CN112020348A - 用于制备高度可吸入颗粒的半胱胺新盐 - Google Patents
用于制备高度可吸入颗粒的半胱胺新盐 Download PDFInfo
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- CN112020348A CN112020348A CN201980022774.5A CN201980022774A CN112020348A CN 112020348 A CN112020348 A CN 112020348A CN 201980022774 A CN201980022774 A CN 201980022774A CN 112020348 A CN112020348 A CN 112020348A
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- cysteamine
- hyaluronic acid
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Abstract
本发明提供了包含半胱胺透明质酸盐的可吸入微粒。还提供了其制备方法及其药物组合物。
Description
背景技术
半胱胺是已知可用于治疗胱氨酸病的活性成分。迄今为止,欧洲已经批准了几种具有这种治疗适应症的药物产品,例如Cystagon®(酒石酸半胱胺胶囊),Procysbi®(酒石酸半胱胺抗胃酸胶囊)和Cystadrops®(盐酸半胱胺盐酸盐滴眼剂)。
在相对较近的时期,半胱胺已被授予囊性纤维化的孤儿称号。囊性纤维化(CF)是一种遗传性疾病,会影响分别分泌粘液或消化液等液体的小肠/胰腺中肺和腺体中的细胞。结果,这些液体变得粘稠,阻塞了呼吸道和消化液的流动。这不仅导致食物的消化吸收问题,甚至最糟糕的是,导致长期感染和肺部炎症。由于肺功能下降,通常由于细菌感染导致的CF肺症状加重或急性加重发作是发病和死亡的主要原因。
迄今为止,囊性纤维化中的肺部疾病主要是用抗生素、抗炎药、支气管扩张药和粘液溶解剂联合治疗。
半胱胺已被证明可通过减少粘液厚度使其更容易清除(粘液溶解活性),并同时直接对抗肺部细菌(抗菌活性)来治疗CF症状。
因此,半胱胺的整体多活性特性(降低气道中过多的粘液,杀死引起反复呼吸道感染的细菌并破坏它们定殖的生物膜)在CF患者中具有治疗上的益处(参见Graham Devereux等人的“半胱胺作为对当前和新兴病原的囊性纤维化的未来干预措施:一项基于患者的离体研究,证实其在痰中具有抗菌和粘液活性”,(Graham Devereux et al. “Cysteamine asa Future Intervention in Cystic Fibrosis Against Current and EmergingPathogens: A Patient-based ex vivo Study Confirming its Antimicrobial andMucoactive Potential in Sputum”)EBioMedicine (2015) 1507-1512; and Charrieret al., 2014: http://dx.doi .orq/10.1 188/st 3023-014-0189-21)。
这些发现的结果是,需要用于治疗肺部疾病的可吸入半胱胺制剂。实际上,为了更好地利用半胱胺在肺部的有效性,该药物应以气雾剂的形式直接输送到患者的气道中。
肺部给药在给药方面具有许多优势,例如非侵入性给药途径,较低的代谢活性,避免首过代谢,迅速的全身吸收以及最重要的是较高的局部药物浓度,可与肺粘膜感染/发炎进行对比并改善组织愈合。然而,面对进入体内的异物颗粒,肺部呈现出多种清除机制(粘膜纤毛运输、肺泡巨噬细胞吸收性和代谢性降解),不幸的是,它们可作为吸入药物的障碍,损害其治疗功效。因此,为了限制肺部清除机制并提供增强的治疗效果和/或受控的药物释放,基于颗粒的给药***已经出现,作为常规吸入药物溶液的创新且有希望的替代方案。
