JP2012180280A - Solid preparation having improved storage stability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solid preparation having platelet aggregation inhibiting activity in which storage stability is improved.SOLUTION: The solid preparation contains (A) a compound having general formula (I) or a pharmacologically acceptable salt thereof, and (B) α-crystals of mannitol. In the solid preparation, the compound having general formula (I) or the pharmacologically acceptable salt thereof is preferably 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine/hydrochloride. As the solid preparation, powder, fine granule, granule, capsules or tablets are enumerated, and especially tablets are preferable.

Description

The present invention
(A) The following general formula (I)

Or a pharmacologically acceptable salt thereof and (B) a solid preparation containing an α crystal of mannitol.

  The compound having the above general formula (I) or a pharmacologically acceptable salt thereof is known as a compound having an inhibitory action on platelet aggregation (Patent Document 1 or 2).

  Patent Document 3 describes that a specific particle size of mannitol improves content uniformity in a preparation of a compound having the above general formula (I) or a pharmacologically acceptable salt thereof. However, this patent document does not describe a crystalline polymorph of mannitol, and contains a mannitol α crystal in a solid preparation containing the compound having the above general formula (I) or a pharmacologically acceptable salt thereof. This does not describe or suggest that storage stability is improved.

JP-A-6-41139 JP 2002-145883 A International Publication Number WO2008 / 072534 Pamphlet

  The subject of this invention is providing the solid formulation excellent in the storage stability containing the compound which has the said general formula (I), or its pharmacologically acceptable salt.

  As a result of intensive studies to solve the above problems, the present inventors contain a compound having the above general formula (I) or a pharmacologically acceptable salt thereof by containing α crystals of mannitol. The solid preparation was found to have excellent storage stability, and the present invention was completed.

That is, the present invention
(1) (A) A solid preparation characterized by containing a compound having the above general formula (I) or a pharmacologically acceptable salt thereof and (B) α crystals of mannitol,
(2) A compound having the general formula (I) or a pharmacologically acceptable salt thereof is represented by the following formula (Ia)

The solid preparation according to (1), which is a compound having
(3) The solid preparation according to (1) or (2), wherein the preparation is a powder, fine granules, granules, capsules or tablets,
(4) The solid preparation according to (1) or (2), wherein the preparation is a tablet,
(5) The solid preparation according to any one of (1) to (4), wherein the α crystal of mannitol is mannitol containing 2 to 100% by weight of α crystal,
(6) The solid preparation according to any one of (1) to (4), wherein the α crystal of mannitol is mannitol containing 45 to 90% by weight of α crystal, or
(7) The solid preparation according to any one of (1) to (4), wherein the α crystal of mannitol is mannitol containing 48 to 88% by weight of α crystal.

  According to this invention, it becomes possible to provide the solid formulation excellent in the storage stability containing the compound which has the said general formula (I), or its pharmacologically acceptable salt.

  The solid preparation of the present invention is effective for the treatment and / or prevention (preferably a thrombosis therapeutic and / or prophylactic agent) such as thrombosis or embolism (preferably thrombosis). is there.

  The following general formula (I), which is an active ingredient of the solid preparation of the present invention

2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, or a pharmacologically acceptable compound thereof The salt is described in JP-A-6-41139 or JP-A-2002-145883, and can be produced.

  As the “pharmacologically acceptable salt” of the present invention, for example, hydrohalide such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide; nitrate, perchlorine Inorganic acid salts such as acid salts, sulfates or phosphates; lower alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; benzenesulfonate or p-toluenesulfonic acid Aryl sulfonates such as salts; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate; or , Glycine salt, lysine salt, arginine salt, ornithine salt, amino acid salt such as glutamate or aspartate, etc. A halogenated hydrogen acid salt or organic acid salt, more preferably a hydrochloride or maleate, and most preferably is the hydrochloride salt.

  In the compound represented by the general formula (I), the α-position of the benzyl group is an asymmetric carbon, and there are optically active isomers based on the asymmetric carbon. The isomers and mixtures thereof are also included in the compound of the present invention. . Similarly, an isomer of a pharmacologically acceptable salt (for example, hydrochloride) of a compound represented by the general formula (I) and a mixture thereof are also pharmaceutically acceptable salts (for example, hydrochloride) of the compound of the present invention. Is included.

