SK6196Y1 - Stable particulate pharmaceutical composition of solifenacin or its salt, mixture for its preparation and tablet comprising same - Google Patents

Abstract

The present solution relates to a stable particulate pharmaceutical composition, comprising solifenacin or a salt thereof and a binder having an action of stabilizing solifenacin or a salt thereof, whereby the binder is one or more substances having a glass transition point or melting point lower than 174 øC selected from the group consisting of polyethylene glycol, polyethylene oxide, a polyoxyethylene /polyoxypropylene block copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, maltose and polyvinyl alcohol. The stable particulate pharmaceutical composition of solifenacin or a salt thereof has spherical form suitable for coating and its degradation can be inhibited during the time when the pharmaceutical composition of solifenacin or a salt supplied for clinical use. Further, there is provided a granular composition of solifenacin or its salt further stabilized by addition of crystallization promoting treatment after production of the granular pharmaceutical composition.

Description

SK 6196 Υ1

Technical field

The present invention relates to a stable particulate pharmaceutical composition obtained using solifenacin or a salt thereof and a specific binder, a method for producing the same, a tablet disintegrating in the oral cavity comprising the particulate pharmaceutical composition, and a method of stabilizing the particulate pharmaceutical composition.

BACKGROUND OF THE INVENTION

Solifenacin is represented by the following formula (I):

(I) and has the chemical name (1A, 3'A) -3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate.

A number of quinuclidine derivatives, including solifenacin or salts thereof, are known to have excellent selective antagonistic activity against muscarinic M ₃ receptors and are useful as prophylactic or therapeutic agents against diseases of the urinary tract such as nerve pollakiuria, neurogenic bladder, nocturnal wetting, unstable bladder bladder contraction and chronic cysticide as well as respiratory diseases such as chronic occlusive lung disease, chronic bronchitis, asthma and rhinitis (see patent document 1).

Example 8 of Patent Document 1 describes a process for producing solifenacin hydrochloride, and it is described that a crystal precipitated in a mixed solvent of acetonitrile and diethyl ether has a melting point of 212 to 214 ° C and has a specific rotation ([α] ²⁵ _D 98.1 (c) = 1.00, EtOH).

Patent Document 1 does not disclose or disclose the amorphous form of solifenacin or a salt thereof, or that when solifenacin succinate is incorporated into the pharmaceutical formulation by a standard preparation process, solifenacin succinate, which is the active ingredient, in the manufactured pharmaceutical formulation degrades significantly over time.

Non-Patent Document 1, published by the Japanese Ministry of Health, Labor and Social Affairs, June 2003, describes drug product specifications, namely the concepts of degradation products in pharmaceutical formulations accepted in stability tests. According to this document, when the amount of active substance administered daily is less than 10 mg, the threshold above which safety authorization of degradation products in a pharmaceutical preparation is required is less than 1.0% in terms of the percentage of degradation products contained in the active substance, and 50 µg in terms of total daily dose of degradation products. In the case where the amount of active substance administered daily is 10 mg or more and 100 mg or less, the threshold above which safety authorization of degradation products in a pharmaceutical preparation is required is less than 0.5% in terms of the percentage of degradation products contained in the medicinal product. and 200 µg in terms of total daily dose of degradation products. Thus, the standard value of the amount of degradation products that can be determined without the approval of the safety of degradation products is, for example, when the pharmaceutical preparation has a drug content of 5 mg, 1.0% or less in terms of the percentage of degradation products contained in the drug substance. and, for example, when the pharmaceutical composition has a content of 10 mg of the drug substance, 0.5% or less in terms of the percentage of degradation products contained in the drug substance.

The solifenacin formulations currently on the market based on clinical trial results are 2.5 mg, 5 mg and 10 mg tablets. In order for these pharmaceutical preparations to have the stability described in Non-Patent Document 1, it is to be understood that the amount of major degradation product (hereinafter abbreviated as F1) solifenacin succinate to the total amount of solifenacin succinate and its degradation product should be set to 0.5% or less, and that this amount should preferably be controlled to 0.4% or less, taking into account batch-to-batch variations and test errors.

On the other hand, it is known that solifenacin and its salts have very high solubility in various solvents and strong bitterness and bitterness. Thus, there is a need for masking bitterness and bitterness to develop a pharmaceutical formulation with solifenacin or a high convenience salt thereof, such as particles or powder incorporated into a tablet disintegrating in the oral cavity. It was therefore necessary to apply film coating methods using a polymeric substrate. In particular, in the case where the drug substance is film-coated with a polymeric substrate, it is necessary to uniformly coat the surface of the drug substance. Thus, the drug substance must have fine spherical particles of similar particle size.

SK 6196 Υ1

Patent Document 1: European Patent EP 801 067 Non-Patent Document 1: PFSB / ELD Notice no. 0624001 "Revision of Guideline on Impurities in Medicinal Products with New Active Ingredients".

The essence of the technical solution

Problem solved

As described, there has been a need to provide a stable particulate pharmaceutical composition of solifenacin or a salt thereof that is spherical in shape suitable for film coating and in which degradation can be inhibited over time as the pharmaceutical formulation of solifenacin or a salt thereof is delivered to clinical practice.

Means to solve the problem

In the development of solifenacin as an excellent drug against frequent urination or urinary incontinence, the inventors have coated the drug substances with a standard binder (polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC)), which is routinely performed by a person skilled in the art by fluid bed granulation or fluid bed granulation. and performed preliminary stability tests of the resulting pharmaceutical formulations for 2 months in an accelerated test (conditions of 40 ° C, 75% RH (relative humidity) and in an airtight container), one of the standard stability tests. As a result, a decrease in the residual proportion of solifenacin succinate was observed, and it was found that 6 months after the start of storage, the time of final determination in the accelerated assay, the ratio of F1 (oxidized form of solifenacin succinate) to total amount of solifenacin succinate and degradation products exceeded 0, 4% (see Table 1 for details). It has been found difficult to obtain a pharmaceutical formulation with a pharmaceutical sufficient stability by such a standard method of preparation.

At this technical level, the inventors of the invention have carried out intensive studies of stabilizing pharmaceutical formulations with solifenacin, and unexpectedly found that solifenacin in amorphous form during the manufacturing process of the pharmaceutical formulation was a major cause of degradation of the active substance over time and that using a standard binder such as HPMC, is largely associated with the formation of the amorphous form of solifenacin.

In order to obtain a granular substance in which bitterness and bitterness are masked, the inventors have taken into account an efficient method of preparing fine particles (particulate pharmaceutical composition) by spraying a drug substance solution onto core particles consisting, for example, of crystalline cellulose and fine particles. are coated with a suitable polymeric film. For the preparation of such fine particles, it is necessary to spray as soon as solifenacin or a salt thereof has dissolved, but solifenacin has been found to tend to pass into the amorphous phase at this point, and a solifenacin-specific problem arises, degradation products are formed into the crystalline form. That is, when the particulate pharmaceutical composition is produced after all or part of the solifenacin has been dissolved in a solvent, it is very difficult to ensure the stability of the solifenacin.

In these circumstances, the inventors for the first time have found that if a binder containing an ethylene oxide chain such as polyethylene glycol (otherwise called Macrogol; hereinafter referred to as PEG) is used as a binder, a pharmaceutical composition is produced in which the degradation of solifenacin may be over time, despite expectation, inhibited by inhibiting the chain of the amorphous form of solifenacin, although PEG itself is a substance that is commonly used for the purpose of converting a drug substance into an amorphous form.

