BG1677U1 - Pharmaceutic composition with stable particles of soliphenacine or of its salt - Google Patents

Abstract

The utility model refers to obtaining a stable pharmaceutical composition with particles of soliphenacine or of its salt, as it has a spherical form suitable for covering and its disintegration in time can be inhibited when a pharmaceutical preparation of soliphenacine or of its salt is being supplied to hospital areas. More specifically the model refers to a pharmaceutical composition with particles which can be obtained by using a binding substance whose Tg or melting point is lower than 174 oC when the composition is being set up of a pharmaceutic preparation with particles of soliphenacine. Besides that, under a treatment promoting crystallization, after the pharmaceutical composition with particles is performed, a more stable composition with particles of soliphenacine, or of its salt,can be obtained.

Description

Technical field

This utility model relates to a stable particulate pharmaceutical composition obtained by the use of solifenacin or a salt thereof and a specific binder, a process for making the same, a tablet disintegrating the oral composition containing the pharmaceutical composition with particles, and a method for stabilizing the pharmaceutical composition with particles.

BACKGROUND OF THE INVENTION

Solifenacin is represented by the following formula (I): (Chemical formula 1)

Formula (I) and its chemical name is (1R, 3R) - quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate. A series of quinuclidinyl derivatives, including solifenacin and its salts, have been shown to have highly selective antagonism to muscarinic M, a receptor, and is useful as a preventive / therapeutic agent for urological diseases such as nerve polacuria, neurogenic bladder, nocturia, unstable metastasis bladder and chronic cystitis or respiratory diseases such as chronic obstructive diseases of the lungs, asthma and rhinitis, (see patent document 1).

In Example 8 of Patent Document 1, a process for the manufacture of solifenacin hydrochloride is presented, and it is described that a crystal placed in a mixed solvent composed of acetonitrile and diethyl ether has a melting point of 212 to 214 ° C and shows a specific rotation [ alpha] ²⁵ _o from 98.1 (c = 1,00, EtOH).

However, patent document 1 lacks a description or even indication of the amorphous form of 5 solifenacin or a salt thereof, or that when solifenacin succinate is formed in the pharmaceutical preparation by a standard formation method, solifenacin succinate, which is the active ingredient, is significant degraded with time in the pharmaceutical preparation produced.

Non-Patent Document 1, issued by the Ministry of Health, Labor and Social Policy in June 2003, outlines the specification for pharmaceutical 15 preparations, which are concepts for degraded products (impurities) in pharmaceutical preparations accepted for stability testing. According to this document, in the case where the amount of the substance of the drug that is prescribed 20 per day is less than 10 mg, the threshold for which the confirmation of the safety of the disintegration products in the pharmaceutical preparation is required is less than 10% the amount of breakdown products contained in the drug substance25 and 50 µg in the total intake of breakdown products per day. In the case where the amount of substance of the drug prescribed per day is 10 mg or more and 100 mg or 30 less, the threshold for which confirmation of the safety of degradation products in the pharmaceutical preparation is required is less than 0.5% in terms of the amount of degradation products contained in the substance of the drug and 200 µg in terms of total intake of the degradation products per day. Therefore, normally, the standard value of the amount of degradation products that can be determined without 40 confirming the safety of the degradation products is, for example, in the case of a pharmaceutical preparation in which the substance content of the drug is 5 mg, 1.0% or less in terms of the amount of degradation products 45 contained in the drug substance and, for example, in the case of a pharmaceutical preparation in which the drug substance content is 10 mg, 0.5% or less in quantity o products50 of the decomposition contained in the substance of the drug.

Currently, solifenacin pharmaceuticals that will be marketed based on the results of these clinical trials are tablet 2.5 mg, tablet 5 mg and tablet 10 mg. In order for these pharmaceutical preparations to have stability, as described in Non-Patent Document 1, it is considered that the amount of the major decomposition product of solifenacin succinate (hereinafter referred to herein as F1) is related to the total amount of solifenacin succinate and decomposition products should be set at 0.5% or less, preferably there is a need to control at 0.4% or less, including differences and errors between multiple products and during testing.

On the other hand, solifenacin and its salt are known to have very high solubility in various solvents and strong bitterness and porosity. Therefore, in order to develop a pharmaceutical preparation of good benefit, such as particles or powder included in the oral disintegration tablet of solifenacin or a salt thereof, there is a need to conceal bitterness and astringency. Thus, there is a need to apply a film coating method using a polymeric substrate. In particular, in the case where the drug substance is a film coated with a polymeric substrate, there is a need for uniform coverage of the drug substance surface. Thus, the substance of the drug should represent spherical fine particles of similar particle size.

[Patent document 1] EP Patent No. 801067 [Non-patent document 1] RFSB / ELD Notification No. 0624001 “Review of indication of impurities in medicinal products with new active ingredients”

The technical nature of the utility model

Problems that the utility model should solve

As described above, there is a need to provide a pharmaceutical composition with stable solifenacin particles, or a salt thereof, which is spherical, film-coated and in which decay over time can be inhibited when the pharmaceutical product solifenacin or its salt is delivered in clinical areas.

Remedies

In the development of solifenacin succinate as an excellent therapeutic agent for frequent urination or urinary incontinence, the present inventors cover the substance of the drug with a standard binder (polyvinylpyrrolidone (hereinafter abbreviated as PVP) or hydroxypropylmethylcellulose (otc) cotacetate (ot. of the technique is usually carried out by a fluidized bed granulation method or the like, and performs a preliminary stability test for the pharmaceutical preparations obtained from 2 months under conditions of accelerated testing (conditions of 40 ° C, 75% RH relative humidity) and the pressurized bottle), which is one of the standard stability tests. As a result, a decrease in the residual amount of solifenacin succinate is observed and it is shown that at 6 months after the start of storage, which is the time of final determination in the acceleration test, the amount of F1 produced (oxidized form of solifenacin succinate) to total solifenacin succinate and degradation products exceed 0.4% (see Table 1 for more details). It has been found difficult to obtain a pharmaceutical preparation having pharmaceutically sufficient stability by such a standard method of formation.

At such a technical level, the present inventors have carried out extensive studies to stabilize the pharmaceutical preparation of solifenacin and, as a result, have found beyond expectations that solifenacin is an amorphous form formed in the manufacturing process of the pharmaceutical preparation is the main cause of the active drug disintegration. ingredient over time, and the use of the standard binder as HPMC is widely associated with the formation of an amorphous form of solifenacin. In order to obtain a granular substance in which the bitterness and the versatility of solifenacin are concealed, the present inventor considers the method in which a fine particle (pharmaceutical)

1677 Ul particle composition) is obtained by injecting a drug substance solution into the core of a particle composed of, for example, crystalline cellulose and the fine particle coated with a suitable polymeric substance is effective. In order to obtain such a fine particle, it is necessary to spray after solifenacin or its salt once dissolved, however, it has been found that solifenacin is subject to amorphization at this time, and in addition, an additional problem occurs when converts from amorphous form to crystalline form. This is the case where a particle pharmaceutical composition is produced after part or all of the solifenacin is diluted in a solvent, it is found to be very difficult to provide solifenacin stability.

In these circumstances, the present inventors first discover that when a substance having an ethylene oxide chain such as polyethylene glycol (another name: macrogol, sometimes referred to as PEG) is used as a binder, a pharmaceutical preparation in which the breakdown of solifenacin with time can be inhibited by inhibiting the retention of an amorphous form of solifenacin produced beyond expectation, although PEG itself is a substance mainly used for the purpose of amorphizing a dosage form.

