TW202245772A - A pharmaceutical composition of a capsid protein inhibitor and preparation method thereof - Google Patents

A pharmaceutical composition of a capsid protein inhibitor and preparation method thereof Download PDF

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TW202245772A
TW202245772A TW111104084A TW111104084A TW202245772A TW 202245772 A TW202245772 A TW 202245772A TW 111104084 A TW111104084 A TW 111104084A TW 111104084 A TW111104084 A TW 111104084A TW 202245772 A TW202245772 A TW 202245772A
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高瑋
石磊
韓清
牛亞軍
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大陸商江蘇恆瑞醫藥股份有限公司
大陸商蘇州盛迪亞生物醫藥有限公司
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Abstract

The invention provides a pharmaceutical composition of a capsid protein inhibitor and preparation method thereof. Specifically, the present disclosure provides a composition comprising (S)-N 5-(3,4-Difluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide or pharmaceutically acceptable salt and hydroxypropyl methyl fiber. The composition has good dissolution and superior stability.

Description

一種衣殼蛋白抑制劑的醫藥組成物及其製備方法 A pharmaceutical composition of capsid protein inhibitor and its preparation method

本揭露屬於藥物製劑領域，具體關於一種衣殼蛋白抑制劑的醫藥組成物及其製備方法。具體的，關於一種組成物，包含(S)-N 5-(3,4-二氟苯基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺或其藥學上可接受的鹽和羥丙甲基纖維。 The disclosure belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition of a capsid protein inhibitor and a preparation method thereof. Specifically, regarding a composition comprising (S) -N 5 -(3,4-difluorophenyl)-6-methyl- N 3 -( (R) -1,1,1-trifluoropropane- 2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide or its pharmaceutically acceptable of salt and hypromellose.

慢性B型肝炎病毒(HBV)感染治愈率低與其病毒特性有很大關係，HBV是嗜肝DNA病毒家族(Hepadnaviridae)的一種包膜、部分雙鏈DNA(dsDNA)病毒。成熟的HBV病毒顆粒最外層為包膜蛋白，包裹著HBV核衣殼(Nucleocapsid)。核衣殼又稱核心顆粒(Core particle)，由衣殼蛋白(Capsid protein)、HBV鬆弛環狀DNA(Relaxed circular DNA，rcDNA)及結合在rcDNA負鏈5’端的HBV逆轉錄酶構成。在感染時，rcDNA在宿主细胞核中轉變為共價閉環DNA(cccDNA)，作為HBV複製模板。HBV複製過程中，1個重要步驟就是衣殼裝配(Encapsidation)。cccDNA轉錄出的前基因組RNA(Pregenomic RNA，pgRNA)需要同HBV逆轉錄酶一起被包裹在衣殼蛋白中，完成裝配步驟，才能促發後續逆轉錄。在逆轉錄以前，HBV逆轉錄酶，pgRNA需要被衣殼蛋白正確包裹。因此，阻斷衣殼蛋白裝配， 或加快衣殼蛋白降解，都會阻斷衣殼裝配過程，從而影响病毒複製。此外，構成核心蛋白二聚化基序(Dimerization motif)及裝配結構域(Assemblydomain)的N-端149個氨基酸殘基(Cp149)没有人體蛋白質同源序列。因此，衣殼蛋白裝配抑制劑被視為抗B肝藥物開發的新靶點。由於與傳統抗病毒藥物作用機理不同，衣殼蛋白抑制劑可與DNA聚合酶抑制劑的組合療法協同遏制HBV複製，並且防止出現耐藥性，提供對慢性B型肝炎感染更安全有效的治療。 The low cure rate of chronic hepatitis B virus (HBV) infection has a lot to do with its virus characteristics. HBV is an enveloped, partially double-stranded DNA (dsDNA) virus of the hepadnaviridae family. The outermost layer of the mature HBV virus particle is the envelope protein, wrapping the HBV nucleocapsid (Nucleocapsid). Nucleocapsid, also known as core particle, is composed of capsid protein, HBV relaxed circular DNA (Relaxed circular DNA, rcDNA) and HBV reverse transcriptase bound to the 5' end of the negative strand of rcDNA. Upon infection, rcDNA is converted into covalently closed circular DNA (cccDNA) in the host cell nucleus, which serves as a template for HBV replication. In the HBV replication process, an important step is the capsid assembly (Encapsidation). The pregenomic RNA (Pregenomic RNA, pgRNA) transcribed by cccDNA needs to be wrapped in the capsid protein together with HBV reverse transcriptase to complete the assembly step to trigger subsequent reverse transcription. Before reverse transcription, HBV reverse transcriptase, pgRNA needs to be properly encapsulated by capsid protein. Thus, blocking capsid protein assembly, Or accelerating the degradation of capsid protein will block the capsid assembly process, thereby affecting virus replication. In addition, the N-terminal 149 amino acid residues (Cp149) that constitute the core protein dimerization motif (Dimerization motif) and assembly domain (Assembly domain) have no human protein homologous sequence. Therefore, capsid protein assembly inhibitors are regarded as new targets for the development of anti-hepatitis B drugs. Due to the different mechanism of action from traditional antiviral drugs, capsid protein inhibitors can synergistically curb HBV replication with DNA polymerase inhibitor combination therapy, prevent drug resistance, and provide a safer and more effective treatment for chronic hepatitis B infection.

