CN103687596A

CN103687596A - Solid pharmaceutical composition

Info

Publication number: CN103687596A
Application number: CN201280018783.5A
Authority: CN
Inventors: 坂浦启介; 田村哲哉; 片川好史; 迫和博
Original assignee: Kotobuki Seiyaku Co Ltd; Yamanouchi Pharmaceutical Co Ltd
Current assignee: Kotobuki Seiyaku Co Ltd; Astellas Pharma Inc; Yamanouchi Pharmaceutical Co Ltd
Priority date: 2011-04-22
Filing date: 2012-04-20
Publication date: 2014-03-26
Anticipated expiration: 2032-04-20
Also published as: KR101841087B1; JPWO2012144592A1; KR20140022002A; CN103687596B; WO2012144592A1; JP6063379B2

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

Technical field

The present invention relates to maintain (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] the good stripping property of-D-glucitol and the solid pharmaceutical composition of stripping stability.

In addition, the invention still further relates to and maintain (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] manufacture method of the good stripping property of-D-glucitol and the solid pharmaceutical composition of stripping stability.

Background technology

(1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol (hereinafter referred to as " C-glycocide derivant A " or " known compound A ") is Astellas Pharma Inc's (アステラス System medicine) and the (Shou System of Kotobuki Seiyaku Co., Ltd. medicine) Na of development ⁺-glucose body the inhibitor that cotransports, has been reported as and has can be used for diabetes such as insulin dependent diabetes mellitus (IDDM) (type Ⅰ diabetes mellitus), non-insulin-dependent diabetes mellitus (type Ⅱdiabetes mellitus) and insulin resistance disease and fat treatment and the compound (patent documentation 1) of their prevention.

In addition, about the cocrystallization body of known compound A and L-PROLINE, disclose the crystallization relating to as the crude drug for medicine manufacture and there is certain quality and storage stability cocrystallization body good and L-PROLINE and comprise this cocrystallization body as the invention (patent documentation 2) of the medical composition that particularly can be used as Remedies for diabetes of effective ingredient.In addition, the crystallization of known compound A forms inclusion hydrate, show the character that is reversibly changed to non-stoichiometric hydrate according to humiture environment by anhydride, therefore as the crude drug for medicine, be difficult to the quality that keeps certain, so as the crystallization with the crude drug for medicine that certain quality and storage stability are good, known compound A provides with the form of the cocrystallization body with L-PROLINE.

Prior art document

Patent documentation

Patent documentation 1: International Publication WO2004/080990 text

Patent documentation 2: International Publication WO2007/114475 text

The summary of invention

Invent technical problem to be solved

By known method, manufactured the medicine preparation (for example tablet) of the cocrystallization body that comprises known compound A and L-PROLINE, the strong compendency that result has due to the cocrystallization body of known compound A and L-PROLINE and disintegrative is poor, thereby find to exist the problem of the slow and dissolution rate generation rheological parameters' change with time of the dissolution rate of medicine.If the disintegrative of preparation is poor, the dissolution rate of medicine is slow, likely produces bioavailability (BA) and reduce, cannot obtain the problems such as sufficient therapeutic effect on pharmacology.

Therefore, the object of the present invention is to provide the medical composition with good stripping property made by the cocrystallization system of known compound A and L-PROLINE and the manufacture method of this medical composition.

In addition, the present invention also aims to provide by the medical composition with good stripping property of the episome manufacture of known compound A and the manufacture method of this medical composition.

The technical scheme that technical solution problem adopts

The inventor is by adopting the wet granulation of known stirring granulating machine own to prepare the granules of the cocrystallization body that comprises known compound A and L-PROLINE; and then while manufacturing tablet by this granules; recognize that this tablet has good drug dissolution after just manufacturing; but find that disintegration properties changes, and stripping property also exist through time the problem such as reduction.

The inventor is conceived to the drug condition in preparation manufacture and is studied, found that in the cocrystallization body of known compound A and L-PROLINE, the water that L-PROLINE is used in manufacturing by preparation departs from from cocrystallization body structure, known compound A forms episome, drug dissolution temporarily improves, but forms agglutinator through after a period of time.

In addition, manufactured the cocrystallization body of known compound A and L-PROLINE and the capsule preparations that has mixed lactose, result can not obtain good stripping property.

So the inventor thinks if can prevent from again forming cocrystallization body because of the known compound A that L-PROLINE forms episome from the disengaging of cocrystallization body structure, can maintain good stripping property.In addition, while conscientiously finding the medical composition that comprises specific cellulose derivative to be applicable to the cocrystallization body of known compound A and L-PROLINE after research, realize good stripping property etc., thereby completed the present invention.

In addition, find to manufacture the compositions that comprises known compound A and specific cellulose derivative and can realize good stripping property etc., thereby completed the present invention.

