TW202143972A - A multiple formulation of ticagrelor - Google Patents

A multiple formulation of ticagrelor Download PDF

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TW202143972A
TW202143972A TW110112264A TW110112264A TW202143972A TW 202143972 A TW202143972 A TW 202143972A TW 110112264 A TW110112264 A TW 110112264A TW 110112264 A TW110112264 A TW 110112264A TW 202143972 A TW202143972 A TW 202143972A
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sustained
ticagrelor
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張強
陳昊
曹秀秀
何花
王捷
盧韻
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大陸商江蘇恆瑞醫藥股份有限公司
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Abstract

The disclosure relates to a multiple formulation of ticagrelor. Specifically, the disclosure relates to a multiple formulation for once-a-day administration, which comprises ticagrelor or a pharmaceutically acceptable salt thereof, said multiple formulation comprising an immediate-release multiple unit portion and a sustained-release multiple unit portion, the immediate-release multiple unit portion comprising separate immediate-release units and the sustained-release multiple unit portion comprising separate sustained-release units, each unit comprising the multiple formulation having a maximum diameter of less than 5.0 mm. The present disclosure provides The multiformulations can achieve once-a-day administration with little individual variability.

Description

一種替格瑞洛的多元製劑 A kind of multiple preparation of ticagrelor

一種含替格瑞洛或其可藥用鹽的一日一次給藥的多元製劑，屬於製藥領域。 A multicomponent preparation containing ticagrelor or a pharmaceutically acceptable salt thereof for once-a-day administration belongs to the field of pharmacy.

替格瑞洛片，為阿斯利康生產的速釋製劑，其作用機制為一種血小板聚集抑制劑，能夠可逆性地與血小板P2Y12ADP受體相互作用，阻斷信號傳導和血小板活化，需聯合阿司匹林用於急性冠脈症候群患者、心肌梗死病史患者或動脈粥樣硬化血栓事件高危患者，以降低血栓性心血管事件的發生率。 Ticagrelor Tablet, an immediate-release preparation produced by AstraZeneca, its mechanism of action is a platelet aggregation inhibitor, which can reversibly interact with platelet P2Y12ADP receptors, block signal transduction and platelet activation, and needs to be combined with aspirin. To reduce the incidence of thrombotic cardiovascular events in patients with acute coronary syndrome, patients with a history of myocardial infarction, or patients at high risk of atherothrombotic events.

替格瑞洛的上市規格為90mg和60mg，首劑量服用替格瑞洛180mg，維持劑量90mg，一日兩次給藥，一年以後，可長期小劑量服用替格瑞洛(60mg，一日兩次)以預防心血管事件發生。由於已上市的速釋製劑需一日兩次服藥，患者在長期用藥中漏服替格瑞洛易引起急性血栓形成而導致心梗或中風的風險。因此有必要開發一日一次緩釋製劑，減少患者服用次數，從而改善服藥依從性，進一步降低由於漏服而引起的急性血栓形成而導致的心梗或中風的風險。 The marketed specifications of ticagrelor are 90mg and 60mg, the first dose of ticagrelor is 180mg, and the maintenance dose is 90mg, twice a day. twice) to prevent cardiovascular events. Because the marketed immediate-release preparations require twice-daily administration, patients who miss taking ticagrelor during long-term medication may be at risk of acute thrombosis, leading to myocardial infarction or stroke. Therefore, it is necessary to develop a once-a-day sustained-release formulation to reduce the number of patients taking it, thereby improving medication compliance and further reducing the risk of myocardial infarction or stroke due to acute thrombosis caused by missed doses.

CN106074357A公開了一種一日一次給藥的製劑，其包含替格瑞洛或其藥學上可接受的鹽，其中該製劑在給藥於需要其治療的受試者之後表現 出下列特徵：a)在受試者中在2小時內的時間可達到大於約0.2μg/mL的替格瑞洛的血漿濃度；和b)在受試者中服藥在12小時後仍可達到大於約0.2μg/mL的替格瑞洛的血漿濃度；和c)在受試者中產生在約0.2μg/mL至約0.8μg/mL之間的替格瑞洛或其藥學上可接受的鹽的最大血漿濃度(Cmax)。 CN106074357A discloses a once-daily administration formulation comprising ticagrelor or a pharmaceutically acceptable salt thereof, wherein the formulation behaves after administration to a subject in need of its treatment The following characteristics: a) a plasma concentration of ticagrelor greater than about 0.2 μg/mL can be achieved in a subject over a period of 2 hours; and b) a ticagrelor can be achieved in a subject 12 hours after dosing a plasma concentration of ticagrelor greater than about 0.2 μg/mL; and c) producing in a subject between about 0.2 μg/mL and about 0.8 μg/mL ticagrelor, or a pharmaceutically acceptable form thereof Maximum plasma concentration of salt (Cmax).

CN110507624A公開一種替格瑞洛的控釋放製劑，藉由在緩釋組分中加入羧甲基纖維素鈉解決CN106074357A中處方放大批量後緩釋組分釋放不完全的問題。 CN110507624A discloses a controlled-release preparation of ticagrelor, which solves the problem of incomplete release of the sustained-release component in CN106074357A by adding sodium carboxymethyl cellulose to the sustained-release component.

本揭露提供一種一日一次給藥的多元製劑，其包含替格瑞洛或其可藥用鹽，該多元製劑含有速釋多單元部分和緩釋多單元部分，組成多元製劑的每一個單元的最大直徑小於5.0mm，可選小於3.0mm，可選小於2.5mm。 The present disclosure provides a once-a-day multi-formulation, comprising ticagrelor or a pharmaceutically acceptable salt thereof, the multi-formulation contains an immediate-release multi-unit portion and a sustained-release multi-unit portion, and each unit of the multi-formulation is composed of a The maximum diameter is less than 5.0mm, optional less than 3.0mm, optional less than 2.5mm.

可選的實施方案中，組成多元製劑的每一個單元的最大直徑為0.1至5.0mm，可選為0.5至3.0mm，可選為1至2.5mm。 In an alternative embodiment, the largest diameter of each unit comprising the multicomponent formulation is 0.1 to 5.0 mm, optionally 0.5 to 3.0 mm, optionally 1 to 2.5 mm.

可選的實施方案中，本揭露提供的多元製劑的速釋多單元部分，由多個獨立的速釋單元組成，單元數目

Figure 110112264-A0202-12-0002-8
3，可選
Figure 110112264-A0202-12-0002-9
4，可選
Figure 110112264-A0202-12-0002-10
5。 In an optional embodiment, the immediate-release multi-unit portion of the multi-component formulation provided by the present disclosure is composed of a plurality of independent immediate-release units, and the number of units
Figure 110112264-A0202-12-0002-8
3, optional
Figure 110112264-A0202-12-0002-9
4, optional
Figure 110112264-A0202-12-0002-10
5.

可選的實施方案中，本揭露提供的多元製劑的緩釋多單元部分，由多個獨立的緩釋單元組成，單元數目

Figure 110112264-A0202-12-0002-11
5，可選
Figure 110112264-A0202-12-0002-12
8，可選
Figure 110112264-A0202-12-0002-13
10。 In an optional embodiment, the sustained-release multi-unit portion of the multi-component formulation provided by the present disclosure is composed of a plurality of independent sustained-release units, and the number of units
Figure 110112264-A0202-12-0002-11
5, optional
Figure 110112264-A0202-12-0002-12
8, optional
Figure 110112264-A0202-12-0002-13
10.

可選的實施方案中，患者單次服用的多元製劑中替格瑞洛或其可藥用鹽的含量是患者每日服用的倍林達®中替格瑞洛的含量的1至1.2倍。 Alternative embodiment, the polyol formulation in patients administered for a single content, or a pharmaceutically acceptable salt thereof ticagrelor times Linda ® patient is administered daily for ticagrelor content of 1 to 1.2 times.

