JP2014015442A - Manufacturing method of tablet containing clopidogrel sulfate - Google Patents
Manufacturing method of tablet containing clopidogrel sulfate Download PDFInfo
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本発明は、抗血小板凝集薬として有用なクロピドグレル硫酸塩（日本医薬品名一般名称）を含有する錠剤の製造方法に関する。 The present invention relates to a method for producing a tablet containing clopidogrel sulfate (Japanese drug generic name) useful as an antiplatelet aggregating agent.
従来、クロピドグレル硫酸塩のように水に不安定な医薬を含有する錠剤を製造する場合、通常、打錠前の工程で乾式造粒法により顆粒を造り、これに打錠障害を防止するための滑沢剤を添加、混合した後、その混合物を打錠成形する方法が行われている。
ところが、このようにして得られた錠剤は、長期又は高温、高湿度下での保存等により、生体内投与後又は溶液中で錠剤が長時間にわたり崩壊しない場合があり、医薬の溶出速度の観点から問題となっていた。
そこで、松本らは、前記問題点を克服した製剤として、水に不安定な薬剤、ショ糖脂肪酸エステル、硬化油及びポリエチレングリコールを含有する錠剤を提案している（特許文献１）。しかし、その錠剤における薬剤の保存安定性については何ら記載されていない。
Conventionally, when manufacturing a tablet containing a water-unstable drug such as clopidogrel sulfate, granules are usually made by dry granulation in the process before tableting, and this is used to prevent tableting troubles. After adding and mixing the bulking agent, the mixture is tableted.
However, the tablets obtained in this way may not disintegrate for a long time after in vivo administration or in solution due to long-term or high-temperature, high-humidity storage, etc. It was a problem.
Therefore, Matsumoto et al. Have proposed a tablet containing a water-unstable drug, sucrose fatty acid ester, hydrogenated oil, and polyethylene glycol as a preparation overcoming the above-mentioned problems (Patent Document 1). However, nothing is described about the storage stability of the drug in the tablet.
本発明の課題は、水に不安定で打錠障害を生じやすいクロピドグレル硫酸塩を含有する錠剤の簡便な製造方法であって、打錠障害を生じず、かつその保存安定性を長期間維持できる錠剤の製造方法を提供することにある。 An object of the present invention is a simple method for producing a tablet containing clopidogrel sulfate, which is unstable in water and easily causes tableting trouble, and does not cause tableting trouble and can maintain its storage stability for a long period of time. It is to provide a method for producing a tablet.
本発明者らは、前記課題を解決するため種々検討したところ、クロピドグレル硫酸塩は、水に不安定だけでなく、乾式造粒の際に繁用されているステアリン酸マグネシウムによっても分解が促進されることが判った。そこで、ステアリン酸マグネシウム以外の滑沢剤を使用すると、スティッキング等の打錠障害防止効果を上げるためステアリン酸マグネシウムより相対的に多量を使用する必要があること、そして滑沢剤の増量が、主薬の溶出遅延につながることも判明した。これらの知見を踏まえ、さらに検討した結果、クロピドグレル硫酸塩とできるだけ少量の滑沢剤（但し、ステアリン酸マグネシウムを除く）とを予め混合した後、必要な添加剤を加えてさらに混合し、常法により打錠することにより、前記課題を解決できることを見出し、本発明を完成することができた。 The inventors of the present invention have made various studies to solve the above problems. As a result, clopidogrel sulfate is not only unstable to water but also decomposed by magnesium stearate frequently used in dry granulation. I found out. Therefore, if a lubricant other than magnesium stearate is used, it is necessary to use a relatively larger amount than magnesium stearate in order to increase the effect of preventing tableting troubles such as sticking, and the amount of lubricant increases. It has also been found that this leads to a delay in elution. As a result of further investigation based on these findings, after mixing clopidogrel sulfate and as little lubricant as possible (excluding magnesium stearate) in advance, the necessary additives were added and further mixed. It was found that the above-mentioned problems can be solved by tableting according to the present invention, and the present invention was completed.
