JP4636445B2 - Stable particulate pharmaceutical composition of solifenacin or a salt thereof - Google Patents

Description

  The present invention relates to a stable particulate pharmaceutical composition using solifenacin or a salt thereof and a specific binder, a method for producing the same, an orally disintegrating tablet containing the particulate pharmaceutical composition, and the particulate pharmaceutical composition It relates to the stabilization method.

で示され、化学名を（１Ｒ，３′Ｒ）−３′−キヌクリジニル １−フェニル−１，２，３，４−テトラヒドロ−２−イソキノリンカルボキシレートと称する。
該ソリフェナシンまたはその塩を含む一連のキヌクリジン誘導体が、ムスカリンＭ₃受容体に対する優れた選択的拮抗作用を有し、神経性頻尿、神経因性膀胱、夜尿症、不安定膀胱、膀胱痙縮や慢性膀胱炎等の泌尿器疾患や慢性閉塞性肺疾患、慢性気管支炎、喘息や鼻炎等の呼吸器疾患の予防治療剤として有用であることは報告されている（特許文献１参照）。
該特許文献１の実施例８には、ソリフェナシン塩酸塩の製法が記載されており、アセトニトリル及びジエチルエーテルからなる混合溶媒中で結晶化された結晶が２１２〜２１４℃の融点であったこと、比旋光度（［α］²⁵ _Dが９８．１（ｃ＝１．００，EtOH））を示したことが記載されている。Solifenacin has the following formula (I)

The chemical name is referred to as (1R, 3′R) -3′-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate.
A series of quinuclidine derivatives including the solifenacin or a salt thereof have an excellent selective antagonism for muscarinic M ₃ receptor, and include neurogenic urination, neurogenic bladder, nocturnal urine, unstable bladder, bladder spasm and chronic bladder It has been reported to be useful as a preventive and therapeutic agent for respiratory diseases such as urological diseases such as inflammation, chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis (see Patent Document 1).
Example 8 of Patent Document 1 describes a method for producing solifenacin hydrochloride, in which crystals crystallized in a mixed solvent consisting of acetonitrile and diethyl ether had a melting point of 212 to 214 ° C, The optical rotation ([α] ²⁵ _D is 98.1 (c = 1.00, EtOH)) is described.

  However, when solifenacin or its salt is amorphous, or when succinate of solifenacin is formulated by a general formulation method, solifenacin succinate, which is the main drug in the manufactured formulation, is significantly degraded over time. This is not described in Patent Document 1, and is not even suggested.

  Non-patent document 1, published by the Ministry of Health, Labor and Welfare in June 2003, describes the concept regarding the decomposition products (impurities) in the preparations that are recognized in the standard setting of the preparations, that is, the stability test. According to this, when the amount of drug substance administered daily is less than 10 mg, the threshold value for the safety confirmation of the degradation product in the drug product is the threshold of the degradation product contained in the drug substance. If the percentage is 1.0% or the total daily intake of degradation products is 50 μg, whichever is lower, and the amount of drug substance administered daily is 10 mg or more and 100 mg or less, degradation in the drug product The threshold at which product safety confirmation is required is stated as the lower of the percentage of degradation products in the drug substance, either 0.5% or the total daily intake of degradation products of 200 μg . Therefore, as a standard value of degradable biomass that can be set without confirming the safety of degradation products in general, for example, in the case of a drug product with a drug content of 5 mg, the degradation contained in the drug substance The percentage of product is 1.0% or less. For example, in the case of a preparation having a drug content of 10 mg, the percentage of degradation products contained in the drug substance is 0.5% or less.

  Solifenacin preparations currently scheduled to be marketed based on the results of clinical trials are 2.5 mg tablets, 5 mg tablets and 10 mg tablets. In order for these preparations to have the stability described in Non-Patent Document 1, The amount of the main degradation product of solifenacin succinate (hereinafter abbreviated as F1) relative to the total amount of solifenacin succinate and its degradation products should be set to 0.5% or less, more preferably between product lots or during testing It was considered necessary to control it to 0.4% or less.

On the other hand, solifenacin and its salts are known to have very high solubility and very strong bitterness and astringency in various solvents. Therefore, it is necessary to mask bitterness and astringency in order to develop highly convenient preparations such as particles or powders to be included in orally disintegrating tablets of solifenacin or a salt thereof, and a polymer base was used. It was necessary to apply a film coating method. Specifically, when a polymer base is film-coated on a drug, it is necessary to uniformly coat the drug surface, so that the drug needs to be spherical fine particles having a uniform particle size.
European Patent No. 801067 Medicinal Approval No. 0624001 “Revision of Guidelines on Impurities of Drugs Among Drugs Containing New Active Ingredients”

  Thus, in providing a formulation of solifenacin or a salt thereof to a clinical site, a spherical pharmaceutical composition suitable for film coating and stable solifenacin or a salt thereof capable of suppressing degradation over time is provided. There was a need.

Means to solve the problem

In developing solifenacin succinate as an excellent therapeutic agent for frequent urination and urinary incontinence, the present inventors generally used a general binder (polyvinylpyrrolidone (hereinafter referred to as PVP) which is usually used by those skilled in the art by fluidized bed granulation method or the like. (Abbreviated) or hydroxypropylmethylcellulose (hereinafter abbreviated as HPMC)), and the resulting drug product was subjected to accelerated test conditions (40 ° C, 75% RH (relative humidity)), which is one of the general stability tests. ), Bottle sealing conditions), a preliminary stability test was conducted for 2 months. As a result, a decrease in the residual rate of solifenacin succinate was observed, and the amount of F1 (oxidized form of solifenacin succinate) relative to the total amount of solifenacin succinate and its degradation products after 6 months of storage, which was the final judgment in the accelerated test Was found to exceed 0.4% (see Table 1 below for details). It has been found that it is difficult to obtain a preparation having sufficient pharmacological stability by such a general preparation.
As a result of diligent research on the stabilization of solifenacin preparations under such a technical level, unexpectedly, amorphous solifenacin produced in the manufacturing process of the preparation is the main cause of the degradation of the main drug over time. It was found that the use of binders such as HPMC was greatly involved in the formation of solifenacin amorphous.

  On the other hand, in order to obtain a granular substance masking the bitterness and astringency of solifenacin, the present inventor prepares fine particles (particulate pharmaceutical composition) by spraying a drug solution onto core particles made of crystalline cellulose, for example. Therefore, it was considered effective to apply a film coating to the fine particles with an appropriate polymer substance. However, in order to prepare the fine particles, it is necessary to dissolve solifenacin or a salt thereof once and then spray, but at that time, solifenacin is easily amorphized and changes from an amorphous body to a crystalline body. It has been found that there is a problem specific to solifenacin that a decomposition product is generated. That is, it was found that it is very difficult to ensure the stability of solifenacin when a particulate pharmaceutical composition is produced after part or all of solifenacin is dissolved in a solvent.

