CN113908124A - 油性组合物 - Google Patents
油性组合物 Download PDFInfo
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- CN113908124A CN113908124A CN202111112447.4A CN202111112447A CN113908124A CN 113908124 A CN113908124 A CN 113908124A CN 202111112447 A CN202111112447 A CN 202111112447A CN 113908124 A CN113908124 A CN 113908124A
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- particles
- lipiodol
- beads
- emulsion
- oil
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Abstract
本发明提供油或乳液制剂形式的包含栓塞颗粒的药物组合物,所述栓塞颗粒任选地包含药物活性物质,所述药物组合物可用于治疗性栓塞术,尤其是用于治疗血管性肿瘤,诸如肝癌。
Description
本申请是申请号为201480050868.0的申请的分案申请。
本发明涉及治疗性栓塞领域,尤其涉及用于执行经导管动脉化疗栓塞(TACE)的材料和方法。
治疗性栓塞是一种微创技术,其中将通往某组织区域的血流在物理上通过部分或完全阻断供养该组织的血管而受到限制,从而导致局部组织坏死。该技术已证实可用于治疗血管肿瘤和纤维瘤,并且既已使用了液体也已使用了栓塞剂。TACE是这种方法的一种改良,其涉及与栓塞剂一起局部递送化疗剂,其中一般通过将药物掺入栓塞制剂中。该方法已用于治疗不能切除的富血管性肝肿瘤,诸如肝细胞癌(HCC),和某些其它肝转移,包括转移性结直肠癌(mCRC)和神经内分泌肿瘤。
(Lipiodol Ultra Fluide)是罂粟籽油脂肪酸的碘化乙酯,其用作放射造影剂,但目前还与化疗剂联合用于TACE(Lipiodol是Guerbet S.A.France的商标)。当用于TACE时,通过以下方式制备栓塞剂:将一种或多种化疗剂(诸如多柔比星或顺铂)的溶液与Lipiodol用力混合以形成乳液,然后将乳液引入由导管提供给组织的容器。该方法称为传统TACE(cTACE)。当用于治疗HCC时,将Lipiodol乳液引入为恶性肿瘤供血的肝动脉分支。该药剂通过穿过为肿瘤供血的两个***之间的胆管周围血管丛或跨过血窦,不仅能够栓塞为肿瘤供血的肝小动脉,还能栓塞门静脉小静脉。这导致增加的缺血和瘤内药物递送,然而,由于是液体,Lipiodol的栓塞作用相对较弱。cTACE也可与栓塞剂(例如,蛋白质泡沫颗粒或永久性微球栓塞剂)结合使用,该栓塞剂在乳化后递送,从而减少Lipiodol乳液和药物的洗出。
由Lipiodol和水性药物制备的乳液是动态的,从而导致在手术期间注射的产品组成存在波动。一旦施用后,乳液完整性降低,乳液所含的药物快速释放,从而导致大量的全身性暴露。
各种材料的栓塞颗粒最近已变得广泛用于温和栓塞术和TACE术,从而可能提供更持久的栓塞作用和在更长的时间段更好的标准化药物递送。平均直径通常在40至1200uM范围内的聚合物微珠是一种这样的材料。它们通过包含化疗剂而适于TACE,该化疗剂在数小时或数天的时间段中缓慢释放。该方法称为药物洗脱珠粒-TACE或DEB-TACE,并且还已用于治疗HCC,但由于其尺寸,栓塞颗粒通常不能进入肝门静脉小静脉,因此无法进入一定比例的肿瘤循环。
