WO2007129522A1

WO2007129522A1 - Preparation produced by dry process

Info

Publication number: WO2007129522A1
Application number: PCT/JP2007/057832
Authority: WO
Inventors: Naoki Wakiyama; Tomoyuki Watanabe; Atsutoshi Ito
Original assignee: Daiichi Sankyo Company, Limited
Priority date: 2006-04-10
Filing date: 2007-04-09
Publication date: 2007-11-15
Also published as: TW200810767A

Abstract

Disclosed is a pharmaceutical composition comprising a fructose 1,6-bisphosphatase (FBPase) inhibitor, which has excellent drug dissolution property, drug content uniformity, mass uniformity, hardness and wear resistance. Also disclosed is a solid preparation comprising the step of formulating a composition comprising a fructose 1,6-bisphosphatase inhibitor into a preparation by a dry process.

Description

Specification

Dry formulation

Technical field

[0001] The present invention relates to a solid preparation comprising a step of formulating a composition containing a fructose 1,6-bisphosphatase (FBPase) inhibitor by a dry production method. Background art

[0002] The FBPase inhibitor is a therapeutic agent and Z or preventive agent for diabetes, hyperglycemia, glucose intolerance, obesity, diabetic complications, etc. (preferably a therapeutic agent and Z or preventive agent for diabetes). It is a drug expected as such (see Patent Document 1).

In the prior art, there is no known solid preparation characterized by including a step of formulating a composition containing the FBPase inhibitor of the present invention by a dry production method. Patent Document 1: Pamphlet of International Publication No. 2001/047935

Disclosure of the invention

Problems to be solved by the invention

[0004] An object of the present invention is to provide a solid preparation containing an FBPase inhibitor and excellent in drug dissolution, content uniformity, mass uniformity, hardness and abrasion resistance.

Means for solving the problem

[0005] As a result of diligent research to solve the above problems, the present inventors include a step of formulating a composition containing an FBPase inhibitor by a dry production method. As a result, it was found that the drug dissolution and content uniformity, mass uniformity, hardness and abrasion resistance were improved, and the present invention was completed.

[0006] The present invention includes a solid preparation (particularly a preparation for the prevention or treatment of diabetes) characterized by comprising a step of formulating a composition containing an FBPase inhibitor by a dry production method, Use of an FBPase inhibitor to produce a preparation (especially a preparation for the prevention or treatment of diabetes), and a solid preparation containing a pharmacologically effective amount of an FBPase inhibitor to a warm-blooded animal (particularly human) The present invention provides a method for the prevention or treatment of diseases (particularly diabetes) administered to).

That is, the present invention provides: (1) A solid preparation characterized in that a composition containing an FBPase inhibitor is formulated in a process including a dry production method. However, the above FBPase inhibitor has the following general formula (I)

[Chemical 1]

(I)

[Wherein, X ^a represents a nitrogen atom, an oxygen atom or a sulfur atom, R ^la represents a hydrogen atom, a halogen atom, a C1-6 alkyl group or an amino group (the amino group is a C1-6 alkyl group, 1 or 2 R ^2a and R ^3a are the same or different and each represents a hydrogen atom or a C1-4 alkyl group, R ^4a represents a C 1-4 alkyl group, and R ^5a represents A hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkylthio group; Or a pharmacologically acceptable salt thereof.

(2) The solid preparation according to the above (1), wherein X ^a represents ^a sulfur atom, R ^la represents an amino group, and R ^5a represents a C1-4 alkyl group,

(3) Phosphoric acid amide compound power Jetyl N, N '-[5- (2-Amino-5-isobutyl-1,3-thiazol-4-yl) -2-furylphosphonoyl] di-L -The solid preparation according to the above (1) which is an alcoholate or a salt thereof,

(4) The solid preparation according to any one of (1) to (3) above, wherein the FBPase inhibitor elution is improved by formulating in a process including a dry production method,

(5) The solid preparation according to any one of the above (1) to (3), wherein disintegration is improved by formulating in a process including a dry production method,

(6) The solid preparation according to any one of (1) to (5) above, wherein the dry production method is a dry granulation method,