例如,US 2017/0348254公开了通过将活性成分与稳定剂(例如海藻糖和亮氨酸)一起喷雾干燥而制备的酒石酸半胱胺酒石酸微粒。然而,在雾化约160至270mg之间的喷雾干燥的粉末的量之后,所得粉末的空气动力学性能低并且细颗粒剂量的报告最小酒石酸半胱胺酒石酸盐的细颗粒剂量仅在3至6.9mg之间。因此,考虑到在雾化超过100mg的粉末后这种非常少量的药物沉积到肺中,仍然需要具有高呼吸性的有效的半胱胺可吸入制剂。
要解决的另一个问题是,鉴于通过吸入给药,半胱胺在固态下的不稳定性。不幸的是,用现有的半胱胺盐制成的可吸入肺微粒(例如美国专利2017/0348254中所述的),也处于肺输送的最佳尺寸范围(1-5 pm),显示出非常差的肺渗透性,这主要是由于灵敏度高活性成分对环境条件的影响。实际上,所述盐是吸湿的、潮解性的并且易于氧化降解。此外,从市售产品已知的半胱胺盐,例如盐酸盐和酒石酸氢盐,具有不利的粒度,这决定了差的空气动力学性质,使得所述盐不适合作为干粉制剂吸入。
此外,CN101367884公开了一种共价的巯基化透明质酸共轭物。氨基(酰胺键)半胱胺及其制备方法。该方法包括在透明质酸溶液中加入1-乙基-3-(3-二甲基氨基丙基)-碳二亚胺(EDAC)和N-羟基琥珀酰亚胺(NHS)以活化羧基。然后,加入半胱胺盐酸盐并冻干反应混合物,得到药物/聚合物共轭物,可用作非注射制剂的生物粘附材料。但是,该方法涉及EDAC和NHS,这两种试剂都不被认为可安全吸入。此外,共轭物是一种新的化学实体,可改变半胱胺对于人类使用的公认安全性。最后,所获得的共轭物是冻干粉末,甚至不适合在干粉吸入器中吸入。
因此,使用半胱胺作为干粉吸入治疗肺部疾病还需要发现新的稳定且可呼吸的药物干衍生物。
发明内容
迄今为止,从未使用诸如透明质酸的聚合物质来制备新的半胱胺盐。
HA是天然存在的多糖,由D-葡萄糖醛酸和N-乙酰氨基葡萄糖的直链组成,并且是***、滑液、胚胎间质和玻璃体液的细胞外基质的丰富成分。尽管透明质酸以其抗炎活性而闻名,但从未被认为是制造半胱胺盐的抗衡离子。实际上,由于其酸度差,预计HA不会与固体形式的弱碱半胱胺形成稳定的盐。而且,可商购以透明质酸的钠盐形式的HA,所述透明质酸钠盐防止HA与弱碱半胱胺形成盐。
经过广泛的实验,本发明的发明人现已出人意料地发现,可以容易地获得以固体形式稳定并且可以有利地用于制备高度可呼吸微粒的半胱胺透明质酸盐。
因此,本发明的第一个目的是制备半胱胺透明质酸盐微粒的方法,所述方法包括以下步骤:
a、溶解透明质酸钠;
b、添加离子交换树脂;
c、过滤获得的溶液;
d、添加半胱胺碱;
e、喷雾干燥获得的溶液。
具体地,步骤a:将分子量为22kDa-2MDa,优选30kDa-1MDa,的透明质酸钠溶解在合适的溶剂中。所述溶剂可以是极性溶剂,优选为水。透明质酸盐溶液的pH值在6.1至6.9之间。
步骤b:向透明质酸溶液中添加离子交换树脂,优选阳离子交换树脂。在一个优选的实施例中,使用强酸阳离子交换树脂(例如,苯乙烯-DVB凝胶的Dowex MonosphereTM 650C(H)基质和作为官能团的磺酸)。强阳离子树脂可以分批或连续使用。优选地,以分批模式使用树脂,这意味着透明质酸盐溶液与树脂直接接触一段完整的离子交换所需的时间,然后除去。为了增加透明质酸钠与树脂之间的接触,可以将溶液在搅拌下保持适当的时间段,例如1-3小时。因此,通过利用树脂与钠离子交换H+离子的能力,可以从透明质酸溶液中获得游离的透明质酸。所获得的HA溶液的pH值在2.2至2.8之间。