  Mannitol has five crystal polymorphs, among which anhydrous crystals include α crystals, β crystals, and γ crystals, and β crystals are known to be the most stable thermodynamically (for example, Pharm.Res.Vol.25, No. 10, 2292-2301 (2008)). Examples of the method for measuring crystal polymorphism in mannitol crystals include powder X-ray diffraction, infrared spectroscopy, near infrared spectroscopy, Raman spectroscopy, solid state NMR, differential thermal analysis, etc. In the invention, the content of each crystal polymorph can be measured by powder X-ray diffraction. In order to measure the crystalline polymorph of mannitol by powder X-ray diffraction, for example, J. Org. Pharm. Biomed. Anal. Vol. 28, 1149-1159 (2002) can be used. Specifically, for example, when only the α crystal and β crystal peaks are observed in the mannitol used, and it is known that the mixture is a mixture of the α crystal and the β crystal, a powder X-ray diffraction shows a value around 14.6 °. The β crystal content was calculated from the observed peak intensity inherent to the β crystal, and the value obtained by subtracting the calculated β crystal content from 100% was defined as the α crystal content.

  The mannitol used may be 100% α crystal or a mixture of α crystal and other crystal polymorphs. When mannitol is a mixture of α crystals and other crystal polymorphs, the lower limit of the content of α crystals in mannitol is preferably 2%, more preferably 45%, and even more preferable. The upper limit is preferably 95%, and more preferably 88%.

  The amount of mannitol to be used is usually 10.0 to 93.5% by weight, and preferably 44.0 to 90.0% by weight, based on the total weight of the solid preparation. Therefore, the lower limit of the content of mannitol α crystals to be used relative to the total weight of the solid preparation is preferably 1%, more preferably 5%, still more preferably 20%, and particularly preferably. The upper limit is preferably 94%, more preferably 90%, still more preferably 84%, and particularly preferably 79%.

  The solid preparation of the present invention may further comprise an appropriate pharmacologically acceptable excipient other than mannitol, a lubricant, a binder, an emulsifier, a stabilizer, a flavoring agent, and / or a disintegrant, if necessary. Can be included.

  “Excipients other than mannitol” used include, for example, lactose, sucrose, glucose, other crystals of mannitol or sugar derivatives such as sorbitol; starch such as corn starch, potato starch, α-starch or dextrin Derivatives; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; or organic excipients such as pullulan; or light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate Examples include inorganic excipients such as silicate derivatives; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; or sulfates such as calcium sulfate. One or more additives selected from cellulose derivatives and sugar derivatives; An agent, more preferably, lactose, and other crystalline and one or more excipients selected from microcrystalline cellulose mannitol, and most preferably lactose and / or microcrystalline cellulose.

  “Lubricants” used include, for example, stearic acid; metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or whale wax; boric acid; adipine Acids; sulfates such as sodium sulfate; glycols; fumaric acid; sodium stearyl fumarate; sucrose fatty acid esters; sodium benzoate; D, L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; Silicic acids such as silicic acid or silicic acid hydrate; or the above-mentioned starch derivatives and the like can be mentioned, and metal stearates are preferred.

  Examples of the “binder” used include hydroxypropyl cellulose, hypromellose, polyvinyl pyrrolidone, polyethylene glycol, and the same compounds as the above-mentioned excipients, preferably hydroxypropyl cellulose or hypromellose. is there.

  “Emulsifiers” used include, for example, colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate A cationic surfactant such as benzalkonium chloride; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.

  “Stabilizers” used include, for example, paraoxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenol or cresol Phenols; thimerosal; dehydroacetic acid; or sorbic acid.

  Examples of the “flavoring agents” used include sweeteners such as sodium saccharin or aspartame; acidifiers such as citric acid, malic acid or tartaric acid; or flavorings such as menthol, lemon or orange. Can do.

  “Disintegrants” used include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or carboxymethyl starch or carboxymethyl starch Examples thereof include starch and cellulose modified chemically such as sodium.

  Although there is no restriction | limiting in particular in the compounding quantity of the compound which has the said general formula (I) in a solid formulation, or its pharmacologically acceptable salt, For example, 1.0-30.0 weight% with respect to solid formulation total weight (Suitably, 1.3 to 20.0% by weight) is preferably blended.

  The amount of the additive in the total amount of the solid preparation is not particularly limited. For example, the excipient including mannitol is 10.0 to 93.5% by weight (preferably with respect to the total weight of the solid preparation). Is 44.0-90.0% by weight), the lubricant is 0.5-5.0% by weight (preferably 0.5-3.0% by weight), and the binder is 0.0-15%. 0.0 wt% (preferably 2.5 to 10.0 wt%) and 2.5 to 40.0 wt% (preferably 5.0 to 30.0 wt%) disintegrant Is preferred.

  The solid preparation of the present invention includes, for example, tablets (including sublingual tablets and orally disintegrating agents), capsules (including soft capsules and microcapsules), granules, fine granules, powders, pills, chewable agents, and troches. It is preferably a powder, fine granule, granule, capsule or tablet, and most preferably a tablet.