可選的實施方案中，一個或者兩個多元製劑中替格瑞洛或其可藥用鹽的含量是患者每日服用的倍林達®中替格瑞洛的含量的1至1.2倍。 Alternative embodiments, one or more than two yuan formulation for the content, or a pharmaceutically acceptable salt thereof ticagrelor times Linda ® is administered daily for the patient ticagrelor content of 1 to 1.2 times.

本揭露提供的多元製劑，一日一次服用該多元製劑與患者一日兩次口服倍林達®生物等效(原型藥)的效果。 Polyol formulation of the present disclosure provide a once daily administration equivalent times (parent drug) Linda ® biological effect of the polyol formulation patient orally twice a day.

化學藥物製劑生物等效性評價，通常採用平均生物等效性(Average bioequivalence,ABE)方法，等效標準為受試製劑與參比製劑的主要藥物代謝動力學參數(AUC和Cmax)幾何均值比的90%信賴區間落在80.00%至125.00%範圍內。 The bioequivalence evaluation of chemical drug preparations usually adopts the average bioequivalence (ABE) method, and the equivalence standard is the geometric mean ratio of the main pharmacokinetic parameters (AUC and Cmax) of the test preparation and the reference preparation The 90% confidence interval for , falls within the range of 80.00% to 125.00%.

CV值指變異係數，RSD值指相對標準偏差，個體間差異的CV值，即RSD，本揭露中採用RSD值表徵個體差異性的大小。 The CV value refers to the coefficient of variation, and the RSD value refers to the relative standard deviation. The CV value of inter-individual differences, namely RSD, is used in the present disclosure to represent the magnitude of individual differences.

具體的，本揭露提供的多元製劑的AUC0-t的RSD值小於42，可選小於40，可選小於38。本揭露提供的多元製劑的AUC0-∞的RSD值小於40，可選小於38，可選小於36；本揭露提供的多元製劑的Cmax的RSD值小於44，可選小於42，可選小於40。 Specifically, the RSD value of the AUC 0-t of the multi-component preparation provided by the present disclosure is less than 42, optionally less than 40, and optionally less than 38. The RSD value of the AUC 0-∞ of the multi-component preparation provided by the present disclosure is less than 40, optionally less than 38, and optionally less than 36; the RSD value of the Cmax of the multi-component preparation provided by the present disclosure is less than 44, optionally less than 42, and optionally less than 40 .

可選的實施方案中，本揭露提供的多元製劑的AUC0t的RSD值小於42，可選小於40，可選小於38；本揭露提供的多元製劑的Cmax的RSD值小於44，可選小於42，可選小於40。 In an optional embodiment, the RSD value of the AUC 0t of the multi-component preparation provided by the present disclosure is less than 42, optionally less than 40, and optionally less than 38; the RSD value of the Cmax of the multi-component preparation provided by the present disclosure is less than 44, optionally less than 42 , optional less than 40.

可選的實施方案中，本揭露提供的多元製劑，其中任一緩釋單元含有含藥核心和緩釋材料包衣層。 In an optional embodiment, the present disclosure provides a multi-component formulation, wherein any sustained-release unit comprises a drug-containing core and a sustained-release material coating layer.

可選的實施方案中，該緩釋材料選自乙基纖維素、海藻酸鈉、甲基纖維素、羥乙纖維素、羥丙基甲基纖維素、羥丙基乙基纖維素、羧甲基纖維素鈉、殼多糖、半乳糖甘露聚糖、聚維酮、聚乙烯醇。 In an optional embodiment, the sustained-release material is selected from ethyl cellulose, sodium alginate, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, carboxymethyl cellulose Sodium cellulose, chitin, galactomannan, povidone, polyvinyl alcohol.

可選的實施方案中，該緩釋材料選自丙烯酸樹脂類、羥丙基甲基纖維素鄰苯二甲酸酯(HPMCP)、醋酸羥丙基甲基纖維素琥珀酸酯 (HPMCAS)、鄰苯二甲酸醋酸纖維素(CAP)、聚乙烯醇酞酸酯(PVAP)、醋酸纖維素苯三酸酯(CAT)中的一種或多種的腸溶材料。 In an optional embodiment, the sustained-release material is selected from acrylic resins, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate Enteric material of one or more of (HPMCAS), cellulose acetate phthalate (CAP), polyvinyl phthalate (PVAP), and cellulose acetate trimellitate (CAT).

可選的實施方案中，本揭露提供的多元製劑，其中任一緩釋單元含有核心和緩釋材料包衣層，該緩釋材料為選自丙烯酸樹脂類、羥丙基甲基纖維素鄰苯二甲酸酯、醋酸羥丙基甲基纖維素琥珀酸酯、鄰苯二甲酸醋酸纖維素、聚乙烯醇酞酸酯、醋酸纖維素苯三酸酯中的一種或多種的腸溶材料，緩釋材料包衣層即為腸溶材料包衣層。 In an optional embodiment, the multi-component formulation provided by the present disclosure, wherein any sustained-release unit contains a core and a coating layer of a sustained-release material, and the sustained-release material is selected from acrylic resins, hydroxypropyl methylcellulose o-phthalate. One or more enteric materials selected from diformate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinyl phthalate, and cellulose acetate trimellitate. The release material coating layer is the enteric material coating layer.

可選的實施方案中，本揭露提供的多元製劑，其中任一緩釋單元含有核心和腸溶材料包衣層，該腸溶材料選自丙烯酸樹脂類，例如尤特奇L100、尤特奇S100、尤特奇L30D-55中的一種或多種。 In an optional embodiment, the multi-component formulation provided by the present disclosure, wherein any sustained-release unit contains a core and a coating layer of enteric material, and the enteric material is selected from acrylic resins, such as Eudragit L100, Eudragit S100 , One or more of Eudragit L30D-55.

可選的實施方案中，本揭露提供的多元製劑，其中任一緩釋單元含有核心和腸溶材料包衣層，該腸溶材料為尤特奇L100。 In an optional embodiment, the present disclosure provides a multi-component preparation, wherein any sustained-release unit contains a core and a coating layer of an enteric material, and the enteric material is Eudragit L100.

可選的實施方案中，本揭露提供的多元製劑，該緩釋材料包衣層的重量是核心總重的1%至50%，可選10%至35%(質量百分比)。 In an optional embodiment, in the multi-component preparation provided by the present disclosure, the weight of the sustained-release material coating layer is 1% to 50% of the total weight of the core, optionally 10% to 35% (mass percentage).

本揭露提供的多元製劑，該速釋單元和/或緩釋單元選自顆粒、微丸或微片，可選微片。 In the multi-component preparation provided by the present disclosure, the immediate-release unit and/or the sustained-release unit is selected from granules, pellets or microtablets, and optional microtablets.

可選的實施方案中，本揭露提供的多元製劑，其中替格瑞洛或以替格瑞洛計的替格瑞洛可藥用鹽的含量為45mg至220mg。 In an optional embodiment, the present disclosure provides a multi-component preparation, wherein the content of ticagrelor or a pharmaceutically acceptable salt of ticagrelor based on ticagrelor is 45 mg to 220 mg.

可選的實施方案中，該多元製劑中替格瑞洛或以替格瑞洛計的替格瑞洛可藥用鹽的含量為60mg、90mg、100mg、108mg、120mg、133mg、144mg、180mg、200mg或216mg。 In an optional embodiment, the content of ticagrelor or a pharmaceutically acceptable salt of ticagrelor in terms of ticagrelor in the multi-component preparation is 60 mg, 90 mg, 100 mg, 108 mg, 120 mg, 133 mg, 144 mg, 180 mg, 200mg or 216mg.

可選的實施方案中，該多元製劑中替格瑞洛或以替格瑞洛計的替格瑞洛可藥用鹽的含量為100mg、108mg、133mg、144mg、200mg或216mg。 In an optional embodiment, the content of ticagrelor or a pharmaceutically acceptable salt of ticagrelor calculated as ticagrelor in the multi-component formulation is 100 mg, 108 mg, 133 mg, 144 mg, 200 mg or 216 mg.

