JP2019508464A - Combined preparation containing clopidogrel and aspirin - Google Patents
Combined preparation containing clopidogrel and aspirin Download PDFInfo
- Publication number
- JP2019508464A JP2019508464A JP2018548696A JP2018548696A JP2019508464A JP 2019508464 A JP2019508464 A JP 2019508464A JP 2018548696 A JP2018548696 A JP 2018548696A JP 2018548696 A JP2018548696 A JP 2018548696A JP 2019508464 A JP2019508464 A JP 2019508464A
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- Prior art keywords
- clopidogrel
- aspirin
- tablet
- preparation according
- composite preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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Abstract
本発明は、クロピドグレル及びアスピリンを含む複合製剤及びその製造方法に関し、保管及び流通中にも安定性を維持し、クロピドグレル錠剤の崩解速度が速い効果を奏する。The present invention relates to a composite preparation containing clopidogrel and aspirin and a method for producing the same, maintaining stability during storage and distribution, and exhibiting an effect of rapid disintegration of clopidogrel tablets.
Description
本発明は、クロピドグレル及びアスピリンを含む複合製剤及びその製造方法に関する。 The present invention relates to a composite preparation comprising clopidogrel and aspirin and a method of producing the same.
本発明においてクロピドグレルは、脳卒中、血栓症、塞栓症、心筋梗塞のような末梢または冠状動脈疾患の治療に効果的な血小板凝集抑制剤であり、化学名称はメチル（＋）−（Ｓ）−α−（２−クロロフェニル）−６，７−ジヒドロチエノ［３，２−ｃ］ピリジン−５（４Ｈ）−アセテートである。 In the present invention, clopidogrel is a platelet aggregation inhibitor effective for the treatment of peripheral or coronary artery disease such as stroke, thrombosis, embolism, myocardial infarction, and the chemical name is methyl (+)-(S) -α -(2-Chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate.
クロピドグレルは、血栓の形成に重要な役割をすることが知られているアデノシン二リン酸（Adenosinediphosphate、以下「ＡＤＰ」という）受容体に対するＡＤＰ結合の直接的な抑制及びそれに続く糖タンパク質ＧＰＩＩｂ／ＩＩａ複合体のＡＤＰ−媒介された活性化の直接的な抑制により、ＡＤＰ−誘導された血小板凝集を特異的に抑制する。また、クロピドグレルは、放出されたＡＤＰによる血小板活性化の増幅を遮断することによりＡＤＰを除いたアゴニスト（agonist）により誘発された血小板凝集を抑制する。 Clopidogrel is known to play an important role in thrombus formation. Direct inhibition of ADP binding to adenosine diphosphate (Adenosine diphosphate, hereinafter referred to as "ADP") receptor and subsequent glycoprotein GPIIb / IIa complex Direct suppression of ADP-mediated activation of the body specifically suppresses ADP-induced platelet aggregation. Clopidogrel also suppresses ADP-elicited platelet aggregation induced by blocking the amplification of platelet activation by released ADP.
このようなクロピドグレルの薬理作用は、クロピドグレルが経口投与された後、肝臓で代謝されて形成される活性型代謝体により行われる。この活性型代謝体は選択的に、そして不可逆的に血小板にあるＡＤＰ受容体を変形させることにより、ＡＤＰがＡＤＰ受容体と結合することを妨害する。したがって、クロピドグレルの効果は、肝臓でクロピドグレルを代謝させる酵素に大きく依存する。 Such pharmacological actions of clopidogrel are performed by active metabolites formed by being metabolized in the liver after clopidogrel is orally administered. This active metabolite selectively and irreversibly deforms the ADP receptor present on platelets, thereby blocking ADP from binding to the ADP receptor. Thus, the effects of clopidogrel are largely dependent on enzymes that metabolize clopidogrel in the liver.
クロピドグレルの代表的な製薬原料であるクロピドグレルビスルフェート（またはクロピドグレル硫酸水素塩）の化学名称はメチル（＋）−（Ｓ）−α−（２−クロロフェニル）−６，７−ジヒドロチエノ［３，２−ｃ］ピリジン−５（４Ｈ）−アセテート硫酸（１：１）であり、分子量は４１９．９であり、実験式はＣ１６Ｈ１６ＣｌＮＯ２Ｓ・Ｈ２ＳＯ４である。 The chemical name of clopidogrel bisulfate (or clopidogrel hydrogensulfate), which is a representative pharmaceutical material of clopidogrel, is methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2- c] Pyridine-5 (4H) -acetate sulfuric acid (1: 1), molecular weight 419.9, empirical formula C 16 H 16 ClNO 2 S · H 2 SO 4
クロピドグレルビスルフェートは急性（recent）心筋梗塞（myocardial infarction、以下「ＭＩ」という）、急性脳卒中（stroke）、または確立された（established）動脈疾患（arterial disease）のような血栓性イベント（thrombotic event）の減少のために処方され、新たな（new）虚血性脳卒中（ischemic stroke）、新たなＭＩ、及びその他の血管性死亡（vascular death）の複合した終点（combined end point）の速度を減少させることが明らかになった。急性冠症候群の患者の場合、クロピドグレルビスルフェートは、心臓血管死、ＭＩ、脳卒中、または難治性虚血（refractory ischemia）の複合した終点の速度を減少させることが明らかになった。 Clopidogrel bisulphate is a thrombotic event such as acute myocardial infarction (recent) myocardial infarction (myocardial infarction, hereinafter referred to as "MI"), acute stroke (stroke), or established arterial disease (arterial disease) To reduce the rate of the combined end point of new ischemic stroke, new MI, and other vascular death, prescribed for reduction of It became clear. In patients with acute coronary syndrome, clopidogrel bisulfate has been shown to reduce the rate of the combined end point of cardiovascular death, MI, stroke, or refractory ischemia.
また、血栓の生成を予防する最も効果的な薬物の一つとして知られているアスピリン（一般名：アセチルサリチル酸）は、鎮痛剤（わずかな痛みや疼痛に対して）、解熱剤（発熱に対して）、及び抗炎症剤としてしばしば使用される。アスピリンはまた、抗凝固（血液を薄くする、blood thinning）の効果があり、長期間の低投与量で心臓発作（heart attack）を防止するために使用される。 In addition, aspirin (generic name: acetylsalicylic acid), which is known as one of the most effective drugs for preventing the formation of blood clots, is an analgesic (for slight pain and pain) and an antipyretic (for fever And is often used as an anti-inflammatory agent. Aspirin is also effective in anticoagulation (blood thinning, blood thinning) and is used to prevent heart attack at long-term, low doses.
アスピリンは、一過性虚血発作の予防及び動脈血栓症の予防のために、投与は、一般に、１回または数回の投与で、一日当り３０ｍｇ〜１２００ｍｇが投与される。アスピリンは、危険な血液凝固物（blood clot）が生成することを防ぐことにより、心臓発作、脳卒中、または血管が血液凝固物により詰まったときに発生し得るその他の問題の可能性を減らすために使用することができる。 Aspirin is generally administered in an amount of 30 mg to 1200 mg per day, in one or several administrations, for the prevention of transient ischemic stroke and the prevention of arterial thrombosis. Aspirin prevents the formation of dangerous blood clots and thereby reduces the possibility of a heart attack, stroke, or other problems that can occur when blood vessels become clogged with blood clots. It can be used.
アスピリンは、長期間の少ない投与量でも、血小板においてトロンボキサンＡ２の生成を不可逆的に遮断し、血小板の凝集を抑制する効果を奏し、このように血液を薄くする特徴が心臓発作の発生率を減少させるのに有用である。 Aspirin irreversibly blocks the formation of thromboxane A2 in platelets and exerts an effect of suppressing platelet aggregation even at a low dose for a long period of time, and the characteristics of thinning blood in this way cause the incidence of heart attack. Useful for reducing.
また、アスピリンはクロピドグレルを肝臓で活性型代謝体に変化させる酵素を活性化させることが知られている。したがって、クロピドグレルとアスピリンを共に投与する剤形について多くの研究がなされてきたが、両薬物が直接接触する場合、共晶（eutectic）現象が発生する問題がある。何よりも、アスピリンは、胃腸の吸収が少ない物質であるため、一定量以上を投与しなければならないが、アスピリン自体が胃腸を損傷させる性質があり、その使用量に制限が相当である。このような危険性は、クロピドグレルの代謝増大のためにアスピリンが先に溶出される剤形において、その問題がさらに深刻になる。 Aspirin is also known to activate an enzyme that converts clopidogrel to an active metabolite in the liver. Therefore, although many studies have been conducted on dosage forms in which clopidogrel and aspirin are coadministered, there is a problem that eutectic phenomenon occurs when the two drugs are in direct contact. Above all, aspirin is a substance with low gastrointestinal absorption, so it must be administered at a certain dose or more, but aspirin itself has the property of damaging the gastrointestinal tract, and its usage is quite limited. Such risks are exacerbated in dosage forms where aspirin is first eluted due to increased metabolism of clopidogrel.