然后通过过滤从HA溶液中除去废树脂(步骤c)。术语“过滤”旨在涵盖本领域普通技术人员已知的任何过滤方法,例如通过布氏漏斗或通过膜的过滤。回收HA溶液后,加入半胱胺游离碱(步骤d),形成半胱胺碱/透明质酸的盐溶液。在步骤d中获得的盐溶液具有的半胱胺碱:透明质酸(透明质酸)的重量比(w/w)为1:3至1:10,优选为1:5至1:8之间,更优选约1:7。所获得的盐溶液的pH值在约3.7至6.9之间。
最后将盐溶液进行喷雾干燥处理(步骤e)。借助于合适的喷雾干燥器,例如BGchi微型喷雾干燥器B-191或B-290进行喷雾干燥。为了本发明的目的,优选的但非限制性的操作条件范围可以如下:入口温度在120至160℃之间,抽吸在80至100%之间,进料速度在2至6mL / min之间,并且空气流速在400至700 L / h之间。此外,将喷嘴清洁间隔调整为5级(每7秒钟一次压力吹除)。
有利地,所述干燥步骤e允许容易地获得可吸入的半胱胺透明质酸盐微粒。
实际上,所述微粒具有对数正态尺寸分布,中值粒径(DV50)低于10 pm,优选低于5pm,平均值的标准偏差小于或等于±0.5 pm。通过激光散射(SprayTec,Malvern,UK)测定喷雾干粉的粒度分布。将大约10 mg的粉末分散在20 ml的0.1%(w / V)跨度80的环己烷溶液中,并超声处理5分钟。在表1中报告的#2和#8配方中,DV50值和标准偏差分别为2.66±0.03和2.57±0.06。
通过扫描电子显微镜(SEM、SUPRA 40、Carl Zeiss NTS GmbH、Oberkochen,DE)研究了喷雾干燥微粒的形态特征。具体地,半胱胺碱(图1(a))显示出类似于薄片的颗粒,而半胱胺透明质酸喷雾干燥的微粒(b)则显示出带有收缩表面的圆形结构。这种结构表明盐颗粒是空的,这是由于空颗粒制成的粉末的堆积密度值低,因此呼吸量具有重要优势。粉末的堆积密度根据欧洲药典(Ph.Eur)最后一版确定。粉末#2的堆积密度值为0.24±0.02 g /cm3,粉末#8的堆积密度值为0.22±0.01 g / cm3。
另外,喷雾干燥条件提供了物理和化学稳定的微粒粉末。如上所述,半胱胺游离碱(pKa 9.42)是不仅在溶液中而且在环境条件下呈粉末形式都非常不稳定的分子。透明质酸作为盐抗衡离子,可稳定硫醇盐胺。由于半胱胺嵌入透明质酸的聚合物结构中,所得的用于吸入的喷雾干燥的微粒粉末比其他半胱胺盐对储存的环境条件更具抵抗力。
在另一方面,本发明涉及包括半胱胺透明质酸盐和任选地,药学上可接受的添加剂的微粒。在此程度上,步骤d可进一步包括向透明质酸溶液中添加对改善颗粒成形或增加颗粒稳定性有用的添加剂。药学上可接受的添加剂,例如,可以选自氨基酸(例如亮氨酸)、作为海藻糖的糖类或有机酸类(例如抗坏血酸或乙酸)。
在另一方面,本发明涉及半胱胺透明质酸盐的涂覆微粒。在此程度上,步骤e可以相对于喷嘴同时喷雾两种分离的溶液,一种是在内部的活性成分(内孔),另一种是在外部的添加剂(外孔)。具体地,内孔供给半胱胺碱/透明质酸溶液,而外孔供给包含添加剂的溶液。然后将两种溶液同时但分别通过喷嘴,优选直径为0.5至0.9mm,优选等于0.7mm的同轴喷嘴喷雾,从而获得具有均匀特性的喷雾干燥的涂覆微粒。
在一个优选实施例中,选择的添加剂是L-亮氨酸。亮氨酸被认为是适合于制备可吸入颗粒的润滑剂。然而,根据本发明,从外部沉积的亮氨酸促进了对半胱胺透明质酸盐的保护作用,从而提高了半胱胺透明质酸盐微粒的物理/化学稳定性。实际上,发明人惊奇地发现亮氨酸具有抵消透明质酸的粘附性和半胱胺的吸湿性的有价值性质。
根据本发明的优选实施方式的微粒包括:
10至30%w/w的半胱胺,
50至80%w/w的透明质酸,以及
6-20%w/w的亮氨酸。