That is, the invention provides following technology contents.

[1] solid pharmaceutical composition, wherein comprise (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol and crystalline cellulose and/or cross-linking sodium carboxymethyl cellulose, should (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol do not form cocrystallization body.

[2] solid pharmaceutical composition as described in [1], wherein, also comprises L-PROLINE.

[3] solid pharmaceutical composition as described in [1] or [2], wherein, the amount of crystalline cellulose and/or cross-linking sodium carboxymethyl cellulose is more than 5 % by weight below 90 % by weight in medical composition.

[4] solid pharmaceutical composition as described in any one in [1]～[3], wherein, in the dissolution test of recording in the 15th revised edition of Japanese Pharmacopoeia, (1S)-1 in the time of 30 minutes more than 60%, 5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol stripping.

[5] solid pharmaceutical composition as described in any one in [2]～[4], wherein, said composition is by (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] cocrystallization body, crystalline cellulose and/or the cross-linking sodium carboxymethyl cellulose of-D-glucitol and L-PROLINE and be that water below above 400 weight portions of 50 weight portions is manufactured by wet granulation with respect to this cocrystallization body of 100 weight portions.

[6] solid pharmaceutical composition as described in any one in [1]～[5], wherein, solid pharmaceutical composition is tablet.

[7] manufacture method of solid pharmaceutical composition, wherein, comprising:

(1) by (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol and crystalline cellulose and/or the cross-linking sodium carboxymethyl cellulose operation of mixing; And

(2) by the operation of the mixture compression molding of gained.

[8] manufacture method of the solid pharmaceutical composition as described in [7], wherein, comprising:

Before the operation of compression molding, mixture is carried out to wet granulation, obtain comprise do not form cocrystallization body state should (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] operation of granules of-D-glucitol.

[9] manufacture method of solid pharmaceutical composition, wherein, comprising:

(1) by (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol and the cocrystallization body of L-PROLINE and the operation of crystalline cellulose and/or cross-linking sodium carboxymethyl cellulose mixing; And

(2) mixture of gained is carried out to wet granulation, acquisition comprise not with this L-PROLINE form cocrystallization body state should (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] operation of granules of-D-glucitol.

[10] manufacture method as described in [9], wherein, with respect to (1S)-1 of 100 weight portions, 5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] the cocrystallization body of-D-glucitol and L-PROLINE uses the solvent below above 400 weight portions of 50 weight portions to carry out wet granulation.

[11] manufacture method as described in [10], wherein, also comprises that (3) carry out the operation of compression molding to granules.

[12] manufacture method as described in any one in [7]～[11], wherein, solid pharmaceutical composition is tablet.

The effect of invention

The invention is characterized in: the medicine preparation that (1) comprises known compound A shows good stripping property; (2) can provide dissolution rate not rheological parameters' change with time and stable medicine preparation; (3) owing to showing good stripping property, bioavailability (BA) also improves, and performance can obtain sufficient therapeutic effect etc. on pharmacology.

The simple declaration of accompanying drawing

Fig. 1 is (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] x-ray diffractogram of powder (condition determination: Cu K alpha ray of cocrystallization body of-D-glucitol and L-PROLINE, 50kV, 5 degrees/min, from 0 degree to 40 degree, peak position: 8.9 °, 12.3 °, 17.4 °, 20.5 ° of the angles of diffraction (2 θ)).

Fig. 2 is (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] x-ray diffractogram of powder (condition determination: Cu K alpha ray of crystallization of-D-glucitol, 50kV, 5 degrees/min, from 0 degree to 40 degree, peak position: 9.8 °, 11.8 °, 15.1 °, 19.8 ° of the angles of diffraction (2 θ)).

Fig. 3 is the x-ray diffractogram of powder of the solid pharmaceutical composition made in embodiment 1.

Fig. 4 means the figure of the stripping curve of test example 2.

Fig. 5 means the figure of the stripping curve of test example 3.

Fig. 6 means the figure of rheological parameters' change with time of Plasma of the known compound A of test example 5.

Fig. 7 means the figure of the stripping curve of test example 6.

The mode carrying out an invention

Below, solid pharmaceutical composition of the present invention is elaborated.

In present disclosure, " episome of known compound A " refers to the state that known compound A exists not form the mode of cocrystallization body in drugs in solid compositions.

In this description, " the cocrystallization body of known compound A and L-PROLINE " refers to the cocrystallization body that known compound A and L-PROLINE form with the mol ratio of 1:1.The evaluation of cocrystallization body structure is illustrated by the result of differential scanning calorimetry (DSC) analysis (dsc analysis) and/or powder X-ray diffraction etc.For example, in patent documentation 2, disclose, in the situation of powder X-ray diffraction, using the angle of diffraction of collection of illustrative plates (2 θ (°)) and relative intensity as the feature (table 1, table 2) of the cocrystallization body of known compound A and L-PROLINE.In addition, for powder X-ray diffraction, data in nature, importantly spacing of lattice and whole pattern in the establishing identity of crystallization; For relative intensity, may be because of the direction of crystalline growth, the size of particle, condition determination slightly change, therefore should not resolve closely.In addition,, in X-ray diffraction, even if there is the distinctive peak of known compound A structure, if little of ignoring completely, also regarding as is the cocrystallization body of known compound A and L-PROLINE.