Moreover, in the development and manufacture of a solid solifenacin pharmaceutical composition or film-coated film salt thereof, the present inventors have come to the idea that, for example, in the case where solifenacin dissolved is injected into the core of the particle together with a polymeric substance (binder) such as PEG, whether or not solifenacin may or may not retain an amorphous form after injection may depend on the flowability of solifenacin in the polymeric substance (binder). Therefore, they have done extensive research and paid attention to physical values (a glass transition point (abbreviated here as Tg) or a melting point (abbreviated here as a tr) specific to the polymer that can affect the drug substance's flowability as a binder As a result, they found that when a binder having Tg was used for a pharmaceutical composition with particles, the initial value for the bound substance, which becomes an index of However, when a specific binder has a Tg lower than the value used for a pharmaceutical composition with particles, they found that the initial value of the bound substance was expected to be lower than the given value. then both are low and stable and even more so, the particle size is uniform and spherical, which is suitable for film coating.

In addition, as a result of intensive research, it has been found that when crystallization-assisted treatment such as wetting and drying treatment is carried out, a more stable pharmaceutical composition with particles is produced, thus the present utility model is carried out.

This utility model relates to:

A stable particulate pharmaceutical composition comprising solifenacin or a salt thereof and a binder having the action of stabilizing solifenacin or a salt thereof,

2. The pharmaceutical composition according to item 1 above, wherein the binder has the action of stabilizing solifenacin or a salt thereof is a binder having the action of inhibiting the retention of an amorphous form of solifenacin or a salt thereof,

3. The pharmaceutical composition according to the above points 1 or 2, characterized in that the binder is a binder having a glass transition point or melting point lower than 174 ° C,

The pharmaceutical composition according to item 3 above, wherein the binder is one or more substances selected from the group consisting of polyethylene glycol, polyethylene oxide, polyoxyethylene / polypropylene blocking copolymer, hydroxypropole cellulose, hydroxyethyl cellulose, ethyl cellulose, cellulose cellulose, ethyl cellulose L, methacrylic acid copolymer LD, methacrylic acid copolymer

5, corn starch, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS and maltose,

5. The pharmaceutical composition according to item 4 above, wherein the binder is one or more substances selected from the group consisting of polyethylene glycol, polyoxyethylene / polyoxypropylene blocking copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose and maltose,

6. The pharmaceutical composition according to item 3 above, wherein the binder is one or more substances selected from the group consisting of polyethylene glycol, polyoxyethylene / polyoxypropylene blocking copolymer and hydroxypropyl cellulose,

7. A stable particulate pharmaceutical composition solifenacin or a salt thereof, which may be prepared by the use of a mixture in which solifenacin or its salt and a binder having the action of stabilizing solifenacin or its salt are co-soluble and / or suspended,

8. The pharmaceutical composition according to item 7 above, wherein the binder having the action of stabilizing solifenacin or a salt thereof is a binder having the action of inhibiting the retention of an amorphous form of solifenacin or a salt thereof,

A pharmaceutical composition according to the above points 7 or 8, characterized in that the binder is a binder having a glass transition point lower than 174 ° C,

10. The pharmaceutical composition according to item 9 above, wherein the binder is one or more substances selected from the group consisting of polyethylene glycol, polyethylene oxide, polyoxyethylene / polypropylene blocking copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, ethyl cellulose copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, corn starch, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS and maltose,

11. The pharmaceutical composition according to item 9 above, wherein the binder is one or more substances selected from the group consisting of polyethylene glycol, polyoxyethylene / polyoxypropylene blocking copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose and maltose,

12. The pharmaceutical composition according to item 9 above, wherein the binder is one or more substances selected from the group consisting of polyethylene glycol, polyoxyethylene / polyoxypropylene blocking copolymer and hydroxypropyl cellulose,

13. The pharmaceutical composition according to any one of the above points 1 to 12, the stability of which is enhanced by the additional presentation of crystallization-assisted treatment, and

A disintegrating tablet in the oral cavity containing the pharmaceutical composition according to any one of the above points 1 to 13.

In summary, as a flow index, thermodynamic parameters characteristic of a substance as a glass transition point (Tg, unit: ° C) or a melting point (unit: ° C) based on an amorphous section at a polymer and melting point (tr, unit, ° C) based on the crystalline region, in the polymer are used in many cases. These values indicate a temperature indicating a change in the thermodynamic state of a substance, but because molecular motion is suppressed at a temperature lower than Tg, the substance is in a state close to crystalline state or a glass state where plasticity is subject to decrease . But when the temperature of the substance is Tg or higher, the degree of activity of the molecule increases, where the substance is in a rubber-like state, and flexibility increases. Furthermore, a condition where, by increasing in temperature, the crystalline region of a polymer decomposes to show liquidity, means the melting of the polymer. With this in mind, when an amorphous drug substance exists in a polymer at a certain temperature, the higher the Tg of the polymer, the more difficult the polymer itself flows. It is therefore amenable to being in an amorphous form, which is in its original state, and vice versa, means that the lower the Tg of the polymer, the sooner the crystal is deposited (Int. J. Pharm. 282 (2004) 151-162 ). On the other hand, as regards the low molecular weight compound, because the structure of the substance is crystalline, it does not have Tg in many cases, therefore a melting point is used as a low molecular weight index for a parameter indicating a change in thermal mobility.

1677 Ul compound. As for the polymer, Tg is used, which is the temperature at which the change occurs more rapidly.

In addition, the utility model relates to:

15. A method of stabilizing solifenacin or a salt thereof by subjecting a pharmaceutical composition comprising solifenacin or a salt thereof and a binder having the action of stabilizing solifenacin or a salt thereof to a crystallization-promoting treatment; and

16. A method of transferring an amorphous form of solifenacin or a salt thereof to crystalline form thereof by subjecting a stable partial composition comprising solifenacin or a salt thereof and a binder having the action of stabilizing solifenacin or a salt thereof to a crystallization promoting treatment.

Henceforth, the composition of the utility model will be described in detail.

Examples of "solifenacin salt" to be used in the utility model include solifenacin hydrochloride as described in Patent Document 1, acid addition salts with mineral acids such as hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malonic acid, citric acid, tartaric acid , Carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid, and quaternary ammonium salts. Among these, solifenacin succinate is preferred over the provision as a pharmaceutical.

The "solifenacin or salt thereof" to be used in the present utility model may be readily prepared by or in accordance with the method described in Patent Document 1 or by the standard method.

The "crystal" or "crystalline form" of solifenacin or a salt thereof means a literal interpretation of a substance of solifenacin or a salt thereof having a crystallographically crystalline structure. However, in the present utility model, this means a substance other than an "amorphous form" which exhibits significant degradation over time of solifenacin when contained within a range, which does not affect the stability of the product in the pharmaceutical preparation. On the other hand, the "amorphism" or "amorphous form" of solifenacin or a salt thereof in the present utility model means a substance having a crystallographically amorphous structure. But in the present utility model, this means a substance other than "crystal" or "crystalline form" which exhibits extremely low degradation over time of solifenacin when contained in an amount exceeding the range which does not affect the stability of the product in the pharmaceutical formula .

The amount of mixing of solifenacin and / or its salt used in the present utility model is generally selected appropriately according to the type of drug or its medical use (indication), but is not specifically limited insofar as it is a therapeutically effective amount or a prophylactically effective amount. In particular, it is from 0.01 mg to 100 mg, preferably from 0.5 mg to 50 mg, more preferably from 0.5 mg to 10 mg, and most preferably from 0.5 mg to 4 mg, per daily amount of solifenacin or a salt thereof.

In addition, the amount of mixing solifenacin or its salt in the disintegrating tablet in the buccal cavity of the present utility model may be any as long as an effective amount per unit of administration of the pharmaceutical preparation is present, but is preferably 0.001% relative to up to 97% by weight, more preferably from 0.05% by weight to 50% by weight, more preferably from 0.05% by weight to 10% by weight, and most preferably from 0.05% by weight to 4% by weight .