(7) The solid preparation according to (6) above, wherein the content uniformity and mass uniformity have been improved by formulating in a process including a dry granulation method, (8) The solid preparation according to (6) above, wherein in the granulation step of the dry granulation method, the hardness and abrasion resistance are increased by reducing the density of the powder before pulverization. ,

(9) The solid preparation according to (8), having a hardness of 5.0 kg or more,

(10) The solid preparation according to any one of (1) to (5) above, wherein the dry production method is a direct tableting method,

(11) The solid preparation according to any one of the above (1) to (10), wherein the preparation is a tablet,

(12) The solid preparation according to any one of (1) to (11) above, which is a preventive or therapeutic agent for diabetes,

(13) The dissolution property of the FBPase inhibitor is improved, comprising a step of producing the solid preparation according to any one of (1) to (12) above by a dry production method. A method for producing a solid preparation,

(14) A solid preparation with improved disintegration, characterized by comprising a step of preparing the solid preparation according to any one of (1) to (12) above by a dry production method Production method,

(15) The production method according to the above (13) or (14), wherein the dry production method is a dry granulation method,

(16) The production method according to (15) above, wherein content uniformity and mass uniformity are improved by using a dry granulation method,

(17) In the granulation step of the dry granulation method, by reducing the density of the powder before pulverization, hardness and wear resistance are increased, the production method according to (15) above,

(18) The production method according to (17), wherein the hardness is 5.0 kg or more,

(19) The production method according to the above (13), wherein the dry production method is a direct tableting method,

(20) improving the dissolution of an FBPase inhibitor, comprising a step of producing the solid preparation according to any one of (1) to (12) above by a dry production method Method,

(21) A method for improving the disintegration property of a solid preparation, comprising a step of producing the solid preparation according to any one of (1) to (12) above by a dry production method ,

(22) The method according to (20) or (21) above, wherein the dry production method is a dry granulation method,

(23) The method according to (20) or (21) above, wherein the dry production method is a direct tableting method,

(24) A solid preparation comprising a step of formulating a composition containing an FBPase inhibitor in a step including a dry production method. [0010]

In the present invention, the “FBPase inhibitor” is not particularly limited as long as it is a drug that inhibits the action of FBPase (fructose 1,6-bisphosphatase), but for example, in WO 00/14095 pamphlet And the compounds described in International Publication No. 01/47935 pamphlet, and the phosphoric acid ester amide compounds having a prodrug skeleton of the phosphoric acid ester amide described in the above patent document are particularly preferable. Include jetyl N, Ν '-[5- (2-amino-5-isobutyl-1,3-thiazol-4-yl) -2-furylphosphonol] di-L-alaninate and its salts. is there.

The invention's effect

[0011] According to the present invention, it is possible to provide a solid preparation containing an FBPase inhibitor as an active ingredient and having improved FBPase inhibitor elution.

[0012] The solid preparation of the present invention can be used, for example, for the treatment and Z or prevention of diabetes, hyperglycemia, glucose intolerance, obesity, diabetes complications, etc. (preferably treatment and Z or prevention of diabetes). It is valid.

[0013] Furthermore, the solid preparation of the present invention is excellent in content uniformity, mass uniformity, hardness and abrasion resistance of the FBPase inhibitor. Therefore, the solid preparation of the present invention is useful as a preparation having good quality and stable drug efficacy with little variation in FBPase inhibitor content per single preparation (for example, one tablet).

BEST MODE FOR CARRYING OUT THE INVENTION

[0014] The active ingredient of the solid preparation of the present invention is an FBPase inhibitor.

[0015] As the "FBPase inhibitor" that is an active ingredient in the solid preparation of the present invention, various drugs have been proposed, and those skilled in the art can select an appropriate drug that exhibits the effects of the present invention. is there. Such FBPase inhibitors include, for example, general formula (I)

[0016] [Chemical 2]

[In the formula, X ^a represents a nitrogen atom, an oxygen atom or a sulfur atom, R ^la represents a hydrogen atom, a halogen atom, a C1-6 alkyl group or an amino group (the amino group is a C1-6 alkyl group) 1 or 2 may be substituted), R ^2a and R ^3a are the same or different and represent a hydrogen atom or a C1-4 alkyl group, R ^4a represents a C 1-4 alkyl group, R ^5a represents a hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkylthio group. Or a pharmacologically acceptable salt thereof

