CN113164388A - 浆料和溶液组合物 - Google Patents
浆料和溶液组合物 Download PDFInfo
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- CN113164388A CN113164388A CN201980080238.0A CN201980080238A CN113164388A CN 113164388 A CN113164388 A CN 113164388A CN 201980080238 A CN201980080238 A CN 201980080238A CN 113164388 A CN113164388 A CN 113164388A
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Abstract
浆料包含液态水、按体积计约2%至约70%的冰和一种或多种影响浆料的流动性和/或张力的添加剂。用于制备浆料的溶液包含液态水和一种或多种影响浆料的流动性的添加剂。浆料的流动性相关于能够流过例如针的插管的冰粒。所述浆料适合注射至人类受试者的皮下脂肪中以去除脂肪组织。
Description
技术领域
本发明涉及可注射的浆料和溶液组合物。
背景技术
皮下脂肪的存在量不同通常与遗传和生活方式因素相关。皮下脂肪过多可能会影响健康、身体素质和外貌。在许多情况下,人们希望减少皮下脂肪,而仅通过饮食和锻炼很难做到。
例如像抽脂术这样的外科手术的皮下脂肪去除的常规方法通常是痛苦的,治疗时间长,需要去医疗机构就诊,并且可能具有长久的恢复期。特别地,传统方法可能在治疗部位引起痛苦的炎症反应和变色。
冷冻溶脂是指冷诱导的脂肪(adipose(fat))组织减少。鉴于富含脂质的细胞(例如皮下脂肪和内脏脂肪)比富含水分的细胞(例如皮肤和肌肉)对冷损伤更为敏感,对组织进行低温处理会选择性地靶向脂肪细胞,而其它细胞类型则不受影响。冷冻溶脂的这一概念已广泛用于放置在皮肤上以去除皮下脂肪从而达到美观目的的器械中。
然而,局部冷冻溶脂法存在许多局限性。治疗比选择性靶向脂肪所需要的时间更长、温度更低,因为低温需要通过皮肤扩散到下面的皮下脂肪。此外,局部冷冻溶脂法依赖于施用器,其极大地限制了可以治疗的组织学区域(即,只有可以容纳标准施用器的区域才能够进行治疗)。局部冷冻溶脂法也缺乏精确性,因为在局部应用所需的漫长的治疗时间内,寒冷不受控地扩散到了广阔的区域。因为脂肪的冷却只能通过使寒冷透过皮肤扩散到皮下脂肪来实现,所以这极大地限制了可以去除的脂肪的深度和数量。
发明内容
本发明提供一种用于制备浆料的溶液以及浆料。本发明的浆料可用于注射冷冻溶脂法以去除脂肪,选择性地靶向非脂肪细胞、富含脂质的组织和结缔组织重塑,同时避免对组织的非特异性高渗性损伤。通过使浆料具有高百分比的冰,可以增强冷冻溶脂法的效果。通过调节或调整浆料或溶液组合物的组分,例如渗透压摩尔浓度、张力、pH值和温度,可以减少或避免不希望的效果,例如在注射部位的损伤或炎症反应。
可注射的、生物相容的、无菌的冰浆提供了在各种治疗性应用中选择性冷却组织的新颖手段。浆料注射使冷却能够递送至所述注射部位。治疗性浆料的应用包括但不限于用于下述的脂肪去除:为了美容目的(例如皮下脂肪)和医学目的(例如内脏脂肪)而选择性地靶向和去除脂肪细胞或其它富含脂质的组织、刺激结缔组织重塑、阻塞性睡眠呼吸暂停和治疗学体温过低。
在对脂肪细胞的治疗中,一旦将浆料注射到例如人的受试者中,该浆料通过冷冻脂肪细胞而引起冷冻溶脂或细胞死亡。浆料中的冰百分比(称为冰系数)和浆料温度很重要,因为这些属性可产生所希望的脂肪去除效果。浆料的温度应足够冷以引起脂肪细胞死亡。然而,温度应足够温暖以避免组织泛红、起泡、组织坏死和周围组织(例如肌肉和皮肤)溃疡。例如,浆料的温度可以在约-25℃至约10℃的范围内。
