose.

  Moreover, when using these binders, it is preferable that it is normally a ratio of about 1 mass% or more with respect to the amorphous amount of solifenacin or its pharmaceutically acceptable salt. Furthermore, the ratio is more preferably about 20% by mass or more, and the best ratio is 100% by mass. The blending ratio in the pharmaceutical composition is not particularly limited as long as it does not interfere with the effects of the present invention, but is appropriately selected within a range such that it is usually contained in the pharmaceutical composition at a ratio of 0.1 to 40% by mass. Can be used. From the viewpoint of manufacturability, it is preferably 0.2% by mass or more, and more preferably 0.5% by mass or more. Moreover, it is preferably 35% by mass or less, and more preferably 25% by mass or less.

  In the pharmaceutical composition of the present embodiment, various additives can be further blended as necessary in addition to the above components. Specific additives are not particularly limited as long as they are pharmaceutically acceptable and pharmacologically acceptable. For example, excipients, disintegrants, binders, acidulants, foaming agents, sweeteners, fragrances, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants, coating agents, etc. Is done.

  Examples of the excipient include sugars such as dextran, dextrin, glucose, powdered sugar, and lactose, starches such as corn starch, and sugar alcohols such as crystalline cellulose and mannitol.

  Examples of the disintegrant include starches such as corn starch, partially pregelatinized starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose.

  Examples of the binder include hydroxypropyl cellulose, hypromellose, methyl cellulose, partially pregelatinized starch, polyvinyl pyrrolidone, and polyvinyl alcohol.

  Examples of the sour agent include benzoic acid and its compound, tartaric acid, ascorbic acid and the like.

  Examples of the foaming agent include sodium bicarbonate and sodium carbonate.

  Sweeteners include, for example, sugars and sugar alcohols such as sucrose, fructose, maltose, sucrose, glucose, fructose, isomerized liquid sugar, fructooligosaccharides, cyclic oligosaccharides, saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, Examples include thaumatin.

  Examples of the fragrances include menthol, orange extract, camphor, and vanillin.

  Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated oil, sodium stearyl fumarate, sucrose fatty acid ester and the like.

  Examples of the colorant include yellow ferric oxide, ferric oxide, iron oxide, titanium oxide, yellow No. 5, blue No. 1, yellow No. 4, red No. 2, red No. 3, red No. 102, copper chlorophyll and the like. It is done.

  Examples of the buffer include citric acid, sodium citrate, sodium hydrogen carbonate, sodium carbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate and the like.

  Examples of the antioxidant include tocopherol, hydroquinone, sodium hydrogen sulfite, sodium sulfite, butylhydroxyanisole and the like.

  Examples of the surfactant include macrogol, polysorbate, polyoxyethylene hydrogenated castor oil, and sodium lauryl sulfate.

  Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid. Acid copolymer LD, methacrylic acid copolymer S, etc. are mentioned.

  Any of these additives can be appropriately added in an appropriate amount by combining one kind or two or more kinds as necessary.

  The dosage unit form of the pharmaceutical composition of the present embodiment can be appropriately selected depending on the therapeutic purpose. Representative examples include solid dosage forms such as tablets, pills, powders, powders, granules, capsules and the like. These are further classified into oral preparations, parenteral preparations, nasal preparations, vaginal preparations, suppositories, sublingual preparations, ointments, etc., depending on the route of administration. Can do.

  Moreover, the administration method of the pharmaceutical composition of this embodiment is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, disease severity, and the like. For example, tablets, pills, granules and capsules are administered orally, injections are mixed with normal fluids such as glucose and amino acids and administered intravenously, and if necessary alone, intramuscularly, intradermally, subcutaneously or Administered intraperitoneally, suppositories administered rectally, vaginal preparations administered vaginally, nasal preparations administered intranasally, sublingual preparations administered orally, ointments administered topically transdermally .

  Among these, from the viewpoint of portability and ease of taking, it is preferably in the form of a solid preparation, particularly an intraoral quick disintegrating agent (OD tablet).