[table 1]

The angle of diffraction of the crystallization of table 1: known compound A (2 θ (°)) and relative intensity

The angle of diffraction	Relative intensity	The angle of diffraction	Relative intensity
				9.80	Medium	18.8	By force
11.9	Medium	20.1	By force
				15.4	Medium	23.9	By force

[table 2]

The angle of diffraction of the cocrystallization body of table 2: known compound A and L-PROLINE (2 θ (°)) and relative intensity

The angle of diffraction	Relative intensity	The angle of diffraction	Relative intensity
				4.14	Medium	17.5	By force
8.98	Medium	18.7	By force
				12.4	Medium	20.5	By force
16.5	Medium	21.5	Medium

Powder X-ray diffraction is measured according to following condition.

Standard test: use " MAC Science MXP18TAHF22 ", manage ball: Cu, tube current: 200mA, tube voltage: 40kV, sampling width: 0.020 °, scanning speed: 3 °/minute, wavelength: measure angle of diffraction scope (2 θ): under the condition of 3～40 °, measure.°

In this description, " good stripping property " refers to have and immediate release preparation equal extent or the stripping property suitable with it.For example, stipulate that when carrying out dissolution test by the dissolution test method of recording in the 15th revised edition of Japanese Pharmacopoeia, the dissolution rate of the known compound A after 30 minutes is more than 60%

In this description, " stripping stability " refers to for known compound A is the degree that BA does not change in fact from the stripping property of medical composition.For example, stipulate when carrying out dissolution test by the dissolution test method of recording in the 15th revised edition of Japanese Pharmacopoeia, compare with preserving while starting, the rheological parameters' change with time of the dissolution rate of known compound A is few.As another form, the difference of stipulating to start the dissolution rate after 30 minutes for the dissolution test after preserving with preserve before compare in ± 15%.As preservation condition, preserve 2 weeks, 1 month, 2 months, 3 months or 6 months at for example can exemplifying 40 ℃.

Solid pharmaceutical composition of the present invention is using known compound A and crystalline cellulose and/or cross-linking sodium carboxymethyl cellulose as essential constituent.In addition, as another form, using known compound A and L-PROLINE and crystalline cellulose and/or cross-linking sodium carboxymethyl cellulose as essential constituent.

In solid pharmaceutical composition of the present invention, known compound A does not form cocrystallization body.Here, " known compound A does not form cocrystallization body with L-PROLINE " refers in the situation of the powder X-ray diffraction of measuring solid pharmaceutical composition and almost do not observe the peak that derives from cocrystallization body.Specifically, stipulate as with Cu K alpha ray, 50kV, 5 degrees/min, when the condition of the measurement range of 0 degree to 40 degree is measured powder X-ray diffraction near discovery feature peak not 8.9 °, 12.3 °, 17.4 ° and 20.5 ° of the angles of diffraction (2 θ).

As another form, regulation for Cu K alpha ray, 50kV, 5 °/minute, when the condition of the measurement range of 0 ° to 40 ° is measured powder X-ray diffraction, near 9.8 °, 11.8 °, 15.1 ° or 19.8 ° of the angles of diffraction (2 θ), find the characteristic peak of the crystallization of known compound A.As another form, refer to while measuring DSC with the condition of 20 ℃/min of programming rates to there is endothermic peak near deriving from 145～150 ℃ of known compound A.As another form, refer to while measuring DSC with the condition of 20 ℃/min of programming rates, near approximately 209 ℃ of cocrystallization body of deriving from known compound A and L-PROLINE, there is not endothermic peak.

In the present invention, known compound A used is following formula I

[changing 1]

Expression, chemistry (1S)-1 by name, 5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol (below also referred to as " C-glycocide derivant A " or referred to as " known compound A ").Known compound A forms the cocrystallization body structure with L-PROLINE as follows shown in formula II.

[changing 2]

This cocrystallization body has endothermic peak in 201～213 ℃ in dsc analysis, and/or in powder X-ray diffraction in 2 θ (°) there is peak near 4.14,8.98,12.4,16.5,17.5,18.7,20.5 and 21.5.

The angle of diffraction of the cocrystallization body of known compound A and known compound A and L-PROLINE in can composing by x-ray diffractogram of powder (2 θ (°)) and relative intensity or the peak position based on DSC collection of illustrative plates etc. as feature differentiation.