More preferably, the general formula (la)

[0018] [Chemical 3]

[In the formula, R ^la represents an amino group (the amino group may be substituted with one or two C1-6 alkyl groups), and R ^3a represents a hydrogen atom or a C1-4 alkyl group. R ^½ represents a C 1-4 alkyl group. ], Jetyl N, N '-[5- (2-Amino-5-propylthio-1,3-thiazol-4-yl) -2-furylphosphonoyl] di-L-ala -Nate or pharmacologically acceptable salt thereof. Particularly preferred is jetyl N, N ′-[5- (2-amino-5-isobutyl-1,3-thiazol-4-yl) -2-furylphosphonoyl] di-L-ara. -Nate or pharmacologically acceptable salt thereof. [0020] The compounds represented by the general formulas (1) and (la) and pharmacologically acceptable salts thereof are described in WO 01/47935 and can be produced.

[0021]

In the present invention, the “Cl-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include the above-mentioned “Cl-4 alkyl group”. N-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3 , 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, or 2-ethylbutyl group R ^la and R ^5a are preferably a linear or branched alkyl group having 1 to 4 carbon atoms.

[0022] The "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and ^Rla is preferably a bromine atom, a chlorine atom or a fluorine atom, and more preferably a bromine atom or a chlorine atom. Is an atom.

[0023] The "C1_4 alkylthio group" is a group to which the "C1_4 alkyl group" is bonded via a sulfur atom. For example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, Examples thereof include an isobutylthio group, a s-butylthio group, and a tert-butylthio group, and R ^5a is preferably an n-propylthio group.

[0024]

In the present invention, X ^a is preferably a sulfur atom.

In the present invention, R ^la is preferably an amino group (which may be substituted with a C 1-6 alkyl group), and more preferably an amino group. It is.

In the present invention, R ^2a is the same or different and is preferably a hydrogen atom.

In the present invention, R ^3a is the same or different and is preferably a C 1-4 alkyl group.

In the present invention, R ^½ is the same or different and is preferably a methyl group or an ethyl group.

[0029] In the present invention, R is preferably a C1-6 alkyl group or a C1-6 alkylthio group, and more preferably a C1-4 alkyl group. [0030]

If necessary, the solid preparation of the present invention may further contain appropriate pharmacologically acceptable excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, and the like. An agent can be included.

[0031] Examples of the "excipient" used include sugar derivatives such as lactose, sucrose, sucrose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, OC-starch or dextrin; Cellulose derivatives such as crystalline cellulose, methylcellulose; gum arabic; dextran; or organic excipients such as pullulan; or silicates such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate Derivatives; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; or inorganic excipients such as sulfates such as calcium sulfate.

[0032] The "lubricant" used is, for example, stearic acid; a stearic acid metal salt such as calcium stearate or magnesium stearate; talc; colloidal silica; a wax such as bead wax or cocoon Boric acid; adipic acid; sulfate such as sodium sulfate; fumarate such as fumaric acid and sodium stearyl fumarate; glycol; sodium benzoate; fatty acid ester such as glycerin fatty acid ester and sucrose fatty acid ester D, L-leucine; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid or silicic acid hydrate; or the above-mentioned starch derivative.

[0033] Examples of the "binder" used include hydroxypropylcellulose, hydroxypropyl pillmethylcellulose, polybulurpyrrolidone, macrogol, synthetic hydrotalcite, or compounds similar to the above-mentioned excipients. Can do.

[0034] Examples of the "disintegrant" used include cellulose derivatives such as low-substituted hydroxypropylcellulose, force-ruboxymethylcellulose, carboxymethylcellulose calcium or sodium carboxymethylcellulose; cross-linked polybutyrididone; or Mention may be made of chemically modified starch such as carboxymethyl starch or carboxymethyl starch sodium. [0035] "Emulsifiers" used include, for example, colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; sodium lauryl sulfate or Anionic surfactants such as calcium stearate; cationic surfactants such as salt benzalkonium; or polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester Nonionic surfactants.