根据本发明的方法允许获得一种粉末,该粉末的粒径、密度和形状适合于形成具有缓慢空气通量的稳定气雾剂。所获得的气雾剂通过吸入以可预测和可复制的方式促进药物颗粒向肺的输送,到达呼吸道的支气管和肺泡部分。
根据本发明的任一方面,所获得的微粒粉末的可呼吸级分(FPF)可以令人惊奇地达到高于60%的值。这在添加了添加剂亮氨酸的粉末中特别明显。当使用同轴喷嘴喷涂亮氨酸百分比高于10%w / v的亮氨酸溶液时,可以获得最佳结果。相反,使用传统喷嘴时,亮氨酸浓度较低的溶液性能更高。
在另一方面,本发明涉及包含根据本发明的半胱胺透明质酸微粒的药物组合物。在另一方面,本发明涉及半胱胺透明质酸盐微粒或其组合物在干粉吸入器中的用途。
本发明开始解决或要解决的重要问题是提供一种新的稳定的半胱胺盐衍生物。有利地,本发明的方法允许获得新型的半胱胺盐,其为透明质的半胱胺。因此,本发明的另一个目的是半胱胺透明质酸盐。
通过傅立叶变换红外(FT-IR)谱图法证明了通过本发明的方法形成的新型半胱胺透明质酸盐。
FT-IR谱图测量是在室温下使用Jasco FT / IR -460 Plus Jasco以透射率模式在4000-650 nm-1的波数范围内进行的。通过在研钵中将粉末与KBr的比例为1:9(w/w)分散,制备了分析样品,然后用水压机压实共混物。透明质酸喷雾干燥微粒的FT-IR谱图(图2(c))与透明质酸钠粉末(b)的谱图有所不同,这是由于存在由三个峰构成的叉形带,这归因于羧基C=O峰(1734 cm-1)的拉伸振动,仲酰胺基团的C=O峰(1641 cm-1)的拉伸振动和NH变形(II酰胺)(1561 cm-1)。此外,相对于透明质酸钠,观察到在1417 cm-1、1378 cm-1和1320 cm-1处峰的强度和位移方面变化。最后,在1043 cm-1处的谱带中有明显差异,其中1077 cm-1处的肩峰成为峰值。
关于半胱胺透明质酸喷雾干粉的FT-IR谱图(图3),在-1645cm-1处的谱带既对应于半胱胺的-NFh基团的延伸,又对应于透明质酸的羧基C=O的延伸。与半胱胺游离碱和透明质酸的FT-IR谱图相比,表明半胱胺透明质酸喷雾干粉中这些官能团相互作用的差异是明显的。此外,从半胱胺透明质酸盐喷雾干粉的FT-IR谱图分析,观察到在1370 cm-1处峰强度降低(透明质酸甲酯的拉伸振动),在1410 cm-1处成为谱带的肩峰。 1077 cm-1处的峰强度对应于羧基C=O的拉伸振动,如其在肩峰的转变(如透明质酸钠的谱图所示)所证实的那样降低。这进一步支持了在透明质酸的羧基和半胱胺的氨基水平上的半胱胺碱和透明质酸之间的相互作用。
在固态下,通过13C-NMR分析进一步研究了新型半胱胺透明质酸盐的形成。在固态下,半胱胺游离碱、透明质酸钠、透明质酸喷雾干粉和半胱胺透明质酸喷雾干粉的谱图采用JNM-ECZR 400 NMR谱图仪(Jeol,Peabody,美国)收集。比较透明质酸半胱胺和其他半胱氨酸的谱图,两个抗衡离子都存在峰(图4),清楚地证明了盐的形成,与其他抗衡离子相比,由于不同邻域的影响,这些峰有很小的偏移(透明质酸和半胱胺)。此外,在透明质酸钠和透明质酸的谱图中观察到显着差异。特别地,在透明质酸的谱图中,肩峰出现在约175ppm的峰上,并且透明质酸钠谱图中存在的约69ppm的峰消失。
半胱胺透明质酸盐在环境条件下稳定,不易发生氧化降解,不吸湿,不潮解。
实际上,在25°C / 60%相对湿度下一个月后,通过HPLC分析评估了化学稳定性,并通过体外呼吸性测试评估了物理稳定性。关于在时间0的半胱胺透明质酸喷雾干粉,在半胱胺杂质的含量和细颗粒分数方面未观察到变化。