Under such conditions, first, when using a substance having an ethylene oxide chain such as polyethylene glycol (also referred to as macrogol, hereinafter sometimes abbreviated as PEG) as a binder, the PEG itself is used. Although it is a substance that is generally used for the purpose of making a drug amorphous, it suppresses the degradation of solifenacin over time by unexpectedly suppressing the solifenacin from becoming amorphous. It was found to create a pleasing formulation.
In addition, when creating a stable pharmaceutical composition of solifenacin or a salt thereof suitable for film coating, for example, when dissolved solifenacin is sprayed onto the core particles together with a polymer substance (binder) such as PEG, The idea was that whether solifenacin could subsequently maintain an amorphous form might be due to the fluidity of solifenacin within the polymeric material (binder). Therefore, as a result of intensive studies, regarding the binder used when spraying onto the core particles, the physical property values (glass transition point (hereinafter abbreviated as Tg)) of the polymer that may affect the fluidity of the drug, Focusing on the melting point (hereinafter abbreviated as mp), the particulate pharmaceutical composition using a binder with a high Tg had a low initial value of a related substance that was an indicator of degradation, but was stable thereafter. We found that it was unstable with respect to sex. On the other hand, regarding the particulate pharmaceutical composition using a specific binder having a Tg lower than a certain value, both the initial value of the related substance and the value of the related substance generated thereafter are both low and stable, and the particle size Has been found to be suitable for uniform and spherical film coating.
Furthermore, as a result of intensive studies, it has been found that a more stable particulate pharmaceutical composition can be created by performing crystallization promotion treatment such as humidification drying treatment, and the present invention has been completed.

That is, the present invention
1. A stable particulate pharmaceutical composition comprising solifenacin or a salt thereof, and a binder having a stabilizing action of solifenacin or a salt thereof,
2. 2. The pharmaceutical composition according to 1 above, wherein the binder having a stabilizing action of solifenacin or a salt thereof is a binder having an amorphous maintenance inhibitory action of solifenacin or a salt thereof,
3. 3. The pharmaceutical composition according to 1 or 2 above, wherein the binder is a binder having a glass transition point or melting point of less than 174 ° C.
4). Binder is polyethylene glycol, polyethylene oxide, polyoxyethylene polyoxypropylene block polymer, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, corn starch, aminoalkyl 4. The pharmaceutical composition according to 3 above, which is one or more substances selected from the group consisting of methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, and maltose;
5. 4. The pharmaceutical composition according to 3 above, wherein the binder is one or more substances selected from the group consisting of polyethylene glycol, polyoxyethylene polyoxypropylene block polymer, hydroxypropylcellulose, hydroxyethylcellulose, and maltose,
6. The pharmaceutical composition according to 3 above, wherein the binder is one or two or more substances selected from the group consisting of polyethylene glycol, polyoxyethylene polyoxypropylene block polymer, and hydroxypropylcellulose;
7). A stable particulate pharmaceutical composition of solifenacin or a salt thereof, which can be obtained by co-dissolving and / or suspending solifenacin or a salt thereof and a binder having a stabilizing action of solifenacin or a salt thereof,
8. The pharmaceutical composition according to 7 above, wherein the binder having a stabilizing action of solifenacin or a salt thereof is a binder having an action of suppressing the maintenance of amorphous substance with solifenacin or a salt thereof,
9. The pharmaceutical composition according to 7 or 8 above, wherein the binder is a binder having a glass transition point or a melting point of less than 174 ° C.
10. The binder is polyethylene glycol, polyethylene oxide, polyoxyethylene polyoxypropylene block polymer, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, corn starch, 10. The pharmaceutical composition according to 9 above, which is one or more substances selected from the group consisting of aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, and maltose;
11. The pharmaceutical composition according to 9 above, wherein the binder is one or more substances selected from the group consisting of polyethylene glycol, polyoxyethylene polyoxypropylene block polymer, hydroxypropylcellulose, hydroxyethylcellulose and maltose. ,
12. The pharmaceutical composition according to 9 above, wherein the binder is one or two or more substances selected from the group consisting of polyethylene glycol, polyoxyethylene polyoxypropylene block polymer, and hydroxypropylcellulose;
13. The pharmaceutical composition according to any one of 1 to 12 above, wherein the stability is further improved by performing a crystallization promoting treatment,
14. An orally disintegrating tablet containing the pharmaceutical composition according to any one of 1 to 13 above.

  Generally, the flowability index is as follows: glass transition point (Tg, unit ° C) or softening point (unit ° C) due to amorphous part in polymer and melting point (mp, unit ° C) due to crystal part In many cases, the material-specific thermodynamic parameters are used. These values are the temperatures that indicate the thermodynamic state change of the substance, but at temperatures below Tg, the molecular movement is suppressed, so that the plasticity tends to decrease in a crystalline or glassy state. On the other hand, when the temperature of the substance is above Tg, the activity of the molecule increases, and it becomes rubbery and increases its flexibility. Furthermore, the melting of the polymer causes the crystal part in the polymer to break and show fluidity as the temperature rises. Based on this, when a drug in an amorphous state exists in a polymer at a certain temperature, the higher the Tg of the polymer, the more difficult the polymer itself flows. This means that the lower the polymer, the faster the crystal precipitation (Int. J. Pharm. 282 (2004) 151-162). On the other hand, low molecular weight compounds often have no Tg due to their crystalline structure, but in terms of parameters indicating changes in thermal motility, low molecular weight compounds are used as an index of melting point. Adopted the Tg of the temperature at which the change appeared earlier.

The present invention also provides:
15. A method of stabilizing solifenacin or a salt thereof by subjecting solifenacin or a salt thereof and a pharmaceutical composition comprising a solifenacin or a salt thereof having a stabilizing action to crystallization promotion treatment,
16. A stable particulate pharmaceutical composition comprising solifenacin or a salt thereof and a binder having a stabilizing action of solifenacin or a salt thereof is subjected to a crystallization promoting treatment, whereby an amorphous form of solifenacin or a salt thereof is obtained. A method of transferring the body to crystals,
About.

Hereinafter, the composition of the present invention will be described in detail.
The “solifenacin salt” used in the present invention refers to mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid of solifenacin described in Patent Document 1, formic acid, acetic acid Acids with organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid Examples include addition salts and quaternary ammonium salts. Among them, succinate of solifenacin is preferable in providing as a pharmaceutical product.

“Solifenacin or a salt thereof” used in the present invention can be easily obtained by the method described in the above-mentioned Patent Document 1, or in accordance therewith, or by a conventional method.
The term “crystal” or “crystal” of solifenacin or a salt thereof literally means a substance that means solifenacin or a salt thereof having a crystallographic crystal structure, and in the present invention, In the present invention, it means a substance different from an “amorphous substance” that exhibits significant temporal degradation of solifenacin when present within a range that does not affect stabilization. ”Or“ amorphous ”means a substance having a crystallographically amorphous structure, but in the present invention, it exists in a range that does not affect the stabilization of the product. Sometimes, solifenacin means a substance different from “crystal” or “crystal” with very little degradation over time.

The amount of solifenacin or a salt thereof used in the present invention is usually selected as appropriate depending on the type of drug or pharmaceutical use (indication), but if it is a therapeutically effective amount or a prophylactically effective amount. There is no particular limitation. Specifically, the daily dose of solifenacin or a salt thereof is 0.01 mg to 100 mg, preferably 0.5 mg to 50 mg, more preferably 0.5 mg to 10 mg, most preferably 0.5 mg to 4 mg.
In addition, the amount of solifenacin or a salt thereof in the orally disintegrating tablet of the present invention may contain an effective amount per dosage unit preparation, but is preferably 0.001 to 97% by weight, more preferably It is 0.05 weight%-50 weight%, More preferably, it is 0.05 weight%-10 weight%, Most preferably, it is 0.05 weight%-4 weight%.

