CN111032031B - 用于治疗hiv感染的药物纳米混悬液 - Google Patents
用于治疗hiv感染的药物纳米混悬液 Download PDFInfo
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- CN111032031B CN111032031B CN201880041004.0A CN201880041004A CN111032031B CN 111032031 B CN111032031 B CN 111032031B CN 201880041004 A CN201880041004 A CN 201880041004A CN 111032031 B CN111032031 B CN 111032031B
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Abstract
本发明涉及用于长效可注射(LAI)药物的药物组合物(纳米混悬液)，其用于HIV/AIDS的长期支持疗法。要求保护用于HIV感染的长期支持疗法的呈可注射药物使用的药物纳米混悬液，包括含有作为活性成分的晶型或多晶型的通式1化合物的组合物，
其中R为C2H5CON‑Na+、NH2。
Description
发明领域
本发明涉及用于长效可注射(LAI)药物的药物组合物(纳米混悬液)，其预期用于HIV/AIDS的长期支持疗法。
发明背景
人类免疫缺陷性病毒(HIV)是一种引起惰性疾病-HIV-感染的慢病毒(逆转录病毒亚群)[Weiss R.A.How does HIV cause AIDS.Science 1993,260(5112),1273–1279.Douek D.C.,Roederer M.,Koup R.A.Emerging Concepts in theImmunopathogenesis of AIDS》.Annu.Rev.Med.2009,60,471–84]。在1983年，人类免疫缺陷性病毒在两个实验室中被独立发现：一个是在法国的巴斯德研究所(PasteurInstitute)由Luc Montagnier领导的研究组，另一个是在美国的国家癌症研究所(theNational Cancer Institute)由Robert Gallo领导的研究组。讨论了从具有AIDS症状的患者组织中首次分离新的逆转录病毒的研究结果于1983年5月20日发表在科学期刊(journalScience)中。[Barré-Sinoussi F.et al.Isolation of a T-lymphotropic retrovirusfrom a patient at risk for acquired immune deficiency syndrome(AIDS).Science1983,220(4599),868—871.Gallo R.C.at al.Isolation of human T-cell leukemiavirus in acquired immune deficiency syndrome(AIDS).Science 1983,220(4599),865—867.]。在2008年，Luc Montagnier和
Barré-Sinoussi因为他们的“人类免疫缺陷性病毒的发现”共享生理学和医学诺贝尔奖。
HIV病毒感染它们的表面上具有CD4受体的免疫系统细胞：T辅助细胞、单核细胞、巨噬细胞、朗氏细胞、树突细胞、小神经胶质细胞。这导致免疫抑制和获得性免疫缺陷综合征(AIDS)的进展；患者身体保护自身对抗感染和肿瘤的能力丧失；出现对于具有正常免疫状态的人而言非典型的继发性机会性疾病(opportunistic diseases)。在没有治疗下，感染HIV之后的平均存活时间估计为9至11年，取决于HIV亚型[https://https://en.wikipedia.org/wiki/HIV]。
根据全世界全球统计，在2015年，全球现存3670万携带HIV的人，210万人重新感染HIV，并且110万人死于与AIDS相关的疾病。自疫情爆发以来，已有7800万人感染HIV，其中3500万人死于与AIDS相关的疾病。
截止2015年12月，现存携带HIV的1700万人接受抗逆转录病毒治疗，而在2015年6月，该数字为1580万人，在2010年，该数字为750万人。
在2015年，现存携带HIV的所有成年人的46％得到治疗，而在2010，其仅为23％。
