WO2012144592A1

WO2012144592A1 - Solid pharmaceutical composition

Info

Publication number: WO2012144592A1
Application number: PCT/JP2012/060701
Authority: WO
Inventors: 啓介坂浦; 田村　哲哉; 片川　好史; 迫　和博
Original assignee: アステラス製薬株式会社; 壽製薬株式会社
Priority date: 2011-04-22
Filing date: 2012-04-20
Publication date: 2012-10-26
Also published as: KR101841087B1; CN103687596A; JPWO2012144592A1; KR20140022002A; JP6063379B2; CN103687596B

Abstract

Provided is a solid pharmaceutical composition comprising (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol and crystalline cellulose and/or croscarmellose sodium, wherein the (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol does not form cocrystals. Also provided is a method for producing the composition.

Description

Solid pharmaceutical composition

The present invention maintains good dissolution properties and dissolution stability of (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol It is related with the solid pharmaceutical composition formed.

In addition, the present invention relates to (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol having good dissolution property and dissolution stability. It is related with the manufacturing method of the solid pharmaceutical composition formed by maintaining.

(1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol (hereinafter referred to as “C-glycoside derivative A” or “known compound A”) ) Is a Na ⁺ -glucose cotransporter inhibitor created by Astellas Pharma Inc. and Sakai Pharmaceutical Co., Ltd., for example, insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), etc. It has been reported as a compound useful for the treatment of insulin resistance disease and obesity, and prevention thereof (Patent Document 1).

Further, regarding a co-crystal of known compound A and L-proline, as a drug substance crystal used in the manufacture of a pharmaceutical, a co-crystal of L-proline having a certain quality and excellent storage stability, and An invention relating to a pharmaceutical composition containing as an active ingredient and particularly useful as a therapeutic agent for diabetes has been disclosed (Patent Document 2). In addition, since the crystal of known compound A forms clathrate hydrate and reversibly changes from an anhydride to a non-stoichiometric hydrate depending on the temperature and humidity environment, the drug substance used for pharmaceuticals Since it was difficult to maintain a certain quality, the known compound A was obtained as a co-crystal with L-proline as a crystal of a drug substance having a certain quality and excellent storage stability. Is provided.

International Publication No. WO2004 / 080990 Pamphlet International Publication No. WO2007 / 114475 Pamphlet

When a pharmaceutical preparation (for example, a tablet) containing a co-crystal of a known compound A and L-proline is produced by a known method, the disintegration is poor due to the strong cohesiveness of the co-crystal of the known compound A and L-proline. As a result, the elution rate of the drug became slow, and the problem that the elution rate changed with time became clear. When the disintegration property of the preparation is poor and the drug dissolution rate is slow, there is a concern that the bioavailability (BA) is lowered, and problems such as inability to obtain a sufficient pharmacological therapeutic effect occur.

Therefore, an object of the present invention is to provide a pharmaceutical composition having a good dissolution property produced from a co-crystal of a known compound A and L-proline, and a method for producing the pharmaceutical composition.

Another object of the present invention is to provide a pharmaceutical composition having a good dissolution property produced from a free form of known compound A and a method for producing the pharmaceutical composition.

The present inventors prepared a granulated product containing a co-crystal of a known compound A and L-proline by a wet granulation method using a known agitation granulator, and then tableted from the granulated product. As a result, it was found that the tablets had good drug dissolution immediately after the manufacture, but there were problems such as changes in disintegration characteristics and a decrease in dissolution over time. .

As a result of examining the state of the drug during preparation production, the present inventors have found that the co-crystal of the known compound A and L-proline is released from the co-crystal structure by water used during the preparation production. As a result, it was found that the known compound A becomes a free form, and the drug dissolution properties are temporarily improved, but aggregates are formed over time.

Further, when a capsule preparation in which a co-crystal of known compound A and L-proline and lactose were mixed was produced, good elution was not obtained.

Therefore, the present inventors can maintain good elution if it can prevent the known compound A, which has become a free form by detachment of L-proline from the co-crystal structure, from reforming the co-crystal. I thought. As a result of intensive studies, it has been found that, when a pharmaceutical composition containing a specific cellulose derivative is applied to a co-crystal of a known compound A and L proline, it achieves good dissolution properties and the present invention is completed. I came to let you.