The “binder having a stabilizing action of solifenacin or a salt thereof” used in the present invention means a binder capable of suppressing the degradation of solifenacin or a salt thereof over time, specifically, suppressing the maintenance of an amorphous body. It is a binding agent that can suppress degradation of solifenacin or a salt thereof over time by action. In addition, even if it is a binder that does not have a stabilizing action of solifenacin or a salt thereof alone, for example, a binder such as HPMC or PVP, the binder used in the present invention for the purpose of enhancing the action as a binder. Can be used within a range not exceeding the standard setting of the stability of the preparation which is the subject of the present invention.
The meaning of the “amorphous maintenance inhibiting action” as used in the present invention means an action that makes it difficult to exist in an amorphous state and / or an action that can easily make the transition from an amorphous body to a crystal. .

  Further, as the binder having the action of stabilizing solifenacin or a salt thereof used in the present invention or maintaining the amorphous body, it is a binder that can reduce the amount of F1 of solifenacin to 0.5% or less, and more preferably. It is a binder that can reduce the amount of F1 to 0.4% or less. Specifically, the range of Tg or mp is less than 174 ° C, preferably 0 ° C or more and less than 174 ° C, more preferably 0 ° C or more and less than 156 ° C, and still more preferably 0 ° C. More than ℃ and less than 137 ℃. Most preferably, it is 10 ° C or higher and lower than 137 ° C. Specifically, the type of binder is not particularly limited as long as Tg is less than the above range, but is preferably a substance having an ethylene oxide chain, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyvinyl alcohol, Acrylic acid copolymers, aminoalkyl methacrylate copolymers, starch and maltose. However, from the viewpoint of the production method, among the above binders, polyvinyl alcohol, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, and starch are assumed to have a low binding force and are difficult to coat particles. Preferably, a substance having an ethylene oxide chain, such as PEG, polyethylene oxide, polyoxyethylene polyoxypropylene block copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose and maltose, more preferably PEG, polyoxyethylene polyoxypropylene block copolymer, Hydroxypropyl cellulose, particularly preferably PEG and hydroxypropyl cellulose, and most preferably PEG. These binders are not particularly limited in molecular weight species, degree of polymerization, etc., as long as they achieve the object of the present invention which suppresses the amorphization of solifenacin or a salt thereof by addition, but the molecular weight species are not limited. The weight average molecular weight is preferably in the range of 400 to 1,000,000, more preferably in the range of 2,000 to 200,000. In addition, two or more kinds of binders described above can be used together.

  The substance having an ethylene oxide chain here is not particularly limited as long as it has an ethylene oxide chain, but the addition thereof achieves the object of the present invention which suppresses solifenacin or its salt from becoming amorphous. As long as the molecular weight species and the degree of polymerization are not particularly limited, the molecular weight species preferably have a weight average molecular weight in the range of 400 to 1,000,000, more preferably a weight average molecular weight in the range of 2,000 to 200,000. The substance having an ethylene oxide chain may be used alone or in combination of two or more. In the present invention, specific examples of the substance having an ethylene oxide chain include PEG, polyethylene oxide, polyoxyethylene polyoxypropylene block copolymer and the like. Among these, in the present invention, PEG, polyoxyethylene polyoxy Propylene block copolymers are preferred, and PEG is particularly preferred. As PEG, PEG solid at normal temperature is suitable. Specifically, Macrogol 4000 (JP, molecular weight 2600-3800, product name: Macrogol 4000 / Sanyo Kasei, Nippon Oil, Lion, etc.), Macrogol 6000 (JP, molecular weight 7,300-9,300, product name: Macrogol 6000 / Sanyo Chemical Industries, Nippon Oil & Fats, Lion, etc.), Macrogol 20000 (Japan Pharmacopoeia, Molecular Weight 15,000-25,000, Product Name: Macrogol 20000 / Sanyo Chemical Industries, Nippon Oils & Fats, Lion, etc.), Polyethylene Glycol 8000 (USP) / NF, molecular weight 7,000 to 9,000, trade name: Polyethylene glycol 8000 / Dow Chemical, etc.). A preferred weight average molecular weight of PEG is in the range of 400 to 40,000, more preferably in the range of 2,000 to 25,000, and still more preferably in the range of 2,000 to 10,000.

The polyoxyethylene polyoxypropylene block copolymer of the present invention is a copolymer of propylene oxide and ethylene oxide, and there are various types depending on the composition ratio thereof, but it suppresses the amorphization of solifenacin or a salt thereof. Any composition having a property may be used. Specifically, polyoxyethylene (105) polyoxypropylene (5) glycol and polyoxyethylene (160) polyoxypropylene (30) glycol (also known as Pluronic F68) are used.
In the present invention, “solifenacin or a salt thereof and a solifenacin or a binding agent having a stabilizing action of the salt co-dissolved and / or suspended” refers to a solution of solifenacin or a salt thereof in a solvent such as water. Together with a solifenacin or its salt-stabilizing binder dissolved therein, but it is not always necessary that all of the solifenacin or its salt be dissolved in the solvent. If it is within the range where drug-containing particles suitable for coating, etc. can be obtained, particles produced by using solifenacin or a part of its salt dissolved in a solvent in a suspended state will be obtained. Also included.

  In the present invention, a composition that can be obtained by co-dissolving solifenacin or a salt thereof and a binder having a stabilizing action of solifenacin or a salt thereof is a composition containing a drug suitable for coating such as bitterness masking. For example, a composition obtained by spray-coating a solution-like drug on a core particle such as crystalline cellulose, or a liquid drug is not sprayed, but insoluble core particles are co-dissolved with these particles. Examples thereof include a composition that can be obtained by mixing the prepared materials and then precipitating the drug to uniformly dispose the drug around the insoluble core particles. Examples of the product produced without using core particles include, for example, powders obtained by spray drying or freeze-drying a drug and binder solution. Can be used for the particles. However, in view of production efficiency, a composition that can be obtained by spray-coating solufenacin or a salt thereof and a solifenacin or a binder having a stabilizing action of solifenacin in the core particle is preferable.

The “stable particulate pharmaceutical composition” referred to in the present invention is not particularly limited as long as it is a particle that can be obtained using solifenacin or a salt thereof and the like, and is a stable particle that suppresses degradation over time. As used herein, “stable” specifically means particles in which the amount of F1 produced by solifenacin or a salt thereof is 0.5% or less, more preferably 0.4% or less. In addition, when the pharmaceutical composition of the present invention is a particle such as a granule, the particle size of the particulate pharmaceutical composition is not particularly limited as long as the longest diameter is 2 mm or less. The case where it is contained in the orally disintegrating tablet is not particularly limited as long as it does not give an unpleasant feeling of roughness such as sand when taken, but the average particle diameter is preferably adjusted to 350 μm or less. A more preferable average particle diameter is 1 to 350 μm, and particularly preferably 20 to 350 μm. From the viewpoint of particle size distribution, it is not particularly limited as long as it is a particle suitable for coating such as bitterness masking, but preferably 80% of the total weight is distributed in 1 to 350 μm, more preferably 50 to 300 μm. 80% of the weight is distributed, particularly preferably 80% of the total weight is distributed between 100 and 250 μm.
The shape of the particulate composition of the present invention is not particularly limited as long as it can be coated such as bitterness masking, but from the viewpoint of coating efficiency, a spherical shape, that is, a sphericity as close as possible to 1 is desirable. .