自从2010年，新的HIV感染下降6％。在2015年，HIV感染的全球数量为210万人，而在2010年，其为220万人。
与2005年的最高图相比，AIDS-相关死亡率降低45％，而在2015年，全世界由于AIDS死亡的个体数量为110万人，与之相比，在2005年，其为200万人。
可以通过包括三种以上抗逆转录病毒药物的联合抗逆转录病毒疗法(ART)抑制HIV。ART不能治愈HIV感染，但是抑制病毒在人身体内的复制，并且能够增强个体的免疫系统和恢复抵御感染的能力。接受ART的患者的预期寿命可以延长至70-80岁。
在2016年，WHO发布了“关于使用抗逆转录病毒药物治疗和预防HIV感染的统一指南(Consolidated Guidelines on the Use of Antiretroviral Drugs for Treatingand Preventing HIV Infection)”的第二版。
在2016年中期，全世界1820万HIV阳性人类，即46％[43-50％]接受ART。
基于WHO对于治疗现存携带HIV的所有人和提供抗逆转录病毒剂作为处于“实质”风险中人类额外预防选择的新建议，适于抗逆转录病毒治疗的人类数量从2800万增加至3670万人。扩大治疗是2020年新目标组的核心，目标为到2030年终结AIDS流行。[http://www.who.int/mediacentre/factsheets/fs360/ru/]。
迄今为止，使用ART有效安全的方案预防和治疗HIV在HIV/AIDS疗法中已经获得了相当大的成功。现在，正在俄罗斯国家卫生部进行注册程序的最新药物是用于HIV/AIDSART的艾法韦林(Elsulfavirine)(
VM1500)[(a)A.Kravchenko et al.Safetyand antiviral effect of Elpida(VM-1500),a novel NNRTI(+Truvada)in treatment-
HIV1 infected patients at 24-48weeks therapy.HIV Drug Therapy 2016,23-26October 2016,P024.Glasgo,UK.(b)R.L.Murphy et al.Elsulfavirine as Comparedto Efavirenz in Combination with TDF/FTC:48-week Study.CDRI 2017,Seattle,WAhttp://www.prnewswire.com/news-releases/viriom-reports-positive-findings-in-phase-iib-study-of-elpida-as-compared-to-efavirenz-in-combination-with-tdfftc-at-croi-2017-300409372.html],(c)Viriom,Inc.announced interim resultsfrom Phase 3clinical trials with Elsulfavirine,which were presented at alarge conference on HIV/AIDS in Moscow[https://www.viriom.com/press-releases/2016/12/13/viriom-announces-interim-results-from-phase-3-clinical-trials-with-elpida-were-presented-at-largest-events-on-hivaids-in-moscow.]。
艾法韦林(Elsulfavirine)/Elpida/VM-1500(1a)是活性化合物VM-1500A(1b)的前药，VM-1500A(1b)是一种非核苷逆转录酶抑制剂(NNRTI)，其有效地预防MT-4细胞系中HIV-1HXB2菌株复制。VM-1500A(1b)对于野生型HXB2菌株和抑制含有V106A、G190A、L100I/K103N和K103N/Y181C突变的HIV-1突变体病毒所得到的平均IC50值如下：1.3±0.4nM(HXB2),1.2±0.2nM(V106A).0.6±0.6nM(G190A),1.3±0.3nM(L100I/K103N)和1.3±0.4nM(K103N/Y181C)。
其中R为C2H5CON-Na+、NH2；