在一些实施方案中,本发明是一种用于生成浆料的溶液,其包含溶剂例如(例如液态水)和一种或多种影响该浆料和由该溶液制成的浆料的张力和/或流动性的添加剂。
在一些实施方案中,本发明是一种浆料,其包含液态水,按体积计约2%至约70%的冰,以及一种或多种影响该浆料的张力和/或流动性的添加剂。
本发明的浆料可以配置为通过注射引入到例如人的受试者体内,因此其可以包含影响浆料冰粒流过输送装置(例如插管(cannula))的能力的添加剂。例如,可以考虑冰粒形状、冰粒尺寸和冰系数。通常,影响流动性的添加剂包括影响粘度的试剂。影响粘度的生物相容的试剂的实例包括:例如,纤维素(即羧甲基纤维素,羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素)、聚乙烯醇、聚乙烯吡咯烷酮、黄原胶、聚乙二醇、瓜尔豆胶、槐树豆胶、角叉菜胶、藻酸、明胶、阿拉伯胶和卡波姆。
另外,因为所述浆料可以配置为引入人类受试者,所以所述浆料包括在注射部位降低张力、减轻不利的炎症和其它作用的添加剂。张力是与重量渗透压摩尔浓度和容量渗透压摩尔浓度密切相关的特征。张力是有效渗透压梯度的量度,或者是两种溶液之间渗透压的量度。容量渗透压摩尔浓度是每体积溶液的溶质的渗透压摩尔数(Osm/L),而重量渗透压摩尔浓度是每质量溶剂中的溶质的渗透压摩尔数(Osm/kg)。容量渗透压摩尔浓度和重量渗透压摩尔浓度可以通过任何合适的方法来测量,例如通过凝固点降低(FPD)和蒸气点亏损(VPD)。当溶液具有与某些其它溶液相同的渗透压时,例如与细胞或体液具有相同的渗透压时,该溶液是等渗的。当渗透压低于特定流体时,该溶液是低渗的。类似地,当渗透压高于特定流体的时,该溶液是高渗的。当考虑用于注射到例如人的患者中的组合物和制剂时,重量渗透压摩尔浓度和容量渗透压摩尔浓度是重要的。如果重量渗透压摩尔浓度/容量渗透压摩尔浓度过高,则治疗区域可能导致组织泛红、起泡、组织坏死和溃疡。此外,皮下给药的高渗性诱导效应包括增强的部位刺激和疼痛、增强的组织通透性以及可能的组织损伤。
照此,本发明调整重量渗透压摩尔浓度,以最小化这些与浆料的注射或给药相关的不希望的作用。在一些实施方案中,浆料的重量渗透压摩尔浓度可小于约2200毫渗透压摩尔/千克。在一些实施方案中,浆料的重量渗透压摩尔浓度小于约600毫渗透压摩尔/千克。影响张力的添加剂的实例包括盐、阳离子、阴离子、多原子阳离子、多原子阴离子、糖和糖醇。影响张力的试剂(也称为渗透活性化合物)含量的提高使得能够产生小的、球形的、可注射的冰粒,这些冰粒能够穿过针而不会发生堵塞。然而,影响渗透压的试剂含量增加能够导致对组织的高渗损伤,因为一旦将它们注射到体内,浆料的高重量渗透压摩尔浓度就可以使邻近组织脱水。本发明提供了使组织很好地耐受重量渗透压摩尔浓度的组合物。
此外,浆料组合物的pH是重要的。如果浆料组合物的pH太高或太低,则受试者可能在注射部位经历疼痛。在一个实施方案中,本发明的浆料和溶液组合物的pH为约4.5至约9。
本发明的浆料和溶液可包含生物相容的成分,例如水、冰和公认为可安全用于人类的添加剂。例如,本发明的组合物还包含一种或多种添加剂,例如氯化钠,丙三醇、羧甲基纤维素钠(CMC)等。可以在冷却和浆料生产之前或过程中将添加剂加入水中。
本发明的浆料可以通过任何合适的方式给药。例如,可以通过输送装置(例如插管)注射浆料。在一些实施方案中,所述插管是针。选择针的规格尺寸时,冰的粒径是重要的。在本发明的一些实施方案中,每个冰粒的粒径小于约1mm。在某些情况下,粒径小于约0.25mm。本发明的浆料和溶液组合物适合与具有约8G至约25G规格尺寸的针一起使用。
附图说明
图1示出了本发明的溶液的属性的功能图。
