CN110719770A - 使用透明质酸酶改性多糖填充剂和递送系统的试剂盒和方法 - Google Patents
使用透明质酸酶改性多糖填充剂和递送系统的试剂盒和方法 Download PDFInfo
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Abstract
本发明的实施方案涉及通过应用透明质酸酶改性和改变多糖填充剂和药物递送系统的试剂盒、组合物和方法。
Description
相关申请信息
本申请要求于2017年2月18日提交的美国临时申请No.62/460,756的优先权,该申请的内容通过引用并入本文。
关于联邦资助的声明
在没有联邦资助的情况下,构思并实施本发明的实施方案。
背景技术
多糖被用作化妆品填充剂以及可注射药物递送系统的组分。当将多糖作为填充剂或药物递送系统置于体内时,多糖可能在通过代谢或其他方式再吸收到体内之前存在很长一段时间。
用作填充剂的多糖具有某些性质,例如粘度、抗降解性、质地、手感、耐压性等。这些性质由衍生或分离出所述多糖的生物决定。
发明内容
本发明的实施方案促进多糖的使用,特别是当这种多糖用作填充剂和药物递送载体时。本发明的实施方案允许在体内或体外改性多糖以赋予特殊的物理和化学性质。例如但不限于,可以在体内或体外改变或改进质地、手感、耐压性、粘度等物理性质。类似地,可以改进或改变抗降解性和降解速度的化学性质。
用作填充剂或药物递送系统的多糖的物理和化学性质的改变允许保健医生在将填充剂团块(filler mass)放入体内之后或在放入体内之前改性填充剂团块。如本文所用的,术语“团块(mass)”是指多糖材料及其占据的周围空间。例如,用于化妆目的的多糖填充剂通常包括1.0至5.0%的溶液。这些溶液还可以包含其他材料以改善填充剂的流动或手感,例如包含透明质酸和麻醉剂以解决填充剂施用期间潜在的不适。麻醉剂是本领域熟知的,包括但不限于利多卡因。将这些填充剂施用于皮肤的深层。在Ghimas SPA的PCT/IB2014/060322中描述了这种类型的填充剂的实例,其全部内容通过引用并入本文。
本发明的一个实施方案涉及改变或改性保持在动物体内的包含多糖的团块的方法。所述方法包括向所述团块施用有效量的透明质酸酶的步骤。透明质酸酶可以在将团块放入体内之前或在将团块放入体内之后施用于所述团块。
该方法的一个实施方案的特征在于具有一个或多个选自D-半乳糖和3,6-脱水-L-吡喃半乳糖的糖的多糖。这些糖是琼脂糖的组分。琼脂糖用作真皮填充剂和药物递送载体。如本文所用的,“药物递送载体”包含多糖和一种或多种药物。
如本文所用的,术语“透明质酸酶”是指裂解透明质酸的β-1,4键的酶。术语透明质酸酶包括保留其酶活性的盐和衍生物。以商标(Halozyme,Inc.,圣地亚哥,加利福尼亚州)售卖的人注射用重组形式的透明质酸酶是经FDA批准的酶,并且是治疗基于透明质酸(HA)的真皮填充剂的过度矫正的超说明书使用的现行标准。透明质酸酶通过裂解葡糖胺和葡糖醛酸之间的β-1,4键来水解HA。
令人惊讶且出乎意料的是,透明质酸酶改变了多糖的形式,增加了多糖的溶解,分解团块并使其流态化。这是令人惊讶且出乎意料,因为诸如透明质酸酶的酶是底物高度特异性的。具有一个或多个选自D-半乳糖和3,6-脱水-L-吡喃半乳糖的糖的多糖(例如琼脂糖)是透明质酸酶可作用于其上的一种这样的多糖。如本文所用的,术语“有效量”是指使多糖呈现所需的流态化形式的量。所需的流态化形式是指与具有相同聚合物组成和不存在透明质酸酶的情况下水解的琼脂糖相比,更加液态化的形式。
其中团块是一种或多种药物的递送载体,透明质酸酶可用于促进多糖的去除,控制药物的递送或释放,解决团块中的硬度、颗粒状或结节问题,并使皮肤上来自药物注射的标记最小化。例如但不限于,涉及药物递送系统的本发明的一个实施方案包括保持在容器中以用于重构的多糖和透明质酸酶。重构后,将透明质酸酶注入多糖团块中以作用于多糖并使多糖处于更加流态化的状态。