すなわち、本発明によれば、下記（１）〜（３）を提供することができる。
（１）クロピドグレル硫酸塩と滑沢剤（但し、ステアリン酸マグネシウムを除く）とを水の不存在下で予め混合した後、添加剤を加えてさらに混合し、打錠することを特徴とするクロピドグレル硫酸塩含有錠剤の製造方法。
（２）滑沢剤が硬化油、脂肪酸エステル、軽質無水ケイ酸及び含水二酸化ケイ素から選ばれる一種または二種以上である前記（１）に記載の製造方法。
（３）クロピドグレル硫酸塩の１０％粒子径が４０μｍ以上であり、かつ、９０％粒子径が１５０μｍ以下である前記（１）〜（２）に記載の製造方法。
That is, according to the present invention, the following (1) to (3) can be provided.
(1) Clopidogrel sulfate and lubricant (excluding magnesium stearate) are mixed in advance in the absence of water, then added with additives, further mixed, and tableted. A method for producing a sulfate-containing tablet.
(2) The production method according to (1), wherein the lubricant is one or more selected from hydrogenated oil, fatty acid ester, light anhydrous silicic acid, and hydrous silicon dioxide.
(3) The manufacturing method as described in said (1)-(2) whose 10% particle diameter of a clopidogrel sulfate is 40 micrometers or more and 90% particle diameter is 150 micrometers or less.
本発明によれば、クロピドグレル硫酸塩と滑沢剤とを水の不存在下で予め混合することにより、滑沢剤の使用量が少なくてもピッキング等の打錠障害を効果的に防ぐことができ、当該主薬の溶出遅延の問題もなく、しかも当該主薬を長期間安定に保持できる錠剤を容易に製造することができる。 According to the present invention, by previously mixing clopidogrel sulfate and lubricant in the absence of water, it is possible to effectively prevent tableting troubles such as picking even if the amount of lubricant used is small. In addition, it is possible to easily produce a tablet that can hold the active ingredient stably for a long period of time without any problem of dissolution delay of the active ingredient.
本発明に係るクロピドグレル硫酸塩は、粉末状にして使用するが、その１０％粒子径が４０μｍ以上であり、かつ、９０％粒子径が１５０μｍ以下のものが好ましい。 The clopidogrel sulfate according to the present invention is used in the form of a powder, but preferably has a 10% particle diameter of 40 μm or more and a 90% particle diameter of 150 μm or less.
本発明において使用される滑沢剤としては硬化油、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、軽質無水ケイ酸、含水二酸化ケイ素等が挙げられるが、なかでも硬化油および軽質無水ケイ酸が好ましい。
これらの滑沢剤の使用量は、錠剤全重量の０．１重量％〜１０重量％が好ましく、より好ましくは、０．５重量％〜５重量％である。
なお、クロピドグレル硫酸塩と滑沢剤との混合において、必要に応じ他の製剤上の添加剤を少量加えても何ら差し支えない。
Examples of the lubricant used in the present invention include hardened oil, glycerin fatty acid ester, sucrose fatty acid ester, light anhydrous silicic acid, hydrous silicon dioxide, and the like. Among them, hardened oil and light anhydrous silicic acid are preferable.
The amount of these lubricants to be used is preferably 0.1% to 10% by weight, more preferably 0.5% to 5% by weight, based on the total weight of the tablet.
In addition, in the mixing of clopidogrel sulfate and a lubricant, it is possible to add a small amount of additives on other preparations as needed.
本発明において使用することができる製剤上の添加物としては、通常使用されている賦形剤、崩壊剤、結合剤、矯味剤等その他の添加剤が使用できる。
例えば賦形剤としては、乳糖、結晶セルロース、トウモロコシ澱粉、バレイショ澱粉、Ｄ−マンニトール、白糖、ショ糖、ブドウ糖等が挙げられる
結合剤としては、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポビドン等を挙げることができる。
崩壊剤としては、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、カルボキシメチルスターチナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、部分アルファー化澱粉等を挙げることができる。
As additives in the preparation that can be used in the present invention, other additives such as excipients, disintegrants, binders, and corrigents that are commonly used can be used.
