CN111635315B - 一种解热镇痛药物及其制备方法和用途 - Google Patents
一种解热镇痛药物及其制备方法和用途 Download PDFInfo
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- CN111635315B CN111635315B CN201910157251.3A CN201910157251A CN111635315B CN 111635315 B CN111635315 B CN 111635315B CN 201910157251 A CN201910157251 A CN 201910157251A CN 111635315 B CN111635315 B CN 111635315B
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
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- C07C69/616—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety polycyclic
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Abstract
本发明提供了一种解热镇痛药物,或其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物、药学上可接受的盐或前药,该解热镇痛药物结构为式I所示:
Description
技术领域
本发明涉及一种新型解热镇痛药物及其制备方法和用途,属于医药技术领域。
背景技术
洛索洛芬钠(Loxoprofen Sodium)是一种对环氧化酶COX-1和COX-2均有抑制作用的消炎镇痛药。作为首个被合成的芳基丙酸类的前体型的非甾体抗炎药,洛索洛芬钠的疗效主要表现为镇痛作用显著,消炎、解热作用与其他同类药疗效相当。临床试验表现为口服后在人体内代谢为trans-OH型药物,同时在肝和血浆中浓度分布比其他部位高,之后便迅速转变为葡萄糖类结合物,最后以尿液的形式排出体外。洛索洛芬钠的镇痛效果比酮洛芬、吲哚美辛、萘普生要强10-20倍,还具有作用效果迅速且显著、毒副作用小、临床应用范围广等优点。
经过长期临床实践,早先被视为“完美”的COX-2特异性抑制剂也逐步暴露出如下:
问题:(1)疗效并未增加,(2)不良反应并未减少;(3)导致溃疡率短期内降低,长期使用无差异;(4)严重的心肌梗塞出现。因此,如何寻找毒副作用小的、生物利用度更高,更为安全有效的非甾体抗炎药成为业界研发的热点之一。
迄今为止关于洛索洛芬钠衍生物有很多种,如日本特开昭58-4699号公报、日本特开昭54-103852号公报、国际公开WO93/02999号、国内专利申请号为201680000788.3都发明了洛索洛芬钠衍生物,但都表现出各种不同的缺点。
所以改善药物吸收效率,提高代谢稳定性,降低其毒副作用,是目前临床上要解决的问题。
发明内容
鉴于上述现有技术存在的缺陷,本发明的目的是提供一种新型解热镇痛药物,该解热镇痛药物有更优临床疗效,更大的生物利用度、更小的毒性,进而能够治疗解热镇痛类疾病。
本发明的目的通过以下技术方案得以实现:
一种解热镇痛药物,该解热镇痛药物的结构通式为I所示:
Ⅰ
式I所示的结构,其中R1代表卤素、氢、三氟甲基、二氟甲基、氟甲基、氘代甲基、甲基;
R2代表卤素、氢、甲酸基、乙酯基、丙酯基、甲基、三氟甲基、二氟甲基、氟甲基、氘代甲基、甲基;
R3代表氢、碱金属、甲基、乙基、异丙基、氨基酸、;
R4代表、/>、、/>、、/>、、/>、,其中R1代表卤素、氢、三氟甲基、二氟甲基、氟甲基、氘代甲基、甲基;
R2代表卤素、氢、甲酸基、乙酯基、丙酯基、甲基、三氟甲基、二氟甲基、氟甲基、氘代甲基、甲基;
R5代表羟基、酮基、乙酯基、丙酯基、富马酸酯基、酒石酸酯基、磷酸酯基、磷酸酯盐。
式I所示的结构,其中包括如下化合物:
化合物1
化合物2
化合物3
化合物4
化合物5
化合物6
化合物7
化合物8
化合物9
化合物10
化合物11
化合物12
化合物13
化合物14
化合物15
化合物16
化合物17
化合物18
化合物19
化合物20
化合物21
化合物22
化合物23
化合物24
化合物25
化合物26
化合物27
化合物28
化合物29
化合物30
化合物31
化合物32
化合物33
化合物34
化合物35
化合物36
化合物37
化合物38
化合物39
化合物40
化合物41
化合物42
化合物43
化合物44
对比化合物1
对比化合物2
对比化合物3
本发明还提供上述的解热镇痛药物,或其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物、药学上可接受的盐或前药,在解热镇痛中应用。
本发明还提供一种解热镇痛药物组合物,其组分包括上述解热镇痛的药物(即式I结构的化合物),或其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物、药学上可接受的盐或前药。
