KR101841087B1 - Solid pharmaceutical composition - Google Patents

Abstract

(1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol and crystalline cellulose and / or croscarmellose sodium (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol forms a co-crystal A solid pharmaceutical composition and a method for producing the composition.

Description

[0001] SOLID PHARMACEUTICAL COMPOSITION [0002]

The present invention relates to a process for the preparation of (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] And the dissolution stability of the solid pharmaceutical composition is maintained.

In addition, the present invention relates to a process for preparing a compound represented by the general formula (I), which is characterized by excellent dissolution property of (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4- fluorophenyl] , And a method for producing a solid pharmaceutical composition, which is obtained by maintaining elution stability.

(Hereinafter referred to as " C-glycoside derivative A (hereinafter referred to as " C-glycoside derivative A Is a Na ⁺ -glucose cotransporter inhibitor created in Asperase Seiyaku and Gotobukeyaeku, and includes, for example, insulin-dependent diabetes mellitus (type 1 diabetes), non-insulin dependent diabetes mellitus (2 Diabetes mellitus) and the like, as well as in the treatment of insulin-resistant diseases and obesity, and in the prevention thereof (Patent Document 1).

Also, with regard to the co-crystallization of the known compound A and L-proline, it is preferable to use, as crystals of the pharmaceutical preparation used in the production of pharmaceuticals, co-crystals with L-proline having a constant quality and excellent storage stability, An invention relating to a pharmaceutical composition useful as a therapeutic agent for diabetes has been disclosed (Patent Document 2). Further, since the crystals of the known compound A form a clathrate hydrate and exhibit a property of being reversibly changed from an anhydride to a non-stoichiometric hydrate by a temperature and humidity environment, it is difficult to maintain a constant quality as a raw material to be supplied to a medicine , The known compound A is provided as a co-crystal with L-proline as a crystal of a medicine to be provided to a medicine having a constant quality and excellent storage stability.

Patent Document 1: International Publication WO2004 / 080990 pamphlet Patent Document 2: International Publication WO2007 / 114475 pamphlet

As a result of preparing a pharmaceutical preparation (for example, a tablet) containing a co-crystal of the known compound A and L-proline by a known method, the collapsibility of the known compound A and the co- As a result, it has become clear that the dissolution rate of the drug is slowed and that the dissolution rate changes with time. When the disintegration property of the preparation is poor and the dissolution rate of the drug is slowed down, it is worried that the bioavailability (BA) is lowered, and a problem that the pharmacologically sufficient therapeutic effect can not be obtained arises.

Accordingly, an object of the present invention is to provide a pharmaceutical composition having good elution properties, which is prepared from co-crystallization of 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 good dissolution properties, which is prepared from a free compound of known compound A, and a method for producing the pharmaceutical composition.

The present inventors prepared granules containing the co-crystals of the known compound A and L-proline by a wet granulation method using a well-known stirring granulator, After the preparation of the tablets from the granules, it was found that the tablets had good drug elution properties immediately after preparation, but they showed problems such as a change in the collapse characteristics and deterioration of elution with time.

The inventors of the present invention focused on the state of the drug in the preparation of the preparation, and found that the co-crystallization of the known compound A and L-proline resulted in the dissociation of L-proline from the co- It became clear that the drug eluting property was temporarily improved but the agglomerates were formed after a lapse of time.

Further, as a result of preparing a capsule preparation in which the known compound A and the L-proline co-crystal and lactic acid were mixed, good elution properties were not obtained.

Therefore, the present inventors thought that if the known compound A, which is made free from the liberation of L-proline from the co-crystal structure, can prevent the co-crystals from being reshaped, good elution properties will be maintained. As a result of intensive studies, it has been found that when a pharmaceutical composition containing a specific cellulose derivative is applied to the co-crystallization of the known compound A and L-proline, good dissolution is achieved, and the present invention has been accomplished.

Further, it has been found that a composition containing the known compound A and a specific cellulose derivative is prepared to achieve good elution properties, and the present invention has been accomplished.