Furthermore, the inventors have found that a composition containing known compound A and a specific cellulose derivative is produced to achieve good elution, and the present invention has been completed.

That is, the present invention
[1] (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and crystalline cellulose and / or croscarmellose sodium A solid pharmaceutical composition comprising (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol which does not form a co-crystal object;
[2] The solid pharmaceutical composition according to [1], further comprising L-proline;
[3] The solid pharmaceutical composition according to [1] or [2], wherein the amount of crystalline cellulose and / or croscarmellose sodium is 5% by weight or more and 90% by weight or less in the pharmaceutical composition;
[4] In the dissolution test described in the 15th revision Japanese Pharmacopoeia, (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol Is a solid pharmaceutical composition according to any one of [1] to [3], which elutes 60% or more in 30 minutes;
[5] (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L-proline co-crystal, crystalline cellulose and / or Alternatively, any one of [2] to [4] produced by wet granulation from croscarmellose sodium and 50 to 400 parts by weight of water with respect to 100 parts by weight of the co-crystal. A solid pharmaceutical composition according to claim 1;
[6] The solid pharmaceutical composition according to any one of [1] to [5], wherein the solid pharmaceutical composition is a tablet;
[7] (1) (1S) -1,5-Anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and crystalline cellulose and / or croscarme A step of mixing roast sodium, and (2) a step of compression molding the resulting mixture,
A process for producing a solid pharmaceutical composition comprising:
[8] Before the compression molding step, the mixture is wet granulated to form the (1S) -1,5-anhydro-1- [3- (1-benzothien-2- (Ilmethyl) -4-fluorophenyl] -D-glucitol to obtain a granulated product,
A method for producing a solid pharmaceutical composition according to [7], comprising:
[9] (1) (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L-proline co-crystal, and (2) a step of mixing crystalline cellulose and / or croscarmellose sodium, and (2) the obtained mixture is wet granulated to form (1S) -1, Obtaining a granulated product comprising 5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol;
A process for producing a solid pharmaceutical composition comprising:
[10] To a co-crystal of 100 parts by weight of (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L-proline The production method according to [9], wherein wet granulation is performed using a solvent of 50 parts by weight or more and 400 parts by weight or less;
[11] (3) The production method according to [10], further comprising a step of compression-molding the granulated product;
[12] The production method according to any one of [7] to [11], wherein the solid pharmaceutical composition is a tablet;
Is to provide.

The characteristics of the present invention are as follows: (1) a pharmaceutical preparation containing the known compound A exhibits good dissolution properties, (2) the dissolution rate does not change with time, and a stable pharmaceutical preparation can be provided. 3) Since it exhibits a good dissolution property, the bioavailability (BA) is improved, and an effect such as a sufficient pharmacological therapeutic effect is obtained.

FIG. 1 shows X-ray powder of co-crystal of (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L-proline It is a diffractogram (measurement conditions: CuαKα line 50 kV, 5 ° / min, 0 ° to 40 °, peak position: diffraction angle (2θ) 8.9 °, 12.3 °, 17.4 °, 20.5 °). FIG. 2 is a powder X-ray diffraction pattern of a crystal of (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol (measurement) Conditions: Cu Kα ray 50 kV, 5 ° / min, 0 ° to 40 °, peak position: diffraction angle (2θ) 9.8 °, 11.8 °, 15.1 °, 19.8 °). 3 is a powder X-ray diffraction pattern of the solid pharmaceutical composition produced in Example 1. FIG. FIG. 4 is a view showing an elution profile of Test Example 2. FIG. 5 is a view showing an elution profile of Test Example 3. FIG. 6 is a graph showing the change in plasma concentration of the known compound A in Test Example 5 over time. FIG. 7 is a view showing an elution profile of Test Example 6.

Hereinafter, the solid pharmaceutical composition of the present invention will be described in detail.

In the present specification, the “free form of the known compound A” means a state in which the known compound A exists without forming a co-crystal in the solid pharmaceutical composition.