当递送栓塞剂时,通常通过注射不透射线的成像剂(通常为碘化化合物)来观察血管,并且这些成像剂可与栓塞剂同时递送以便有助于放置栓塞剂并告知栓塞剂的最终位置。然而,此类组合物被快速洗出血管床,而不能帮助栓塞。此外,由于这些药剂与珠粒之间物理性质的差异,两种组分不一定停留在组织中的相同位置。这连同随着时间推移而被洗出的趋势导致在确定栓塞颗粒的位置时精度不够。WO2006/119968公开了栓塞颗粒与此类成像剂的组合,并列出了常用的药剂。
为微珠加载化疗剂可能是耗时的,并且方案可能需要珠粒与治疗剂接触60分钟到数小时之间的时间。因此,从业者通常制备超出需要的制剂,以免停止手术来制备另外的栓塞剂的需要。已经作出了努力来提供预加载的珠粒,然而,这不是那么灵活,而需要储备大量的珠粒-药物组合。
不透射线的珠粒已通过将Lipiodol掺入珠粒中而制备,以便能够通过X射线观察珠粒(EP1810698)。Sharma等(J Vasc Interv Radiol 2010;21:865-876)例如公开了载有Lipiodol的PVA-AMPS水凝胶珠粒(LC-Biocompatibles UK Ltd)的制备,并且Dreher等(J Vasc Interv.Radiol.2012;23:257-264)公开了载有Lipiodol和多柔比星的PVA-AMPS水凝胶珠粒(DC或LC-Biocompatibles UK Ltd)的制备,以用于TACE。
Lipiodol乳液制剂在TACE中的使用仍然流行。仍然需要用于TACE的制剂,该制剂提供可预测的药代动力学,提供良好的栓塞程度,长时间向组织递送药物,在使用点的制备简单而快速,需要的组分数量最少,提供栓塞门静脉的可能性,提供放射学反馈,并且可靠地稳定足够的时间。
本发明人已令人惊讶地确定:可通过将栓塞颗粒掺入组合物中而简单快速地制备用于TACE的具有改善的特性的乳液。该制剂可容易地在使用点制备,无需另外的特殊制备设备,且具有良好的稳定性。该制剂另外的优点在于:具有为供养肿瘤的动脉和门静脉均提供栓塞的潜力,降低药物体循环的暴露量,以及提供更能预测的药代动力学和改善的局部递送。此外,吸收Lipiodol的微颗粒仍不透射线,因此可原位观察。
本发明因此提供包含Lipiodol和一个或多个栓塞颗粒的药物组合物,其呈水性乳液或油制剂的形式。本发明还提供:用于治疗方法的此类组合物,使用该组合物栓塞组织和***及超血管化病症的方法,以及用于该组合物的制备的方法、试剂盒和装置。
通常,此类组合物中的颗粒包含药物活性物质,但不含活性物质的组合物也可用于被动(温和)栓塞术。
用于制备乳液的栓塞颗粒可为用于栓塞术的任何类型,但可向其中载入药物活性物质并且药物活性物质在生理条件下可从中洗脱的那些颗粒是优选的。其中的材料在加载和/或生理条件(诸如pH 7.4)下带负电荷或正电荷的颗粒是优选的,因为该电荷至少部分地导致离子相互作用,这些作用隔离带电的治疗剂,并因此改善保持和洗脱性质。在一个实施方案中,颗粒在性质上为亲水的(也就是说,它们能够容易地与水溶液混合,而不排斥水)。
聚合物颗粒是优选的,因为这使得能够更好地控制颗粒的性质,尤其是当聚合物为合成聚合物时(即,不是天然存在的聚合物,诸如蛋白质)。
许多类型的聚合物可用于制备栓塞微球,此类聚合物包括:聚丙交酯、聚乙交酯和这些酯的共聚物,诸如聚丙交酯-乙交酯共聚物;丙烯酸酯及丙烯酰胺、乙烯醇聚合物和共聚物,诸如由基于丙烯酸、丙烯酰胺及丙烯酸酯的单体制备的那些;聚己内酯、聚戊内酯、聚酸酐、聚乙二醇(PEG)和PEG的共聚物,诸如由丙烯酸酯和丙烯酰胺制备的那些(例如,PEG甲醚甲基丙烯酸酯和PEG双丙烯酰胺);聚氧乙烯,包括酰基聚氧乙烯及其共聚物,吡咯烷酮及乙烯基吡咯烷酮和多糖,诸如藻酸盐、葡聚糖和硫酸葡聚糖。