  The dosage of the preparation using the pharmaceutical composition of the present embodiment is appropriately determined according to individual cases in consideration of the administration route, disease symptoms, age of the administration subject, sex, and the like. As an example, when solifenacin succinate is used as an active ingredient, the dose of the active ingredient per adult is usually about 0.01 mg / kg to 100 mg / kg / day for oral administration, and this can be performed once or Administer in 2 to 4 divided doses. In addition, when intravenously administered depending on symptoms, it is usually administered once to several times a day in the range of 0.01 mg / kg to 10 mg / kg per adult.

  The pharmaceutical composition of the present embodiment can be produced by a conventionally known ordinary method. A method of mixing or subsequently pulverizing "solifenacin or a pharmaceutically acceptable salt thereof, specifically, solifenacin or a pharmaceutically acceptable salt thereof" and any additive, A method of dissolving "Solifenacin or a pharmaceutically acceptable salt thereof" in some solvent and then drying again, such as freeze-drying or spray-drying, "Solifenacin or a pharmaceutically acceptable solution thereof" Examples of the method include, but are not limited to, a method of adsorbing the “salt” to a certain carrier. Preferably, it is a method of adsorbing “Solifenacin or a pharmaceutically acceptable salt thereof” dissolved in some form on a carrier. The solvent that can be used in the method is not particularly limited as long as the effects of the invention are not impaired. Specific examples include purified water, methyl alcohol, ethyl alcohol, and propyl alcohol. Preferably, purified water can be used as a solvent.

  Further, the addition method of the amorphous body maintenance agent is not particularly limited as long as it can be brought into contact with the “amorphous body of solifenacin or a pharmaceutically acceptable salt thereof”. For example, the “amorphous form of solifenacin or a pharmaceutically acceptable salt thereof” and the amorphous body maintaining agent can be contacted by physically mixing them. In addition, the physical mixing can include pulverization and the like. In that case, the “amorphous form of solifenacin or a pharmaceutically acceptable salt thereof” may be “a crystalline form of solifenacin or a pharmaceutically acceptable salt thereof”. Further, “amorphous form of solifenacin or a pharmaceutically acceptable salt thereof” or “a crystalline form of solifenacin or a pharmaceutically acceptable salt thereof” and an amorphous body maintenance agent are dissolved in a solvent or It can also be suspended and adsorbed to the other using the solution. Furthermore, “amorphous form of solifenacin or a pharmaceutically acceptable salt thereof” and / or “a crystalline form of solifenacin or a pharmaceutically acceptable salt thereof” and an amorphous body maintenance agent are used as a solvent. Both substances can also be brought into contact by dissolving or suspending and drying. In this case, there is no particular problem as long as it is a general method for removing the solvent. Specifically, a freeze drying method or a spray drying method can be used. Moreover, it can also contact as a result by making it adsorb | suck to another additive. The solvent that can be used in the method is not particularly limited as long as the effects of the invention are not impaired. Specific examples include purified water, methyl alcohol, ethyl alcohol, and propyl alcohol. Preferably, purified water can be used as a solvent. In this case, it can be adsorbed by a method such as a fluidized bed granulation method, an agitation granulation method, or a rolling fluidized bed method.