WO2019020070公開了一種新型結構的衣殼蛋白抑制劑，如式I所示化合物，其化合物名稱為(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺，該抑制劑表現出較強的衣殼蛋白抑制活性和治療慢性B型肝炎病毒(HBV)的作用， WO2019020070 discloses a capsid protein inhibitor with a novel structure, such as the compound shown in formula I, and its compound name is (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 - ( (R) -1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5 (4 H )-Diformamide, the inhibitor shows strong capsid protein inhibitory activity and the effect of treating chronic hepatitis B virus (HBV),

Figure 111104084-A0202-12-0002-3
Figure 111104084-A0202-12-0002-3

為了滿足患者用藥需求，需要將上述化合物(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺或其可藥用鹽製備成合適的製劑，就固體製劑而言，製劑需要具有良好的溶出特性和製劑穩定性。 In order to meet the medication needs of patients, the above compound (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 -( (R) -1,1,1-trifluoropropane -2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide or its pharmaceutically acceptable Salts are prepared into suitable formulations, and in the case of solid formulations, the formulation needs to have good dissolution properties and formulation stability.

本揭露目的在於提供一種包含活性成分(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺或其可藥用鹽的醫藥組成物，該組成物具有良好的溶出度和製劑穩定性。 The purpose of this disclosure is to provide an active ingredient (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 -( (R) -1,1,1-trifluoropropane- 2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide or its pharmaceutically acceptable salt A pharmaceutical composition, which has good dissolution rate and formulation stability.

本揭露提供了一種醫藥組成物，該組成物包含活性成分(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪- 3,5(4H)-二甲醯胺或其可藥用鹽和羥丙基甲基纖維素。 The present disclosure provides a pharmaceutical composition comprising the active ingredient (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 -( (R) -1,1, 1-trifluoroprop-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide Or its pharmaceutically acceptable salt and hydroxypropyl methylcellulose.

在某些實施方案中，該羥丙基甲基纖維素的含量基於組成物總重量的0.01-25%，較佳0.05-20%，更佳0.1-15%，非限制性實施例包括0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1.0%、1.2%、1.4%、1.6%、1.8%、2.0%、2.2%、2.4%、2.6%、2.8%、3.0%、3.2%、3.4%、3.6%、3.8%、4.0%、4.2%、4.4%、4.6%、4.8%、5.0%、5.2%、5.4%、5.6%、5.8%、6.0%、6.2%、6.4%、6.6%、6.8%、7.0%、7.2%、7.4%、7.6%、7.8%、8.0%、8.2%、8.4%、8.6%、8.8%、9.0%、9.2%、9.4%、9.6%、9.8%、10.0%、10.2%、10.4%、10.6%、10.8%、11.0%、11.2%、11.4%、11.6%、11.8%、12.0%、12.2%、12.4%、12.6%、12.8%、13.0%、13.2%、13.4%、13.6%、13.8%、14.0%、14.2%、14.4%、14.6%、14.8%、15.0%或任意兩者數之間任意值。 In certain embodiments, the content of the hydroxypropyl methylcellulose is 0.01-25% based on the total weight of the composition, preferably 0.05-20%, more preferably 0.1-15%, non-limiting examples include 0.1% , 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6 %, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0%, 6.2%, 6.4%, 6.6%, 6.8%, 7.0%, 7.2%, 7.4%, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%, 9.2% , 9.4%, 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%, 11.4%, 11.6%, 11.8%, 12.0%, 12.2%, 12.4%, 12.6 %, 12.8%, 13.0%, 13.2%, 13.4%, 13.6%, 13.8%, 14.0%, 14.2%, 14.4%, 14.6%, 14.8%, 15.0% or any value in between.

在某些實施方案中，醫藥組成物還包含崩解劑，該崩解劑選自澱粉、交聯羧甲基纖維素鈉、羧甲基澱粉鈉、交聯聚維酮中的一種或多種。在某些實施方案中，該崩解劑選自交聯羧甲基纖維素鈉、羧甲基澱粉鈉和交聯聚維酮中的一種或多種，較佳交聯羧甲基纖維素鈉和羧甲基澱粉鈉中的一種或多種，更佳交聯羧甲基纖維素鈉。 In some embodiments, the pharmaceutical composition further comprises a disintegrant, which is selected from one or more of starch, croscarmellose sodium, carboxymethyl starch sodium, and crospovidone. In certain embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch and crospovidone, preferably croscarmellose sodium and One or more of sodium carboxymethyl starch, more preferably croscarmellose sodium.

在某些實施方案中，該崩解劑的含量為基於組成物總重量的0.01-25%，較佳0.05-20%，更佳0.1-15%，非限制實施例包括：0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1.0%、1.2%、1.4%、1.6%、1.8%、2.0%、2.2%、2.4%、2.6%、2.8%、3.0%、3.2%、3.4%、3.6%、3.8%、4.0%、4.2%、4.4%、4.6%、4.8%、5.0%、5.2%、5.4%、5.6%、5.8%、6.0%、6.2%、6.4%、6.6%、6.8%、7.0%、7.2%、7.4%、7.6%、7.8%、8.0%、8.2%、8.4%、8.6%、8.8%、9.0%、9.2%、 9.4%、9.6%、9.8%、10.0%、10.2%、10.4%、10.6%、10.8%、11.0%、11.2%、11.4%、11.6%、11.8%、12.0%、12.2%、12.4%、12.6%、12.8%、13.0%、13.2%、13.4%、13.6%、13.8%、14.0%、14.2%、14.4%、14.6%、14.8%、15.0%或任意兩者數之間任意值。 In certain embodiments, the content of the disintegrant is 0.01-25%, preferably 0.05-20%, more preferably 0.1-15%, based on the total weight of the composition, non-limiting examples include: 0.1%, 0.2% , 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8 %, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0%, 6.2%, 6.4%, 6.6%, 6.8%, 7.0%, 7.2%, 7.4%, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%, 9.2%, 9.4%, 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%, 11.4%, 11.6%, 11.8%, 12.0%, 12.2%, 12.4%, 12.6% , 12.8%, 13.0%, 13.2%, 13.4%, 13.6%, 13.8%, 14.0%, 14.2%, 14.4%, 14.6%, 14.8%, 15.0% or any value in between.