具有游离磺酸根、羧酸根、羟基和/或胺基团的聚合物是优选的,以便提供上述带电性质。水凝胶聚合物是尤其优选的。优选的聚合物的实例包括含有聚乙烯醇(PVA)、PVA共聚物、PEG聚合物和共聚物以及丙烯酸、丙烯酰胺和丙烯酸酯的聚合物和共聚物的那些。聚合物可以为共价、离子或物理交联的。优选的是,聚合物为可水溶胀的但不溶于水。水凝胶已提供了良好的结果。
具体地讲,包含以下聚合物的颗粒是优选的:PVA、PVA共聚物或其交联形式(诸如在WO2004071495、US 8,226,926中所公开的交联PVA-AMPS,以及PVA-丙烯酸酯共聚物和交联PVA-丙烯酸酯共聚物),含N-三-羟甲基甲基丙烯酰胺单体、二乙基氨乙基丙烯酰胺单体或N,N-亚甲基-双丙烯酰胺单体的共聚物。
微珠形式的颗粒通常是优选的,因为它们主要呈球形可导致良好的流动性和易处理性。
可以使用适于栓塞疗法的任何粒度。由于优选的是,颗粒不穿过毛细血管床到达肿瘤之外的静脉***,和肺,因此至少15微米的颗粒是优选的。一般来讲,提供一定范围的尺寸,例如,可以使用15至1200微米的颗粒,并且制剂通常提供适于计划治疗的尺寸范围内的颗粒,例如100-300、300-500、500-700或700-900微米。较小的颗粒往往进入血管床中较深,因此对于一些目的,在诸如15-35、30-60、40-90或70-150微米范围内的颗粒是优选的。在15至100或15至150微米范围内的颗粒是尤其优选的。如果颗粒以尺寸范围提及,则这意味着除非另外规定,否则该范围涵盖制剂中至少80%,优选90%的颗粒。
可以提供预加载有一种或多种药物活性物质的颗粒。在一种有利的方法中,提供干燥的栓塞颗粒,并可提供具有或不具有预加载的药物活性物质的栓塞颗粒。
本发明还设想了为栓塞颗粒提供另外的功能,诸如不透射线,或掺入放射性核素,或可转化成放射性核素的元素以用于放射疗法目的。
通常,组合物中颗粒与Lipiodol的比率将介于1∶100与1∶1之间,优选1∶20至1∶1之间,更优选地介于1∶10或1∶5与1∶1vol/vol之间。然而,在实践中,由于将被颗粒吸收的Lipiodol的体积,较低的范围将为1∶2,尤其是在使用干燥颗粒的情况下。除非另外指明,否则体积是指在生理盐水(1mM磷酸钠pH7.2-7.4,0.9%NaCl)中完全水化的颗粒的填充体积(诸如可使用量筒进行测量),并呈实心颗粒;其不包括内部空间。
颗粒可以干燥的形式提供。在一个优选的实施方案中,在存在一种或多种冻干保护剂的情况下对颗粒进行干燥。这有助于在干燥时保持颗粒的结构。合适的冻干保护剂包括药学上可接受的水溶性多羟基化合物,诸如多元醇,以及单糖、二糖和多糖。例如,可以使用蔗糖、葡萄糖、右旋糖和海藻糖;甘露糖醇已提供了良好的结果。冻干保护剂在移除结构水可能损害颗粒结构的情况下是尤其有用的,例如,就通过水凝胶制备的颗粒而言。以这种方式处理的颗粒具有改善的载药特性。
虽然本发明根据提供特定优势(诸如由于掺入的碘而不透射线)的Lipiodol的用途进行描述,但是也可以使用其它油。水溶性脂质,尤其是单、二和三甘油酯及其游离脂肪酸和氢化衍生物及酯和/或卤化(例如,碘化或溴化)衍生物因其容易代谢的潜力而是优选的,例如罂粟籽油、蓖麻油、玉米油、棉籽油、橄榄油、花生油、薄荷油、红花油、芝麻油、大豆油及其游离脂肪酸(诸如亚油酸、油酸、棕榈酸和硬脂酸)、其氢化产物和/或酯和/或其卤化(例如,碘化或溴化)衍生物。在实践中,此类油应优选地为在药学上可被注射途径接受的。衍生自已知有可能引起过敏反应的物质的油(诸如花生油和芝麻油)因可能在油中留下痕量过敏原而应当避免,甚至在经历了移除过敏原的工序的制剂中。