图2示出了本发明的浆料的属性的功能图。
图3示出了根据本发明的一个实施方案的浆料的图像。
图4示出了根据本发明的一个实施方案的浆料的图像。
图5示出了根据本发明的一个实施方案的浆料的图像。
具体实施方式
本发明提供了一种用于制备浆料的溶液和浆料。在一个实施方案中,可以将本发明的溶液或浆料给药(例如注射)至受试者(例例如人类受试者),以去除富含脂质的组织(例如脂肪组织或脂肪)。通常,人类受试者具有脂肪沉积物,即皮肤下方和肌肉上方的皮下脂肪沉积物。内脏脂肪沉积物可能在腹部肌肉下方,并且可能包围人类受试者的器官。本发明的组合物依赖于例如流动性和张力的属性,以便实现最佳效果以及对治疗区域的最小疼痛和/或刺激。例如,本发明使得能够使用低张力溶液和浆料,因此使与高张力溶液和浆料相关的疼痛、肿胀和其它不利影响最小化。流动性是指浆料在装置或受试者体内流过的能力。例如,流动性描述了浆料在浆料生成器、用于给药的输送装置(例如插管)内或在人类患者体内的移动容易程度。流动性取决于几个因素,包括冰粒尺寸、冰粒形状(因为它们与输送装置的配置有关,例如针的规格)以及粘度。
在某些实施方案中,本发明是一种用于制备包含液态水和一种或多种添加剂的浆料的溶液。在某些实施方案中,本发明是一种浆料,其包含液态水,按体积计约2%至约70%的冰,以及一种或多种添加剂。可以选择一种或多种添加剂(及其各自的浓度)以影响给药于受试者的浆料的流动性和张力。
如图1所示,溶液的影响流动性和张力的各种属性包括容量渗透压摩尔浓度/重量渗透压摩尔浓度、粘度、pH、微粒、剪切行为以及无菌性。如图2所示浆料的影响流动性和张力的各种属性包括溶液的那些属性以及冰系数和冰粒尺寸和形态。
轮流考虑每种属性,容量渗透压摩尔浓度是每体积溶液的溶质的渗透压摩尔数(Osm/L),而重量渗透压摩尔浓度是每质量溶剂中的溶质的渗透压摩尔数(Osm/kg)。容量渗透压摩尔浓度和重量渗透压摩尔浓度可以通过任何合适的方法来测量,例如通过凝固点降低(FPD)和蒸气点亏损(VPD)。张力是与容量渗透压摩尔浓度和重量渗透压摩尔浓度密切相关的特征。张力是有效渗透压梯度的量度,或者是两种溶液之间渗透压的量度。当溶液具有与某些其它溶液相同的渗透压时,例如与细胞或体液具有相同的渗透压时,该溶液是等渗的。当渗透压低于特定流体时,该溶液为低渗溶液。类似地,当渗透压高于特定流体时,该溶液是高渗的。
溶液配制过程中需要考虑的是注射后高渗浆料的局部和全身耐受性。副作用取决于高渗程度。此外,在肌肉内注射的疼痛感通常是最严重的,其次是皮下注射以及静脉内或血管内注射。作为示例性的应用,本发明针对适合于注射到受试者的皮下脂肪中的溶液和浆料。因此,减少或最小化受试者的疼痛感和不良反应的可能性是本溶液的制剂的一个考虑因素。
通常,重量渗透压摩尔浓度大于约300mOsm/kg的溶液是高渗的。重量渗透压摩尔浓度低于约300mOsm/kg的溶液是低渗的。根据本发明,可以基于治疗方法和希望的结果来调节重量渗透压摩尔浓度。例如,对于肌肉内或皮下注射,重量渗透压摩尔浓度上限可以低于约1500mOsm/kg。虽然对于静脉内或血管内注射,通常是较小体积的注射,例如100mL或更少,但上限可以低于约2200mOsm/kg。此外,对于较大体积的注射,例如大于100mL的注射,上限可以低于约600mOsm/kg。