上述具有羟基的解热镇痛药物与磷酸酯反应形成解热镇痛药物前体药物。这种前体药物比未形成前体药物的化合物具有更优异的溶解性;前体药物的溶解性大于100mg/ml,前体药物在水溶液中稳定,并通过血液中的酯酶和磷酸酯酶转化成活性成分,由此开发用于注射或口服的制剂。
本发明的组合物可以包括至少一种具有类似于解热镇痛药物功能的有效成分。
至于配制药物组合物,至少一种式Ⅰ的化合物可以与至少一种药物可接受载体混合。药物可接受载体可以包括生理盐水、无菌水、林格氏溶液(Ringer's solution)、生理盐水缓冲溶液、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇等。根据用户需要,药物组合物可以含有常规赋形剂,如抗氧剂、缓冲、清污剂(soil cleaner)等。组合物也与稀释剂、崩解剂(diaintegrant)、表面活性剂、粘合剂、润滑剂、水溶液、悬浮液等混合,形成注射剂、粉剂、胶囊、颗粒、片剂等。优选情况下,根据疾病或组分,制剂通过使用Remington'sPharmaceutical Science(最新版)(Mack Publishing Company,Easton PA等)所述的方法制备。
本发明的化合物可以口服或肠道外给药,例如静脉、皮下、腹内、局部给药等。化合物的剂量可以随使用的具体化合物、给药方式、所要治疗的病症的症状和严重性、以及与治疗个体相关的各种身体因素而变化。
在急性毒性测试中,解热镇痛药物的半致死剂量(LD50)显示大于300mg/kg,因此发现该解热镇痛药物是安全的。
本发明的解热镇痛药物显有更小的毒性、更高的生物利用度、更高的治愈率。通过具有羟基的化合物与磷酸酯反应制待的前体药物具有高水溶性。
因此,将含有该解热镇痛药物的组合物用于解热镇痛。
上述的抗厌氧菌的药物组合物可以包括式I所示的解热镇痛药物,式I所示的解热镇痛药物结构的立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物和药学上可接受的盐或前药中的至少一种与本领域己知的抗菌药物的联用。
本发明还提供上述的药物组合物在解热镇痛中的应用。
本发明的突出效果为:
本发明的解热镇痛药物,或其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物、药学上可接受的盐或前药,显有更小的毒性、更高的生物利用度、更高的治愈率。
具体实施方式
为了对本发明的技术特征、目的和有益效果有更加清楚的理解,现对本发明的技术方案进行以下详细说明,但不能理解为对本发明的可实施范围的限定。下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
实施例1:化合物1的制备
取(S)-2-(3-氟-4 - (((R)-2-氧代环戊基)甲基)苯基)丙酸10g、
(S)-2-(3-氟-4 - (((1R,2S)-2-羟基环戊基)甲基)苯基)丙酸10g
硫酸0.35g和丙酮100ml,加热回流6小时,反应完成后减压蒸干,残余物过层析住分离,得化合物1 17.3g。
实施例2:化合物2的制备
取(S)-2-(4 - (((1R,2S)-2-乙酰氧基环戊基)甲基)-3-氟苯基)丙酸10g、(S)-2-(3-氟-4 - (((1R,2S)-2-羟基环戊基)甲基)苯基)丙酸10g、硫酸0.35g和丙酮100ml,加热回流6小时,反应完成后减压蒸干,残余物过层析住分离,得化合物1 18.5g。
实施例3:化合物3的制备
取化合物2 10g 乙酸-2-氯乙酯,加热回流6小时,反应完成后减压蒸干,残余物过层析住分离,得化合物3 7.2g。
实施例4:化合物4的制备
同化合物3制备方法,将乙酸-2-氯乙酯换为甘氨酸,得化合物4 9.3g。
实验实施例l药物引发的胃溃疡的形成
参考Biochemical Pharmacology,2004 (67):575-585中记载的方法进行试验。
将试验用雄性大鼠(体重约200g)断食24h,口服给予试验化合物1-20,使给药剂量与对比化合物1-3相等的摩尔量,12h后摘除胃部,测定胃内部产生的溃疡面积。对全部溃疡的面积进行合计,作为溃疡系数。剂量是0.15mmol。结果如表1所示。
表1
化合物 | 溃疡系数(mm2) |
化合物1 | 0.9 |
化合物2 | 1.1 |
化合物3 | 1.3 |
化合物4 | 1.8 |
化合物6 | 0.8 |
化合物8 | 1.6 |
化合物10 | 0.8 |
化合物11 | 1.6 |
化合物13 | 1.3 |
化合物15 | 1.5 |
化合物16 | 1.3 |
化合物19 | 1.4 |
化合物22 | 2.0 |
化合物25 | 1.9 |
化合物27 | 1.4 |
化合物29 | 1.6 |
化合物30 | 1.2 |
化合物35 | 1.0 |
化合物37 | 1.7 |
化合物40 | 1.3 |
化合物43 | 0.9 |
化合物44 | 1.4 |
对比化合物1 | 3.3 |