Furthermore, in the development and manufacture of a stable particulate pharmaceutical composition of solifenacin or a salt thereof suitable for film coating, the inventors have come to the idea that, for example, when solifenacin is dissolved onto core particles together with a polymeric substance (binder) such as PEG, it depends on whether or not the solifenacin can remain in the amorphous form after spraying, on the fluidity of the solifenacin in the polymeric substance (binder). Therefore, they conducted intensive investigations and paid attention to the polymer-specific physical values (glass transition temperature (hereinafter referred to as Tg) or melting point (hereinafter referred to as bt)) that may affect the fluidity of the drug substance in the binder used to spray the core particle. They found that when a binder having a high Tg temperature was used for the particulate pharmaceutical composition, the starting value of the respective substance, which is indicative of degradation, was low but later unstable. On the other hand, when a specific binder with a Tg lower than a given value was used for the particulate pharmaceutical composition, they unexpectedly found that both the starting value of the substance and the value of the substance formed later were both low and stable, and moreover the particles were spherical and uniform. size, which is suitable for film coating.

Further, as a result of intensive research, the inventors have found that when a crystallization-promoting treatment such as wetting and drying is performed, a more stable particulate pharmaceutical composition is formed, thereby providing a technical solution.

SK 6196 Υ1

The technical solution therefore concerns:

1. a stable particulate pharmaceutical composition comprising solifenacin or a salt thereof and a binder with the effect of stabilizing solifenacin or a salt thereof;

2. The pharmaceutical composition of item 1, wherein the binder with the effect of stabilizing solifenacin or a salt thereof is a binder with the effect of inhibiting the retention of the amorphous form of solifenacin or a salt thereof;

3. The pharmaceutical composition of claim 1 or 2, wherein the binder is a binder having a glass transition temperature or melting point of less than 174 ° C;

4. The pharmaceutical composition of item 3, wherein the binder is one or more selected from the group consisting of polyethylene glycol, polyethylene oxide, polyoxyethylene-polyoxypropylene block copolymer, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, L methacrylic acid copolymer, LD copolymer, LD copolymer, methacrylic, corn starch, E copolymer of aminoalkyl methacrylate, RS copolymer of aminoalkyl methacrylate and maltose;

5. The pharmaceutical composition of item 3, wherein the binder is one or more selected from the group consisting of polyethylene glycol, a polyoxyethylene-polyoxypropylene block copolymer, hydroxypropylcellulose, hydroxyethylcellulose, and maltose;

6. The pharmaceutical composition of item 3, wherein the binder is one or more selected from the group consisting of polyethylene glycol, a polyoxyethylene-polyoxypropylene block copolymer and hydroxypropylcellulose;

7. a stable particulate pharmaceutical composition of solifenacin or a salt thereof, which can be obtained using a mixture in which solifenacin or a salt thereof is co-dissolved and / or suspended and a binder with the effect of stabilizing solifenacin or a salt thereof;

8. The pharmaceutical composition of item 7, wherein the binder with the effect of stabilizing solifenacin or a salt thereof is a binder with the effect of inhibiting the retention of the amorphous form of solifenacin or a salt thereof;

9. The pharmaceutical composition of claim 7 or 8, wherein the binder is a binder having a glass transition temperature or melting point of less than 174 ° C;

10. The pharmaceutical composition of item 9, wherein the binder is one or more selected from the group consisting of polyethylene glycol, polyethylene oxide, polyoxyethylene-polyoxypropylene block copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, L methacrylic acid copolymer, LD copolymer, LD copolymer, methacrylic, corn starch, E copolymer of aminoalkyl methacrylate, RS copolymer of aminoalkyl methacrylate and maltose;

11. The pharmaceutical composition of item 9, wherein the binder is one or more selected from the group consisting of polyethylene glycol, a polyoxyethylene-polyoxypropylene block copolymer, hydroxypropylcellulose, hydroxyethylcellulose, and maltose;

12. The pharmaceutical composition of item 9, wherein the binder is one or more selected from the group consisting of polyethylene glycol, a polyoxyethylene-polyoxypropylene hydroxypropylcellulose block copolymer;

13. Mixtures for the preparation of a stable particulate pharmaceutical composition of solifenacin or a salt thereof, comprising dissolved and / or suspended solifenacin or a salt thereof and a binder with the effect of stabilizing solifenacin or a salt thereof, wherein the binder is one or more substances with a glass transition temperature or melting point lower than 174 ° C selected from the group consisting of polyethylene glycol, polyethylene oxide, polyoxyethylene / polyoxypropylene block copolymer, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, maltose and polyvinyl alcohol; and

14. tablets disintegrating in the oral cavity consisting of a pharmaceutical composition according to any one of items 1 to 13 above.

In general, in numerous cases, substance-specific thermodynamic parameters are commonly used as a fluidity indicator, such as a glass transition temperature (Tg, in ° C) or a softening point (in ° C) for an amorphous region in a polymer, and a melting point (bt, v). ° C) for the crystalline region in the polymer. These temperature values indicate a change in the thermodynamic state of the substance, and since the molecular motion is suppressed at a temperature lower than Tg, the substance is in a near crystalline or glass state, whereby plasticity tends to decrease. However, when the temperature of the substance is Tg or higher, the activity rate of the molecules increases, with the substance being plasticized and the flexibility increasing. The state in which the crystalline region of the polymer is degraded and fluidity occurs by increasing the temperature then represents the melting of the polymer. Since the drug substance in the amorphous state is present in the polymer at a certain temperature, the higher the Tg of the polymer, the more difficult the flow of the polymer is. Thus, it may exist in the amorphous form, which is the starting state, and vice versa, the lower the Tg of the polymer, the earlier crystals are precipitated (Int. J. Pharm. 282 (2004) 151-162). On the other hand, with respect to the low molecular weight compound, since the structure of the substance is crystalline and hence in many cases is not a Tg parameter representing a change in thermal mobility, the melting point has been used for the low molecular weight substance. For the polymer, the temperature Tg was used, which is the temperature at which the change appears faster.

The technical solution also concerns:

15. a method of stabilizing solifenacin or a salt thereof by subjecting a pharmaceutical composition comprising with

Lifenacin or a salt thereof and a binder with the effect of stabilizing solifenacin or a salt thereof to a crystallization-promoting treatment; and

16. A process for converting an amorphous form of solifenacin or a salt thereof into a crystalline form by subjecting a stable particulate composition comprising solifenacin or a salt thereof and a binder with the effect of stabilizing solifenacin or a salt thereof to a treatment promoting crystallization.

The technical solution will be described in detail below.

Examples of "solifenacin salt" for use in the present invention 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, phosphoric acid, or organic acids such as formic acid, acetic acid, 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 and glutamic acid , and quaternary ammonium salts. Among these, solifenacin succinate is preferred as a pharmaceutical product.

"Solifenacin or a salt thereof" for use according to the invention is readily available by the method described in Patent Document 1 or by another standard method.

A "crystal" or "crystalline substance" of solifenacin or a salt thereof means, in a literal interpretation, a solifenacin substance or a salt thereof with a crystalline structure. However, according to the invention, this means a substance other than the "amorphous form" which exhibits significant degradation of solifenacin over time when the substance is present in an amount in which it does not affect the stability of the product in the pharmaceutical composition. On the other hand, the "amorphous" or "amorphous form" of solifenacin or a salt thereof according to the invention means a substance with a crystallographic amorphous structure. According to the invention, this means a substance other than the "crystal" or "crystalline form" which exhibits extremely low degradation of solifenacin over time when the substance is present in an amount above the limit which does not affect the stability of the product in the pharmaceutical composition.

The amount of solifenacin or a salt thereof for use according to the invention is generally suitably selected according to the type of drug substance or its medical use (indication), but is not particularly limited as to its therapeutically effective amount or prophylactically effective amount. Specifically, the daily dose of solifenacin or a salt thereof is 0.01 mg to 100 mg, preferably 0.5 mg to 50 mg, even more preferably 0.5 mg to 10 mg, most preferably 0.5 mg to 4 mg.

