CN103945831A - 医药制剂 - Google Patents

医药制剂 Download PDF

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CN103945831A
CN103945831A CN201280056985.9A CN201280056985A CN103945831A CN 103945831 A CN103945831 A CN 103945831A CN 201280056985 A CN201280056985 A CN 201280056985A CN 103945831 A CN103945831 A CN 103945831A
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dosage form
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D·维尔玛
Y·克里斯纳马哈里
沈晓宏
H·李
P·李
R·辛格
L·谭
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Novartis AG
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Abstract

本发明涉及(S)-甲基(1-((4-(3-(5-氯-2-氟-3-(甲基磺酰氨基)苯基)-1-异丙基-1H-吡唑-4-基)嘧啶-2-基)氨基)丙-2-基)氨基甲酸酯(化合物A)的固体口服医药制剂，和这些制剂于治疗增殖性疾病，例如实体肿瘤疾病，的用途。

Description

医药制剂
技术领域
本发明涉及(S)-甲基(1-((4-(3-(5-氯-2-氟-3-(甲基磺酰氨基)苯基)-1-异丙基-1H-吡唑-4-基)嘧啶-2-基)氨基)丙-2-基)氨基甲酸酯(化合物A)的固体口服医药制剂，和这些制剂于治疗增殖性疾病，例如实体肿瘤疾病，的用途。
背景技术
化合物A具有以下化学结构：
WO2011/025927全文以引用的方式并入本文，其中公开了化合物A的制备及其作为B-RAF抑制剂用于治疗增殖性疾病，例如实体肿瘤疾病(如黑色素瘤和结肠直肠癌)，的用途。
化合物A为一种在弱酸性和中性pH下水溶性较差的II类BCS化合物，这对口服生物利用度和疗效构成挑战。该化合物呈现典型弱碱性溶解特性，且在低pH下高度可溶，在约pH3.0下开始下降，且在中性pH范围内仍处在低固有溶解度程度上。在胃排空下，化合物A因在肠道pH中溶解度急速下降而易于快速从溶液中沉淀析出。这显著降低化合物A的肠道吸收利用性。本发明涉及化合物A的口服生物可利用的医药固体分散制剂。
附图说明
图1表示实施例1所述制剂的2阶段溶解曲线。
图2表示实施例2至7所述制剂的2阶段(首先60分钟pH为2，之后60分钟至6.8)溶解情况。
图3表示实施例8所述片剂制剂的溶解曲线。
发明详述
化合物A为一种通常呈现弱碱性溶解特性的II类BCS化合物：在低pH下溶解度较高，且在中性pH左右溶解度有限。具有这样溶解特性的治疗化合物通常给医药制剂科学家在试图制备能够提高治疗性化合物口服生物利用度的口服制剂时带来挑战。根据本发明，这样的挑战在制备化合物A的固体口服制剂时通过将化合物配制成固体分散体得以克服。
固态分散体是专用医药制剂。最适宜的固态分散体制剂是可以提高溶解度和溶解速度、并保持呈非晶态的原料药稳定性的那些。在典型的固态分散体制剂中，原料药均匀地分散于固体基质中，这促进了药物在胃肠道中的溶解并且使药物保持在高能量非晶态下。
医药固态分散体由本领域已知技术制造，例如，溶剂蒸发、捏和及熔融挤出。
根据本发明，制备内相。内相为一种于合适聚合物基质中包含化合物A的固态分散体，其是由(例如)亲水性粘合剂、表面活性剂和任选地额外赋形剂组成的，这些是本领域已知的，随后研磨以降低粒径。
在压片或囊封前，内相优选组合有额外的赋形剂，本文将这些额外赋形剂统称为外相。外相通常包括酸化剂、填充剂、崩解剂、助流剂与润滑剂中的一或多种。
因此，本发明涉及一种固体口服医药制剂，其包含含化合物A的固态分散体。
在一种实施方式中，本发明涉及一种固体口服医药制剂，其包含：
(a)内相，其是包含化合物A的固态分散体，和
(b)外相，其包含额外赋形剂。