本揭露的醫藥組成物進一步還包含填充劑、潤滑劑、助流劑中的一種或多種。 The pharmaceutical composition of the present disclosure further includes one or more of fillers, lubricants, and glidants.

在某些實施方案中，該填充劑選自微晶纖維素、糊精、乳糖、蔗糖、甘露醇、磷酸氫鈣中的一種或多種，較佳微晶纖維素和乳糖中的一種或多種，更佳微晶纖維素和乳糖。 In some embodiments, the filler is selected from one or more of microcrystalline cellulose, dextrin, lactose, sucrose, mannitol, calcium hydrogen phosphate, preferably one or more of microcrystalline cellulose and lactose, Better Microcrystalline Cellulose and Lactose.

在某些實施方案中，該填充劑含量為基於組成物總重量的20-95%，較佳50-95%，非限制實施例包括：51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%或任意兩者數之間任意值。 In certain embodiments, the content of the filler is 20-95%, preferably 50-95%, based on the total weight of the composition. Non-limiting examples include: 51%, 52%, 53%, 54%, 55% , 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or any value in between.

在某些實施方案中，該助流劑選自硬脂酸、硬脂酸鎂、硬脂酸鋅、硬脂酸鈣、聚乙二醇、硬脂富馬酸鈉、山崳酸甘油酯、二氧化矽、氫化植物油、月桂基硫酸鈉、滑石粉中的一種或多種，較佳二氧化矽。 In certain embodiments, the glidant is selected from stearic acid, magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, glyceryl behenate, One or more of silicon dioxide, hydrogenated vegetable oil, sodium lauryl sulfate, and talcum powder, preferably silicon dioxide.

在某些實施方案中，該助流劑的含量基於組成物總重量的0.01-10%，較佳0.05-5%，非限制實施例包括：0.05%、0.06%、0.07%、0.08%、0.09%、0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1%、1.2%、1.4%、1.6%、1.8%、2.0%、2.2%、2.4%、2.6%、2.8%、3.0%、3.2%、3.4%、3.6%、3.8%、 4.0%、4.2%、4.4%、4.6%、4.8%、5.0%或任意兩者數之間任意值。 In some embodiments, the content of the glidant is 0.01-10%, preferably 0.05-5%, based on the total weight of the composition. Non-limiting examples include: 0.05%, 0.06%, 0.07%, 0.08%, 0.09% %, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, or any value in between.

在某些實施方案中，該潤滑劑選自硬脂酸、硬脂酸鎂、硬脂酸鋅、硬脂酸鈣、聚乙二醇、硬脂富馬酸鈉、山崳酸甘油酯、二氧化矽、氫化植物油、月桂基硫酸鈉、滑石粉中的一種或多種，較佳硬脂酸鎂。 In certain embodiments, the lubricant is selected from the group consisting of stearic acid, magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, glyceryl behenate, di One or more of silicon oxide, hydrogenated vegetable oil, sodium lauryl sulfate, talc, preferably magnesium stearate.

在某些實施方案中，該潤滑劑的含量基於組成物總重量的0.01-10%，較佳0.05-5%，非限制實施例包括：0.05%、0.06%、0.07%、0.08%、0.09%、0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1%、1.2%、1.4%、1.6%、1.8%、2.0%、2.2%、2.4%、2.6%、2.8%、3.0%、3.2%、3.4%、3.6%、3.8%、4.0%、4.2%、4.4%、4.6%、4.8%、5.0%或任意兩者數之間任意值。 In some embodiments, the content of the lubricant is 0.01-10% based on the total weight of the composition, preferably 0.05-5%, non-limiting examples include: 0.05%, 0.06%, 0.07%, 0.08%, 0.09% , 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4 %, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0% or any value in between.

在某些實施方案中，活性成分(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺或其可藥用鹽的含量為基於組成物總重量的0.1-40%，較佳1-35%，非限制實施例包括：1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%或任意兩者數之間任意值。 In certain embodiments, the active ingredient (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 -( (R) -1,1,1-trifluoropropane- 2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide or its pharmaceutically acceptable salt The content is 0.1-40% based on the total weight of the composition, preferably 1-35%, non-limiting examples include: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% , 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% %, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, or any value in between.

本揭露提供了一種醫藥組成物，其包含以組成物總重量計的， The present disclosure provides a pharmaceutical composition, which comprises, based on the total weight of the composition,

活性成分1-35%，該活性成分為(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺或其可藥用鹽，羥丙基甲基纖維素0.1-15%， Active ingredient 1-35%, the active ingredient is (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 -( (R) -1,1,1-trifluoro Propan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide or its druggable With salt, hydroxypropyl methylcellulose 0.1-15%,

填充劑50-95%，該填充劑選自微晶纖維素和乳糖中的一種或多種， Filler 50-95%, the filler is selected from one or more of microcrystalline cellulose and lactose,

崩解劑0.1-15%，該崩解劑為交聯羧甲基纖維素鈉。 Disintegrating agent 0.1-15%, the disintegrating agent is croscarmellose sodium.

崩解劑是指能使固體製劑在胃液中迅速裂碎成細小顆粒的物質， 從而使功能成分迅速溶解吸收，發揮作用，大都具有良好的吸水性和膨脹性，從而實現口服製劑崩解。不同崩解劑的種類較多，不同崩解劑對固體製劑的崩解影響程度不同，對於期望的溶出特性，需要選擇合適的崩解劑。 A disintegrant refers to a substance that can rapidly disintegrate a solid preparation into fine particles in gastric juice. Thereby, the functional ingredients can be quickly dissolved and absorbed to play a role, and most of them have good water absorption and swelling properties, so as to realize the disintegration of oral preparations. There are many types of different disintegrants, and different disintegrants have different effects on the disintegration of solid preparations. For the desired dissolution characteristics, it is necessary to select a suitable disintegrant.