[0036] Examples of the "stabilizer" used include parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenolethyl alcohol; Mention may be made of benzalco-um; phenols such as phenol or talesol; thimerosal; dehydroacetic acid; or sorbic acid.

[0037] Examples of the “flavoring agents” used include sweeteners such as saccharin sodium or aspartame; acidulants such as citrate, malic acid or tartaric acid; or menthol, lemon or orange. A fragrance like this can be mentioned.

[0038] Examples of the "diluent" used include latatose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycolol, Mention may be made of propylene glycolol, glycerol, starch, polybulur pyrrolidone, magnesium aluminate metasilicate or mixtures thereof.

[0039]

Examples of the “solid preparation” in the present invention include tablets (including uncoated tablets, film-coated tablets, sugar-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, Fine granules, powders, pills, lozenges and the like can be mentioned, and preferred are powders, fine granules, granules, capsules or tablets, and most preferred are tablets.

[0040]

The dry production method in the present invention includes a direct tableting method and a dry granulation method.

[0041] The "direct tableting method" is a method for preparing a raw material powder by direct compression molding. “Dry granulation method” means that raw material powder is compression-molded into slug or sheet form, It is a method of formulating using granules produced by crushing and dividing. These manufacturing methods are The T heory and Practice of Industrial Pharmacy (Third Edition (Leon Lachman et al .: LEA & FEBIGER 1986) P.317-320, Pharmaceutical Dosage Forms: Tablets volume 1 (Second Edition) (Herbert A 丄 ieberman et al. : MARCEL DEKKER INC. 1989) P.135-139, P.297.

[0042] Here, granulation refers to an operation for producing granules having a substantially uniform shape and size from raw materials such as powder, lump, solution or liquid melt, and is the final form of granules, powders, fine granules, etc. There are granulations that produce products and granulations that produce intermediate products such as tablets and capsules.

[0043] The compression molding process is a process in which the raw material powder is pressurized by mechanical force to make the raw material powder into a lump, such as a rotary tablet machine (manufactured by Kikusui Seisakusho, Hata Iron Works, Sugawara Seiki Etc.), dry granulators such as roller compactors, roll dullers, chillers, etc. (Freund, Turbo, Kurimoto, Matsubo, Nippon Dura-Yureta, Fuji Powder, etc.) There is. For dry granulation, is not particularly limited density of the compressed powder slugs or the like in the granulating step, usually the upper limit is 4MgZmm ³ or less, as preferably 3MgZmm ³ hereinafter, and further preferably a 2MgZmm ³ or less To do.

[0044] The crushing 'division process is a process of crushing the lump formed in the compression molding process to an appropriate size with a knife' cutter or the like. Examples of the apparatus used include power mill, Fitz mill, Fiore, There are pulverizers such as Comil and granulators (Fuji Padal, Deoksugaku Factory, manufactured by Paurek, etc.).

[0045] The granulated product thus obtained is sized to a desired particle size, and can be made into a preparation in the form of powder, fine granule or granule. The granulated product thus obtained may be provided with at least one coating layer. These preparations can be filled into capsules to form capsules, or further, disintegrating agents, lubricants, etc. are added as necessary, and compressed into tablets using a tableting machine, etc. to form tablet-form preparations. You can also. Operations such as mixing and granulation are all commonly used in the field of pharmaceutical technology, and those skilled in the art can appropriately perform them. Also, the tablet should have at least one coating layer.

[0046]

Coating is performed using, for example, a coating apparatus, and as a coating base Examples include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like.

[0047] As the sugar coating base, sucrose is used, and further, talc, precipitated calcium carbonate, phosphate phosphate, calcium sulfate, gelatin, gum arabic, polybulurpyrrolidone, pullulan, etc., one or two selected A combination of the above can also be used.

[0048] Examples of the water-soluble film coating base include cellulose derivatives such as hydroxypropylcellulose, hydroxypropinoremethinoresenorelose, hydroxyethinoresenorelose, methinorehydroxyethylcellulose, sodium carboxymethylcellulose; Synthetic polymers such as acetal jetylaminoacetate, aminoalkyl methacrylate copolymer, polybulur pyrrolidone, polybulal alcohol; polysaccharides such as pullulan.