优选地，内相，或者更优选，外相包含酸化剂。
本发明还涉及一种固体口服医药制剂，其包含：
(a)内相，其是包含化合物A、亲水性粘合剂和表面活性剂的固态分散体；和
(b)外相，其包含额外赋形剂。
在另一实施例中，本发明涉及一种固体口服医药制剂，其包含：
(a)内相，其是包含化合物A、亲水性粘合剂、表面活性剂的固态分散体，和
(b)外相，其包含酸化剂、填充剂、崩解剂、助流剂和润滑剂的一或多种。
亲水性粘合剂应适于与化合物A完全混溶，且在制剂溶解时用作化合物A的沉淀抑制剂。内相所包含的适宜亲水性粘合剂包括共聚维酮(copovidone)、羟丙基甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素，和甲基丙烯酸酯共聚物、聚环氧乙烷、HPMC醋酸丁二酸酯、HPMC邻苯二甲酸酯。共聚维酮尤其适用作亲水性粘合剂。KOLLIDON VA64是质量比6:4的1-乙烯基-2-吡咯啶酮与醋酸乙烯酯的共聚物，可得自BASF，极适合用作内相的亲水性粘合剂。
表面活性剂应适用于熔融挤出，以提高化合物A的溶解和増溶。在一些情况中，表面活性剂可通过其增塑作用而帮助降低加工温度。内相所包含的适宜表面活性剂包括泊洛沙姆类(poloxamers)，例如Poloxamer188，十二烷基硫酸钠、Tween80、山梨糖醇、聚山梨醇酯20、聚山梨醇酯80、维生素E TPGS、和聚乙二醇。
可任选地包含于内相中的其他赋形剂包括酸化剂和增塑剂。
在优选实施方式中，内相，或优选外相，包含一种酸化剂，以将微环境pH控制在酸性范围内。适宜酸化剂包括有机酸，诸如柠檬酸、琥珀酸、马来酸、酒石酸、苹果酸和己二酸。
适宜填充剂、崩解剂、助流剂和润滑剂是为本领域技术人员已知的。
尤其适用填充剂包括乳糖、麦芽糊精、甘露糖醇、微晶纤维素、预糊化淀粉和蔗糖酯。
有用的崩解剂包括交联聚维酮(crospovidone)、交联羧甲纤维素钠、淀粉羟乙酸钠、微晶纤维素和预糊化淀粉。
有用的助流剂包括胶体二氧化硅、滑石粉、硬脂酸镁和甘露糖醇。
有用的润滑剂包括硬脂酸镁、硬脂酸钙、单硬脂酸甘油酯、氢化蓖麻油、月桂基硫酸钠、硬脂基富马酸钠、硬脂酸、硬脂酸锌、滑石粉、微晶纤维素和蔗糖酯。
在本发明的不同实施方式中，内相包含各种％w/w范围的活性剂、亲水性粘合剂和表面活性剂。例如，本发明内相可包含5-70％化合物A、10-90％亲水性粘合剂和5-30％表面活性剂，优选5-50％化合物A、30-80％亲水性粘合剂和5-30％表面活性剂，更优选，5-40％化合物A、50-80％亲水性粘合剂和5-20％表面活性剂。
在本发明的不同实施方式中，外相包含各种％w/w范围的酸化剂、填充剂、崩解剂、助流剂和润滑剂。例如，本发明外相可包含1-70％酸化剂、20-70％填充剂、0-30％崩解剂、0-10％助流剂和0-10％润滑剂，优选地，2-60％酸化剂、30-70％填充剂、5-20％崩解剂、0.5-5％助流剂和0.5-5％润滑剂，更优选，10-40％酸化剂、20-40％填充剂、1-15％崩解剂、1-5％助流剂和1-5％润滑剂。
在本发明的不同实施方式中，固态口服制剂(例如胶囊或片剂)是内相与外相以100:0至30:70，优选80:20至40:60，最优选75:25至50:50的比例的混合物。
化合物A的非晶形式在固态分散体制剂中的稳定可提高生物利用度，归因于非晶形式的溶解速率与动力溶解度高于其结晶形式。
当化合物A处于非晶形式时，利用固态分散体制剂可实现动力溶解度与溶解速率和口服生物利用度的提高。
在一个实施方式中，本发明被配制成胶囊，例如硬明胶胶囊或软弹性胶囊。或者，本发明是呈片剂或丸剂的形式。在这些固体口服制剂中，化合物A可以如下范围的量存在：1-1500mg、2.5-800mg或5-400mg，优选实施例包括10mg、20mg、25mg、50mg、100mg、200mg、400mg和500mg。
可施用本发明固体口服制剂来治疗对B-RAF的抑制有反应的疾病，尤其是以B-RAF突变为特征的疾病，特别是黑色素瘤和结肠直肠癌。
因此，本发明还涉及上述固体口服医药制剂用于制备治疗增殖性疾病的药剂的用途，尤其其中所述增殖性疾病为以B-RAF突变为特征的实体肿瘤疾病，例如黑色素瘤或结肠直肠癌。
本发明还涉及治疗增殖性疾病的方法，尤其是其中所述增殖性疾病为以B-RAF的突变为特征的实体肿瘤疾病，例如黑色素瘤或结肠直肠癌，其包括向有此治疗需求的患者施用治疗有效量的本文所述制剂。