また、クロピドグレルまたはその塩は、物性が非常に悪く、製剤化が非常に困難な代表的な薬物である。これらは水分に敏感であり、水溶液と接触すると、互いに固まってゲル化する現象が発生するなど、崩解が遅延される問題がある。特にクロピドグレルまたはその塩は、吸湿性が非常に高く、水分の存在下で加水分解され、安定性が低くなるため、保管に特別の注意が要求される。 In addition, clopidogrel or a salt thereof is a representative drug which has very poor physical properties and is very difficult to formulate. These are sensitive to moisture, and when they come in contact with an aqueous solution, there is a problem that disintegration is delayed, such as a phenomenon in which they are solidified and gelled. In particular, clopidogrel or its salt is very hygroscopic, hydrolysed in the presence of moisture, and less stable, requiring special care for storage.
そこで、本発明者らはクロピドグレルを含む製剤の保管及び流通中の安定性低下の問題を解決し、クロピドグレルが錠剤の場合に発生する崩解速度減少の問題を解決するために、以下のような発明を考案した。 Therefore, in order to solve the problem of decreased stability during storage and distribution of a formulation containing clopidogrel, and to solve the problem of reduced disintegration rate caused by clopidogrel in the case of tablets, I devised an invention.
本発明は、保管及び流通中に安定性が高められたクロピドグレル錠剤及びアスピリン含有粒子を含む複合製剤を提供しようとし、前記アスピリン含有粒子は、顆粒またはペレットの形態であってもよい。 The present invention seeks to provide a composite formulation comprising clopidogrel tablet and aspirin-containing particles with increased stability during storage and distribution, said aspirin-containing particles may be in the form of granules or pellets.
また、本発明は、前記複合製剤中に存在するクロピドグレル錠剤の崩解速度が増加した複合製剤を提供しようとする。 The present invention also seeks to provide a composite preparation having an increased disintegration rate of clopidogrel tablet present in the composite preparation.
さらに、本発明は、クロピドグレルを錠剤形態で含む、クロピドグレル及びアスピリンの複合製剤をカプセル形態で提供しようとする場合、カプセル内に含まれるように錠剤の大きさを調節しなければならないが、この場合、錠剤内のクロピドグレルの含有量比の増加に応じて、打錠時にパンチにくっつくスティッキング（sticking）、キャッピング（capping）現象が発生することがある。このような問題を防止するために、本発明では、また、コロイド性二酸化ケイ素を主成分とまず混合して製造したクロピドグレル錠剤及びこれを含む複合製剤を提供しようとする。 Furthermore, when the present invention is to provide a combined preparation of clopidogrel and aspirin in the form of a capsule, which comprises clopidogrel in tablet form, the size of the tablet must be adjusted to be contained in the capsule, in this case Depending on the increase in the content ratio of clopidogrel in the tablet, sticking and capping phenomena may occur that stick to the punch during tableting. In order to prevent such problems, the present invention also seeks to provide a clopidogrel tablet prepared by first mixing colloidal silicon dioxide with the main component and a composite preparation comprising the same.
前記の目的を達成するための一つの様態として、本発明は、クロピドグレル、その異性体またはその薬学的に許容可能な塩を含むクロピドグレル錠剤；及びアスピリン、その異性体またはその薬学的に許容可能な塩を含むアスピリンコア、及び前記コアを包む腸溶性コーティング層を含むアスピリン粒子を含む複合製剤を提供する。 In one embodiment to achieve the above object, the present invention relates to clopidogrel tablets comprising clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof; and aspirin, an isomer thereof or a pharmaceutically acceptable salt thereof There is provided a composite preparation comprising aspirin core comprising a salt, and aspirin particles comprising an enteric coating layer covering said core.
本明細書において、「クロピドグレル」について開示した部分は、「クロピドグレル、その異性体またはその薬学的に許容可能な塩」を全て含む意味で解釈されてもよい。 In the present specification, the portion disclosed for "clopidogrel" may be interpreted to include all "clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof".
もう一つの様態として、本発明は、クロピドグレル、その異性体またはその薬学的に許容可能な塩、及びコロイド性二酸化ケイ素をまず混合した後、崩壊剤を添加してクロピドグレル錠剤を準備する段階を含む、複合製剤の製造方法を提供する。 In another embodiment, the present invention comprises the steps of first mixing clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof, and colloidal silicon dioxide, and then adding a disintegrant to prepare clopidogrel tablets. , Provide a method for producing a combined preparation.
本発明は、クロピドグレル、その異性体またはその薬学的に許容可能な塩を含むクロピドグレルを錠剤形態にすることにより、保管及び流通中に複合製剤の安定性が低下する問題を解決した。 The present invention solves the problem of reduced stability of the combined preparation during storage and distribution by tableting clopidogrel containing clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof.
前記複合製剤は、クロピドグレル錠剤及びアスピリン含有粒子を含むカプセルであってもよく、一実施形態において前記カプセルは硬質カプセルであってもよい。 The composite formulation may be a capsule comprising clopidogrel tablet and aspirin containing particles, and in one embodiment the capsule may be a hard capsule.
クロピドグレルを顆粒形態ではなく、錠剤形態にしてカプセル内に封入する場合、クロピドグレルの崩解が遅延される問題が発生することがあり、これに対し、本発明は、クロピドグレル錠剤の総重量基準で崩解剤を２〜８重量％、より具体的には３〜５重量％を含むことにより、これを解決した。崩壊剤の含有量がクロピドグレル錠剤の総重量基準で２重量％未満である場合、望ましい崩解速度を得ることができず、８重量％を超える場合、錠剤が大気中に露出時、安定性が低下する問題が発生する。一般に知られているクロピドグレル及びアスピリンの複合製剤内に存在するクロピドグレル錠剤の崩解時間は１２分以上であるが、本発明の複合製剤では、これよりクロピドグレルがより速い速度で崩解できる点をもう一つの特徴とする。本発明の複合製剤では、クロピドグレルを錠剤形態として含み、顆粒形態のクロピドグレルを含む場合に比べて崩解速度の減少の問題を示しうるが、崩壊剤を前記のようにさらに含むことにより、このような問題を改善することができる。また、本発明の複合製剤は、まず胃でクロピドグレルが溶出され、アスピリン顆粒は、後で腸で溶出されるが、前記のように崩解速度を改善させることにより、クロピドグレルとアスピリンの接触による問題を防止し、薬剤の安定性を向上させることができる。 When clopidogrel is not in the form of granules, and is enclosed in a capsule in the form of tablets, problems may occur that the disintegration of clopidogrel is delayed, whereas the present invention is based on the total weight of clopidogrel tablets. This was solved by including 2 to 8 wt.%, More specifically 3 to 5 wt. If the disintegrant content is less than 2% by weight based on the total weight of the clopidogrel tablet, the desired disintegration rate can not be obtained, and if it is more than 8% by weight, the tablet has stability when exposed to the atmosphere The problem of falling occurs. Although the disintegration time of clopidogrel tablets present in the commonly known combined preparation of clopidogrel and aspirin is 12 minutes or more, in the combined preparation of the present invention, clopidogrel can be disintegrated at a faster rate than this. One of the features. Although the combination preparation of the present invention contains clopidogrel as a tablet form and may exhibit the problem of reduction in the disintegration rate as compared to the case of containing clopidogrel in the form of granules, the inclusion of a disintegrant as described above makes Problems can be improved. In addition, although the complex preparation of the present invention elutes clopidogrel in the stomach first and aspirin granules later in the intestine, the problem caused by contact with clopidogrel and aspirin by improving the disintegration rate as described above To improve the stability of the drug.
本発明の複合製剤内に存在するクロピドグレル錠剤は崩壊剤を含むことにより、崩解時間がそれ未満、具体的には１１分以下、より具体的には７分以下に短縮することができる。 The clopidogrel tablet present in the composite preparation of the present invention can reduce the disintegration time to less than 11 minutes, more specifically to 7 minutes or less, by containing a disintegrant.