Further, the amount of solifenacin or salt thereof incorporated into a tablet disintegrating in the oral cavity of the present invention may be any as long as an effective amount is contained in the unit dose of the pharmaceutical composition, but is preferably 0.001% by weight. % to 97 wt.%, more preferably 0.05 wt. % to 50 wt.%, even more preferably 0.05 wt. % to 10 wt.%, and most preferably 0.05 wt. % to 4 wt.

"Binder with the effect of stabilizing solifenacin or its salt" for use according to the present invention means a binder that can inhibit the degradation of solifenacin or its salt over time, and specifically refers to a binder that can inhibit the degradation of solifenacin or its salt by inhibiting the retention of amorphous form. In addition, when a binder that does not itself have the effect of stabilizing solifenacin or a salt thereof, such as HPMC or PVP, is used together with a binder for use according to the invention to increase the binder effect, it may be used in an amount not exceeding the specification determining the stability of the pharmaceutical preparation which is the object of the technical solution.

"Effect of inhibiting amorphous form retention" in the sense of the present invention means an effect causing a compound to be difficult to exist in an amorphous state and / or an effect causing the compound to be easily transformed from an amorphous form to a crystalline form.

Further, a binder having the effect of stabilizing solifenacin or a salt thereof or inhibiting amorphous form retention for use according to the present invention is a binder capable of reducing the amount of F1 solifenacin degradation products to 0.5% or less, more preferably a binder capable of reducing the amount of F1 solifenacin to 0.4 % or lower. The binder has a Tg or b. t. less than 174 ° C, preferably has a Tg or b. t. 0 ° C or higher and less than 174 ° C, more preferably Tg or b. t. 0 ° C or greater and less than 156 ° C, more preferably Tg or b. t. 0 ° C or greater and less than 137 ° C, and most preferably has a Tg or b. t. 10 ° C or greater and less than 137 ° C. A particular type of binder is not particularly limited as long as it has a Tg in this range, but preferred examples thereof include ethylene oxide chain, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, polyvinyl alcohol, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, starch and maltose. Of these binders, however, from the point of view of the production process, polyvinyl alcohol, methacrylic acid copolymer, aminoalkyl methacrylate copolymer and starch have poor binding strength, and that coating of particles is difficult. Accordingly, a more preferred material with an ethylene oxide chain such as PEG, polyethylene oxide or block copolymer of polyoxyethylene / polyoxypropylene, hydroxypropylcellulose, hydroxyethylcellulose or maltose, even more preferably PEG, block copolymer of polyoxyethylene / polyoxypropylene or particularly preferably hydroxypropylcellulose, or most preferably hydroxypropylcellulose. As for the pier

The binder mass, degree of polymerization or the like is not particularly limited as long as the addition of the binder can inhibit the formation of the amorphous phase of solifenacin or its salt according to the invention. In terms of molecular weight, the weight average molecular weight is preferably in the range of 400 to 1,000,000, more preferably the weight average molecular weight is 2000 to 200,000. In addition, two or more types of the described binders may be used in combination.

An ethylene oxide chain substance as referred to herein is any substance with an ethylene oxide chain without any particular limitation. The molecular weight, degree of polymerization or the like is not particularly limited as long as the purpose of inhibiting the formation of the amorphous phase of solifenacin or a salt thereof according to the invention is achieved by the addition of the substance. However, with respect to molecular weight, the molecular weight is preferably in the range of the average molecular weight of 400 to 1,000,000, more preferably in the range of the average molecular weight of 2,000 to 200,000. The ethylene oxide chain materials may be used alone or two or more may be used. substances in the mixture. According to the invention, specific examples of the ethylene oxide chain substance include PEG, polyethylene oxide, polyoxyethylene-polyoxypropylene block copolymer, and the like. Of these, however, according to the invention, PEG and polyoxyethylene-polyoxypropylene block copolymer are preferred, PEG being particularly preferred. As PEG, PEG in solid form at normal temperature is preferred. Specific examples include Macrogol 4000 (Japanese Pharmacopoeia, molecular weight 2600-3,800, trade name Macrogol 4000 / Sanyo Chemical Industries, Ltd., NOF Corporation, Lion Corporation, and the like), Macrogol 6,000 (Japanese Pharmacopoeia, molecular weight 7). Macrogol 6,000 (Sanyo Chemical Industries, Ltd., NOF Corporation, Lion Corporation, and the like), Macrogol 20,000 (Japanese Pharmacopoeia, molecular weight 15,000-25,000, Macrogol 20,000 / Sanyo) Chemical Industries, Ltd., NOF Corporation, Lion Corporation, and the like), polyethylene glycol 8,000 (USP / NF, molecular weight 7,000-9,000, trade name Polyethylene Glycol 8,000 (The Dow Chemical Company, and the like)). The weight 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 even more preferably in the range of 2,000 to 10,000.

The polyoxyethylene-polyoxypropylene block copolymer of the present invention may be a copolymer of propylene oxide and ethylene oxide, there are different types according to its composition, but must have a composition in which it inhibits the formation of the amorphous phase of solifenacin or its salt. Specifically, for example, polyoxyethylene (105) polyoxypropylene (5) glycol and polyoxyethylene (160) polyoxypropylene (30) glycol (trade name Pluronic F68) or the like can be used.

The term "mixture in which solifenacin or its salt is dissolved and / or suspended together and a binder with the effect of stabilizing solifenacin or its salt" in the technical solution means a mixture in which the binder with the effect of stabilizing solifenacin or its salt is dissolved together with the solution obtained by dissolution solifenacin or a salt thereof in a solvent such as water. However, it is not always necessary that all solifenacin or a salt thereof be dissolved in the solvent, and if a drug-containing particle suitable for subsequent coating, for example, to mask bitterness, can be obtained in the resulting mixture, such a mixture is also included to provide particles obtained with using a suspension mixture in which part of the solifenacin or salt thereof is dissolved.

A composition that "can be obtained by using" a mixture in which solifenacin or a salt thereof is co-dissolved and a binder with the effect of stabilizing solifenacin or a salt thereof, according to the invention, comprises particles containing the drug substance suitable for bitter masking coatings. Examples thereof include a composition obtained by coating core particles of, for example, crystalline cellulose by spraying a drug substance in the form of a solution, a composition that can be obtained not by spraying the drug substance in liquid form but mixing the mixture obtained by co-dissolving these substances with insoluble core particles and storing the drug substance for arrangement. drug substance uniformly around the insoluble core of the particle, and the like. Further, examples of the product prepared by the process without the use of core particles include powder alone obtained by spray drying or freeze-drying of the drug substance and binder solution, and this powder can be applied to drug substance-containing particles intended to mask bitterness or the like. However, from the viewpoint of production efficiency, a composition that can be obtained by spray coating the core particles with a mixture in which solifenacin or a salt thereof and a binder with the effect of stabilizing solifenacin or a salt thereof is dissolved together is preferred.

A "stable particulate pharmaceutical composition" according to the invention is particles that can be obtained using solifenacin or a salt thereof or the like, and is not particularly limited as long as they are stable particles in which degradation over time is inhibited. Specifically, the term "stable" herein means particles in which the amount of F1 products of degradation of solifenacin or salt thereof is 0.5% or less, more preferably 0.4% or less. Further, in the case where the pharmaceutical composition according to the invention consists of particles such as granules, the particle size of the particulate pharmaceutical composition is not particularly limited as long as the longest dimension is 2 mm or less. In the case where it is incorporated into a tablet disintegrating in the oral cavity, the particle size is not particularly limited, unless an unpleasant sandy taste is experienced, but is preferably prepared with an average particle size of 350 µm or less. A more preferred average particle size is 1 to 350 µm, and a particularly preferred average particle size

The particle size is 20 to 350 µm. The particle size distribution is not particularly limited as long as the particles are suitable for coating, for example bitterness masking, but preferably 80% of the total particle weight is between 1 and 350 µm, more preferably 80% of the particles are between 50 and 50 µm in size. 300 µm, and particularly preferably 80% of the particles are between 100 and 250 µm in size.