"Binder having the action of stabilizing solifenacin or a salt thereof" as used in the present utility model means a binder that can inhibit the degradation in time of solifenacin or a salt thereof, and more particularly means a binder that can to inhibit the degradation over time of solifenacin or a salt thereof by the action of inhibiting the retention of an amorphous form. In addition, in the case where the binder

1677 A substance which does not have the action of stabilizing solifenacin or its salt alone, for example even a binder such as HPMC or PVP, is used in conjunction with the binder for use in this useful model for the purpose of improving its action as a binder, it may be used in an amount in a range that does not exceed the specific stability setting of the pharmaceutical preparation that is the subject of this utility model.

The "inhibition of amorphous form retention", as used in the present utility model, refers to the action of making a compound difficult to exist in an amorphous state and / or an action that can make the compound easy to transform from an amorphous form to crystalline form.

In addition, a binder having the action of stabilizing solifenacin or a salt thereof, or inhibiting the retention of an amorphous form used in the present utility model, is a binder that can reduce the amount of F1 of solifenacin by up to 0.5% or a lower, preferably binder that can reduce the amount of F1 of solifenacin to 0.04% or less. More specifically, it is a binder having a Tg or wr lower than 174 ° C, preferably a binder having a Tg or wr of 0 ° C or more to lower than 174 ° C, even more preferably a binder having a Tg or wr of 0 ° C or more to less than 156 ° C, and even more preferably a binder having a Tg or wr of 0 ° C or more to a low of 137 ° C, and most preferably a binder having a Tg or tr of 10 ° C or more and less than 137 ° C. The specific type of binder is not specifically limited insofar as HMaTg with the aforementioned ranges, preferred examples of these include a substance having ethylene oxide chain, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyvinyl alcohol, methacrylic acid copolymer copolymer copolymer copolymer copolymer copolymers. However, from the point of view of the manufacturing process, polyvinyl alcohol, methacrylic acid copolymer, aminoalkyl methacrylate copolymer and starch have a low bonding strength between the aforementioned binders, therefore the particle coating is considered difficult. Accordingly, more preferably a substance having an ethylene oxide chain such as PEG, polyethylene oxide or polyoxyethylene / polyoxypropylene block copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose or maltose, more preferably PEG, polyoxyethylene / polyoxypropylene hypoxypropylene hydroxypropylene, hydroxypropyl cellulose, most preferably PEG. With respect to such a binder, the molecular weight, degree of polymerization or the like are not specifically limited to the subject matter of this useful model for inhibiting the amorphization of solifenacin or a salt thereof, which may be retained by the addition of the binder. However, regarding the type of molecular weight, the average molecular weight is preferably in the range of 400 to 1000000, and most preferably in the range of 2000 to 200000. In addition, the binders described above can be used in combination with two or more types.

The substance having an ethylene oxide chain as used herein is not particularly limited as long as there is an ethylene oxide chain. Its molecular weight, degree of polymerization or the like are not specifically limited to the extent that the subject of the present utility model for inhibiting the amorphization of solifenacin or a salt thereof can be retained by the addition of the substance. But as far as the molecular weight type is concerned, the average molecular weight is preferably in the range of 400 to 1000000, and even more preferably, the average molecular weight is in the range of 2000 to 200000. Substances having an ethylene oxide chain can be used alone or by mixing two or more types. In the present utility model, specific examples of a substance having an ethylene oxide chain include PEG, polyethylene oxide, a block copolymer of polyoxyethylene / polyoxypropylene and the like. In the present utility model, however, of these, PEG and block copolymer polyoxy 1667 H ethylene / polyoxypropylene are preferred, and PEG is particularly preferred. Like PEG, PEG in solid form at normal temperature is preferred. Specific examples include Macrogol 4000 (Japanese Pharmacopoiea, molecular weight: 2600 to 3800, trade name: Macrogol 4000 / Sanyo Chemical Industries Ltd., NOF Corporation, Lion Corporation, etc.), Macrogol 6000 (Japanese Pharmacopoiea, molecular weight: 7300 to 9300, trade name: Macrogol 6000 / Sanyo Chemical Industries Ltd., NOF Corporation, Lion Corporation, etc.), Macrogol 20000 (Japanese Pharmacopoiea, molecular weight: 15000 to 25000, trade name: Macrogol 20000 / Sanyo Chemical Industries Ltd. , NOF Corporation, Lion Corporation and the like), polyethylene glycol 8000 (USP / NF, molecular weight: 7000 to 9000, trade name: Poliethylene glycol 8000 / The Dow Chemic al Company, etc.), and the like. The average molecular weight of PEG is preferably in the range of 400 to 40,000, more preferably in the range of 2,000 to 25,000, and most preferably in the range of 2,000 to 10,000.

The polyoxyethylene / polyoxypropylene copolymer block of the present utility model is a copolymer of propylene oxide and ethylene oxide, and there are different types depending on the composition ratio, but may have a composition ratio that has the property of inhibiting the amorphization of solifenacin or a salt thereof. More specifically, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol (another name: Pluronic F68) or the like are used.

"Mixture in which solifenacin or its salt and a binder having an action to stabilize solifenacin or its salt are co-dissolved and / or suspended", as used in the present utility model, means a mixture in which a binder having action to stabilize solifenacin or a salt thereof are dissolved together with a solution obtained by dissolving solifenacin or a salt thereof in a solvent such as water. However, it is not always necessary to dissolve all solifenacin or a salt thereof in the solvent, and insofar as the particle containing the drug is suitable for coating such as, for example, masking, which can then be obtained with the resulting mixture, such a mixture to a particular particle obtained by using the mixture in a suspended state in which part of solifenacin or a salt thereof is dissolved in a solvent is also included.

The composition "obtainable by use" of a mixture in which solifenacin or its salt and a binder having the action of stabilizing solifenacin or its salt are co-dissolved, in the present utility is a drug-containing particle which is suitable for coverage such as bitterness masking. Examples therefore include a composition obtained by spray coating the core particle with such crystalline cellulose with the drug in dissolved form, a composition which can be obtained, not by spraying the drug substance in liquid form, but by mixing the mixture obtained by co-dissolving these substances with an insoluble particle nucleus and depositing the drug substance to arrange the drug substance equally over the insoluble nucleus of the particle, and the like. In addition, examples of a product obtained from a non-core particle method include powder obtained by spray drying or freeze drying a drug and binder solution, and such powder may be used for a drug containing particle substance to be used to mask bitterness or the like. However, in terms of production efficiency, a composition which can be obtained by spray coating the core of a particle with a mixture in which solifenacin or a salt thereof and a binder having the action of stabilizing solifenacin or a salt thereof is co-dissolved, is preferred.

A " stable particle pharmaceutical composition " as used herein in the utility model is a particle that can be prepared by the use of solifenacin or a salt thereof, and is not specifically limited insofar as it is a stable particle in which degradation over time is inhibited . The term " stable ", as used in the present utility model, specifically1677 Ul but means a particle in which the production of F1 amount of solifenacin or a salt thereof is 0.5% or less, more preferably 0.4% or less. Furthermore, in the case where the pharmaceutical composition of the present utility model is a particle such as a granule, the particle size of the pharmaceutical particle composition is not particularly limited as long as the longest diameter is 2 mm or less. As for the case where it is included in a disintegrating tablet in the buccal cavity, the particle size is not specifically limited as long as there is no unpleasant grain sensation similar to sand when ingested, but preferably obtained at an average particle size of 350 micrometer or less. A more preferred average particle size is from 1 to 350 µm, and a particularly preferred average particle size is from 20 to 350 µm. In terms of particle size distribution, it is not specifically limited insofar as it is a particle suitable for covering such bitterness masking, but preferably 80% of the total weight is distributed between 1 and 350 µm, preferably 80% of the total weight is distributed between 50 and 300 µm, and most preferably 80% of the total weight is distributed between 100 and 250 µm.

Furthermore, the shape of the particulate composition of the present utility model is not specifically limited insofar as it is in a state where a coating such as bitterness masking can be accomplished, but regarding the coating efficiency, it is preferably spherical, i.e. . Its sphericity is preferably as close as possible to 1.