Known compound A can consider that for people's clinical administration amount (treatment effective dose) applicable patient's symptom, body weight, age and sex etc. suitably determine, conventionally oral in the situation that, per day for adults 0.1～500mg, by its 1 time or minute give for several times.Dosage has change according to various conditions, sometimes just enough lower than the amount of above-mentioned dosage scope

The present invention's crystalline cellulose used refers to by the alpha-cellulose being obtained by fibrous plant slurrying being carried out to partial solution coalescence with acid and carries out the material (the 15th revised edition of Japanese Pharmacopoeia) that purification obtains.In addition, so long as the good stripping property allowing on pharmacopedics, can maintain known compound A and the material of stripping stability, the use of crystalline cellulose can be not particularly limited its bulk density and average degree of polymerization etc.Specifically, comprise CEOLUS PH101, CEOLUS PH102, CEOLUS PH101D, CEOLUS KG802, CEOLUS UF711, CEOLUS UF702, CEOLUS KG1000, CEOLUS PH301, CEOLUS PH301D, CEOLUS PH301Z, CEOLUS PH302, CEOLUS PH F20JP (being Asahi Kasei Corporation (Asahi Chemical Industry)), Avicel PH101, Avicel PH112, Avicel PH113, Avicel PH200, Avicel PH301, Avicel PH302, Avicel HFE-102, Avicel (being FMC biopolymer company (FMC Biopolymer)), Celex101 (International Specialty Products company (International Specialty Products)), Emcocel90M (the auspicious Mel father and son company (J.Rettenmaier & Sohne) of stepping on), Vivacel12 (the auspicious Mel father and son company of stepping on), セ Le Off ィア (San-Ei Gen F.F.I., Inc. (three Sakae source エ Off エ Off アイ)) etc.

Being shaped as of crystalline cellulose is granular, needle-like etc., is not particularly limited.Also after acicular crystal cellulose can being pulverized, use.Crystalline cellulose also can be used as the commercially available product of the mixture forming with other additives (chondrus ocellatus Holmes polysaccharide, sodium carboxymethyl cellulose, guar gum etc.) Composite.Being shaped as when granular of crystalline cellulose, mean diameter is preferably 20～200 μ m while measuring by the method 2 (sieve method) of the powder granularity algoscopy of recording in Japanese Pharmacopoeia.The different crystalline celluloses such as grade, shape, mean diameter can be used a kind, also can be appropriately combined two or more use.

The incorporation of crystalline cellulose is so long as common known compound A can show the amount of good stripping property, be not particularly limited, in medical composition of the present invention, be for example below above 90 % by weight of 5 % by weight, another form is below above 70 % by weight of 20 % by weight, weight with respect to known compound A is below above 1500 % by weight of 20 % by weight, another form is below above 1100 % by weight of 50 % by weight, and another form is below above 350 % by weight of 40 % by weight again.

Cross-linking sodium carboxymethyl cellulose is the sodium salt (the 15th revised edition of Japanese Pharmacopoeia) of cellulosic multivalence carboxymethyl ester cross-linking agent.In addition, cross-linking sodium carboxymethyl cellulose so long as the material allowing on pharmacopedics be not particularly limited.Specifically, comprise Ac-Di-Sol (FMC biopolymer company) and Kiccolate (Asahi Kasei Corporation) etc.

The incorporation of cross-linking sodium carboxymethyl cellulose is so long as common known compound A can show the amount of good stripping property, be not particularly limited, in medical composition of the present invention, be for example below above 90 % by weight of 5 % by weight, another form is below above 70 % by weight of 20 % by weight, weight with respect to known compound A is below above 1500 % by weight of 20 % by weight, another form is below above 1100 % by weight of 50 % by weight, and another form is below above 350 % by weight of 40 % by weight again.

In the situation that crystalline cellulose is used together with cross-linking sodium carboxymethyl cellulose, take their total amount in medical composition more than 5 % by weight below 90 % by weight, in another form, more than 5 % by weight, the condition below 70 % by weight is used.

In addition, in solid pharmaceutical composition of the present invention, also can suitably use as required various auxiliary pharmaceutical adjuvants.As this auxiliary pharmaceutical adjuvant, so long as the auxiliary pharmaceutical adjuvant above allowing with pharmacology on pharmacopedics is not particularly limited.For example, can use excipient, binding agent, disintegrating agent, acidic flavoring agent, foaming agent, artificial sweetening agent, spice, lubricant, coloring agent, stabilizing agent, buffer agent, antioxidant, surfactant, coating materials etc.

As excipient, can exemplify D-mannital, lactose etc.

As binding agent, can exemplify such as hydroxypropyl emthylcellulose, hydroxypropyl cellulose, Radix Acaciae senegalis etc.

