CN111465412A - Nk-1拮抗剂的口服药物组合物 - Google Patents
Nk-1拮抗剂的口服药物组合物 Download PDFInfo
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- CN111465412A CN111465412A CN201880081773.3A CN201880081773A CN111465412A CN 111465412 A CN111465412 A CN 111465412A CN 201880081773 A CN201880081773 A CN 201880081773A CN 111465412 A CN111465412 A CN 111465412A
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- telmapitant
- oral pharmaceutical
- animal
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Abstract
一种包含telmapitant、非水性溶剂和一种或多种其他药学上可接受的赋形剂的口服药物组合物,其中telmapitant在组合物中处于溶解状态。一种治疗或预防动物呕吐的方法,包括施用口服药物组合物。
Description
背景
美国专利号7,049,320公开了式I的化合物,其为NK1拮抗剂,并且可用于治疗延迟开始的呕吐,例如在接受化疗后的一至几天经历的呕吐。美国专利号7,049,320公开了式I的化合物可以为液体形式制剂,包括溶液、悬浮液和乳液。还公开了口服施用。
化合物罗拉吡坦(VarubiTM)是美国专利号7,049,320中公开的化合物,已批准用于人类。它已显示出对于预防化疗引起的恶心和呕吐是有效和安全的(Rapoport等人,European Journal of Cancer, 57 (2016) pp26-30)。
化合物telmapitant或(5R,8S)-8-[[(1R)-1-[3,5-双(三氟甲基)苯基]乙氧基]甲基]-8-苯基-1,3,9-三氮杂螺[4.5]癸烷-2,4-二酮(CAS # 552292-58-7)也公开于美国专利号7,049,320。
速激肽NK-1受体是还包括NK-2和NK-3受体的受体家族的一部分(L Quartara和CA Maggi, 1997, The tachykinin NK1 receptor. Part I: ligands and mechanisms ofcellular activation. Neuropeptides 31(6), 537-563)。
NK-1受体的天然和最有效的激动剂是速激肽P物质。在CNS中,NK-1受体已显示与行为反应、调节心血管和呼吸功能以及激活呕吐反射有关。NK-1拮抗剂已被证明是非常有效的止吐药,相对于其他种类的止吐药具有明显的优势。NK-1拮抗剂已在人类(阿瑞吡坦,即Emend®,和罗拉吡坦,即Varubi®)和狗(马罗吡坦,即Cerenia®)中都获得了止吐适应症的监管批准。在狗中,马罗吡坦已显示出对中枢作用的催吐原(emetogen)(阿扑吗啡IV)和外周作用的催吐原(口服吐根糖浆)均有效。(参见H S Sedlecek等人,2008, J. Vet. Pharmacol. Therap. 31(6) 533-537)。
NK-1拮抗剂还有效地治疗手术后/麻醉后引起的呕吐、运动引起的呕吐和来自疾病的呕吐(D S Ramsey等人,2008, Safety and efficacy of injectable and oralmaropitant, a selective neurokinin1 receptor antagonist, in a randomizedclinical trial or treatment of vomiting in dogs. J. Vet. Pharmacol. Therap.31(6) 538-543)。
Cerenia® (柠檬酸马罗吡坦)片剂被批准用于预防急性呕吐和晕动病引起的呕吐(参见NADA 141-262, 2007年1月29日批准)。 Cerenia®也可作为批准用于治疗急性呕吐的注射液得到(参见NADA 141-263, 2007年1月29日批准)。
上述参考文献均未公开本发明的非水性telmapitant溶液制剂。
发明概述
包含telmapitant、非水性溶剂和一种或多种另外的药学上可接受的赋形剂的口服药物组合物,其中telmapitant在组合物中处于溶解状态。