前記崩壊剤は、澱粉グリコール酸ナトリウム、トウモロコシ澱粉、ジャガイモ澱粉またはプレゼラチン化澱粉などの澱粉または変性澱粉と、ベントナイト、モンモリロナイト、ビーガム（veegum）などのクレイと、微結晶性セルロース、ヒドロキシプロピルセルロースまたはカルボキシメチルセルロースなどのセルロース類と、アルギン酸ナトリウムまたはアルギン酸などのアルギン類と、クロスカルメロース（croscarmellose）ナトリウムなどの架橋セルロース類と、グアーガム、キサンタンガムなどのガム類と、架橋ポリビニルピロリドン（crospovidone）及びその混合物からなる群から選択された一つ以上であってもよい。より具体的には、前記崩解剤は、ポリビニルピロリドンなどであってもよい。 The disintegrant is starch or sodium starch glycolate, corn starch, potato starch or starch such as pregelatinized starch or modified starch, bentonite, montmorillonite, clay such as veegum (veegum), microcrystalline cellulose, hydroxypropyl cellulose or Cellulose such as carboxymethyl cellulose, algins such as sodium alginate or alginic acid, crosslinked cellulose such as croscarmellose sodium, gums such as guar gum and xanthan gum, crosslinked polyvinyl pyrrolidone (crospovidone) and mixtures thereof It may be one or more selected from the group consisting of More specifically, the disintegrant may be polyvinyl pyrrolidone or the like.
また、カプセル内にクロピドグレル錠剤を封入する場合、クロピドグレル錠剤の重量は１２０〜３５０ｍｇ、具体的には１５０〜２５０ｍｇ、より具体的には、１８０〜２４０ｍｇであってもよく、実処方基準に基づいて異なって製造することができる。 Also, when clopidogrel tablet is enclosed in a capsule, the weight of clopidogrel tablet may be 120 to 350 mg, specifically 150 to 250 mg, more specifically 180 to 240 mg, based on the actual formulation standard. It can be manufactured differently.
カプセル内にクロピドグレル錠剤を封入した場合、クロピドグレルの錠剤サイズに制限があり、クロピドグレル錠剤重量に対するクロピドグレルの重量比が５０％程度またはそれ以上まで高くなることがあるため、打錠時にパンチにくっつくスティッキング（sticking）、キャッピング（capping）現象が発生する問題がある。 When clopidogrel tablets are enclosed in a capsule, there is a limitation on the tablet size of clopidogrel, and the weight ratio of clopidogrel to clopidogrel tablet weight can be as high as 50% or more, so sticking to the punch during tableting ( There is a problem that sticking and capping phenomenon occur.
これを解決するために、コロイド性二酸化ケイ素をクロピドグレルとまず混合した後、崩壊剤などの他の添加剤を添加してクロピドグレル錠剤を製造することができる。 In order to solve this, colloidal silicon dioxide can be first mixed with clopidogrel and then other additives such as disintegrants can be added to make clopidogrel tablets.
また、クロピドグレル錠剤は、乾燥減量が５重量％未満、より好ましくは１．５重量％以下の賦形剤を使用することができる。ここで、賦形剤の乾燥減量が５重量％以上である場合、スティッキングなどの打錠障害が発生することがある。 In addition, clopidogrel tablets can use an excipient with a loss on drying of less than 5% by weight, more preferably 1.5% by weight or less. Here, when the loss on drying of the excipient is 5% by weight or more, tableting problems such as sticking may occur.
前記賦形剤は、白糖、Ｄ−マンニトール、微結晶セルロース、ポリエチレングリコール、低置換度ヒドロキシプロピルセルロース、コロイド性二酸化ケイ素及びこれらの組み合わせなどからなる群から選択されてもよく、前記賦形剤は微結晶セルロース（microcrystalline cellulose、MCC）であってもよい。また、一実施形態において、前記賦形剤はＭＣＣ １１２である。 The excipient may be selected from the group consisting of sucrose, D-mannitol, microcrystalline cellulose, polyethylene glycol, low substituted hydroxypropyl cellulose, colloidal silicon dioxide, combinations thereof and the like, and the excipient is It may be microcrystalline cellulose (MCC). Also, in one embodiment, the excipient is MCC112.
一実施形態において、カプセルの素材は、ゼラチンまたはヒドロキシプロピルメチルセルロース（ＨＰＭＣ）であってもよく、ＨＰＭＣであることがより好ましいが、特にこれに限定されるものではない。 In one embodiment, the material of the capsule may be gelatin or hydroxypropyl methylcellulose (HPMC), more preferably HPMC, but is not particularly limited thereto.
以下、本発明における複合製剤を具体的に説明する。一方、本願で開示されたそれぞれの説明及び実施形態は、それぞれの異なる説明及び実施形態にも適用することができる。即ち、本願で開示された多様な要素のすべての組み合わせが本発明の範囲に属する。また、下記記述された具体的な叙述により、本発明の範疇が限定されるとは見られない。 Hereinafter, the composite preparation in the present invention will be specifically described. On the other hand, each description and embodiment disclosed in the present application can be applied to each different description and embodiment. That is, all combinations of the various elements disclosed in the present application fall within the scope of the present invention. In addition, the scope of the present invention is not considered to be limited by the specific descriptions described below.
本発明の複合製剤に含まれるクロピドグレル及びアスピリンは薬学的に許容可能な塩の形態で存在することができる。塩としては、薬学的に許容可能な遊離酸（free acid）により形成された酸付加塩が有用でありうるが、特にこれに限定されない。 Clopidogrel and aspirin contained in the combined preparation of the present invention can be present in the form of pharmaceutically acceptable salts. As a salt, an acid addition salt formed by a pharmaceutically acceptable free acid may be useful, but it is not particularly limited thereto.
前記塩の種類は特に限定されない。ただし、個体、例えば、哺乳類に安全かつ効果的な形態であることが望ましいが、特にこれに限定されるものではない。 The type of the salt is not particularly limited. However, it is desirable that the form is safe and effective for an individual, for example, a mammal, but it is not particularly limited thereto.
前記用語、「薬学的に許容可能な」とは、医薬学的判断の範囲内で、過度の毒性、刺激、またはアレルギー反応などを引き起こすことなく、目的とする用途に効果的に使用可能な物質を意味する。 The term "pharmaceutically acceptable" is a substance that can be effectively used for the intended application without causing excessive toxicity, irritation, or allergic reaction within the scope of pharmaceutical judgment. Means
本発明において、用語、「薬学的に許容可能な塩」とは、薬学的に許容される無機酸、有機酸、または塩基から誘導された塩を含む。適切な酸の例としては、塩酸、臭素酸、硫酸、硝酸、過塩素酸、フマル酸、マレイン酸、リン酸、グリコール酸、乳酸、サリチル酸、コハク酸、トルエン−ｐ−スルホン酸、酒石酸、酢酸、クエン酸、メタンスルホン酸、ギ酸、安息香酸、マロン酸、ナフタレン−２−スルホン酸、ベンゼンスルホン酸などを挙げることができる。適切な塩基から誘導された塩は、ナトリウム、カリウムなどのアルカリ金属、マグネシウムなどのアルカリ土類金属、及びアンモニウムなどを含むことができる。 In the present invention, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids or bases. Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid And citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Salts derived from appropriate bases can include sodium, alkali metals such as potassium, alkaline earth metals such as magnesium, and ammonium.
酸付加塩は、通常の方法、例えば、化合物を過量の酸水溶液に溶解させ、この塩を水混和性有機溶媒、例えば、メタノール、エタノール、アセトンまたはアセトニトリルを使用して沈殿させて製造することができる。同モル量の化合物及び水中の酸またはアルコール（例えば、グリコールモノメチルエーテル）を加熱し、次いで混合物を蒸発させて乾燥させるか、または析出された塩を吸引濾過することができる。 The acid addition salts may be prepared by conventional methods, for example by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. it can. The equimolar amounts of the compound and the acid or alcohol (eg glycol monomethyl ether) in water can be heated and then the mixture can be evaporated to dryness or the precipitated salt can be suction filtered.
また、塩基を使用して薬学的に許容可能な金属塩を作ることができる。アルカリ金属塩またはアルカリ土類金属塩は、例えば、化合物を過量のアルカリ金属水酸化物またはアルカリ土類金属水酸化物の溶液中に溶解させ、非溶解化合物の塩をろ過した後、ろ液を蒸発、乾燥させて得ることができる。 Also, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in a solution of an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide and filtering the salt of the undissolved compound, and then filtering the filtrate. It can be obtained by evaporation and drying.
より具体的には、本発明のクロピドグレルの薬学的に許容可能な塩は、クロピドグレルの硫酸水素塩、樹脂酸塩、カムシラート、ベシル酸塩、ナパジシル酸一水和物塩、塩酸塩及びその混合物からなる群から選択されることができる。 More specifically, the pharmaceutically acceptable salts of clopidogrel according to the present invention can be prepared from a hydrogensulfate of clopidogrel, resin acid salt, camsylate, besylate, napadisilic acid monohydrate salt, hydrochloride and mixtures thereof Can be selected from the group consisting of
コロイド性二酸化ケイ素（fumed silica、colloidal silicon dioxide）は、ＣＡＳ Ｎｏ．７６３１−８６−９であり、本発明では、賦形剤としての役割をし、打錠時に打錠障害を減少させる効果を有する。 Colloidal silicon dioxide (fumed silica, colloidal silicon dioxide) is disclosed in CAS No. 7631-86-9, which serves as an excipient and has the effect of reducing tableting failure at the time of tableting.