As disintegrating agent, can exemplify such as corn starch, potato starch, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, part alphalysed starch, polyvinylpolypyrrolidone, sodium starch glycollate etc.

As acidic flavoring agent, can exemplify such as citric acid, tartaric acid, malic acid etc.

As foaming agent, can exemplify such as sodium bicarbonate etc.

As artificial sweetening agent, can exemplify, stevioside sweet such as saccharin sodium, glycyrrhizic acid dipotassium, A Siba, sweet protein etc.

As spice, can exemplify such as Fructus Citri Limoniae, lemon green lemon, orange, menthol etc.

As lubricant, can exemplify such as magnesium stearate, calcium stearate, sucrose fatty acid ester, Polyethylene Glycol, Talcum, stearic acid etc.

As coloring agent, can exemplify for example iron oxide yellow, iron oxide red, edible yellow No. 4, No. 5, edible red No. 3, No. 102, edible blue No. 3 etc.

As buffer agent, can exemplify citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or its esters, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or its esters, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or its esters etc.

As antioxidant, can exemplify such as ascorbic acid, dibenzylatiooluene, propyl gallate etc.

As surfactant, can exemplify such as polyoxyethylene sorbitan monoleate (Tween 80), sodium lauryl sulphate, polyoxyethylene hardened castor oil etc.

As coating materials, can exemplify such as Pulvis Talci, Polyethylene Glycol, hydroxypropyl emthylcellulose, titanium oxide etc.

As auxiliary pharmaceutical adjuvant, can suitably add in right amount one kind or two or more combination.

The incorporation of auxiliary pharmaceutical adjuvant is 0.1～70 % by weight in medical composition of the present invention.

For solid pharmaceutical composition of the present invention, can be by (1) by (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol and crystalline cellulose and/or cross-linking sodium carboxymethyl cellulose mixing, and (2) by the mixture compression molding of gained, thereby make required form.In addition, can comprise that the mixture to recording in (2) carried out wet granulation before the operation of compression molding, acquisition comprise do not form cocrystallization body state should (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] operation of granules of-D-glucitol.

In addition, solid pharmaceutical composition of the present invention can be by comprising that (1) is by (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol and crystalline cellulose and/or the cross-linking sodium carboxymethyl cellulose operation of mixing and (2) mixture of gained is carried out to wet granulation and obtain comprise not with L-PROLINE form cocrystallization body state should (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] the method manufacture of operation of granules of-D-glucitol.In addition, also the granules compression molding of gained (operation (3)) can be made to required form.

Wet granulation is when pelletize, to add the prilling process that solvent carries out, the various comminution granulations such as known stirring-granulating method, fluidized bed comminution granulation, rotation comminution granulation and kneading comminution granulation.

While using above-mentioned various auxiliary pharmaceutical adjuvant as required, this auxiliary pharmaceutical adjuvant can be in (1) operation, in (1) operation and (2) inter process, (2) operation and any stage such as (2) operation and (3) inter process add.

The cocrystallization body of known compound A and L-PROLINE, cellulose derivative and arbitrarily auxiliary pharmaceutical adjuvant can carry out respectively pulverizing process before mixed processes, are adjusted into size arbitrarily.Pulverizing process is so long as conventionally can, by the method for medicine and/or auxiliary pharmaceutical adjuvant pulverizing, all be not particularly limited device, method on pharmacopedics.The mixed processes of each composition after pulverizing is so long as the method that conventionally each composition can be mixed equably on pharmacopedics, to installing, method is all not particularly limited.

In wet granulation, to adding solvent in the cocrystallization body of known compound A and L-PROLINE and the mixture of cellulose derivative, carry out pelletize.Solvent comprises such as water, ethanol, methanol or their mixed solvent etc.In solvent, can comprise binding agent (that is, binder solution).The interpolation speed of solvent (or binder solution) is because of the scale difference of prilling process or manufacture, for example, while utilizing wet granulation method to manufacture with the scale of 1kg, can add solvent (or binder solution) by the speed that in 1～30g/ minute, another form is 5～20g/ minute.In addition, also can adopt in advance and add binding agent in the mixture of the cocrystallization body that comprises known compound A and L-PROLINE and cellulose derivative, on one side the form that then solubilizer carries out pelletize on one side.

In wet granulation, with respect to the cocrystallization body of 100 weight portion known compound A and L-PROLINE, can use that above 400 weight portions of 50 weight portions are following, be the solvents below above 330 weight portions of 80 weight portions in another form.

In the situation that solid pharmaceutical composition of the present invention is made by the cocrystallization system of known compound A and L-PROLINE, in solid pharmaceutical composition, known compound A and L-PROLINE do not form cocrystallization body.That is, by with above-mentioned condition wet granulation, in pelletize, L-PROLINE departs from from cocrystallization body structure, thereby known compound A forms episome and maintains the state of its episome.