研究表明高渗对人类患者有影响。基于这些研究,本发明针对具有重量渗透压摩尔浓度的溶液和浆料,其将使人类受试者的炎症反应的影响最小化。例如,一项研究证明,皮下注射应小于600mOsm(Wang,2015,Tolerability of hypertonic injectables,Int.J.Pharm.,490(1-2):308-315)。研究报告了一项临床试验,该试验进行了845mOsm/L的皮下给药,其中患者在12天内每天接受1000mL,共7天(Zaloga et al.,2017,Safety andefficacy of subcutaneous parenteral nutrition in older patients:a prospectiverandomized multicenter clinical trial,JPEN J Parenter Enteral Nutr,41(7):1222-1227)。研究还报道了在5天的时间内以660mOsm/L在腹部、胸部或大腿的进行的皮下营养(Ferry et al.,1990,L’hypodermoclyse ou perfusion,Med et Hyg,48:1533-1537),以及4天内以9.4g氮,1660mOsm/L,pH 7,进行腹部皮下输注,由Kabi Pharmacia SA,Saint-Quentin-Yvelines,法国进行(Ferry et al.,1997,Comparison of subcutaneousand intravenous administration of a solution of amino acids in olderpatients,J.Am.Geriatr.Soc.,45(7):857-860)。
皮下给药的高渗诱导效应包括增强的部位刺激和疼痛、增强的组织通透性以及可能的组织损伤。照此,本发明调整了重量渗透压摩尔浓度以最小化与浆料的注射或给药相关的炎症反应(热、泛红、肿胀和疼痛)。在一些实施方案中,本发明的浆料的重量渗透压摩尔浓度可小于约2200毫渗透压摩尔/千克。在一些实施方案中,浆料的重量渗透压摩尔浓度可小于约600毫渗透压摩尔/千克。通过调整浆料和溶液组合物的重量渗透压摩尔浓度,本发明减少或最小化了与注射相关的疼痛,同时在导致脂肪组织目标细胞死亡的温度下仍然有效地提供浆料。
影响浆料粘度的添加剂可能影响浆料的流动性。影响粘度的生物相容试剂的实例包括,例如,纤维素(即羧甲基纤维素钠(CMC)、羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素)、聚乙烯醇、聚乙烯吡咯烷酮、黄原胶、聚乙二醇、瓜尔豆胶、槐树豆胶、角叉菜胶、藻酸、明胶、阿拉伯胶和卡波姆。作为实例,相对于无糖溶液,添加CMC或黄原胶可以充分增加溶液的粘度以在实质上改善流动性。
为了进一步减轻与皮下给药相关的疼痛,可以避免极限产品pH值和高缓冲液浓度,可以使用麻醉剂,可以减少注射量,或者可以选择更不痛苦的途径。在一些实施方案中,所述组合物的pH为约4.5至约9。
为了安全起见,可以使溶液和/或浆料中的微粒最小化,但是可能存在一些用以诱导成核的微粒(成核是在浆料生成过程中冰粒开始形成的初始过程)。作为实例,更多的微粒可能导致自发成核,而更少的微粒可能需要诱导成核以引发浆料的生成。
剪切行为或牛顿行为是一种影响各种浆料生成过程/过程参数(例如搅拌和泵速)以及通过插管(例如针)的表达的属性。例如,冰粒可能导致剪切增稠,而CMC可能导致剪切稀化。
无菌性是与安全相关的属性,因为所述浆料设计为用于注射到人类或非人类动物中。在一个实施方案中,所述溶液的每种成分都是无菌的。因此,所述溶液或溶液成分可以在生成浆料之前通过任何合适的已知的灭菌技术进行灭菌,例如高压灭菌和UV灭菌技术。
所述冻结温度也是溶液的属性。所述冻结温度是溶液中有冰时溶液的温度。为了产生浆料,必须将所述溶液冷却以生成冰粒。所述冻结温度可通过改变添加剂的浓度(例如盐和糖的含量)来影响。此外,所述浆料的温度是重要的属性,这是因为所述浆料需要对治疗是有效的,但对患者给药是安全的。在一些实施方案中,所述浆料温度可以在约-25℃至约10℃的范围内。