前記コロイド性二酸化ケイ素の含有量は、クロピドグレル錠剤の総重量基準で２〜１０重量％であってもよい。前記範囲未満で含まれる場合には、打錠時にスティッキングが起こり商業的に連続生産が難しく、前記範囲を超えて含まれる場合には、打錠時にキャッピングが起こり崩解が遅延することがある。 The content of the colloidal silicon dioxide may be 2 to 10% by weight based on the total weight of clopidogrel tablet. If the content is less than the above range, sticking may occur at the time of tableting to make commercially continuous production difficult, and if it is included beyond the range, capping may occur at the time of tableting and disintegration may be delayed.
コロイド性二酸化ケイ素の粒径は、約７〜１６ｎｍであってもよく、２００〜４００ｍ２／ｇの比表面積を有してもよい。 The particle size of the colloidal silicon dioxide may be about 7 to 16 nm and may have a specific surface area of 200 to 400 m 2 / g.
本発明のクロピドグレル錠剤は、さらにコーティングされてもよく、コーティング物質としては制限なく可能であり、一実施形態においてコーティング物質はネオコート（neocoat）であってもよい。 The clopidogrel tablet of the present invention may be further coated, and is possible without limitation as a coating substance, and in one embodiment the coating substance may be neocoat.
アスピリン含有粒子は、粉末、顆粒、ペレット、ミニ錠剤形態であってもよく、一実施例において顆粒またはペレットであってもよい。 The aspirin-containing particles may be in the form of powder, granules, pellets, mini-tablets, and in one embodiment may be granules or pellets.
前記アスピリン含有粒子は、具体的に、賦形剤を含む内核、前記内核の外部に隣接し、薬理学的活性成分としてアスピリン、その異性体またはその薬剤学的に許容可能な塩及び結合剤を含むアスピリン外核、及び前記外核の外部に隣接し、腸溶性コーティング剤を含む腸溶性コーティング層を含むことができる。前記内核及びアスピリン外核はアスピリンコアに相当する。具体的には、前記内核の賦形剤は、球状白糖であってもよく、前記腸溶性コーティング層は、可塑剤をさらに含むことができる。 Specifically, the aspirin-containing particle is an inner core containing an excipient, adjacent to the outside of the inner core, and aspirin, an isomer thereof or a pharmaceutically acceptable salt thereof and a binder as a pharmacologically active ingredient. It may include an aspirin outer core, and an enteric coating layer adjacent to the outside of the outer core and including an enteric coating. The inner core and the aspirin outer core correspond to aspirin core. Specifically, the excipient of the inner core may be spherical sucrose, and the enteric coating layer may further include a plasticizer.
アスピリンコアを囲む腸溶性コーティング層は、前記アスピリンコアを保護するために前記コアを包む層を意味し、コーティング層の素材である腸溶性コーティング剤は、高ｐＨである腸液環境で崩解される物質であれば制限なく使用可能であり、例えば、シェラック、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、ヒドロキシプロピルメチルセルロースフタレート、セルロースアセテートフタレート、セルロースアセテート、ポリビニルアルコールフタレート、メタクリル酸−メタクリル酸メチル共重合体、メチルアクリル酸−メタクリル酸メチル−メタクリル酸共重合体、メタクリル酸−エチルアクリル酸共重合体及びその混合物からなる群から選択された一つ以上の物質を含むことができる。 The enteric coating layer surrounding the aspirin core means the layer that wraps the core to protect the aspirin core, and the enteric coating agent which is the material of the coating layer is disintegrated in the intestinal fluid environment which is high pH Any substance can be used without limitation. For example, shellac, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate, polyvinyl alcohol phthalate, methacrylic acid-methyl methacrylate copolymer, methyl acrylic One or more materials selected from the group consisting of acid-methyl methacrylate-methacrylic acid copolymers, methacrylic acid-ethyl acrylic acid copolymers, and mixtures thereof can be included.
この中でメタクリル酸−メタクリル酸メチル共重合体は、エボニック・デグサ（Evonik Degussa）（ドイツ）のオイドラギット（Eudragit）Ｌ １００、オイドラギットＬ １２．５、オイドラギットＬ １００ Ｐのようなメタクリル酸、メチルメタクリル酸のモル比が１：１であるか、オイドラギットＳ １００、オイドラギットＳ １２．５、オイドラギットＳ １００ Ｐのようなメタクリル酸、メチルメタクリル酸のモル比が１：２であることが望ましい。 Among them, methacrylic acid-methyl methacrylate copolymer is methacrylic acid, methyl methacrylate such as Eudragit L 100, Eudragit L 12.5, Eudragit L 100 P of Evonik Degussa (Germany). It is desirable that the molar ratio of the acid is 1: 1, or the molar ratio of methacrylic acid such as Eudragit S 100, Eudragit S 12.5, Eudragit S 100 P, and methyl methacrylic acid is 1: 2.
また、メチルアクリル酸−メタクリル酸メチル−メタクリル酸共重合体は、エボニック・デグサ（ドイツ）のオイドラギットＦＳ ３０Ｄのようなメチルアクリル酸、メタクリル酸メチル、メタクリル酸のモル比が７：３：１であることが望ましい。 In addition, the methyl acrylic acid-methyl methacrylate-methacrylic acid copolymer is a mixture of methyl acrylic acid such as Eudragit FS 30 D of Evonik Degussa (Germany), methyl methacrylate, and methacrylic acid at a molar ratio of 7: 3: 1. It is desirable to have.
さらに、メタクリル酸−エチルアクリル酸共重合体は、エボニック・デグサ（ドイツ）のオイドラギットＬ ３０、Ｄ−５５、オイドラギットＬ １００−５５のようなメタクリル酸、エチルアクリル酸のモル比が１：１であることが望ましい。 Furthermore, methacrylic acid-ethyl acrylic acid copolymer has a molar ratio of 1: 1 of methacrylic acid and ethyl acrylic acid such as Eudragit L 30, D-55, Eudragit L 100-55 of Evonik Degussa (Germany). It is desirable to have.
前記腸溶性コーティング層は、アスピリン粒子の総重量基準で一実施形態において２．０重量％〜２０重量％、他の一実施形態において５〜１５重量％、また他の一実施形態において５〜１２重量％で含まれてもよい。前記範囲未満でコーティング層を形成する場合、胃で目的としない放出が起こることがあり、前記範囲を超えてコーティング層を形成する場合、溶出率が減少し、酸抵抗性が不良であり、生体利用率が減少する欠点があり、長期投与時に問題が発生することがある。 The enteric coating layer is 2.0 wt% to 20 wt% in one embodiment, 5 to 15 wt% in another embodiment, 5 to 12 in another embodiment based on the total weight of aspirin particles It may be included by weight%. If the coating layer is formed below the above range, an unintended release may occur in the stomach, and if the coating layer is formed above the above range, the elution rate decreases and the acid resistance is poor, There is a disadvantage of reduced availability and problems may occur during long-term administration.
また、前記クロピドグレル錠剤またはアスピリン含有粒子は、希釈剤、結合剤、滑沢剤、安定化剤、フィルムコーティング剤、可塑剤及びその混合物からなる群から選択された添加剤をさらに含むことができる。 In addition, the clopidogrel tablet or aspirin-containing particles may further include an additive selected from the group consisting of a diluent, a binder, a lubricant, a stabilizer, a film coating agent, a plasticizer and a mixture thereof.
前記結合剤は、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、ポリビニルピロリドン、コポビドン、マクロゴール、硬質無水ケイ酸、合成ケイ酸アルミニウム、ケイ酸カルシウムまたはマグネシウムメタシリケートアルミネートのようなケイ酸塩誘導体；リン酸水素カルシウムのようなリン酸塩；炭酸カルシウムのような炭酸塩；及びこれらの混合物からなる群から選択されてもよく、より好ましくはヒプロメロース、ポリビニルピロリドン及びその混合物からなる群から選択されてもよい。錠剤または粒子の総重量を基準に、前記結合剤は１重量％〜５重量％であり、より具体的には１重量％〜４重量％である。 The binder is hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, copovidone, macrogol, hard anhydrous silicic acid, synthetic aluminum silicate, silicate derivative such as calcium silicate or magnesium metasilicate aluminate; phosphoric acid It may be selected from the group consisting of phosphates such as calcium hydrogen; carbonates such as calcium carbonate; and mixtures thereof, more preferably selected from the group consisting of hypromellose, polyvinyl pyrrolidone and mixtures thereof . Based on the total weight of the tablet or particles, the binder is 1% to 5% by weight, more specifically 1% to 4% by weight.