In the present specification, “co-crystal of known compound A and L-proline” means a co-crystal formed of known compound A and L-proline in a molar ratio of 1: 1. Identification of the co-crystal structure is shown from results such as differential scanning calorimetry analysis (DSC analysis) and / or powder X-ray diffraction. For example, Patent Document 2 discloses that in the case of powder X-ray diffraction, a co-crystal of a known compound A and L-proline is characterized by a spectral diffraction angle (2θ (°)) and a relative intensity. (Table 1, Table 2). Powder X-ray diffraction is based on the nature of the data, and the crystal lattice spacing and overall pattern are important in identifying the identity of the crystal. The relative intensity depends somewhat on the crystal growth direction, particle size, and measurement conditions. Since it can change, it should not be interpreted strictly. In addition, if a peak peculiar to the structure of the known compound A appears in X-ray diffraction, it is defined as a co-crystal of the known compound A and L-proline if it is negligibly small.

Powder X-ray diffraction was measured under the following conditions.
Standard measurement: using “MAC Science MXP18TAHF22”, tube: Cu, tube current: 200 mA, tube voltage: 40 kV, sampling width: 0.020 °, scanning speed: 3 ° / min, wavelength: 1.54056 mm, measurement times Folding angle range (2θ): Measured under conditions of 3 to 40 °.

In the present specification, “good dissolution” means that the dissolution is equivalent to or equivalent to that of the immediate-release preparation. For example, when the dissolution test is performed according to the 15th revised Japanese Pharmacopoeia-Dissolution test method, the dissolution rate of the known compound A after 30 minutes is defined as 60% or more.

In the present specification, “elution stability” means that BA does not substantially change in the elution of the known compound A from the pharmaceutical composition. For example, when the dissolution test is performed by the dissolution test method described in the 15th revised Japanese Pharmacopoeia, it is defined that the dissolution rate of the known compound A is less changed with time than when the storage was started. As another embodiment, it is defined that the difference in dissolution rate 30 minutes after the start of the dissolution test after storage is within ± 15% compared to that before storage. Examples of the storage conditions include 40 weeks at 2 weeks, 1 month, 2 months, 3 months, or 6 months.

The solid pharmaceutical composition of the present invention comprises the known compound A and crystalline cellulose and / or croscarmellose sodium as essential components. In another embodiment, known compound A and L-proline, and crystalline cellulose and / or croscarmellose sodium are essential components.

In the solid pharmaceutical composition of the present invention, the known compound A does not form a co-crystal. Here, “the known compound A does not form a co-crystal with L-proline” means that when a powder X-ray diffraction of a solid pharmaceutical composition is measured, a peak derived from the co-crystal is hardly observed. To do. Specifically, when the powder X-ray diffraction is measured under the conditions of Cu Kα ray 50 kV, 度 5 ° / min, 0 ° to 40 °, the diffraction angle (2θ) is 8.9 °, 12.3 °, 17.4 °, It is defined that no characteristic peak is observed around 20.5 °.

As another embodiment, when the powder X-ray diffraction is measured under the conditions of Cu Kα ray 50kV, 5 ° / min, measurement range of 0 ° to 40 °, diffraction angle (2θ) is 9.8 °, 11.8 °, 15.1 ° Or a characteristic peak of the crystal of the known compound A around 19.8 °. As a further embodiment, it means that the DSC has an endothermic peak around 145 to 150 ° C. derived from the known compound A when the DSC is measured at a temperature rising rate of 20 ° C./min. Furthermore, as another embodiment, when DSC is measured at a temperature rising rate of 20 ° C./min, it means an embodiment that does not show an endothermic peak around 209 ° C. derived from a co-crystal of known compound A and L-proline. .

The known compound A used in the present invention is represented by the following formula (I)

The chemical name is (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol (hereinafter referred to as “C-glycoside derivative A”). Or simply “known compound A”). The known compound A can form a co-crystal structure with L-proline as shown by the following formula (II).