治疗或预防动物呕吐的方法,包括向动物口服施用有效剂量的上述口服药物组合物。
附图简述
图1-实施例1的对比例制剂(可注射、片剂和悬浮液制剂)与溶液制剂的长期PK曲线的比较。
图2-实施例1的对比例制剂(可注射、片剂和悬浮液制剂)和溶液制剂的短期PK曲线的比较。
图3A-3E-实施例1的溶液制剂(图3A-3C)和对比例制剂(可注射、片剂和悬浮液制剂)(图3D和3E)的PK曲线的个体间差异。
图4A-4B-液体和固体telmapitant制剂之间止吐作用开始的差异。呕吐次数(图4A)和恶心次数(图4B)。
图5A-5B-在狗中的阿扑吗啡引起的呕吐模型的呕吐次数(图5A)和恶心次数(图5B):以2 mg/kg的日剂量施用的Cerenia®(马罗吡坦)和以5和7 mg/kg的单次剂量施用的telmapitant。
详述
定义
d-α-生育酚聚乙二醇1000琥珀酸酯(CAS # 9002-96-4 (TPGS)或维生素E TPGS)是维生素E, d-α-生育酚天然形式的水溶性衍生物。它是通过聚乙二醇1000酯化结晶d-α-生育酚琥珀酸酯而产生的。它是难溶药物的增溶剂和吸收促进剂。
Phosal® 50 PG是标准化的磷脂酰胆碱浓缩物(PC),具有在丙二醇中的至少50%PC(参见FDA药物主文件第13931号)。
丙二醇(CAS # 57-55-6)是丙烷-1,2-二醇,一种可与多种溶剂混溶的有机化合物。
油酸(CAS # 112-80-1)是具有式CH3(CH2)7CH=CH(CH2)7COOH的ω9脂肪酸。
乙二胺四乙酸四钠盐二水合物(CAS # 10378-23-1 (EDTA 4Na))用于医学和工业用途,包括用作抗氧化剂。
三氯蔗糖或1,6-二氯-1,6-二脱氧-β-D-呋喃果糖基-4-氯-4-脱氧-α-D-吡喃半乳糖苷(CAS # 56038-13-2)是一种人造甜味剂和糖替代品。
Soluplus是一种聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,是一种用于改善难溶性活性成分的溶解度和生物利用度的赋形剂。
Transcutol HP-高度纯化的二甘醇单乙醚NF,一种多功能溶剂。
中链甘油三酯(MCT)是甘油三酯,其脂肪酸具有6-12个碳原子的脂族尾。
Miglyol® 810和Miglyol ®812N是C8和C10的分馏植物脂肪酸的甘油三酯。它们是椰子油的甘油三酯。它们是辛酸癸酸甘油三酯。MIGLYOL® 810/812仅在其C8/C10-比率方面有所不同。由于其低C10-含量,MIGLYOL® 810的粘度和浊点较低。
非水性溶剂是有机溶剂或液体脂质材料。
止吐作用是指控制呕吐。一旦做出定性诊断,就将止吐药用于控制呕吐以预防晕动病和心因性呕吐并控制来自放射或化疗的呕吐(参见The Merck Veterinary Manual,8th Ed, 1998, p 1682)。
阿扑吗啡是有效的催吐药(即引起呕吐)。
阿扑吗啡引起的呕吐模型是一种确立已久的研究新化合物止吐作用的犬模型,并已用于研究新的NK1拮抗剂(Furukawa等人,Biol Pharm Bull 36:974-979, 2013)以及Cerenia和 其他用于狗的止吐药(Sedlacek等人,J Vet Pharmacol Therap 31:533-537,2008)的研究。
在一个实施方案中,telmapitant的剂量为约1 mg/kg至约10 mg/kg,或约2 mg/kg至约3 mg/kg或约5 mg/kg至约7 mg/kg或约5 mg/kg或约7 mg/kg。
在一个实施方案中,telmapitant的% w/v为约1%至约10%或约2%至约9%或约3%至约8%或约5%至约7%或约5%或约7%。
在一个实施方案中,非水性溶剂是油。
在一个实施方案中,非水性溶剂是油酸。
在另一个实施方案中,非水性溶剂是脂肪酸、长链甘油三酯、中链甘油三酯或其混合物。
在一个实施方案中,非水性溶剂是Miglyol 810或Miglyol 812N或两者的混合物。
在一个实施方案中,组合物包含一种或多种表面活性剂。
在一个实施方案中,表面活性剂是d-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)、磷脂酰胆碱或其混合物。
在一个实施方案中,表面活性剂是聚乙氧基化蓖麻油,例如Cremophor RH 40、Cremophor RH 60、Cremophor EL、聚乙二醇15羟基硬脂酸酯(Solutol HS 15®)、聚乙氧基化脱水山梨糖醇脂肪酸酯如聚山梨酯20、40、60或 80、聚氧乙烯-聚氧丙烯嵌段共聚物如泊洛沙姆188、181或407,和蔗糖脂肪酸酯或其混合物。