  As a method for producing the preparation in the present invention, it is produced using a general method described in a publication such as Powder Technology and Pharmaceutical Process (D. Chulia et al., Elser Science Pub Co (December 1, 1993)). In particular, a dry process is preferred.

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

  The “direct tableting method” is a method for preparing a raw material powder by direct compression molding.

  The “dry granulation method” is a method in which a raw material powder is compression-molded into slugs or sheets, and is formulated using granules produced by crushing and dividing by an appropriate method. These processes The Theory and Practice of Industrial Pharmacy (Third Edition) (Leon Lachman other: LEA & FEBIGER 1986) and, Pharmaceutical Dosage Forms: Tablets volume 1 (Second Edition) (Herbert A.Lieberman other:. MARCEL DEKKER INC 1989 ).

  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 molten liquid, and produces final products such as granules, powders or fine granules. There are granulations and granulations that make intermediate products for production such as tablets or capsules.

  The compression molding process is a process of applying pressure to the raw material powder with mechanical force to make the raw material powder a lump. Examples of the equipment used include a rotary tablet machine (manufactured by Kikusui Seisakusho Co., Ltd. Dry granulators such as Iron Works, Ebara Seiki, etc., Roller Compactor, Roll Granulator, or Chill Sonator (Freund Sangyo Co., Ltd., Turbo Kogyo Co., Ltd. Rator Co., Ltd., Fuji Paudal Co., etc.).

  The crushing / splitting process is a process of crushing the lump formed in the compression molding process to an appropriate size with a knife / cutter, etc. Examples of the equipment used include power mill, Fitzmill, Fiore or Comil Or a granulator (manufactured by Fuji Powder Co., Ltd., Deoksugaku Kogakusho Co., Ltd., Paulek Co., etc.).

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

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

  As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan and the like can be used in combination. .

  Examples of water-soluble film coating bases include cellulose derivatives such as hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, methylhydroxyethylcellulose or sodium carboxymethylcellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer or polyvinylpyrrolidone. A molecule; or a polysaccharide such as pullulan.

  Examples of enteric film coating bases include cellulose derivatives such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose or cellulose acetate phthalate; (meth) acrylic acid copolymer L, (meth) acrylic acid Examples thereof include acrylic acid derivatives such as copolymer LD or (meth) acrylic acid copolymer S; or natural products such as shellac.

  Examples of the sustained-release film coating base include cellulose derivatives such as ethyl cellulose; or acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS or ethyl acrylate / methyl methacrylate / copolymer emulsion. be able to.

  Two or more kinds of the coating bases may be mixed and used at an appropriate ratio. Furthermore, additives such as appropriate pharmacologically acceptable plasticizers, excipients, lubricants, masking agents, coloring agents and / or preservatives can be further included as necessary.

  The kind of plasticizer that can be used in the present invention is not particularly limited, and can be appropriately selected by those skilled in the art. Examples of such plasticizers include propylene glycol, polyethylene glycol, polypropylene glycol, glycerin and sorbitol, glycerin triacetate, diethyl phthalate and triethyl citrate, lauric acid, sucrose, dextrose, sorbitol, triacetin, and acetyl triethyl titrate. , Triethyl titrate, tributyl titrate, acetyl tributyl titrate and the like.

  Examples of the concealing agent that can be used in the present invention include titanium oxide.

  Examples of the colorant that can be used in the present invention include titanium oxide, iron oxide, ferric oxide, yellow ferric oxide, and yellow No. 5 aluminum lake talc.

  Examples of preservatives that can be used in the present invention include parabens.

  The dose of the compound having the above general formula (I) or a pharmacologically acceptable salt thereof, which is an active ingredient of the solid preparation of the present invention, varies depending on various conditions such as drug activity, patient symptoms, age or body weight. Can do. In the case of oral administration, the dose is usually 0.01 mg (preferably 1 mg) as the lower limit for adults, and 200 mg (preferably 100 mg) as the upper limit. can do.

  EXAMPLES Hereinafter, although an Example, a comparative example, and a test example demonstrate this invention further in detail, this invention is not limited to these.

  “Compound A” used in Examples and Comparative Examples has the following structural formula (Ia)

And can be produced according to the method described in JP-A-2002-145883.

Example 1
Compound A (6.9 g), mannitol (α crystal content: 70%, β crystal content: 30%, 325.6 g), low-substituted hydroxypropylcellulose (75 g), hydroxypropylcellulose (37.5 g) and Crystalline cellulose (50 g) was mixed with a V-type mixer for 30 minutes. After sieving the obtained mixed powder, magnesium stearate (5 g) was added and mixed again with a V-type mixer to obtain a mixed powder for tableting.