That is,

(1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol, and crystalline cellulose and / or (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol in the presence of sodium croscarmellose sodium A solid pharmaceutical composition which does not form a co-crystal;

[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 in the pharmaceutical composition is 5 wt% or more and 90 wt% or less;

[4] In the dissolution test described in the 15th Japanese Pharmacopoeia of Japan, the (1S) -1,5-anhydro-1- [3- (1-benzothiene- -Fluorovinyl] -D-glucitol is eluted at 60% or more in 30 minutes, the solid pharmaceutical composition according to any one of [1] to [3]

[5] Co-determination of (1S) -1,5-anhydro- 1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L- , Any one of [2] to [4], which is produced by wet granulation from 50 parts by weight or more and 400 parts by weight or less of water with respect to 100 parts by weight of the crystalline cellulose and / or croscarmellose sodium, A solid pharmaceutical composition according to the present invention;

[6] The solid pharmaceutical composition according to any one of [1] to [5], wherein the solid pharmaceutical composition is a tablet.

[7] (1) Synthesis of (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol and crystalline cellulose / Or sodium croscarmellose, and

(2) a step of compression-molding the obtained mixture

A method for producing a solid pharmaceutical composition,

[8] Before the compression molding process, the mixture is wet-assembled and the (1S) -1,5-anhydro-1- [3- (1-benzothiene- ) -4-fluorophenyl] -D-glucitol obtained in the step

A method for producing a solid pharmaceutical composition according to [7], which comprises:

[9] (1) Synthesis of (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L- And a step of mixing crystalline cellulose and / or croscarmellose sodium, and

(2) The obtained mixture was wet-granulated, and the resulting (1S) -1,5-anhydro-1- [3- (1-benzothien- Ylmethyl) -4-fluorophenyl] -D-glucitol obtained in the step

A method for producing a solid pharmaceutical composition,

[10] A pharmaceutical composition comprising 100 parts by weight of (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L- Wherein the solvent is wet-assembled using a solvent in an amount of not less than 50 parts by weight and not more than 400 parts by weight based on the co-crystal of the binder resin.

[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

.

A feature of the present invention is that (1) the pharmaceutical preparation containing the known compound A exhibits good elution properties, (2) the elution rate does not change over time, a stable pharmaceutical preparation can be provided, and (3) (BA) is also improved because it shows elution property, and the effect such as sufficient pharmacological therapeutic effect is obtained.

Brief Description of the Drawings Fig. 1 is a schematic diagram showing the co-determination of (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4- fluorophenyl] (Measurement conditions: Cu K? Line 50 kV, 5 degrees / min, 40 degrees at 0 degree, peak positions: diffraction angle (2?) 8.9, 12.3, 17.4, 20.5).
FIG. 2 shows the powder X-ray diffraction of crystals of (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] (Measurement conditions: Cu Kα line 50 kV, 5 degrees / min, 40 degrees at 0 degree, peak positions: diffraction angle (2θ) 9.8 °, 11.8 °, 15.1 °, 19.8 °).
3 is a powder X-ray diffraction chart of the solid pharmaceutical composition prepared in Example 1. Fig.
4 is a view showing a dissolution profile of Test Example 2. Fig.
5 is a view showing a dissolution profile of Test Example 3. Fig.
6 is a graph showing changes over time in the plasma concentration of the known compound A of Test Example 5. Fig.
7 is a view showing a dissolution profile of Test Example 6. Fig.

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 is present in the solid pharmaceutical composition without forming a co-crystal.

In the present specification, " co-crystallization of known compound A and L-proline " means a co-crystal in which known compound A and L-proline are formed in a molar ratio of 1: 1. Identification of the co-crystal structure is shown from results of 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, the co-crystallization of the known compound A and L-proline is characterized by the diffraction angle (2? (°) of the spectrum and the relative intensity 1, Table 2). In powder X-ray diffraction, the crystal lattice spacing and the overall pattern are important in recognizing the identity of crystals in terms of the nature of the data, and the relative intensities can vary somewhat depending on the crystal growth direction, particle size, and measurement conditions , It should not be interpreted strictly. Further, when the peak specific to the known compound A structure in X-ray diffraction is small enough to be neglected, it is defined as the co-determination of the known compound A and L-proline.

Powder X-ray diffraction was measured under the following conditions.

Measured diffraction angle range (2?) Was measured using "MAC Science MXP18TAHF22" as standard measurement: Cu: tube current: 200 mA, tube voltage: 40 kV, sampling width: 0.020 °, scanning speed: 3 ° / min, wavelength: 1.54056 Å, : 3 to 40 [deg.].