The co-crystal has an endothermic peak at 201 to 213 ° C. by DSC analysis and / or 2θ (°) 4.14, 8.98, 12.4, 16.5, 17.5 by powder X-ray diffraction. , 18.7, 20.5, and 21.5.

The known compound A and the co-crystal of known compound A and L-proline can be characterized by the diffraction angle (2θ (°)) and relative intensity in the powder X-ray diffraction spectrum, or the peak position by the DSC spectrum.

The clinical dose (therapeutically effective amount) of the known compound A to humans is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to be applied. It is ˜500 mg, which is administered once or divided into several times. Since the dosage varies depending on various conditions, an amount smaller than the above dosage range may be sufficient.

The crystalline cellulose used in the present invention is obtained by partially depolymerizing and purifying α-cellulose obtained as a pulp from a fibrous plant with an acid (15th revised Japanese Pharmacopoeia). And if it is pharmacologically acceptable and can maintain the favorable elution property and elution stability of the well-known compound A, crystalline cellulose can be used without a restriction | limiting in particular in the bulk density, an average degree of polymerization, etc. . Specifically, Theolas PH101, Theolas PH102, Theolas PH101D, Theolas KG802, Theolas UF711, Theolas UF702, Theolas KG1000, Theolas PH301, Theolas PH301D, Theolas PH301Z, Theolas PH302, Theolas PH F20JP (A) Avicel PH112, Avicel PH113, Avicel PH200, Avicel PH301, Avicel PH302, Avicel HFE-102, Avicel (all of which are FMC Biopolymer), Celex 101 (International SpecialityR & D). hne), it is included Vivacel 12 (J.Rettenmaier & Sohne) CELPHERE (San-Ei Gen FFI), and the like.

The shape of crystalline cellulose is not particularly limited, such as granular or acicular. Needle-shaped ones can also be crushed and used. As the crystalline cellulose, a commercially available mixture as a mixture with other additives (carrageenan, sodium carboxymethyl cellulose, guar gum, etc.) can be used. When the shape of the crystalline cellulose is granular, the average particle size is preferably 20 to 200 μm when measured by the second method (sieving method) of the powder particle size measurement method described in the Japanese Pharmacopoeia. As the crystalline cellulose, ones having different grades, shapes, average particle sizes and the like can be used alone or in combination of two or more.

The blending amount of the crystalline cellulose is not particularly limited as long as the known compound A can usually exhibit good dissolution properties. For example, it is 5% by weight to 90% by weight in the pharmaceutical composition of the present invention. 20 wt% or more and 70 wt% or less, 20 wt% or more and 1500 wt% or less with respect to the weight of the known compound A, another embodiment is 50 wt% or more and 1100 wt% or less, and yet another embodiment is 40 wt% or more and 350 wt% or less. % Or less.

Croscarmellose sodium is a sodium salt of a crosslinked polyvalent carboxymethyl ether of cellulose (15th revised Japanese Pharmacopoeia). And croscarmellose sodium will not be restrict | limited especially if it is pharmaceutically acceptable. Specifically, Ac-Di-Sol (FMC Biopolymer), Kiccolate (Asahi Kasei) and the like are included.

The amount of croscarmellose sodium is not particularly limited as long as the known compound A can usually exhibit good dissolution properties. For example, it is 5% by weight to 90% by weight in the pharmaceutical composition of the present invention. As an aspect, 20 weight% or more and 70 weight% or less, 20 weight% or more and 1500 weight% or less with respect to the weight of the well-known compound A, As another aspect, 50 weight% or more and 1100 weight% or less, Furthermore, as another aspect, 40 weight% or more 350% by weight or less.

When crystalline cellulose and croscarmellose sodium are used together, the total amount is 5% by weight to 90% by weight in the pharmaceutical composition, and in another embodiment, 5% by weight to 70% by weight. Used.

In addition, various pharmaceutical additives are appropriately used in the solid pharmaceutical composition of the present invention as desired. Such a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, excipients, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, flavors, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants, coating agents, etc. used.

Excipients include D-mannitol, lactose and the like.

Examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, gum arabic and the like.

Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, partially pregelatinized starch, crospovidone, and sodium starch glycolate.

Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.