此外,发现透明质酸钠可以限制多种肺部清除机制,从而可以对所携带药物的肺部获得更有效和更长时间的治疗效果(请参见Ibrahim M. El-Sherbiny等人,“对于给药的吸入纳米和微粒”,《全球心血管科学杂志(2015),2,1-14(Ibrahim M. El-Sherbiny etal. “Inhaled nano- and microparticles for drug delivery”, Glob Cardiol SciPract (2015), 2, 1-14)))。因此,必须将半胱胺透明质酸盐的治疗效果分配给半胱胺和透明质酸部分。
因此,发明人惊奇地发现了一种新的半胱胺盐,其不仅克服了本领域已知的缺点,不仅因为其有利的化学/物理特性,而且还因为对肺上皮的更有效和更长时间的治疗作用。
本发明还提供了用作药物的半胱胺透明质酸盐,特别是用于治疗肺部疾病,更特别是用于治疗囊性纤维化感染病症。
总而言之,本发明的制造方法允许获得已经以易于吸入的微粒形式存在的稳定半胱胺盐衍生物,即半胱胺透明质酸盐。
附图说明
图1:a)半胱胺基础颗粒和b)半胱胺透明质酸喷雾干燥微粒的SEM照片。喷雾干燥微粒显示出圆形结构和收缩表面,而半胱胺碱显示出类似于薄片的颗粒。
图2:a)半胱胺碱、b)透明质酸钠和c)透明质酸喷雾干燥微粒的FT-IR谱图。
图3:半胱胺透明质酸喷雾干燥微粒的FT-IR谱图。
图4:透明质酸钠、半胱胺透明质酸喷雾干燥微粒、透明质酸喷雾干粉和半胱胺碱的13C-NMR谱图。比较半胱胺透明质酸的谱图与其他谱图,盐的形成可以通过抗衡离子、透明质酸和半胱胺两个峰的存在来清楚地证明。然而,与单独的抗衡离子和透明质酸钠的谱图相比,半胱胺透明质酸喷雾干燥微粒的谱图显示出差异。
图5:半胱胺透明质酸喷雾干燥微粒的SEM图像:
a)配方#2:2.2%半胱胺/ 87.8%透明质酸钠。
b)制剂#5:13.1%的半胱胺/ 78.2%的透明质酸钠/ 8.7%的L-亮氨酸。
c)制剂#7:13.4%的半胱胺/ 69.1%的透明质酸钠/ 17.5%的L-亮氨酸。
d)制剂#8:12.1%的半胱胺/ 70.2%的透明质酸钠/ 17.7%的L-亮氨酸。
定义
为了本发明的目的,术语“呼吸量”是指相对于要雾化的粉末量,沉积到肺中的药物量。
术语“精细颗粒剂量”(FPD)是指所输送剂量中具有空气动力学直径小于5 pm的颗粒的药物量。这些颗粒在吸入过程中能够穿透肺。术语“精细颗粒级分”(FPF)是表示为所输送剂量百分比的FPD,该百分比是离开吸入器的粉末量。
术语“中值粒径”描述了以pm为单位的粒径,其中粒径分布平均分为两个总体。为了本发明的目的,中值粒径是根据体积分布(DV50)计算的。
当称为离子交换树脂时,术语“总容量”是指每重量单位抗衡离子可以连接用于离子交换的可用位点的总数。它以毫克当量/克(meq / g)表示。
术语“肺部疾病”包括任何影响肺部的呼吸***疾病,例如囊性纤维化和COPD。
缩写词“NaHA”表示透明质酸钠,而“HA”表示透明质酸。术语“约”在涉及一个值时是指规定值正负5%,而在涉及一个范围时是指最远值正负5%。
具体实施方式
本文描述的实施例仅具有说明性目的,并不意味着限制本发明的范围。此外,对本领域技术人员显而易见的是,以下实施例的修改和变更旨在由所附权利要求书涵盖。
半胱胺透明质酸的喷雾干燥颗粒的表征
从透明质酸钠0.35MDa(#2-#6)或0.9MDa(#1)开始,已根据本发明制备了具有或不具有添加剂的半胱胺透明质酸钠的喷雾干粉(表1)。就半胱胺测定,喷雾干粉的堆积密度和粒度分布而言,使用不同分子量的透明质酸钠不会不利地影响最终产品的性能。
表1:半胱胺喷雾干粉的成分。
通过热重分析(TGA),在25°C至150°C的温度范围内评估残留水量。
通过HPLC分析,以梯度模式测定喷雾干粉中半胱胺的含量。具体地,HPLC配备了Shimadzu LC-10AT色谱仪,该色谱仪配有LC-10AS泵和SPD-10A UV-VIS光谱仪。C18柱用作固定相,而流动相由溶剂A(11.52 g十二烷基硫酸钠溶于380 ml Milli-Q级水/ 300 ml乙腈/ 320 ml甲醇和1.4 ml H3PO4 85%v / v)和溶剂B(乙腈)组成,以1.4 ml / min的流速通过梯度法混合。检测波长设定为210nm。