In the present specification, the term " good dissolution property " means that the dissolution property is the same as or equivalent to that of the formulation. For example, when the dissolution test is carried out by the dissolution test described in the 15th Japanese Pharmacopoeia, it is defined that the dissolution rate of the known compound A after 30 minutes is 60% or more.

In the present specification, the "elution stability" means that the elution property of the known compound A from the pharmaceutical composition is such that the BA is substantially unchanged. For example, when the dissolution test is carried out by the dissolution test described in the 15th edition of the Japanese Pharmacopoeia, it is stipulated that the dissolution rate of the known compound A is less change with time than that at the start of storage. As another mode, it is stipulated that the difference in dissolution rate after 30 minutes from the start of the dissolution test after storage is within ± 15% as compared with that before storage. Preservation conditions include, for example, 40 DEG C for 2 weeks, 1 month, 2 months, 3 months or 6 months.

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

In the solid pharmaceutical composition of the present invention, the known compound A does not form a crystal. Here, " the known compound A does not form a co-crystal with L-proline " means that when the powder X-ray diffraction of the solid pharmaceutical composition is measured, the peak derived from the co-crystal is hardly observed. Specifically, when the powder X-ray diffraction was measured under the conditions of a measurement range of Cu k? Line of 50 kV, 5 degrees / minute and 40 degrees in the degree of O, diffraction angles (2?) Of 8.9 degrees, 12.3 degrees, 17.4 degrees, and 20.5 degrees It is determined that a characteristic peak is not confirmed in the vicinity of the peak.

In another form, when the powder X-ray diffraction is measured under conditions of a measurement range of Cu k? Line of 50 kV, 5 占 min and 0 占 to 40 占 the diffraction angles? Of 9.8 占 11.8 占 15.1 占 or And that the characteristic peak of the known compound A crystal is confirmed at around 19.8 °. In another form, it means that the DSC has an endothermic peak at 145 to 150 DEG C derived from the known compound A when measured at a temperature raising rate of 20 DEG C / min. In another embodiment, when the DSC is measured at a heating rate of 20 캜 / min, it means that the endothermic peak does not appear near about 209 캜 from the co-crystal of the known compound A and L-proline.

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

(I)

(Hereinafter referred to as "(1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol 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).

[Formula II]

The co-crystals have an endothermic peak at 201 to 213 ° C. in DSC analysis and / or have peaks at about 2θ (degrees) 4.14, 8.98, 12.4, 16.5, 17.5, 18.7, 20.5 and 21.5 in powder X-ray diffraction .

The co-crystallization of the known compound A and L-proline can be characterized by the diffraction angle (2? (?)) In the powder X-ray diffraction spectrum and the peak position by relative intensity or DSC spectrum.

The clinical dose (therapeutically effective dose) of the known compound A to humans is appropriately determined in consideration of symptoms, weight, age, sex, etc. of the patient to be treated, but is usually 0.1 to 500 mg orally per adult per day, Or in several divided doses. Since the dosage varies with various conditions, an amount less than the above-mentioned dosage range may suffice.

The crystalline cellulose used in the present invention is obtained by partially depolymerizing an a-cellulose obtained as a pulp in a fibrous plant with an acid (15th Japanese Pharmacopoeia). And, as long as it is pharmaceutically acceptable and can maintain good dissolution and elution stability of the known compound A, the crystalline cellulose can be used without particular limitation, such as its bulk density and average degree of polymerization. Specific examples of the cationic surfactant include CEOLUS PH101, SEORAS PH102, SEORAS PH101D, SEORAS KG802, SEORAS UF711, SEORAS UF702, SEORAS KG1000, SEORAS PH301D, SEORAS PH301D, SEORAS PH301Z, SEORAS PH302 Avicel PH111, Avicel PH113, Avicel PH200, Avicel PH301, Avicel PH302, Avicel HFE-102, Avicel (all FMC Biopolymer), Celex 101 (International Specialty Products), Emcocel PH20JP (all Asahi Kasei) 90M (J. Rettenmaier & Sohne), Vivacel 12 (J. Rettenmaier & Sohne) and Selphia (SANEEN F.F.I).