下列实施例意欲说明但不限制本发明。
实施例1
以15％的固定载药量制备下列组合物，并配制为10、25、50mg和100mg胶囊。
成分 ％w/w
内相
化合物A 15
Kollidon VA64 45
泊洛尼克(Pluronic)F68 5
外相
琥珀酸 13
纤维素MKGR 16
交联聚维酮 5
硬脂酸镁 0.5
气相二氧化硅(Aerosil) 0.5
总量 100
制造方法：
利用18mm双螺杆Leistriez挤压机进行热熔挤压，接着研磨挤出物，与外相掺合并过筛，完成加工。掺合后，将掺合物囊封至分别对应于50与100mg药物剂量的尺寸为0与00的粉色硬胶囊中。下文按步骤显示方法：
称量所需量的化合物A、Kollidon VA64和泊洛沙姆188
掺合混合物
在18mm Leistreiz双螺杆挤压机上以1kg/小时的喂送速率挤压掺合物，将挤压机内温度保持在50至160℃
研磨挤出物
添加过筛的琥珀酸和微晶纤维素
添加并掺合经研磨的挤出物，琥珀酸和微晶纤维素
添加交联聚维酮和气相二氧化硅
掺合混合物
添加预先过筛的硬脂酸镁
掺合混合物
利用H&K囊封机囊封
所得胶囊的猴子体内PK数据显示适于口服给药的生物可利用度，其平均Cmax为11833ng/ml，Tmax为4小时，且AUC为32686ng*hr/ml。
XRPD数据显示，非晶固态分散体制剂在40℃/75％RH的加速的稳定条件下储存4周后的物理稳定性(无转化为结晶原料药的迹象)。
体外2-阶段溶解性研究显示，固态分散体的溶解动力学在初始点(0周)和在加速的稳定储存条件下储存4-周时间点之间没有变化，这表明固态分散体的物理稳定性无变化。
本发明制剂呈现97℃的玻璃转变温度(Tg)，其高于所建议的不超过30℃的药物产品储存温度，这证实了其物理稳定性，非晶原料药不会转化为水溶性差的结晶原料药。
本发明制剂在40℃/75％RH的加速稳定条件下储存后显示优越的化学稳定性，没有任何降解产物的证据，且化合物A的含量测定结果为100％。
实施例2
以下制剂以类似于实施例1所述方式制得。
成分 ％w/w
内相
LGX818 17
PVP-K30 51
山梨糖醇 5
外相
琥珀酸 9
纤维素MKGR 12
交联聚维酮 5
硬脂酸镁 0.5
气相二氧化硅 0.5
总量 100
该制剂呈现109℃的玻璃转变温度(Tg)，这证实了其物理稳定性，非晶原料药不会转化为水溶性差的结晶原料药。
实施例3
下表描述了，将化合物A配制为剂量为50mg/kg的微乳液、以及剂量为200mg化合物A的实施例1(固态分散体1)与实施例2(固态分散体2)制剂，在猴子中进行的药物动力学研究的结果。
实施例2-7
以类似实施例1所述的技术制备下列制剂，但仅有单相。图2出示这些制剂的溶解曲线。
制剂2：
成分 ％W/W
化合物A 25.00
维生素E TPGS 41.67
聚乙二醇4000 26.33
羟丙基甲基纤维素 5.00
滑石粉 2.00
制剂3：
成分 ％W/W
化合物A 25.00
维生素E TPGS 41.67
聚乙二醇4000 16.33
羟丙基甲基纤维素 15.00
滑石粉 2.00
制剂4：
制剂5：
成分 ％W/W
化合物A 25.00
维生素E TPGS 41.67
聚乙二醇4000 5.92
羟丙基甲基纤维素 5.00
马来酸 5.41
丙烯酸树脂L100-55 15.00
滑石粉 2.00
制剂6：
成分 ％W/W
化合物A 24.00
维生素E TPGS 40.00
羟丙基甲基纤维素 14.40
马来酸 5.20
丙烯酸树脂L100-55 14.40
滑石粉 2.00
制剂7：
成分 ％W/W
化合物A 24.00
维生素E TPGS 40.00
聚乙二醇4000 1.20
羟丙基甲基纤维素 14.40
乳酸 4.00
丙烯酸树脂L100-55 14.40
滑石粉 2.00
实施例8
以类似实施例1所述的技术制备下列制剂，但呈片剂制剂。图3出示此制剂在0.1N HCl介质中的溶解曲线。
制剂8：
成分 ％w/w
内相
化合物A 10.0
Kollidon VA64 30.1
泊洛尼克F68 3.4
外相
Kollidon VA64 3.0
纤维素MKGR 37.5
交联聚维酮 15.0
硬脂酸镁 1.0
总量 100