前記希釈剤は、炭酸カルシウム、リン酸カルシウム、セルロース、デキストリン、デキストロース、エチルセルロース、果糖、グリセリルパルミトステアレート、マルトース、スクロース、澱粉、微結晶性セルロース、乳糖、ブドウ糖、マンニトール、アルギネート、アルカリ土金属類塩、クレイ、ポリエチレングリコール、ジカルシウムホスフェート及びその混合物からなる群から選択されてもよい。 The diluent is calcium carbonate, calcium phosphate, cellulose, dextrin, dextrose, ethylcellulose, fructose, glyceryl palmitostearate, maltose, sucrose, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts , Clay, polyethylene glycol, dicalcium phosphate and mixtures thereof.
前記滑沢剤は、タルク、ステアリン酸及びその塩類、ラウリル硫酸ナトリウム、水素化植物油、ナトリウムベンゾエート、ステアリルフマル酸ナトリウム、グリセリルモノステアレート、ポリエチレングリコール及びその混合物からなる群から選択されることができ、より好ましくは、ステアリルフマル酸ナトリウムであってもよい。 The lubricant may be selected from the group consisting of talc, stearic acid and its salts, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol and mixtures thereof And more preferably sodium stearyl fumarate.
前記安定化剤は、ブチルヒドロキシトルエン（ＢＨＴ）、ブチルヒドロキシアニソール（ＢＨＡ）、アスコルビン酸、トコフェロール、エデト酸（ＥＤＴＡ）及びその混合物からなる群から選択されてもよい。 The stabilizing agent may be selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid, tocopherol, edetic acid (EDTA) and mixtures thereof.
前記フィルムコーティング剤は、ゼラチン、メチルセルロース、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、ポリエチレングリコール、シェラック、エチルセルロース、メチルヒドロキシエチルセルロース、ヒドロキシエチルセルロース、カルボキシメチルセルロースナトリウム、ポリビニルアルコール、ポリビニルピロリドン、ビニルピロリドンと酢酸ビニルの重合体、アクリル酸エチルメタクリル酸メチルメタクリル酸塩化トリメチルアンモニウムエチル共重合体（例えば、商品名、オイドラギット（Eudragit）ＲＳまたはＲＬ、デグサ）、メタクリル酸メチルアクリル酸エチル共重合体（例えば、商品名、オイドラギット（Eudragit）ＮＥ３０Ｄ、デグサ）、ポリビニルアセチルジメチルアミノアセテート及びその混合物からなる群から選択されてもよい。 The film coating agent may be gelatin, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, shellac, ethyl cellulose, methyl hydroxyethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium, polyvinyl alcohol, polyvinyl pyrrolidone, a polymer of vinyl pyrrolidone and vinyl acetate Ethyl acrylate methacrylate methyl methacrylate methacrylated trimethylammonium ethyl copolymer (for example, trade name Eudragit RS or RL, degussa), methyl methacrylate acrylic acid ethyl methacrylate copolymer (for example trade name Eudragit ( Eudragit) NE30D, Degussa), polyvinyl acetyl dimethylamino acetate and the like It may be selected from the group consisting of a mixture of
前記可塑剤は、グリコール、エステル、オイル、グリセリン、グリセリン誘導体及びその混合物からなる群から選択されてもよいが、この中でグリコールはプロピレングリコール、ポリエチレングリコール、及びその混合物からなる群から選択されてもよく、エステルはフタル酸ジエチル、フタル酸ジブチル、ジブチルセバケート、トリエチルシトレート、アセチルトリエチルシトレート、アセチルトリブチルシトレート、トリアセチン及びその混合物からなる群から選択されてもよい。前記オイルはヒマシ油、ココナッツ油及びその混合物からなる群から選択されてもよく、グリセリン及びグリセリン誘導体はグリセリン、モノステアリングリセリン及びその混合物からなる群から選択されてもよい。 The plasticizer may be selected from the group consisting of glycols, esters, oils, glycerin, glycerin derivatives and mixtures thereof, wherein glycol is selected from the group consisting of propylene glycol, polyethylene glycol and mixtures thereof Also, the ester may be selected from the group consisting of diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triacetin and mixtures thereof. The oil may be selected from the group consisting of castor oil, coconut oil and mixtures thereof, and the glycerin and glycerin derivatives may be selected from the group consisting of glycerin, monostearin glycerol and mixtures thereof.
本発明の複合製剤において、前記クロピドグレル錠剤またはアスピリン含有粒子は、速放出物質をさらに含んで放出速度を増加させることができ、前記速放出物質は発泡剤、緩衝剤及びその混合物から選択することができる。 In the composite preparation of the present invention, the clopidogrel tablet or aspirin-containing particles may further contain a fast release substance to increase the release rate, and the fast release substance may be selected from a foaming agent, a buffer and a mixture thereof. it can.
前記発泡剤は、炭酸を含む無機物及び有機酸を含むことができる。 The blowing agent may include an inorganic substance containing carbonic acid and an organic acid.
前記緩衝剤は、炭酸カルシウム、リン酸二水素ナトリウム、リン酸一水素ナトリウム、グルタミン酸ナトリウム、クエン酸カリウム、炭酸水素ナトリウム、クエン酸ナトリウム、水酸化ナトリウム、リン酸カルシウム、リン酸水素カルシウム、または多様な塩及びその混合物からなる群から選択することができる。 The buffer may be calcium carbonate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, sodium glutamate, potassium citrate, sodium bicarbonate, sodium citrate, sodium citrate, sodium hydroxide, calcium phosphate, calcium hydrogen phosphate, or various salts. And a mixture thereof.
一実施形態において、複合製剤内のクロピドグレル錠剤１００重量部に対して、アスピリンの総粒子は１０〜１０００重量部、具体的には３０〜２００重量部であってもよい。 In one embodiment, the total particles of aspirin may be 10 to 1000 parts by weight, specifically 30 to 200 parts by weight, based on 100 parts by weight of clopidogrel tablet in the combined preparation.
一実施例において、複合製剤はクロピドグレルとして７５ｍｇ及びアスピリンとして１００ｍｇ、またはクロピドグレルとして７５ｍｇ及びアスピリンとして７５ｍｇを含むことができる。 In one example, the combined preparation can include 75 mg as clopidogrel and 100 mg as aspirin, or 75 mg as clopidogrel and 75 mg as aspirin.
本発明の複合製剤は、まず胃でクロピドグレル錠剤が溶出され、アスピリン粒子は腸で溶出される。したがって、クロピドグレルとアスピリンの相互補完的な薬理効果を発現させることができ、かつ、アスピリンによる胃壁の損傷を防止することができる。さらに、クロピドグレルとアスピリンが直接接触することを遮断することにより、共晶現象を防止し、含有量や溶出特性の変化を防ぎ、薬剤の安定性を向上させることができる。 In the composite preparation of the present invention, clopidogrel tablets are first eluted in the stomach, and aspirin particles are eluted in the intestine. Therefore, the mutually complementary pharmacological effects of clopidogrel and aspirin can be exhibited, and damage to the stomach wall by aspirin can be prevented. Furthermore, by blocking direct contact between clopidogrel and aspirin, the eutectic phenomenon can be prevented, changes in the content and elution characteristics can be prevented, and drug stability can be improved.
本発明の複合製剤の製造方法は、クロピドグレル、その異性体またはその薬学的に許容可能な塩、及びコロイド性二酸化ケイ素を混合した後、添加剤を添加してクロピドグレル錠剤を準備する段階；アスピリン、その異性体またはその薬学的に許容可能な塩を含むアスピリンコアを準備する段階；及び前記アスピリンコアを腸溶性コーティング剤でコーティングする段階を含むことができる。また、前記クロピドグレル錠剤及びコーティングされたアスピリン粒子をカプセルに充填する段階をさらに含むことができる。 The method for producing the composite preparation of the present invention comprises the steps of mixing clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof and colloidal silicon dioxide and adding an additive to prepare clopidogrel tablets; aspirin, Preparing an aspirin core comprising the isomer, or a pharmaceutically acceptable salt thereof; and coating the aspirin core with an enteric coating. Also, the method may further include the step of filling the clopidogrel tablet and the coated aspirin particles into a capsule.
本発明の複合製剤は、薬学的に有効な量のクロピドグレル錠剤及びアスピリン含有粒子を含むことができる。 The combination formulations of the present invention can include pharmaceutically effective amounts of clopidogrel tablets and aspirin containing particles.
