CN111246851A - 双层药物片剂制剂 - Google Patents
双层药物片剂制剂 Download PDFInfo
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- CN111246851A CN111246851A CN201880066314.8A CN201880066314A CN111246851A CN 111246851 A CN111246851 A CN 111246851A CN 201880066314 A CN201880066314 A CN 201880066314A CN 111246851 A CN111246851 A CN 111246851A
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- tablet
- dolutegravir
- lamivudine
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- auc
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Abstract
一种新型双层片剂制剂,包含HIV整合酶链转移抑制剂度鲁特韦与核苷逆转录酶抑制剂拉米夫定。
Description
发明领域
本发明涉及用于治疗HIV的新型双层药物片剂制剂。特别地,本发明涉及包含整合酶链转移抑制剂度鲁特韦钠(缩写“DTG Na”)与核苷逆转录酶易位抑制剂(NRTTI)拉米夫定(也称为“3TC”)的双药物片剂制剂,以及使用此类制剂治疗其中抑制HIV整合酶或逆转录酶是有益的的病况(例如HIV)的方法。
发明背景
在过去几十年中,高效抗逆转录病毒疗法(ART)方面的进展改善了对HIV患者的治疗效果,改善了患者的生存和生活质量。但是,正确遵循治疗方案仍然是一个挑战,其中不佳的依从性可导致治疗失败和耐药突变的出现。为了帮助遵守治疗,正在研究简化治疗。口服和长效可注射ART可以向患者提供控制HIV感染的方便和谨慎的方法。
度鲁特韦是表现出亚纳摩尔效力和对多种HIV-1毒株的抗病毒活性的整合酶链转移抑制剂(INSTI)。口服施用度鲁特韦表现出可接受的安全性和耐受性概况,并且几乎没有药物-药物相互作用。为了最小化耐药性突变的出现,度鲁特韦目前与一种或多种其它抗HIV药剂组合施用,最通常为度鲁特韦、阿巴卡韦和拉米夫定的三元组合,称为TRIUMEQ。
在与拉米夫定的二元组合中的度鲁特韦目前接受针对三元治疗的非劣效性临床研究以评估长期抗病毒活性、耐受性和安全性参数。与目前的三元方案相比,二元组合(双药物方案)具有降低药物负担、潜在毒性和潜在相互作用的潜力。
期望提供一种药物组合物,其以安全和有效的双药物方案提供包含度鲁特韦和拉米夫定的单一剂型。
发明概述
本发明提供了拉米夫定和度鲁特韦钠的双层片剂制剂,其具有良好的溶出特性,并提供先前仅在独立剂型中可得的良好的药代动力学性质。
本发明的片剂是一种双层片剂,其包含含有拉米夫定的第一层和含有度鲁特韦钠的第二层。根据一个实施方案,该第一层包含大约300 mg的拉米夫定和至少一种附加的赋形剂,且该第二层包含大约50 mg的度鲁特韦和至少一种附加的赋形剂。根据另一实施方案,该第一层包含大约300 mg的拉米夫定、填充剂、崩解剂和润滑剂。根据一个实施方案,该第一层包含大约300 mg的拉米夫定、大约277.5 mg的微晶纤维素、淀粉羟乙酸钠和硬脂酸镁。根据一个实施方案,该第二层包含大约50 mg的度鲁特韦、一种或多种稀释剂、粘合剂和崩解剂。根据一个实施方案,该第二层包含大约50 mg的度鲁特韦、D-甘露醇、微晶纤维素、聚维酮和淀粉羟乙酸钠。根据一个实施方案,该片剂进一步包含薄膜包衣。