对比化合物2 | 4.2 |
对比化合物3 | 3.8 |
洛索洛芬钠 | 10.3 |
结果如下:洛索洛芬钠的溃疡系数为10.3(mm2),对比化合物1-3的溃疡系数是3-4范围,本发明的化合物溃疡系数均小于为2(mm2)。这表明,本发明的化合物几乎不形成副作用的溃疡,胃部的溃疡面积很小,溃疡系数很低优于对比化合物。
实验实施例2镇痛试验
对小鼠腹腔给药醋酸溶液后出现的扭体次数进行计数,并基于对照组计算扭体的抑制率。90只小鼠被分成了15个小组,每组6只。对照组,给空白制剂;对比化合物1-3、洛索洛芬和本发明化合物等摩尔量给药。在给药醋酸溶液60min前将被测化合物给药于小鼠,结果如表2所示。
表2扭体试验结果
化合物 | 剂量 | 扭体次数 | 抑制百分比(%) |
空白溶剂 | 0 | 45.2 | 无 |
化合物1 | 0.15mmol | 12.4 | 85 |
化合物2 | 0.15mmol | 16.2 | 79 |
化合物3 | 0.15mmol | 18.3 | 77 |
化合物4 | 0.15mmol | 20.1 | 76 |
化合物6 | 0.15mmol | 19.2 | 75 |
化合物8 | 0.15mmol | 15.5 | 82 |
化合物10 | 0.15mmol | 19.1 | 76 |
化合物11 | 0.15mmol | 21.3 | 75 |
化合物13 | 0.15mmol | 15.2 | 83 |
化合物15 | 0.15mmol | 18.5 | 79 |
化合物16 | 0.15mmol | 19.6 | 77 |
化合物19 | 0.15mmol | 21.1 | 75 |
化合物22 | 0.15mmol | 12.3 | 84 |
化合物25 | 0.15mmol | 15.0 | 82 |
化合物27 | 0.15mmol | 18.4 | 81 |
化合物29 | 0.15mmol | 13.3 | 86 |
化合物30 | 0.15mmol | 18.3 | 82 |
化合物35 | 0.15mmol | 19.2 | 79 |
化合物37 | 0.15mmol | 17.6 | 79 |
化合物40 | 0.15mmol | 15.5 | 80 |
化合物43 | 0.15mmol | 15.1 | 74 |
化合物44 | 0.15mmol | 15.5 | 84 |
对比化合物1 | 0.15mmol | 23.5 | 53 |
对比化合物2 | 0.15mmol | 29.4 | 67 |
对比化合物3 | 0.15mmol | 31.2 | 70 |
洛索洛芬钠 | 0.15mmol | 36.4 | 73 |
结果表明:本发明的化合物的镇痛作用好于对照化合物。
实验实施例3:本发明化合物对小鼠静脉给药的急性毒性测试
为测试本发明化合物和对比化合物的急性毒性,进行下述实验。
本发明化合物溶解到水中,对5只ICR小鼠给药(5周大,雄性,体重20克±2克的小鼠)。静脉给药以确定半数致死量(LD50,mg/kg)。使用对比化合物1-3、洛索洛芬钠作为对照。结果如表3所示。
表3
化合物 | 半数致死量(LD50,mg/kg) |
洛索洛芬钠 | 143 |
对比化合物1 | 154 |
对比化合物2 | 150 |
对比化合物3 | 150 |
化合物1 | >300 |
化合物2 | >300 |
化合物3 | >300 |
化合物4 | >300 |
化合物6 | >300 |
化合物8 | >300 |
化合物10 | >300 |
化合物11 | >300 |
化合物13 | >300 |
化合物15 | >300 |
化合物16 | >300 |
化合物19 | >300 |
化合物22 | >300 |
化合物25 | >300 |
化合物27 | >300 |
化合物29 | >300 |
化合物30 | >300 |
化合物35 | >300 |
化合物37 | >300 |
化合物40 | >300 |
化合物43 | >300 |
化合物44 | >300 |
根据表3,本发明的化合物的毒性小于对照药物,表明本发明化合物具有优异的低毒性,安全性更高。
实验实施例4:本发明化合物的组合物生物利用度的效果的评估
对含有本发明的组合物生物利用度的效果评估如下。
步骤1.测试动物及样品的准备和处理
准备400只平均体重为23.55g的雄性ICR小鼠作为测试动物。将它们分为25组(4组对照组,21组测试组),每组各有16只。待以普通饲料喂养一周后,禁食12个小时,按照表4所述地将样品口服给药至小鼠。
表4
组 | 处理方法 |
对照组1(对比化合物1) | 取含对比化合物1的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
对照组2(对比化合物2) | 取含对比化合物2的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