From promoting the angle of the disengaging of the L-PROLINE pelletize, be better to carry out pelletize by stirring-granulating.In stirring-granulating, strong shearing force is applied in granulation thing, infers that this strong shearing force promotes the disengaging of L-PROLINE.

The granules of making as mentioned above can be made into the various preparations such as tablet, capsule, powder, granule and dry syrup.In the example having, solid pharmaceutical composition of the present invention is tablet.

Various preparations can be manufactured by known method.For example, can be dry by comprising, the known method of the operation such as tabletting and film coating manufactures various preparations.

For example, prepared granules can be dried by any means.マ Le チプレッ Network ス) and the drying device such as clothes hanger formula drying machine for example, can use fluidized bed drying machine, Multiplex drying machine (Japanese:.Baking temperature is for example 40～90 ℃.Then, the granules of drying is carried out to tabletting and manufacture tablet.As tabletting method, so long as manufacture the method for compression molding thing on common pharmacopedics, be not particularly limited.Can exemplify after disintegrating agent and mix lubricant are entered to granules and carry out method of tabletting etc.As preforming device, so long as manufacture the method for compression molding thing on common pharmacopedics, device is also not particularly limited, can exemplify such as rotary tablet machine, single-stroke tablet machine etc.Tablet hardness is for example 40～250N, is 50～200N in another form.

Can also carry out film coating to the tablet surface after tabletting.As its method, so long as the coating method on common pharmacopedics is not particularly limited.Can exemplify such as pan coating method etc.As film coating agent, so long as can carry out the medicine additive of coating on common pharmacopedics, be not particularly limited.As film coating agent, can suitably add in right amount one kind or two or more combination.

For coating rate, as long as can carry out coating to common tablet surface, be not particularly limited.For example, the former weight with respect to the tablet as before coating is below above 5.0 % by weight of 1.0 % by weight.

As the manufacture method of solid pharmaceutical composition of the present invention or its pharmaceutical preparation, so long as the method for appropriately combined above-mentioned record or known method itself, manufacture the method for the pharmaceutical preparation with the desired effect of the present invention, be not particularly limited.

Embodiment

Below, the present invention will be described in more detail to exemplify embodiment, comparative example and test example, but the present invention is not limited thereto.The cocrystallization body of known compound A and L-PROLINE adopts the cocrystallization body of manufacturing according to the method for recording in No. 2007/114475 text of International Publication.In addition, known compound A is used the compound of manufacturing according to the method for recording in International Publication WO2004/080990 text.

< embodiment 1>

By the cocrystallization body of 1.8g known compound A and L-PROLINE and 1.8g crystalline cellulose (goods name: CEOLUS PH101, Asahi Kasei Corporation's system, down together) after mixing, add about 3g water and carry out wet method stirring-granulating (prilling granulator (pony mixer, Xie Li science and engineering Co., Ltd. (AssociationLi science and engineering Co., Ltd.) system), the approximately 1 minute pelletize time).Granules to gained is dried (40 ℃, 12 hours), makes solid pharmaceutical composition of the present invention.

< embodiment 2>

Except use 1.8g cross-linking sodium carboxymethyl cellulose (goods name: Ac-Di-Sol, FMC biopolymer company system, lower with) replace, outside crystalline cellulose, making similarly to Example 1 solid pharmaceutical composition of the present invention.

< comparative example 1～7>

Except using respectively D-mannital (goods name: Pearitol, Lip river Kate company (Roquette) system, lower same), hydroxypropyl emthylcellulose (goods name: TC5E, Shin-Etsu Chemial Co., Ltd's (SHIN-ETSU HANTOTAI's chemistry) system), hydroxypropyl cellulose (goods name: HPC-L, Tso Tat Co., Ltd., Japan (this Cao of Da) system), Polyethylene Glycol (goods name: PEG6000, Sanyo Chemical Industries, Ltd.'s (Sanyo changes into) system), copolyvidone (goods name: Kollidon K30, BASF AG (BASF society) system, goods name: KollidonVA64, BASF AG's system) and poly(ethylene oxide) (goods name: Polyox, Dow Chemical (DowChemical society) system) replace outside crystalline cellulose, make similarly to Example 1 the solid pharmaceutical composition of comparative example 1～7.

The crystalline evaluation of < test example 1>

For the solid pharmaceutical composition of manufacturing in embodiment 1, embodiment 2 and comparative example 1～7, after just making, (preserve while starting) and 40 ℃, 75% relative humidity under carry out powder X-ray diffraction mensuration after preserving 1 month.

In the solid pharmaceutical composition of embodiment 1 and embodiment 2, after just making and after preserving, do not observe the peak corresponding with the cocrystallization body of known compound A and L-PROLINE, 9.8 °, 11.8 °, 15.1 °, 19.8 ° of the angle of diffraction corresponding to the crystallization with known compound A (2 θ), observe peak on the other hand.The x-ray diffractogram of powder of embodiment 1 is shown in Fig. 3.Therefore, can think in embodiment 1 and embodiment 2, in pelletize, L-PROLINE departs from from cocrystallization body structure, thereby known compound A forms episome.