本揭露提供的多元製劑，其中速釋多單元部分和緩釋多單元部分中替格瑞洛或其鹽的重量比為1：0.5至1：10，可選1：1至1：8，可選1：2。 The present disclosure provides a multi-component preparation, wherein the weight ratio of ticagrelor or its salt in the immediate-release multi-unit part and the sustained-release multi-unit part is 1:0.5 to 1:10, optionally 1:1 to 1:8, or Pick 1:2.

本揭露提供的多元製劑，該速釋單元含有替格瑞洛或其可藥用鹽及任選自稀釋劑、黏合劑、崩解劑、潤滑劑中的至少一種輔料。 In the multi-component preparation provided by the present disclosure, the immediate-release unit contains ticagrelor or a pharmaceutically acceptable salt thereof and optionally at least one auxiliary material selected from a diluent, a binder, a disintegrant, and a lubricant.

可選的實施方案中，該速釋單元中替格瑞洛或其可藥用鹽的含量為速釋單元總重的5%至60%，可選10%至50%，可選20%至45%(質量百分比)。 In an optional embodiment, the content of ticagrelor or a pharmaceutically acceptable salt thereof in the immediate-release unit is 5% to 60% of the total weight of the immediate-release unit, optionally 10% to 50%, and optionally 20% to 50%. 45% (mass percentage).

可選的實施方案中，該速釋單元的稀釋劑選自乳糖、澱粉、預膠化澱粉、甘露醇、微晶纖維素、葡萄糖、磷酸氫鈣、無水磷酸氫鈣中的一種或幾種，可選甘露醇和磷酸氫鈣。 In an optional embodiment, the diluent of the immediate-release unit is selected from one or more of lactose, starch, pregelatinized starch, mannitol, microcrystalline cellulose, glucose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, Optional mannitol and dibasic calcium phosphate.

可選的實施方案中，該速釋單元中稀釋劑的含量為速釋單元總重的10%至80%，可選30%至70%，可選45%至75%(質量百分比)。 In an optional embodiment, the content of the diluent in the immediate release unit is 10% to 80% of the total weight of the immediate release unit, optionally 30% to 70%, and optionally 45% to 75% (mass percentage).

可選的實施方案中，該速釋單元的黏合劑選自聚乙烯吡咯烷酮、澱粉、羧甲基纖維素、羥丙基纖維素、羥丙甲基纖維素中的一種或幾種，可選羥丙基纖維素。 In an optional embodiment, the adhesive of the immediate-release unit is selected from one or more of polyvinylpyrrolidone, starch, carboxymethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. propyl cellulose.

可選的實施方案中，該速釋單元中黏合劑的含量為速釋單元總重的0.1%至20%，可選1%至10%(質量百分比)。 In an optional embodiment, the content of the binder in the immediate-release unit is 0.1% to 20% of the total weight of the immediate-release unit, optionally 1% to 10% (mass percentage).

可選的實施方案中，該速釋單元的崩解劑選自交聯羧甲基纖維素鈉、乾澱粉、羧甲基澱粉鈉、低取代羥丙基纖維素、交聯聚乙烯吡咯烷酮、預膠化澱粉的一種或者幾種，可選羧甲基澱粉鈉或交聯羧甲基纖維素鈉。 In an optional embodiment, the disintegrant of the immediate-release unit is selected from the group consisting of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, pre- One or more kinds of gelatinized starch can be selected from sodium carboxymethyl starch or croscarmellose sodium.

可選的實施方案中，該速釋單元中崩解劑的含量為速釋單元總重的0.1%至20%，可選1%至10%(質量百分比)。 In an optional embodiment, the content of the disintegrant in the immediate-release unit is 0.1% to 20% of the total weight of the immediate-release unit, optionally 1% to 10% (mass percentage).

可選的實施方案中，該速釋單元的潤滑劑選自硬脂酸鎂、山崳酸甘油酯、氫化植物油、硬脂酸鈣、微粉矽膠、富馬酸硬脂酸鈉中的一種或幾種，可選硬脂酸鎂。 In an optional embodiment, the lubricant of the immediate-release unit is selected from one or more of magnesium stearate, glyceryl behenate, hydrogenated vegetable oil, calcium stearate, micropowder silica gel, and sodium stearate fumarate. species, optional magnesium stearate.

可選的實施方案中，該速釋單元中潤滑劑的含量為速釋單元總重的0.1%至10%，可選1%至5%(質量百分比)。 In an optional embodiment, the content of the lubricant in the immediate-release unit is 0.1% to 10% of the total weight of the immediate-release unit, optionally 1% to 5% (mass percentage).

本揭露提供的多元製劑，該緩釋單元含有替格瑞洛或其可藥用鹽及任選自稀釋劑、崩解劑、助流劑、潤滑劑中的至少一種輔料。 In the multi-component preparation provided by the present disclosure, the sustained-release unit contains ticagrelor or a pharmaceutically acceptable salt thereof and optionally at least one auxiliary material from among diluents, disintegrants, glidants, and lubricants.

可選的實施方案中，該緩釋單元中替格瑞洛或其可藥用鹽的含量為緩釋核芯總重的5%至70%，可選10%至45%(質量百分比)。 In an optional embodiment, the content of ticagrelor or a pharmaceutically acceptable salt thereof in the sustained-release unit is 5% to 70% of the total weight of the sustained-release core, optionally 10% to 45% (mass percentage).

可選的實施方案中，該緩釋單元的稀釋劑選自乳糖、微晶纖維素、甘露醇、磷酸氫鈣中的一種或幾種，可選微晶纖維素。 In an optional embodiment, the diluent of the sustained-release unit is selected from one or more of lactose, microcrystalline cellulose, mannitol, and calcium hydrogen phosphate, and microcrystalline cellulose can be selected.

可選的實施方案中，該緩釋單元中稀釋劑的含量為緩釋核芯總重的1%至80%，可選5%至60%(質量百分比)。 In an optional embodiment, the content of the diluent in the sustained-release unit is 1% to 80% of the total weight of the sustained-release core, optionally 5% to 60% (mass percentage).

可選的實施方案中，該緩釋單元的崩解劑選自交聯羧甲基纖維素鈉、乾澱粉、羧甲基澱粉鈉、低取代羥丙基纖維素、交聯聚乙烯吡咯烷酮、預膠化澱粉的一種或者幾種，可選交聯羧甲基纖維素鈉。 In an optional embodiment, the disintegrant of the sustained-release unit is selected from the group consisting of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, pre- One or several kinds of gelatinized starch, and croscarmellose sodium can be selected.

可選的實施方案中，該緩釋單元中崩解劑的含量為緩釋核芯總重的1%至35%，可選5%至25%(質量百分比)。 In an optional embodiment, the content of the disintegrant in the sustained-release unit is 1% to 35% of the total weight of the sustained-release core, optionally 5% to 25% (mass percentage).

可選的實施方案中個，該緩釋單元的助流劑選自滑石粉或二氧化矽，可選二氧化矽。 In an optional embodiment, the glidant of the sustained-release unit is selected from talc or silica, optionally silica.

可選的實施方案中，該緩釋單元中助流劑的含量為緩釋核芯總重的0.1%至15%，可選0.5%至5%(質量百分比)。 In an optional embodiment, the content of the glidant in the sustained-release unit is 0.1% to 15% of the total weight of the sustained-release core, optionally 0.5% to 5% (mass percentage).

可選的實施方案中，該緩釋單元的潤滑劑選自硬脂酸鎂、硬脂酸鈣、山崳酸甘油酯、氫化植物油中的一種或幾種，可選硬脂酸鎂。 In an optional embodiment, the lubricant of the sustained-release unit is selected from one or more of magnesium stearate, calcium stearate, glyceryl behenate, hydrogenated vegetable oil, and optionally magnesium stearate.