Examples of foaming agents include baking soda.

Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.

Examples of fragrances include lemon, lemon lime, orange and menthol.

Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.

Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.

Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.

Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.

Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

Coating agents include talc, polyethylene glycol, hypromellose, titanium oxide and the like.

As a pharmaceutical additive, an appropriate amount can be appropriately added in combination of one or more kinds.

The blending amount of the pharmaceutical additive is 0.1 to 70% by weight in the pharmaceutical composition of the present invention.

The solid pharmaceutical composition of the present invention comprises (1) (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol, and crystals. A step of mixing cellulose and / or croscarmellose sodium; and (2) the resulting mixture may be compression molded into a desired form. Further, before the step of compression molding the mixture described in (2), the (1S) -1,5-anhydro-1- [3- (1 A step of obtaining a granulated product comprising —benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol can be included.

Further, the solid pharmaceutical composition of the present invention comprises (1) (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L A step of mixing a co-crystal with proline and crystalline cellulose and / or croscarmellose sodium, and (2) a state in which the resulting mixture is wet granulated to form no co-crystal with L-proline To obtain a granulated product containing (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol. be able to. Furthermore, the obtained granulated product can be compression molded (step (3)) to obtain a desired form.

Wet granulation is a granulation method performed by adding a solvent during granulation, and various granulation methods such as stirring granulation method, fluidized bed granulation method, rolling granulation method and kneading granulation method are known. It has been.

When the above various pharmaceutical additives are used as desired, the pharmaceutical additives are used in the step (1), between the steps (1) and (2), in the step (2), and ( It can be added at any stage such as between step 2) and step (3).

The co-crystal of the known compound A and L-proline, the cellulose derivative, and any pharmaceutical additive can be adjusted to any size by subjecting them to a pulverization step before the mixing step. The pulverization step is not particularly limited to any device and means as long as the drug and / or pharmaceutical additive can be pharmaceutically pulverized normally. The mixing step of each component continuous with the pulverization is not particularly limited to any device or means as long as it is a method that can generally uniformly mix each component pharmaceutically.

In wet granulation, granulation is performed by adding a solvent to a mixture of a cocrystal of a known compound A and L-proline and a cellulose derivative. Examples of the solvent include water, ethanol, methanol, or a mixed solvent thereof. The solvent may contain a binder (ie, a binder solution). The rate of addition of the solvent (or binder solution) varies depending on the granulation method or the scale to be produced. For example, when producing a 1 kg scale by the wet granulation method, the solvent (or binder solution) is 1 to It can be added at a rate of 30 g / min, in other embodiments 5-20 g / min. In addition, a mode in which a binder is added in advance to a mixture of a co-crystal of a known compound A and L-proline and a cellulose derivative, followed by granulation while adding a solvent can also be employed.

In the wet granulation, a solvent of 50 parts by weight or more and 400 parts by weight or less is used with respect to 100 parts by weight of the co-crystal of the known compound A and L-proline. it can.

When the solid pharmaceutical composition of the present invention is produced from a co-crystal of known compound A and L-proline, the known compound A and L-proline do not form a co-crystal in the solid pharmaceutical composition. That is, by wet granulation under the above conditions, L-proline is released from the co-crystal structure during granulation, whereby the known compound A becomes a free body and the state of the free body is maintained.

Granulation is preferably performed by stirring granulation from the viewpoint of promoting the separation of L-proline during granulation. Agitation granulation gives a strong shearing force to the material to be granulated, and it is presumed that the strong shearing force promotes the detachment of L-proline.

The granulated product prepared as described above can be made into various preparations such as tablets, capsules, powders, granules, and dry syrup. In certain embodiments, the solid pharmaceutical composition of the present invention is a tablet.

Various preparations can be produced by known methods. For example, various preparations can be produced by a known method including steps such as drying, tableting and film coating.