[0049] Enteric film coating bases include, for example, cellulose derivatives such as hydroxypropyl methylcellulose phthalate, hydroxypropenolemethinolecellulose acetate succinate, canoleboxymethylethyl cellulose, cellulose acetate phthalate; Examples include acrylic acid derivatives such as copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; and natural products such as shellac.

[0050] Examples of sustained-release film coating bases include cell mouth derivatives such as ethyl cellulose; acrylic acid such as aminoalkyl methacrylate copolymer RS, ethyl acrylate acrylate 'methyl methacrylate copolymer emulsion, etc. Derivatives and the like.

[0051] Two or more of the above coating bases may be mixed and used at an appropriate ratio. Further, if necessary, additives such as appropriate pharmacologically acceptable plasticizers, excipients, lubricants, masking agents, coloring agents, preservatives and the like can be included.

[0052] In the present invention, "hardness" refers to the hardness of a tablet, ie, an uncoated tablet, to which a coating or the like is applied, and the value is a commercially available tablet hardness measuring device (tablet continuous measuring device WHT- 2, etc., manufactured by P harmatest). The hardness of the tablet (plain tablet) is preferably 5.0 kg or more and 20.0 kg or less, more preferably 5.0 kg or more and 17.5 kg or less, and most preferably 5.0 kg or more and 15.0 kg or less.

[0053] The dose of the FBPase inhibitor, which is an active ingredient of the solid preparation of the present invention, depends on the activity of the drug, It may vary depending on various conditions such as a person's symptoms, age, weight, and the like. The dose varies depending on symptoms, age, etc., but in the case of oral administration, it is usually lmg (preferably 10 mg, more preferably 25 mg) as the lower limit for adults, and 2000 mg as the upper limit. (Preferably 400 mg, more preferably 200 mg) can be administered.

Example

[0054] Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited thereto. Jetyl N, N '-[5- (2-Amino-5-isobutyl-1,3-thiazol-4-yl) -2-furylphosphonoyl] di-L-ala-nate (hereinafter referred to as compound) A) can be produced according to the method described in International Publication No. 01/47935.

[0055]

Direct tableting formulation

Compound A (3g), crystalline cellulose (3.66g), low substituted hydroxypropylcellulose (1.8g), hydroxypropylmethylcellulose (0.45g), magnesium stearate (0.09g) were mixed in an agate mortar for 2 minutes The mixture was sieved with a 40 mesh sieve and mixed again with an agate mortar to obtain a mixed powder.

[0056] Next, after adding 300 mg of the obtained mixed powder to a φ 9.0 mm die,

Tableting was performed with a Φ 9.0πιπι2 double R punch and a tableting pressure of 10 kN. Table 1 shows the results of disintegration and dissolution tests on the obtained tablets.

[0057]

Wet granulation formulation

Compound A (3g), crystalline cellulose (3.66g), low-substituted hydroxypropylcellulose (1.8g), hydroxypropylmethylcellulose (0.45g) were mixed in an agate mortar, and then purified water (amount of water added to the mixed powder was about 53%). The resulting kneaded product is dried with a vacuum dryer, then sieved with a 20 mesh sieve, magnesium stearate (0.09 g) is added and mixed for 5 minutes with a V-type mixer to obtain mixed granules. It was.

[0058] Next, 300 mg of the obtained mixed granule was put into a φ 9.0 mm die, and then placed in a high-pressure shear tester. Then, tableting was performed with φ 9.0πιπι2 double R punch and tableting pressure lOkN. Table 1 shows the results of disintegration and dissolution tests on the obtained tablets.

Disintegration test method

According to the disintegration test method described in the 14th revision of the Japanese Pharmacopoeia, the time required for the tablet to completely disintegrate was measured by using water as the test liquid without an auxiliary board. [Toyama Sangyo Co., Ltd. Collapse Tester]

Dissolution test method

In accordance with the dissolution test method (second method) described in the 14th revision of the Japanese Pharmacopoeia, the test was conducted using 50 mL of citrate buffer (pH 2.5) 900 mL as the test solution at 50 rpm. Test solutions at 5 minutes, 10 minutes, 15 minutes and 30 minutes after the start of the test were collected, and the elution rate of Compound A was measured by absorbance measurement. [Toyama Sangyo Co., Ltd .: Dissolution tester, Shimadzu Corporation spectrophotometer]. The test was conducted with 6 tablets, and the average value of the dissolution rate was calculated.