可選的實施方案中，該緩釋單元中潤滑劑的含量為緩釋核芯總重的0.1%至15%，可選0.5%至5%(質量百分比)。 In an optional embodiment, the content of the lubricant in the sustained-release unit is 0.1% to 15% of the total weight of the sustained-release core, optionally 0.5% to 5% (mass percentage).

可選的實施方案中，本揭露提供的多元製劑，該緩釋單元中替格瑞洛或其藥用鹽與選自聚維酮、共聚維酮、聚乙二醇、泊洛沙姆、丙烯酸樹脂類、羥丙甲基纖維素類或其混合物的載體成固體分散體，該載體可選共聚維酮。其中替格瑞洛或其鹽與載體的重量比為1：0.2至5，可選1：0.5至2，可選1：1。 In an optional embodiment, in the multi-component preparation provided by the present disclosure, in the sustained-release unit, ticagrelor or a pharmaceutically acceptable salt thereof is combined with a compound selected from the group consisting of povidone, copovidone, polyethylene glycol, poloxamer, and acrylic acid. The carrier of resin, hypromellose or its mixture is a solid dispersion, and the carrier can be selected from copovidone. The weight ratio of ticagrelor or its salt to the carrier is 1:0.2 to 5, optionally 1:0.5 to 2, and optionally 1:1.

本揭露中所述固體分散體可採用一般製程方法製備，例如溶劑法、熔融法、固相沉積蒸發法、球磨機研磨、噴霧乾燥法、熱熔擠出法等。本揭露可選噴霧乾燥法製備固體分散體，即將藥物、載體溶解至適宜溶劑中，而後經噴霧乾燥除去有機溶劑後製得固體分散體。其中該溶劑選自無水乙醇、丙酮、乙酸乙酯、二氯甲烷等，本揭露進一步可選溶劑為無水乙醇。 The solid dispersion described in the present disclosure can be prepared by general process methods, such as solvent method, melting method, solid phase deposition evaporation method, ball mill grinding, spray drying method, hot melt extrusion method, and the like. In the present disclosure, a spray-drying method can be used to prepare the solid dispersion, that is, the drug and the carrier are dissolved in a suitable solvent, and then the organic solvent is removed by spray-drying to obtain the solid dispersion. Wherein, the solvent is selected from absolute ethanol, acetone, ethyl acetate, dichloromethane, etc., and a further optional solvent in the present disclosure is absolute ethanol.

可選的實施方案中，本揭露提供的多元製劑，其為膠囊。 In an optional embodiment, the present disclosure provides a multicomponent formulation, which is a capsule.

可選的實施方案中，本揭露提供的多元製劑，緩釋單元組成如下： In an optional embodiment, the multi-component formulation provided by the present disclosure, the sustained-release unit is composed of the following:

核芯(以核芯總重計) Core (total core weight)

替格瑞洛10%至45%(質量百分比)； Ticagrelor 10% to 45% (mass percentage);

共聚維酮10%至45%(質量百分比)； Copovidone 10% to 45% (mass percentage);

微晶纖維素5%至60%(質量百分比)； Microcrystalline cellulose 5% to 60% (mass percentage);

交聯羧甲基纖維素鈉5%至25%(質量百分比)； Croscarmellose sodium 5% to 25% (mass percent);

微粉矽膠0.5%至5%(質量百分比)； Micro powder silica gel 0.5% to 5% (mass percentage);

硬脂酸鎂0.5%至5%(質量百分比)； Magnesium stearate 0.5% to 5% (mass percentage);

另含有占核心總重15%至35%(質量百分比)的緩釋材料包層衣。 It also contains a slow-release material coating layer of 15% to 35% (mass percentage) of the total core weight.

可選的實施方案中，本揭露提供的多元製劑，組成如下：速釋單元(以速釋單元總重計)： In an optional embodiment, the multi-component preparation provided by the present disclosure is composed of the following: immediate-release unit (calculated by the total weight of the immediate-release unit):

替格瑞洛20%至45%(質量百分比)； Ticagrelor 20% to 45% (mass percentage);

甘露醇20%至60%(質量百分比)； Mannitol 20% to 60% (mass percentage);

磷酸氫鈣10%至45%(質量百分比)； Calcium hydrogen phosphate 10% to 45% (mass percentage);

羧甲基澱粉鈉1%至10%(質量百分比)； Sodium carboxymethyl starch 1% to 10% (mass percentage);

羥丙基纖維素1%至10%(質量百分比)； Hydroxypropyl cellulose 1% to 10% (mass percentage);

硬脂酸鎂1%至5%(質量百分比)； Magnesium stearate 1% to 5% (mass percentage);

緩釋單元 Sustained release unit

核芯(以緩釋單元核芯總重計) Core (based on the total weight of the sustained-release unit core)

替格瑞洛10%至45%(質量百分比)； Ticagrelor 10% to 45% (mass percentage);

共聚維酮10%至45%(質量百分比)； Copovidone 10% to 45% (mass percentage);

微晶纖維素5%至60%(質量百分比)； Microcrystalline cellulose 5% to 60% (mass percentage);

交聯羧甲基纖維素鈉5%至25%(質量百分比)； Croscarmellose sodium 5% to 25% (mass percent);

微粉矽膠0.5%至5%(質量百分比)； Micro powder silica gel 0.5% to 5% (mass percentage);

硬脂酸鎂0.5%至5%(質量百分比)； Magnesium stearate 0.5% to 5% (mass percentage);

另含有占核心總重15%至35%(質量百分比)的緩釋材料包層衣。 It also contains a slow-release material coating layer of 15% to 35% (mass percentage) of the total core weight.

可選的實施方案中，緩釋材料包衣選歐巴代。 In an optional embodiment, the sustained-release material coating is selected from Opadry.

本揭露提供的多元製劑，依照釋放度測定法(中國藥典2015版四部0931第二法)進行溶出試驗，首先以750mL的0.2%吐溫pH1.0為溶出介質，2h後加入250mL的無水磷酸鈉溶液調節介質為0.2%吐溫pH6.8，然後採用紫外-可見分光光度法測定釋放度，不低於總含量的10%，可選20%；12小時釋放不低於總含量的80%，可選85%，可選90%。 The multi-component preparation provided by the present disclosure is subjected to the dissolution test according to the release test method (the second method of Chinese Pharmacopoeia 2015 Edition IV 0931). First, 750 mL of 0.2% Tween pH 1.0 is used as the dissolution medium, and 250 mL of anhydrous sodium phosphate is added after 2 hours. The solution adjustment medium is 0.2% Tween pH 6.8, and then the release degree is measured by UV-Vis spectrophotometry, which is not less than 10% of the total content, optional 20%; the release in 12 hours is not less than 80% of the total content, 85% optional, 90% optional.

本揭露提供的多元製劑，患者單次口服後體內血漿藥物濃度達峰時間Tmax為自服藥後4至12小時。 In the multi-component preparation provided by the present disclosure, the time Tmax of the peak plasma drug concentration in the patient after a single oral dose is 4 to 12 hours after taking the drug.

可選的實施方案中，患者單次口服含有200mg的替格瑞洛計或以替格瑞洛計的替格瑞洛可藥用鹽的多元製劑，C2h及C12h均大於200ng/mL。 In an optional embodiment, a patient takes a single oral dose of a multi-component preparation containing 200 mg of ticagrelor or a pharmaceutically acceptable salt of ticagrelor, and both C 2h and C 12h are greater than 200 ng/mL.

本揭露提供一種上述多元製劑在製備預防或治療心肌梗死、血栓形成中風、暫時性局部缺血發作和/或外周血管疾病、不穩定或穩定心絞痛、血小板聚集疾病的藥物中的用途。 The present disclosure provides the use of the above multi-component preparation in the preparation of a medicament for preventing or treating myocardial infarction, thrombotic stroke, transient ischemic attack and/or peripheral vascular disease, unstable or stable angina pectoris, and platelet aggregation diseases.