In the case where the partial pharmaceutical composition of the present utility model is a granule, the amount of mixing of the binder in the partial pharmaceutical composition is not specifically limited insofar as it is an amount that enables co-coating with solifenacin or a salt thereof and achieves the object of the present utility model . However, it is preferably from 0.01 to 91% by weight, and even more preferably from 0.5 to 75% by weight, of the total particulate pharmaceutical composition. The most preferred amount of mixing is from 5 to 50% by weight. In addition, by taking the amount of mixing of the binder in the case where the pharmaceutical composition of the present utility model is a particle, such as a granule, taking into account the ratio of 1 part to the weight of solifenacin or its salt in crystalline form and amorphous form, for it is preferably a ratio ranging from 1 to 10000% by weight, more preferably a ratio in the range of 5 to 500% by weight, and further a preferred ratio in the range between 10 to 100% by weight.

The particulate pharmaceutical composition of the present utility model is prepared with solifenacin or a salt thereof in solution. However, in the case where the core of the particle is spray coated with a solution of solifenacin, examples of the core of the particle include sodium chloride, microcrystalline cellulose, calcium carbonate, lactose, maltose and mannitol, and preferred such examples include microcrystalline cellulose, lactose, mannitol, mannitol, mannitol, mannitol, mannitol similar. Microcrystalline cellulose and lactose are preferred. In the present utility model, among the group of these substances, one type or two or more types may be used in combination.

In addition, crystallization promotion treatment as used herein is not specifically limited insofar as it is a crystallization promotion treatment, and examples thereof include humidification, microwave irradiation, ultrasonic irradiation, low frequency irradiation, thermal electronic radiation and the like. . Furthermore, humidification treatment refers to treatment whereby, for example, humidity is carried out at a temperature of 20 to 30 ° C and at a humidity of 60 to 85% RH for 6 to 24 hours, and then drying at a temperature of 30 to 40 ° C and humidity from 30 to 40% RH for 2 to 6 hours. Microwave irradiation may not generally be limited, but for example microwave irradiation may be used at a wavelength of 10 MHz to 25 GHz. Further, the treatment time depends on the degree of crystallization in the initial phase and the selected base material, but for example treatment for 10 s to 60 min may be used. The irradiation per se can be carried out continuously or intermittently and at any time limits after any particle composition has been produced.

Treatment with ultrasonic irradiation cannot be restricted in the general case, but for example ultrasonic waves with a frequency of 10 kHz to 600 kHz may be used. Furthermore, the treatment time depends on the degree of crystallization in the initial phase and the selected base material, but for example it can be carried out for 10 s to 24 h. The irradiation per se can be carried out continuously or intermittently and at any time limits after any particle composition has been produced.

Moisture, microwave, and ultrasonic irradiation are preferred as crystallization-promoting treatments.

In the particulate pharmaceutical composition of the present utility model, each of a number of pharmaceutical excipients is suitably used and formulated in a pharmaceutical preparation. Examples of such pharmaceutical excipients include lactose and the like. In addition, another additive may be used in a range that does not impair the object of the present utility model insofar as it is pharmaceutically and pharmacologically acceptable. For example, a disintegrant, oxidizing agent, foaming agent, artificial sweetener, fragrance, lubricant, colorant, stabilizer, buffering agent, antioxidant, surfactant or the like can be used, and there is no limit. Examples of self-integrating agents include corn starch, potato starch, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose and others. Examples of oxidants include citric acid, tartaric acid, malonic acid and the like. Examples of foam agents include sodium bicarbonate and the like. Examples of artificial colors include saccharin sodium, dicalium glycyrrhizinate, aspartame, stevia, somatine and the like. Examples of flavors include lemon, lime, orange, menthol and the like. Examples of lubricants include magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, stearic acid and the like. Examples of colorants include yellow iron sesquioxide, red iron sesquioxide, food yellow No. 4 and 5, food red No. 3 and 102, food blue No. 3 and the like. Examples of buffering agents include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or its salt, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or its salt, magnesium oxide, zinc oxide, magnesium oxide, magnesium acid, boric acid or a salt thereof and the like. Examples of an antioxidant include ascorbic acid, sodium nitrite, sodium sulfite, sodium hydrogen sulfite, sodium edetate, erythorbic acid, tocopherol acetate, tocopherol, butylhydroxyanisole, dibutyl hydroxytoluene, other propyl galat. Examples of surfactants include sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid ester (polysorbate 80), polyoxyethylene hydrogenated castor oil, and the like. With respect to the pharmaceutical excipient, the aforementioned substances may conveniently be added alone or in combination with two or more groups in an appropriate amount.

"Amorphous form content" as used in the present utility model means the ratio of the total amorphous form to the crystalline form of solifenacin or a salt thereof.

Examples of a pharmaceutical preparation using the above-mentioned particle include powder, granule, pill, tablet, capsule, disintegrating tablet in the buccal cavity, dry syrup and the like, but more specifically disintegrating tablet in the buccal cavity is preferred.

Henceforth, a disintegrating tablet in the buccal cavity containing the particulate pharmaceutical composition of the present utility model will be described.

"Disintegrating tablet in the buccal cavity" in the present embodiment means a tablet that disintegrates in the buccal cavity with real saliva only within 2 min, preferably for 1 min, more preferably for 30 s, when the tablet is taken without water, and a pharmaceutical drug close to the tablet.

The particulate pharmaceutical composition of the present utility model may be included in such a disintegrating tablet in the buccal cavity, for example a disintegrating tablet in the buccal cavity may be obtained by administering the pharmaceutical particle with 10 tray as the drug substance in a known disintegrating tablet in the buccal cavity, described in each of International Publication No. 9520380 (corresponding to U.S. Patent 5576014), International Publication No. 200292057 (corresponding to U.S. Patent Publication 2003/099701), U.S. Patent 43055 02, US patent 4371516, Japanese patent 2807346 (corresponding to US patent 5466464), JP-A-5-271054 (corresponding to European patent 553777), JP-A-10-182436 (corresponding to European patent 5958453), Japanese patent 3412694 (corresponding to U.S. Patent 5223264), and International Publication No. WO 1998/002185 (corresponding to U.S. Patent 6287596) using the base material of a disintegrating tablet in the buccal cavity described in each publication and following the method described in each publication . Thus, as a disintegrating tablet in the buccal cavity containing the particulate pharmaceutical composition, the disintegrating tablet in the buccal cavity described in Japanese Patent 3412694 (corresponding to U.S. Patent 5223264) and JP-A-2003-55197 can be exemplified , and the particulate pharmaceutical composition of the present utility model may be incorporated into such a disintegrating tablet in the buccal cavity.

In general, the disintegrating tablet in the buccal cavity, as illustrated above, is roughly classified into a molded, wetted type and a standard tablet type, and the particulate pharmaceutical composition of the present utility model may be included in any type of disintegrating tablet in the buccal cavity . The type of molded disintegrating tablet in the buccal cavity is prepared, for example, by filling a matrix with a solution or suspension of such excipient and drying it, as disclosed in Japanese Patent 2807346 (corresponding to U.S. Patent 5466464). The molded type of disintegrating tablet in the buccal cavity containing the particulate pharmaceutical composition of the present utility can be prepared, for example, by filling a blister pack with a solution or suspension of the pharmaceutical composition of the present utility model, an excipient such as saccharide and a binder such as for example gelatin or agar, and removal of moisture by a method such as freeze drying, reduced pressure drying or low temperature drying. The wetted type of disintegrating tablet in the buccal cavity is obtained by wetting an excipient such as saccharide, and preforming low pressure tabletting and then drying, as described in Japanese Patent 3069458 (corresponding to U.S. Patent 5501861 and U.S. Pat. 572974). Therefore, for example, the particulate pharmaceutical composition of the present utility model and excipient such as saccharide are moistened with a small amount of water or a mixed solution of water and alcohol, and the resulting humidified mixture is molded at low pressure and then the molded mixture is dried, from which the wetting type of decay take a tablet in the buccal cavity can be obtained.