如本文所用的,术语“药物”用于指用于实现生物学变化或治疗医学病症的任何化合物。可以在重构之前或在重构之后将药物掺入多糖中。药物的实例包括但不限于利多卡因和其他麻醉剂,onabotulinemtoxin A(Allergan)和其他美容剂。
本发明的另一个实施方案涉及用于实施真皮填充手术或用于施用药物的试剂盒。该试剂盒包含用于在动物体内形成团块的多糖,以及用于维持或使多糖更流态化的透明质酸酶,所述透明质酸酶用于施用至保持在体内的团块以实现改性、矫正或加速团块的再吸收。
本发明试剂盒的一个实施方案的特征在于具有一个或多个选自D-半乳糖和3,6-脱水-L-吡喃半乳糖的糖的多糖。这些糖是多糖,琼脂糖,的组分。
本发明的另一个实施方案涉及用于真皮填充剂的制剂。该制剂包含琼脂糖和透明质酸酶的反应产物。一种反应产物是新琼六糖。一种制剂包含琼脂糖和新琼六糖。将新琼六糖加入到琼脂糖中以产生具有所需质地、粘度、可注射性和抗降解性特性的真皮填充剂或药物递送载体。
在阅读在下文中简要描述的附图并研究下文的细节描述后,这些和其他特征和优点对于本领域技术人员而言将是显而易见的。
附图说明
图1示出了体现本发明的特征的试剂盒;
图2A示出了琼脂糖的结构;
图2B示出了具有本发明的特征的琼脂糖的裂解;
图3是显示HA裂解的图像;
图4是具有本发明的特征的样品的离子色谱图;
图5是具有本发明的特征的样品的另一离子色谱图。
具体实施方式
现在将详细描述关于实施真皮填充手术或用于施用药物的试剂盒的本发明的实施方案。本说明书涉及在撰写本说明书时被认为是实施本发明的最佳方式的实施方案。本领域技术人员将认识到,对最佳模式的理解可能会适时改变。本领域技术人员还将认识到,所描述的本发明的特征可以进行改变和修改,并且使得本讨论不应被视为是限制性的。
现在回到图1,示出了体现本发明的特征的试剂盒,该试剂盒通常用数字11表示。术语“试剂盒”用于表示用于实施方法的部件和组件的捆绑集合。试剂盒11包括两个小瓶,第一小瓶13和第二小瓶15,第一小瓶13含有用于在动物体内形成团块的多糖,第二小瓶15含有用于使多糖流态化的透明质酸酶,其用于施用至保持在体内的团块。第一小瓶13和第二小瓶15与用于施用多糖的装置和用于施用酶的装置(为第一注射器19和第二注射器21的形式)以及说明书23一起被捆扎或保持在包装17中。
第一小瓶13包含用于在动物或患者体内形成团块的多糖。多糖可以预先制备并且是最终准备施用的形式,或者被冻干以用水重构。第一注射器19用于抽取重构的或预制的多糖以注射至动物或患者。例如,人类个体可以使用团块来隐藏皱纹或者在显示出萎缩迹象或需要更饱满外观的身体区域填充体积。
第二小瓶15含有透明质酸酶以实现改进或加速再吸收或改变团块的流动性。透明质酸酶可以预先制备并且是最终准备施用的形式或被冻干以用水重构。第二注射器21用于抽取重构的或预制的透明质酸酶以注射到团块中。例如,在使用团块来掩盖皱纹或在显示萎缩迹象的身体区域填充体积的人个体中,个体可能希望团块具有更柔软的手感,或者团块可能表现出颗粒状或结节或者团块可能被过度注射。如本文所用的,术语“过度注射”是指对于所期望的效果而言团块看起来太大的情况。将透明质酸酶置于团块中并操纵团块以分散透明质酸酶,其中透明质酸酶可以实现多糖的改性。多糖呈现更加流态化的形式,能够更快地代谢,去除颗粒状和结节,并且呈现更软的团块和/或尺寸快速减小了的或尺寸将快速减小的团块。
本发明的实施方案促进多糖的使用,特别是当这样的多糖用作填充剂和药物递送载体时。本发明的实施方案允许多糖在体内或体外被改性以赋予特殊的物理和化学性质。也就是说,透明质酸酶可以在施用多糖之前或在施用多糖之后分布到多糖中以产生所需的质地、手感、耐压性、粘度等物理性质。类似地,可以改进或改变抗降解性和降解速度的化学性质。