Further, the shape of the particulate composition of the present invention is not particularly limited as long as it is in a state where a coating can be made, for example, to mask bitterness, but preferably within the coating efficiency terms it is preferably spherical in shape. j. its sphericity is preferably as close as possible to 1.

In the case where the particulate pharmaceutical composition according to the invention is granules, the admixed amount of binder is not particularly limited as long as it permits the coating of solifenacin or a salt thereof and allows the object of the invention to be achieved. However, it is preferably from 0.01 to 91% by weight, more preferably from 0.5 to 75% by weight. the total amount of the particulate pharmaceutical composition. Most preferably, the admixed amount of binder is from 5 to 50 wt. Furthermore, the admixed amount of binder when the pharmaceutical composition according to the invention is constituted by particles such as granules, based on 1 part by weight of solifenacin or its salt in crystalline and amorphous form, is preferably in a ratio of from 1 to 1000% by weight. more preferably in a ratio of from 5 to 500 wt%, and even more preferably in a ratio of from 10 to 100 wt%.

The particulate pharmaceutical composition of the invention is prepared with solifenacin or a salt thereof in solution state. However, when the core particles are sprayed with solifenacin solution, examples of the core particles include sodium chloride, microcrystalline cellulose, calcium carbonate, lactose, maltose, and mannitol, with preferred examples including microcrystalline cellulose, lactose, mannitol, and the like. Most preferred are microcrystalline cellulose and lactose. According to the invention, one or more substances in combination may be used from the group of these substances.

Further, the crystallization promoting treatment as set forth herein is not particularly limited and may be any crystallization enhancing treatment, examples of which include wetting treatment, microwave irradiation treatment, ultrasonic treatment, low-frequency radiation treatment, thermoelectronic treatment, and the like. Further, a humidification treatment is a treatment in which humidification is carried out, for example, at a temperature of 20 to 30 ° C and a humidity of 60 to 85% RH for 6 to 24 hours, and then drying at a temperature of 30 to 40 ° C and a humidity of 30 up to 40% RH in 2 to 6 hours. Microwave irradiation treatment is generally not limited, but microwaves with, for example, a wavelength of 10 MHz to 25 GHz can be used. Furthermore, the treatment time depends on the degree of crystallization in the starting state and on the selected base material, but the treatment can be carried out, for example, from 10 seconds to 60 minutes. The irradiation can be performed continuously or intermittently, and at any point in time after the particulate composition has been produced.

Ultrasonic treatment is generally not limited, but ultrasonic waves at frequencies from 10 kHz to 600 kHz can be used, for example. Furthermore, the treatment time depends on the degree of crystallization in the starting state and on the selected base material, but the treatment can be carried out, for example, from 10 seconds to 24 hours. The treatment may be carried out continuously or intermittently, and at any point in time after the production of the particulate composition.

Preference is given to wetting, microwave irradiation and ultrasonic treatment as crystallization enhancing treatments.

In the particulate pharmaceutical composition of the present invention, one or more of a number of pharmaceutical excipients is suitably used and incorporated into the pharmaceutical composition. Examples of such a pharmaceutical excipient include lactose and the like. Further, other additives may be used, within the limits of which they do not compromise the subject matter of the invention and as long as they are pharmaceutically and pharmacologically acceptable. For example, disintegrants, acidifying agents, foaming agents, artificial sweeteners, flavors, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants or the like can be used, without particular limitation. Examples of the disintegrant include corn starch, potato starch, carboxymethylcellulose calcium, carboxymethylcellulose sodium, low-substitution hydroxypropylcellulose, and the like. Examples of the acidifying agent include citric acid, tartaric acid, malic acid, and the like. Examples of foaming agents include, for example, sodium bicarbonate and the like. Examples of artificial sweeteners include sodium saccharin, glycyrrhizinic dipotassium salt, aspartame, stevia, somatin 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 esters, talc, stearic acid and the like. Examples of dyes include yellow iron oxide, red iron oxide, food yellow no. 4 and no. 5, food red no. 3 and no. 102, food blue no. 3 and the like. Examples of 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 antioxidants include ascorbic acid, sodium nitrite, sodium sulfite, sodium bisulfite, sodium ethylenediaminetetraacetic acid, erythorbic acid, tocopherol acetate, tocopherol, butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate and the like. Examples of surfactants include sodium lauryl sulfate

Polyoxyethylene sorbitan fatty acid ester (Polysorbate 80), polyoxyethylene hardened castor oil and the like. With respect to the pharmaceutical excipient, any of said agents may be added alone or two or more types of such agents in a suitable amount.

"Amorphous form content" in the technical solution means the ratio to the total amount of the amorphous form and the crystalline form of solifenacin or a salt thereof.

Examples of the pharmaceutical composition using said particles include powder, granules, dragees, tablets, capsules, oral disintegrating tablets, dry syrup, and the like, but oral disintegrating tablets are particularly preferred.

Next, a tablet disintegrating in the oral cavity comprising a pharmaceutical composition according to the present invention will be described.

"Oral disintegrating tablet" in the present invention means a tablet which, when taken without water, disintegrates in the oral cavity essentially only by saliva for 2 minutes, preferably for 1 minute, more preferably for 30 seconds, and a tablet-like pharmaceutical preparation.

The particulate pharmaceutical composition of the invention may be incorporated into such a tablet disintegrating in the oral cavity, for example, a tablet disintegrating in the oral cavity may be prepared by administering the particulate pharmaceutical composition as a drug substance in the known tablet disintegrating in the oral cavity described in published international application no. No. 95-20380 (corresponding to US Patent 5,576,014), in International Publication No. US-A-5,199,178; 2002-92057 (corresponding to US patent application 2003/099701), US patent 4305502, 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 US patent 5958453), Japanese patent 3412694 (corresponding to US patent 5223264) and International patent application WO 98/02185 (corresponding to US patent 6287596), using the base material of a tablet disintegrating in the oral cavity described in some from these publications, and by the method described in any of these publications. As an example of a tablet comprising a particulate pharmaceutical composition disintegrating in the oral cavity, said tablet disintegrating in the oral cavity may be described in Japanese patent no. 3412694 (corresponding to US patent 5223264) and JP-A-2003-55197, and the particulate pharmaceutical composition of the invention may be incorporated into such a tablet disintegrating in the oral cavity.

In general, the disclosed tablet disintegrating in the oral cavity is of the form, wetted and standard type tablets, and the particulate pharmaceutical composition of the invention may be incorporated into any type of tablet disintegrating in the oral cavity. A form-type tablet disintegrating in the oral cavity is prepared, for example, by filling the form with a solution or suspension of such an excipient and drying it as described in Japanese Patent No. 5,960,549. 2807346 (corresponding to US Patent No. 5466464). Oral disintegrating tablet form containing a particulate pharmaceutical composition according to the invention may be prepared, for example, by filling the blister pack with a solution or suspension of the particulate pharmaceutical composition according to the invention, an excipient such as a carbohydrate and a binder such as gelatin or agar and freeze-drying, vacuum-drying or low-temperature drying. Tablets of the humidified type disintegrating in the oral cavity are prepared by moistening an excipient such as a saccharide, and tabletting at low pressure and then drying as described in Japanese Patent No. 5,960,549. 3069458 (corresponding to US Patent No. 5501861 and US Patent No. 5720974). Thus, the particulate pharmaceutical composition of the present invention and an excipient such as a carbohydrate are wetted with a small amount of water and alcohol, and the resulting wetted mixture is formed under low pressure, and then the shaped mixture is dried to form a wetted tablet disintegrating in the oral cavity. .