  When the particulate pharmaceutical composition of the present invention is a granule, the amount of the binder in the particulate pharmaceutical composition is an amount that can be coated with solifenacin or a salt thereof and can achieve the object of the present invention. Although not particularly limited, it is preferably 0.01 to 91% by weight, more preferably 0.5 to 75% by weight, based on the whole particulate pharmaceutical composition. The most preferable blending amount is 5 to 50% by weight. Further, when the amount of the binder in the case where the pharmaceutical composition of the present invention is a particle such as a granule is considered with respect to 1 part by weight of crystalline and amorphous solifenacin or a salt thereof, preferably 1 It is a ratio of -1,000 weight%, More preferably, it is a ratio of 5-500 weight%, More preferably, it is a ratio of 10-100 weight%.

  The particulate pharmaceutical composition of the present invention is produced from a solution of solifenacin and a salt thereof. When the solifenacin solution is spray-coated on the core particles, for example, sodium chloride, microcrystalline cellulose, calcium carbonate, lactose is used as the core particles. , Maltose, mannitol, preferably microcrystalline cellulose, lactose, mannitol and the like. More preferred are microcrystalline cellulose and lactose. In the present invention, one or two or more of these substance groups can be used in combination.

The crystallization promotion treatment here is not particularly limited as long as it is a treatment that promotes crystallization. For example, humidification treatment, microwave irradiation treatment, ultrasonic irradiation treatment, low frequency irradiation treatment, thermoelectron irradiation treatment, etc. Can be mentioned. Humidification treatment is, for example, a temperature of 20 to 30 ° C, a humidity of 60 to 85%, and a humidity of 6 to 24 hours, followed by drying at a temperature of 30 to 40 ° C, a humidity of 30 to 40% RH, and 2 to 6 hours. To do. The microwave irradiation treatment cannot be generally limited, but, for example, a wavelength of 10 MHz to 25 GHz can be used. The treatment time depends on the initial crystallization degree and the selected base, but can be carried out, for example, from 10 seconds to 60 minutes. Irradiation itself may be performed continuously or intermittently, and any particulate composition may be performed at any timing after production.
The ultrasonic irradiation treatment cannot be generally limited, but, for example, a sound wave having a frequency of 10 kHz to 600 kHz can be used. The treatment time depends on the initial crystallization degree and the selected base, but can be carried out, for example, from 10 seconds to 24 hours. Irradiation itself may be performed continuously or intermittently, and any particulate composition may be performed at any timing after production.
As these crystallization promotion treatments, humidification treatment, microwave irradiation treatment, and ultrasonic irradiation treatment are preferable.

  In the particulate pharmaceutical composition of the present invention, various pharmaceutical excipients are appropriately used and formulated. Examples of such pharmaceutical excipients include lactose. Further, other additives can be used as long as they are pharmaceutically acceptable and pharmacologically acceptable without impairing the object of the present invention. For example, disintegrating agents, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, coloring agents, stabilizers, buffers, antioxidants, surfactants and the like can be used, and are not particularly limited. . For example, examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, and low-substituted hydroxypropylcellulose. Examples of the sour agent include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include baking soda. Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin. Examples of the fragrances include lemon, lemon lime, orange and menthol. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, stearic acid and the like. Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow Nos. 4 and 5, edible red Nos. 3 and 102, and edible blue No. 3. Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof. Examples of the antioxidant include ascorbic acid, sodium nitrite, sodium sulfite, sodium hydrogen sulfite, sodium edetate, erythorbic acid, tocopherol acetate, tocopherol, butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and the like. Examples of the surfactant include sodium lauryl sulfate, polyoxyethylene sorbitan aliphatic ester (polysorbate 80), polyoxyethylene hydrogenated castor oil, and the like. As the pharmaceutical excipient, one or a combination of two or more can be added as appropriate.

The “amorphous content” as used in the present invention means the ratio of solifenacin or a salt thereof to the total of the amorphous and crystalline forms.
In addition, powders, granules, pills, tablets, capsules, orally disintegrating tablets, dry syrups and the like can be considered as preparations using the above-mentioned particles, and orally disintegrating tablets are particularly preferable.

The orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention will be described below.
In the present invention, "orally disintegrating tablet" means that when taking a tablet without ingesting water, it is within 2 minutes, preferably within 1 minute, more preferably within 30 seconds, substantially only in the oral cavity with saliva. It means tablets that disintegrate into tablets and other preparations similar to tablets.

  The particulate pharmaceutical composition of the present invention can be contained in such an orally disintegrating tablet. For example, International Publication No. 95-20380 (US Patent No. 5576014), International Publication No. 2002-92057 (U.S. Patent Application Publication No. 2003/099701), U.S. Pat.No. 4,305,502, U.S. Pat.No. 4,371,516, U.S. Pat.No. 2,807,346 (U.S. Pat. No. 271054 (European Patent No. 553777), JP-A-10-182436 (U.S. Pat.No. 5958543), Patent No. 3412694 (U.S. Pat.No. 5223264), and International The particulate pharmaceutical composition is applied as a drug of a known orally disintegrating tablet described in the published pamphlet WO 98/02185 (US Patent No. 6287596), and the orally disintegrating tablet base described in the publication is used. According to the method described in the publication, an orally disintegrating tablet can be obtained. As such orally disintegrating tablets containing the particulate pharmaceutical composition, Patent No. 3412694 (U.S. Patent No. 5223264 specification), orally disintegrating tablets described in JP-A-2003-55197 can be mentioned, The particulate pharmaceutical composition of the present invention can be contained in these orally disintegrating tablets.

  As exemplified above, the orally disintegrating tablets are generally roughly classified into a mold type, a moist type, and a normal tableting type, and the particulate pharmaceutical composition of the present invention is contained in any type of orally disintegrating tablet. Also good. The mold-type orally disintegrating tablet is filled with a solution or suspension such as an excipient in a mold, as disclosed in, for example, Patent No. 2807346 (U.S. Pat.No. 5466464) and dried. To make. The mold-type orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention is, for example, a solution or suspension of the particulate pharmaceutical composition of the present invention, excipients such as sugars, and binders such as gelatin and agar. After filling the PTP pocket with the liquid, it can be produced by removing moisture by a method such as freeze drying, drying under reduced pressure, or low temperature drying. As shown in Patent No. 3069458 (U.S. Patent No. 5501618, U.S. Pat.No. 5720974), a wet type orally disintegrating tablet is moistened with excipients such as sugars, After tableting with, dried and manufactured. Therefore, for example, the particulate pharmaceutical composition of the present invention, an excipient such as a saccharide can be wetted with a small amount of water or a mixture of water and alcohol, and the wet mixture can be molded at a low pressure and dried.