In the case of a standard-type tablet, it is obtained by the standard tableting step, as disclosed in International Publication No. 95-20380 (corresponding to U.S. Patent 5576014), International Publication 200292057 (corresponding to U.S. Patent Application Publication No. 2003/099701, JP-A-ΙΟΙ 82436 (U.S. Patent No. 5958453), JP-A-9-48726, JP-A-8-19589 (U.S. Patent 5672364), Japanese Patent 2919771, Japanese Patent 3069458 (U.S. Patent 5501861) and U.S. Patent 5720974) to obtain the standard tablet type of disintegrating tab a fly in the buccal cavity containing the particulate pharmaceutical composition of the present utility model, for example the partial pharmaceutical composition of the present utility model, and an excipient such as a low-moldable saccharide are granulated using a solution or suspension of a high-moldability saccharide and / or a water-soluble polymer , and then the resulting granular substance is molded directly to form a directly molded substance, or further obtained the directly molded substance is moistened and dried is where a disintegrating tablet in the buccal cavity can be obtained, as disclosed in International Publication 95-20380 (corresponding to U.S. Patent 5576014) and Japanese Patent 2919771.

1677 In addition, to obtain a standard type of disintegrating tablet in the buccal cavity, as shown in International Publication 99-47124 (corresponding to U.S. Patent 6589554), for example, the particulate pharmaceutical composition of the present utility and excipient such as crystalline saccharide, are formulated directly using an amorphous saccharide, and the resulting substance is subjected to wetting and drying, whereby a disintegrating tablet in the buccal cavity can be obtained. In addition, to obtain the standard tablet type of disintegrating tablet in the buccal cavity, as disclosed in International Publication 200292057 (corresponding to U.S. Patent Application Publication Number 2003/099701), for example, a mixture of the particulate pharmaceutical composition of the utility model and a saccharide excipient with a melting point lower than the excipient are molded directly, and the resulting substance is heated to form a cross-link with the molten solidified product of the saccharide with a lower melting point, thereby decomposing yes that Letcani in the buccal cavity can be obtained. By wetting and drying or heating as described above, the tablet strength of such a disintegrating tablet in the buccal cavity can be improved.

As the excipient used in a disintegrating tablet in the buccal cavity of the present utility model, a standard excipient may also be used, for example a more pharmaceutically acceptable saccharide is used as a preference. In a technique using saccharide moldability, a low moldability saccharide may be used. When using a technique to improve tablet strength by the crystalline / amorphous property of saccharide and wetting and drying, crystalline saccharide may be used. When a cross-linking technique using a molten saccharide solidified product is used, a high melting point saccharide may also be used in addition to the standard excipient.

"Low moldability saccharide" means a saccharide that provides a tablet hardness of 0 to 2 cr when, for example, 150 mg of saccharide is tableted at a tableting pressure of 10 to 50 kg / cm ² using a stroke of 8 mm diameter. The "low formability saccharide" is a saccharide that provides a tablet hardness of 2 cr or more by the same method. Low formability saccharide is a pharmaceutically acceptable one, and examples thereof may include lactose, mannitol, glucose, sucrose, xylitol, erythriol and the like. These saccharides can be used alone or by actually combining two or more types. Highly formable saccharide is a pharmaceutically acceptable one, and examples thereof may include maltose, maltitol, sorbitol, trehalose and the like. These saccharides may also be used alone or by an appropriate combination of two or more types.

"Crystalline saccharide" is a pharmaceutically acceptable one, and examples thereof may include mannitol, maltitol, erythritol, xylitol and the like. These saccharides can be used alone or by actually combining two or more types. "Amorphous saccharide" is a pharmaceutically acceptable one, and examples thereof may include lactose, sucrose, glucose, sorbitol, maltose, trehalose and the like. These saccharides can also be used alone or by actually combining two or more types.

Furthermore, a "melting point excipient higher than a low melting point saccharide" is a pharmaceutically acceptable one and may be selected from, for example, xylitol, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and similar. These saccharides can be used alone or by actually combining two or more types. "Low melting point saccharide" is a pharmaceutically acceptable one and may be selected from, for example, xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. Also, these saccharides can be used alone or by actually combining two or more types. As a binder for a disintegrating tablet in the buccal cavity, maltitol, copolividone, erythritol and the like can be exemplified. Also, these binders can be used alone or by an appropriate combination of two or more types.

When using water-soluble poly12

1677 A high-molded saccharide site measure, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, polyvinyl alcohol, gum arabic powder, gelatin, purulan and the like are preferred.

The amount of mixing of the excipient used in a disintegrating tablet in the buccal cavity containing the particulate pharmaceutical composition of the present utility model is suitably adjusted according to the amount of mixing of the particulate pharmaceutical composition of the present utility model and / or the tablet size and the like , but is preferably from 20 to 1000 mg in the general case, preferably from 50 to 9090 mg, and especially preferably from 100 to 800 mg per tablet.

Further, the amount of blending of the high-molded saccharide, the water-soluble polymer, the amorphous saccharide or the low melting point saccharide is not specifically limited as far as is appropriately selected and used according to the relevant techniques, but is preferably from 0.5 to 40% by weight, more preferably from 2 to 30% by weight, and more particularly from 5 to 20% by weight of the excipient's weight, or preferably from 1 to 20% by weight of the general pharmaceutical composition.

With respect to the type of other optional additive, formula or amount thereof, or the like, or the like, the description of the aforementioned patent documents concerning disintegrating tablets in the buccal cavity is cited as a description of this specification.

Further, in the case where the particulate pharmaceutical composition of the present utility model is included in the disintegrating tablet in the buccal cavity, the particulate pharmaceutical composition may be included in an amount corresponding to 0.5 to 90% by weight, preferably from 1 to 80 % by weight, and more preferably from 5 to 60% by weight, of the total disintegrating tablet in the buccal cavity.

Hereinafter, a process for preparing the particulate pharmaceutical composition of the present utility model will be described.

To obtain the particulate pharmaceutical composition of the present utility model, solifenacin or a salt thereof and a binder having the action of stabilizing solifen zinc or a salt thereof are dissolved or suspended by agitation in water or a mixed solution obtained by the addition of an organic solvent such as for example, ethanol to water using a stirrer to form a drug solution. In this case, the water or the organic solvent contained in the drug may be suitably adjusted. As a technique for dusting (granulating) a solution of the drug substance solifenacin or a salt thereof, for example, freeze drying, spray drying, high power agitation granulation, liquid bed granulation, cylinder granulation and the like can be used. Insofar as the method allows the solifenacin to be pulverized (granulated) after it has dissolved, the device and the technique are not particularly limited, but spray-drying and the liquid bed granulation are particularly preferred. A more particularly particulate additive (e.g., crystalline cellulose (particle), purified sucrose spherical granule, sucrose starch granule, or the like) for the core is spray-coated with the drug solution to give the particulate composition. the current utility model.

For example, a fluid bed granulator (FLO-1 made by Glatt Co., Ltd.), a spray dryer (DL41 made by Yamato Scientific Co. Ltd.) and the like can be used as a device for use in spray coating.

Hereinafter, a process for producing a disintegrating tablet in the buccal cavity containing the particulate pharmaceutical composition of the present utility will be described.