  When a binder and an adsorbent are further used in the “amorphous form of solifenacin or a pharmaceutically acceptable salt thereof” and the amorphous body maintenance agent, the effects of the present invention should not be impaired with respect to the production method. There is no particular limitation. A method of mixing or / and pulverizing "solifenacin or an pharmaceutically acceptable salt thereof" and these additives together, or dissolving these substances all in a solvent, followed by lyophilization or The preparation of the present invention can also be obtained by a method of removing the solvent such as spray drying. The following forms can be cited as the best forms. "Amorphous form of solifenacin or a pharmaceutically acceptable salt thereof", "Amorphous form of solifenacin or a pharmaceutically acceptable salt thereof" or a mixture thereof and a binder are dissolved in a solvent or Suspend. The pharmaceutical composition of the present invention can be produced by adsorbing this solution or suspension to an amorphous substance maintenance agent and an adsorbent. At that time, the solvent used is not particularly limited as long as it can dissolve or suspend solifenacin or a pharmaceutically acceptable salt thereof. Specific examples include purified water, methyl alcohol, ethyl alcohol, and propyl alcohol. Preferably, purified water can be used as a solvent. Further, the method for adsorbing to the adsorbent is not particularly limited as long as the effects of the invention are not impaired. Specific examples include a fluidized bed granulation method, a stirring granulation method, a rolling fluidized bed granulation method, and a fine particle coating method using a Wurster granulator. Preferably, it can be produced by a fluidized bed granulation method or a fine particle coating method. At this stage, solifenacin becomes amorphous.

  The solifenacin-containing granule thus produced can be produced as a preparation having the dosage form described above by a conventional method.

  As an example, a method for producing an intraoral rapidly disintegrating tablet will be specifically described. About the design of an intraoral quick disintegrating tablet, it can manufacture by the method etc. which are described in patent gazette 4601271, patent publication gazette 2006-282551, patent publication gazette 2010-51841, etc. Specifically, using a solution in which polyvinyl alcohol and partially pregelatinized starch are dissolved in purified water, delta-type mannitol and solifenacin-containing granules produced as described above are granulated. Granulation can be performed by fluidized bed granulation, stirring granulation, rolling fluidized bed granulation or the like. A disintegrant and a lubricant are added to the obtained granules and compression molded. If necessary, the solifenacin granules can be coated to suppress bitterness, to provide sustainability, or to exert a medicinal effect on a timely basis. Any base may be used for the coating as long as the effects of the present invention are not impaired.

  The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to these examples.

  In the following examples, recrystallization of solifenacin succinate was confirmed by the XRD method using RINT Ultimate III manufactured by Rigaku Corporation. If there was no specific peak around 2θ = 10 ° C., it was determined to be amorphous.

[Test Example 1]
20 g of solifenacin succinate was dissolved in an appropriate amount of purified water. Next, 10 g of calcium silicate (florite) as an adsorbent and 10 g of various amorphous body maintaining agents shown in Table 1 were mixed in a mortar, and the solifenacin succinate solution previously dissolved in the mixture was added to the mortar. Granulation was carried out by kneading in a kneading machine. After granulation, it was dried for 4 hours in a drier (manufactured by ASONE, “DO-450A”, 60 ° C.) to produce sample granules of Examples 1-2 and Comparative Examples 1-10.

[Evaluation]
The obtained granule was allowed to stand for 1 week in a thermostatic device (CRH-220 manufactured by Nagano Science Co., Ltd.) set at a temperature of 60 ° C. Then, the presence or absence of an amorphous body was confirmed by the method described above. The results are summarized in Table 1 below. In the table, “◯” indicates that an amorphous body was confirmed, and “X” indicates that an amorphous body was not confirmed.

  From this test result, it was found that by adding malic acid and / or meglumine, an amorphous body can be maintained even when stored for a long time.

[Test Example 2]
First, 20 g of solifenacin succinate and 20 g of hypromellose 2910 as a binder were dissolved in purified water. Next, 10 g of the adsorbent shown in Table 2 and the amorphous maintenance agent (except Comparative Example 11) also shown in Table 2 were mixed in a mortar, and the solifenacin succinate solution previously dissolved in the mixture was added, Granulation was carried out by kneading in a mortar. After granulation, the sample granules of Examples 3 to 7 and Comparative Example 11 were produced by drying for 4 hours with a drier (manufactured by ASONE, “DO-450A”, 60 ° C.).

[Evaluation]
The obtained granule was allowed to stand for 1 week in a thermostatic device (CRH-220 manufactured by Nagano Science Co., Ltd.) set at a temperature of 60 ° C. Thereafter, the presence of crystals of solifenacin succinate and the presence of impurities derived from solifenacin succinate were confirmed.