(table 1)

From Table 1, the disintegration test of the wet granulation formulation (Comparative Example 1) was strong even after 30 minutes from the start of the test. On the other hand, the direct tableting formulation (Example 1) disintegrated rapidly in 1 minute. Furthermore, the direct tableting formulation (Example 1) is superior to the wet granulation formulation (Comparative Example 1) in terms of disintegration of the formulation, and accordingly, the dissolution property of the FBPase inhibitor is also superior. It was confirmed that Therefore, when manufacturing FBPase inhibitor preparations, it is clear that the production by the dry production method is more suitable than the wet granulation method. [0061]

Dry granulation formulation 1

Compound V (14000g), crystalline cellulose (15694g), low-substituted hydroxypropyl cellulose (3500g), light anhydrous caustic acid (56g), magnesium stearate (700g), talc (1050g) After mixing for 15 minutes, tableting was performed with a rotary tableting machine at a tableting pressure of 30 kN so that the tablet mass was about 500 mg. The obtained tablets were crushed with a granulator to obtain condyles for tableting.

[0062] Next, the obtained granule for tableting was mixed with a V-type mixer for 5 minutes, and then a rotary tableting machine was used to boil 15 X 7.3mm Oval type double R, and the tablet mass force was 00mg. Tableting was performed at a tableting pressure of 30 kN. Table 2 shows the results of a content uniformity test on the obtained tablets.

[0063]

Direct tableting formulation

Compound V (14000g), crystalline cellulose (15694g), low-substituted hydroxypropyl cellulose (3500g), light anhydrous caustic acid (56g), magnesium stearate (700g), talc (1050g) And mixed for 15 minutes to obtain a mixed powder.

[0064] Next, the obtained mixed powder was tableted using a rotary tableting machine with a 15 X 7.3 mm Oval type double R punch at a tableting pressure of 30 kN so that the tablet mass force was 00 mg. . Table 2 shows the results of a content uniformity test on the obtained tablets.

[0065]

Content uniformity test

In accordance with the content uniformity test method described in the 14th revision of the Japanese Pharmacopoeia, the test was conducted by a liquid chromatograph (HPLC) method using an internal standard method using an ultraviolet absorptiometer as a detector. [Shimadzu: HPLC] From the obtained data, the content uniformity test judgment value was calculated by the method described in the Japanese Pharmacopoeia, 14th revision, content uniformity test judgment value and tablet mass standard Relative standard deviation (RSD) calculated from deviation and average tablet weight Shown in 2

[0066]

Relative standard deviation (%) = (standard deviation Z average value) X 100

(Table 2)

[0067] * 1: Calculated value calculated by mass correction from the average content value

From Table 2, the content uniformity test judgment value of the dry granulation preparation (Example 2) was 4.9, which was significantly lower than that of the direct compression tablet preparation (Comparative Example 2). Furthermore, the dry granulation method formulation (Example 2) had an RSD value of 2.89, which was significantly lower than the direct tableting formulation (Comparative Example 2). The remarkably less mass variation. Therefore, in the production of FBPase inhibitor preparations, it can be proved that the dry granulation method is particularly suitable among the dry production methods.

[0068]

Dry granulation formulation 2

Compound V (14000g), crystalline cellulose (15694g), low-substituted hydroxypropyl cellulose (3500g), light anhydrous caustic acid (56g), magnesium stearate (700g), talc (1050g) After mixing for 15 minutes, the tableting pressure (A1: 10kN A2: 30kN) is changed so that the tablet weight becomes about 500mg and various densities by using a rotary tableting machine. Got. The obtained tablet A was crushed with a granulator to obtain granules for tableting. [0069] Next, the obtained granule for tableting was mixed with a V-type mixer for 5 minutes, and then using a rotary tableting machine, the tablet mass became 250 mg with a double R punch of 8.5 mm. Thus, tableting was performed at a tableting pressure of 10 kN. The obtained tablet B was measured for hardness and friability.