所述冰系数是测量所述浆料中冰量的浆料属性,其至少影响所述浆料的流动性和治疗的有效性。在某些实施方案中,所述浆料的冰系数为约2%至约70%。可以预期,更多的冰与每单位注射量的更高的有效性有关,然而,在保持所述浆料的流动性的情况下可以平衡冰量。图3是冰系数为25%的浆料的图像;图4是冰系数为28%的浆料的图像;图5是冰系数为22%的浆料的图像。
类似地,冰粒尺寸和形态是浆料的属性,其至少影响浆料的流动性和治疗的有效性。在优选的实施方案中,将冰粒的尺寸确定为可流过所希望的尺寸的插管。例如,所述插管可以是针,并且可以基于针的规格尺寸来确定所希望的尺寸。作为实例,约100μm的冰粒尺寸可允许通过具有约1.0mm或更小内径的针进行注射。关于冰粒的形态或形状,所述冰粒可以大体上呈圆形或球形。
在一些实施方案中,可以选择一种或多种添加剂以影响溶液或浆料的一种或多种属性。在一些实施方案中,一种或多种添加剂可具有低分子量,因此在影响某些属性的同时使对其它属性的影响最小化。例如,包括更多的添加剂可以改善流动性,并且也可以增加容量渗透压摩尔浓度而使溶液更加高渗。
在一些实施方案中,添加剂是非活性的生物相容性成分。可以将任何合适的添加剂添加到溶液或浆料中,包括FDA GRAS列表中的任何的物质/浓度,其以全部内容并入本文。
一种或多种添加剂的任何可接受的浓度可以用于本发明中,并且可以基于治疗来选择。例如,对于皮内、皮下或肌内给药途径,添加剂包括氯化钠(盐水)、甘油/丙三醇、葡萄糖、羧甲基纤维素钠、黄原胶和聚乙二醇。例如,氯化钠的可接受浓度为:用于软组织时为约0.9%,用于皮下时为约2.25%;而甘油/丙三醇的可接受浓度为:用于皮肤时为约1.6%至约2.0%,用于皮下时为约15%。此外,葡萄糖的可接受浓度为:用于肌内时为约5%w/v,用于肌内-皮下时为每单位剂量约7.5%。例如,羧甲基纤维素钠的可接受浓度为:用于病灶内时为约0.75%,用于肌内时为约3%,用于软组织时为约0.5%至约0.75%。作为另一个实例,黄原胶的可接受浓度为:用于动物研究的关节内时为约1%,用于FDA的眼药时为约0.6%。此外,聚乙二醇(例如聚乙二醇3350)的可接受浓度为:用于FDA软组织时为约2.0%至约3.0%,用于皮下时为约4.42%。
在一些实施方案中,所述盐是盐水,氯化钠(NaCl)在水中的溶液。盐水用于许多医疗应用中,可以作为水和电解质的来源而增加价值。尽管已显示盐水可产生治疗学成效,但必须注意所用的量,以免引起注射疼痛。研究表明,用2%利多卡因进行预处理可减轻与高渗盐水有关的疼痛反应,并且,经600秒肌内注射(1.0cm至2.0cm深度)4.8mL高渗的5.8%的盐水显示可产生局部疼痛和牵涉疼痛(Lei J,2012,Variation of pain and vasomotorresponses)。盐的其它实例包括钾盐、钙盐、镁盐、磷酸氢盐、碳酸氢盐。
在一些实施方案中,丙三醇是添加剂。例如,腹膜透析已作为血液透析的替代方法使用,以通过向腹膜内注入称为“透析液”的液体来帮助从体内去除毒素。研究表明,采用0.6%的氨基酸和1.4%的丙三醇进行腹膜透析对患者是安全且耐受性良好的,并且进一步证明48%的丙三醇是超适应症的硬化剂(Van Biesen,2004,A RCT with 0.6%aminoacids/1.4%peritoneal dialysis solution以及Dietzek,2007,Sclerotherapy:Introduction to Solutions and Techniques)。
在一些实施方案中,葡萄糖是添加剂。研究显示了5%的葡萄糖注射液的镇痛效果,10%的葡萄糖对伴有ACL松弛的膝关节骨关节炎的治疗学成效,5%的葡萄糖对肌筋膜疼痛综合征的治疗学成效(Maniquis-Smigel,2017,Short Term Analgesic Effects of5%Dextrose;Reeves&Hassanein 2000 and Reeves&Hassanein 2003;and Kim MY,1997)。