  In the case of a normal tablet type, International Publication No. 95-20380 (U.S. Patent No. 5576014), International Publication No. 2002-92057 (U.S. Publication No. 2003/099701), JP No. 10-182436 (U.S. Pat.No. 5958543), JP-A-9-48726 JP-A-8-19589 (U.S. Pat.No. 5672364), Patent 2919771, Patent 3069458 (US) As disclosed in US Pat. No. 5,501,861 and US Pat. No. 5,720,974), it is prepared through a normal tableting process. To prepare a normal tablet type orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention, for example, disclosed in International Publication No. 95-20380 (US Patent No. 5576014), Patent No. 2919771 As described above, after granulating the particulate pharmaceutical composition of the present invention and an excipient such as a low-moldability saccharide using a solution or suspension of a high-moldability saccharide or a water-soluble polymer. The granulated product can be compression-molded to obtain a compression-molded product, or the compression-molded product can be further humidified and dried to produce an orally disintegrating tablet. In order to prepare a normal tablet type orally disintegrating tablet as shown in International Publication No. 99-47124 (US Pat. No. 6,658,954), for example, the particulate pharmaceutical composition of the present invention An oral disintegrating tablet can be produced by compression molding using an excipient such as crystalline saccharide and an amorphous saccharide, followed by humidification and drying. Furthermore, in order to prepare a normal tablet type orally disintegrating tablet as disclosed in International Publication No. 2002-92057 (U.S. Patent Application Publication No. 2003/099701), for example, the particles of the present invention Orally disintegrating tablets by compression-molding a mixture of a pharmaceutical composition, an excipient, and a saccharide having a melting point lower than that of the excipient, followed by heating and forming a cross-link by a melt-solidified product of the saccharide having a lower melting point Can be prepared. By such humidification drying or heat treatment, the tablet strength of the orally disintegrating tablet can be improved.

  As the excipient used in the orally disintegrating tablet of the present invention, a general excipient can be used, but it is particularly preferable to use a pharmaceutically acceptable saccharide, and a technique utilizing the moldability of the saccharide. In the case of using saccharides with low moldability, crystal / amorphous saccharides, and tablet strength improvement technology by humidified drying, it is common to use cross-linking technology with crystalline saccharides and melted solids of saccharides. In addition to typical excipients, high melting point saccharides can be used.

`` Saccharide with low moldability '' means, for example, a tablet having a tablet hardness of 0 to ² kp when tableting 150 mg of saccharide with a punch of 8 mm in diameter at a tableting pressure of 10 to 50 kg / cm ² , Further, “highly moldable saccharide” means one having a hardness of 2 kp or more by the same method. Saccharides with low moldability are pharmaceutically acceptable, and examples thereof include lactose, mannitol, glucose, sucrose, xylitol, and erythritol. One or two or more of these may be used in appropriate combination. Highly moldable saccharides are pharmaceutically acceptable, and examples thereof include maltose, maltitol, sorbitol, trehalose and the like. These saccharides can also be used alone or in combination of two or more.
“Crystalline sugars” are pharmaceutically acceptable and include, for example, mannitol, maltitol, erythritol, xylitol and the like. These may be used alone or in combination of two or more. “Amorphous saccharides” are pharmaceutically acceptable and include, for example, lactose, sucrose, glucose, sorbitol, maltose, trehalose, etc., and these saccharides may be used alone or in combination of two or more. It is also possible to use it.

  The “excipient having a higher melting point than the saccharide having a lower melting point” is pharmaceutically acceptable, and is selected from, for example, xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol, etc. I can do it. One or two or more of these may be used in appropriate combination. The “low melting point saccharide” is pharmaceutically acceptable and can be selected from, for example, xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. These saccharides can also be used alone or in combination of two or more. Examples of the binder for orally disintegrating tablets include maltitol, copolyvidone, and erythritol. These binders can be used alone or in combination of two or more.

When a water-soluble polymer is used in place of a highly moldable saccharide, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like are suitable.
The amount of the excipient used in the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention is appropriately determined according to the blending amount of the particulate pharmaceutical composition of the present invention and / or the size of the tablet, etc. Although adjusted, usually 20 to 100 mg per tablet is preferable, more preferably 50 to 900 mg, and particularly preferably 100 to 800 mg.

In addition, the amount of saccharides with high moldability, water-soluble polymers, amorphous saccharides, and saccharides with a low melting point is not particularly limited as long as they are appropriately selected and used according to individual techniques. The content is preferably 0.5 to 40% by weight, more preferably 2 to 30% by weight, particularly 5 to 20% by weight, or 1 to 20% by weight based on the whole preparation.
Regarding the types of other optional additives, their blending and blending amounts, the description in the patent document of the orally disintegrating tablet is cited as the description of this specification.
When the orally disintegrating tablet contains the particulate pharmaceutical composition of the present invention, the particulate pharmaceutical composition corresponding to 0.5 to 90% by weight of the whole orally disintegrating tablet can be contained. Preferably it is 1-80 weight%, More preferably, it is equivalent to 5-60 weight%.

The method for producing the particulate pharmaceutical composition of the present invention will be described below.
In order to obtain the particulate pharmaceutical composition of the present invention, a solifenacin or a salt thereof and a binder having a stabilizing action of solifenacin or a salt thereof are mixed with water or an organic solvent such as ethanol using a stirrer. Dissolve or suspend with stirring to prepare the drug solution. In this case, the water and the organic solvent contained in the drug solution can be arbitrarily set. Examples of the method for powdering solifenacin or a salt solution thereof into powder (particles) include, for example, a freeze-drying method, a spray-drying method, a high-speed stirring granulation method, a fluidized bed granulation method, and a rolling granulation method. It is done. There are no particular limitations on the apparatus and means as long as solifenacin can be converted into powder (particles) after dissolution, but it is particularly preferably a spray drying method or fluidized bed granulation method. The particulate composition of the present invention can be obtained by spray coating a drug solution onto additive particles (for example, crystalline cellulose (particles), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.).

  Examples of the apparatus used for spray coating include a fluidized bed granulator (FLO-1, manufactured by Glatt) and a spray dryer (DL41, manufactured by Yamato Chemical Co., Ltd.).

Hereinafter, a method for producing an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention will be described.
In the case of an orally disintegrating tablet described in International Publication No. 95-20380 (U.S. Patent No. 5576014), the particulate pharmaceutical composition of the present invention and a saccharide with low moldability are mixed, A step of spraying and molding the mixture by spraying such a mixture with a saccharide having a high moldability as a binder and / or granulating the mixture can be employed. Furthermore, in order to increase the hardness of the prepared molded product, humidification and drying processes can be employed. “Humidification” is determined by the apparent critical relative humidity of the saccharides contained, but usually humidifies above its critical relative humidity. For example, the humidity is 30 to 100 RH%, preferably 50 to 90 RH%. The temperature at this time is preferably 15 to 50 ° C, more preferably 20 to 40 ° C. The treatment time is 1 to 36 hours, preferably 12 to 24 hours. “Drying” is not particularly limited as long as it is a step of removing moisture absorbed by humidification. For example, 10-100 degreeC can be set as temperature conditions of drying, Preferably it is 20-60 degreeC, More preferably, 25-40 degreeC can be set. The treatment time can be 0.5 to 6 hours, preferably 1 to 4 hours.