本揭露提供了一種醫藥組成物，其包含活性成分(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺或其可藥用鹽和崩解劑。 The disclosure provides a pharmaceutical composition comprising the active ingredient (S)-N5-(3,4-difluorophenyl)-6-methyl-N3-((R)-1,1,1-trifluoro Propan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dimethylamide or its pharmaceutically acceptable salt and disintegrants.

在某些實施方案中，該崩解劑選自澱粉、交聯羧甲基纖維素鈉、羧甲基澱粉鈉、交聯聚維酮中的一種或多種。在某些實施方案中，該崩解劑選自交聯羧甲基纖維素鈉、羧甲基澱粉鈉和交聯聚維酮中的一種或多種，較佳交聯羧甲基纖維素鈉和羧甲基澱粉鈉中的一種或多種，更佳交聯羧甲基纖維素鈉。 In some embodiments, the disintegrant is selected from one or more of starch, croscarmellose sodium, carboxymethyl starch sodium, and crospovidone. In certain embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch and crospovidone, preferably croscarmellose sodium and One or more of sodium carboxymethyl starch, more preferably croscarmellose sodium.

在某些實施方案中，該崩解劑的含量為基於組成物總重量的0.01-25%，較佳0.05-20%，更佳0.1-15%，非限制實施例包括：0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1.0%、1.2%、1.4%、1.6%、1.8%、2.0%、2.2%、2.4%、2.6%、2.8%、3.0%、3.2%、3.4%、3.6%、3.8%、4.0%、4.2%、4.4%、4.6%、4.8%、5.0%、5.2%、5.4%、5.6%、5.8%、6.0%、6.2%、6.4%、6.6%、6.8%、7.0%、7.2%、7.4%、7.6%、7.8%、8.0%、8.2%、8.4%、8.6%、8.8%、9.0%、9.2%、9.4%、9.6%、9.8%、10.0%、10.2%、10.4%、10.6%、10.8%、11.0%、11.2%、11.4%、11.6%、11.8%、12.0%、12.2%、12.4%、12.6%、12.8%、13.0%、13.2%、13.4%、13.6%、13.8%、14.0%、14.2%、14.4%、14.6%、14.8%、15.0%或任意兩者數之間任意值。 In certain embodiments, the content of the disintegrant is 0.01-25%, preferably 0.05-20%, more preferably 0.1-15%, based on the total weight of the composition, non-limiting examples include: 0.1%, 0.2% , 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8 %, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0%, 6.2%, 6.4%, 6.6%, 6.8%, 7.0%, 7.2%, 7.4%, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%, 9.2%, 9.4% , 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%, 11.4%, 11.6%, 11.8%, 12.0%, 12.2%, 12.4%, 12.6%, 12.8 %, 13.0%, 13.2%, 13.4%, 13.6%, 13.8%, 14.0%, 14.2%, 14.4%, 14.6%, 14.8%, 15.0% or any value in between.

在某些實施方案中，組成物還包含羥丙基甲基纖維素。 In certain embodiments, the composition further comprises hydroxypropylmethylcellulose.

在某些實施方案中，該羥丙基甲基纖維素的含量基於組成物總重 量的0.01-25%，較佳0.05-20%，更佳0.1-15%，非限制實施例包括0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1.0%、1.2%、1.4%、1.6%、1.8%、2.0%、2.2%、2.4%、2.6%、2.8%、3.0%、3.2%、3.4%、3.6%、3.8%、4.0%、4.2%、4.4%、4.6%、4.8%、5.0%、5.2%、5.4%、5.6%、5.8%、6.0%、6.2%、6.4%、6.6%、6.8%、7.0%、7.2%、7.4%、7.6%、7.8%、8.0%、8.2%、8.4%、8.6%、8.8%、9.0%、9.2%、9.4%、9.6%、9.8%、10.0%、10.2%、10.4%、10.6%、10.8%、11.0%、11.2%、11.4%、11.6%、11.8%、12.0%、12.2%、12.4%、12.6%、12.8%、13.0%、13.2%、13.4%、13.6%、13.8%、14.0%、14.2%、14.4%、14.6%、14.8%、15.0%或任意兩者數之間任意值。 In certain embodiments, the content of the hydroxypropyl methylcellulose is based on the total weight of the composition 0.01-25% of the amount, preferably 0.05-20%, more preferably 0.1-15%, non-limiting examples include 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0% , 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, 6.0%, 6.2%, 6.4%, 6.6%, 6.8%, 7.0%, 7.2%, 7.4 %, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%, 9.2%, 9.4%, 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%, 11.4%, 11.6%, 11.8%, 12.0%, 12.2%, 12.4%, 12.6%, 12.8%, 13.0%, 13.2%, 13.4%, 13.6%, 13.8%, 14.0% , 14.2%, 14.4%, 14.6%, 14.8%, 15.0%, or any value in between.

進一步地，本揭露提供了一種醫藥組成物，該組成物為固體形式，可以片劑、顆粒或丸劑的形式存在，較佳片劑。 Furthermore, the present disclosure provides a pharmaceutical composition, which is in solid form and can exist in the form of tablets, granules or pills, preferably tablets.

藥物製劑領域中，藥物活性成分本身的療效固然重要，但製劑的釋放特性對藥物療效也是也起到至關重要的作用。例如，製成速釋製劑，加快藥物的溶出速度，改善溶出度從而提高生物利用度。 In the field of pharmaceutical preparations, the curative effect of the active ingredient itself is important, but the release characteristics of the preparation also play a vital role in the curative effect of the drug. For example, it is made into an immediate release preparation to accelerate the dissolution rate of the drug, improve the dissolution rate and thereby increase the bioavailability.