在一些实施方案中,用于影响粘度的添加剂包括羧甲基纤维素和黄原胶。兔子研究检验了以1%w/v进行关节内注射的方法(Guanying,2017,Low molecular weightxanthan gum for the treatment of osteoarthritis)。在另一项研究中,受试者在250-350mOsm下于1分钟内接受3.5mL安慰剂缓冲液(醋酸盐)和羧甲基纤维素钠(Na CMC 7mg/mL)的皮下注射。报告了疼痛,但未报告坏死(Dias C,Tolerability High VolumeSubcutaneous Injections,2015)。此外,CMC用作多糖皮肤填充剂的关键成分,浓度为20-45mg/mL(Falcone SJ,Novel Synthetic Dermal Fillers based on sodiumcarboxymethylcellulose,2007)。
在一些实施方案中,添加剂可包含缓冲剂以稳定pH。在一些实施方案中,添加剂可包含乳化剂以产生光滑的质地。在一些实施方案中,添加剂可包含纳米颗粒,例如TiO2。所述溶液中较小尺寸的颗粒可能会增加成核位点的数量,因此能够产生较小的冰粒。在一些实施方案中,添加剂可以包含配置为用于冰粒的涂层的试剂,其可以防止在冰粒形成期间和之后的附聚。在一些实施方案中,添加剂可包含:IVF合成胶体,其量为在约0.9%氯化钠中含有约6.0%羟乙基纤维素;泊洛沙姆188,其皮下量为约0.2%;丙二醇,其量为约0.47%至约1.4%;苄醇,其量为约0.9%至约1.4%;明胶,其量为约16%;以及艾考糊精(常用于腹膜透析),其量为约7.5%。
一种或多种添加剂影响所述溶液和浆料的容量渗透压摩尔浓度。在某些实施方案中,浆料和溶液组合物的容量渗透压摩尔浓度低于约2200mOsm/L。在一些实施方案中,容量渗透压摩尔浓度小于约600mOsm/L。在这样的实施方案中,所述浆料可以包含:约0.9%的盐水、约1.0%至约2.0%的葡萄糖、约1.0%至约1.6%的丙三醇、小于约0.5%的羧甲基纤维素钠以及小于约0.6%的黄原胶。在一个实施方案中,所述浆料组合物可以为约500mOsm/kg至约700mOsm/kg,并且包含约0.9%至约1.4%的盐水、约2.0%至约4.0%的葡萄糖、约1.7%至约2.0%的丙三醇、约0.6%至约1.0%的羧甲基纤维素钠以及约0.6%至约1.0%的黄原胶。在另一个实施方案中,所述浆料组合物可以为约700mOsm/kg至约900mOsm/kg,并且包含约1.5%至约1.7%的盐水、约5.0%至约7.5%的葡萄糖、约3.0%至约5.0%的丙三醇、约1.0%至约3.0%的羧甲基纤维素钠以及约1.0%的黄原胶。在一些实施方案中,所述浆料组合物可以大于约1000mOsm/kg。在这样的实施方案中,所述浆料可包含:约1.8%至约3.0%的盐水、约10%的葡萄糖、大于约5.0%的丙三醇、羧甲基纤维素钠以及黄原胶。
在一些实施方案中,添加剂包含盐、糖和增稠剂中的一种或多种。在一个实施方案中,所述盐是按质量计约2.25%或更低的NaCl。在一个实施方案中,所述糖是按质量计约2%或更低的丙三醇。在一个实施方案中,所述增稠剂是按质量计约0.75%或更低的羧甲基纤维素或黄原胶。
在一些实施方案中,所述浆料可以具有小于约2200mOsm/kg或更低的重量渗透压摩尔浓度,约-25℃至约10℃的温度范围,约2%至约70%的冰系数,并且可以穿过具有约8G至约25G的规格大小的针,以选择性地靶向和去除脂肪组织。在一些实施方案中,所述浆料可以具有小于约600mOsm/kg的重量渗透压摩尔浓度,在约-6℃至约0℃的温度范围内,并且能够穿过最小直径为约8-25G规格尺寸的针,以选择性地靶向和去除脂肪组织。