向人类施用该片剂产生的药代动力学很重要。具体而言,该片剂有利地提供了与先前批准的药代动力学概况(例如由监管机构,例如U.S. F.D.A.批准的度鲁特韦钠和利匹韦林的单独剂型的组合施用的那些)一致的药代动力学。根据一个实施方案,本发明的片剂在口服施用时向患者提供与FDA批准的50毫克TIVICAY产品基本相同的度鲁特韦的AUC(0-∞)。根据另一实施方案,本发明的片剂在口服施用时向患者提供与FDA批准的300毫克EPIVIR产品基本相同的拉米夫定的AUC(0-∞)。根据另一实施方案,本发明的片剂在口服施用时向禁食患者提供13.3至13.9 mcgh/mL的拉米夫定的AUC(0-∞)。根据另一实施方案,本发明的片剂在口服施用时向禁食患者提供50.5至58.9 mcgh/mL的度鲁特韦的AUC(0-∞)。
组合制剂的溶出概况很重要。这里,已知拉米夫定在典型生理条件下具有高可溶性和高可渗透性。相比之下,度鲁特韦在典型生理条件下仅略微可溶和可渗透。根据一个实施方案,本发明的片剂包含含有大约300 mg的拉米夫定的第一层,和含有大约50 mg的度鲁特韦的第二层,其中如采用USP Apparatus II测得的那样,大约35%至40%的度鲁特韦在与1.6 pH模拟胃液接触后在大约60分钟内释放。根据另一实施方案,在500毫升模拟胃液中在37.0 +/- 0.5℃和65 rpm的桨叶速度下测量度鲁特韦的释放。
详细描述
根据本发明的一个实施方案,本发明的双层片剂是用于口服施用的薄膜包衣片剂。该片剂含有52.6 mg的度鲁特韦钠(其等效于50 mg的度鲁特韦游离酸)和300 mg的拉米夫定。未包衣片剂的主要组分是度鲁特韦钠、拉米夫定、D-甘露醇、微晶纤维素、聚维酮、淀粉羟乙酸钠、硬脂酰醇富马酸钠和硬脂酸镁。可以施加任选的薄膜包衣。
根据本发明的一个实施方案,提供了含有表1中所示量的组分的双层片剂。
表1
根据另一实施方案,提供了一种双层片剂,其含有表1中所示量的组分作为片剂核心,进一步包含薄膜包衣。
根据另一实施方案,提供了一种双层片剂,其含有表1中显示的示例性范围重量%的组分。根据更特别的实施方案,提供了一种双层片剂,其含有表1的示例性量重量%的组分。
度鲁特韦通过与整合酶活性位点结合并阻断逆转录病毒脱氧核糖核酸(“DNA”)整合的链转移步骤(该步骤对HIV复制周期至关重要)来抑制HIV整合酶。DTG是一种整合酶链转移抑制剂(INSTI)。使用纯化的HIV-1整合酶和预先处理过的底物DNA进行的链转移生化测定得出2.7 nM的IC50(50%处的抑制浓度)值(Kalama and Murphy, Dolutegravir forthe Treatment of HIV, 2012 Exp. Op. Invest. Drugs 21(4): 523-530)。
度鲁特韦的化学名称是(4R,12aS)-N-[(2,4-二氟苯基)甲基]-7-羟基-4-甲基-6,8-二氧代-3,4,12,12a-四氢-2H-吡啶并[5,6]吡嗪并[2,6-b][1,3]噁嗪-9-甲酰胺(CAS登记号1051375-16-6)。根据本发明,使用度鲁特韦钠。度鲁特韦的钠盐及该钠盐的特定晶形公开在美国专利号9,242,986中。除非另行说明,度鲁特韦的重量(mg)按其游离形式的度鲁特韦的重量计。
度鲁特韦被批准用于HIV感染患者的广泛群体。度鲁特韦于2013年8月获得FDA批准,2013年11月获得加拿大卫生部(Health Canada)批准,且2014年1月获得欧洲EMA批准为药物产品TIVICAYTM,目前可以50 mg、10 mg和5 mg的剂量(以度鲁特韦游离碱当量的重量测得)获得。其可用于治疗从未接受过HIV治疗的HIV感染的成人(初治)和先前接受过HIV治疗的HIV感染的成人(复治),包括已经用其它整合酶链转移抑制剂治疗过的那些。
优选将度鲁特韦钠微粉化,例如X90为5.7 μm-26.3 μm,尽管已经发现根据本发明,微粉化程度对度鲁特韦钠的加工性、溶解度、溶出或生物利用度并非至关重要。