本揭露提供的醫藥組成物溶出十分迅速且完全，該醫藥組成物按照中國藥典2015年版四部通則0931第二法，使用pH為6.8的磷酸鹽緩衝液加2%吐溫80作為溶出介質，在37±0.5℃下以75rpm的漿速進行溶出度測定，15分鐘內累計溶出度不小於60%，較佳不小於65%，更佳不小於70%，非限制實施例包括不小於：70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%。 The pharmaceutical composition provided by this disclosure dissolves very quickly and completely. According to the second method of the Chinese Pharmacopoeia 2015 Edition Four General Rules 0931, the pharmaceutical composition uses a phosphate buffer solution with a pH of 6.8 and 2% Tween 80 as the dissolution medium. The dissolution rate is measured at a slurry speed of 75 rpm at ±0.5°C. The cumulative dissolution rate within 15 minutes is not less than 60%, preferably not less than 65%, more preferably not less than 70%. Non-limiting examples include not less than: 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% .

在某些實施方案中，組成物30分鐘內累計溶出度不小於75%，較佳不小於80%，更佳不小於85%，非限制實施例包括不小於：85%、86%、87%、 88%、89%、90%、91%、92%、93%、94%、95%。 In some embodiments, the cumulative dissolution rate of the composition within 30 minutes is not less than 75%, preferably not less than 80%, more preferably not less than 85%, non-limiting examples include not less than: 85%, 86%, 87% , 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%.

本揭露提供的醫藥組成物具有良好的穩定性，該組成物在60℃條件穩定箱中閉口存放28天，組成物中3,4-二氟苯胺含量不大於0.15%，較佳不大於0.12%，非限制實施例包括不大於：0.12%、0.11%、0.10%、0.09%、0.08%、0.07%、0.06%、0.05%、0.04%、0.03%。 The pharmaceutical composition provided by this disclosure has good stability, and the composition is stored closed for 28 days in a stable box at 60°C, and the content of 3,4-difluoroaniline in the composition is not more than 0.15%, preferably not more than 0.12% , non-limiting examples include no more than: 0.12%, 0.11%, 0.10%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%.

在某些實施方案中，該組成物在60℃條件穩定箱中閉口存放28天，組成物中雜質(RRT為0.25)含量不大於0.8%，較佳不大於0.7%，非限制實施例包括不大於：0.7%、0.69%、0.68%、0.67%、0.66%、0.65%、0.64%、0.63%、0.62%、0.61%、0.60%。 In certain embodiments, the composition is stored closed for 28 days in a stable box at 60°C for 28 days, and the content of impurities (RRT is 0.25) in the composition is not more than 0.8%, preferably not more than 0.7%. Non-limiting examples include Greater than: 0.7%, 0.69%, 0.68%, 0.67%, 0.66%, 0.65%, 0.64%, 0.63%, 0.62%, 0.61%, 0.60%.

本揭露中“可藥用鹽”是指(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺的鹽，這類鹽用於哺乳動物體內時具有安全性和有效性，具有應有的生物活性。 "Pharmaceutically acceptable salt" in this disclosure refers to (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 -( (R) -1,1,1-trifluoro Propan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide salt, which The quasi-salt is safe and effective when used in mammals, and has proper biological activity.

在某些實施方案中，可藥用鹽選自鹽酸鹽。 In certain embodiments, pharmaceutically acceptable salts are selected from hydrochlorides.

本揭露提供的醫藥組成物在製備衣殼蛋白抑制劑中的用途。 Use of the pharmaceutical composition provided by this disclosure in the preparation of capsid protein inhibitors.

本揭露提供的醫藥組成物在製備用於預防和/或治療病毒性感染疾病的藥物中的用途。該病毒為B型肝炎病毒、流感病毒、皰疹病毒和艾滋病毒，該疾病為B型肝炎、流感、皰疹和艾滋病。 Use of the pharmaceutical composition provided by the present disclosure in the preparation of medicaments for preventing and/or treating viral infectious diseases. The viruses are hepatitis B virus, influenza virus, herpes virus and HIV and the diseases are hepatitis B, flu, herpes and AIDS.

本揭露提供的醫藥組成物用作藥物。該藥物可用於預防和/或治療病毒性感染疾病的藥物。該病毒為B型肝炎病毒、流感病毒、皰疹病毒和艾滋病毒，該疾病為B型肝炎、流感、皰疹和艾滋病。 The pharmaceutical composition provided by the present disclosure is used as a medicine. The medicine can be used as a medicine for preventing and/or treating viral infectious diseases. The viruses are hepatitis B virus, influenza virus, herpes virus and HIV and the diseases are hepatitis B, flu, herpes and AIDS.

本揭露提供了一種預防和/或治療病毒性感染疾病的方法，其包括向需要其的患者施用治療有效量的該醫藥組成物。該病毒為B型肝炎病毒、流 感病毒、皰疹病毒和艾滋病毒，該疾病為B型肝炎、流感、皰疹和艾滋病。 The present disclosure provides a method of preventing and/or treating viral infectious diseases, which comprises administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof. The virus is hepatitis B virus, Infection virus, herpes virus and HIV, the disease is hepatitis B, flu, herpes and AIDS.

本揭露另一方面提供了一種製備該組成物的方法，包括：1)活性成分和羥丙基甲基纖維素混合的步驟。在某些實施方案中，進一步包括將混合物進行乾法製粒、濕法製粒或粉末直接混合的步驟，較佳濕法製粒。在某些實施方案中，包括進一步壓製成片的步驟。 Another aspect of the present disclosure provides a method for preparing the composition, including: 1) a step of mixing the active ingredient and hydroxypropyl methylcellulose. In certain embodiments, it further comprises the step of subjecting the mixture to dry granulation, wet granulation or direct mixing of powders, preferably wet granulation. In certain embodiments, a further step of tableting is included.