在本文将栓塞颗粒描述为包含诸如Lipiodol的油的情况下,油存在于整个颗粒中。就Lipiodol和其它卤化油而言,优选的是达到颗粒不透至少500亨斯菲尔德单位(Houndsfield Unit,HU),更优选地至少1000HU的射线的程度。通常,此类颗粒不透至少2000HU的射线,如通过微CT(阳极工作电压64kv,电流155μA,铝滤光片(500μm))所测量。
本发明的组合物在包含一种或多种药物活性物质时是尤其有利的,所述药物活性物质可存在于颗粒、油和/或水相中。存在油、水和颗粒相提供了将不同类型的药物掺入每一者中的机会,例如,本发明设想了提供油相包含疏水性药物(其可以为固体形式或溶于油中)而水相包含亲水性药物(其可以为固体形式或溶于水相中)的乳液。本发明还设想了在颗粒和水相中提供不同的亲水性药物。
抗肿瘤或抗血管生成药物是优选的。尤其是喜树碱(诸如伊立替康)、蒽环类(诸如多柔比星)、含铂药物(诸如螺铂、顺铂、米铂或卡铂)、抗代谢药(诸如胸苷酸合成酶抑制剂,诸如5-FU)、激酶抑制剂(诸如VEGFR和EGFR抑制剂,例如舒尼替尼、索拉非尼和凡德他尼)、有丝***毒物(诸如紫杉烷类,例如紫杉醇或多西他赛;或长春花生物碱,例如长春碱和长春新碱以及合成形式,诸如长春瑞滨)、芳香酶抑制剂(诸如阿那曲唑)、17α-羟化酶/C17,20裂解酶抑制剂(CYP17A1)(例如,阿比特龙或其醋酸酯前药)、抗叶酸类(诸如甲氨蝶呤)、激素受体拮抗剂(诸如他莫昔芬和地加瑞克)或激动剂(诸如布舍瑞林)、烷基化剂(诸如苯丁酸氮芥、白消安、链脲霉素、洛莫司汀和环磷酰胺)、类视色素活化剂(诸如贝沙罗汀)。
如果颗粒在加载条件下具有电荷,则优选的是,药物在相同的条件下携带相反的电荷,以便促进药物的加载。尤其优选的是用于TACE的药物。
设想的药物包括
放线菌素D、阿比特龙或其醋酸酯前药、阿地白介素、阿利维A酸、别嘌呤醇、六甲蜜胺、氨磷汀、氨鲁米特、两性霉素B、安吖啶、阿那曲唑、安丝菌素、***糖腺嘌呤、苯达莫司汀、苯甲酰胺、贝沙罗汀、博莱霉素、3-溴丙酮酸、布舍瑞林、白消安、卡鲁睾、卡培他滨、卡铂、苯丁酸氮芥、卡铂、顺铂、米铂、螺铂、卡折来新、卡莫司汀、塞来考昔、苯丁酸氮芥、克拉屈滨、环磷酰胺、阿糖胞苷、氟达拉滨、达卡巴嗪、多柔比星、柔红霉素、表柔比星、伊达比星、地尼白介素、***、屈他雄酮、地加瑞克、埃罗替尼、吉非替尼、伊马替尼、拉帕替尼、舒尼替尼、索拉非尼、雌莫司汀、依托泊苷、依西美坦、非格司亭和聚乙二醇化衍生物、5-FU、氟尿苷、氟他胺、氟维司群、demcitabine、吉西他滨、醋酸戈舍瑞林、羟基脲、伊达比星、异环磷酰胺、干扰素、伊立替康、拓扑替康、兰瑞肽、雷利度胺、来曲唑、甲酰四氢叶酸、醋酸亮丙瑞林、亮丙瑞林、洛莫司汀、meciorthamine、甲地孕酮、美法仑、巯嘌呤、巯基多聚赖氨酸、甲氨蝶呤、培美曲塞、雷替曲塞、甲氧沙林、光辉霉素、丝裂霉素、米托坦、米托蒽醌、苯丙酸诺龙、奥曲肽、奥普瑞白介素、奥沙利铂、紫杉醇、帕米膦酸钠、喷司他丁、胍血生、普卡霉素、卟吩姆钠、丙卡巴肼、奎纳克林、雷替曲塞、链脲霉素、他莫昔芬、优福定、替莫唑胺、替尼泊苷、睾内酯、硫鸟嘌呤、噻替派、拓扑替康、托瑞米芬、苏消安、维甲酸、曲洛司坦、曲普瑞林、戊柔比星、凡德他尼、长春碱、长春新碱、长春地辛、长春瑞滨、唑来膦酸。