When the case of a disintegrating tablet in the buccal cavity described in International Publication 95-20380 (corresponding to U.S. Patent 5576014) is cited, the steps of mixing the particulate pharmaceutical composition of the present utility and low-form saccharide can be used; spraying the resulting mixture using a highly moldable saccharide as a binder for coating and / or granulation; and subjecting the obtained granular fabric to direct molding. Further, wetting and drying steps may be used to increase the hardness of the molded material obtained. "Moisture" is determined by the apparent critical relative humidity of the saccharide contained but generally moistened to the crystalline relative humidity or higher. For example, the humidity is from 30 to 100 RH%, preferably from 50 to 90 RH%. In this case, the temperature is preferably from 15 to 50 ° C, more preferably from 20 to 40 ° C. The treatment time is from 1 to 36 hours, preferably from 12 to 24 hours. "Drying" is not specifically limited insofar as it is a moisture-absorbing step of moisture absorption. For example, as a drying condition with temperature, it can be set from 10 to 100 ° C, preferably from 20 to 60 ° C, more preferably from 25 to 40 ° C. The treatment time can be set from 0.5 to 6 hours, preferably from 1 to 4 hours.

In the case of a disintegrating tablet in the buccal cavity described in International Publication 2002-92057 (corresponding to US Patent Publication 2003/099701), the particulate pharmaceutical composition of the present utility, high melting point and low melting point saccharide are mixed and the resulting mixture is sprayed using a disintegrating tablet binder in the buccal cavity to perform coating and / or granulation, and then the granular material may be subjected to direct molding. As a spray condition, for example, when using a fluid bed granulator (FLO-1 manufactured by Glatt Co., Ltd.), the concentration of the solifenacin solution is not limited insofar as it allows a viscosity that can be dispensed of the solution with the pump, but preferably it is from 0.01 to 30% (w / w) on the solids concentration. The spreading rate is not limited to the extent that spray drying can be carried out, but is preferably from 0.1 to 20 g / min. The spray temperature is not specifically limited insofar as it can be adjusted to give the product a temperature of 10 to 60 ° C. These spray conditions vary depending on the production scale and the type of device, but they are not particularly limited insofar as they provide a partial composition. In addition, when a high melting point excipient and a low melting point saccharide are combined to increase the hardness of the molded material obtained, a heating step may be used. The "heat" is determined by the melting point of the low melting point of the saccharide contained therein. However, it is generally heated to a temperature not lower than the melting point of the low melting point saccharide and lower than the melting point of the high melting point excipient. The treatment time can be set from 0.5 to 120 minutes, preferably from 1 to 60 minutes.

Further, the method of stabilizing the particulate pharmaceutical material of the present utility model and the method of converting the amorphous form of solifenacin or its crystalline salt into the particulate pharmaceutical material of the present utility model may be performed for the particulate pharmaceutical material of the present utility model produced as described above using the crystallization-promoting treatment method mentioned above.

Short description of the figures

Figure 1 shows the results of powder X-ray diffraction for solifenacin succinate in crystalline form; PEG 8000 (trade name: Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.); spray dried solifenacin succinate product obtained using PEG 8000; spray dried solifenacin succinate product obtained using HPMC (trade name: TC5E, manufactured by Shinetsu Chemical Co., Ltd.); and a solifenacin succinate spray product obtained using polyvinylpyrrolidone (trade name: PVP K90 manufactured by BASF, hereinafter abbreviated as PVP), respectively.

Figure 2 shows the results of powder x-ray diffraction for a coated product obtained by coating crystalline cellulose (trade name: Celphere manufactured by Asahi Chemical Industry Co., Ltd.) with PEG 800 (trade name: Macrogol 6000 manufactured by Sanyo Chemical Industries , Ltd.) in Example 3; and a coated product obtained using HPMC in Comparative Example 1.

1677 Sh

Figure 3 shows the relationship between the amount of production of F1, which is a major decomposition product of solifenacin, and the Tg or tr of a binder used in combination after a two-month storage period (O: no wetting; ·: wetting).

The best way to carry out a utility model

The partial pharmaceutical composition of solifenacin or a salt thereof according to the present utility model will be described in detail. From now on, the present utility model will be described in more detail in connection with the Examples and Comparative Examples, but the present utility model is not considered to be limiting thereto.

Example 1

Coated product obtained by coating the crystalline cellulose core of a particle with solifenacin succinate using HPC-SL as a binder

Ten parts of solifenacin succinate and 3.4 parts of hydroxypropyl cellulose (trade name: HPC-SL, manufactured by Nippon Soda Co., Ltd., hereinafter abbreviated as HPC) were dissolved by excitation in mixed solution of 26.6 parts of water and 26.6 parts of methanol using agitator (MGM-66, manufactured by SHIBATA) to form a drug solution. Then, 60 parts of crystalline cellulose (trade name: Celphere, manufactured by Asahi Chemical Industry Co., Ltd.) are placed in a liquid bed granulator (FLO-1 made by Glatt co., Ltd.), and Celphere is coated with spraying with the drug solution at an inlet air temperature of 50 ° C, an airflow volume of 1.00 m ³ / min, a spray rate of the binder solution of 4.0 g / min and a spray pressure of 3.0 kg / cm ² , with which is the composition of the present utility model.

Example 2

The particle composition obtained in Example 1 was crystallized by moistening at 25 ° C and 75% for 12 h and then dried at 30 ° C and 40% for 3 h, yielding the particle composition of the present utility model. .

Example 3

Coated product obtained by coating the crystalline cellulose core of the particle with solifenacin succinate using PEG 6000 as a binder.

Ten parts solifenacin succinate and 3.4 parts PEG (trade name: Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.) were dissolved by excitation in a mixed solution of 26.6 parts water and 26.6 parts methanol using a stirrer (MGM-66, manufactured by SHIBATA ) to give a solution of a drug substance. The 60 Celphere parts (manufactured by Asahi Chemical Industry Co., Ltd.) were then placed in a liquid bed granulator (FLO-1 made by Glatt co., Ltd.), and the Celphere was spray coated with the drug solution. at an inlet air temperature of 50 ° C, an airflow volume of 0.97 m ³ / min, a spray rate of the binder solution of 10 g / min, and a spray pressure of 3.0 kg / cm ² , which yields the composition of the present useful model.

Example 4

The particle composition obtained in Example 3 was crystallized by moistening at 25 ° C and 75% for 12 h and then dried at 30 ° C and 40% for 3 h to give the particle composition of the present utility model. .

Example 5

Coated product obtained by coating the crystalline cellulose core of a particle with solifenacin succinate using maltose as a binder

Ten parts solifenacin succinate and 3.4 parts maltose (trade name: SunMalto S, manufactured by Sanwa Cornstarch Co., Ltd.) were dissolved by excitation in a mixed solution of 26.6 parts water and 26.6 parts methanol using a stirrer (MGM-66 manufactured by SHIBATA) to give a solution of a drug substance. The 60 Celphere parts (manufactured by Asahi Chemical Industry Co., Ltd.) were then placed in a liquid bed granulator (FLO-1 made by Glatt co., Ltd.), and the Celphere was spray coated with the drug solution. at an inlet air temperature of 60 ° C, an airflow volume of 0.98 m ³ / min, a spray rate of the binder solution of 3.0 g / min, and a spray pressure of 3.0 kg / cm ² , which yields the composition of the present useful model.

Example 6

The particle composition obtained in Example 5 was crystallized by moistening at 25 ° C and 75% for 12 h and then dried at 30 ° C and 40% for 3 h to give the particle composition of the present utility model. .

Example 7

Coated product obtained by coating the crystalline cellulose core of a particle with solifenacin succinate using HEC as a binder

Ten parts solifenacin succinate and 3.4 parts hydroxyethyl cellulose (trade name: HEC SE400 manufactured by Daicel Chemical Industries, Ltd.) were dissolved by excitation in a mixed solution of 26.6 parts water and 26.6 parts methanol using a stirrer (MGM-66, manufactured by SHIBATA) to give a solution of a drug substance. The 60 Celphere parts (manufactured by Asahi Chemical Industry Co., Ltd.) were then placed in a liquid bed granulator (FLO-1 made by Glatt co., Ltd.), and Celphere was spray coated with the drug solution. at an inlet air temperature of 60 ° C, a flow volume of air of 0.98 m ³ / min, a spray rate of the binder solution of 3.0 g / min and a spray pressure of 3.0 kg / cm ² , which yields the composition of the present useful model.