可選的實施方案中，本揭露提供一種上述多元製劑在製備預防或治療急性冠脈症候群的藥物中的用途。 In an optional embodiment, the present disclosure provides the use of the above-mentioned multi-component preparation in the preparation of a medicament for preventing or treating acute coronary syndrome.

本揭露提供一種治療急性冠脈症候群的方法，包括給予患者上述多元製劑。 The present disclosure provides a method for treating acute coronary syndrome, comprising administering the above-mentioned multi-preparation to a patient.

本揭露提供一種上述多元製劑的製備方法，包括將替格瑞洛或其藥用鹽與至少一種速釋單元中的輔料濕法製粒後壓片的步驟。 The present disclosure provides a preparation method of the above-mentioned multi-component preparation, which includes the steps of wet granulation of ticagrelor or a pharmaceutically acceptable salt thereof and at least one auxiliary material in an immediate-release unit, followed by tableting.

可選的實施方案中，本揭露提供的製備多元製劑的方法，包括1)將替格瑞洛或其藥用鹽的固體分散體與至少一種緩釋單元中的輔料乾法製粒後壓片成核芯的步驟，2)緩釋材料包衣的步驟。 In an optional embodiment, the method for preparing a multi-component preparation provided by the present disclosure includes 1) compressing the solid dispersion of ticagrelor or its pharmaceutically acceptable salt and at least one auxiliary material in the sustained-release unit by dry granulation into a tablet; The step of the core, 2) the step of coating the sustained-release material.

可選的實施方案中，本揭露提供的製備多元製劑的方法包括將顆粒、微丸、微片等按照有效劑量填入膠囊的步驟。 In an optional embodiment, the method for preparing a multi-component preparation provided by the present disclosure includes the step of filling granules, pellets, microtablets, etc. into capsules according to an effective dose.

由於已上市的速釋製劑需一日兩次，患者在長期用藥中漏服替格瑞洛易引起急性血栓形成而導致心梗或中風的風險，本揭露提供的一日一次給藥的多元製劑，可以減少服用次數，從而改善患者服藥的依從性，降低由於漏服而引起的急性血栓形成而導致的心梗或中風的風險。 Since the marketed immediate-release preparations need to be administered twice a day, patients who miss taking ticagrelor during long-term medication are likely to cause acute thrombosis and lead to the risk of myocardial infarction or stroke. , which can reduce the number of doses, thereby improving patient compliance with medication, and reducing the risk of myocardial infarction or stroke due to acute thrombosis due to missed doses.

本揭露提供一種降低患者心梗或中風的風險的方法，給與患者本揭露提供的多元製劑。 The present disclosure provides a method of reducing the risk of myocardial infarction or stroke in a patient by administering to the patient the multiple formulations provided by the present disclosure.

本揭露提供一種降低服藥患者個體差異性的方法，包括給予需要治療的患者本揭露提供的多元製劑。本揭露提供的多元製劑為替格瑞洛或其可藥用鹽提供更為均勻的吸收並為個體之間和個體內提供較小的藥物代謝動力學分佈波動。 The present disclosure provides a method for reducing the individual variability of patients taking medication, comprising administering the multiple formulations provided by the present disclosure to patients in need of treatment. The multiple formulations provided by the present disclosure provide for more uniform absorption of ticagrelor or a pharmaceutically acceptable salt thereof and less fluctuations in the pharmacokinetic profile between and within individuals.

本揭露中將包含在例如膠囊中的許多小單元，例如顆粒、微丸或微片組成的那些製劑命名為多元製劑。 Those formulations consisting of a number of small units, such as granules, pellets or microtablets, contained in, for example, capsules, are designated in the present disclosure as multicomponent formulations.

本揭露中涉及的藥物代謝動力學參數為一群個體中得到的數據，具體的，零到t時間的血藥濃度-時間曲線下面積(AUC0-t)、零到無限時間的血藥濃度-時間曲線下面積(AUC0-∞)、最大血漿濃度(Cmax)用的是GeoLSM(數值上與幾何平均值相當)，Tmax取中位數，2小時時的血藥濃度(C2h)、12小時時的血藥濃度(C12h)為算數均值。 The pharmacokinetic parameters involved in this disclosure are data obtained from a group of individuals, specifically, the area under the plasma concentration-time curve from zero to t (AUC 0-t ), the plasma concentration from zero to infinite time- The area under the time curve (AUC 0-∞ ) and the maximum plasma concentration (Cmax) were calculated using GeoLSM (values were equivalent to the geometric mean), the median Tmax was taken, the plasma concentration at 2 hours (C 2h ), 12 The blood concentration at hour (C 12h ) is the arithmetic mean.

本揭露中最大直徑理解為最小單元的平均直徑在0.1至5.0mm的範圍內。 The largest diameter in this disclosure is understood to mean that the average diameter of the smallest cells is in the range of 0.1 to 5.0 mm.

藉由下面的具體實施例可以進一步描述本揭露，但它們不是對本揭露的內容起限定作用。 The present disclosure can be further described by the following specific embodiments, but they are not intended to limit the content of the present disclosure.

實施例1、替格瑞洛膠囊的製備及溶出度測試 Example 1. Preparation and dissolution test of ticagrelor capsules

速釋微片製備方法：將替格瑞洛及甘露醇、磷酸氫鈣、羧甲基澱粉鈉、羥丙基纖維素混合後進行濕法製粒，與硬脂酸鎂總混，壓片(沖模

Figure 110112264-A0202-12-0011-14
2mm)，即可； Preparation method of immediate-release microtablets: mix ticagrelor, mannitol, calcium hydrogen phosphate, sodium carboxymethyl starch, and hydroxypropyl cellulose, carry out wet granulation, mix with magnesium stearate, and press into tablets (punching die).
Figure 110112264-A0202-12-0011-14
2mm), you can;

腸溶緩釋微片製備方法：將替格瑞洛和共聚維酮溶解於無水乙醇中，經噴霧乾燥後，製備成為替格瑞洛固體分散體；將替格瑞洛固體分散體及微晶纖維素、交聯羧甲基纖維素鈉、微粉矽膠混合後，進行乾法製粒，與硬脂酸鎂總混後，壓片(沖模

Figure 110112264-A0202-12-0011-15
2mm)，使用薄膜包衣預混劑(腸溶型)進行包衣，即可； Preparation method of enteric-coated sustained-release microtablets: dissolve ticagrelor and copovidone in absolute ethanol, and after spray drying, prepare ticagrelor solid dispersion; ticagrelor solid dispersion and microcrystalline Cellulose, croscarmellose sodium and micropowder silica gel are mixed, then dry granulated, mixed with magnesium stearate, and compressed into tablets (die
Figure 110112264-A0202-12-0011-15
2mm), use film coating premix (enteric-coated type) to coat, and get final product;

將速釋微片與腸溶緩釋微片按照一定的比例灌裝於膠囊中，即製備成為替格瑞洛緩釋膠囊。 The immediate-release microtablets and enteric-coated sustained-release microtablets are filled into capsules according to a certain proportion, namely, ticagrelor sustained-release capsules are prepared.

表1.處方組成

Figure 110112264-A0202-12-0012-1
Table 1. Formulation Composition
Figure 110112264-A0202-12-0012-1

2、溶出度測試 2. Dissolution test

將緩釋膠囊，照釋放度測定法(中國藥典2015版四部0931第二法)進行溶出試驗，首先以750mL的0.2%吐溫pH1.0為溶出介質，2h後加入250mL的無水磷酸鈉溶液調節介質為0.2%吐溫pH6.8，然後採用紫外-可見分光光度法測定釋放度，結果見表2。 The sustained-release capsules were subjected to the dissolution test according to the release test method (the second method of Chinese Pharmacopoeia 2015 Edition IV 0931). First, 750 mL of 0.2% Tween pH 1.0 was used as the dissolution medium, and 250 mL of anhydrous sodium phosphate solution was added to adjust after 2 hours. The medium was 0.2% Tween pH 6.8, and then the release degree was measured by UV-Vis spectrophotometry. The results are shown in Table 2.