已经在健康成人对象和HIV-1感染的成人对象中评估了度鲁特韦的药代动力学性质。健康对象和HIV-1感染的对象之间对度鲁特韦的暴露的情况通常相似。在HIV-1感染的对象中,与每天一次50 mg相比,在每天两次50 mg后存在度鲁特韦的非线性暴露(表2),这归因于临床试验中每天两次接受度鲁特韦50 mg的对象的背景抗逆转录病毒方案中的代谢诱导剂的使用。
表2. HIV-1感染的成人中度鲁特韦稳态药代动力学参数估算
参数 | 每天一次50 mg 几何平均值<sup>a</sup> (%CV) | 每天两次50 mg 几何平均值<sup>b</sup> (%CV) |
AUC(0-24) (mcg.h/mL) | 53.6 (27) | 75.1 (35) |
Cmax (mcg/mL) | 3.67 (20) | 4.15 (29) |
Cmin (mcg/mL) | 1.11 (46) | 2.12 (47) |
a基于群体药代动力学分析,使用来自SPRING-1和SPRING-2临床试验的数据。
b基于群体药代动力学分析,使用来自VIKING(ING112961)和VIKING-3临床试验的数据。
本发明的片剂试图复制批准的度鲁特韦钠药物产品的相关AUC、Cmax和Cmin药代动力学参数。
拉米夫定(也称为“3TC”),一种具有对抗HIV-1和HBV的活性的合成核苷类似物。拉米夫定化学名称是(2R,顺式)-4-氨基-1(2-羟甲基-1,3-氧杂硫杂环戊烷-5-基)-(1H)-嘧啶-2-酮。拉米夫定是胞苷的双脱氧类似物的(-)对映体。拉米夫定也被称为(-) 2′,3′-双脱氧, 3′硫杂胞苷。其分子式为C8H11N3O3S。拉米夫定已获FDA批准,商品名为EPIVIRTM(目前以300 mg剂型销售),被指示用于与其它抗逆转录病毒药剂联合用于治疗HIV-1感染。
每天两次150 mg施用于成人的EPIVIR的药代动力学信息报告为AUC(0-12)的几何平均值(95%CI)为5.53(4.58/6.67)mcg.h/mL,且Cmax的几何平均值(95%CI)为1.40(1.17、1.69)mcg/mL。在60名健康对象的交叉试验中评估了持续7天的每天一次EPIVIR 300毫克片剂的稳态药代动力学性质,并与持续7天的每天两次EPIVIR 150毫克片剂进行了比较。就血浆AUC24,ss而言,每天一次300 mg EPIVIR获得了类似于每天两次150 mg EPIVIR的拉米夫定暴露;但是,与每天两次150 mg的方案相比,Cmax,ss高66%,且谷值低53%。因此,如批准的那样,拉米夫定的Cmax和Cmin可以在相对宽的范围内变化,同时仍然是安全和有效的。
本发明的片剂试图复制批准的拉米夫定药物产品的相关AUC、Cmax和Cmin药代动力学参数。
值得注意的是,拉米夫定在标准生理条件下是高度可溶的,因此并未显著关注拉米夫定或多组分片剂的拉米夫定部分的溶出。
“填充剂”和“稀释剂”在本文中可互换使用(并统称为填充剂,如下文更特别地描述的那样)来描述提高组合物的体量,以使最终产品具有实用的尺寸或体积,例如对于片剂而言具有用于适当压缩的实用尺寸的材料。可以使用与活性成分相容并具有良好的流动性和溶出的任何合适的填充剂。示例性的填充剂包括但不限于乳糖、蔗糖或糖粉、甘露醇、山梨糖醇、木糖醇、肌醇、磷酸钙、碳酸钙、硫酸钙、干淀粉、纤维素(包括微晶纤维素或硅化微晶纤维素等等)及其组合。
微晶纤维素优选在本发明的拉米夫定层中用作填充剂。微晶纤维素优选以每个未包衣的片剂核心249.5-305.3 mg的量存在于拉米夫定层中。或者,微晶纤维素优选以未包衣片剂核心的27.7-33.9重量/重量%的范围存在于拉米夫定层中。
微晶纤维素和D-甘露醇优选在度鲁特韦层中用作稀释剂。微晶纤维素优选以每个未包衣的片剂核心47.3-57.9 mg的量存在于度鲁特韦层中。或者,微晶纤维素优选以未包衣片剂核心的5.3-6.4重量/重量%的范围存在于度鲁特韦层中。D-甘露醇优选以每个未包衣的片剂核心161.6-159.9 mg的量存在于度鲁特韦层中。或者,D-甘露醇优选以未包衣片剂核心的18.0-17.8重量/重量%的范围存在于度鲁特韦层中。