[0070]

Hardness test

The hardness of the tablets was measured using a continuous tablet measuring device (WHT-2) manufactured by Pharmatest. The test was performed on 10 tablets, and the average hardness obtained was calculated and shown in Table 3.

Abrasion test

Put 10 tablets into a glass cylinder covered with rubber stoppers on both sides, shake up and down at 250 rpm for 2 minutes, and calculate the friability using the following formula from the mass before and after shaking. Indicated.

[0072]

Friction (%) = [(mass before shaking—mass after shaking) / mass before shaking] X 100 (Table 3)

[0073] From Table 3, tablet B1, which was produced under the condition of low density of tablet A, had higher hardness and lower friability than tablet B2 with higher density of tablet A. Therefore, it was shown that the compression density of the granulation process in the dry granulation method affects the hardness and friability, and that a tablet with better quality can be produced with a smaller compression density.

Industrial applicability

[0074] According to the present invention, the dissolution property and content uniformity of a drug containing an FBPase inhibitor, In addition, a solid preparation excellent in mass uniformity, hardness and abrasion resistance can be obtained.

Claims

A solid preparation characterized in that a composition containing an FBPase inhibitor is formulated in a process including a dry production method. However, the above FBPase inhibitor has the following general formula (I)

[Chemical 1]

[2] X ^a represents a sulfur atom, R ^la represents an amino group, solid preparation according to claim 1 R ^5a is C1-4 alkyl group.

[3] Phosphoric acid amide compound power Jetyl N, N '-[5- (2-Amino-5-isobutyl-1,3-thiazol-4-yl) -2-furylphosphonol] di-L- The solid preparation according to claim 1, which is a alcoholate or a salt thereof.

[4] The solid preparation according to any one of claims 1 to 3, wherein the dissolution of the FBPase inhibitor is improved by making the preparation in a process including a dry production method.

[5] The solid preparation according to any one of claims 1 to 3, wherein disintegration is improved by formulating in a process including a dry production method.

6. The solid preparation according to any one of claims 1 to 5, wherein the dry production method is a dry granulation method.

[7] By formulating in a process that includes dry granulation, content uniformity and mass uniformity are achieved. 7. The solid preparation according to claim 6, which is improved.

[8] In the granulation step of the dry granulation method, the hardness and wear resistance are increased by reducing the density of the powder before pulverization. Formulation.

[9] The solid preparation according to claim 8, having a hardness of 5.0 kg or more.

[10] The solid preparation according to any one of claims 1 to 5, wherein the dry production method is a direct compression method.

[11] The solid preparation according to any one of claims 1 to 10, wherein the preparation is a tablet.

12. The solid preparation according to any one of claims 1 to 11, which is a prophylactic or therapeutic agent for diabetes.

[13] A solid preparation with improved dissolution of an FBPase inhibitor, comprising the step of formulating the solid preparation according to any one of claims 1 to 12 by a dry production method. Production method.

[14] A method for producing a solid preparation with improved disintegration, comprising the step of formulating the solid preparation according to any one of claims 1 to 12 by a dry production method.

15. The production method according to claim 13 or 14, wherein the dry production method is a dry granulation method.

16. The production method according to claim 15, wherein the content uniformity and the mass uniformity are improved by using a dry granulation method.

17. The production method according to claim 15, wherein in the granulation step of the dry granulation method, the hardness and wear resistance are increased by reducing the density of the powder before pulverization.

[18] The production method according to claim 17, wherein the hardness is 5.0 kg or more.

19. The production method according to claim 13 and 14, wherein the dry production method is a direct tableting method.

[20] A method for improving the dissolution of an FBPase inhibitor, comprising the step of formulating the solid preparation according to any one of claims 1 to 12 by a dry production method.

[21] A method for improving the disintegration property of a solid preparation, comprising the step of formulating the solid preparation according to any one of claims 1 to 12 by a dry production method.

22. The method according to claim 20 or 21, wherein the dry production method is a dry granulation method.

23. The method according to claim 20 or 21, wherein the dry production method is a direct tableting method.

[24] A step of formulating a composition containing an FBPase inhibitor in a step including a dry production method A solid preparation characterized by containing.