In the solid pharmaceutical composition of comparative example 1～7, same with Fig. 1,8.9 °, 12.3 °, 17.4 °, 20.5 ° of the angles of diffraction (2 θ), observe the peak corresponding with the cocrystallization body of known compound A and L-PROLINE, so can think that known compound A and L-PROLINE form cocrystallization body structure.

< embodiment 3>

Formula based on table 3 is made tablet (numeral in table is the weight (mg) of used each composition).

By cocrystallization body, cross-linking sodium carboxymethyl cellulose, D-mannital and hydroxypropyl cellulose (the goods name: HPC-SL of known compound A and L-PROLINE, Tso Tat Co., Ltd., Japan's system, down together) after mixing, the condition that is 84 weight portions according to the cocrystallization body of every 100 weight portion known compound A and L-PROLINE is added water and carries out wet method stirring-granulating (prilling granulator (pony mixer, Xie Li science and engineering Co., Ltd. system), the approximately 2 minutes pelletize time).Granules to gained is dried (40 ℃, 12 hours), mixes magnesium stearate tabletting, obtains solid pharmaceutical composition of the present invention (pestle footpath: 9.5mm).

< comparative example 8>

Formula based on table 3 is made tablet.

Except using low degree of substitution hydroxypropyl cellulose (L-HPC) (goods name: LH-11, Shin-Etsu Chemial Co., Ltd's system) to replace, outside cross-linking sodium carboxymethyl cellulose, making similarly to Example 3 the solid pharmaceutical composition of comparative example.

< comparative example 9>

Formula based on table 3 is made tablet.

Except using polyvinylpolypyrrolidone (material name: Kollidon CL, BASF Japanese firm system) to replace, outside cross-linking sodium carboxymethyl cellulose, making similarly to Example 3 the solid pharmaceutical composition of comparative example.

[table 3]

Table 3

The evaluation of < test example 2> stripping property

For the solid pharmaceutical composition of embodiment 3, comparative example 8 and comparative example 9, carry out the dissolution test of the tablet after preparation has just been made.Dissolution test carries out according to the oar method of recording in the 15th revised edition of Japanese Pharmacopoeia.Experimental liquid adopts 900mL the first dissolution test liquid (hydrochloric acid of 0.1N).The rotating speed of oar adopts 50 revs/min.After on-test, the dissolution rate of the known compound A of 30 minutes is shown in table 4.In addition, stripping curve is illustrated in Fig. 4.

[table 4]

Table 4

Tablet	Dissolution rate (%)
		Embodiment 3	93
Comparative example 8	17
		Comparative example 9	20

< embodiment 4>

Formula based on table 5 is made tablet (numeral in table is the weight (mg) of used each composition).

The cocrystallization body of known compound A and L-PROLINE, cross-linking sodium carboxymethyl cellulose, crystalline cellulose and hydroxypropyl cellulose are dropped into stirring granulating machine (VG01; Pa Laike Co., Ltd. (パウレック society) system), in the time of water spray, carry out stirring-granulating.Granules to gained is dried (40 ℃, 12 hours), with the sieve of the mesh size 710 μ m granulate that sieves, obtains granule.In granule, mix magnesium stearate, tabletting and obtain solid pharmaceutical composition of the present invention.

< comparative example 10>

Use cocrystallization body, D-mannital, hydroxypropyl cellulose and the magnesium stearate of known compound A and L-PROLINE, obtain similarly to Example 4 the solid pharmaceutical composition of comparative example.

[table 5]

Table 5

The evaluation of < test example 3> stripping property

For the solid pharmaceutical composition of embodiment 4 and comparative example 10, the dissolution test of the tablet of (initially) after similarly just having made with test example 2.Stripping curve is illustrated in Fig. 5.In addition,, for embodiment 4, be illustrated in the stripping curve of 40 ℃ standing 2 weeks rear (40 ℃ of 2W).

< embodiment 5>

Formula based on table 6 is made solid pharmaceutical composition (numeral in table is the weight (mg) of used each composition).

After the cocrystallization body of known compound A and L-PROLINE, cross-linking sodium carboxymethyl cellulose, crystalline cellulose, hydroxypropyl cellulose and magnesium stearate are mixed, add the water of about 290g and carry out stirring-granulating (prilling granulator (VG05, Pa Laike Co., Ltd.), the 12 minutes pelletize time).The granules of gained is dried to (approximately 60 ℃ with drying machine, approximately 1 hour), with rotary tablet machine, be shaped, then use film coating agent (OPADRY blocks happy Kanggong department (カラコン society) and makes) coating and make solid pharmaceutical composition of the present invention.