  In the case of an orally disintegrating tablet described in International Publication No. 2002-92057 (U.S. Patent Application Publication No. 2003/099701), the particulate pharmaceutical composition of the present invention, an excipient with a high melting point, a melting point of It is also possible to mix the low sugars and spray the mixture with an orally disintegrating tablet binder to coat and / or granulate and compress the granulation. As a spraying condition, for example, when using a fluidized bed granulator (FLO-1, manufactured by Glatt), the solution concentration of solifenacin is not limited as long as it is a viscosity that can be pumped, but the solid content concentration is 0.01 to 30% (w / w) is desirable. The spray rate is not limited as long as it can be spray-dried, but is preferably 0.1 to 20 g / min. The spraying temperature is not particularly limited as long as the product temperature can be set to 10 to 60 ° C. These spraying conditions vary depending on the production scale and device type, but there is no particular limitation as long as the particulate composition is obtained. Moreover, when combining the excipient | filler with high melting | fusing point and low saccharides, in order to raise the hardness of the prepared molded object, the process of a heating can be employ | adopted. “Heating” is determined by the melting point of the saccharide having a low melting point, and is usually heated to a temperature not lower than the melting point of the low saccharide and lower than the melting point of the high excipient. The treatment time can be 0.5 to 120 minutes, preferably 1 to 60 minutes.

  In addition, the method for stabilizing the particulate pharmaceutical composition of the present invention and the method for transferring the amorphous form of solifenacin or a salt thereof in the particulate pharmaceutical composition of the present invention to a crystalline form are produced as described above. The particulate composition of the present invention can be performed using the above-described crystallization promotion treatment method.

Crystalline of solifenacin succinate, PEG8000 (trade name Macrogol 6000, manufactured by Sanyo Chemical), spray-dried product of solifenacin succinate manufactured using PEG8000, manufactured using HPMC (trade name TC-5E, manufactured by Shin-Etsu Chemical) 2 shows powder X-ray diffraction results of the solifenacin succinate spray-dried product and the solifenacin succinate spray-dried product produced using polyvinylpyrrolidone (trade name PVP K90, manufactured by BASF, hereinafter abbreviated as PVP). Coating product to crystalline cellulose (trade name SELPHYA, manufactured by Asahi Kasei) using PEG8000 (trade name Macrogol 6000, manufactured by Sanyo Kasei) obtained in Example 3 and coated product using HPMC obtained in Comparative Example 1 The respective powder X-ray diffraction results are shown. This figure shows the relationship between the amount of F1 produced by the main degradation product of solifenacin when stored for 2 months and the Tg or mp of the binder used together (○: no humidification, ●: with humidification).

  The particulate pharmaceutical composition of solifenacin or a salt thereof in the present invention will be described in detail. EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated further in detail, this invention is not limitedly interpreted by these.

Coating product of solifenacin succinate to crystalline cellulose core particles using HPC-SL as a binder Solifenacin succinate 10 parts, hydroxypropylcellulose (trade name HPC-SL, Nippon Soda, hereinafter abbreviated as HPC) 3.4 parts water 26.6 A drug solution was prepared by stirring and dissolving a mixture of 16.6 parts and 26.6 parts of methanol using a stirrer (MGM-66, manufactured by SHIBATA). Next, crystalline cellulose (trade name Celphere, manufactured by Asahi Kasei) 60 parts of a fluidized bed granulator (FLO-1, manufactured by Glatt Co.) were charged in a previous intake air temperature 50 ° C. The drug solution Celphere, fluidized air volume 1.00 m ³ / min, binder solution spray rate 4.0 g / min, to obtain a particulate composition of the present invention by spraying the coating with atomizing air pressure 3.0 kg / cm ² below.

  The particulate composition obtained in Example 1 was humidified at 25 ° C. for 75% for 12 hours, and further dried at 30 ° C. for 40% for 3 hours to obtain a particulate composition of the present invention subjected to crystallization treatment.

Solifenacin succinate coated with PEG6000 as a binder on crystalline cellulose core particles Solifenacin succinate 10 parts, polyethylene glycol (trade name Macrogol 6000, manufactured by Sanyo Chemical) 3.4 parts water 26.6 parts methanol and 26.6 parts methanol A drug solution was prepared by stirring and dissolving using a stirrer (MGM-66, manufactured by SHIBATA). Next, Celphere (manufactured by Asahi Kasei Corporation) 60 parts of a fluidized bed granulator (FLO-1, manufactured by Glatt Co.) were charged in a previous intake air temperature 50 ° C. The drug solution Celphere, fluidized air volume 0.97 m ³ / min, binding solution The particulate composition of the present invention was obtained by spray coating at a spray rate of 10 g / min and a spray air pressure of 3.0 kg / cm ² .

  The particulate composition obtained in Example 3 was humidified at 25 ° C. for 75% for 12 hours, and further dried at 30 ° C. for 40% for 3 hours to obtain a particulate composition of the present invention subjected to crystallization treatment.

Solifenacin succinate coated with maltose as a binder to crystalline cellulose core particles Solifenacin succinate 10 parts, maltose (trade name Sanmalto-S, Sanwa Starch) 3.4 parts water 26.6 parts methanol and 26.6 parts methanol The solution was stirred and dissolved using a stirrer (MGM-66, manufactured by SHIBATA) to prepare a drug solution. Next, Celphere (manufactured by Asahi Kasei Corporation) 60 parts of a fluidized bed granulator (FLO-1, manufactured by Glatt Co.) were charged in a previous intake air temperature 60 ° C. The drug solution Celphere, fluidized air volume 0.98 m ³ / min, binding solution The particulate composition of the present invention was obtained by spray coating at a spray rate of 3.0 g / min and a spray air pressure of 3.0 kg / cm ² .

  The particulate composition obtained in Example 5 was humidified at 25 ° C. for 75% for 12 hours and further dried at 30 ° C. for 40% for 3 hours to obtain a particulate composition of the present invention subjected to crystallization treatment.

Solifenacin succinate coated with HEC as a binder on crystalline cellulose core particles Solifenacin succinate 10 parts, hydroxyethyl cellulose (trade name HEC SE400, manufactured by Daicel Chemical Industries) 3.4 parts water 26.6 parts methanol and 26.6 parts methanol A drug solution was prepared by stirring and dissolving using a stirrer (MGM-66, manufactured by SHIBATA). Next, Celphere (manufactured by Asahi Kasei Corporation) 60 parts of a fluidized bed granulator (FLO-1, manufactured by Glatt Co.) were charged in a previous intake air temperature 60 ° C. The drug solution Celphere, fluidized air volume 0.98 m ³ / min, binding solution The particulate composition of the present invention was obtained by spray coating at a spray rate of 3.0 g / min and a spray air pressure of 3.0 kg / cm ² .

  The particulate composition obtained in Example 7 was humidified at 25 ° C. for 75% for 12 hours, and further dried at 30 ° C. for 40% for 3 hours to obtain a particulate composition of the present invention subjected to crystallization treatment.

Solifenacin succinate coated with pluronic as a binder to crystalline cellulose core particles Solifenacin succinate 10 parts, Pluronic F68 (trade name Lutrol F68, manufactured by BASF) 3.4 parts Stirrer (MGM- 66, manufactured by SHIBATA), and dissolved by stirring to prepare a drug solution. Next, 60 parts of crystalline cellulose (trade name SELPHYA: manufactured by Asahi Kasei) was charged into a fluidized bed granulator (FLO-1, manufactured by Glatt). ^The particulate composition of the present invention was obtained by spray coating at ³ / min, a binder spray rate of 3.0 g / min, and a spray air pressure of 3.0 kg / cm ² .