对照组3(对比化合物3) | 取含对比化合物3的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
对照组4(洛索洛芬钠) | 取含洛索洛芬钠的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组1(化合物1) | 取含化合物1的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组2(化合物2) | 取含化合物2的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组3(化合物3) | 取含化合物3的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组4(化合物4) | 取含化合物4的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组5(化合物6) | 取含化合物6的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组6(化合物8) | 取含化合物8的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组7(化合物10) | 取含化合物10的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组8(化合物11) | 取含化合物11的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组9(化合物13) | 取含化合物13的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组10(化合物15) | 取含化合物15的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组11(化合物16) | 取含化合物16的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组12(化合物19) | 取含化合物19的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组13(化合物22) | 取含化合物22的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组14(化合物25) | 取含化合物25的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组15(化合物27) | 取含化合物27的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组16(化合物29) | 取含化合物29的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组17(化合物30) | 取含化合物30的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组18(化合物35) | 取含化合物35的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组19(化合物40) | 取含化合物40的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组20(化合物43) | 取含化合物43的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
测试组21(化合物44) | 取含化合物44的组合物,然后以0.15mmol/kg的剂量口服给药至小鼠 |
步骤2.血液样本的采集和血清的分离
待口服给药10、20、30和60分钟及2、4、8和24小时后,使用扁平毛细管从小鼠的眼眶后静脉丛中采集血液。将每组16只小鼠再分成4小组,并且在每个时间周期(10分钟和2小时;20分钟和4小时;30分钟和8小时;60分钟和24小时)从4只小鼠中采集2次血液。所述血液在13000rpm下离心(Micro 12,Hanil,Korea) 10分钟,从而分离出用于分析的血清。
步骤3.药理分析
根据以前报道的方法(Wang BYG et.al,Biol .Pharm. Bull. 30 (9) 1657-1662)处理血清,以用于药理分析。利用UPLC/MS (SIR模式)分析待测化合物的含量。其量化精度为5ng/mL(检出限:1ng/mL),而且使用作为内部标准。本发明化合物的生物利用度可以表示为Cmax、Tmax和AUC值。结果如表5所示。
表5
实验组 | Cmax(ng/ml) | Tmax(hr) | AUC(ng·hr/ml) |
对照组1(对比化合物1) | 20.4±13.2 | 0.8±0.2 | 123.4±49.2 |
对照组2(对比化合物2) | 12.4±10.2 | 0.4±0.2 | 78.3±44.2 |