Claims (10)

1.一种固体口服医药制剂，其包含含化合物A的固态分散体。
2.如权利要求1的固体口服医药制剂，其包含：
内相，其是包含化合物A的固态分散体，和
外相，其包含其他赋形剂。
3.如权利要求2的固体口服医药制剂，其中所述内相或所述外相包含酸化剂。
4.本发明还涉及一种如权利要求2的固体口服医药制剂，其包含：
内相，其是包含化合物A、亲水性粘合剂和表面活性剂的固态分散体；和
外相，其包含其他赋形剂。
5.如权利要求1的固体口服医药制剂，其包含：
内相，其是包含化合物A、亲水性粘合剂、表面活性剂的固态分散体；和
外相，其包含酸化剂、填充剂、崩解剂、助流剂与润滑剂中的一或多种。
6.如权利要求1的固体口服医药制剂用于制备治疗增殖性疾病的药剂的用途。
7.一种治疗增殖性疾病的方法，其包括向有治疗需求的患者施用治疗有效量的如权利要求1的制剂。
8.如权利要求1的固体口服制剂用于治疗对B-RAF的抑制有反应的疾病的用途。
9.如权利要求8的用途，其中所述疾病的特征在于B-RAF突变。
10.如权利要求9的用途，其中所述疾病为黑色素瘤或结肠直肠癌。
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US20140309250A1 (en) 2014-10-16
EA201491007A1 (ru) 2014-08-29
JO3493B1 (ar) 2020-07-05

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Application publication date: 20140723