本揭露還提供了一種製備該組成物的方法，包括：1)活性成分和崩解劑混合的步驟。在某些實施方案中，該崩解劑選自交聯羧甲基纖維素鈉、羧甲基澱粉鈉和交聯聚維酮中的一種或多種，較佳交聯羧甲基纖維素鈉。在某些實施方案中，進一步包括將混合物進行乾法製粒、濕法製粒或粉末直接混合的步驟，較佳濕法製粒。在某些實施方案中，包括進一步壓製成片的步驟。 The present disclosure also provides a method for preparing the composition, including: 1) the step of mixing the active ingredient and the disintegrating agent. In certain embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch and crospovidone, preferably croscarmellose sodium. In certain embodiments, it further comprises the step of subjecting the mixture to dry granulation, wet granulation or direct mixing of powders, preferably wet granulation. In certain embodiments, a further step of tableting is included.

通過以下實施例進一步詳細說明本揭露。這些實施例僅用於說明性目的，而并不用於限制本揭露的範圍。 The present disclosure is further illustrated by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

實施例1：含不同崩解劑的組成物Example 1: Compositions containing different disintegrants

1、片劑製備1. Tablet preparation

表1：含不同崩解劑的組成物處方

Figure 111104084-A0202-12-0009-7
Table 1: Composition formulations with different disintegrants
Figure 111104084-A0202-12-0009-7

Figure 111104084-A0202-12-0010-8
Figure 111104084-A0202-12-0010-8

稱取處方量活性成分(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺與除硬脂酸鎂和二氧化矽以外的組分混合。加入8.5%(w/w)羥丙甲纖維素水溶液進行濕法製粒。濕顆粒在流化床上乾燥。乾顆粒加入硬脂酸鎂和二氧化矽混合後，使用單衝壓片機進行壓片。按上述方案製備即得處方1、處方2和處方3的片劑。 Weigh the prescription amount of active ingredient (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 -( (R) -1,1,1-trifluoropropan-2-yl )-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide with magnesium stearate and dioxide Components other than silicon are mixed. Wet granulation was performed by adding 8.5% (w/w) hypromellose in water. The wet granules are dried on a fluidized bed. The dry granules are mixed with magnesium stearate and silicon dioxide and compressed using a single punch tablet machine. Prepare the tablets of prescription 1, prescription 2 and prescription 3 according to the above scheme.

2、溶出度檢測2. Dissolution testing

按照溶出度與釋放度測定法(中國藥典2015版四部通則0931第二法)，以磷酸鹽緩衝液(pH 6.8)(2%吐溫80)900ml為溶出介質，轉速為每分鐘75轉，分別在10、15、30、45、60 90分鐘和120分鐘時，取溶液2ml，用0.45μm濾膜過濾，作為供試品溶液。 According to the dissolution and release assay method (Chinese Pharmacopoeia 2015 edition four general rules 0931 second method), with phosphate buffer (pH 6.8) (2% Tween 80) 900ml as the dissolution medium, the rotating speed is 75 revolutions per minute, respectively At 10, 15, 30, 45, 60, 90 minutes and 120 minutes, take 2ml of the solution and filter it with a 0.45 μm filter membrane as the test solution.

對照品溶液：另取活性物質對照品適量，加溶出介質溶解並定量稀釋製成對照品溶液。將供試品溶液和對照品溶液分別注入液相色譜儀，記錄色譜圖，量取峰面積，分別計算每片在不同時間的溶出量。 Reference substance solution: Take another appropriate amount of active substance reference substance, add dissolution medium to dissolve and quantitatively dilute to make reference substance solution. The test solution and the reference solution were injected into the liquid chromatograph respectively, the chromatogram was recorded, the peak area was measured, and the dissolution amount of each tablet at different times was calculated respectively.

表2：含不同崩解劑的片劑的溶出度

Figure 111104084-A0202-12-0011-9
Table 2: Dissolution Rates of Tablets Containing Different Disintegrants
Figure 111104084-A0202-12-0011-9

實驗結果表明：交聯羧甲基纖維素鈉為崩解劑，在片劑崩解時間和溶出度上明顯效果優於使用羧甲基澱粉鈉或交聯聚維酮，採用交聯羧甲基纖維素鈉為崩解劑的片劑可以達到快速釋放，15min內釋放大於87%，基本上釋放完全。 The experimental results show that: cross-linked carboxymethyl cellulose sodium is a disintegrant, and it is better than using sodium carboxymethyl starch or cross-linked povidone on the disintegration time and dissolution rate of the tablet. Tablets with cellulose sodium as a disintegrant can achieve rapid release, and the release is greater than 87% within 15 minutes, and the release is basically complete.

實施例2：製備不同處方的片劑Embodiment 2: prepare the tablet of different prescription

表3：含不同組分的處方

Figure 111104084-A0202-12-0011-11
Table 3: Formulations with different components
Figure 111104084-A0202-12-0011-11

Figure 111104084-A0202-12-0012-12
Figure 111104084-A0202-12-0012-12

1、片劑製備1. Tablet preparation

按照實施例1片劑製備方法製備處方4-6的片劑。 The tablet of prescription 4-6 is prepared according to the tablet preparation method of embodiment 1.

2、高溫穩定性研究2. High temperature stability research

處方4-6的片劑分别置於温度60℃穩定箱中閉口分别放置14天、28天，然後定期取樣，採用HPLC法測定雜質和活性成分的含量，實驗結果見表4。 Tablets of prescriptions 4-6 were placed in a stable box with a temperature of 60°C and closed for 14 days and 28 days, respectively, and then samples were taken regularly, and the contents of impurities and active ingredients were determined by HPLC. The experimental results are shown in Table 4.

表4：不同處方的穩定性

Figure 111104084-A0202-12-0012-14
Table 4: Stability of different formulations
Figure 111104084-A0202-12-0012-14

註：ND表示未檢測出，RRT表示相對保留時間。 Note: ND means not detected, RRT means relative retention time.