With respect to standard-type tablets, these are prepared by standard tableting procedures as described in International Patent Application Publication No. WO 97/32711. 95-20380 (corresponding to US Patent No. 5,576,014); 2002-92057 (corresponding to US Patent Application No. 2003/099701), JP-A-10-182436 (corresponding to US Patent No. 5958453), JP-A-9-48726, JP-A-8-19589 (corresponding to US Patent No. 5,672,364); 2919771 and Japanese patent no. 3069458 (corresponding to US Patent No. 5501861 and corresponding US Patent No. 5720974). For the preparation of a standard type tablet disintegrating in the oral cavity comprising a particular pharmaceutical composition of the present invention, the particulate pharmaceutical composition of the present invention and an excipient such as poor formability saccharide is granulated using a high formability saccharide solution or suspension or water-soluble polymer. , and the resulting granular material is compressed to form a compressed substance, or the resulting compressed substance is subjected to wetting and drying, wherein a tablet disintegrating in the oral cavity can be prepared as described in International Patent Application No. WO 97/32711. No. 95-20380 (corresponding to US Patent No. 5,576,014) and Japanese Patent No. 5,702,049. Further, for the preparation of a standard type tablet disintegrating in the oral cavity, as described in International Patent Application Ser. 99-47124 (corresponding to US Patent No. 6,589,554), the particulate pharmaceutical composition of the present invention and an excipient such as a crystalline saccharide are molded by pressing using amorphous sachari

And the resulting substance is subjected to moistening and drying, whereby a tablet disintegrating in the oral cavity can be prepared. Further, for the preparation of a standard type tablet disintegrating in the oral cavity, as described in International patent application no. 2002-92057 (corresponding to US Patent Application No. 2003/099701), for example, a mixture of a particulate pharmaceutical composition of the invention and an excipient with a carbohydrate with a melting point lower than the excipient is molded by compression, and the resulting substance is heated to form a fusion bond. solidifying the saccharide with a lower melting point, whereby a tablet disintegrating in the oral cavity can be prepared. By wetting and drying or by heating treatment as described, the strength of such a tablet disintegrating in the oral cavity can be improved.

Standard excipients may also be used as an excipient for use in a tablet disintegrating in the oral cavity of the present invention, but a pharmaceutically acceptable carbohydrate is particularly preferred. In a process utilizing carbohydrate formability, carbohydrates with low formability may be used. When a process is used to improve the strength of a crystalline / amorphous carbohydrate containing tablet and to moisten and dry, a crystalline carbohydrate may be used. When a melting-solidifying saccharide bonding method is used, a high melting sugar can be used in addition to the standard excipient.

"Low formability carbohydrate" means a carbohydrate that provides a tablet with a hardness of 0 to 2 kp when, for example, 150 mg of carbohydrate is tableted at a tableting pressure of 10 to 50 kg / cm ² using a punch having a diameter of 8 mm. 'High formability carbohydrate' means a carbohydrate which, in the same procedure, gives the tablet a hardness of 2 kp or higher. A low formability carbohydrate is a pharmaceutically acceptable carbohydrate, examples of which may include lactose, mannitol, glucose, sucrose, xylitol, erythritol, and the like. These carbohydrates may be used alone or in a suitable combination of two or more types. A high formability carbohydrate is a pharmaceutically acceptable carbohydrate, and examples thereof may include maltose, maltitol, sorbitol, trehalose, and the like. Also, these carbohydrates may be used alone or in a suitable combination of two or more types.

A "crystalline carbohydrate" is a pharmaceutically acceptable carbohydrate, and examples thereof may include mannitol, maltitol, erythritol, xylitol and the like. These carbohydrates may be used alone or in suitable combinations of two or more types. An "amorphous carbohydrate" is a pharmaceutically acceptable carbohydrate, and examples thereof may include lactose, sucrose, glucose, sorbitol, maltose, trehalose, and the like. Also, these saccharides may be used alone or in suitable combinations of two or more types.

Further, an "excipient with a melting point higher than the melting point of a low-melting saccharide" is a pharmaceutically acceptable excipient, and may be selected, for example, from xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol, and Similarly. These carbohydrates may be used alone or in suitable combinations of two or more types. A "low melting carbohydrate" is a pharmaceutically acceptable carbohydrate, and can be selected, for example, from xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol, and the like. Also, these saccharides may be used alone or in suitable combinations of two or more types. An example of a binder for a tablet disintegrating in the oral cavity may be maltitol, copolyvidone, erythritol and the like. Also, these binders can be used alone or in suitable combinations of two or more types.

When a water-soluble polymer is used instead of a high-formability saccharide, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, gum arabic powder, gelatin, purulan and the like are preferred.

The admixed amount of excipient for use in a tablet disintegrating in the oral cavity containing the particulate pharmaceutical composition of the invention is suitably adjusted according to the admixed amount of the particulate pharmaceutical composition of the invention and / or tablet size and the like, but preferably is from 20 to 1000 mg in general , more preferably from 50 to 900 mg and particularly preferably from 100 to 800 mg per tablet.

Furthermore, the admixed amount of high formability carbohydrate, water-soluble polymer, amorphous carbohydrate, or low-melting carbohydrate is not particularly limited as long as it is suitably selected and used in accordance with appropriate procedures, but is preferably from 0.5 to 40% %, more preferably from 2 to 30 wt.%, and in particular from 5 to 20 wt. % by weight of the excipient, or preferably from 1 to 20 wt. of the total amount of the pharmaceutical preparation.

With respect to other optional ingredients, their preparation or admixture or the like, it is cited as part of the description for tablets disintegrating in the oral cavity the contents of said patent documents.

Furthermore, in the case where the particulate pharmaceutical composition according to the invention is incorporated in a tablet disintegrating in the oral cavity, the particulate pharmaceutical composition may be incorporated in an amount corresponding to 0.5 to 90% by weight, preferably 1 to 80% by weight, and still further. more preferably 5 to 60 wt. the total weight of the tablet disintegrating in the oral cavity.

Next, a method for producing a particulate composition according to the present invention will be described.

To obtain a particulate pharmaceutical composition according to the invention, solifenacin or a salt thereof and a binder with the effect of stabilizing solifenacin or a salt thereof are dissolved or suspended by means of

Mixing in water or a mixed solution obtained by adding an organic solvent, such as ethanol, to water by means of a stirring apparatus to prepare a solution of the active substance. In this case, the water or organic solvent content of the drug substance solution may be appropriately adjusted. As the pulverization (granulation) solution of the solifenacin drug substance or salt thereof, for example, a freeze-drying method, a spray-drying method, a high-speed granulation method, a fluid bed granulation method, a roll grinding granulation method and the like. Insofar as this method permits pulverization (granulation) of solifenacin after dissolution, it is not limited to any particular device or technique, but the spray drying method and fluid bed granulation method are particularly preferred. Specifically, particles of a suitable additive (e.g., crystalline cellulose particles, purified sucrose spherical granules, sucrose starch spherical granules or the like) to be core-coated are spray coated with a drug substance solution to obtain a particulate composition according to the present invention.

Spray coating equipment includes, for example, a fluid bed granulator (FLO-1, from Glatt Co., Ltd.), a spray dryer (DL41, from Yamato Scientific Co. Ltd.) and the like.