The shape of the crystalline cellulose is not particularly limited, such as granular or needle-shaped. It is also possible to use pulverized paper. A commercially available mixture of crystalline cellulose and another additive (carrageenan, sodium carboxymethyl cellulose, guar gum, etc.) may be used. When the shape of the crystalline cellulose is granular, the average particle diameter is preferably 20 to 200 占 퐉 as measured by the second method (sieving method) of the powder particle size measurement method described in the Japanese Pharmacopoeia. The crystalline cellulose may be used singly or in a combination of two or more thereof with different grades, shapes and average particle diameters.

The blending amount of crystalline cellulose is not particularly limited as far as the amount of the known compound A can exhibit good dissolution properties. For example, the amount of crystalline cellulose may be 5 wt% or more and 90 wt% or less in the pharmaceutical composition of the present invention, 20 wt% or more To 70% by weight or less, 20% by weight or more and 1500% by weight or less based on the weight of the known compound A, 50% by weight or more and 1100% by weight or less, and 40% by weight or more and 350%

Croscarmellose sodium is a sodium salt of a polyvalent carboxymethyl ether cross-linked cellulose (Japanese Pharmacopoeia 15th Edition). And, sodium croscarmellose is not particularly limited as long as it is pharmaceutically acceptable. Specifically, Ac-Di-Sol (FMC biopolymer) and Kiccolate (Asahi Kasei) are included.

The amount of croscarmellose sodium to be compounded is not particularly limited as far as the amount of the known compound A can exhibit good dissolution properties. For example, the amount of croscarmellose sodium may be 5 wt% or more and 90 wt% or less in the pharmaceutical composition of the present invention, Not less than 70% by weight, not less than 20% by weight and not more than 1,500% by weight based on the weight of the known compound A, 50% by weight or more and 1100% by weight or less as another form, and 40%

When crystalline cellulose and croscarmellose sodium are used together, the total amount thereof is used in an amount of not less than 5% by weight and not more than 90% by weight of the pharmaceutical composition, and as another form, not less than 5% by weight and not more than 70% by weight.

In addition, various pharmaceutical additives may be suitably used in the solid pharmaceutical composition of the present invention as required. Such pharmaceutical additives are not particularly limited as long as they are pharmaceutically acceptable and pharmacologically acceptable. For example, an excipient, a binder, a disintegrant, an acidifier, a foaming agent, an artificial sweetener, a flavoring agent, a lubricant, a colorant, a stabilizer, a buffer, an antioxidant, a surfactant and a coating agent are used.

Examples of the excipient include D-mannitol, lactose and the like.

Examples of the binder include hydroxypropyl methylcellulose, hydroxypropyl cellulose, and gum arabic.

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

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

As the foaming agent, for example, sodium bicarbonate and the like can be mentioned.

Examples of the artificial sweetener include sodium saccharin, potassium glutilate, aspartame, stevia, and somatin.

Examples of the perfume include lemon, lemon lime, orange, menthol, and the like.

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

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

Examples of the buffering agent include buffers such as 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, .

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

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

Examples of the coating agent include talc, polyethylene glycol, hypromellose, and titanium oxide.

The pharmaceutical additive may be appropriately added in an appropriate amount, either singly or in combination of two or more.

The compounding 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-benzothiene-2-ylmethyl) -4-fluorophenyl] Tosylate, crystalline cellulose and / or croscarmellose sodium, and (2) compression molding the resulting mixture. The mixture described in (2) was wet-assembled before the compression molding to obtain the (1S) -1,5-anhydro-1- [3- (1-benzothiene- 2-ylmethyl) -4-fluorophenyl] -D-glucitol. ≪ / RTI >

Also, the solid pharmaceutical composition of the present invention comprises (1) (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] A step of mixing the co-crystal of glucitol and L-proline with the crystalline cellulose and / or croscarmellose sodium, and (2) wet-granulating the obtained mixture to obtain a state in which co-crystals with L- Step of obtaining a granulation containing (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol . ≪ / RTI > Further, the obtained granulated product can be formed into a desired shape by compression molding (step (3)).

Wet type assembling is a method of assembling by adding a solvent at the time of assembling, and various assembling methods such as an agitation method, a fluidized bed method, a power assembly method and a combined assembly method are known.

When the above various pharmaceutical additives are used as desired, the pharmaceutical additive may be used in the process of (1), between the process of (1) and the process of (2), during the process of (2) (3) during the process, or the like.