在一个实施方案中,组合物包含另外的溶剂。
在一个实施方案中,另外的溶剂是丙二醇。
在一个实施方案中,另外的溶剂是2-吡咯烷酮。
在一个实施方案中,另外的溶剂是二甘醇单乙醚。
在一个实施方案中,该组合物包含抗氧化剂。
在一个实施方案中,抗氧化剂是乙二胺四乙酸(EDTA)四钠盐二水合物。
在一个实施方案中,抗氧化剂是EDTA、EDTA二钠、生育酚、焦亚硫酸钠、没食子酸丙酯、抗坏血酸、抗坏血酸棕榈酸酯、BHT、BHA、单硫代甘油或其组合。
在一个实施方案中,组合物包含适口性试剂(palatability agent)。
在一个实施方案中,适口性试剂是三氯蔗糖、蜂蜜香料或其混合物。
本发明的一个实施方案是一种口服药物组合物,其包含
a. telmapitant;
b. TPGS和磷脂酰胆碱的混合物;
c. 丙二醇;和
d. 油酸;
其中telmapitant在组合物中处于溶解状态。
本发明的一个实施方案是一种口服药物组合物,其包含
a. telmapitant;
b. TPGS和磷脂酰胆碱的混合物;
c. 2-吡咯烷酮;
d. 乙醇;和
e. 辛酸癸酸甘油三酯;
其中telmapitant在组合物中处于溶解状态。
本发明的一个实施方案是一种口服药物组合物,其包含
a. telmapitant;
b. 二甘醇单乙醚;和
c. 油酸;
其中telmapitant在组合物中处于溶解状态。
在一个实施方案中,该组合物进一步包含乙二胺四乙酸四钠盐二水合物。
在一个实施方案中,该组合物进一步包含三氯蔗糖、蜂蜜香料或其混合物。
在一个实施方案中,施用是施用单次剂量的口服药物组合物。
在一个实施方案中,止吐作用持续至少7天。
在一个实施方案中,动物是哺乳动物或鸟。
在一个实施方案中,动物是狗。
在一个实施方案中,动物是猫。
在一个实施方案中,动物是长尾小鹦鹉或鹦鹉。
在一个实施方案中,动物与口服药物组合物的施用同时或相继接受放疗或化疗。
在一个实施方案中,动物由于胃肠道病症而显示出呕吐。
在一个实施方案中,动物由于晕动病而显示出呕吐。
所要求保护的组合物可以单独施用或与食物或饮用水组合施用。
实施例
实施例1-1: 对比制剂
对比制剂1 – 可注射制剂
组分 | % w/v |
Telmapitant | 2.5 |
Soluplus | 4 |
TPGS | 4.18 |
乙醇 | 7.2 |
水 | QS |
乳酸 | 2.5 |
配制该组合物以向动物递送5 mg/kg的剂量。
对比制剂2-通过湿法制粒方法用以下组合物制备压缩片剂:
片剂 | |
组分 | % w/w |
Telmapitant | 35.25 |
PVP K30 | 1.9 |
泊洛沙姆188 | 0.48 |
肝脏香料 | 17.1 |
交聚维酮 | 9.75 |
Avicel PH102 | 23.75 |
乳糖一水合物 | 13.0 |
硬脂酸镁 | 0.76 |
对比制剂3 – 用以下组合物制备液体悬浮液制剂:
水性悬浮液 | |
组分 | % w/v |
Telmapitant | 7 |
黄原胶 | 0.25 |
泊洛沙姆188 | 0.5 |
丙二醇 | 5.0 |
对羟基苯甲酸甲酯 | 0.2 |
对羟基苯甲酸丙酯 | 0.02 |
水 | QS |
二甲基硅油 | 0.4 |
三氯蔗糖 | 0.2 |
蜂蜜香料 | 1 |
实施例1 – 2: 非水性溶液制剂– 根据本发明的制剂
制剂1A
组分 组成(%w/v) 作用
Telmapitant | 5.0 – 7.0 | 活性成分 |
d-α-生育酚聚乙二醇1000琥珀酸酯(TPGS) | 20.0 | 表面活性剂 |
Phosal<sup>®</sup> 50 PG (液体) | 10.0 | 表面活性剂 |
丙二醇(液体) | 30.0 | 共溶剂 |
油酸(液体) | QS | 非水性溶剂 |
乙二胺四乙酸四钠盐二水合物(固体) | 0.01 | 抗氧化剂 |
三氯蔗糖(固体) | 0.5 | 适口性试剂 |
蜂蜜香料(液体) | 1.0 | 适口性试剂 |
制造方法
1.熔化TPGS
2.合并液体赋形剂;加热混合直至获得均匀的澄清溶液。
3.加入固体赋形剂并混合至分散
4.加入telmapitant并加热混合直至完全溶解。
制剂1B&1C
1B | 1C | |
组分 | % w/v | % w/v |
Telmapitant | 7 | 7 |
TPGS | 5 | - |
Phosal 50 PG | 60 | - |
丙二醇 | - | - |
油酸 | - | QS |