表2.膠囊在不同介質中釋放度結果

Figure 110112264-A0202-12-0013-2
Table 2. Capsule release results in different media
Figure 110112264-A0202-12-0013-2

以上數據可以看出，緩釋膠囊中的速釋部分能夠在介質中快速溶出，2h加入鹼液之後腸溶部分開始緩慢釋放，至12h藥物的累積釋放度均在90%以上。 It can be seen from the above data that the immediate-release part in the sustained-release capsule can be rapidly dissolved in the medium, and the enteric-coated part starts to release slowly after 2 hours of adding lye, and the cumulative release of the drug to 12 hours is more than 90%.

實施例2、藥物代謝動力學數據測試 Example 2. Pharmacokinetic data test

上述實施例中的處方進行人體藥物代謝動力學(血藥濃度)分析體外釋放與藥物代謝動力學(PK)之間的關係，探究替格瑞洛的體內外相關性。 The formulations in the above examples were subjected to human pharmacokinetic (blood drug concentration) analysis of the relationship between in vitro release and pharmacokinetics (PK) to explore the in vitro and in vivo correlation of ticagrelor.

將不同處方採用健康志願受試者進行隨機、交叉、單中心、對照試驗研究，該研究評價了健康受試者(8位)中替格瑞洛的藥物代謝動力學和藥效學。在該項研究中，本發明處方為180mg和200mg劑量一日一次給藥，市售 的速釋製劑為90mg劑量一日二次給藥。採集血漿樣本用於確定替格瑞洛的血藥濃度和血小板抑制情況。藉由HPLC/MS/MS分析樣本。 A randomized, crossover, single-center, controlled trial study of different prescriptions in healthy volunteer subjects evaluated the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects (8 subjects). In this study, the present invention was formulated in 180 mg and 200 mg once-daily doses, commercially available The immediate release formulation is a 90 mg dose administered twice a day. Plasma samples were collected for determination of ticagrelor plasma concentrations and platelet inhibition. Samples were analyzed by HPLC/MS/MS.

表3.處方1藥物代謝動力學參數

Figure 110112264-A0202-12-0014-4
Table 3. Formulation 1 Pharmacokinetic Parameters
Figure 110112264-A0202-12-0014-4

表4. 處方2藥物代謝動力學參數

Figure 110112264-A0202-12-0014-6
Table 4. Formulation 2 Pharmacokinetic Parameters
Figure 110112264-A0202-12-0014-6

對比例、comparison,

將CN110507624A實施例中處方6進行藥物代謝動力學數據測試(健康受試者8位)，具體數值見表5。 Pharmacokinetic data test (8 healthy subjects) was performed on prescription 6 in the example of CN110507624A, and the specific values are shown in Table 5.

表5. 藥物代謝動力學參數

Figure 110112264-A0202-12-0015-7
Table 5. Pharmacokinetic parameters
Figure 110112264-A0202-12-0015-7

從以上數據可以看出，

Figure 110112264-A0202-12-0015-16
2mm微片組成的製劑具有緩釋動力學特徵，且與
Figure 110112264-A0202-12-0015-17
6.0mm的製劑相比較，個體差異性明顯減小。 From the above data, it can be seen that
Figure 110112264-A0202-12-0015-16
The formulation consisting of 2mm microtablets has sustained release kinetics and is consistent with
Figure 110112264-A0202-12-0015-17
Compared with the 6.0mm preparation, the individual differences were significantly reduced.

Claims (36)