Examples of excipients include lactose, crystalline cellulose, corn starch, potato starch, D-mannitol, sucrose, sucrose, and glucose. Binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone, and the like. Can be mentioned.
Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, partially pregelatinized starch and the like.
本発明で得られた錠剤には、必要に応じてフィルムコーティングを施すことができる。
コーティング剤としては、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、アミノアルキルメタアクリレートコポリマー（Ｅ，ＲＳ）、メタアクリル酸コポリマー（Ｌ，ＬＤ、Ｓ）、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、エチルセルロース系水分散液及び、酸化チタン、タルク、三二酸化鉄、ポリエチレングリコール、クエン酸トリエチル等が挙げられる。
The tablet obtained by the present invention can be film-coated as necessary.
Coating agents include hydroxypropylcellulose, hypromellose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer (E, RS), methacrylic acid Examples thereof include copolymers (L, LD, S), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, ethylcellulose aqueous dispersion, titanium oxide, talc, iron sesquioxide, polyethylene glycol, triethyl citrate and the like.
なお、本発明に係る錠剤の製造工程に特に困難はなく、常法により容易に目的の錠剤を製造することができる。
以下、実施例を挙げて本発明を説明する。
In addition, there is no particular difficulty in the manufacturing process of the tablet which concerns on this invention, and the target tablet can be manufactured easily by a conventional method.
Hereinafter, the present invention will be described with reference to examples.
１０％粒子径が４５μｍ、９０％粒子径が１２５μｍのクロピドグレル硫酸塩２４４７．３ｇ、硬化油７５ｇ及び軽質無水ケイ酸７．５ｇを撹拌造粒機（パウレック製：ＶＧ−１０型）に投入し、ブレード回転数３７０毎分、クロススクリュウ回転数５００毎分にて、３０分間混合を行った。得られた混合品と、結晶セルロース２５６２．８ｇ、低置換度ヒドロキシプロピルセルロース２６２５ｇ、硬化油７５ｇおよび軽質無水ケイ酸７．５ｇをタンブラー型混合機に投入し２０分間混合した。得られた混合物をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で直径６．８ｍｍに圧縮成型し、下記組成の錠剤を得た。
［成 分］ ［１錠１０４ｍｇ当たりの重量（ｍｇ）］
クロピドグレル硫酸塩 ３２．６３
硬化油 ２．００
軽質無水ケイ酸 ０．２０
結晶セルロース ３４．１７
低置換度ヒドロキシプロピルセルロース ３５．００
2447.3 g of clopidogrel sulfate having a 10% particle size of 45 μm and a 90% particle size of 125 μm, 75 g of hardened oil and 7.5 g of light anhydrous silicic acid were charged into a stirring granulator (Paurek: VG-10 type). Mixing was performed for 30 minutes at a blade rotation speed of 370 and a cross screw rotation speed of 500 per minute. The obtained mixed product, 2562.8 g of crystalline cellulose, 2625 g of low-substituted hydroxypropyl cellulose, 75 g of hardened oil and 7.5 g of light anhydrous silicic acid were put into a tumbler type mixer and mixed for 20 minutes. The obtained mixture was compression-molded to a diameter of 6.8 mm using a rotary tableting machine (Kikusui Seisakusho: VIRGO type) to obtain tablets having the following composition.