For example, the prepared granulated product can be dried by any means. For example, drying apparatuses such as a fluidized bed dryer, a multiplex, and a shelf dryer can be used. The drying temperature is, for example, 40 to 90 ° C. Thereafter, the dried granulated product can be tableted to produce a tablet. The tableting method is not particularly limited as long as it is a method in which a compression-molded product is usually produced pharmaceutically. For example, there may be mentioned a method of tableting by mixing a disintegrant and a lubricant into the granulated product. The tableting device is not particularly limited as long as it is a method in which a compression-molded product is usually produced pharmaceutically, and examples thereof include a rotary tableting machine and a single tableting machine. The tablet hardness is, for example, 40 to 250 N, and in another embodiment, 50 to 200 N.

After tableting, the tablet surface may be coated with a film. The method is not particularly limited as long as it is a pharmaceutically coating method. For example, pan coating and the like can be mentioned. The film coating agent is not particularly limited as long as it is a pharmaceutical additive that is usually pharmaceutically coated. As the film coating agent, one or a combination of two or more can be added as appropriate.

The coating rate is not particularly limited as long as the tablet surface can be normally coated. For example, it is 1.0 wt% or more and 5.0 wt% or less with respect to the weight of the uncoated tablet which is a tablet before coating.

The method for producing the solid pharmaceutical composition of the present invention or the pharmaceutical formulation thereof is not particularly limited as long as it is a method for producing a pharmaceutical formulation having the desired effect of the present invention by appropriately combining the above-described methods or methods known per se. Not.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto. The co-crystal of the known compound A and L-proline was prepared according to the method described in International Publication No. 2007/114475 pamphlet. Moreover, the well-known compound A used what was manufactured according to the method of international publication WO2004 / 080990 pamphlet.

<Example 1>
After mixing 1.8 g of co-crystal of known compound A and L-proline and 1.8 g of crystalline cellulose (product name: Theolas PH101, manufactured by Asahi Kasei, the same shall apply hereinafter), about 3 g of water is added and wet stirring granulation is performed. (A granulator (small agitator, manufactured by Kyoritsu Riko Co., Ltd., granulation time: about 1 minute)). The obtained granulated product was dried (40 ° C., 12 hours) to prepare a solid pharmaceutical composition of the present invention.

<Example 2>
The solid of the present invention was the same as in Example 1 except that 1.8 g of croscarmellose sodium (product name: Ac-Di-Sol, manufactured by FMC Biopolymer Co., Ltd., hereinafter the same) was used instead of crystalline cellulose. A pharmaceutical composition was prepared.

<Comparative Examples 1 to 7>
Instead of crystalline cellulose, D-mannitol (product name: Pearitol, manufactured by Roquette, the same shall apply hereinafter), hydroxypropyl methylcellulose (product name: TC5E, manufactured by Shin-Etsu Chemical), hydroxypropyl cellulose (product name: HPC-L, manufactured by Nippon Soda) ), Polyethylene glycol (product name: PEG6000, manufactured by Sanyo Kasei), copolyvidone (product name: Kollidon K30, manufactured by BASF, and product name: Kollidon VA64, manufactured by BASF), and polyethylene oxide (product name: Polyox, manufactured) The solid pharmaceutical compositions of Comparative Examples 1 to 7 were prepared in the same manner as in Example 1, except that Dow Chemical Co., Ltd.) was used.

<Test Example 1> Evaluation of crystallinity For the solid pharmaceutical compositions produced in Example 1, Example 2, and Comparative Examples 1 to 7, immediately after production (at the start of storage) and 1 at 40 ° C. and 75% relative humidity Powder X-ray diffraction measurement was performed after storage for months.

In the solid pharmaceutical compositions of Example 1 and Example 2, no peak corresponding to the co-crystal of the known compound A and L-proline was observed immediately after production and after storage, while the peak corresponding to the crystal of the known compound A was observed. Peaks were observed at folding angles (2θ) of 9.8 °, 11.8 °, 15.1 °, and 19.8 °. The powder X-ray diffraction pattern of Example 1 is shown in FIG. Therefore, in Example 1 and Example 2, it is considered that L-proline was released from the co-crystal structure during granulation, so that known compound A became a free form.

In the solid pharmaceutical compositions of Comparative Examples 1 to 7, as in FIG. 1, peaks corresponding to cocrystals of the known compound A and L-proline are observed at diffraction angles (2θ) of 8.9 °, 12.3 °, 17.4 °, and 20.5 °. From the observation, it is considered that the known compound A and L-proline form a co-crystal structure.