对照组3(对比化合物3) | 17.1±19.2 | 0.4±0.2 | 68.3±40.3 |
对照组4(洛索洛芬钠) | 11.7±14.2 | 0.4±0.2 | 54.5±55.1 |
测试组1(化合物1) | 24.5±20.4 | 0.8±0.2 | 143.2±98.2 |
测试组2(化合物2) | 30.1±23.4 | 0.8±0.2 | 163.2±100.4 |
测试组3(化合物3) | 28.3±21.1 | 0.8±0.2 | 139.3±77.7 |
测试组4(化合物4) | 25.6±20.4 | 0.8±0.2 | 159.2±74.9 |
测试组5(化合物6) | 24.1±19.3 | 0.8±0.2 | 151.8±63.2 |
测试组6(化合物8) | 28.4±21.1 | 0.8±0.2 | 161.0±82.1 |
测试组7(化合物10) | 26.3±17.9 | 0.8±0.2 | 173.1±71.6 |
测试组8(化合物11) | 25.9±18.3 | 0.8±0.2 | 162.2±66.3 |
测试组9(化合物13) | 27.3±22.2 | 0.8±0.2 | 193.1±84.0 |
测试组10(化合物15) | 30.4±20.0 | 0.8±0.2 | 179.3±77.1 |
测试组11(化合物16) | 26.4±18.3 | 0.8±0.2 | 168.2±69.2 |
测试组12(化合物19) | 31.4±15.3 | 0.8±0.2 | 160.1±73.2 |
测试组13(化合物22) | 29.6±20.1 | 0.8±0.2 | 186.3±69.5 |
测试组14(化合物25) | 27.0±18.8 | 0.8±0.2 | 198.2±88.9 |
测试组15(化合物27) | 28.4±18.2 | 0.8±0.2 | 182.1±74.2 |
测试组16(化合物29) | 30.7±18.9 | 0.8±0.2 | 178.3±79.3 |
测试组17(化合物30) | 28.7±17.4 | 0.8±0.2 | 188.3±87.3 |
测试组18(化合物35) | 30.4±18.3 | 0.8±0.2 | 193.2±78.5 |
测试组19(化合物40) | 32.1±20.1 | 0.8±0.2 | 182.2±67.3 |
测试组20(化合物43) | 28.4±19.9 | 0.8±0.2 | 175.3±70.6 |
测试组21(化合物44) | 30.8±20.2 | 0.8±0.2 | 180.3±68.6 |
*Cmax(ng/mL):从观察的血清浓度或浓度一时间曲线中计算或评价而得的最大血清浓度。
*Tmax(hr):Cmax出现的时间点。
* AUC(ng·hr/ml)(曲线下方的面积;ng·hr/ml):血清浓度一时间曲线下方的面积。
如表5所示,对照组2,3,4 Tmax都为0.4小时,对照组1和测试组1-21 Tmax都为0.8小时并无显著差异。然而,测试组与对照组相比,表示生物利用度的Cmax值和AUC值分别增长3倍和2倍。因此,这表明本发明化合物生物利用度明显优于对照组。
制剂实施例l:片剂
本发明化合物 100g
淀粉 100g
羟丙基纤维素 150g
硬脂酸镁 0.5g
制备工艺:将本发明化合物过100目筛,淀粉,羟丙甲纤维素过80目筛,将化合物与淀粉,羟丙甲纤维素混合均匀,制软材,30目制粒,60℃干燥1.5h,得干物料,加入硬脂酸镁,混合10min,24目整粒,压片,即得。
制剂实施例2:片剂
本发明化合物 50g
淀粉 30g
微晶纤维素 150g
羧甲基淀粉钠 20g
1.5%羧甲基纤维素钠溶液 适量
硬酯酸镁 0.8g
制备工艺:将本发明化合物过100目筛,乳糖,淀粉,羧甲基淀粉钠过80目筛,将化合物与羧甲基淀粉钠,淀粉,乳糖,混合均匀,加入1.5%羧甲基纤维素钠溶液制得软材,30目制粒,60℃干燥1.5h,得干物料,加入硬脂酸镁,混合10min,24目整粒,压片,即得。
制剂实施例3:颗粒剂
化合物 250mg
蔗糖 l00mg
玉米淀粉 150mg
以上述配方为基础,通过常规方法制备在500mg颗粒中含有50mg有效成分的颗粒。
制剂实施例4:注射剂
本发明化合物 60g
氯化钠 20g
PH调节剂 适量
注射用水 10L
制备方法:将配方量的化合物溶于70%注射用水,加入配方量的氯化钠,用pH调节剂调节溶液的pH=4.0-9.0,再用注射用水定容,向定容后的溶液中加入0.1%(g/ml)的活性炭吸附20min后过滤除炭,将溶液通过0.22um的滤膜精滤,中间体检测含量合格后灌装成l0ml每支,将灌装得到的半成品至于灭菌柜中121℃灭菌15min后,灯检合格后分装即得成品。
Claims (2)
1.一种解热镇痛药物,具体包括如下化合物、氘代物或药学上可接受的盐:
2.一种解热镇痛药物组合物,其特征在于,组合物包括权利要求1所述的化合物、氘代物或药学上可接受的盐。
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