The co-crystals of the known compounds A and L-proline, the cellulose derivative and any pharmaceutical additive can each be subjected to a grinding process before the mixing process and adjusted to any size. The pulverization process is not particularly limited as long as the drug and / or the pharmaceutical additive can be usually pharmacologically pulverized. The mixing step of each of the components successively to the pulverization is not particularly limited as long as it is a method capable of uniformly mixing each component in a pharmaceutical manner.

In the wet granulation, the solvent is added to the mixture of the known compound A and the co-crystal of the L-proline and the cellulose derivative, and the assembly is carried out. The solvent includes, for example, water, ethanol, methanol, a mixed solvent thereof, and the like. The solvent may contain a binder (i.e., a binder solution). The solvent (or binder solution) may be added at a rate of 1 to 30 g / min, and the solvent (or binder solution) may be added at a rate of 1 to 30 g / And may be added at a rate of 5 to 20 g / min. It is also possible to adopt a form in which a binder is previously added to a mixture of the known compound A and the co-crystal of L-proline and a cellulose derivative, and then the solvent is added to the mixture.

In the wet granulation, a solvent in an amount of 50 parts by weight or more and 400 parts by weight or less relative to 100 parts by weight of the co-crystals of known compound A and L-proline, and alternatively 80 parts by weight or more and 330 parts by weight or less,

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

It is preferable to be assembled by stirring assembly in that it promotes the release of L-proline during assembly. Although strong shear force is given to the assemblies during agitation, it is presumed that the strong shear force promotes the escape of L-proline.

The granules prepared as described above may be formulated into various preparations such as tablets, capsules, powders, granules and dry syrup. In some embodiments, the solid pharmaceutical composition of the present invention is a tablet.

Various formulations can be prepared by known methods. For example, various preparations can be prepared by known methods including processes such as drying, tableting and film coating.

For example, the prepared granulate can be dried by any means. For example, a drying apparatus such as a fluidized bed dryer, a multiplexer and a lathe dryer can be used. The drying temperature is, for example, 40 to 90 占 폚. The dried granulation can then be tabletted to produce tablets. As a tableting method, there is no particular limitation as long as it is a method in which a compression molded product is usually produced pharmaceutically. For example, there can be mentioned a method of mixing and kneading a collapse agent and a lubricant in a granulated product. The tableting apparatus is not particularly limited as long as it is a method in which a compression molded article is usually produced by a pharmaceutical method. Examples of the tableting apparatus include a rotary tabletting machine and a single-shot tableting machine. The refined hardness is, for example, from 40 to 250 N, and the other is from 50 to 20ON.

After tableting, the tablet surface may be coated with a film. The method is not particularly limited as long as it is a method that is usually pharmaceutical-coated. For example, a pan coating. The film coating agent is not particularly limited as long as it is a pharmaceutical additive usually coated with a pharmaceutical. The film coating agent may be appropriately added in an appropriate amount, either singly or in combination.

The coating rate is not particularly limited as long as it can be coated on the tablet surface. For example, it is 1.0% by weight or more and 5.0% by weight or less based on the weight of the tablet (pre-coating) before coating.

The solid medicinal composition of the present invention or a method for producing the medicinal preparation is not particularly limited as long as it is a method for producing a medicinal preparation having a desired effect of the present invention by suitably combining the above-described methods or known methods.

Example

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-determination of known compound A and L-proline was carried out according to the method described in WO 2007/114475 pamphlet. In addition, Known Compound A was prepared according to the method described in WO 2004/080990.

≪ Example 1 >

1.8 g of the co-crystals of the known compound A and L-proline, and 1.8 g of crystalline cellulose (product name: SEORAS PH101, manufactured by Asahi Kasei Corporation, hereinafter the same) were mixed and about 3 g of water was added to perform wet stirring and assembly (Small stirrer, manufactured by Kyoritsu Tsuriko Kabushiki Kaisha), about 1 minute in assembly time). The resulting granule was dried (40 DEG C, 12 hours) to prepare a solid pharmaceutical composition of the present invention.