  Next, the obtained mixed powder was tableted with a rotary tableting machine at a tableting pressure of about 5 kN so that the tablet mass was about 100 mg. The obtained uncoated tablet was sprayed with a coating solution comprising hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a film-coated tablet. The film-coated tablet was dried to obtain a tablet containing the test compound. The stability test was done about the obtained tablet. The test results are shown in Table 1.

(Example 2)
Compound A (13.8 g), mannitol (α crystal content: 88%, β crystal content: 12%, 726.3 g), low-substituted hydroxypropylcellulose (150 g), hydroxypropylcellulose (50 g) and crystalline cellulose (50 g) was mixed with a V-type mixer for 30 minutes. After sieving the obtained mixed powder, magnesium stearate (10 g) was added and mixed again with a V-type mixer to obtain a mixed powder for tableting. Next, the obtained mixed powder was rotary. The tablet was pressed with a tableting pressure of about 5 kN so that the tablet mass was about 100 mg. The obtained uncoated tablet was sprayed with a coating solution comprising hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a film-coated tablet. The film-coated tablet was dried to obtain a tablet containing the test compound. The stability test was done about the obtained tablet. The test results are shown in Table 1.

(Comparative Example 1)
Compound A (6.9 g), mannitol (β crystal content: 100%, 325.6 g), low-substituted hydroxypropylcellulose (75 g), hydroxypropylcellulose (37.5 g) and crystalline cellulose (50 g) Mix for 30 minutes with a blender. After sieving the obtained mixed powder, magnesium stearate (5 g) was added and mixed again with a V-type mixer to obtain a mixed powder for tableting. Next, the obtained mixed powder was rotary. The tablet was pressed with a tableting pressure of about 3 kN using a tablet press so that the tablet mass was about 100 mg. The obtained uncoated tablet was sprayed with a coating solution comprising hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a film-coated tablet. The film-coated tablet was dried to obtain a tablet containing the test compound. The stability test was done about the obtained tablet. The test results are shown in Table 1.

(Test Example 1) Stability test The tablets obtained in Example 1, Example 2 and Comparative Example 1 were sealed in a brown glass bottle and allowed to stand in a sealed state at 40 ° C / 75% relative humidity. After 3 and 6 months, the related substance of the active ingredient (compound A) in the test tablet was measured by high performance liquid chromatography, and the total content (%) of the related substance was calculated from the area (%) of the peak obtained. Obtained. The measurement conditions for high performance liquid chromatography are as follows.
Column: Synergi 4u MAX-RP 80A (4.6 mm ID × 150 mm, manufactured by Phenomenex)
Mobile phase A: 25 mmol / L phosphate buffer (pH 4.0) / acetonitrile mixture (9: 1)
Mobile phase B: acetonitrile / water mixture (9: 1)
Gradient:
Elapsed time (minutes) 0 2 30 37 38 45
Mobile phase A 100 100 0 0 100 100 100
Mobile phase B 0 0 100 100 0 0
Column temperature: Constant temperature around 45 ° C Detection wavelength: 210 nm
Flow rate: 1.50 mL / min (Table 1)
―――――――――――――――――――――――――――――――――――――
Total content of related substances with respect to Compound A at the time of measurement (%)
――――――――――――――――――――――――――――――――
Test tablet 1 month later 2 months later 3 months later 6 months later ――――――――――――――――――――――――――――――― ―――――
Example 1 1.51 2.18 2.76 4.43
Example 2 1.45 − − −
-------------------
Comparative Example 1 4.07-8.26 13.92
―――――――――――――――――――――――――――――――――――――
In the table, “-” indicates unmeasured.

According to the present invention, a solid preparation having improved storage stability containing the compound having the above general formula (I) or a pharmacologically acceptable salt thereof, and α crystals of mannitol can be obtained.

Claims (7)

(A) The following general formula (I)

Or a pharmacologically acceptable salt thereof, and (B) a solid preparation containing α crystals of mannitol. The compound having the general formula (I) or a pharmacologically acceptable salt thereof is represented by the following formula (Ia)

The solid preparation according to claim 1, which is a compound having   The solid preparation according to claim 1 or 2, wherein the preparation is a powder, a fine granule, a granule, a capsule or a tablet.   The solid preparation according to claim 1 or 2, wherein the preparation is a tablet.   The solid preparation according to any one of claims 1 to 4, wherein the α crystal of mannitol is mannitol containing 2 to 100% by weight of α crystal.   The solid preparation according to any one of claims 1 to 4, wherein the α crystal of mannitol is mannitol containing 45 to 90% by weight of α crystal. The solid preparation according to any one of claims 1 to 4, wherein the α crystal of mannitol is mannitol containing 48 to 88% by weight of α crystal.