[Components] [Weight per mg of 104 mg (mg)]
Clopidogrel sulfate 32.63
Hardened oil 2.00
Light anhydrous silicic acid 0.20
Crystalline cellulose 34.17
Low substituted hydroxypropylcellulose 35.00
１０％粒子径が４５μｍ、９０％粒子径が１２５μｍのクロピドグレル硫酸塩２４４７．３ｇ、硬化油７５ｇ及び軽質無水ケイ酸７．５ｇを撹拌造粒機（パウレック製：ＶＧ−１０型）に投入し、ブレード回転数３７０毎分、クロススクリュウ回転数５００毎分にて、３０分間混合を行った。得られた混合品と、結晶セルロース１５９０．５ｇ、低置換度ヒドロキシプロピルセルロース１８７５ｇ、硬化油５０ｇおよび軽質無水ケイ酸５ｇをタンブラー型混合機に投入し２０分間混合した。得られた混合物をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で、直径８．７ｍｍに圧縮成型し、下記組成の錠剤を得た。
［成 分］ ［１錠２４２ｍｇ当たりの重量（ｍｇ）］
クロピドグレル硫酸塩 ９７，８８
硬化油 ５．００
軽質無水ケイ酸 ０．５０
結晶セルロース ６３．６２
低置換度ヒドロキシプロピルセルロース ７５．００
2447.3 g of clopidogrel sulfate having a 10% particle size of 45 μm and a 90% particle size of 125 μm, 75 g of hardened oil and 7.5 g of light anhydrous silicic acid were charged into a stirring granulator (Paurek: VG-10 type). Mixing was performed for 30 minutes at a blade rotation speed of 370 and a cross screw rotation speed of 500 per minute. The obtained mixture, 1590.5 g of crystalline cellulose, 1875 g of low-substituted hydroxypropyl cellulose, 50 g of hardened oil and 5 g of light anhydrous silicic acid were put into a tumbler type mixer and mixed for 20 minutes. The obtained mixture was compression-molded to a diameter of 8.7 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) to obtain a tablet having the following composition.
[Components] [Weight per mg of 242 mg (mg)]
Clopidogrel sulfate 97,88
Hardened oil 5.00
Light anhydrous silicic acid 0.50
Crystalline cellulose 63.62
Low substituted hydroxypropylcellulose 75.00
〔比較例１〕
１０％粒子径が４５μｍ、９０％粒子径が１２５μｍのクロピドグレル硫酸塩２４４７．３ｇ、硬化油１５０ｇ、軽質無水ケイ酸１５ｇ、結晶セルロース２５６２．８ｇおよび低置換度ヒドロキシプロピルセルロース２６２５ｇをタンブラー型混合機に投入し２０分間混合した。以下実施例１と同様の操作を行い、下記組成の錠剤を得た。
［成 分］ ［１錠１０４ｍｇ当たりの重量（ｍｇ）］
クロピドグレル硫酸塩 ３２．６３
硬化油 ２．００
軽質無水ケイ酸 ０．２０
結晶セルロース ３４．１７
低置換度ヒドロキシプロピルセルロース ３５．００
[Comparative Example 1]
A tumbler-type mixer comprising 2447.3 g of clopidogrel sulfate having a 10% particle size of 45 μm and a 90% particle size of 125 μm, 150 g of hardened oil, 15 g of light anhydrous silicic acid, 2562.8 g of crystalline cellulose and 2625 g of low-substituted hydroxypropylcellulose. Charged and mixed for 20 minutes. Thereafter, the same operation as in Example 1 was performed to obtain tablets having the following composition.
[Components] [Weight per mg of 104 mg (mg)]
Clopidogrel sulfate 32.63
Hardened oil 2.00
Light anhydrous silicic acid 0.20
Crystalline cellulose 34.17
Low substituted hydroxypropylcellulose 35.00
〔比較例２〕
１０％粒子径が４５μｍ、９０％粒子径が１２５μｍのクロピドグレル硫酸塩２４４７．３ｇ、ステアリン酸マグネシウム７５ｇ、結晶セルロース２６５２．８ｇおよび低置換度ヒドロキシプロピルセルロース２６２５ｇをタンブラー型混合機に投入し２０分間混合した。以下実施例１と同様の操作を行い、下記組成の錠剤を得た。
［成 分］ ［１錠１０４ｍｇ当たりの重量（ｍｇ）］
クロピドグレル硫酸塩 ３２．６３
ステアリン酸マグネシウム １．００
結晶セルロース ３５．３７
低置換度ヒドロキシプロピルセルロース ３５．００
[Comparative Example 2]
2447.3 g of clopidogrel sulfate having a 10% particle size of 45 μm and a 90% particle size of 125 μm, 75 g of magnesium stearate, 2652.8 g of crystalline cellulose, and 2625 g of low-substituted hydroxypropyl cellulose were put into a tumbler type mixer and mixed for 20 minutes. did. Thereafter, the same operation as in Example 1 was performed to obtain tablets having the following composition.