Next, a method of making a tablet disintegrating in the oral cavity comprising a particulate pharmaceutical composition according to the present invention will be described.

In the case of a tablet disintegrating in the oral cavity described in international patent application no. 95-20380 (corresponding to US Patent No. 5,576,014), from this reference it is possible to assume the steps of mixing a pharmaceutical composition according to the invention and a low formability carbohydrate; spraying the resulting mixture using a high formability carbohydrate as a binder to effect coating and / or granulation; and subjecting the resulting granular material to compression molding. Furthermore, to increase the hardness of the formed molded material, it is possible to take the wetting and drying steps. 'Humidification' is determined by the apparent critical relative humidity of the carbohydrate contained, but this is generally humidified to a critical relative humidity or above. The humidity is, for example, from 30 to 100% RH, preferably from 50 to 90% RH. In this case, the temperature is preferably from 15 to 50 ° C, even 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 particularly limited as long as it is a step of removing moisture absorbed by humidification. For example, the drying temperature may be set to 10 to 100 ° C, preferably 20 to 60 ° C, even more preferably 25 to 40 ° C. The processing time can be set to 0.5 to 6 hours, preferably 1 to 4 hours.

In the case of a tablet disintegrating in the oral cavity described in international patent application no. 2002-92057 (corresponding to US Patent Application No. 2003/099701), the particulate pharmaceutical composition of the invention, the high melting point excipient and the low melting point saccharide are mixed, and the resulting mixture is sprayed to be carried out after towing and / or granulation with using a binder for a tablet disintegrating in the oral cavity, and then the granular material can be subjected to compression molding. With respect to spray conditions, for example using a fluid bed granulator (FLO-1, from Glatt Co., Ltd.), the concentration of solifenacin solution is not limited as long as it provides a viscosity allowing the solution to be transported by pump, but preferably from 0.01 % to 30 wt. in terms of solids content. The spray rate is not limited as long as spray spraying can be performed, but is preferably from 0.1 to 20 g / min. The spray temperature is not particularly limited as long as it can be set to provide a product temperature of 10 to 60 ° C. These spraying conditions vary depending on the scale of manufacture and the type of equipment, but are not particularly limited as long as they provide a particulate composition. Further, in the case of a combination of a high melting point excipient and a low melting point saccharide, a heating step may be added to increase the hardness of the formed molded material. 'Warming up' is determined by the melting point of the low-melting saccharide contained. Generally, however, the heating is carried out to a temperature not lower than the melting point of the low melting saccharide and lower than the melting point of the high melting point excipient. The treatment time can be set to 0.5 to 120 minutes, preferably 1 to 60 minutes.

Further, a method of stabilizing a particulate pharmaceutical composition of the present invention and a method of converting an amorphous form of solifenacin or a salt thereof into a crystalline form in a particulate pharmaceutical composition of the present invention can be performed for a particulate composition of the present invention using said method as described using crystallization enhancements.

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BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the X-ray scattering results for powdered solifenacin succinate in crystalline form; PEG 8,000 (tradename Macrogol 6,000, from Sanyo Chemical Industries, Ltd.); spray dried product with solifenacin succinate prepared using PEG 8,000; spray-dried solifenacin succinate product prepared using HPMC (tradename TC-5E, from Shinetsu Chemical Co., Ltd.); and a spray-dried solifenacin succinate product prepared using polyvinylpyrrolidone (trade name PVP K90, from BASF, hereinafter PVP).

Fig. 2 shows X-ray scattering results for a coated product obtained by coating crystalline cellulose (trade name Celphere, from Asahi Chemical Industry Co., Ltd.) using PEG 8,000 (trade name Macrogol 6,000, from Sanyo Chemical Industries, Ltd.). in Example 3; and a coated product obtained using HPMC in Comparative Example 1.

Fig. 3 shows the relationship between the amount of F1 produced, which is the major product of solifenacin degradation, and Tg or b. t. binder used in combination after two months storage (O: no wetting treatment, ·: wetting treatment).

EXAMPLES

The pharmaceutical composition of solifenacin or a salt thereof according to the invention will be described in detail below. The technical solution will be described in more detail by way of examples and comparative examples, but the technical solution is not limited by these examples.

Example 1

Coated product obtained by coating crystalline cellulose core particles with solifenacin succinate using hydroxypropylcellulose (HPC-SL) as a binder

Ten parts of solifenacin succinate and 3.4 parts of hydroxypropylcellulose (tradename HPC-SL, from Nippon Sodium Co., Ltd., hereinafter HPC) were dissolved by mixing in a mixed solution of 26.6 parts of water and 26.6 parts of methanol using mixer (MGM-66, from SHIBATA) to prepare a drug solution. Then 60 parts of crystalline cellulose (trade name Celphere, from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and crystalline cellulose Celphere was spray coated with a solution. of the drug substance at an injection air temperature of 50 ° C, an air volume flow rate of 1.00 m ³ / min, a binder solution spray rate of 4.0 g / min. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate composition according to the invention.

Example 2

The particulate composition obtained in Example 1 was subjected to crystallization treatment by humidifying at 25 ° C and 75% RH for 12 hours, and then drying at 30 ° C and 40% RH for 3 hours to obtain the particulate composition according to the invention.

Example 3

Coated product obtained by coating crystalline cellulose core particles with solifenacin succinate using PEG 6000 as a binder

Ten parts of solifenacin succinate and 3.4 parts of PEG (tradename Macrogol 6000, from Sanyo Chemical Industries, Ltd.) were dissolved by stirring in a mixed solution of 26.6 parts of water and 26.6 parts of methanol using a mixer (MGM- 66, from SHIBATA) to prepare a drug substance solution. Then 60 parts of crystalline Celphere cellulose (from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and crystalline Celphere cellulose was spray coated with the drug substance solution at injection air temperature 50 ° C, 0.97 m ³ / min air flow rate, 10 g / min binder solution spray rate. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate composition according to the invention.

Example 4

The particulate composition obtained in Example 3 was subjected to crystallization treatment by humidifying at 25 ° C and 75% RH for 12 hours, and then drying at 30 ° C and 40% RH for 3 hours to obtain the particulate composition according to the invention.

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Example 5

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

Ten parts of solifenacin succinate and 3.4 parts of maltose (trade name SunMalto S, from Sanwa Comstarch Co., Ltd.) were dissolved by stirring in a mixed solution of 26.6 parts of water and 26.6 parts of methanol using a mixer (MGM- 66, from SHIBATA) to prepare a drug substance solution. Then 60 parts of crystalline Celphere cellulose (from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and crystalline Celphere cellulose was spray coated with the drug substance solution at injection air temperature 60 ° C, air volume flow 0.98 m ³ / min, binder solution spray rate 3.0 g / min. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate composition according to the invention.

Example 6

The particulate composition obtained in Example 5 was subjected to crystallization treatment by humidifying at 25 ° C and 75% RH for 12 hours, and then drying at 30 ° C and 40% RH for 3 hours to obtain the particulate composition according to the invention.

Example 12

Coated product obtained by coating crystalline cellulose core particles with solifenacin succinate using hydroxyethylcellulose (HEC) as a binder

Ten parts of solifenacin succinate and 3.4 parts of hydroxyethylcellulose (tradename HEC SE400, from Daicel Chemical Industries, Ltd.) were dissolved by stirring in a mixed solution of 26.6 parts of water and 26.6 parts of methanol using a mixer (MGM-66). , from SHIBATA) to prepare a drug substance solution. Then 60 parts of crystalline Celphere cellulose (from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and crystalline Celphere cellulose was spray coated with the drug substance solution at injection air temperature 60 ° C, air volume flow 0.98 m ³ / min, binder solution spray rate 3.0 g / min. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate composition according to the invention.