本文中所用的“崩解剂”的功能是确保或促进施用后该组合物的分解或崩解,由此促进活性物质的溶出。可以使用与活性成分相容并具有良好的流动性和溶出的任何合适的崩解剂。示例性的崩解剂包括但不限于淀粉、纤维素和纤维素衍生物(如甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、乙基纤维素和交联的羧甲基纤维素钠)、交联的聚乙烯吡咯烷酮、淀粉羟乙酸钠、琼脂、膨润土、黄原胶及其混合物。优选地,本发明的崩解剂是淀粉羟乙酸钠。崩解剂优选以每个未包衣片剂核心35.1-42.9 mg的范围存在。或者,崩解剂优选为未包衣片剂核心的3.9-4.8重量/重量%的范围存在。
本文中所用的“润滑剂”用于防止材料在片剂形成中粘附到模具和冲头的表面,减少颗粒间的摩擦,促进片剂从模具腔中弹出,并可以改善粉末或颗粒的流动特性。可以使用与活性成分相容并具有良好的流动性和溶出概况的任何合适的润滑剂。示例性的润滑剂包括但不限于滑石、硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酰醇富马酸钠、硬脂酸、山萮酸甘油酯、氢化植物油、聚乙二醇及其混合物。硬脂酸镁优选在该片剂的拉米夫定层中用作润滑剂。硬脂酰醇富马酸钠优选用作该片剂制剂中的润滑剂颗粒外赋形剂。根据本发明的一个实施方案,硬脂酸镁是药用级硬脂酸镁,其理解为包含可估计的量的棕榈酸镁和其它杂质。根据另一实施方案,该硬脂酸镁是硬脂酸镁本身。
本文中所用的“粘合剂”用于赋予粉末材料以粘着性,以使形成的片剂或颗粒保持在一起,并不会散落。可以使用与活性成分相容并具有良好的流动性和溶出的任何合适的粘合剂。示例性的粘合剂包括但不限于明胶、淀粉、纤维素、纤维素衍生物(如甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、乙基纤维素和羧甲基纤维素)、蔗糖、聚乙烯吡咯烷酮(即聚维酮)、天然糖(如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶(如阿拉伯胶、黄蓍胶或藻酸钠)、聚乙二醇、蜡等等。本发明的优选粘合剂是聚维酮。该聚维酮(例如聚维酮K29/32)优选以未包衣片剂的大约1.7重量/重量%用在该片剂的度鲁特韦层中。
本文中所用的“AUC”(曲线下的面积)是血浆中药物浓度vs时间的曲线图中的定积分。在实践中,在某些离散的时间点测量药物浓度,并使用梯形法则来估算AUC。AUC可以用0到t的时间分量来表示,其中t是某个时间,或者为0到无穷大,其中基于在某些时间间隔处的测量值将AUC值外推到无穷大。
本文中所用的“双层”是指具有两个独立的层的单位剂型,其中每一层相对于另一层具有不同的药物和赋形剂组成。双层片剂可以具有中间层(不含大量药物成分)。优选地,两个含药物层彼此直接接触。
本文中所用的“Cmax”是在施用药物之后并在施用第二剂量之前药物在身体的特定隔室或测试区域中达到的最大(或峰值)血清浓度。
本文中所用的术语“共同施用”是指彼此在24小时内施用两种或更多种药剂,例如作为临床治疗方案的一部分。在其它实施方案中,“共同施用”是指彼此在2小时内施用两种或更多种药剂。在其它实施方案中,“共同施用”是指彼此在30分钟内施用两种或更多种药剂。在其它实施方案中,“共同施用”是指彼此在15分钟内施用两种或更多种药剂。在其它实施方案中,“共同施用”是指作为单一制剂的一部分或作为通过相同或不同途径施用的多种制剂的同时施用。
本文中所用的“禁食”描述这样的情况——在非摄食状态下对个体进行投药和监测。这样做的目的是消除脂肪或其它GI内容物(如果有的话)可能对受测药物的测量的药代动力学的影响。通常,禁食是在开始测试(即第一次给药)之前12小时内没有摄取除水以外的任何东西的状态。相反,“进食”描述了个体在首次给药之前,通常在4到6个小时内进食中等至高脂膳食的情况。