本発明において、用語「薬学的に有効な量」とは、医学的治療に適用可能な合理的な恩恵／リスク比で疾患を治療するのに十分な量を意味し、一般に０．００１〜１０００ｍｇ／ｋｇの量、好ましくは０．０５〜２００ｍｇ／ｋｇ、より好ましくは０．１〜１００ｍｇ／ｋｇの量を一日１回〜数回に分けて投与することができる。しかし、本発明の目的上、特定の患者に対する具体的な治療的有効量は、達成しようとする反応の種類と程度、場合によっては他の製剤が使用されるかどうかをはじめとした具体的な組成物、患者の年齢、体重、一般的な健康状態、性別及び食事、投与時間、投与経路及び組成物の分泌率、治療期間、具体的な組成物と共に使用されたり、同時に使用される薬剤をはじめとする多様な因子と医薬分野においてよく知られている類似因子に応じて異なって適用することが望ましい。 In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, generally 0.001 to 1000 mg. The amount of 1 / kg, preferably 0.05 to 200 mg / kg, more preferably 0.1 to 100 mg / kg can be administered once to several times a day. However, for the purposes of the present invention, a specific therapeutically effective amount for a particular patient will depend on the type and extent of the response to be achieved, and in some cases, whether or not other preparations are used. The composition, age, weight, general health, sex and diet of the patient, dosing time, route of administration and secretion rate of the composition, duration of treatment, medication used together with the specific composition, and concomitant medications It is desirable to apply differently depending on various factors such as those mentioned above and similar factors well known in the pharmaceutical field.
本発明に係る複合製剤は、さらに薬学的に活性のある別途の成分を含むことができる。 The combined preparation according to the present invention may further comprise additional pharmaceutically active ingredients.
本発明の製剤は、粉末形状を含むことができ、固体形態の製剤として製造されることが望ましいが、液体の形態への製造が不可能ではなく、これを権利範囲から排除することはない。 The formulations of the present invention may comprise a powder form and are preferably manufactured as a solid form formulation, but manufacturing into a liquid form is not impossible and is not excluded from the scope of the invention.
本発明の製剤は、個別の治療剤として投与することもでき、他の治療剤と併用して投与することができ、従来の治療法とは、順次または同時に投与することができる。そして、単一または多重投与されてもよい。 The formulations of the invention can also be administered as individual therapeutic agents, and can be administered in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapies. And may be single or multiple doses.
本発明で使用される用語「投与」とは、任意の適切な方法で患者に本発明の薬学的組成物を導入することを意味し、本発明の組成物の投与経路は、目的とする組織に到達することができる限り、経口または非経口の多様な経路を通じて投与することができる。好ましくは、経口投与であってもよい。本発明に係る製剤は、目的とする投与方法に応じて、多様な剤形に製作することができる。一実施形態において、複合製剤は、カプセル形態であってもよく、硬質カプセルであってもよい。カプセルの素材は、ゼラチンまたはＨＰＭＣであり、ＨＰＭＣであることがより好ましい。 As used herein, the term "administration" refers to the introduction of the pharmaceutical composition of the invention into a patient in any suitable manner, and the route of administration of the composition of the invention is the target tissue. As long as it can reach, it can be administered through various routes of oral or parenteral. Preferably, it may be orally administered. The preparation according to the present invention can be manufactured into various dosage forms depending on the intended administration method. In one embodiment, the combined preparation may be in the form of a capsule or may be a hard capsule. The material of the capsule is gelatin or HPMC, more preferably HPMC.
投与は、予防的にまたは治療的に実施することができる。 Administration can be performed prophylactically or therapeutically.
本発明の製剤の投与頻度は、特にこれに限定されないが、１日１回投与するか、または容量を分割して数回投与することができる。 The administration frequency of the formulation of the present invention is not particularly limited, but can be administered once a day or divided into several doses for divided doses.
本発明に係る製剤の投与対象となる個体は、ヒトを含めたすべての動物を意味することができる。前記動物は、ヒトだけでなく、これと類似した症状の治療を必要とする牛、馬、羊、豚、ヤギ、ラクダ、カモシカ、犬、猫などの哺乳動物であってもよいが、これらに限定されない。 The individual to whom the preparation according to the present invention is to be administered can mean all animals including humans. The animal may be not only human but also mammals such as cattle, horses, sheep, pigs, pigs, goats, camels, antelopes, dogs, cats, etc. which require treatment for symptoms similar thereto. It is not limited.
本発明の複合製剤は、保管及び流通中にも安定性が維持され、クロピドグレル錠剤の崩解速度を速くすることにより、カプセル内にクロピドグレル錠剤を含ませることによるクロピドグレルの溶出遅延を防ぐことができる。また、その他の添加剤を加える前に、コロイド性二酸化ケイ素を主成分と混合して錠剤を製造することにより、主成分であるクロピドグレル、その異性体またはその薬学的に許容可能な塩の含有量比が高まることによる、打錠時にパンチにくっつくスティッキング（sticking）、キャッピング（capping）現象が発生することを防止することができる。また、本発明は、カプセル内に錠剤を含める場合に発生する問題を解決することができる。 The composite preparation of the present invention maintains its stability even during storage and distribution, and the dissolution rate of clopidogrel tablet can be increased to prevent the dissolution delay of clopidogrel due to inclusion of clopidogrel tablet in the capsule. . In addition, the content of clopidogrel, its isomer or its pharmaceutically acceptable salt, which is the main component, is prepared by mixing colloidal silicon dioxide with the main component to produce a tablet before adding other additives. It is possible to prevent the sticking and capping phenomena from sticking to the punch at the time of tableting due to the increase of the ratio. The present invention can also solve the problems that occur when including tablets in capsules.
本発明の複合製剤は、有効成分であるクロピドグレルとアスピリンが物理的に直接接触しないように設計することにより、両成分の共晶（eutectic）現象を根本的に遮断することができる。また、共晶現象を排除し、各成分の物理化学的性質の変化を防止することにより、短期的に製剤の含有量、溶出特性、生物学的同等性（bioequivalence）の変化を防止し、長期的に製剤の安定性を向上させる効果がある。 The composite preparation of the present invention can fundamentally block the eutectic phenomenon of both components by designing the active ingredients clopidogrel and aspirin so as not to be in direct physical contact. In addition, by eliminating eutectic phenomena and preventing changes in the physicochemical properties of each component, changes in formulation content, dissolution characteristics, and bioequivalence can be prevented in the short term. It has the effect of improving the stability of the preparation.
それだけではなく、本発明の複合製剤は、アスピリンが胃壁を刺激して損傷を引き起こす問題の予防のために、アスピリンは腸のみで溶出され、胃では溶出しないようにアスピリンを腸溶層でコーティングした。したがって、本発明の複合製剤を経口投与すると、クロピドグレルが胃で先に溶出され、アスピリンは腸で後で溶出されることにより、胃壁の損傷を予防する効果がある。 Not only that, the composite preparation of the present invention is coated with enteric coating so that aspirin is eluted only in the intestine and not in the stomach to prevent the problem of aspirin stimulating the stomach wall and causing damage. . Therefore, when orally administered the complex preparation of the present invention, clopidogrel is eluted first in the stomach, and aspirin is later eluted in the intestine, which has the effect of preventing gastric wall damage.
さらに、クロピドグレルとアスピリンを同時にまたは時間差をおいて、別々に服用する場合に比べて、服用の利便性とコンプライアンスを増大させることはもちろん、相互に補完的な両薬物の薬理作用により従来の製剤に比べて少ない用量でも同様な結果を奏することができ、薬理成分による副作用と製造コストを削減するという利点がある。 Furthermore, compared with taking clopidogrel and aspirin at the same time or at different times, and increasing their convenience and compliance as well as taking them separately, the pharmacological action of both mutually complementary drugs can be used in conventional preparations. Similar results can be obtained with a smaller dose, and there is an advantage of reducing side effects and manufacturing costs due to the pharmacological component.
以下、本発明を下記例により詳しく説明する。ただし、下記例は、本発明を例示するためのものに過ぎず、下記例により、本発明の範囲が制限されるものではない。 The invention will now be described in more detail by means of the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited by the following examples.
比較例１及び２
クロピドグレル硫酸水素塩とＰＥＧ ６０００、マンニトール３００ ＤＣ、ＭＣＣ １０２及びＬ−ＨＰＣを下記表１の含有量で混合した。表１の含有量は、１錠剤当りの含有量を示す。その後、前記混合物とコロイダルシリコンジオキシド、タルク及びステアリルフマル酸ナトリウム（ＰＲＵＶ（登録商標））を後混合した後、打錠した。その結果、打錠時にスティッキングとキャッピング現象が発生した。
Comparative Examples 1 and 2
Clopidogrel hydrogen sulfate and PEG 6000, mannitol 300 DC, MCC 102 and L-HPC were mixed at contents shown in Table 1 below. The content in Table 1 indicates the content per tablet. Thereafter, the mixture was post-mixed with colloidal silicon dioxide, talc and sodium stearyl fumarate (PRUV (registered trademark)), and then tableted. As a result, sticking and capping phenomena occurred during tableting.