用作填充剂或药物递送系统的多糖的物理和化学特征的改变允许保健医生在将填充剂团块放入体内之后或在放入体内之前改性填充剂团块。例如,在施用透明质酸酶后,团块可被流态化,以通过抽取团块来除去或最小化。团块的流态化允许团块被重新分布并有助于团块的再吸收。
现在将描述与涉及改变或改性包含保持在动物体内的多糖的团块的方法的本发明实施方案有关的试剂盒11和说明书23的使用。如果需要重构,说明书23指导使用者重构保持在第一小瓶13中的多糖和保持在第二小瓶15中的透明质酸酶。说明书23指导使用者施用保持在第一小瓶13中的多糖。说明书23进一步指导使用者将有效量的用于多糖的透明质酸酶施用至团块。透明质酸酶可以在将团块放入体内之前或在将团块放入体内之后施用于团块。可以使用一次以上的透明质酸酶应用来获得所需的团块一致性。可轻轻地捏合或操纵团块以将透明质酸酶分布在整个团块结构中。可以将流态化的团块操纵到所需位置或通过施用透明质酸酶的同一注射器抽吸除去流态化的团块。
所述方法和试剂盒的实施方案的特征在于具有一个或多个选自D-半乳糖和3,6-脱水-L-吡喃半乳糖的糖的多糖。这些糖是琼脂糖的组分。琼脂糖用真皮填充剂和药物递送载体。
该方法和试剂盒的实施方案的特征在于透明质酸酶。透明质酸酶耐受性良好,其量基于多糖的质量。这种酶的专论可从各自的制造商获得,并通过引用并入本文。
本发明的另一个实施方案涉及用于真皮填充剂的制剂。该制剂包含琼脂糖和透明质酸酶与琼脂糖的反应产物。一种反应产物是新琼六糖。一种制剂包含琼脂糖和新琼六糖。将新琼六糖加入到琼脂糖中以产生具有所需质地、粘度、可注射性和抗降解性特性的真皮填充剂或药物递送载体。
选择琼脂糖和新琼六糖的相对百分比以获得所需的质地、粘度、可注射性和抗降解性。例如但不限于,具有较高百分比的新琼六糖和较低百分比的琼脂糖的制剂可显示出较高的体内再吸收速率、较高的可注射性、较低的粘度和较光滑的质地。本发明制剂的一个实施方案包含50-99%的琼脂糖和余量的新琼六糖,另一个实施方案的特征在于75-95%的琼脂糖和余量的新琼六糖,另一个实施方案的特征在于90-99%的琼脂糖和余量的新琼六糖。
根据以下实施例,这些和其他特征将是显而易见的。
实施例
方法:首先,将纯琼脂糖暴露于重组体(透明质酸酶人注射液)和β-琼脂糖酶。液相色谱/质谱(LC/MS)用于检测寡糖的存在,寡糖是已知的琼脂糖分解产物。最后,用真皮填充剂比较透明质酸酶和β-琼脂糖酶的效果。
结果:重组体(透明质酸酶人注射液)是所谓的用于治疗透明质酸真皮填充剂的过度注射或负面副作用的金标准。透明质酸酶裂解透明质酸的β-1,4键。虽然透明质酸和琼脂糖的结构非常不同,但透明质酸酶有可能在β-1,4键处水解琼脂糖。如所预期的,β-琼脂糖酶在β-1,4糖苷键处裂解琼脂糖,产生二聚体、四聚体和六聚体新琼寡糖。在暴露于的琼脂糖样品中也观察到六聚体的存在。
结论:β-琼脂糖酶对纯琼脂糖的酶促水解产生了三种化合物,新琼二糖、新琼四糖和新琼六糖,这是β-1,4糖苷键裂解所导致的。通过酶促水解琼脂糖产生一种产物,即新琼六糖。当暴露于β-琼脂糖酶和时,在DF的酶促降解中观察到类似的结果。
如图2A所示,琼脂糖是由通过α-1,3和β-1,4糖苷键连接的、D-半乳糖和3,6-脱水-L-吡喃半乳糖的重复单元组成的线性聚合物。图2B显示β-琼脂糖酶通过在D-半乳糖(G)和3,6-脱水-L-吡喃半乳糖(A)之间的β-1,4键处裂解琼脂糖进行水解,产生一系列具有重复二糖单元的新琼寡糖1。根据裂解的位点,可以产生具有不同分子量的新琼寡糖,包括新琼二糖(324.28g/mol),新琼四糖(630.55g/mol)和新琼六糖(936.82g/mol)。
重组体(透明质酸酶人注射液)是经FDA批准的酶,并且是治疗基于透明质酸(HA)的真皮填充剂的过度矫正的超说明书使用的现行标准2-4。HA由通过β-1,3和β-1,4键连接的、N-乙酰基-D-葡糖胺和D-葡糖醛酸的重复单元组成。透明质酸酶通过裂解葡糖胺和葡糖醛酸之间的β-1,4键水解HA,产生一系列重复的二糖单元,如图3所示(图片来自:www.sigmaaldrich.com)。