[Components] [Weight per mg of 104 mg (mg)]
Clopidogrel sulfate 32.63
Magnesium stearate 1.00
Crystalline cellulose 35.37
Low substituted hydroxypropylcellulose 35.00
〔比較例３〕
１０％粒子径が５μｍ、９０％粒子径が４５μｍのクロピドグレル硫酸塩２４４７．３ｇ、硬化油７５ｇ及び軽質無水ケイ酸７．５ｇを撹拌造粒機（パウレック製：ＶＧ−１０型）に投入し、以下実施例１と同様の操作を行い、下記組成の錠剤を得た。
［成 分］ ［１錠１０４ｍｇ当たりの重量（ｍｇ）］
クロピドグレル硫酸塩 ３２．６３
硬化油 ２．００
軽質無水ケイ酸 ０．２０
結晶セルロース ３４．１７
低置換度ヒドロキシプロピルセルロース ３５．００
[Comparative Example 3]
2447.3 g of clopidogrel sulfate having a 10% particle size of 5 μm and a 90% particle size of 45 μm, 75 g of hardened oil, and 7.5 g of light anhydrous silicic acid were charged into a stirring granulator (manufactured by POWREC: Model VG-10). Thereafter, the same operation as in Example 1 was performed to obtain tablets having the following composition.
[Components] [Weight per mg of 104 mg (mg)]
Clopidogrel sulfate 32.63
Hardened oil 2.00
Light anhydrous silicic acid 0.20
Crystalline cellulose 34.17
Low substituted hydroxypropylcellulose 35.00
〔比較例４〕
１０％粒子径が４５μｍ、９０％粒子径が１２５μｍのクロピドグレル硫酸塩２４４．７ｇ、軽質無水ケイ酸１．５ｇ、結晶セルロース２３８．３ｇ、低置換度ヒドロキシプロピルセルロース２６２．５ｇおよびヒドロキシプロピルセルロース１８ｇを撹拌造粒機（パウレック製：ＶＧ−１０型）に投入し、精製水６００ｇを加え、ブレード回転数２９０毎分、クロススクリュウ回転数３０００毎分にて、３分間造粒した。得られた造粒物を流動乾燥機で乾燥した後、整粒機で整粒した。得られた整粒品および硬化油１５ｇをタンブラー型混合機に投入し、２０分間混合した。得られた混合物をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で直径６．８ｍに圧縮成型し、錠剤を得た。
［成 分］ ［１錠１０４ｍｇ当たりの重量（ｍｇ）］
クロピドグレル硫酸塩 ３２．６３
硬化油 ２．００
軽質無水ケイ酸 ０．２０
結晶セルロース ３３．９３
低置換度ヒドロキシプロピルセルロース ３５．００
ヒドロキシプロピルセルロース ０．２４
[Comparative Example 4]
244.7 g of clopidogrel sulfate having a 10% particle size of 45 μm and a 90% particle size of 125 μm, 1.5 g of light anhydrous silicic acid, 238.3 g of crystalline cellulose, 262.5 g of low-substituted hydroxypropylcellulose and 18 g of hydroxypropylcellulose The mixture was put into an agitation granulator (manufactured by Paulek: Model VG-10), 600 g of purified water was added, and granulated for 3 minutes at a blade rotation speed of 290 per minute and a cross screw rotation speed of 3000 per minute. The obtained granulated product was dried with a fluid dryer and then sized with a sizing machine. The obtained granulated product and 15 g of hardened oil were put into a tumbler type mixer and mixed for 20 minutes. The obtained mixture was compression-molded to a diameter of 6.8 m using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) to obtain tablets.