“基本相同的AUC”描述了与参照产品生物等效的状态。在这种情况下,监管指南通常会提供范围为参照产品的80%-125%的药代动力学参数的生物等效性推定。例如,如测试的那样,如果测得的测试AUC落在测得的参照AUC的80%-125%之内,则该测试产品将被视为与参照产品具有基本相同的AUC。
“治疗有效量”或“有效量”是指将预防病况或在一定程度上减轻治疗的病症的一种或多种症状的施用的化合物的量。适用于本文的药物组合物包括其中以足以实现预期目的的量包含活性成分的组合物。治疗有效量的确定完全在本领域技术人员的能力范围内,尤其是根据本文中提供的详细公开内容。
本文中所用的术语“治疗(“treatment”或“treating”)”在治疗方法的背景下指的是减轻特定病况、消除或减轻病况的症状、延缓或消除病况的进展、侵袭或扩散,以及减少或延迟先前患病的对象的病况的复发。本发明进一步提供了本发明的化合物在制备用于治疗需要其的哺乳动物(例如人)中的若干病况的药物中的用途。
本文中所用的术语“预防(“prevention”或“preventing”)”在治疗方法的背景下指的是排除指定的病况或病况的症状,或在发生先前感染的情况下排除病况的再次发生。本发明进一步提供了本发明化合物在制备用于预防需要其的哺乳动物(例如人)中的若干病况的药物中的用途。
如所提及的那样,本文中的剂型可用于治疗或,可替代地,预防HIV,除非进一步阐明,其意在指HIV-1。作为替代性的实施方案,本发明的组合还可以有效对抗HIV-2,或对抗患有双重HIV-1/HIV-2感染的患者。
实施例
实施例1A:双层片剂的组成
根据本发明的一个实施方案,提供了表3的示例性双层片剂组成。
表3. “双层片剂1”
备注:
1.等效于50 mg的度鲁特韦游离酸(GSK1349572B)
2.基于每批药物物质的纯度和水含量因子,可以调节D-甘露醇的量以保持片剂核心重量。
3.纯净水在加工过程中除去。
4.该片剂薄膜包衣以Aquarius Film Coat在纯净水中的12重量/重量%悬浮液形式施加。
实施例1B:双层片剂的制造方法
在图2中给出了双层片剂的制造方法的流程图。
为了产生拉米夫定层压缩共混物,将拉米夫定与微晶纤维素和淀粉羟乙酸钠在滚筒式混合机中共混。随后将硬脂酸镁添加到该共混物中。
为了产生度鲁特韦层压缩共混物,首先通过装料并随后在高剪切制粒机的钵中混合微粉化度鲁特韦钠、甘露醇、微晶纤维素、聚维酮K29/32和淀粉羟乙酸钠来制备度鲁特韦颗粒。通过添加纯净水将混合物造粒。通过将湿颗粒通过叶轮式磨机使湿颗粒解聚。接着将该颗粒在流化床干燥器中干燥。随后将干燥的颗粒在叶轮式磨机中研磨。
随后将干燥的颗粒与淀粉羟乙酸钠和硬脂酰醇富马酸钠在滚筒式混合机中共混。
使用双层旋转压片机压缩层1和层2压缩共混物。调节层1和层2的填充深度以分别达到600 mg和300 mg的平均层重,由此获得900 mg的总双层重量。调节压缩力以获得合适的层粘附力。
然后将压缩的双层片剂核心薄膜包衣。通过在容器中将薄膜包衣分散在纯净水中来制备水性薄膜包衣悬浮液。将预热的片剂核心放置在包衣锅中,并且在用包衣悬浮液喷涂片剂核心时,该包衣锅连续旋转,直到获得所需的重量增加。
实施例2:单层片剂的组成
根据一个实施方案,在表4中提供了用于与本发明比较的单层片剂组成。
表4. “单层片剂1”
备注:
5.等效于50 mg的度鲁特韦游离酸(GSK1349572B)
6.基于每批药物物质的纯度和水含量因子,可以调节D-甘露醇的量以保持片剂核心重量。
7.纯净水在加工过程中除去。
8.该片剂薄膜包衣以Aquarius Film Coat在纯净水中的12重量/重量%悬浮液形式施加。
实施例3:溶出测试
表5总结了本文中配制的片剂的分析方法和条件。
表5. 溶出方法条件
溶出参数 | 值 |