实验
对照样品-0.2%琼脂糖凝胶
将琼脂糖粉末(0.2g)加入100ml水(99℃)中并在水浴中冷却至42℃。使用1000μl熔融琼脂糖(2mg)制备三个对照样品。将样品在42℃温育2小时,然后1)在4℃下以3000g离心5分钟,2)在4℃下以12000g离心5分钟或3)在90℃下加热10分钟(“杀死酶”步骤)并在4℃下以12000g离心5分钟。使用0.2μm尼龙膜过滤器过滤上清液。通过LC/MS分析所有样品以确定样品制备方法是否降解琼脂糖凝胶。此外,对所有样品进行了Molisch糖测试。
酶降解-0.2%琼脂糖凝胶
将琼脂糖凝胶(0.2%)暴露于重组体(透明质酸酶人注射液)和β-琼脂糖酶以比较酶促降解对两个样品的效果。简而言之,将(200μl-30个单位)加入到琼脂糖(200μl-0.4mg琼脂糖)中并在37℃下温育2小时。另外,将β-琼脂糖酶(5μl-5个单位)加入到琼脂糖(1000μl-2mg琼脂糖)中并在37℃下温育2小时。将样品在4℃下以12000g离心5分钟。使用0.2μm尼龙膜过滤器过滤上清液,并通过LC/MS分析。此外,对所有样品进行了Molisch糖测试。
将DF(3.5%琼脂糖)和UltraPlus XC(2.4%HA)暴露于重组体(透明质酸酶人注射液)以比较酶促降解的效果。此外,将DF暴露于β-琼脂糖酶以用于进行比较。简而言之,将酶加入到真皮填充剂中并在室温下搅拌(800rpm)6小时。表1显示了用于每个反应的真皮填充剂和酶的量。反应后,将样品在90℃下加热10分钟(“杀死酶”),然后在4℃下以10000g离心5分钟。使用0.2μm尼龙膜过滤器过滤上清液,并通过LC/MS分析。此外,对所有样品进行了Molisch糖测试。
表1
LC/MS
在配有冷却自动进样器托盘(4℃)和控温柱温箱(20℃)的Agilent1260LC/MS上进行分离,其具有2.1×100mm内径,3.5mm粒径的C18Zorbax Eclipse Plus柱(Agilent,圣克拉拉,加利福尼亚州)。样品注射量为5μL。使用梯度洗脱,流动相组成为18Ω微孔水(A)和乙腈(B),流速为0.4mL/min。梯度分布如表2所示。
表2
对于琼脂糖,MS以正电离模式操作,对于透明质酸,以负电离模式操作,碎裂电压100V。以300-2000m/z的全扫描模式记录光谱。当暴露于β-琼脂糖酶时,琼脂糖的已知降解产物新琼四糖用于确认酶活性。
实验(进行中)
酶降解-3.5%琼脂糖凝胶
将琼脂糖凝胶(3.5%)暴露于重组体(透明质酸酶人注射液)和β-琼脂糖酶以比较酶促降解的效果。简而言之,将(200μl-30个单位)加入到琼脂糖(400μl-14mg琼脂糖)中并在37℃下温育2小时。另外,将β-琼脂糖酶(30μl-30个单位)加入到琼脂糖(400μl-14mg琼脂糖)中并在37℃下温育2小时。将样品在4℃下以10000g离心5分钟。使用0.2μm尼龙膜过滤器过滤上清液,并通过LC/MS分析。此外,对所有样品进行了Molisch糖测试。
将DF(3.5%琼脂糖)和UltraPlus XC(2.4%HA)暴露于重组体(透明质酸酶人注射液)以比较酶促降解的效果。此外,也将DF暴露于β-琼脂糖酶以用于进行比较。简而言之,将酶加入到真皮填充剂中并在37℃温育48小时。表3显示了用于每个反应的真皮填充剂和酶的量。温育期后,将样品在90℃下加热10分钟(“杀死酶”),然后在4℃下以10000g离心5分钟。使用0.2μm尼龙膜过滤器过滤上清液,并通过LC/MS分析。此外,对所有样品进行了Molisch糖测试。
表3
结果
0.2%琼脂糖凝胶