実施例１
下記表２の成分及び含有量に応じて錠剤を製造した。クロピドグレル硫酸水素塩とコロイダルシリコンジオキシドをまず混合した後、前記混合物とＰＥＧ ６０００、マンニトール３００ ＤＣ、ＭＣＣ １０２、及びＬ−ＨＰＣを後混合した。その後、滑沢剤であるタルク及びＰＲＵＶ（登録商標）を添加した後、打錠した。表２の含有量は、１錠剤当りの含有量を示す。この場合、コロイダルシリコンジオキシドを後混合し、ＭＣＣ １０２を使用した前記比較例１及び２とは異なり、実施例１の錠剤は、打錠時にスティッキングやキャッピングの障害が発生しなかった。前記成分の含有量を表２に示した。
Example 1
Tablets were produced according to the ingredients and contents in Table 2 below. After clopidogrel hydrogen sulfate and colloidal silicon dioxide were mixed first, PEG 6000, Mannitol 300 DC, MCC 102 and L-HPC were post-mixed with the above mixture. Thereafter, lubricants such as talc and PRUV (registered trademark) were added, and the mixture was tableted. The content in Table 2 indicates the content per tablet. In this case, unlike the Comparative Examples 1 and 2 in which the colloidal silicon dioxide was post-mixed and the MCC 102 was used, the tablet of Example 1 did not have a sticking or capping failure at the time of tableting. The contents of the components are shown in Table 2.
実施例２〜７
打錠時のスティッキング及びキャッピング障害現象をさらに向上させるために、乾燥減量が低い（１．５重量％）ＭＣＣ１１２を使用した。クロピドグレル硫酸水素塩とコロイダルシリコンジオキシドをまず混合した後、前記混合物とＰＥＧ ６０００、マンニトール３００ ＤＣ、ＭＣＣ １１２、Ｌ−ＨＰＣ、ＣＬ−ＰＶＰ及びＰＶＰ Ｋ−３０を後混合した。その後、滑沢剤であるＰＲＵＶ（登録商標）を添加した後、打錠した。前記成分の含有量をそれぞれ表３に示した。表３の含有量は、１錠剤当りの含有量を示す。
Examples 2 to 7
In order to further improve sticking and capping problems during tableting, MCC 112 with a low loss on drying (1.5 wt%) was used. After clopidogrel hydrogen sulfate and colloidal silicon dioxide were mixed first, PEG 6000, mannitol 300 DC, MCC 112, L-HPC, CL-PVP and PVP K-30 were post-mixed. Thereafter, lubricant PRUV (registered trademark) was added, and the mixture was tableted. The contents of the components are shown in Table 3, respectively. The content in Table 3 indicates the content per tablet.
実施例８〜１０及び比較例３〜６
コロイダルシリコンジオキシドが崩解剤を含む本願の剤形に及ぼす影響を把握するために、前記実施例２〜７と、主にコロイダルシリコンジオキシドの含有量を変えて下記表４の組成を有する錠剤を製造した。
Examples 8 to 10 and Comparative Examples 3 to 6
In order to grasp the influence of the colloidal silicon dioxide on the dosage form of the present application containing the disintegrating agent, the contents of the above-mentioned Examples 2 to 7 and mainly the colloidal silicon dioxide are changed to have the composition of Table 4 below. The tablets were manufactured.
実験例１．実施例２〜７の崩解試験
前記実施例２〜７により製造された錠剤を対象に崩解試験を行った。崩解試験は、大韓薬典の一般試験法中、崩解試験法に従った（試験液：水）。その結果は、下記表５の通りであり、対照群としてプラビックス錠を使用した。実施例２〜７の場合、崩解時間が１１分以内と示され、対照群より崩解時間が短縮されることが分かった。実施例２〜７の場合、打錠の障害なしに打錠が可能であった。
Experimental Example 1 Disintegration Test of Examples 2 to 7 The disintegration test was performed on the tablets manufactured according to Examples 2 to 7 above. The disintegration test was in accordance with the disintegration test method in the Korean Medical Code General Test Method (Test solution: water). The results are as shown in Table 5 below, and PLAVIX Tablets were used as a control group. In the case of Examples 2-7, it turned out that disintegration time is shown as less than 11 minutes, and it turned out that disintegration time is shortened from a control group. In the case of Examples 2-7, tableting was possible without obstacle of tableting.
実験例２．実施例８〜１０及び比較例３〜６の崩解試験及びキャッピング及びスティッキング有無の確認試験
前記表４で記載された実施例８〜１０及び比較例３〜６のクロピドグレル錠剤をもってスティッキング、キャッピング実験及び崩解時間の実験（本願実験例１と同様の方法を使用）をした結果は下記表６の通りである。
Experimental Example 2 Disintegration test and confirmation test of presence or absence of capping and sticking of Examples 8 to 10 and Comparative Examples 3 to 6 Sticking and capping experiments with the clopidogrel tablets of Examples 8 to 10 and Comparative Examples 3 to 6 described in Table 4 above The results of the experiment of disintegration time (using the same method as Experimental Example 1 of the present application) are as shown in Table 6 below.
コロイド性二酸化ケイ素をクロピドグレル錠剤の総重量基準で１重量％使用した比較例３及び４の場合、打錠時にスティッキング及び／またはキャッピング障害が発生し、また、コロイド性二酸化ケイ素を１１重量％使用した比較例５の場合、キャッピング障害が発生し、比較例６の場合には、崩解時間が１５分と非常に大きな値を示したことを確認することができた。 In Comparative Examples 3 and 4 where 1% by weight of colloidal silicon dioxide was used based on the total weight of clopidogrel tablets, sticking and / or capping failure occurred during tableting and 11% by weight of colloidal silicon dioxide was used In the case of Comparative Example 5, a capping failure occurred, and in the case of Comparative Example 6, it could be confirmed that the disintegration time showed a very large value of 15 minutes.
一方、コロイド性二酸化ケイ素をクロピドグレル錠剤の総重量を基準として、３または１０重量％を使用した実施例８〜１０は、スティッキング及びキャッピングが発生せず、かつ、崩解時間が１１分以内と示された。 On the other hand, Examples 8 to 10 using 3 or 10% by weight of colloidal silicon dioxide based on the total weight of the clopidogrel tablet show no sticking and capping and a disintegration time of less than 11 minutes. It was done.
このような結果を通じて、崩解剤を含有し、コロイダルシリコンジオキシドをクロピドグレル錠剤の総重量を基準として２〜１０重量％で含む錠剤が短縮された崩解時間を有し、同時に打錠に優れることが分かった。 Through these results, a tablet containing a disintegrant and containing colloidal silicon dioxide in an amount of 2 to 10% by weight based on the total weight of clopidogrel tablet has a shortened disintegration time and is simultaneously excellent in tableting I found that.
製剤例１
− クロピドグレル硫酸塩コーティング錠の製造
１錠剤当りヒドロキシプロピルセルロース０．５ｍｇ及びネオコート８０３８ＨＰ ３．５ｍｇと、有機溶媒である塩化メチレン（有機溶媒中、５重量％）及びエタノール（有機溶媒中、９９．５重量％）を混合してフィルムコーティング液を調製した後、前記実施例３で製造したクロピドグレル硫酸塩の裸錠をコーティングした。
Formulation example 1
-Preparation of clopidogrel sulfate coated tablets 0.5 mg hydroxypropylcellulose and 3.5 mg Neocoat 8038 HP per tablet, methylene chloride (5 wt% in organic solvent) and ethanol (99.5 in organic solvent) %) Were mixed to prepare a film coating solution, and then coated with the clopidogrel sulfate bare tablet prepared in Example 3 above.
− アスピリン顆粒の製造
これとは別途に、１カプセル当り塩化メチレン６００ｍｇ及びエタノール３００ｍｇの混合溶媒にアスピリン（Rhodia、タイ）１００ｍｇ及びヒドロキシプロピルメチルセルロース（Shin-Etsu、日本）５．０ｍｇを溶解させた後、平均粒径６００〜７１０μｍの球状白糖（ＩＰＳ、イタリア）顆粒３０ｍｇに流動層コーティング機（Glatt GmbH Process Technology、ドイツ）で、前記混合物を噴霧してアスピリン外核を形成した。次いで、塩化メチレン２５０ｍｇ及びエタノール２５０ｍｇの混合溶媒にヒドロキシプロピルメチルセルロースフタレート（Shin-Etsu、日本、置換度２００７３１、粘度４０ｍＰａ．ｓ）９．５ｍｇ、ヒドロキシプロピルメチルセルロース（置換度２９１０、粘度１５ｍＰａ．ｓ）５ｍｇ及びトリエチルシトレート（Morimurabros．ＩＮＣ、日本）０．５ｍｇを溶解させた後、前記アスピリン外核に噴霧して腸溶層を形成することにより、アスピリン顆粒を製造した。
-Preparation of aspirin granules Separately after dissolving 100 mg of aspirin (Rhodia, Thailand) and 5.0 mg of hydroxypropyl methylcellulose (Shin-Etsu, Japan) in a mixed solvent of 600 mg of methylene chloride and 300 mg of ethanol per capsule The mixture was sprayed to 30 mg of spherical white sugar (IPS, Italy) granules having an average particle diameter of 600 to 710 μm with a fluid bed coater (Glatt GmbH Process Technology, Germany) to form an aspirin outer core. Then, in a mixed solvent of 250 mg of methylene chloride and 250 mg of ethanol, 9.5 mg of hydroxypropyl methylcellulose phthalate (Shin-Etsu, Japan, degree of substitution 200731, viscosity 40 mPa · s), 5 mg of hydroxypropyl methylcellulose (degree of substitution 2910, viscosity 15 mPa · s) After dissolving 0.5 mg of and triethyl citrate (Morimurabros. INC, Japan), aspirin granules were sprayed to form an enteric layer, thereby producing aspirin granules.