[table 6]

Table 6

Composition	Embodiment	5
			The cocrystallization body of known compound A and L-PROLINE	128.5
Crystalline cellulose	187.1
		Ac-Di-Sol	30.0
HPC-SL	10.8
		Magnesium stearate	3.6
Film coating agent	10.8
		Add up to	370.8

The evaluation of < test example 4> stripping property and stripping stability

For the solid pharmaceutical composition of making in embodiment 5, the dissolution test of the compositions of (at 40 ℃ 1 month, 2 months, 3 months, 6 months) after similarly just having made with test example 2 and after preserving.The results are shown in table 7.

[table 7]

Table 7

< test example 5> dog oral test

By the solid pharmaceutical composition of making in embodiment 5 and crystalline cellulose suspension (form: the cocrystallization body that makes 128.5mg known compound A and L-PROLINE be suspended in 10mL0.5% methylated cellulose aqueous solution and solution) dog is carried out to oral administration (N=6), through time measure the Plasma of known compound A, evaluate absorbability.The results are shown in Fig. 6 (in figure, " Tab " represents the absorbability of solid pharmaceutical composition, and " MCsus " represents the absorbability of methylcellulose suspension).

Consequently, the AUC of the solid pharmaceutical composition of embodiment 5 is 121% with respect to the AUC of methylcellulose suspension.Therefore, solid pharmaceutical composition of the present invention also demonstrates good absorbability in testing in vivo.

From test example 2～5, comprise the solid pharmaceutical composition that known compound A and L-PROLINE and crystalline cellulose and/or cross-linking sodium carboxymethyl cellulose and known compound A and L-PROLINE do not form cocrystallization body and demonstrate good stripping property and stripping stability.Known compound A is considered to be cocrystallization body structure by the hydrogen bond based on OH base and L-PROLINE, thus infer that the hydrogen bond formation between known compound A and L-PROLINE is hindered, thereby known compound A maintains episome.

< embodiment 6>

Formula based on table 8 is made tablet (numeral in table is the weight (mg) of used each composition).

After known compound A, crystalline cellulose and cross-linking sodium carboxymethyl cellulose are mixed, with single-stroke tablet machine, be shaped, make tablet of the present invention.

[table 8]

Table 8

Composition	Embodiment 6
		Known compound A	128.5
Crystalline cellulose	187.1
		Ac-Di-Sol	30
HPC-SL	10.8
		Magnesium stearate	3.6
Add up to	360

The evaluation of < test example 6> stripping property

For the tablet of making in embodiment 6, the dissolution test of the compositions after similarly just having made with test example 2.Result of the test is shown in Fig. 7.

Claims

1. solid pharmaceutical composition, it is characterized in that, comprise (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol and crystalline cellulose and/or cross-linking sodium carboxymethyl cellulose, should (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol do not form cocrystallization body.

2. solid pharmaceutical composition as claimed in claim 1, is characterized in that, also comprises L-PROLINE.

3. solid pharmaceutical composition as claimed in claim 1 or 2, is characterized in that, the amount of crystalline cellulose and/or cross-linking sodium carboxymethyl cellulose is more than 5 % by weight below 90 % by weight in medical composition.

4. the solid pharmaceutical composition as described in any one in claim 1～3, it is characterized in that, in the dissolution test of recording in the 15th revised edition of Japanese Pharmacopoeia, (1S)-1 in the time of 30 minutes more than 60%, 5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol stripping.

5. the solid pharmaceutical composition as described in any one in claim 2～4, it is characterized in that, said composition is by (1S)-1,5-dehydration-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl] cocrystallization body, crystalline cellulose and/or the cross-linking sodium carboxymethyl cellulose of-D-glucitol and L-PROLINE and be that water below above 400 weight portions of 50 weight portions is manufactured by wet granulation with respect to this cocrystallization body of 100 weight portions.

6. the solid pharmaceutical composition as described in any one in claim 1～5, is characterized in that, solid pharmaceutical composition is tablet.

7. the manufacture method of solid pharmaceutical composition, is characterized in that, comprising:

(2) by the operation of the mixture compression molding of gained.

8. the manufacture method of solid pharmaceutical composition as claimed in claim 7, is characterized in that, comprising:

9. the manufacture method of solid pharmaceutical composition, is characterized in that, comprising:

10. manufacture method as claimed in claim 9, is characterized in that, with respect to 100 weight portion cocrystallization bodies, uses the water below above 400 weight portions of 50 weight portions to carry out wet granulation.

11. manufacture methods as claimed in claim 10, is characterized in that, also comprise that (3) carry out the operation of compression molding to granules.

12. manufacture methods as described in any one in claim 7～11, is characterized in that, solid pharmaceutical composition is tablet.