尽管HIV/AIDS抗逆转录病毒疗法领域得到了发展，但是开发更有效且安全的HIV预防和治疗的方案仍然是一个主要的挑战。
实际上，对于长期支持性HIV/AIDS疗法，还没有注册任何长效(LA)药物。
本发明涉及用于长效可注射(LAI)药物的药物组合物(纳米混悬液)，用于HIV/AIDS的长期支持疗法。
下面列出的是用于描述本发明的各种术语的定义。这些定义单独地或作为较大部分的组成部分适用于贯穿于本说明书和权利要求书中使用的术语，除非在特定情况下另有限制。
术语“活性成分”(药物物质)指合成或其他(生物技术，植物，动物，细菌等)来源的生理活性化合物，其显示出药理学活性并且是药物组合物的活性成分。
术语“晶型”指其中分子排列形成晶格的物质结构。
术语“多晶型(polycrystalline form)”指由多个单晶或某些晶型的微晶组成的多晶物质结构。
术语“药物”指片剂、胶囊、注射剂、软膏剂形式或预期用于恢复、改善或改变人类和动物生理功能并且用于治疗和预防疾病、用于诊断、麻醉、避孕、美容等的其他成品剂型的化合物(或形成药物组合物的化合物的混合物)。
术语“药物组合物”指包含通式1的化合物和至少一种选自下述可药用和药理学相容的组分的组合物：填充剂、溶剂、稀释剂、载体、赋形剂、分布剂和接受剂(receptiveagents)、递送剂比如防腐剂、稳定剂、填充剂、崩解剂、润湿剂、乳化剂、助悬剂、增稠剂、甜味剂、矫味剂、芳香剂、抗菌剂、杀真菌剂、润滑剂和延长递送控制剂，其选择和比例取决于给药的性质和途径以及剂量。合适的助悬剂的实例是乙氧基化异硬脂醇、聚氧乙烯、山梨醇和山梨醇醚、微晶纤维素、偏氢氧化铝、膨润土、琼脂和西黄蓍胶及其混合物。可以使用各种抗菌剂和抗真菌剂比如尼泊金酯类、氯丁醇、山梨酸等提供对微生物的防护。所述组合物也可包括等渗剂，比如糖、氯化钠等。使用减慢活性成分吸收的试剂，例如单硬脂酸铝和明胶，可以实现组合物的持续作用。合适的载体、溶剂、稀释剂和递送剂的实例包括水、乙醇、多元醇及其混合物、天然油(比如橄榄油)和用于注射的有机酯(比如油酸乙酯)。填料的实例是乳糖、奶糖、柠檬酸钠、碳酸钙、磷酸钙等。崩解剂和分配剂的实例是淀粉、海藻酸及其盐和硅酸盐。润滑剂的实例是硬脂酸镁、月桂基硫酸钠、滑石和高分子量的聚乙二醇。用于口服、舌下、透皮、肌内、静脉内、皮下和局部或直肠给药活性成分的单独或与另一种活性化合物组合的药物组合物，可以作为与传统的药物载体的混合物以标准给药形式施用于动物和人。适合的标准给药形式包括口服形式，比如片剂、胶囊、丸剂、粉剂、颗粒剂、口香糖和口服溶液或混悬液；舌下和经口含给药形式；气雾剂；植入物；局部、透皮、皮下、肌内、静脉内、鼻内或眼内形式；和直肠给药形式。
如本文使用的术语“惰性填充剂”指用于形成药物组合物并且通常是安全的、无毒的、既不是生物学上也不是其他方面不合乎需要的化合物，并且包括兽医和人类药物用途可接受的赋形剂。本发明化合物可以单独施用，但通常与一种或多种可药用赋形剂、稀释剂或载体混合物的形式给药，其选择取决于预期的给药途径和标准药学实践。
如本文使用的术语“治疗有效量”指减轻受试者中疾病症状所需的物质，前药或药物的量。物质、前药或药物的剂量将满足每种特定情况下的个体需求。所述剂量可以在很宽的范围内变化，这取决于许多因素，例如待治疗的疾病的严重程度、患者的年龄和一般状况、用于患者治疗的其他药物，给药方式和途径，以及主治医生的经验。对于口服给药，在单一疗法和/或组合治疗中，日剂量约为0.01-10g，包括其间的所有值。优选的日剂量为约0.1-7g。通常，为了快速减轻或消除病毒，在治疗开始时给予较高的负荷剂量，随后将剂量减少至足以防止感染爆发的水平。
术语“受试者”指哺乳动物，优选人类。推定受试者的治疗方法可涉及通式1的前药、其立体异构体、同位素富集的类似物、可药用盐、水合物、溶剂合物和晶型或多晶型中任一种或它们与另一种化合物和药物的组合，用于HIV/AIDS的组合逆转录病毒疗法。
发明简述
本发明人令人惊奇地发现包括作为活性成分的晶型或多晶型的通式1的化合物的药物纳米混悬液作为HIV感染的长期支持疗法的可注射药物是有效的。
本发明的主题为纳米组合物，其包括治疗有效量的作为活性成分的晶型或多晶型的通式1的化合物任选地与用于制备药物纳米混悬液的可药用填充剂、添加剂或稀释剂的组合。
更优选地为包括作为活性成分的晶型或多晶型的式1b的化合物与增溶剂(例如，泊洛沙姆Р338)和去垢剂(例如，甘露醇或蔗糖)的冻干纳米组合物。