[Components] [Weight per mg of 104 mg (mg)]
Clopidogrel sulfate 32.63
Hardened oil 2.00
Light anhydrous silicic acid 0.20
Crystalline cellulose 33.93
Low substituted hydroxypropylcellulose 35.00
Hydroxypropylcellulose 0.24
〔試験例１〕（打錠障害の発生レベル）
実施例及び比較例について、打錠開始直後および打錠開始１時間について、打錠杵表面への粉末付着状態を目視にて観察し、打錠障害発生レベルを評価した結果を表１に示した。
表１より、クロピドグレル硫酸塩と滑沢剤とを予め混合することにより打錠障害の発生が抑制されること、そして打錠障害の発生は、クロピドグレル硫酸塩の粒子径によっても影響を受け、実施例１又は２の粒子径が好ましいことも判った。
[Test Example 1] (Occurrence level of tableting failure)
For the examples and comparative examples, the powder adhesion state on the surface of the tablet punch was visually observed immediately after the start of tableting and for 1 hour after tableting, and the results of evaluating the level of occurrence of tableting failure are shown in Table 1. .
From Table 1, the occurrence of tableting failure is suppressed by mixing clopidogrel sulfate and lubricant in advance, and the occurrence of tableting failure is also affected by the particle size of clopidogrel sulfate. It has also been found that the particle size of Example 1 or 2 is preferred.
〔試験例２〕（保存安定性）
実施例及び比較例の錠剤をそれぞれ乾燥剤とともにポリエチレン製容器に入れ、密栓後、温度４０℃、相対湿度７５％の条件下に保存した。保存開始から１ヶ月および３ヶ月経過後、各錠剤中の分解物を高速液体クロマトグラフィーにより測定した。その結果から、それぞれ総分解物量（面積百分率）を算出し、結果を表２に示した。
表２より、錠剤中のクロピドグレル硫酸塩は、水やステアリン酸マグネシウムによって影響を受け、その分解が促進されることが判った。
以上、試験例１及び試験例２の結果、本発明の方法で製造した錠剤は、打錠障害の発生が認められず、クロピドグレル硫酸塩の保存安定性に優れていることが判明した。
[Test Example 2] (Storage stability)
The tablets of Examples and Comparative Examples were each placed in a polyethylene container together with a desiccant, and after sealing, stored under conditions of a temperature of 40 ° C. and a relative humidity of 75%. After 1 month and 3 months from the start of storage, the degradation product in each tablet was measured by high performance liquid chromatography. From the results, the total amount of decomposition products (area percentage) was calculated, and the results are shown in Table 2.
From Table 2, it was found that clopidogrel sulfate in the tablet was affected by water and magnesium stearate, and its decomposition was accelerated.
As described above, as a result of Test Example 1 and Test Example 2, it was found that the tablets produced by the method of the present invention showed no occurrence of tableting trouble and excellent storage stability of clopidogrel sulfate.
〔試験例３〕（溶出性）
実施例１及び２で得た錠剤について溶出試験（試験液日本薬局方第１液、パドル回転数５０ｒｐｍ）によりクロピドグレルの溶出率を測定し、表３の結果を得た。
表３の結果から、本発明に係る実施例１及び２の錠剤は、市販製剤と同等の溶出性を示すことが判った。
[Test Example 3] (Elution)
For the tablets obtained in Examples 1 and 2, the dissolution rate of clopidogrel was measured by a dissolution test (test solution Japanese Pharmacopoeia 1st liquid, paddle rotation speed 50 rpm), and the results shown in Table 3 were obtained.
From the results in Table 3, it was found that the tablets of Examples 1 and 2 according to the present invention showed the same dissolution properties as the commercially available preparation.
本発明によれば、抗血小板凝集薬として有用なクロピドグレル硫酸塩を含有する保存安定性に優れた錠剤を工業的に製造して、医療現場に提供することができる。
ADVANTAGE OF THE INVENTION According to this invention, the tablet excellent in the storage stability containing the clopidogrel sulfate useful as an antiplatelet aggregation agent can be manufactured industrially, and can be provided to a medical field.
Claims (3)
The method according to claim 1 or 2, wherein the clopidogrel sulfate has a 10% particle size of 40 µm or more and a 90% particle size of 150 µm or less.
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| CN109069436A (en) * | 2016-03-16 | 2018-12-21 | 韩国联合制药株式会社 | Compound formulation containing clopidogrel and aspirin |
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| WO2005070464A2 (en) * | 2004-01-21 | 2005-08-04 | Biofarma Ilac Sanayi Ve Ticaret A.S. | A tablet formulation of clopidogrel bisulphate |
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