一種一日一次給藥的多元製劑，其包含替格瑞洛或其可藥用鹽，該多元製劑含有速釋多單元部分和緩釋多單元部分，速釋多單元部分由獨立的速釋單元組成，緩釋多單元部分由獨立的緩釋單元組成，組成多元製劑的每一個單元的最大直徑小於5.0mm，較佳小於3.0mm，最佳小於2.5mm。 A once-a-day multi-unit formulation comprising ticagrelor or a pharmaceutically acceptable salt thereof, the multi-formulation comprising an immediate-release multi-unit portion and a sustained-release multi-unit portion, the immediate-release multi-unit portion being composed of separate immediate-release units The sustained-release multi-unit part is composed of independent sustained-release units, and the maximum diameter of each unit constituting the multi-component preparation is less than 5.0 mm, preferably less than 3.0 mm, and most preferably less than 2.5 mm. 如請求項1所述的多元製劑，其中，患者每日服用多元製劑中替格瑞洛或其可藥用鹽的含量是患者每日服用的倍林達®中替格瑞洛的含量的1至1.2倍。 The polyol formulation of claim 1 request entries, wherein the patient is administered daily polyol formulation administered twice daily in patients in Linda ® ticagrelor for content for content of 1 or a pharmaceutically acceptable salt thereof ticagrelor to 1.2 times. 如請求項1所述的多元製劑，其中一個或者兩個多元製劑中替格瑞洛或其可藥用鹽的含量是患者每日服用的倍林達®中替格瑞洛的含量的1至1.2倍。 The requested item polyol formulation of claim 1, wherein one or both of the content of polyol formulation for ticagrelor or a pharmaceutically acceptable salt thereof is administered twice daily in patients with Linda ® for the content of 1 to ticagrelor 1.2 times. 如請求項2或3所述的多元製劑，其中患者一日一次服用該多元製劑與患者一日兩次口服倍林達®生物等效。 Agents such as polyhydric request item 2 or 3, wherein the polyhydric patient once a day administration of the formulation twice a day patient Linda ® bioequivalent oral times. 如請求項1所述的多元製劑，其中任一緩釋單元含有含藥核心和緩釋材料包衣層。 The multi-component preparation according to claim 1, wherein any sustained-release unit comprises a drug-containing core and a coating layer of sustained-release material. 如請求項5所述的多元製劑，其中該緩釋材料選自乙基纖維素、海藻酸鈉、甲基纖維素、羥乙纖維素、羥丙基甲基纖維素、羥丙基乙基纖維素、羧甲基纖維素鈉、殼多糖、半乳糖甘露聚糖、聚維酮、聚乙烯醇，以及選自丙烯酸樹脂類、羥丙基甲基纖維素鄰苯二甲酸酯、醋酸羥丙基甲基纖維素琥珀酸酯、鄰苯二甲酸醋酸纖維素、聚乙烯醇酞酸酯、醋酸纖維素苯三酸酯中的一種或多種的腸溶材料，較佳丙烯酸樹脂類、羥丙基甲基纖維素鄰苯二甲酸酯、醋酸羥丙基甲基纖維素琥珀酸酯、鄰苯二甲酸醋酸纖維素、聚乙烯醇酞酸酯、醋酸纖維 素苯三酸酯中的一種或多種，最佳丙烯酸樹脂類，特別佳尤特奇L100、尤特奇S100、尤特奇L30D至55中的一種或多種。 The multicomponent formulation of claim 5, wherein the sustained-release material is selected from the group consisting of ethyl cellulose, sodium alginate, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose carboxymethyl cellulose sodium, chitin, galactomannan, povidone, polyvinyl alcohol, and selected from acrylic resins, hydroxypropyl methylcellulose phthalate, hydroxypropyl acetate Enteric material of one or more of methyl cellulose succinate, cellulose acetate phthalate, polyvinyl phthalate, and cellulose acetate trimellitate, preferably acrylic resin, hydroxypropyl Methylcellulose Phthalate, Hydroxypropyl Methylcellulose Acetate Succinate, Cellulose Acetate Phthalate, Polyvinyl Phthalate, Cellulose Acetate One or more of trimellitate, the best acrylic resin, especially one or more of Eudragit L100, Eudragit S100, Eudragit L30D to 55. 如請求項5所述的多元製劑，其中該緩釋材料包層衣的重量是核心總重的1%至50%，較佳10%至35%。 The multi-component formulation of claim 5, wherein the weight of the sustained-release material coating is 1% to 50% of the total core weight, preferably 10% to 35%. 如請求項1至7中任一項所述的多元製劑，其中該速釋單元和/或緩釋單元選自顆粒、微丸或微片，較佳微片。 The multicomponent formulation according to any one of claims 1 to 7, wherein the immediate release unit and/or the sustained release unit is selected from granules, pellets or microtablets, preferably microtablets. 如請求項8所述的多元製劑，其中替格瑞洛或以替格瑞洛計的替格瑞洛可藥用鹽的含量為45mg至220mg，較佳60mg、90mg、100mg、108mg、120mg、133mg、144mg、180mg、200mg或216mg，最佳100mg、108mg、133mg、144mg、200mg或216mg。 The multi-component preparation according to claim 8, wherein the content of ticagrelor or a pharmaceutically acceptable salt of ticagrelor in terms of ticagrelor is 45 mg to 220 mg, preferably 60 mg, 90 mg, 100 mg, 108 mg, 120 mg, 133mg, 144mg, 180mg, 200mg or 216mg, optimally 100mg, 108mg, 133mg, 144mg, 200mg or 216mg. 如請求項8或9所述的多元製劑，其中速釋多單元部分和緩釋多單元部分中替格瑞洛或其鹽的重量比為1：0.5至1：10，較佳1：1至1：8，最佳1：2。 The multi-component formulation as claimed in claim 8 or 9, wherein the weight ratio of ticagrelor or its salt in the immediate-release multi-unit fraction and the sustained-release multi-unit fraction is 1:0.5 to 1:10, preferably 1:1 to 1:10. 1:8, best 1:2. 如請求項6所述的多元製劑，其中該速釋單元含有替格瑞洛或其可藥用鹽及任選自稀釋劑、黏合劑、崩解劑、潤滑劑中的至少一種輔料。 The multi-component preparation according to claim 6, wherein the immediate-release unit contains ticagrelor or a pharmaceutically acceptable salt thereof and at least one auxiliary material optionally selected from the group consisting of diluents, binders, disintegrants, and lubricants. 如請求項11所述的多元製劑，其中該速釋單元的稀釋劑選自乳糖、澱粉、預膠化澱粉、甘露醇、微晶纖維素、葡萄糖、磷酸氫鈣、無水磷酸氫鈣中的一種或幾種，較佳甘露醇和磷酸氫鈣的混合物。 The multicomponent formulation of claim 11, wherein the diluent of the immediate-release unit is selected from the group consisting of lactose, starch, pregelatinized starch, mannitol, microcrystalline cellulose, glucose, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate Or several, preferably a mixture of mannitol and calcium hydrogen phosphate. 如請求項11所述的多元製劑，其中該速釋單元的黏合劑選自聚乙烯吡咯烷酮、澱粉、羧甲基纖維素、羥丙基纖維素、羥丙甲基纖維素中的一種或幾種，較佳羥丙基纖維素。 The multi-component preparation according to claim 11, wherein the binder of the immediate-release unit is selected from one or more of polyvinylpyrrolidone, starch, carboxymethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose , preferably hydroxypropyl cellulose. 如請求項11所述的多元製劑，其中該速釋單元的崩解劑選自交聯羧甲基纖維素鈉、乾澱粉、羧甲基澱粉鈉、低取代羥丙基纖維素、交聯聚乙 烯吡咯烷酮、預膠化澱粉的一種或者幾種，較佳羧甲基澱粉鈉或交聯羧甲基纖維素鈉。 The multi-component preparation according to claim 11, wherein the disintegrant of the immediate-release unit is selected from the group consisting of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polymer Second One or more of vinylpyrrolidone and pregelatinized starch, preferably sodium carboxymethyl starch or croscarmellose sodium. 如請求項11所述的多元製劑，其中該速釋單元的潤滑劑選自硬脂酸鎂、山崳酸甘油酯、氫化植物油、硬脂酸鈣、微粉矽膠、富馬酸硬脂酸鈉中的一種或幾種，較佳硬脂酸鎂。 The multicomponent formulation of claim 11, wherein the lubricant of the immediate-release unit is selected from magnesium stearate, glyceryl behenate, hydrogenated vegetable oil, calcium stearate, micronized silica gel, and sodium stearate fumarate One or more of them, preferably magnesium stearate. 如請求項11所述的多元製劑，其中該緩釋單元含有替格瑞洛或其可藥用鹽及任選自稀釋劑、崩解劑、助流劑、潤滑劑中的至少一種輔料。 The multi-component preparation according to claim 11, wherein the sustained-release unit contains ticagrelor or a pharmaceutically acceptable salt thereof and optionally at least one auxiliary material from among diluents, disintegrants, glidants, and lubricants. 如請求項16所述的多元製劑，其中該緩釋單元的稀釋劑選自乳糖、澱粉、預膠化澱粉、甘露醇、微晶纖維素、葡萄糖、磷酸氫鈣、無水磷酸氫鈣中的一種或幾種，較佳微晶纖維素。 The multicomponent preparation as claimed in claim 16, wherein the diluent of the sustained-release unit is selected from the group consisting of lactose, starch, pregelatinized starch, mannitol, microcrystalline cellulose, glucose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate or several, preferably microcrystalline cellulose. 如請求項17所述的多元製劑，其中該緩釋單元的崩解劑選自交聯羧甲基纖維素鈉、乾澱粉、羧甲基澱粉鈉、低取代羥丙基纖維素、交聯聚乙烯吡咯烷酮、預膠化澱粉的一種或者幾種，較佳交聯羧甲基纖維素鈉。 The multi-component preparation according to claim 17, wherein the disintegrant of the sustained-release unit is selected from the group consisting of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polymer One or more of vinylpyrrolidone and pregelatinized starch, preferably croscarmellose sodium. 