The presence or absence of solifenacin succinate crystals was determined by analyzing with the above XRD measuring machine. In the following table, the presence or absence of crystals is represented by the following symbols.
−: Crystallized solifenacin could not be confirmed.
+: Crystallized solifenacin was confirmed.

  Impurities derived from solifenacin succinate were measured using high performance liquid chromatography.

  The above results are shown in Table 3.

  As is clear from Table 3, no solifenacin crystals were confirmed in the granules of Examples 3 to 7 to which malic acid had been added even when stored at 60 ° C. for 1 week. On the other hand, solifenacin crystals were confirmed for the granule of Comparative Example 11 in which no amorphous body maintaining agent was used.

  Moreover, when the presence or absence of the increase of the impurity derived from solifenacin was confirmed, about the granule of the comparative example 11 which is not using the amorphous body maintenance agent, the increase of the impurity of 5% or more was confirmed. On the other hand, about the granule of Examples 3-7 which added malic acid, it confirmed that the increase in the impurity was able to be suppressed. It has also been found that the effect is enhanced by using partially pregelatinized starch, crystalline cellulose, or mannitol as the adsorbent.

[Test Example 3]
20 g of solifenacin succinate and 20 g of each binder shown in Table 4 below were dissolved in an appropriate amount of purified water. Next, 10 g of mannitol as an adsorbent and 10 g of meglumine as an amorphous maintenance agent are mixed in a mortar, and the solifenacin succinate solution previously dissolved in the mixture is added and kneaded in the mortar. Done the grain. After granulation, it was dried for 4 hours with a drier (manufactured by ASONE, “DO-450A”, 60 ° C.) to produce sample granules of Examples 8-12.

  About the obtained granule, by the method similar to Experiment 2, the presence or absence of the crystal | crystallization of solifenacin succinate and the presence or absence of the impurity derived from solifenacin succinate were confirmed. The results are shown in Table 5.

  As is clear from Table 5, no solifenacin crystals were confirmed even when any binder was used, and it was confirmed that an increase in impurities could be suppressed. Moreover, it confirmed collectively that the increase in an impurity can be suppressed most in a binder in polyvinylpyrrolidone.

Claims (10)

  An amorphous form of solifenacin or a pharmaceutically acceptable salt thereof, and at least one selected from malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising:   At least one selected from malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutically acceptable salt thereof is formed of solifenacin or an amorphous form of the pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, which is contained at a ratio of 1: 1 or more with respect to the amount.   The content of at least one selected from malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 25 to 70% by mass. The pharmaceutical composition according to 1 or 2.   Furthermore, the pharmaceutical composition of any one of Claims 1-3 which contains adsorption agent.   The pharmaceutical composition according to claim 4, wherein the adsorbent is at least one selected from the group consisting of mannitol, partially pregelatinized starch, crystalline cellulose, magnesium aluminate metasilicate, and calcium silicate.   Furthermore, the pharmaceutical composition of any one of Claims 1-5 containing the binder.   The pharmaceutical composition according to claim 6, wherein the binder is at least one selected from the group consisting of polyvinylpyrrolidone, hypromellose, pullulan and methylcellulose.   The pharmaceutical composition according to any one of claims 1 to 7, which is an intraoral rapidly disintegrating tablet.   Solifenacin Solifenacin or a pharmaceutically acceptable salt thereof is dissolved in a solvent, and the resulting lysate is selected from malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutically acceptable salt thereof. A method for producing a pharmaceutical composition comprising an amorphous form of solifenacin or a pharmaceutically acceptable salt thereof, comprising the step of amorphizing solifenacin by adding it to a carrier as necessary at least one . Amorphism of solifenacin or a pharmaceutically acceptable salt thereof by adding at least one selected from malic acid or a pharmaceutically acceptable salt thereof and meglumine or a pharmaceutically acceptable salt thereof A method to stabilize the mass.