實驗結果：3,4-二氟苯胺為基因毒性雜質，根據ICH M7按二類控制，本品最大日服用劑量100mg，服藥周期低於30天(可接受日攝入量120μg)， 該雜質限度為0.12%。處方6在60℃高溫條件下放置14天和28天時3,4-二氟苯胺含量分别為0.15%和0.18%，已明顯超出限度，存在安全性隱患，處方4的3,4-二氟苯胺檢測值較小，預計在長期儲存條件下質量可控。處方4和處方5在60℃高溫放置14天和28天時雜質(RRT=0.25)均有增長，但處方5增長幅度更大，相比之下處方4更優，推測處方4在長期儲存條件下質量是可控的。根據以上結果可知，選用羥丙甲纖維素作為處方黏合劑是合適的。 Experimental results: 3,4-difluoroaniline is a genotoxic impurity. According to ICH M7, it is controlled according to the second category. The maximum daily dosage of this product is 100mg, and the medication cycle is less than 30 days (acceptable daily intake 120μg). The impurity limit is 0.12%. The content of 3,4-difluoroaniline in prescription 6 was 0.15% and 0.18% when stored at 60°C for 14 days and 28 days, respectively, which obviously exceeded the limit and had potential safety hazards. The 3,4-difluoroaniline in prescription 4 The detection value of aniline is small, and the quality is expected to be controllable under long-term storage conditions. Impurities (RRT=0.25) both increased when Prescription 4 and Prescription 5 were stored at 60°C for 14 days and 28 days, but Prescription 5 had a larger increase, compared with Prescription 4, which is better. It is speculated that Prescription 4 is under long-term storage conditions The lower quality is controllable. According to the above results, it can be seen that it is appropriate to choose hypromellose as the prescription adhesive.

實施例3：長期加速實驗Embodiment 3: long-term accelerated experiment

表5：製劑處方

Figure 111104084-A0202-12-0013-15
Table 5: Preparation prescription
Figure 111104084-A0202-12-0013-15

按照實施例1片劑製備方法製備上述處方片劑，置於高密度聚乙烯瓶中，分别在25℃±2℃、RH 60%±5%條件下放置6個月，和在5℃±3℃條件下 Prepare above-mentioned prescription tablet according to embodiment 1 tablet preparation method, be placed in high-density polyethylene bottle, place 6 months under 25 ℃ ± 2 ℃, RH 60% ± 5% condition respectively, and at 5 ℃ ± 3 ℃

放置6個月，定期取樣。按照實施1中溶出檢測方法檢測溶出度，按照實施2中HPLC法測定處方雜質和活性成分的含量，檢測結果見表6。 Place it for 6 months and take samples regularly. The dissolution rate was detected according to the dissolution detection method in Implementation 1, and the content of prescription impurities and active ingredients was determined according to the HPLC method in Implementation 2. The test results are shown in Table 6.

表6：片劑的穩定性

Figure 111104084-A0202-12-0014-17
Table 6: Tablet Stability
Figure 111104084-A0202-12-0014-17

結果顯示：上述片劑在長期加速條件下具有良好的穩定性。另外，經檢測，上述片劑放置後具有較好的溶出度。 The results show that the above-mentioned tablet has good stability under long-term accelerated conditions. In addition, after testing, the above-mentioned tablet has a better dissolution rate after being placed.

Claims (16)