Example 8

The particulate composition obtained in Example 7 was subjected to crystallization treatment by humidifying at 25 ° C and 75% RH for 12 hours, and then drying at 30 ° C and 40% RH for 3 hours to obtain the particulate composition according to the invention.

Example 9

Coated product obtained by coating crystalline cellulose core particles with solifenacin succinate using a polyoxyethylene-polyoxypropylene (Pluronic) copolymer as a binder

Ten parts of solifenacin succinate and 3.4 parts of Pluronic F68 (tradename Lutrol F68, from BASF) were dissolved by mixing in a mixed solution of 26.6 parts of water and 26.6 parts of methanol using a shaker (MGM-66, from SHIBATA) ) to prepare a drug solution. Then 60 parts of crystalline cellulose (trade name Celphere, from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and the crystalline cellulose was spray coated with a drug solution. 54 ° C, 0.94 m ³ / min air flow rate, binder solution spray rate 3.0 g / min. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate composition according to the invention.

Example 10

The coated product obtained by coating crystalline cellulose with solifenacin succinate and PEG

Ten parts of solifenacin succinate and 1 part of PEG (tradename Macrogol 6000, from Sanyo Chemical Industries, Ltd.) were dissolved by stirring in a mixed solution of 16 parts of water and 16 parts of methanol using a mixer (MGM-66, from SHIBATA), thereby preparing a drug substance solution. Then 60 parts of crystalline cellulose (trade name Celphere, from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.), and crystalline Celphere cellulose was spray coated. drug solution at an injection air temperature of 45 ° C, air volume flow rate of 1.0 m ³ / min, binder solution spray rate of 2.0 g / min. and an injection air pressure of 2.0 kg / cm ² to obtain a particulate composition according to the invention.

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Example 11

The coated product obtained by coating crystalline cellulose with solifenacin succinate and PEG

Ten parts solifenacin succinate and 10 parts PEG (tradename Macrogol 6000, from Sanyo Chemical Industries, Ltd.) were dissolved by mixing in a mixed solution of 70 parts water and 70 parts methanol using a shaker (MGM-66, from SHIBATA), to prepare a drug substance solution. Then 60 parts of crystalline cellulose (trade name Celphere, from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and the crystalline cellulose was spray coated with a drug solution. 60 ° C, 1 m ³ / min air flow rate, 6.5 g / min binder solution spray rate. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate powder.

Example 13

In case of different solvent composition - coated product obtained by coating crystalline cellulose with solifenacin succinate and PEG

Ten parts of solifenacin succinate and 3.4 parts of PEG (tradename Macrogol 6000, from Sanyo Chemical Industries, Ltd.) were dissolved by stirring in 53.2 parts of water using a mixer (MGM-66, from SHIBATA) to prepared drug substance solution. Then 60 parts of crystalline cellulose (trade name Celphere, from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and the crystalline cellulose was spray coated with a drug solution. at a blown air temperature of 80 ° C, an air flow rate of 0.97 m ³ / min, a binder solution spray rate of 7.0 g / min. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate powder.

Example 13

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

Ten parts of solifenacin succinate and 3.4 parts of PEG (tradename Macrogol 6000, from Sanyo Chemical Industries, Ltd.) were dissolved by stirring in a mixed solution of 26.6 parts of methanol and 26.6 parts of water using a mixer (MGM-66). , from SHIBATA) to prepare a drug substance solution. Then 60 parts of crystalline cellulose (trade name Celphere, from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and the crystalline cellulose was spray coated with a drug solution. 54 ° C, 0.94 m ³ / min air flow rate, binder solution spray rate 3 g / min. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate powder. Next, the resulting powder was re-coated with another drug substance solution of the above composition using the same equipment and conditions to obtain a particulate powder with a higher drug content (drug content 50%).

Comparative Example 1

Coated product obtained by coating crystalline cellulose core particles with solifenacin succinate using hydroxypropylmethylcellulose (HPMC) as a binder

Ten parts of solifenacin succinate and 3.4 parts of hydroxypropyl methylcellulose 2910 (trade name TC-5E, from Shinetsu Chemical Co., Ltd., hereinafter referred to as HPMC) were dissolved by stirring in a mixed solution of 26.6 parts of water and 26.6 parts. of methanol using a shaker (MGM-66, from SHIBATA) to prepare a drug solution. Then 60 parts of crystalline cellulose (trade name Celphere, from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and crystalline cellulose Celphere was spray coated with a solution. at 50 ° C, air volume 0.94 m ³ / min, binder solution spray rate 7.0 g / min. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate composition.

Comparative Example 2

The particulate composition obtained in Comparative Example 1 was subjected to crystallization treatment by humidifying at 25 ° C and 75% RH for 12 hours, and then drying at 30 ° C and 40% RH for 3 hours to obtain the particulate composition.

Comparative Example 3

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

Ten parts of solifenacin succinate and 3.4 parts of polyvinylpyrrolidone (trade name PVP K90, from BASF, hereafter referred to as PVP) were dissolved by stirring in a mixed solution of 26.6 parts of water and 26.6 parts.

A portion of methanol using a stirrer (MGM-66, from SHIBATA) to prepare a drug solution. Then 60 parts of crystalline Celphere cellulose (from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and crystalline Celphere cellulose was spray coated with the drug substance solution at injection air temperature of 50 ° C, 0.97 m ³ / min air flow rate, binder solution spray rate 6 g / min. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate composition.

Comparative Example 4

The particulate composition obtained in Comparative Example 3 was subjected to crystallization treatment by humidifying at 25 ° C and 75% RH for 12 hours, and then drying at 30 ° C and 40% RH for 3 hours to obtain the particulate composition.

Comparative Example 5

Coated product obtained by coating crystalline cellulose core particles with solifenacin succinate using methylcellulose as a binder

Ten parts of solifenacin succinate and 3.4 parts of methylcellulose (tradename Metolose SMI00, from Shinetsu Chemical Co., Ltd., hereinafter MC) were dissolved by stirring in a mixed solution of 53.2 parts of water and 53.2 parts of methanol using a stirring mixer. instrument (MGM-66, from SHIBATA) to prepare a drug solution. Then 60 parts of crystalline Celphere cellulose (from Asahi Chemical Industry Co., Ltd.) was introduced into a fluid bed granulator (FLO-1, from Glatt Co., Ltd.) and crystalline Celphere cellulose was spray coated with the drug substance solution at blowing air temperature 55 ° C, 0.97 m ³ / min air flow rate, binder solution spray rate 5 g / min. and an injection air pressure of 3.0 kg / cm ² to obtain a particulate composition.

Comparative Example 6

The particulate composition obtained in Comparative Example 5 was subjected to crystallization treatment by humidifying at 25 ° C and 75% RH for 12 hours, and then drying at 30 ° C and 40% RH for 3 hours to obtain the particulate composition.

Experimental Examples <X-ray Scattering Measurement Results>

The interaction between drug substance and polymers was evaluated first.

X-ray scattering measurements of powdered, spray-dried products containing PEG and drug substance used in the examples, and HPMC or PVP and drug substance used in the comparative examples (using R1NT 1400: fluorescent: Cu, voltage: 40 kV, current: 40 mA, scanning speed: 3000 ° / min (Rigaku, Denki Co.)) are shown in FIG. 1. Results for solifenacin succinate alone in crystalline form and PEG are also shown as control results. All products prepared using PEG illustrated in the examples have peaks of solifenacin succinate in crystalline form, confirming that the drug substance in powder exists in crystalline form. In contrast, the samples shown in the Comparative Examples have a circular pattern indicating that the drug substance exists in an amorphous state.