2-吡咯烷酮 | 2.5 | - |
乙醇 | 10 | - |
Miglyol® 812N | QS | - |
Transcutol HP | - | 35 |
三氯蔗糖 | 0.5 | 0.5 |
蜂蜜香料 | 2 | 1 |
EDTA 4Na | 0.01 | 0.01 |
制剂1B和1C通过与以上制剂1A相似的方法制备。
实施例2
在药代动力学研究中评价对比例制剂1、2和3以及制剂1A、1B和1C。研究设计:成熟健康的比格犬(组大小:5-6只狗)用于PK研究。单次施用telmapitant后,在施用后的不同时间点进行血液收集以分析血浆浓度,持续长达336小时。将制剂1A中的telmapitant的浓度调整为7% w/v,以与具有7% w/v的telmapitant浓度的其他液体制剂进行比较。
结果呈现在图1-3A-3E中。根据本发明的制剂具有指示活性迅速开始的血液水平;具有低的动物间变异性和优异的telmapitant在血液中的最大浓度。
图1显示制剂1A以及对比例制剂1和3具有比其他制剂优异的Cmax水平。图2显示制剂1A展示出比任何其他制剂优异(更短)的Tmax。图3A-3E显示了用每种制剂测试的不同动物之间表现出的PK曲线的变异性。对比例制剂2(片剂)(图3D)和3(水性悬浮液)(图3E)表现出大的动物间变异性,而溶液制剂显示出相对较小的动物间变异性。制剂1A(图3A)显示出最小的动物间变异性。
表1还显示了上述PK研究的动物间变异性。
表1
通过口服和皮下途径施用不同制剂后,三个PK参数的以百分比计的变异系数(CV)。
显示了三至六个单独实验的平均值。选择半衰期(T1/2)、最大血浆浓度(Cmax)和计算至无穷大的曲线下面积(AUCinf)作为体内药物暴露和药物存在的持续时间的量度。用制剂1A观察到所有三个参数的最低动物间变异性。
实施例3-阿扑吗啡引起的呕吐模型
阿扑吗啡引起的呕吐的犬模型是一种确立已久的研究新化合物止吐作用的模型,并且已用于研究新的NK1拮抗剂(Furukawa等人,Biol Pharm Bull 36:974-979, 2013)以及Cerenia和其他用于狗的止吐药(Sedlacek等人,J Vet Pharmacol Therap 31:533-537,2008)的研究。该模型用于评价telmapitant在非水性溶液制剂和固体制剂中的止吐活性(图4A和4B)。在单次口服施用后研究起效(图4A和4B)以及活性的持续时间(图5A和5B)。在2h、4h、6h、8h、24h和120h (图4A和4B)或1d、3d、5d、6d和7d (图5A和5B)将静脉内(IV)施用阿扑吗啡(催吐原挑战0.03 mg/kg)递送给所有个体。在第0天以5或7 mg/kg体重(BW)的telmapitant溶液通过单次施用对狗口服给药或以2 mg/kg BW的Cerenia®片剂日剂量对狗口服给药。推荐剂量和每日施用的Cerenia®(马罗吡坦)用作阳性对照。记录每次催吐原挑战后的任何催吐事件(呕吐发作和/或恶心),持续20 min。在预测试期间,所有狗均对催吐原挑战反应,在所有组中均相似。此外,在研究持续期间(分别为120h或7天),反应保持稳定。
图4A和4B显示telmapitant非水性溶液制剂(7% telmapitant,未添加EDTA)提供了与阳性对照相当的止吐作用的迅速开始。就起效和止吐作用而言,固体片剂制剂似乎较差。Cerenia® (马罗吡坦)以2 mg/kg施用,并且telmapitant以7 mg/kg施用。在给药前(预测试),和给药后2、4、6、8、24和120小时(仅telmapitant),用静脉内阿扑吗啡对狗进行挑战。所示数据为每组6-12只动物。棒显示平均值和标准偏差(SD)。
在狗的阿扑吗啡引起的呕吐模型中,单次口服剂量的telmapitant非水性溶液制剂显示出止吐作用持续至少7天(图5A和5B)。来自两个不同实验的发现被合并在图5A和5B的图中。单次使用7 mg/kg telmapitant非水性溶液制剂的止吐功效与每天施用Cerenia®的止吐反应相当。5 mg/kg的telmapitant数据与7 mg/kg没有显著差异。Cerenia® (马罗吡坦)以2 mg/kg的日剂量施用,并且telmapitant以5和7 mg/kg的单次剂量施用。在第0天以5或7 mg/kg体重(BW)的telmapitant单次剂量或以2 mg/kg BW的Cerenia®日剂量对狗口服给药。在给药前(预测试)和给药后1、3、5、6和7天,用静脉内阿扑吗啡对狗进行挑战。显示的数据来自每组8只动物。棒显示平均值和SD。
实施例4 – 适口性研究