Example 8

The particle composition obtained in Example 7 was crystallized by moistening at 25 ° C and 75% for 12 h and then dried at 30 ° C and 40% for 3 h to give the particle composition of the present utility model. .

Example 9

Coated product obtained by coating the crystalline cellulose core of a particle with solifenacin succinate using Pluronic as a binder

Ten parts solifenacin succinate and 3.4 parts hydroxyethyl Pluronic F68 (trade name: Lutrol F68 produced by BASF) were dissolved by excitation in a mixed solution of 26.6 parts water and 26.6 parts methanol using a stirrer (MGM-66 manufactured by SHIBATA) with which is a solution of a drug substance. Then 60 parts crystalline cellulose (trade name: Celphere manufactured by Asahi Chemical Industry

Co., Ltd.) were placed in a liquid bed granulator (FLO-1, manufactured by Glatt co., Ltd.), and the crystalline cellulose was coated by spraying with the drug solution at an inlet air temperature of 54 ° C. an airflow volume of 0.94 m ³ / min, a spray rate of the binder solution of 3.0 g / min and a spray pressure of 3.0 kg / cm ² , which yields the composition of the present utility model.

Example 10

Coated product obtained from coating crystalline cellulose with solifenacin succinate and IPEG

Ten parts of solifenacin succinate and 1 part of PEG (trade name: Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.) were dissolved by agitation in a mixed solution of 16 parts of water and 16 parts of methanol using a stirrer (MGM-66, manufactured by SHIBATA ) to give a solution of a drug substance. Then, 60 parts of crystalline cellulose (trade name: Celphere, manufactured by Asahi Chemical Industry Co., Ltd.) are placed in a liquid bed granulator (FLO-1, manufactured by Glatt co., Ltd.), and the crystalline cellulose is coated. by spraying with the drug solution in an inlet air temperature of 45 ° C, an airflow volume of 1.0 m ³ / min, a spray rate of the binder solution of 2.0 g / min and a spray pressure of 2.0 kg / cm ² , thus producing a partial powder.

Example 11

Coated product obtained from crystalline cellulose coating with solifenacin succinate and PEG

Ten parts of solifenacin succinate and 10 parts of PEG (trade name: Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.) were dissolved by excitation in a mixed solution of 70 parts of water and 70 parts of methanol using a stirrer (MGM-66, manufactured by SHIBATA ) to give a solution of a drug substance. Then, 60 parts of crystalline cellulose (trade name: Celphere, manufactured by Asahi Chemical Industry Co., Ltd.) are placed in a liquid bed granulator (FLO-1, manufactured by Glatt co., Ltd.), and the crystalline cellulose is coated. by spraying with the drug solution in the inlet16

1677 Ul air temperature of 60 ° C, air flow volume of 1 m ³ / min, spray rate of the binder solution of 6.5 g / min and spray pressure of 3.0 kg / cm ² to form a particulate powder .

Example 12

In the case where a different solvent composition is used

Coated product obtained from crystalline cellulose coating with solifenacin succinate and PEG

Ten parts of solifenacin succinate and 3.4 parts of PEG (trade name: Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.) were dissolved by agitation in a mixed solution of 53.2 parts of water using a stirrer (MGM-66, manufactured by SHIBATA), whereby a solution of the drug substance is obtained. Then, 60 parts of crystalline cellulose (trade name: Celphere, manufactured by Asahi Chemical Industry Co., Ltd.) are placed in a liquid bed granulator (FLO-1, manufactured by Glatt co., Ltd.), and the crystalline cellulose is coated. by spraying with the drug solution at an inlet air temperature of 80 ° C, an airflow volume of 0.97 m ³ / min, a spray rate of the binder solution of 7.0 g / min and a spray pressure of 3.0 kg / cm ² , thus producing a partial powder.

Example 13

Coated product obtained from coating crystalline cellulose with solifenacin succinate and PEG (drug content: 50%)

Ten parts solifenacin succinate and 3.4 parts PEG (trade name: Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.) were dissolved by excitation in a mixed solution of 26.6 parts methanol and 26.6 parts water using a stirrer (MGM-66, manufactured by SHIBATA ) to give a solution of a drug substance. Then, 60 parts of crystalline cellulose (trade name: Celphere, manufactured by Asahi Chemical Industry Co., Ltd.) are placed in a liquid bed granulator (FLO-1, manufactured by Glatt co., Ltd.), and the crystalline cellulose is coated. by spraying with the drug solution at an inlet air temperature of 54 ° C, an airflow volume of 0.94 m ³ / min, a spray rate of the binder solution of 3.0 g / min and a spray pressure of 3.0 kg / cm ² to produce a particulate powder. The powder obtained is then overlaid with another drug solution prepared at the above mentioned formula ratio using the same device and the same conditions as a particulate powder with a higher drug content (drug content: 50%) it's working.

Comparative Example 1

Coated product obtained by coating the crystalline cellulose core of the particle with solifenacin succinate using HPMC as a binder

Ten parts solifenacin succinate and 3.4 parts hydroxypropylmethyl cellulose 2910 (trade name: TC-5E, manufactured by Shinetsu Chemical Co., Ltd., hereinafter abbreviated as HPMC) were dissolved by excitation in a mixed solution of 26.6 parts water and 26.6 parts methanol using a stirrer (MGM-66 manufactured by SHIBATA) to obtain a drug solution. The 60 Celphere parts (manufactured by Asahi Chemical Industry Co., Ltd.) were then placed in a liquid bed granulator (FLO-1 made by Glatt co., Ltd.), and the Celphere was spray coated with the drug solution. at an inlet air temperature of 50 ° C; an airflow volume of 0.94 m ³ / min; a spray rate of the binder solution of 7.0 g / min; and a spray pressure of 3.0 kg / cm ² to give a partial composition.

Comparative Example 2

The particle composition obtained in Comparative Example 1 was crystallized by moistening at 25 ° C and 75% for 12 h and then dried at 30 ° C and 40% for 3 h to give a particle composition.

Comparative Example 3

Coated product obtained by coating the crystalline cellulose core of the particle with solifenacin succinate using PVP as a binder

Ten parts of solifenacin succinate and 3.4 parts of polyvinylpyrrolidone (trade name: PVP K90 manufactured by BASF, hereinafter abbreviated as PVP) were dissolved by excitation in a mixed solution of 26.6 parts in 1677 Ul and 26.6 parts in methanol using a stirrer (MGM-66, MGM-66). (manufactured by SHIBATA) to form a drug solution. The 60 Celphere parts (manufactured by Asahi Chemical Industry Co., Ltd.) were then placed in a liquid bed granulator (FLO-1 made by Glatt co., Ltd.), and the Celphere was spray coated with the drug solution. at an inlet air temperature of 50 ° C; an airflow volume of 0.97 m ³ / min; a spray rate of the binder solution of 6 g / min; and a spray pressure of 3.0 kg / cm ² to give a partial composition.

Comparative Example 4

The particle composition obtained in Comparative Example 3 was crystallized by moistening at 25 ° C and 75% for 12 h and then dried at 30 ° C and 40% for 3 h to give a particle composition.

Comparative Example 5

Coated product obtained by coating the crystalline cellulose core of a particle with solifenacin succinate using methyl cellulose as a binder

Ten parts of solifenacin succinate and 3.4 parts of methyl cellulose (trade name: Metolose SMI00, manufactured by Shinetsu Chemical Co., Ltd., hereinafter abbreviated as MS) were dissolved by excitation in a mixed solution of 53.2 parts of water and 53.2 parts of methanol using a stirrer. (MGM-66, manufactured by SHIBATA) to form a drug solution. The 60 Celphere parts (manufactured by Asahi Chemical Industry Co., Ltd.) were then placed in a liquid bed granulator (FLO-1 made by Glatt co., Ltd.), and the Celphere was spray coated with the drug solution. at an inlet air temperature of 55 ° C; an airflow volume of 0.97 t ³ / min; a spray rate of the binder solution of 5 g / min; and a spray pressure of 3.0 kg / cm ² to give a partial composition.