<Example 3>
Tablets were prepared based on the formulation in Table 3 (numbers in the table are the weight (mg) of each ingredient used).

Co-crystal of known compound A and L-proline, croscarmellose sodium, D-mannitol, and hydroxypropylcellulose (product name: HPC-SL, manufactured by Nippon Soda Co., Ltd.) Water was added and granulated by wet stirring to 100 parts by weight with 100 parts by weight of co-crystal with proline (granulating device (small agitator, manufactured by Kyoritsu Riko Co., Ltd., granulation time: about 2 minutes)) . The obtained granulated product was dried (40 ° C., 12 hours), mixed with magnesium stearate and tableted to obtain a solid pharmaceutical composition of the present invention (inguinal diameter: 9.5 mm).

<Comparative Example 8>
Tablets were prepared based on the formulation in Table 3.

A solid medicine of a comparative example in the same manner as in Example 3 except that low-substituted hydroxypropylcellulose (L-HPC) (product name: LH-11, manufactured by Shin-Etsu Chemical) was used instead of croscarmellose sodium A composition was prepared.

<Comparative Example 9>
Tablets were prepared based on the formulation in Table 3.

A solid pharmaceutical composition of a comparative example was prepared in the same manner as in Example 3 except that crospovidone (substance name: KollidonCL, manufactured by BASF Japan Ltd.) was used instead of croscarmellose sodium.

<Test Example 2> Evaluation of dissolution property The solid pharmaceutical compositions of Example 3, Comparative Example 8, and Comparative Example 9 were subjected to a tablet dissolution test immediately after the preparation of the preparation. The dissolution test was performed by the paddle method described in the 15th revised Japanese Pharmacopoeia. The test solution was 900 mL (0.1N hydrochloric acid) of the first dissolution test solution. The rotation speed of the paddle was 50 rotations / minute. Table 4 shows the dissolution rate of the known compound A 30 minutes after the start of the test. The elution profile is shown in FIG.

<Example 4>
Tablets were prepared based on the formulation in Table 5 (the numbers in the table are the weight (mg) of each ingredient used).

A co-crystal of a known compound A and L-proline, croscarmellose sodium, crystalline cellulose, and hydroxypropyl cellulose are put into a stirring granulator (VG01, manufactured by POWREC), and stirring granulation is performed while spraying water. It was. The obtained granulated product was dried (40 ° C., 12 hours), passed through a sieve having a sieve opening of 710 μm, and sized to obtain granules. The granules were mixed with magnesium stearate and tableted to obtain a solid pharmaceutical composition of the present invention.

<Comparative Example 10>
A solid pharmaceutical composition of a comparative example was obtained in the same manner as in Example 4 using a known compound A and L-proline co-crystal, D-mannitol, hydroxypropyl cellulose and magnesium stearate.

<Test Example 3> Evaluation of Dissolution The solid pharmaceutical compositions of Example 4 and Comparative Example 10 were subjected to a tablet dissolution test immediately after production (initial) in the same manner as Test Example 2. The elution profile is shown in FIG. Moreover, about Example 4, the elution profile after leaving still at 40 degreeC for 2 weeks (40 degreeC2W) is shown.

<Example 5>
A solid pharmaceutical composition was prepared based on the formulation of Table 6 (the numbers in the table are the weight (mg) of each component used).

After mixing co-crystal of known compound A and L-proline, croscarmellose sodium, crystalline cellulose, hydroxypropyl cellulose and magnesium stearate, about 290 g of water was added and stirring granulation was carried out (granulating apparatus (VG05 , Manufactured by Paulek), granulation time 12 minutes). The obtained granulated product is dried with a dryer (about 60 ° C., about 1 hour), molded with a rotary tableting machine, and then coated with a film coating agent (OPADRY, manufactured by Colorcon). A solid pharmaceutical composition was prepared.