Further, in FIG. 2 shows the X-ray scattering results of the coated product obtained by coating crystalline Celphere with polyethylene glycol PEG in Example 3 and the coated product obtained using HPMC in Comparative Example 1 (using a RINT 2000: fluorescent: Cu, voltage: 50 kV, current: 50 kV, current: 50 kV) mA, scan rate: 60,000 ° / min (Rigaku, Denki Co.). As shown in the drawing, it was also confirmed in the coated products that the PEG sample had solifenacin crystal peaks.

<Preliminary Stability Test Results>

The preliminary stability test results for these particulate compositions are shown in Tables 1 and 2. A series of measurements of the amount of degradation products after the compositions were stored for a period of time by high performance liquid chromatography was performed, and the highest observed value of the respective amounts of degradation products ( i.e. the amount of major degradation product F1). In the 40 ° C and 75% RH harsh tests, when using the HPMC shown in Comparative Example 1, when no humidification treatment was performed, a degradation product of 0.34% was observed within 2 months, which is 8 times concentration of 0.04% at the beginning of storage. Further, in the case of using the PVP shown in Comparative Example 3, when no wetting treatment was performed, a degradation product of 0.53% was observed over 2 months, exceeding the standard of 0.4%. Furthermore, in the case of the use of MC shown in Comparative Example 5, when no wetting treatment was performed, a degradation product of 0.74% was observed within 2 months, a 12-fold concentration of 0.06% at the beginning of storage. Also, when a humidifying treatment has been carried out

The amount of degradation products in all Comparative Examples 2, 4 and 6 is higher than in any of the Examples. In the case of HPMC, a degradation product of 0.92% was observed within 2 months, which is 13 times the concentration of 0.07% at the beginning of storage. Furthermore, in the case of the use of MC, a degradation product of 11.75% was observed already within 2 months, which is 11 times the concentration of 1.09% at the beginning of storage.

On the other hand, with respect to Examples 1 to 7, regardless of whether or not a wetting treatment was performed, the amount of degradation product after 2 months was 0.2% or less, and the absolute values were small, 2 to 390 times lower than in the comparative examples. Furthermore, it has been found that solifenacin in some pharmaceutical formulations is stable over time because the degree of conversion thereof was low. On the other hand, it has been found that the degradation product does not increase here and solifenacin is stable when carrying out a crystallization-promoting humidification treatment as shown in Examples 2, 4, 6 and 8.

The Tg values (if they do not have Tg, bt values) of the binders used are shown in Table 3, and the relationship between the amount of major degradation product (F1 (%)) produced over 2 months and Tg (° C) was investigated by linear regression. As a result, as shown in FIG. 3, a correlation coefficient (R ² ) of 0.73 in the absence of humidification and drying, and 0.60 in the case of humidification and drying, which showed a positive positive correlation.

As described, it is apparent that the thermodynamic parameters of the additive used in combination are the predominant factors for the stability of solifenacin in the pharmaceutical composition. This phenomenon is due to the fluidity, i.e., the glass transition temperature of the Tg of the binder as described, and the higher the Tg, the easier the amorphous form exists continuously in the pharmaceutical formulation in the amorphous state, thereby facilitating product degradation.

Results of preliminary stability test of particulate compositions with solifenacin succinate Storage conditions: 40 ° C and 75% RH, tightly sealed

Packaging: HDPE bottle with metal cap Tested: Relevant substances (amount of major degradation product F1 (%) produced)

Table 1

container HDPE * bottle with metal cap Example 1 Example 3 Example 5 Example 7 Cf.. Example 1 Cf.. Example 3 Cf.. Example 5 Start of storage 0.08 0.03 NZ 0.04 0.04 0.46 0.06 1 month 0.18 0.04 0.10 j 0.05 0.20 0.46 0.39 2 months 0.19 0.04 0.15 NT 0.34 0.53 0.74

container HDPE * bottle with metal cap Example 10 Example 11 Example 12 Example 13 Start of storage NZ 0.02 NZ NZ 1 month 0.09 0.04 0.03 0.04 2 months 0.10 0.04 0.04 0.06

* HDPE: High density polyethylene NZ: Not detected, NT: Not tested

Preliminary Stability Test Results of Particle Formulations with Solifenacin Succinate Under Humidification Treatment

Storage conditions: 40 ° C and 75% RH, tightly closed

Packaging: HDPE bottle with metal cap

Tested: relevant substances (amount of major F1 degradation product produced (%))

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Table 2

container HDPE * bottle with metal cap Example 2 Example 4 Example 6 Example 8 Cf.. Example 2 Cf.. Example 4 Cf.. Example 6 Start of 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

Glass transition temperatures Tg (° C) of binders

Table 3

Macrogol 6000 Maltose *, ** HPC *** HEC *** E0 *** PVP *** HPMC *** MC * *** Tg (° C) 60 102 130 135 (135-140) 157 (152-162) 174 240 298 (290-305) *: Melting point used (m.p. ° C) as an alternative **: Source: 'lyakuhin Tenkabutsu Handbook' Yakuji Nippo, Ltd., animals. 10 October 2001 ***: Source: 'Kobunshi Jiten' Maruzen Co., Ltd., animal. September 20, 1993

Industrial usability

The features of the invention are that a stable particulate pharmaceutical composition can be made using a specific binder in a particulate pharmaceutical composition comprising solifenacin or a salt thereof, and that it allows to provide a more stable particulate pharmaceutical composition over time by performing a crystallization promoting treatment such as wetting and drying, if necessary, which has a significant effect on production. The use of the particulate pharmaceutical composition of the present invention is useful as a technique that can provide various stable pharmaceutical formulations of solifenacin or a salt thereof whose development as an excellent pharmaceutical product for frequent urination or urinary incontinence has been desired.

PROTECTION REQUIREMENTS

Claims (7)

A stable particulate pharmaceutical composition comprising solifenacin or a salt thereof and a binder having the effect of stabilizing solifenacin or a salt thereof, wherein the binder is one or more substances having a glass transition temperature or melting point lower than 174 ° C selected from the group consisting of polyethylene glycol, polyethylene oxide, polyoxyethylene / polyoxypropylene block copolymer, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, maltose and polyvinyl alcohol. Pharmaceutical composition according to claim 1, characterized in that the binder is one or more substances selected from the group consisting of polyethylene glycol, a polyoxyethylene / polyoxypropylene block copolymer, hydroxypropylcellulose, hydroxyethylcellulose and maltose. Pharmaceutical composition according to claim 1, characterized in that the binder is one or more substances selected from the group consisting of polyethylene glycol, a polyoxyethylene / polyoxypropylene block copolymer and hydroxypropylcellulose. 4. A composition for the preparation of a stable particulate pharmaceutical composition of solifenacin or a salt thereof, comprising dissolved and / or suspended solifenacin or a salt thereof and a binder with the effect of stabilizing solifenacin or a salt thereof, characterized in that the binder is one or more glass transition temperatures; a melting point of less than 174 ° C selected from the group consisting of polyethylene glycol, polyethylene oxide, polyoxyethylene / polyoxypropylene block copolymer, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, maltose. The composition of claim 4, wherein the binder is one or more selected from the group consisting of polyethylene glycol, a polyoxyethylene / polyoxypropylene block copolymer, hydroxypropylcellulose, hydroxyethylcellulose, and maltose. SK 6196 Υ1 The composition of claim 4, wherein the binder is one or more selected from the group consisting of polyethylene glycol, a polyoxyethylene / polyoxypropylene block copolymer, and hydroxypropylcellulose. A tablet disintegrating in the oral cavity comprising a pharmaceutical composition according to any one of claims 1 to 3.