一種醫藥組成物，包含活性成分(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺或其可藥用鹽和羥丙基甲基纖維素。 A pharmaceutical composition comprising the active ingredient (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 -( (R) -1,1,1-trifluoropropane-2 -yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide or its pharmaceutically acceptable salt and Hydroxypropylmethylcellulose. 如請求項1所述的醫藥組成物，其中該羥丙基甲基纖維素的含量為基於組成物總重量的0.01-25%，較佳0.05-20%，更佳0.1-15%。 The pharmaceutical composition according to claim 1, wherein the content of the hydroxypropyl methylcellulose is 0.01-25%, preferably 0.05-20%, more preferably 0.1-15% based on the total weight of the composition. 如請求項1或2所述的醫藥組成物，其中還包含崩解劑，其中該崩解劑選自交聯羧甲基纖維素鈉、羧甲基澱粉鈉和交聯聚維酮中的一種或多種，較佳交聯羧甲基纖維素鈉和羧甲基澱粉鈉中的一種或多種，更佳交聯羧甲基纖維素鈉。 The pharmaceutical composition as described in Claim 1 or 2, which also includes a disintegrant, wherein the disintegrant is selected from one of cross-linked carmellose sodium, carboxymethyl starch sodium and cross-linked povidone or more, preferably one or more of croscarmellose sodium and sodium starch glycolate, more preferably croscarmellose sodium. 如請求項3所述的醫藥組成物，其中該崩解劑的含量基於組成物總重量的0.01-25%，較佳0.05-20%，更佳0.1-15%。 The pharmaceutical composition according to claim 3, wherein the content of the disintegrant is 0.01-25%, preferably 0.05-20%, more preferably 0.1-15% based on the total weight of the composition. 如請求項1至4中任意一項所述的醫藥組成物，其中還包含填充劑、潤滑劑、助流劑中的一種或多種。 The pharmaceutical composition according to any one of claims 1 to 4, further comprising one or more of fillers, lubricants, and glidants. 如請求項5所述的醫藥組成物，其中該填充劑選自微晶纖維素、糊精、乳糖、蔗糖、甘露醇、磷酸氫鈣中的一種或多種，較佳微晶纖維素和乳糖中的一種或多種；該填充劑含量為基於組成物總重量的20-95%，較佳50-95%。 The pharmaceutical composition as claimed in item 5, wherein the filler is selected from one or more of microcrystalline cellulose, dextrin, lactose, sucrose, mannitol, calcium hydrogen phosphate, preferably microcrystalline cellulose and lactose One or more of them; the content of the filler is 20-95% based on the total weight of the composition, preferably 50-95%. 如請求項5所述的醫藥組成物，其中該助流劑選自硬脂酸、硬脂酸鎂、硬脂酸鋅、硬脂酸鈣、聚乙二醇、硬脂富馬酸鈉、山崳酸甘油酯、二氧化矽、氫化植物油、月桂基硫酸鈉、滑石粉中的一種或多種，較佳二氧化矽；該助流劑的含量基於組成物總重量的0.01-10%，較佳0.05-5%。 The pharmaceutical composition as described in claim item 5, wherein the glidant is selected from stearic acid, magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, behenic acid One or more of glyceryl glycerides, silicon dioxide, hydrogenated vegetable oil, sodium lauryl sulfate, and talc, preferably silicon dioxide; the content of the glidant is based on 0.01-10% of the total weight of the composition, preferably 0.05-5%. 如請求項5所述的醫藥組成物，其中該潤滑劑選自硬脂酸、硬脂酸鎂、硬脂酸鋅、硬脂酸鈣、聚乙二醇、硬脂富馬酸鈉、山崳酸甘油酯、二氧化矽、氫化植物油、月桂基硫酸鈉、滑石粉中的一種或多種，較佳硬脂酸鎂；該潤滑劑的含量基於組成物總重量的0.01-10%，較佳0.05-5%。 The pharmaceutical composition as described in claim item 5, wherein the lubricant is selected from stearic acid, magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, algae One or more of glyceryl acid esters, silicon dioxide, hydrogenated vegetable oil, sodium lauryl sulfate, talc, preferably magnesium stearate; the content of the lubricant is based on 0.01-10% of the total weight of the composition, preferably 0.05% -5%. 如請求項1至8中任意一項所述的醫藥組成物，其中活性成分的含量為基於組成物總重量的0.1-40%，較佳1-35%。 The pharmaceutical composition according to any one of claims 1 to 8, wherein the content of the active ingredient is 0.1-40%, preferably 1-35%, based on the total weight of the composition. 一種醫藥組成物，其包含以組成物總重量計的， A pharmaceutical composition, which comprises, based on the total weight of the composition, 活性成分1-35%，所述活性成分為(S)-N5-(3,4-二氟苯基)-6-甲基-N3-((R)-1,1,1-三氟丙-2-基)-6,7-二氫-[1,2,3]三唑并[1,5-a]吡嗪-3,5(4H)-二甲醯胺或其可藥用鹽，羥丙基甲基纖維素0.1-15%， Active ingredient 1-35%, said active ingredient is (S) -N 5 -(3,4-difluorophenyl)-6-methyl-N 3 -( (R) -1,1,1-tri Fluoroprop-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazine-3,5( 4H )-dimethylamide or its alternative Medicinal salt, hydroxypropyl methylcellulose 0.1-15%, 填充劑50-95%，該填充劑選自微晶纖維素和乳糖中的一種或多種， Filler 50-95%, the filler is selected from one or more of microcrystalline cellulose and lactose, 崩解劑0.1-15%，該崩解劑為交聯羧甲基纖維素鈉。 Disintegrating agent 0.1-15%, the disintegrating agent is croscarmellose sodium. 如請求項1至10中任意一項所述的醫藥組成物，該組成物以片劑、顆粒或丸劑的形式存在，較佳片劑。 The pharmaceutical composition according to any one of claims 1 to 10, the composition exists in the form of tablets, granules or pills, preferably tablets. 如請求項1至11中任意一項所述的醫藥組成物，該組成物按照中國藥典2015年版四部通則0931第二法，使用pH為6.8的磷酸鹽緩衝液加2%吐溫80作為溶出介質，在37±0.5℃下以75rpm的漿速進行溶出度測定，15分鐘內累計溶出度不小於60%，較佳不小於65%，更佳不小於70%。 As the pharmaceutical composition described in any one of claim items 1 to 11, the composition uses a phosphate buffer solution with a pH of 6.8 plus 2% Tween 80 as the dissolution medium according to the second method of the Chinese Pharmacopoeia 2015 Edition Four General Rules 0931 , at 37±0.5°C with a slurry speed of 75rpm for dissolution testing, the cumulative dissolution rate within 15 minutes is not less than 60%, preferably not less than 65%, more preferably not less than 70%. 如請求項3至12中任意一項所述的醫藥組成物，該組成物在60℃條件穩定箱中閉口存放28天，組成物中3,4-二氟苯胺含量不大於0.15%，較佳不大於0.12%。 The pharmaceutical composition as described in any one of claim items 3 to 12, the composition is stored closed in a stable box at 60°C for 28 days, and the 3,4-difluoroaniline content in the composition is not more than 0.15%, preferably Not more than 0.12%. 一種如請求項1至13中任意一項所述的醫藥組成物在製備衣殼蛋白抑制劑中的用途。 A use of the pharmaceutical composition as described in any one of claims 1 to 13 in the preparation of capsid protein inhibitors. 一種如請求項1至13中任意一項所述的醫藥組成物在製備治療病毒性感染疾病的藥物中的用途，該病毒為B型肝炎病毒、流感病毒、皰疹病毒和艾滋病毒，該疾病為B型肝炎、流感、皰疹和艾滋病。 A use of a pharmaceutical composition as described in any one of Claims 1 to 13 in the preparation of medicines for the treatment of viral infectious diseases, the viruses are hepatitis B virus, influenza virus, herpes virus and HIV, the disease For hepatitis B, flu, herpes and AIDS. 一種製備如請求項1至13中任意一項所述的醫藥組成物的方法，包括將活性成分和羥丙基甲基纖維素混合的步驟。 A method for preparing the pharmaceutical composition according to any one of claims 1 to 13, comprising the step of mixing the active ingredient and hydroxypropylmethylcellulose.
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