更优选地为具有粒径范围200nm至900nm的纳米组合物。
本发明的一个进一步的主题是包括上述纳米组合物、磷酸盐缓冲盐水(PBS)和注射用水的药物纳米混悬液，用于HIV/AIDS-感染个体的长期支持疗法。
本发明的一个更进一步的主题是一种用于制备冻干纳米组合物的方法，所述方法包括利用锆砂旋转研磨在泊洛沙姆水溶液中的晶型或多晶型的通式1的化合物、增溶剂和去垢剂，接着分离锆砂，并冻干得到的悬浮液。
本发明的仍然另一个主题是一种利用混合上述冻干纳米组合物和注射用水制备药物纳米混悬液的方法。
本发明参照附图进行说明。
图1.在用蔗糖研磨24小时之后，三个样品的粒径测定曲线。
图2.在用甘露醇研磨24小时之后，三个样品的粒径测定曲线。
图3.在研磨24小时和沉降20小时(蔗糖)之后，三个样品的粒径测定曲线。
图4.在研磨24小时和沉降20小时(甘露醇)之后，三个样品的粒径测定曲线。
图5.在冷冻干燥和再悬浮之后，来自批次740-1-101.1(蔗糖)的三个样品的粒度分布测定曲线。
图6.在冷冻干燥和再悬浮之后，来自批次740-1-101.2(甘露醇)的三个样品的粒度分布测定曲线。
图7.单剂量SC和IM给药药物纳米混悬液VM-1500-LAI和VM-1500А-LAI(10mg/kg)的狗血浆中VM-1500A浓度-时间曲线。
优选的实施方案
本发明现在将根据一些实施方案进行描述，所述实施方案并不打算限制其范围。相反，本发明涵盖可包括在权利要求范围内的所有替代、修饰和同等物。因此，包括具体实施方案的下述实施例将示例本发明而不限制本发明。
实施例1.用于制备冻干纳米组合物的方法
将锆砂(150ml)(磨料：0.5mm
Zirconia Grinding and Dispersion Media；Tosoh USA,Inc.)与泊洛沙姆Р338(10.0g)和蔗糖或甘露醇(11.6g)在400ml PBS(pH＝7.4)中的溶液放入广口瓶中。将得到的溶液(150ml)放入广口瓶中，并加入锆砂(150ml)(研磨介质∶0.5mm/>
Zirconia Grinding and Dispersion Media；Tosoh USA,Inc.)和化合物VM1500A(15.07g)。将广口瓶放在研磨机(U.S.Stoneware 700Series缸式磨机)，其中将该混合物以104转/分钟研磨24小时。通过在Malvern Zetasizer Nano ZS仪器上进行粒度分布分析检查所述过程的结束。当该过程完成时，停止旋转，并使混合物在2–8℃下静置16-20小时，以使锆砂沉降。将悬浮液过滤穿过玻璃过滤器(滤孔直径：5–15μm)，并分析化合物VM1500A的浓度(标定92-97％)，得到纳米悬浮液，将其无菌倾倒入5ml无菌玻璃小瓶(每个2ml)中，冷冻并冻干，得到具有表1和2及图1、2、3和4中给出的特征的冻干纳米组合物。
表1.在研磨24小时之后纳米悬浮液的粒径(三次测定的平均值)
| 样品 | 样品体积,μl | 粒径,nm | PDI* | 质量 |
| 批次No.740-1-101.1(蔗糖) | 30 | 442.3 | 0.428 | 良好 |
| 批次No.740-1-101.1(蔗糖) | 10 | 357.7 | 0.283 | 良好 |
| 批次No.740-1-101.2(甘露醇) | 30 | 395.6 | 0.31 | 良好 |
| 批次No.740-1-101.2(甘露醇) | 10 | 552.4 | 0.487 | 良好 |
*PDI在此处和别处都指分散指数，其表征颗粒在混合物中的均匀性。
表2.在研磨24小时和沉降20小时之后纳米混悬液的粒径(三次测定的平均值)
| 样品 | 样品体积,μl | 粒径,nm | PDI | 质量 |
| 批次No.740-1-101.1(蔗糖) | 30 | 402.9 | 0.367 | 良好 |
| 批次No.740-1-101.1(蔗糖) | 10 | 362.1 | 0.268 | 良好 |
| 批次No.740-1-101.2(甘露醇) | 30 | 403.5 | 0.28 | 良好 |
| 批次No.740-1-101.2(甘露醇) | 10 | 381.3 | 0.286 | 良好 |
实施例2.用于制备药物纳米混悬液的方法
基于2.2ml/5ml小瓶，向实施例1中得到的纳米混悬液中加入预先制备的无菌PBS溶液(рН＝6.8)，得到具有表3与图5和6中给出的特征的即用药物纳米混悬液。
表3.药物纳米混悬液中的粒度分布