Comparative Example 6

The particle composition obtained in Comparative Example 3 was crystallized by moistening at 25 ° C and 75% for 12 h and then dried at 30 ° C and 40% for 3 h to give a particle composition.

Experimental Examples <X-ray Diffraction Results>

First, the interaction between the drug substance and the polymers is evaluated.

The results of powder X-ray diffraction for spray dried products containing PEG and the drug substance used in Example, HPMC or PVP and the drug substance used in Comparative Examples (as a device using RINT 1400: tube bulb: Cu, tube voltage: 40 kV , tube current: 40 mA, scan speed: 3000 ° / min (Rigaku. Denki Co.)) are shown in FIG. 1. As controls, the results for solifenacin succinate alone in crystalline form and PEG are shown together. As a result, each of the products obtained using PEG shown in the Examples shows peaks derived from solifenacin succinate in crystalline form and it is confirmed that the drug substance in powder exists as a crystalline form. Conversely, the samples shown in the Comparative Examples show a halo pattern typical of an amorphous structure, indicating that the drug exists as an amorphous state.

Further, in FIG. 2 shows the results of powder X-ray diffraction for the coated product obtained by coating Celphere with PEG shown in the Example this time (Example 3) and the coated product obtained using HPMC shown in Comparative Example 1 (as a device using RINT 2000: tube light: Si, tube voltage: 50 kV, tube current: 300 mA, scan speed: 60000 ° / min (Rigaku. Denki Co.)). As shown in the figure, even in the coated products it is shown that the sample using PEG shows crystalline peaks originating in solifenacin.

<Results of the preliminary stability test>

The results of the preliminary stability test for these particulate compositions are shown in Tables 1 and 2. Serial measurements of the amounts of decomposition products after the compositions have been stored for a certain period of time have been performed by high performance liquid chromatography and the maximum value of the corresponding values is shown. quantities of breakdown products (ie the production quantity F1, which is the main breakdown product). In a severe test at 40 ° C and 75% RH, as in the case of the use of HPMC shown in Comparative Example 1, when the wetting was not performed, the degradation product was observed at 0.34% in only a 2-month period in change at a time that is 8 times the concentration at the beginning of storage of 0.04%. Further, as in the case of the use of PVP shown in Comparative Example 3, when no wetting was performed, the degradation product was observed at 0.53% over a two-month change period, exceeding the standard of 0.4%. In addition, as in the case of the use of MS shown in Comparative Example 5, when the wetting was not performed, the degradation product was observed at 0.74% for only a two-month change period, which is 12 times the concentration at the beginning of storage at 0.06%. even when the humidification is carried out to promote crystallization, the amount of degradation product for each of Comparative Examples 2, 4 and 6 is greater than that of each of the Examples. In the case of HPMC use, the degradation product is observed at 0.92% over only a 2-month change period, which is 13 times the concentration at the start of storage of 0.07%. In addition, in the case of MS use, the degradation product is observed at 11.75% for only a 2-month change period, which is 11 times the concentration at the beginning of storage of 1.09%.

On the other hand, as in the examples shown in Examples 1 to 7, whether or not wetting is carried out, the amounts of ore of the decay product over 2 months are 0.2% or less and the absolute values are small, between 2 up to 390 times less than Comparative Examples. In addition, solifenacin in each of the pharmaceutical formulations has been found to be stable over time because the rate of change is small. On the other hand, it has been found that decomposition products tend to increase only appreciably and solifenacin is stable in the case of moisturizing to promote crystallization, as shown in Examples 2, 4, 6 and 8.

The values of Tg (if no Tg, mp) of the binders used during this period are shown in Table 3 and a linear regression for the relationship between the amount of product of the basic decay product (Fl (%)) at 2 months and Tg (° C) have been tested. As a result, as shown in FIG. 3, the squares of the correlation coefficient (R ² ) are 0.73 in the case where the humidification and drying were not carried out, and 0.60 in the case in which the humidification and drying were performed, indicating a favorable positive interconnection.

As described above, it is apparent that the thermodynamic parameters of the additive used in combination are dominant factors for the stability of solifenacin in a pharmaceutical preparation. This phenomenon arises from the flowability, i.e., the Tg of a binder as described above, and the higher the Tg, the more easily the amorphous form persists in a pharmaceutical preparation in an amorphous state, hence the products of breakups are easily generated.

Results of the preliminary stability test for particulate formulations containing solifenacin succinate

Storage conditions: 40 ° C, 75% RH, tightly sealed

Packaging form: HDPE bottle with metal cap

Test item: Bound substance (production quantity of basic decomposition product, F1 (%))

1677 Ul

Table 1

Packaging form HDPE * bottle with metal cap Example 1 Example 3 Example 5 Example 7 Comparative Example 1 Comparative Example 3 Comparative Example 5 Getting started on storage 0.08 0.03 ND 0.04 0.04 0.19 0.06 1 month 0.18 0.04 0.10 0.05 0.20 0.46 0.39 2 months 0.19 0.04 0.15 NT 0.34 0.53 0.74

Packaging form HDPE * bottle with metal cap Example 10 Example 11 Example 12 Example 13 Start storage ND 0.02 ND ND 1 month 0.09 0.04 0.03 0.04 2 months 0.10 0.04 0.04 0.06

* HDPE: high density polyethylene ND: not detected; NT: Not tested

Results of the preliminary stability test for particulate formulations containing solifenacin succinate moistened

Storage conditions: 40 ° C, 75% RH, tightly sealed

Packaging form: HDPE bottle with metal cap

Test item: Bound substance (production quantity of basic decomposition product, F1 (%))

Table 2

Packaging form HDPE * bottle with metal cap Example 2 Example 4 Example 6 Example 8 Comparative Example 2 Comparative Example 4 Comparative Example 6 Start storage 0.09 0.03 0.03 0.02 0.07 0.23 1.09 1 month 0.10 0.03 0.09 0.03 0.70 0.40 12.16 2 months 0.10 0.04 0.10 0.03 0.92 0.40 11.75

The glass transition temperature Tg (° C) of each binder

Table 3

Macrogol 6000 *, ** Maltose % ** LDCs *** NES *** EU PVP *** HPMC ** ♦ MS *, Tg (° C) 60 102 130 137 (135-140) 157 (152-162) 174 240 298 (290-305)

* Use melting point (mp, ° C) as an alternative ** Source: Iyakuhin Tenkabutsu Handbook ”Yakuji Nippo, Ltd. issued on October 10th

2001 ***: Source: Kobunshi Jiten Maruzen Co., Ltd., issued September 20, 1993

Industrial applicability

The technical feature of the utility model is that a stable particle pharmaceutical composition can be produced by its preparation using a specific binder in the particle pharmaceutical composition containing solifenacin or a salt thereof, and that it is possible to provide a stable particle pharmaceutical composition over time by performing crystallization-promoting treatments, such as moisturizing and drying, as appropriate, which have a significant impact on the industry. Further use of the particulate pharmaceutical composition of the present utility model is useful as a technique that can provide various stable pharmaceutical compositions of solifenacin or a salt thereof, the development of which is required as an excellent pharmaceutical product in frequent urination or urinary incontinence.

Claims (2)

Claims A stable particulate pharmaceutical composition comprising solifenacin or a salt thereof and a binder which are optionally dissolved together and / or suspended, characterized in that 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, ethyl cellulose, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, maltose and polyvinyl alcohol. A disintegrating tablet in the buccal cavity comprising a pharmaceutical composition according to claim 1 and an excipient, in particular saccharide.