设备 | USP <711> Apparatus II |
溶出介质 | 模拟胃液 (SgF) pH 1.6 |
体积 | 500 mL |
温度 | 37.0 ±0.5℃ |
采样时间 | 5、10、15、20、30、45、60、90分钟 |
桨叶速度 | 65 rpm |
检测 | HPLC |
提出的溶出方法用于评估从各种制剂(实施例2的单层片剂、实施例1的双层片剂、商业级50 mg TivicayTM片剂和市售Epivir片剂)中释放的度鲁特韦的量和速率。该方法并非设计为区分拉米夫定,因为它始终表现为非常快地溶解的片剂。
每种制剂类型的溶出测试均由n = 2组成。在该实验中,将单层和双层制剂与单一实体TivicayTM片剂进行了比较。为了模拟TivicayTM片剂与EpivirTM片剂一起给药时的临床中发生的情况,将两种单一实体组分均放置到溶出容器中。根据该方法,度鲁特韦成分的溶出概况可见于下图1。可以看出,双层片剂有利地提供了与单一实体片剂相似的60分钟度鲁特韦溶出,即35-40%溶出。
实施例4:单层片剂1和双层片剂1的药代动力学测试
在禁食条件下,将单层片剂1和双层片剂1的药代动力学与共同施用单独的药剂(目前美国FDA批准的单药剂片剂)进行比较,并评估高脂膳食对FDC的生物利用度的影响。
这是一项两部分、开放标签、单一剂量、单中心研究。部分1(N=78)和部分2(N=76)设计相同,具有3个阶段,每个阶段之间的清洗期最少为7天。在前两个阶段中,将对象以交叉方式随机接受参照物或测试FDC(禁食)。完成前两个阶段并同意继续的前16名对象在第三阶段接受与高脂膳食一起施用的测试FDC。由给药前至给药后72小时收集系列药代动力学样品。使用经过验证的LC/MS/MS方法评估血浆DTG和3TC浓度,并使用非房室方法评估药代动力学参数。使用DTG和DTG的混合效应模型,确定了测试/参照物几何最小二乘(GLS)均数比和关键药代动力学参数(取ln后的)的相关90%置信区间(CI)。
在部分1中,73名对象完成了实施例2的单层制剂的两个阶段。计算了AUC(0-inf)、AUC(0-t)和Cmax的GLS均数比(90%CI)。在部分2中,74名对象完成了实施例1的双层制剂的两个阶段。计算了AUC(0-inf)、AUC(0-t)和Cmax的GLS均数比(90%CI)。结果显示在表6中。所有治疗通常耐受良好。
表6
t= t最后.所有治疗的中值t最后大约72小时。
Claims (13)
1.双层片剂制剂,包含:
(i)包含拉米夫定的第一层,和
(ii)包含度鲁特韦钠的第二层。
2.权利要求1的片剂,其中
该第一层包含大约300 mg的拉米夫定和至少一种附加的赋形剂,并且该第二层包含大约50 mg的度鲁特韦和至少一种附加的赋形剂。
3.权利要求2的片剂,其中该第一层包含大约300 mg的拉米夫定、填充剂、崩解剂和润滑剂。
4.权利要求3的片剂,其中该第一层包含大约300 mg的拉米夫定、大约277.5 mg的微晶纤维素、淀粉羟乙酸钠和硬脂酸镁。
5.权利要求2的片剂,其中该第二层包含大约50 mg的度鲁特韦、一种或多种稀释剂、粘合剂和崩解剂。
6.权利要求5的片剂,其中该第二层包含大约50 mg的度鲁特韦、D-甘露醇、微晶纤维素、聚维酮和淀粉羟乙酸钠。
7.权利要求2的片剂,进一步包含薄膜包衣。
8.权利要求1的片剂,其中该片剂在口服施用时向患者提供与FDA批准的50毫克TIVICAY产品基本相同的度鲁特韦的AUC(0-∞)。
9.权利要求1的片剂,其中该片剂在口服施用时向患者提供与FDA批准的300毫克EPIVIR产品基本相同的拉米夫定的AUC(0-∞)。
10.权利要求1的片剂,其中该片剂在口服施用时向禁食患者提供13.3至13.9 mcgh/mL的拉米夫定的AUC(0-∞)。
11.权利要求1的片剂,其中该片剂在口服施用时向禁食患者提供50.5至58.9 mcgh/mL的度鲁特韦的AUC(0-∞)。