前記製造されたクロピドグレル錠剤２０４ｍｇ及びアスピリン顆粒１４５ｍｇをゼラチン及びＨＰＭＣ硬質カプセルにそれぞれ充填してクロピドグレル７５ｍｇ及びアスピリン１００ｍｇを含む複合製剤を製造した。 The prepared clopidogrel tablet 204 mg and aspirin granules 145 mg were filled in gelatin and HPMC hard capsules respectively to prepare a composite preparation containing 75 mg clopidogrel and 100 mg aspirin.
製剤例２
前記製剤例１と同様に実施するものの、前記実施例３で製造したクロピドグレル硫酸塩の裸錠を使用し、アスピリン顆粒の製造時に下記成分の含有量を表７のように製剤例１とは異にして、クロピドグレル錠剤７５ｍｇ及びアスピリン７５ｍｇを含む複合製剤を製造した。
Formulation example 2
Although carried out in the same manner as in Preparation Example 1 above, using the naked tablet of clopidogrel sulfate prepared in Example 3 above, the contents of the following components are different from those in Preparation Example 1 as shown in Table 7 when producing aspirin granules. Then, a composite preparation containing 75 mg clopidogrel tablet and 75 mg aspirin was prepared.
比較製剤例１
− クロピドグレル顆粒の製造
１カプセル当り無水エタノール３００ｍｇ、塩化メチレン１０００ｍｇを溶媒にしてクロピドグレル硫酸水素塩９７．８７５ｍｇ、ヒドロキシプロピルメチルセルロース２５．５ｍｇを溶解させた後、平均粒径６００〜７１０μｍの球状白糖（ＩＰＳ、イタリア）顆粒１０３．６２５ｍｇに流動層コーティング機（Glatt GmbH Process Technology、ドイツ）で、前記混合物を噴霧してクロピドグレル外核を形成した。次いで、無水エタノール２００ｍｇ、塩化メチレン５００ｍｇにヒドロキシプロピルメチルセルロース２０ｍｇとポリエチレングリコール３．０ｍｇを溶解させた後、前記クロピドグレルの外核に噴霧して速放保護層を形成することにより、クロピドグレル顆粒を製造した。
Comparative preparation example 1
-Preparation of clopidogrel granules After dissolving 97. 875 mg of clopidogrel hydrogensulfate and 25.5 mg of hydroxypropyl methylcellulose in a solvent using 300 mg of anhydrous ethanol and 1000 mg of methylene chloride per capsule, spherical sucrose with an average particle size of 600 to 710 μm (IPS , Italy) Granules 103.625 mg of the mixture were sprayed with a fluid bed coater (Glatt GmbH Process Technology, Germany) to form the clopidogrel outer core. Subsequently, after dissolving 20 mg of hydroxypropyl methylcellulose and 3.0 mg of polyethylene glycol in 200 mg of absolute ethanol and 500 mg of methylene chloride, clopidogrel granules were manufactured by forming an immediate release protective layer by spraying the outer core of clopidogrel. .
− アスピリン顆粒の製造
前記製剤例１のアスピリン顆粒と同様の方法で製造した。
-Preparation of aspirin granules: Manufactured in the same manner as the aspirin granules of the above-mentioned Preparation Example 1.
その後、前記製造されたクロピドグレル錠剤２４５ｍｇ及びアスピリン顆粒１４５ ｍｇをゼラチン及びＨＰＭＣ硬質カプセルにそれぞれ充填し、クロピドグレル７５ｍｇ及びアスピリン１００ｍｇを含む複合製剤を製造した。 Thereafter, 245 mg of clopidogrel tablet and 145 mg of aspirin granules were filled into gelatin and HPMC hard capsules, respectively, to prepare a composite preparation containing 75 mg of clopidogrel and 100 mg of aspirin.
実験例３．性状変化の試験
製剤例１で製造された複合製剤を使用してカプセルがゼラチンである場合とＨＰＭＣである場合に分けて、試験条件４０℃、７５％ＲＨに露出して過酷試験を行って性状の変化を観察した。その結果は下記表８の通りである（〇：良好な状態、×：不良状態）。
Experimental Example 3 Test of property change The complex preparation manufactured in Formulation Example 1 is used to divide the case where the capsule is gelatin and HPMC separately, and the test condition is exposed to 40 ° C., 75% RH and subjected to a severe test Change was observed. The results are as shown in Table 8 below (〇: good state, x: bad state).
苛酷試験において、ゼラチンカプセルの場合、４日になるまで性状の変化が観察されず、ＨＰＭＣカプセルの場合、２１日以上経過しても外観上の変化が観察されないため、ゼラチンカプセルに比べてより安定性を示した。 In the severe test, in the case of gelatin capsules, no change in properties is observed until 4 days, and in the case of HPMC capsules, no change in appearance is observed even after 21 days or more, so it is more stable than gelatin capsules. Showed sex.
実験例４．安定性の試験
前記製剤例１により製造された本発明の複合製剤に対して６ヶ月間の加速試験（温度４０℃、７５％ＲＨ ＰＥボトル）を行って安定性を評価し、評価の結果を表９に示した。
Experimental Example 4 Stability Test The composite preparation of the present invention prepared according to Preparation Example 1 was subjected to an accelerated test for 6 months (temperature 40 ° C., 75% RH PE bottle) to evaluate the stability, and the evaluation results It is shown in Table 9.
製剤例１及び比較製剤例１の場合、時間に応じて総不純物量の増加が目立ったが、製剤例１の場合、不純物の増加が顕著に減少した。 In the case of Formulation Example 1 and Comparative Formulation Example 1, the increase in the total amount of impurities was noticeable with time, but in the case of Formulation Example 1, the increase in impurities was significantly reduced.
以上の説明から、本発明が属する技術分野の当業者であれば、本発明がその技術的思想や必須の特徴を変更することなく、他の具体的な形態で実施できることを理解できるだろう。これに関連し、以上で記述した実施例はあくまで例示的なものであり、限定的なものでないことを理解すべきである。本発明の範囲は上記詳細な説明よりは、後述する特許請求の範囲の意味及び範囲、そしてその等価概念から導かれるあらゆる変更または変形された形態が本発明の範囲に含まれるものと解釈すべきである。
From the above description, it will be understood by those skilled in the art to which the present invention belongs that the present invention can be practiced in other specific forms without changing its technical idea and essential features. It is to be understood that the embodiments associated with this and described above are exemplary only and not limiting. The scope of the present invention should be construed as being within the scope of the present invention, from the above detailed description, within the meaning and scope of the claims set forth below, and any modified or derived form derived from equivalent concepts thereof. It is.
Claims (16)
アスピリン、その異性体またはその薬学的に許容可能な塩を含むアスピリンコア、及び前記コアを包む腸溶性コーティング層を含むアスピリン含有粒子を含む複合製剤。 Clopidogrel, clopidogrel tablet comprising the isomer or pharmaceutically acceptable salt thereof; and aspirin, an aspirin core comprising the isomer or pharmaceutically acceptable salt thereof, and an enteric coating layer covering the core Composite formulation containing aspirin-containing particles.
アスピリン、その異性体またはその薬学的に許容可能な塩を含むアスピリンコアを準備する段階；及び
前記アスピリンコアを腸溶性コーティング剤でコーティングする段階を含む、クロピドグレル錠剤及びアスピリンコアを含む複合製剤の製造方法。 Preparing the clopidogrel tablet by first adding clopidogrel, its isomer or its pharmaceutically acceptable salt, and colloidal silicon dioxide, and then adding a disintegrant;
Preparing an aspirin core comprising aspirin, an isomer thereof or a pharmaceutically acceptable salt thereof; and coating the aspirin core with an enteric coating agent, producing a composite preparation comprising clopidogrel tablet and aspirin core Method.
The method according to claim 14, wherein the content of the colloidal silicon dioxide is 2 to 10% by weight based on the total weight of clopidogrel tablet.
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