当考虑本发明的溶液和浆料时,例如重量渗透压摩尔浓度/容量渗透压摩尔浓度、粘度、pH、微粒、剪切行为、无菌性、冰系数、冰尺寸和冰形态的性质会基于所选择的添加剂(及其各自的用量)而受到影响,并且一个或多个属性可能会受到影响,而一个或多个其它属性仍不受影响。
可以使用美国临时专利申请62/743,830号和美国临时专利申请62/743,908号中公开的任何系统和方法从溶液中产生浆料,这两个文献均通过引用整体并入本文。可以使用美国临时专利申请序列号62/741,286中公开的任何方法将浆料用于治疗受试者,该文献通过引用整体并入本文。
实施例
实施例1:浆料
在该实施例中,所述浆料包含无菌水基溶液,其含有用于冰点降低、确保球状冰粒形状、适当的流体动力学和粘度的下述添加剂:氯化钠、丙三醇以及羧甲基纤维素钠(CMC)。选择所述添加剂的原因是它们的安全性和耐受性,并且所有浓度均大大低于FDA GRAS清单中包含的市售批准产品,对于皮下注射,剂量限制为:2.25%的氯化钠、2%的丙三醇以及0.75%的羧甲基纤维素钠。表1总结了示例性的浆料添加剂。
表1:溶液/浆料添加剂
实施例2:兔子模型
进行了一项兔子研究,以鉴别无菌赋形剂溶液的逐渐浓缩或稀释的变体的安全性和耐受性极限。羧甲基纤维素的浓度保持恒定,而羧甲基纤维素影响溶解度的水平上升。羧甲基纤维素不影响冰点降低或冰粒的几何形状,它们是制备可注射浆料的两个关键参数。
在研究中使用每只体重为3-4kg的成年新西兰白兔(Oryctolagus cuniculus),向肩胛内脂肪垫注射3.6mL候选浆料。对于多个部位的人类治疗可包含在每个部位注射30mL的浆料。例如,人类治疗可包含:每次治疗四个部位,每次治疗总共需要120mL。为了对应于60kg人体参考体重的120mL治疗,为1.8kg兔子选择了3.6mL注射。研究的主要终点是通过全身摄影和组织学成像观察到的不良反应发生率。还获得了血液样品和身体状况评分(BCS)。
将具有表2中列出的重量渗透压摩尔浓度的溶液注射入肩胛内间隙进入到脂肪垫。如表2所示,将八种不同的溶液,每种溶液具有不同的重量渗透压摩尔浓度,分别注射入兔子体内。每种溶液代表测试溶液的稀释液或浓缩液,且每种溶液都逐渐变得高渗。
表2:测试组中使用的溶液的重量渗透压摩尔浓度
考虑到其出色的灵敏度和在评估刺激性潜力方面的常规用途,选择了兔子模型。兔子是测试急性皮肤刺激的推荐模型。先前对猪和啮齿动物模型的研究表明了超过1400mOsm/L溶液的安全性和耐受性。
每只兔子在肩胛内脂肪垫中接受3.6mL测试溶液的皮下注射,以模拟可在人类测试的三个部位中的每一个部位使用的浆料快速浓注。在3-4kg兔子中注射3.6mL相当于在60kg成年人中注射54-72mL,这足以模拟体重、血液测试和BCS的任何全身性影响变化的总注射量。
以剂量递增设计进行注射。所有动物都很好地耐受了该程序,当它们返回笼子时,很快(在5-10分钟之内)恢复了正常行为。完成时(初次注射后90分钟),未观察到立即的不良反应。注射后24小时在第6组和第7组中观察到短暂性轻度瘀伤和红斑,注射48小时后症状消失。在第8组中观察到轻度红斑,并且红斑一直持续到注射后一周的牺牲时间。这项工作表明,重量渗透压摩尔浓度约为2200mOsm/kg或更低的溶液具有良好的耐受性,并且可能适合用作可注射的浆料。
参考物引用
在整个本公开中,参考以及引用了其它文件,例如专利、专利申请、专利出版物、期刊、书籍、论文、网页内容。出于所有目的,所有这些文件据此以全文引用的方式并入本文。
等同物