实施例3.药物纳米混悬液VM1500LAI和VM1500A-LAI在狗中的药代动力学
将实施例2中得到的纳米混悬液VM1500LAI和VM1500A-LAI以单次剂量10mg/kg皮下和肌内注射到比格犬中，并在注射之后测量狗血浆中VM1500的含量120天。使用LC-MS/MS方法测量试验化合物的浓度。
为了给药所述剂量，在相同点，将预先制备的纳米混悬液以0.1ml/kg皮下或肌内注射给所述狗。在注射后0、0.5、1、2、4、8、24小时和2、3、6、8、12、15、18、22、29、36、43、50、57、64、71、78、85、92、107、114和121天收集血液。将用于产生血浆的全血收集在含有肝素钠的试管中。为了更好地混合血液和肝素钠，在将血液收集在试管之后立即小心地翻转8次，然后在室温下培养15分钟。接着，通过以3000转/分钟离心10分钟分离血浆。使用自填充(self-filling)移液管，将1ml的血浆等分试样小心地转移到冷冻小瓶(cryovial)中，同时避免所述移液管的尖端和细胞团块/屏障凝胶之间的接触，将来自一个Vacuette管的血浆样品转移到两个冷冻小瓶。将得到的样品冷冻。在分析之前，血浆样品和血细胞应当保存在-80℃。
利用HPLC-MS/MS测量VM-1500和VM-1500A的浓度。使用具有类似结构的化合物VM-6819作为内标准(IS)。总离子流模式(MS1)扫描能够使我们鉴别每种试验化合物和IS的分子离子，而基础产物离子以MS2模式记录。为了以定量分析获得最高灵敏度，以MRM模式优化MS/MS过程。对于每种分析物，记录至少两个MRM变化，其中之一以定量色谱方法使用。
为了获得最佳色谱参数，选择合适的条件经由HPLC系统将在MeCN:Н2О(1:1)混合物中的试验化合物和IS注射到MS/MS检测器中。制备浓度范围为1.0-2000.0ng/ml的VM1500和VM1500A在血浆中的校准标准品。与校准标准品一起，制备0号样品(k0)和含有IS的k0，以及两个系列的低、中和高浓度的对照样品(QC)，用作定量计算质量的指征。由VM1500(2.0mg/mL)和VM1500A(2.0mg/ml)在DMSO中的储备溶液，制备在MeCN:Н2О(1:1)中的10倍工作稀释液。由单个等分试样的VM1500和VM1500A储备溶液制备(k)和QC样品的校准标准品溶液。
将用于制备标准样品的血浆试验样品在室温下解冻，搅拌，并以14000转/分钟离心5分钟。将完整血浆(90μl)转移到1.5-ml试管中，并将10μl的试验化合物混合物的10倍标准稀释液加入到乙腈∶水(1:1)混合物中。向试验样品(90μl)中加入纯的乙腈∶水(1:1)混合物(10μl)。使用涡旋搅拌机将样品充分混合10秒。然后，加入10μl的IS(在乙腈：水1:1中的VM-6819(5mg/ml)，并再涡旋该混合物10秒。向样品中加入1ml的乙酸乙酯：己烷(60:40)混合物，并在涡旋搅拌机混合20秒。然后再搅拌器上以1000转/分钟混合5分钟。将样品以14000转/分钟离心10分钟。
将有机相(0.8ml)收集到1.5-ml试管中，并在氮气流下，在蒸发器中于40℃干燥。将干提取物在150μl的乙腈：水(1:1)混合物中稀释，涡旋10秒，并转移到干净板(cleanplate)中用于HPLC/MS/MS分析。
由标准化为IS面积的在基质(血浆或血细胞)中的标准样品VM1500和VM1500A的色谱峰面积绘制的校正曲线，估计样品中VM1500和VM1500A的浓度。通过拟合足够描述分析信号相对于浓度的关系的最简单模型和使用合适的标准化绘制校正曲线。基于试验来源的每只动物的浓度-时间数据，使用WinNonlin Professional 6.3软件(PharsightCorporation)，通过模型独立方法找到基本药代动力学参数。
-Сmax–最大血浆浓度；
-Тmax–达到最大血浆浓度的时间；
-AUC0-t–从给药药物时到最后一个浓度测量点的PK曲线下面积；
-AUC0-inf–从给药药物时到无穷大的PK曲线下面积；
-T1/2–血浆消除半衰期；
-kel–消除速度常数(表征血浆药物消除速率的参数)；
-MRT–从给药药物时的保留时间中值。
利用描述统计学进行结果的统计加工。计算下述参数：算术平均值(M)、标准偏差(SD)、平均标准误差(SEM)、变异系数(СV)、中值。使用WinNonlin Professional 6.3软件(Pharsight Corporation)，进行统计分析。