12.权利要求1的片剂,其中该第一层包含大约300 mg的拉米夫定,并且该第二层包含大约50 mg的度鲁特韦,并且其中如采用USP Apparatus II测得的那样,大约35%至40%的度鲁特韦在与1.6 pH模拟胃液接触后在大约60分钟内释放。
13.权利要求12的片剂,其中在500毫升模拟胃液中在37.0 +/- 0.5℃和65 rpm的桨叶速度下测量度鲁特韦的释放。
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WO2020163196A1 (en) * | 2019-02-05 | 2020-08-13 | Viiv Healthcare Company | Method for treating hiv with dolutegravir and lamivudine |
WO2021116244A1 (en) * | 2019-12-12 | 2021-06-17 | Sandoz Ag | Modulation of drug release and bioavailability of compositions containing dolutegravir sodium and other anti hiv drugs |
CN111991558B (zh) * | 2020-08-28 | 2022-08-09 | 安徽贝克生物制药有限公司 | 一种抗逆转录病毒药物组合物及其制备方法 |
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ES2688925T3 (es) * | 2010-01-27 | 2018-11-07 | Viiv Healthcare Company | Tratamiento antiviral |
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EP3177629B1 (en) * | 2014-07-29 | 2020-01-29 | LEK Pharmaceuticals d.d. | Novel hydrates of dolutegravir sodium |
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TW201927290A (zh) | 2019-07-16 |
WO2019074826A3 (en) | 2020-04-02 |
WO2019074826A2 (en) | 2019-04-18 |
IL273704B1 (en) | 2024-02-01 |
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RU2020118376A (ru) | 2021-11-15 |
EP3694522A4 (en) | 2021-08-04 |
AU2018347990B2 (en) | 2021-09-09 |
IL273704A (en) | 2020-05-31 |
KR20200070246A (ko) | 2020-06-17 |
CL2020000959A1 (es) | 2021-02-26 |
MX2020003377A (es) | 2020-09-28 |
AU2018347990A1 (en) | 2020-04-23 |
CA3078624A1 (en) | 2019-04-18 |
IL273704B2 (en) | 2024-06-01 |
CN117281788A (zh) | 2023-12-26 |
JP2020536931A (ja) | 2020-12-17 |
US20200230141A1 (en) | 2020-07-23 |
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