≪ Example 2 >

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

≪ Comparative Examples 1 to 7 &

(Product name: HPC-L, manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxypropylmethyl cellulose (product name: TC5E, manufactured by Shin-Etsu Chemical), D- mannitol Manufactured by BASF), polyethylene oxide (product name: Polyox, manufactured by BASF Corporation), polyethylene glycol (product name: PEG6000, manufactured by Sanyo Chemical Industries, Ltd.), copolyvidone (product name: Manufactured by Dow Chemical Co., Ltd.) were respectively used as the solid pharmaceutical compositions of the comparative examples 1 to 7.

≪ Test Example 1 > Evaluation of Crystallinity

Powder X-ray diffraction measurement was carried out for the solid pharmaceutical compositions prepared in Examples 1 and 2 and Comparative Examples 1 to 7 immediately after preparation (at the start of storage) and after storage for 1 month under 40 ° C and 75% relative humidity Respectively.

In the solid pharmaceutical compositions of Examples 1 and 2, peaks corresponding to co-crystals of known compound A and L-proline were not observed immediately after preparation and after storage, while diffraction angles (2 &thetas;) 9.8 DEG, 11.8 DEG, 15.1 DEG and 19.8 DEG. The powder X-ray diffraction pattern of Example 1 is shown in Fig. Therefore, in Examples 1 and 2, it is considered that the known compound A was made to be a free body by releasing L-proline from the co-crystal structure during granulation.

In the solid pharmaceutical compositions of Comparative Examples 1 to 7, peaks corresponding to co-crystals of the known compound A and L-proline were observed at diffraction angles (2?) Of 8.9 °, 12.3 °, 17.4 ° and 20.5 °, , It is considered that the known compound A and L-proline form a co-crystal structure.

≪ Example 3 >

Tablets were prepared based on the prescriptions of Table 3 (the numbers in the tables are the weight of each component used (mg)).

After mixing the known compound A and the co-crystal of L-proline, sodium croscarmellose, D-mannitol, and hydroxypropyl cellulose (product name: HPC-SL, manufactured by Nippon Soda Co., And water was added thereto so as to be 84 parts by weight per 100 parts by weight of the co-crystals. (Assembly device (small stirrer, manufactured by Kyoritsu Rikou Kabushiki Kaisha), assembly time: about 2 minutes). The resulting granules were dried (40 DEG C, 12 hours), mixed with magnesium stearate and tableted to obtain the solid pharmaceutical composition of the present invention (diameter: 9.5 mm).

≪ Comparative Example 8 >

Tablets were prepared on the basis of the prescription of Table 3.

Except that low-substituted hydroxypropyl cellulose (L-HPC) (trade name: LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) was used in place of croscarmellose sodium to prepare a solid pharmaceutical composition of Comparative Example Respectively.

≪ Comparative Example 9 &

Tablets were prepared on the basis of the prescription of Table 3.

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

≪ Test Example 2 >

For the solid pharmaceutical compositions of Example 3, Comparative Example 8 and Comparative Example 9, the dissolution test of the tablet immediately after preparation of the preparation was carried out. The elution test was carried out by the paddle method described in the 15th Japanese Pharmacopoeia. The test solution was prepared as 900 mL of the dissolution test first solution (0.1 N hydrochloric acid). The number of revolutions of the paddle was set to 50 revolutions / minute. The dissolution rate of the known compound A at 30 minutes after the start of the test is shown in Table 4. The elution profile is also shown in Fig.

<Example 4>

Tablets were prepared based on the prescriptions of Table 5 (the numbers in the tables are the weight (mg) of each component used).

The co-crystals of known compound A and L-proline, sodium croscarmellose, crystalline cellulose, and hydroxypropyl cellulose were added to a stirring granulator (VGO1, manufactured by Paurek), and stirring and assembly were performed while spraying water. The obtained granules were dried (40 DEG C, 12 hours), sieved using a sieve having a sieve size of 710 mu m, and granulated to obtain granules. The granules were mixed with magnesium stearate and then tableted to obtain the solid pharmaceutical composition of the present invention.

&Lt; Comparative Example 10 &

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

&Lt; Test Example 3 > Evaluation of dissolution property

With respect to the solid pharmaceutical compositions of Example 4 and Comparative Example 10, the dissolution test of tablets at the initial stage of the preparation was carried out as in Test Example 2. The elution profile is shown in Fig. As for Example 4, the elution profile after standing at 40 占 폚 for 2 weeks (40 占 폚 2W) is shown.

&Lt; Example 5 >

A solid medicinal composition was prepared based on the prescription of Table 6 (the numbers in the tables are the weight (mg) of each component used).