表4概述了表征在向狗皮下(SC)和肌内(IM)注射纳米混悬液VM-1500-LAI和VM-1500А-LAI之后VM-1500和VM-1500A性质的药代动力学参数。
表4.在SC和肌内IM注射10mg/kg剂量的纳米混悬液VM-1500-LAI和VM-1500А-LAI之后，狗血浆中VM-1500和VM-1500А的药代动力学参数。
观察到采用肌肉注射的VM-1500及其代谢物VM-1500A的Cmax值高于采用皮下注射的。然而，对于VM-1500А-LAI制剂，差异没有那么明显。而且，在肌肉注射VM-1500-LAI的情况下VM-1500和VM-1500A的总暴露高于在皮下注射的情况下所述物质的总暴露，而VM-1500A的暴露与给药VM-500А-LAI制剂的方式无关。应当注意到采用肌肉注射，VM-1500А比皮下注射的更早地获得了最大浓度。半衰期基本上不依赖于给药方式。
在单次SC和IM注射纳米混悬液VM1500-LAI和VM1500A-LAI之后狗血浆中的平均VM-1500A浓度(С)在表5和图7中给出。
表5.在单次SC和IM注射10mg/kg的储库制剂VM-1500-LAI和VM-1500А-LAI之后狗血浆中VM-1500А的浓度
表5(续).在单次SC和IM注射10mg/kg的储库制剂VM-1500-LAI和VM-1500А-LAI之后狗血浆中VM-1500А的浓度
| 2208 | 92.0 | BLQ | BLQ | 6.81 | 1.46 | 12.79 | 3.01 | ||
| 2568 | 107 | BLQ | BLQ | 6.43 | 1.38 | 9.59 | 0.39 | ||
| 2736 | 114 | BLQ | BLQ | 9.68 | 1.33 | 5.72 | 1.12 | ||
| 2904 | 121 | BLQ | BLQ | 5.70 | 1.81 | 11.47 | 1.07 |
BLQ–低于定量限
如从表5和图7中可以看出，在向狗IM注射10mg/kg剂量的药物纳米混悬液VM-1500-LAI之后，血浆中药物VM1500A的有效浓度(IC50＝1.3nM或0.74ng/mL)保持约1个月(在29天之后，СVM-1500A＝2.61ng/ml)，而在SC注射之后，其保持约1个半月(在43天之后，СVM-1500A＝4.83ng/ml)。
在向狗IM和SC注射10mg/kg剂量的纳米混悬液VM-1500-LAI之后，观察到更加令人信服的结果。在该情况下，VM1500A的有效浓度保持四个月(在121天之后，在IM注射之后СVM-1500A＝5.70ng/ml，在SC注射之后СVM-1500A＝11.47ng/ml)。
工业实用性
本发明可以用于医学和兽医学中。
Claims (7)
1.用于HIV感染的长期支持疗法的呈可注射药物的药物纳米混悬液，包括作为活性成分的通式1的化合物，
其中R为C2H5CON-Na+、NH2；
选自泊洛沙姆P338的增溶剂，和
选自甘露醇或蔗糖的去垢剂，以及
任选地，可药用填充剂、添加剂或稀释剂；并且
其中所述药物纳米混悬液包含具有200nm至900nm范围的粒径。
2.根据权利要求1所述的药物纳米混悬液，包括作为活性成分的式1b的化合物，
3.冻干物形式的组合物，所述冻干物是由冷冻干燥权利要求1或2所述的药物纳米混悬液得到的。
4.根据权利要求3所述的组合物，所述组合物用于制备药物纳米混悬液。
5.用于HIV感染的长期支持疗法的用作可注射药物的药物纳米混悬液，包括根据权利要求3所述的组合物、磷酸盐缓冲盐水(PBS)和注射用水。
6.用于制备根据权利要求3所述的组合物的方法，包括利用锆砂旋转研磨在泊洛沙姆水溶液中的通式1的化合物，
其中R为C2H5CON-Na+、NH2；
选自泊洛沙姆P338的增溶剂，和
选自甘露醇或蔗糖的去垢剂，接着分离锆砂，并冻干得到的悬浮液。
7.制备药物纳米混悬液的方法，通过混合根据权利要求3所述的组合物、具有pH＝6.8的磷酸盐缓冲盐水(PBS)和注射用水。
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| CN102143943A (zh) * | 2008-09-09 | 2011-08-03 | 弗·哈夫曼-拉罗切有限公司 | 酰基磺酰胺的多晶型物 |
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