如請求項17所述的多元製劑，其中該緩釋單元的助流劑選自滑石粉或二氧化矽，較佳二氧化矽。 The multi-component preparation according to claim 17, wherein the glidant of the sustained-release unit is selected from talc or silica, preferably silica. 如請求項17所述的多元製劑，其中該緩釋單元的潤滑劑選自硬脂酸鎂、硬脂酸鈣、山崳酸甘油酯、氫化植物油中的一種或幾種，較佳硬脂酸鎂。 The multicomponent formulation as claimed in claim 17, wherein the lubricant of the sustained-release unit is selected from one or more of magnesium stearate, calcium stearate, glyceryl behenate, hydrogenated vegetable oil, preferably stearic acid magnesium. 如請求項8所述的多元製劑，其中該緩釋單元中替格瑞洛或其藥用鹽與選自聚維酮、共聚維酮、聚乙二醇、泊洛沙姆、丙烯酸樹脂類、羥丙甲基纖維素類或其混合物的載體成固體分散體，該載體較佳共聚維酮。 The multi-component preparation according to claim 8, wherein ticagrelor or a pharmaceutically acceptable salt thereof in the sustained-release unit is selected from the group consisting of povidone, copovidone, polyethylene glycol, poloxamer, acrylic resin, The carrier of hydroxypropyl methylcellulose or its mixture is a solid dispersion, and the carrier is preferably copovidone. 如請求項1至21中任一項所述的多元製劑，其為膠囊。 The multicomponent formulation of any one of claims 1 to 21, which is a capsule. 如請求項22所述的多元製劑，緩釋單元組成如下： The multi-component preparation as claimed in claim 22, the sustained-release unit is composed as follows: 核芯(以核芯總重計) Core (total core weight) 替格瑞洛10%至45%； Ticagrelor 10% to 45%; 共聚維酮10%至45%； Copovidone 10% to 45%; 微晶纖維素5%至60%； Microcrystalline cellulose 5% to 60%; 交聯羧甲基纖維素鈉5%至25%； Croscarmellose sodium 5% to 25%; 微粉矽膠0.5%至5%； Micronized silica gel 0.5% to 5%; 硬脂酸鎂0.5%至5%； Magnesium stearate 0.5% to 5%; 另含有占核心總重1%至50%的緩釋材料包層衣。 In addition, it contains 1% to 50% of the total core weight of the sustained release material coating. 如請求項23所述的多元製劑，組成如下： The multi-component preparation according to claim 23, composed as follows: 速釋單元(以速釋單元總重計)： Immediate-Release Units (total weight of Immediate-Release Units): 替格瑞洛20%至45%； Ticagrelor 20% to 45%; 甘露醇20%至60%； Mannitol 20% to 60%; 磷酸氫鈣10%至45%； Calcium hydrogen phosphate 10% to 45%; 羧甲基澱粉鈉1%至10%； Sodium carboxymethyl starch 1% to 10%; 羥丙基纖維素1%至10%； Hydroxypropyl cellulose 1% to 10%; 硬脂酸鎂1%至5%； Magnesium stearate 1% to 5%; 緩釋單元 Sustained release unit 核芯(以緩釋單元核芯總重計) Core (based on the total weight of the sustained-release unit core) 替格瑞洛10%至45%； Ticagrelor 10% to 45%; 共聚維酮10%至45%； Copovidone 10% to 45%; 微晶纖維素5%至60%； Microcrystalline cellulose 5% to 60%; 交聯羧甲基纖維素鈉5%至25%； Croscarmellose sodium 5% to 25%; 微粉矽膠0.5%至5%； Micronized silica gel 0.5% to 5%; 硬脂酸鎂0.5%至5%； Magnesium stearate 0.5% to 5%; 另含有占核心總重1%至50%的緩釋材料包層衣。 In addition, it contains 1% to 50% of the total core weight of the sustained release material coating. 如請求項1至24中任一項所述的多元製劑，其中組成多元製劑的每一個單元的最大直徑為0.1至5.0mm，較佳為0.5至3.0mm，最佳為1至2.5mm。 The multicomponent formulation of any one of claims 1 to 24, wherein the largest diameter of each unit making up the multicomponent formulation is 0.1 to 5.0 mm, preferably 0.5 to 3.0 mm, most preferably 1 to 2.5 mm. 如請求項1至25中任一項所述的多元製劑，其中每個多元製劑中速釋多單元的單元數目
Figure 110112264-A0202-13-0005-18
3，較佳
Figure 110112264-A0202-13-0005-20
4，最佳
Figure 110112264-A0202-13-0005-21
5；緩釋多單元的單元數目
Figure 110112264-A0202-13-0005-22
5，較佳
Figure 110112264-A0202-13-0005-23
8，最佳
Figure 110112264-A0202-13-0005-24
10。 The multicomponent formulation of any one of claims 1 to 25, wherein the number of units of the immediate release multiunit in each multicomponent formulation
Figure 110112264-A0202-13-0005-18
3, better
Figure 110112264-A0202-13-0005-20
4. Best
Figure 110112264-A0202-13-0005-21
5; the number of units of the sustained release multi-unit
Figure 110112264-A0202-13-0005-22
5, better
Figure 110112264-A0202-13-0005-23
8. Best
Figure 110112264-A0202-13-0005-24
10. 如請求項1至26中任一項所述的多元製劑，其中依照釋放度測定法(中國藥典2015版四部0931第二法)進行溶出試驗，首先以750mL的0.2%吐溫pH1.0為溶出介質，2h後加入250mL的無水磷酸鈉溶液調節介質為0.2%吐溫pH6.8，然後採用紫外至可見分光光度法測定釋放度，不低於總含量的10%，較佳20%；12小時釋放不低於總含量的80%，較佳85%，最佳90%。 The multi-component preparation according to any one of claims 1 to 26, wherein the dissolution test is carried out according to the release rate determination method (the second method of Chinese Pharmacopoeia 2015 Edition IV 0931), firstly, 750 mL of 0.2% Tween pH 1.0 is used as the dissolution Medium, add 250mL of anhydrous sodium phosphate solution after 2 hours to adjust the medium to 0.2% Tween pH 6.8, and then measure the release degree by UV-visible spectrophotometry, not less than 10% of the total content, preferably 20%; 12 hours The release is not less than 80% of the total content, preferably 85%, and optimally 90%. 如請求項1至26中任一項所述的多元製劑，其中患者單次口服後體內血漿藥物濃度達峰時間Tmax為自服藥後4至12小時。 The multi-component preparation according to any one of claims 1 to 26, wherein the time Tmax of the peak plasma drug concentration in the patient after a single oral dose is 4 to 12 hours after taking the drug. 如請求項1至26中任一項所述的多元製劑，其中AUC0-t的RSD值小於42，較佳小於40，最佳小於38。 The multicomponent formulation of any one of claims 1 to 26, wherein the AUC 0-t has an RSD value of less than 42, preferably less than 40, most preferably less than 38. 如請求項29所述的多元製劑，其中最大血漿濃度(Cmax)的RSD值小於44，較佳小於42，最佳小於40。 The multicomponent formulation of claim 29, wherein the RSD value for the maximum plasma concentration (Cmax) is less than 44, preferably less than 42, most preferably less than 40. 如請求項1至26中任一項所述的多元製劑，其中患者單次口服含有200mg的替格瑞洛或者以替格瑞洛鹽計的替格瑞洛，2小時時的血藥濃度C2h及12小時時的血藥濃度C12h均大於200ng/mL。 The multicomponent formulation of any one of claims 1 to 26, wherein a single oral dose to the patient contains 200 mg of ticagrelor or ticagrelor as a ticagrelor salt, with a plasma concentration of C at 2 hours The plasma concentration C 12h at 2h and 12h was greater than 200ng/mL. 一種製備如請求項1至26中任一項所述的多元製劑的方法，包括將替格瑞洛或其藥用鹽與至少一種速釋單元中的輔料濕法製粒後壓片的步驟。 A method for preparing a multi-component formulation as claimed in any one of claims 1 to 26, comprising the step of wet granulation of ticagrelor or a pharmaceutically acceptable salt thereof and at least one excipient in an immediate-release unit, followed by tableting. 如請求項32所述的製備多元製劑的方法，包括1)將替格瑞洛或其藥用鹽的固體分散體與至少一種緩釋單元中的輔料乾法製粒後壓片成核芯的步驟，2)緩釋材料包衣的步驟。 The method for preparing a multi-component preparation according to claim 32, comprising 1) the step of compressing the solid dispersion of ticagrelor or its pharmaceutically acceptable salt and at least one auxiliary material in the sustained-release unit by dry granulation to form a core , 2) the step of slow-release material coating. 一種如請求項1至26中任一項所述的多元製劑在製備預防或治療心肌梗死、血栓形成中風、暫時性局部缺血發作和/或外周血管疾病、不穩定或穩定心絞痛、血小板聚集疾病的藥物中的用途。 A multi-component preparation according to any one of claims 1 to 26 in the preparation of prevention or treatment of myocardial infarction, thrombotic stroke, transient ischemic attack and/or peripheral vascular disease, unstable or stable angina pectoris, platelet aggregation disease use in medicines. 一種降低患者心梗或中風的風險的方法，一日一次給與患者如請求項1至26中任一項所述的多元製劑。 A method of reducing the risk of myocardial infarction or stroke in a patient by administering to the patient the multi-formulation of any one of claims 1 to 26 once a day. 一種降低服藥患者個體間差異性的方法，包括給予需要治療的患者如請求項1至26中任一項所述的多元製劑。 A method of reducing inter-individual variability among patients taking medication, comprising administering to a patient in need of treatment the multi-formulation of any one of claims 1 to 26.
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