在不脱离本发明的精神或基本特征的情况下,本发明可以以其它特定形式实施。因此,应认为前述实施方案在所有方面都是说明性的,而不是对本文所述发明的限制。因此,本发明的范围由所附权利要求而不是由前述描述限定,并且因此意图将落入权利要求的等同物的含义和范围内的所有改变包含在其中。
Claims (34)
1.一种浆料,其包含:
液态水;
按体积计约2%至约70%的冰;以及
一种或多种影响浆料的流动性和/或张力的添加剂。
2.根据权利要求1所述的浆料,其中,所述浆料的流动性使冰粒能够流过插管。
3.根据权利要求2所述的浆料,其中,所述插管是针。
4.根据权利要求3所述的浆料,其中,所述针的规格尺寸为约8G至约25G。
5.根据权利要求1所述的浆料,其中,所述浆料配置为引入患者体内。
6.根据权利要求1所述的浆料,其中,所述浆料的重量渗透压摩尔浓度小于约2200毫渗透压摩尔/千克。
7.根据权利要求1所述的浆料,其中,所述浆料的重量渗透压摩尔浓度小于约600毫渗透压摩尔/千克。
8.根据权利要求1所述的浆料,其中,所述浆料的温度为约-25℃至约10℃。
9.根据权利要求1所述的浆料,其中,所述浆料的温度为约-6℃至约0℃。
10.根据权利要求1所述的浆料,其中,所述浆料的pH为约4.5至约9。
11.根据权利要求1所述的浆料,其中,所述冰的粒径小于约1mm。
12.根据权利要求11所述的浆料,其中,所述冰的粒径小于约0.25mm。
13.根据权利要求1所述的浆料,其中,所述冰具有大体上呈圆形的颗粒形状。
14.根据权利要求1所述的浆料,其中,所述一种或多种添加剂包含氯化钠、丙三醇、羧甲基纤维素钠(CMC)、葡萄糖、黄原胶、甘油、聚乙二醇、纤维素、聚乙烯醇、聚乙烯吡咯烷酮、瓜尔豆胶、槐树豆胶、角叉菜胶、藻酸、明胶、阿拉伯胶和卡波姆中的至少一种。
15.根据权利要求1所述的浆料,其中,所述一种或多种添加剂包含盐。
16.根据权利要求15所述的浆料,其中,其进一步包含糖。
17.根据权利要求16所述的浆料,其中,其进一步包含增稠剂。
18.一种用于制备浆料的溶液,其包含:液态水;和一种或多种影响浆料的流动性和/或张力的添加剂。
19.根据权利要求18所述的溶液,其中,所述浆料的流动性使冰粒能够流过插管。
20.根据权利要求18所述的溶液,其中,所述插管是针。
21.根据权利要求20所述的溶液,其中,所述针的规格尺寸为约8G至约25G。
22.根据权利要求18所述的溶液,其中,所述浆料配置为引入患者体内。
23.根据权利要求18所述的溶液,其中,所述浆料的重量渗透压摩尔浓度小于约2200毫渗透压摩尔/千克。
24.根据权利要求23所述的溶液,其中,所述浆料的重量渗透压摩尔浓度小于约600毫渗透压摩尔/千克。
25.根据权利要求18所述的溶液,其中,所述浆料的温度为约-25℃至约10℃。
26.根据权利要求25所述的溶液,其中,所述浆料的温度为约-6℃至约0℃。
27.根据权利要求18所述的溶液,其中,所述浆料的pH为约4.5至约9。
28.根据权利要求19所述的溶液,其中,所述冰的粒径小于约1mm。
29.根据权利要求28所述的溶液,其中,所述冰的粒径小于约0.25mm。
30.根据权利要求19所述的浆料,其中,所述冰具有大体上呈圆形的颗粒形状。
31.根据权利要求18所述的溶液,其中一种或多种添加剂包含氯化钠、丙三醇、羧甲基纤维素钠(CMC)、葡萄糖、黄原胶、甘油、聚乙二醇、纤维素、聚乙烯醇、聚乙烯吡咯烷酮、瓜尔豆胶,槐树豆胶、角叉菜胶、藻酸、明胶、阿拉伯胶和卡波姆中的至少一种。
32.根据权利要求18所述的溶液,其中,所述一种或多种添加剂包含盐。
33.根据权利要求32所述的溶液,其中,其进一步包含糖。
34.根据权利要求33所述的溶液,其中,其进一步包含增稠剂。
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