进行纯琼脂糖与β-琼脂糖酶和的分析以确定酶是否水解起始材料。温育后,通过LC/MS分析样品以确定新琼寡糖的存在,从而证实酶是否产生预期的产物。新琼四糖用作参考标准物。正如预期的那样,琼脂糖/β-琼脂糖酶样品的分析产生了三种分解产物,新琼二糖,新琼四糖和新琼六糖,如图4所示。图4包括两个子图,上图是由命名为1、2和3的三个峰表示的三种产物的离子色谱图,下图由三个质谱图组成,分别对应于三种产物。另一方面,琼脂糖/样品的LC/MS分析仅显示了六糖,如图5所示。图5还包括两个子图,上图是由色谱峰表示的六糖的离子色谱图,下图是对应于六糖的质谱图。虽然结果不是定量的,但新琼四糖在琼脂糖/β-琼脂糖酶样品中产生了最高的信号。来自琼脂糖/反应的新琼六糖信号被埋在样品基质中,但是在接近仪器检测极限下使用光谱反卷积软件可观察到该信号。基于这些结果,水解琼脂糖,但是应该进行进一步的研究以确定反应速度和量。注意:所有观察结果均基于一次分析,应重复进行以确认结果。
Molisch测试是一种定性分析,用于指示样品中碳水化合物的存在。阳性结果由样品和浓酸之间的紫环指示。如果样品中不存在糖,则溶液将保持澄清。单糖的存在导致更快的反应,而二糖和多糖将导致更慢的反应时间。
Molisch测试在三个样品上进行:/β-琼脂糖酶,和/水(对照),分别包含在三个试管中。将Molisch试剂加入每个试管后,即刻地,/β-琼脂糖样品变为深紫色,样品保持不变,对照(/水)在样品和浓酸的界面处形成浅紫色环,这可能是由于酸水解。1小时后,/β-琼脂糖酶和对照保持不变,而形成浅紫色环。最后,2小时后,变成了深紫色阴影。基于这些观察结果,与相比,/β-琼脂糖酶很可能存在更少的链糖。将的结果与的结果进行了比较。19小时后,产生了阳性结果(浅紫色/粉红色)。对照(对照J)也显示出了阳性结果,这可能是由于酸水解。当使反应静置时,如用对照所观察到的,溶液可变为黄绿色。还通过LC/MS分析这些样品,得到类似的结果。
因此,已经详细描述了本发明,应理解在不背离教导的情况下,本发明的讨论内容可以进行修改和变化。因此,本发明不应限于精确的细节,而应包括所附权利要求的主题及其等同物。
Claims (16)
1.一种改变或改性包含多糖的团块的方法,所述方法包括以下步骤:
向所述团块施用有效量的透明质酸酶。
2.根据权利要求1所述的方法,其中所述多糖具有一个或多个选自D-半乳糖和3,6-脱水-L-吡喃半乳糖的糖。
3.根据权利要求1或2所述的方法,其中所述透明质酸酶是重组酶。
4.根据权利要求1-3中任一项所述的方法,其中所述多糖是琼脂糖。
5.根据权利要求1-4中任一项所述的方法,其中所述团块是真皮填充剂。
6.根据权利要求1-5中任一项所述的方法,其中所述团块是一种或多种药物的递送载体。
7.根据权利要求1-6中任一项所述的方法,其中所述透明质酸酶在体内施用于所述团块。
8.根据权利要求1-7中任一项所述的方法,其中所述透明质酸酶与所述多糖一起施用。
9.一种药物递送系统,所述药物递送系统包含保持在容器中以用于重构的多糖和透明质酸酶。
10.根据权利要求9所述的药物递送系统,其还包含药物。
11.一种用于实施真皮填充手术的试剂盒,所述试剂盒包括:
a.用于在动物体内形成团块的多糖;和
b.用于改变所述多糖的透明质酸酶,所述透明质酸酶用于与所述多糖一起施用至保持在体内的所述团块以实现对所述团块的改性。
12.根据权利要求11所述的试剂盒,其中所述多糖具有一个或多个选自D-半乳糖和3,6-脱水-L-吡喃半乳糖的糖。
13.根据权利要求11或12所述的试剂盒,其中所述透明质酸酶是重组体。
14.根据权利要求11-13中任一项所述的试剂盒,其中所述多糖是琼脂糖。
15.一种真皮填充制剂,其包含琼脂糖和新琼六糖。
16.一种实施真皮填充的方法,所述方法包括施用一定量的包含琼脂糖和新琼六糖的制剂的步骤。
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US20220098331A1 (en) | 2022-03-31 |
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