After mixing the known compound A and the co-crystal of L-proline, sodium croscarmellose, crystalline cellulose, hydroxypropylcellulose and magnesium stearate, about 290 g of water was added to perform agitation and assembly (assembly apparatus (VG05, Manufactured by Lek Co., Ltd., assembly time: 12 minutes). The resulting granule was dried with a dryer (at about 60 DEG C for about 1 hour), molded with a rotary tablet machine, and then coated with a film coating agent (OPADRY, manufactured by Colorcon) to prepare a solid pharmaceutical composition of the present invention.

Test Example 4 Evaluation of Elution and Elution Stability

With respect to the solid pharmaceutical composition prepared in Example 5, the dissolution test of the composition immediately after preparation and after preservation (1 month, 2 months, 3 months, 6 months at 40 占 폚) was carried out as Test Example 2. The results are shown in Table 7.

<Test Example 5> Oral administration test

The solid pharmaceutical composition prepared in Example 5 and a methylcellulose suspension (composition: a solution in which 128.5 mg of a co-crystal of known compound A and L-proline was suspended in 10 mL of an aqueous 0.5% methylcellulose solution) 6), and the concentration in the plasma of the known compound A was measured with time to evaluate the water absorbency. The results are shown in Fig. 6 (in the figure, "Tab" represents the absorbability of the solid pharmaceutical composition and "MCsus" represents the absorbency of the methylcellulose suspension).

As a result, the AUC of the solid pharmaceutical composition of Example 5 was 121% as compared with the AUC of the methylcellulose suspension. Therefore, the solid pharmaceutical composition of the present invention showed good absorption properties even in the in vivo test.

As can be seen in Test Examples 2 to 5, the solid pharmaceutical composition containing the known compounds A and L-proline and crystalline cellulose and / or croscarmellose sodium and the known compounds A and L-proline did not form a co-crystal Showed good elution and elution stability. Since the known compound A is considered to have a co-crystal structure with L-proline by hydrogen bonding by an OH group, the formation of hydrogen bonds between the known compound A and L-proline is inhibited, I guess.

&Lt; Example 6 >

Tablets were prepared based on the prescriptions of Table 8 (the numbers in the tables are the weight of each component used (mg)).

The known compound A, crystalline cellulose and croscarmellose sodium were mixed and molded into a single tablet machine to prepare tablets of the present invention.

&Lt; Test Example 6 >

With respect to the tablets prepared in Example 6, the dissolution test of the composition immediately after preparation was carried out as in Test Example 2. The test results are shown in Fig.

Claims (12)

(1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol, L-proline and crystalline cellulose, (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] - D-glucitol does not form a co-crystal. delete The solid pharmaceutical composition according to claim 1, wherein the amount of crystalline cellulose, croscarmellose sodium, or both is 5 wt% or more and 90 wt% or less in the pharmaceutical composition. The method according to claim 1 or 3, wherein, in the elution test described in the 15th Japanese Pharmacopoeia, the (1S) -1,5-anhydro-1- [3- (1-benzothiene- 2-ylmethyl) -4-fluorophenyl] -D-glucitol is eluted at 60% or more in 30 minutes. The method according to claim 1 or 3,
(1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L-
Crystalline cellulose, croscarmellose sodium, or both, and
50 parts by weight or more and 400 parts by weight or less of water relative to 100 parts by weight of the co-
, Which is produced by wet granulation. The solid pharmaceutical composition according to any one of claims 1 to 3, wherein the solid medicine composition is purified. delete delete (1) Co-determination of (1S) -1,5-anhydro-1- [3- (1-benzothiene-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L- , And a process of mixing crystalline cellulose, croscarmellose sodium, or both, and
(2) The obtained mixture was wet-granulated to obtain the (1S) -1,5-anhydro-1- [3- (1-benzothiene- Ylmethyl) -4-fluorophenyl] -D-glucitol obtained in the step
&Lt; / RTI &gt; The production method according to claim 9, wherein the water is granulated using 50 parts by weight or more and 400 parts by weight or less of water with respect to 100 parts by weight of the co-crystal. 11. The method of claim 10, further comprising: (3) compression molding the assembly. 12. The method according to any one of claims 9 to 11, wherein the solid pharmaceutical composition is purified.

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