Coated product of solifenacin succinate and PEG on crystalline cellulose 10 parts of solifenacin succinate, 1 part of PEG (trade name Macrogol 6000, manufactured by Sanyo Kasei) in a mixture of 16 parts water and 16 parts methanol (MGM-66, A drug solution was prepared by stirring and dissolving using SHIBATA. Next, 60 parts of crystalline cellulose (trade name SELPHYA: manufactured by Asahi Kasei) is charged into a fluidized bed granulator (FLO-1, manufactured by Glatt), and the pre-drug solution is supplied to crystalline cellulose with an intake temperature of 45 ° C and a flowing air volume of 1.0 m. Particulate powder was obtained by spray coating under a spray rate of ³ / min, a binding liquid spraying rate of 2.0 g / min, and a spraying air pressure of 2.0 kg / cm ² .

Coated product of solifenacin succinate and PEG on crystalline cellulose 10 parts of solifenacin succinate, 10 parts of PEG (trade name Macrogol 6000, manufactured by Sanyo Chemical Co., Ltd.) in a mixture of 70 parts water and 70 parts methanol (MGM-66, A drug solution was prepared by stirring and dissolving using SHIBATA. Next, crystalline cellulose (trade name Celphere: manufactured by Asahi Kasei) 60 parts of a fluidized bed granulator (FLO-1, manufactured by Glatt Co.) were charged in a previous intake air temperature 60 ° C. The drug solution crystalline cellulose, fluidized air volume 1 m ³ Particulate powder was obtained by spray coating under a spraying rate of / g / min, a binding liquid spraying rate of 6.5 g / min, and a spraying air pressure of 3.0 kg / cm ² .

When using different solvent compositions Solifenacin succinate and PEG coated on crystalline cellulose Solifenacin succinate 10 parts, PEG (trade name Macrogol 6000, Sanyo Kasei) 3.4 parts water 53.2 parts Stirrer (MGM-66, A drug solution was prepared by stirring and dissolving using SHIBATA. Next, 60 parts of crystalline cellulose (trade name SELPHYA: manufactured by Asahi Kasei) is charged into a fluidized bed granulator (FLO-1, manufactured by Glatt). Particulate powder was obtained by spray coating under a spray rate of ³ / min, a binding liquid spraying rate of 7.0 g / min, and a spraying air pressure of 3.0 kg / cm ² .

Solifenacin succinate and PEG coated on crystalline cellulose (drug content 50%)
A drug solution was prepared by stirring and dissolving 10 parts of solifenacin succinate and 3.4 parts of PEG (trade name Macrogol 6000, manufactured by Sanyo Kasei) in 26.6 parts of methanol and 26.6 parts of water using a stirrer (MGM-66, manufactured by SHIBATA). Next, 60 parts of crystalline cellulose (trade name SELPHYA: manufactured by Asahi Kasei) was charged into a fluidized bed granulator (FLO-1, manufactured by Glatt). Particulate powder was obtained by spray coating at ³ / min, a binding liquid spray rate of 3.0 g / min, and a spray air pressure of 3.0 kg / cm ² . Further, another drug solution manufactured at the above-mentioned prescription ratio was overcoated under the same equipment and the same conditions to obtain a particulate powder having a high drug content (drug content 50%).

[Comparative Example 1]
Solifenacin succinate coated on crystalline cellulose core particles using HPMC (TC5E) as a binder Solifenacin succinate 10 parts, Hydroxypropylmethylcellulose 2910 (trade name TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd., hereinafter abbreviated as HPMC) 3.4 parts A drug solution was prepared by stirring and dissolving a mixture of 26.6 parts of water and 26.6 parts of methanol using a stirrer (MGM-66, manufactured by SHIBATA). Next, Celphere (manufactured by Asahi Kasei Corporation) 60 parts of a fluidized bed granulator (FLO-1, manufactured by Glatt Co.) were charged in a previous drug solution inlet air temperature 50 ° C. to Celphere a flow amount of air 0.94 m ³ / min, binding solution A particulate composition was obtained by spray coating under a spray rate of 7.0 g / min and a spray air pressure of 3.0 kg / cm ² .
[Comparative Example 2]
The particulate composition obtained in Comparative Example 1 was humidified at 25 ° C. for 75% for 12 hours and further dried at 30 ° C. for 40% for 3 hours to obtain a particulate composition subjected to crystallization treatment.

[Comparative Example 3]
Coated product of solifenacin succinate with PVP (K90) as a binder to crystalline cellulose core particles Solifenacin succinate 10 parts, polyvinylpyrrolidone (trade name PVP K90, BASF, hereinafter abbreviated as PVP) 3.4 parts water 26.6 parts A drug solution was prepared by stirring and dissolving in a mixed solution of 26.6 parts of methanol using a stirrer (MGM-66, manufactured by SHIBATA). Next, Celphere (manufactured by Asahi Kasei Corporation) 60 parts of a fluidized bed granulator (FLO-1, manufactured by Glatt Co.) were charged in a previous intake air temperature 50 ° C. The drug solution Celphere, fluidized air volume 0.97 m ³ / min, binding solution A particulate composition was obtained by spray coating at a spray rate of 6 g / min and a spray air pressure of 3.0 kg / cm ² .
[Comparative Example 4]
The particulate composition obtained in Comparative Example 3 was humidified at 25 ° C. for 75% for 12 hours, and further dried at 30 ° C. for 40% for 3 hours to obtain a particulate composition subjected to crystallization treatment.

[Comparative Example 5]
Coated product of solifenacin succinate with crystalline binder on crystalline cellulose core particles (2)
Solifenacin succinate 10 parts, methylcellulose (trade name Metroles SM100, manufactured by Shin-Etsu Chemical Co., Ltd., hereinafter abbreviated as MC) 3.4 parts are stirred and dissolved in a mixture of 53.2 parts water and 53.2 parts methanol using a stirrer (MGM-66, manufactured by SHIBATA) A drug solution was prepared. Next, Celphere (manufactured by Asahi Kasei Corporation) 60 parts of a fluidized bed granulator (FLO-1, manufactured by Glatt Co.) were charged in a previous intake air temperature 55 ° C. The drug solution Celphere, fluidized air volume 0.97 m ³ / min, binding solution A particulate composition was obtained by spray coating at a spray rate of 5 g / min and a spray air pressure of 3.0 kg / cm ² .
[Comparative Example 6]
The particulate composition obtained in Comparative Example 5 was humidified at 25 ° C. for 75% for 12 hours and further dried at 30 ° C. for 40% for 3 hours to obtain a particulate composition subjected to crystallization treatment.