粉末可吸入性作为可吸入粉末的应用价值通过空气动力学直径测定来表征。
根据本发明获得的喷雾干粉的体外空气动力学评估是使用快速筛选冲击器(FSI)(英国Copley Scientific)进行的。FSI将吸入器排出的粉末分为两个空气动力学颗粒部分,即粗颗粒部分和细颗粒部分(空气动力学直径分别高于和低于5 pm)。粗馏分收集器(CFC)配备了***物,该***物能够以60 L / min的特定截留尺寸:收集所有5 pm以上的颗粒,而所有低于该尺寸的颗粒均通过。未捕获在CFC中的颗粒构成了雾化粉末的可吸入部分,并始终跟随气流。它们都被随后的细馏分收集器(FFC)捕获,例如过滤器(A / E型玻璃过滤器,直径76 mm(美国183号颇尔公司(Pall 183 Corporation, USA))。
为了测量呼吸量,将精确称量的喷雾干粉(约20 mg)手动引入3号硬质HPMC胶囊中。
将胶囊***干粉装置(RS01®,Plastiape Spa,Osnago LC,意大利)的容纳腔中并刺穿。将该装置连接至FSI,并通过气流以60 L / min的速度激活4秒钟(对应于该吸入器的压降4 kPa)。因此,通过HPLC分析定量了FFC过滤器中沉积的半胱胺的百分比与胶囊中负载的半胱氨酸的百分比,也定义为细颗粒部分(FPF)。每种粉末一式两份进行测试。
半胱胺透明质酸喷雾干燥微粒的形态表征通过扫描电子显微镜(SEM)进行。喷雾干燥的微粒既具有圆形结构,又具有小的收缩表面。特别地,当从同轴喷嘴的外孔喷射L-亮氨酸溶液时,获得海绵状微粒(图5b-图5d)。这种颗粒形状可以减少颗粒之间的接触,从而使它们在雾化方面的性能更有效。
示例
透明质酸溶液与碱反应的能力
使用溴百里酚蓝作为指示剂滴定25 ml的含有63.25 mg NaHA 0.35 MDa的透明质酸溶液,所述透明质酸溶液含有63.25mg的NaHA 0.35MDa。缓慢加入滴定剂(0.01 N NaOH溶液),直到指示剂的颜色从黄色变为蓝色(pH约为7.0)。中和HA溶液需要12.13 ml的0.01 N NaOH(即0.1213 meq);因此,平均63.25 mg的NaHA 0.35 MDa含有0.1213毫当量的HA。因此,可以与由63.25mg透明质酸钠得到的透明质酸反应的半胱胺碱(MW 77.15)的量计算如下:0.1213×77.15 =9.358mg。
溶液中半胱胺碱:透明质酸(透明质酸钠MW 0.35 MDa)的重量比为约1:7 w/w。
根据该估计的计算制备用于喷雾干燥的溶液。
半胱胺透明质酸喷雾干燥微粒的制备
示例1
在磁力搅拌下,将50mg透明质酸钠(MW 0.9 MDa)引入到装有170ml 50℃纯净水的烧瓶中。然后,考虑到Dowex Monosphere 650C(H)树脂的容量为2 meq / ml(密度为1.22 g /ml),将500 mg树脂添加到透明质酸溶液中,并在磁力搅拌下于室温放置约两个小时,直到pH值稳定(pH 3.03)。使用布氏漏斗过滤所得的含有透明质酸的溶液,并收集在200ml的容量瓶中。残留在过滤器上的树脂用10 ml的纯净水洗涤,以提取树脂和漏斗上的残留透明质酸。之后,将74mg的半胱胺碱在混合下溶解于HA烧瓶中,得到半胱胺/透明质酸的盐溶液,并用纯净水将容量瓶定容。
溶液中半胱胺碱:透明质酸(透明质酸钠MW 0.35 MDa)的重量比为约1:7 w/w。
然后将如上所公开的溶液进行喷雾干燥。喷雾干燥器(Buchi mini B-290)的操作条件确定如下:
T入口(°C)150