对狗口服施用制剂,二阶段交叉设计。每次单独处理后,由两位不同的观察者使用评分系统(0-3)建立对制剂的接受度。计算接受(得分≤1)和不接受(得分≥2)的狗的百分比。如果至少70%的狗接受该制剂,则该制剂符合“接受的”,并且如果超过30%的狗不接受该制剂,则该制剂符合“不接受的”。
对所有测试的狗物种而言,制剂1A比制剂1B更适口。
Claims (19)
1.一种口服药物组合物,其包含telmapitant、非水性溶剂和一种或多种另外的药学上可接受的赋形剂,其中所述telmapitant在所述组合物中处于溶解状态。
2.权利要求1的组合物,其中所述非水性溶剂是油酸。
3.权利要求1-2中任一项的组合物,其中所述组合物包含一种或多种表面活性剂。
4.权利要求3的组合物,其中所述表面活性剂是d-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)、磷脂酰胆碱或其混合物。
5.权利要求1-4中任一项的组合物,其中所述组合物包含另外的溶剂。
6.权利要求1-5中任一项的组合物,其中所述另外的溶剂是丙二醇。
7.权利要求1-6中任一项的组合物,其中所述组合物包含抗氧化剂。
8.权利要求7的组合物,其中所述抗氧化剂是乙二胺四乙酸四钠盐二水合物。
9.权利要求1-8中任一项的组合物,其中所述组合物包含适口性试剂。
10. 权利要求9的组合物,其中所述适口性试剂是三氯蔗糖、蜂蜜香料或其混合物。
11.一种口服药物组合物,其包含
a. telmapitant;
b. TPGS和磷脂酰胆碱的混合物;
c. 丙二醇;和
d. 油酸;
其中所述telmapitant在所述组合物中处于溶解状态。
12.权利要求11的口服药物组合物,其进一步包含乙二胺四乙酸四钠盐二水合物。
13.权利要求11或12的口服药物组合物,其进一步包含三氯蔗糖、蜂蜜香料或其混合物。
14.一种治疗或预防动物呕吐的方法,包括向所述动物口服施用有效剂量的权利要求1-13中任一项的口服药物组合物。
15.权利要求14的方法,其中所述施用是施用单次剂量的口服药物组合物。
16.权利要求14或15的方法,其中所述止吐作用持续至少7天。
17.权利要求14-16中任一项的方法,其中所述动物是狗。
18.权利要求14-16中任一项的方法,其中所述动物是猫。
19.权利要求14-18中任一项的方法,其中所述动物与所述口服药物组合物的施用同时或相继接受化疗。
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US20070197487A1 (en) * | 2005-12-20 | 2007-08-23 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids having an increased lung deposition |
US20130190252A1 (en) * | 2010-05-18 | 2013-07-25 | Pharmathen S.A. | Pharmaceutical formulation containing lipophilic drugs and milk as a solubilizing/dispensing agent and method for the preparation thereof |
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US7049320B2 (en) * | 2001-12-18 | 2006-05-23 | Schering Corporation | NK1 antagonists |
US20070197487A1 (en) * | 2005-12-20 | 2007-08-23 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids having an increased lung deposition |
US20130190252A1 (en) * | 2010-05-18 | 2013-07-25 | Pharmathen S.A. | Pharmaceutical formulation containing lipophilic drugs and milk as a solubilizing/dispensing agent and method for the preparation thereof |
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