[Experimental example]
<Powder X-ray diffraction results>
First, the interaction between the drug and the polymer used was evaluated.
Fig. 1 shows powder X-ray diffraction results of spray-dried product consisting of PEG and drug used in this example, HPMC, PVP and drug used in Comparative Example (RINT 1400 as tube, tube voltage 40 KV, tube Current 40 mA, scanning speed 3000 ° / min (using Rigaku)). The results for the solifenacin succinate crystal and PEG only are shown as controls. As a result, all of the products produced using PEG shown in the Examples showed peaks derived from the crystalline form of solifenacin succinate, and it was confirmed that the drug in the powder was present as crystals. On the other hand, the sample shown in the comparative example showed a halo pattern peculiar to amorphous, and it was clarified that it existed in an amorphous state.
Further, FIG. 2 shows powder X-ray diffraction results (coated with RINT 2000 as an apparatus) of the coated product using PEG shown in this example (Example 3) and the coated product using HPMC shown in Comparative Example 1. : Tube Cu, tube voltage 50 KV, tube current 300 mA, scan speed 60000 ° / min (Rigaku Denki) is used). As shown in the figure, in the coated product, a crystal peak derived from solifenacin could be confirmed in the sample using PEG.

<Stability preliminary test results>
Tables 1 and 2 show the stability preliminary test results of these particulate compositions. The amount of degradation product after storage over time is measured by high performance liquid chromatography, and indicates the maximum value among the obtained individual degradation product amounts (production amount of F1 which is the main degradation product). In the test under severe conditions of 40 ° C and 75% RH, this is the case of HPMC shown in Comparative Example 1, but in the case of no humidification treatment, 0.04% at the start of storage and only 2 months change over time. A degradation product of 0.34%, 8 times the amount at the start of storage, was observed. In addition, in the case of PVP shown in Comparative Example 3, when no humidification treatment was performed, a degradation product exceeding 0.53% and the standard 0.4% was observed after 2 months of change. Further, in the case of MC shown in Comparative Example 5, when no humidification treatment is performed, a degradation product that is 12 times the amount at the start of storage is 0.74% in just two months with respect to 0.06% at the start of storage. Admitted. Even when humidification was performed to promote crystallization, the amount of decomposition products in Comparative Examples 2, 4, and 6 was larger than that in Examples. When HPMC was used, 0.07% at the start of storage, compared to 0.92% at a slight change of 2 months, a degradation product that was 13 times the amount at the start of storage was observed. Furthermore, when MC was used, a degradation product of 11.75% at the beginning of storage, 11.75%, and 11 times the amount at the start of storage was observed compared to 1.09% at the start of storage.

On the other hand, with respect to the samples shown in Examples 1 to 7, the amount of decomposition product at 2 months is 0.2% or less and the absolute value is 1/2 to 1/390 of the comparative example regardless of whether or not the humidification treatment is performed. Was small. Further, since the degree of change was small, it was found that solifenacin in the preparation was stable over time. On the other hand, as shown in Examples 2, 4, 6 and 8, it was found that the case where the humidification treatment was performed to promote crystallization showed almost no increase in decomposition products and a stable tendency.
Table 3 shows the Tg values of the binders used this time (mp if not available), and the linear regression was examined for the relationship between the amount of main degradation products (F1 (%)) and Tg (° C) at 2 months. However, as shown in FIG. 3, the square of the correlation coefficient indicating the correlation (R ² ) was 0.73 when the humidification drying was not performed, and 0.60 when the humidification drying was performed.

*HDPE: High Density Polyethylene
ND:not detected，NT:not tested
コハク酸ソリフェナシンを含有する加湿処理を施した粒子状組成物の安定性予試験結果
保存条件：40℃75%RH 密栓
包装形態：金属キャップ付HDPE bottle包装
試験項目：類縁物質（主分解物F1生成量，%）

各結合剤のTgガラス転移点(℃)

*融点（mp，℃)にて代用
**出典[医薬品添加物ハンドブック] 薬事日報社 2001年10月10日発行
***出典「高分子辞典」丸善 平成6年9月20日発行As described above, it is clear that the thermodynamic parameters of the additive used in combination are the dominant factors of solifenacin stability in the preparation. As described above, this phenomenon is caused by the fluidity of the binder, that is, Tg, and the higher the Tg, the more the amorphous substance existing in the preparation tends to exist stably in an amorphous state, and the decomposition product is likely to be generated. it was thought.
Preliminary results of the stability of the particulate composition containing solifenacin succinate Storage conditions: 40 ° C 75% RH Sealed stopper Packaging style: HDPE bottle with metal cap Test item: Related substances (Main degradation product F1 production,%)

* HDPE: High Density Polyethylene
ND: not detected, NT: not tested
Preliminary results of stability test of humidified particulate composition containing solifenacin succinate Storage conditions: 40 ° C 75% RH Seal plug Packaging type: HDPE bottle with metal cap Test item: Related substances (main degradation product F1 formation amount,%)

Tg glass transition point of each binder (℃)

* Substituting with melting point (mp, ° C)
** Source [Pharmaceutical Additives Handbook] Yakuji Nippo Publishing October 10, 2001
*** Source "Polymer Dictionary" Maruzen September 20, 1994

The technical feature of the present invention is that a particulate pharmaceutical composition containing solifenacin or a salt thereof can be produced by using a specific binder, and a stable particulate pharmaceutical composition can be produced. Accordingly, by performing crystallization promotion treatment such as humidification drying, it is possible to provide a more stable particulate pharmaceutical composition over time, which has a remarkable industrial effect. In addition, by using the particulate pharmaceutical composition according to the present invention, it is useful as a technology that enables the provision of various stable formulations of solifenacin or its salts that are eagerly desired to be developed as a pharmaceutical with excellent urinary frequency and urinary incontinence. It is.

Claims (10)

  A stable particulate pharmaceutical composition comprising solifenacin or a salt thereof and a binder having a glass transition point or a melting point of 140 ° C or lower.   The binder is selected from the group consisting of polyethylene glycol, polyethylene oxide, polyoxyethylene polyoxypropylene block copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyvinyl alcohol, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, starch, and maltose. The pharmaceutical composition according to claim 1, which is one or more selected substances.   The binder is one or more substances selected from the group consisting of polyethylene glycol, polyethylene oxide, polyoxyethylene polyoxypropylene block copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, and maltose. 2. The pharmaceutical composition according to 2.   The binder according to any one of claims 1 to 3, wherein the binder is one or more substances selected from the group consisting of polyethylene glycol, polyoxyethylene polyoxypropylene block copolymer, and hydroxypropylcellulose. Pharmaceutical composition.   The pharmaceutical composition according to any one of claims 1 to 4, obtained by granulating a drug solution containing solifenacin or a salt thereof and a binder having a glass transition point or a melting point of 140 ° C or lower. .   The particle forming method is one or more methods selected from the group consisting of freeze drying, spray drying, high speed agitation granulation, fluidized bed granulation, and rolling granulation. The pharmaceutical composition according to claim 5.   6. The pharmaceutical composition according to claim 5, wherein the granulation is performed by spray coating the drug solution onto core particles.   The pharmaceutical composition according to any one of claims 1 to 7, wherein the stability is further improved by performing a crystallization promotion treatment.   The crystallization promotion treatment is one or more treatments selected from the group consisting of a humidification treatment, a microwave irradiation treatment, an ultrasonic irradiation treatment, a low frequency irradiation treatment, and a thermionic irradiation treatment. 9. The pharmaceutical composition according to 8.   An orally disintegrating tablet containing the pharmaceutical composition according to any one of claims 1 to 9.

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