T出口(°C)75
吸气率(%)100
进料速度(ml / min)5
风量(L / h)600
该方法的产率为62.5%。通过HPLC分析确定喷雾干燥微粒中的药物含量。所得粉末的半胱胺含量为13.4±1.5%。在25至150℃的温度范围内通过热重量分析(TGA)执行粉末的残留水。该粉末的水含量为7.35%。
示例#3-#4-5#
根据示例#1制备包含添加剂的半胱胺透明质酸盐喷雾干燥的微粒,唯一的区别在于在添加半胱胺碱之前,将添加剂进一步添加至如上公开的获得的透明质酸溶液中。
示例#6
通过喷雾干燥根据示例#5报道的方法制备的半胱胺/透明质酸盐溶液,制备包含添加剂亮氨酸的半胱胺透明质酸盐喷雾干燥微粒。具体地,在磁力搅拌下将透明质酸钠在50℃下引入装有80ml纯水的烧瓶中。然后,将树脂加入透明质酸溶液中,并在磁力搅拌下于室温下接触约两个小时,直到pH值稳定为止。使用布氏漏斗过滤获得的含有透明质酸的溶液,并收集在100ml容量瓶中。残留在过滤器上的树脂用10 ml的纯净水洗涤,以提取树脂和漏斗上的残留透明质酸。 之后,将半胱胺碱溶解于HA烧瓶中,在混合下得到半胱胺/透明质酸的盐溶液,并用纯净水将容量瓶定容。
通过将亮氨酸用纯净水溶解在100 ml容量瓶中来制备添加剂溶液。
在喷雾干燥过程中,通过使用同轴喷嘴将添加剂溶液添加到半胱胺/透明质酸溶液中,在同轴喷嘴中,药物和添加剂的两种溶液保持分开并进行喷雾,以使从喷嘴流出的溶液流为由半胱胺/透明质酸盐溶液的内部物流(浓度为0.46%w / v)和亮氨酸溶液的外部物流(浓度为0.04%w / v)制备。
Claims (15)
1.一种制备半胱胺透明质酸盐微粒的方法,包括以下步骤:
a、溶解透明质酸钠;
b、添加离子交换树脂;
c、过滤获得的溶液;
d、添加半胱胺碱;
e、喷雾干燥获得的溶液。
2.根据权利要求1的方法,其中在步骤d中获得的溶液具有半胱胺碱:透明质酸的重量比为1:3至1:10,优选为1:5至1:8,更优选为1:7。
3.根据权利要求1的方法,其中步骤d还包括添加药学上可接受的添加剂。
4.根据权利要求1的方法,其中步骤e相对于所述喷嘴同时喷雾内部(内孔)包含半胱胺透明质酸盐的溶液和外部(外孔)包含添加剂的溶液。
5.根据权利要求3或4的方法,其中所述添加剂选自亮氨酸、海藻糖、抗坏血酸和乙酸。
6.根据权利要求5的方法,其中所述添加剂是亮氨酸。
7.一种包括半胱胺透明质酸盐的微粒。
8.根据权利要求7的微粒,具有小于5μm的平均粒径。
9.根据权利要求7的微粒,其FPF高于60%。
10.一种药物组合物,其包括根据权利要求7至9中任一项所述的微粒。
11.一种根据权利要求7至9中任一项所述的微粒在粉末吸入器中的用途。
12.一种半胱胺盐,其中所述盐是半胱胺透明质酸盐。
13.一种用作药物的透明质酸半胱胺。
14.一种用于治疗肺部疾病的半胱胺透明质酸盐。
15.一种用于治疗胱氨酸病的半胱胺透明质酸盐。
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IT1271001B (it) * | 1994-07-26 | 1997-05-26 | Poli Ind Chimica Spa | Procedimento di preparazione di acido ialuronico mediante fermentazione con streptococcus |
JP3888753B2 (ja) * | 1997-12-05 | 2007-03-07 | 帝人株式会社 | 持続性粉末状吸入用医薬品組成物 |