<Test Example 4> Evaluation of dissolution property and dissolution stability For the solid pharmaceutical composition produced in Example 5, immediately after production and after storage (1 month, 2 months, 3 months, 6 months at 40 ° C) The dissolution test of the composition was conducted in the same manner as in Test Example 2. The results are shown in Table 7.

<Test Example 5> Oral Administration Test for Dogs The solid pharmaceutical composition produced in Example 5 and a methylcellulose suspension (composition: 128.5 mg of co-crystal of known compound A and L-proline in 10 mL of 0.5% aqueous methylcellulose solution) Was orally administered to dogs (N = 6), and the plasma concentration of known compound A was measured over time to evaluate absorbability. The results are shown in FIG. 6 (in the figure, “Tab” indicates the absorbability of the solid pharmaceutical composition, and “MCsus” indicates the absorbability of the methylcellulose suspension).

As a result, the AUC of the solid pharmaceutical composition of Example 5 was 121% compared to the AUC of the methylcellulose suspension. Therefore, it was shown that the solid pharmaceutical composition of the present invention exhibits good absorbability even in an in vivo test.

As is understood from Test Examples 2 to 5, the known compound A and L-proline, and crystalline cellulose and / or croscarmellose sodium are contained, and the known compound A and L-proline form a co-crystal. The solid pharmaceutical composition not shown showed good dissolution properties and dissolution stability. Since known compound A is considered to have a co-crystal structure with L-proline due to hydrogen bonding by an OH group, formation of hydrogen bond between known compound A and L-proline is inhibited, so that known compound A Guess that the free body will be maintained.

<Example 6>
Tablets were prepared based on the formulation in Table 8 (the numbers in the table are the weight (mg) of each ingredient used).

A known compound A, crystalline cellulose and croscarmellose sodium were mixed and then molded with a single tableting machine to prepare a tablet of the present invention.

<Test Example 6> Evaluation of dissolution property The tablet manufactured in Example 6 was subjected to the dissolution test of the composition immediately after the manufacture in the same manner as in Test Example 2. The test results are shown in FIG.

Claims

(1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol, and crystalline cellulose and / or croscarmellose sodium, A solid pharmaceutical composition wherein the (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol does not form a co-crystal.
The solid pharmaceutical composition according to claim 1, further comprising L-proline.
The solid pharmaceutical composition according to claim 1 or 2, wherein the amount of crystalline cellulose and / or croscarmellose sodium is 5 wt% or more and 90 wt% or less in the pharmaceutical composition.
In the dissolution test described in the 15th revision Japanese Pharmacopoeia, (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol was 30 minutes. The solid pharmaceutical composition according to any one of claims 1 to 3, which is eluted at 60% or more.
(1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L-proline co-crystal, crystalline cellulose and / or croscarme It manufactures by wet granulation from 50 weight part or more and 400 weight part or less of water with respect to 100 weight part of roast sodium, and this co-crystal. Solid pharmaceutical composition.
The solid pharmaceutical composition according to any one of claims 1 to 5, wherein the solid pharmaceutical composition is a tablet.
(1) (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and crystalline cellulose and / or croscarmellose sodium A step of mixing, and (2) a step of compression-molding the obtained mixture,
A method for producing a solid pharmaceutical composition, comprising:
Prior to the compression molding step, the (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl)-in a state where the mixture is wet granulated to form a co-crystal A step of obtaining a granulated product containing 4-fluorophenyl] -D-glucitol,
The manufacturing method of the solid pharmaceutical composition of Claim 7 containing this.
(1) (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L-proline, and crystalline cellulose And / or a step of mixing croscarmellose sodium, and (2) the obtained (1S) -1,5-anhydro in a state where the resulting mixture is wet granulated and does not form a co-crystal with the L-proline. Obtaining a granulated product comprising -1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol;
A method for producing a solid pharmaceutical composition, comprising:
The production method according to claim 9, wherein wet granulation is performed using 50 to 400 parts by weight of water with respect to 100 parts by weight of the co-crystal.
(3) The manufacturing method according to claim 10, further comprising a step of compression molding the granulated product.
The production method according to any one of claims 7 to 11, wherein the solid pharmaceutical composition is a tablet.