DE112008002398A5 (de) | 2007-09-22 | 2010-07-29 | Bayer Consumer Care Ag | Zusammensetzung mit Wirkstoffkombination aus einem Laxans und einem Entschäumer zur Behandlung von Obstipation |
US10905660B2 (en) | 2016-06-07 | 2021-02-02 | Novabiotics Limited | Microparticles |
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CN101367884A (zh) * | 2008-09-25 | 2009-02-18 | 复旦大学 | 一种半胱胺修饰的巯基化透明质酸偶合物及其制备方法和应用 |
WO2017212249A1 (en) * | 2016-06-07 | 2017-12-14 | Novabiotics Limited | Microparticles comprising a sulphur-containing compound |
WO2018083326A1 (en) * | 2016-11-07 | 2018-05-11 | Croma-Pharma Gesellschaft M.B.H. | Hydrogen sulfide releasing polymer compounds |
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DK3796888T3 (da) | 2022-03-14 |
WO2019224130A1 (en) | 2019-11-28 |
IL277933B1 (en) | 2023-10-01 |
EA202092751A1 (ru) | 2021-03-12 |
HUE058805T2 (hu) | 2022-09-28 |
CO2020013561A2 (es) | 2020-12-10 |
CN112020348B (zh) | 2024-04-12 |
MX2020012471A (es) | 2021-02-09 |
US11602509B2 (en) | 2023-03-14 |
KR102640737B1 (ko) | 2024-02-23 |
CA3094909A1 (en) | 2019-11-28 |
KR20200138782A (ko) | 2020-12-10 |
IL277933A (en) | 2020-11-30 |
JP2021523893A (ja) | 2021-09-09 |
EP3796888A1 (en) | 2021-03-31 |
UA126705C2 (uk) | 2023-01-11 |
EP3572068A1 (en) | 2019-11-27 |
ES2908829T3 (es) | 2022-05-04 |
PT3796888T (pt) | 2022-03-11 |
PL3796888T3 (pl) | 2022-05-09 |
US20210236439A1 (en) | 2021-08-05 |
LT3796888T (lt) | 2022-04-11 |
KR20230051306A (ko) | 2023-04-17 |
JP7281485B2 (ja) | 2023-05-25 |
IL277933B2 (en) | 2024-02-01 |
AU2019273612A1 (en) | 2020-10-15 |
BR112020023812A2 (pt) | 2021-02-23 |
EP3796888B1 (en) | 2022-02-16 |
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