多柔比星、伊达比星、丝裂霉素、米托蒽醌、表柔比星、柔红霉素、伊立替康、拓扑替康、舒尼替尼、凡德他尼、米铂和索拉非尼是尤其优选的。
活性物质通常将以治疗有效量使用,也就是说,以足以在所治疗的病症中提供治疗效果的量。
为了制备本发明的乳液,使包含栓塞颗粒、Lipiodol和水相的组合物乳化。
本发明的又一个方面因此提供用于制备药物乳液的方法,该方法包括:提供多个栓塞颗粒、Lipiodol和水相,并使它们乳化以提供乳液。
可以提供具有或不具有预加载的活性物质的颗粒。通常,水相包括药物活性物质的水溶液,但活性物质可以不是必需的,例如,当提供预加载有活性物质的颗粒时,或在活性物质存在于油相中的情况下。在一个有利的实施方案中,首先使优选地不预加载活性物质的栓塞颗粒与Lipiodol接触,再使颗粒-lipiodol或水化的颗粒-Lipiodol混合物与包含药物活性物质的水性组合物接触,并将组合物用力混合以提供乳液。这种方法导致将活性物质快速加载到颗粒中。如果在用力混合混合物之前使活性物质进入颗粒,优选地通过温和搅拌(即,不形成乳液),则颗粒的加载将得到改善。据信,这是因为用力混合导致活性物质远离颗粒螯合在乳液中。颗粒可以干燥的或水合的形式提供。
本发明因此还提供了用于制备药物乳液的方法,该方法包括以下步骤:
a)提供多个栓塞颗粒;
b)使栓塞颗粒与Lipiodol接触以形成Lipiodol:栓塞颗粒混合物;
c)将Lipiodol:栓塞颗粒混合物用水性组合物(通常包含药物活性物质)乳化以提供优选稳定的乳液。
如果制剂保持稳定足够的时间以供医生递送,则它们是足够稳定的。在此背景下,优选的是,当在直立注射器或量筒中测量时,不超过25%的油相在2分钟内分离出来。在更稳定的制剂中,这种分离在3、4、5、10或更多分钟内发生。
使颗粒:Lipiodol组合物与药物活性物质的溶液接触导致活性物质极快地吸收到颗粒中,其提供下文所述的本发明的又一个方面。使用干燥的栓塞颗粒是优选的,因为它们更易吸收Lipiodol。以此方式制备的颗粒同时包含药物和Lipiodol,并具有可易于在体内观察的额外优点。
在使用干燥颗粒的情况下,通常的是,至少最初使Lipiodol:颗粒混合物与足够体积的药物活性物质的水溶液接触以使干燥颗粒至少部分地再水化。完全再水化颗粒所需的溶液体积易于通过以下方式用显微镜测定:连续添加溶液的等分试样,直到未观察到进一步的形状变化(注意,颗粒可能不完全回到其原始形状)或颗粒未进一步吸收溶液时。在水溶液体积足以使颗粒至少部分地再水化但未形成乳液的情况下,所得的油性组合物包含含有lipiodol、水和活性物质的栓塞颗粒,并且还提供以非乳化Lipiodol组合物递送药物的有利方法。该方法提供了在下文进一步讨论的本发明的又一个方面。然而,为了提供稳定的乳液,向Lipiodol:颗粒混合物添加比再水化干燥颗粒所需的更多的过量水相。
优选的乳液为油包水类型的;对于这种结构,油内的水相在离开导管时不与血液接触。这避免水滴立即分散在血液中进而导致药物分散入循环中。乳液中Lipiodol与水相的比率应大于1∶1vol/vol Lipiodol:水相,即,乳液中Lipiodol的比例应超过水相的比例。优选地,该比率介于1.1∶1与3∶1或2∶1之间。尤其是范围10∶9至10∶5或10∶4,尤其是10∶8至10∶6。
应当注意的是,在颗粒水化的情况下,颗粒内的水贡献水相。本文讨论的诸如交联PVA-AMPS颗粒的水凝胶颗粒的水含量可以极高,因此当此类颗粒以干燥状态使用时,所添加的相当高比例的水相有助于颗粒的再水化。因此,用在制备乳液的任何配方中的水相的量取决于颗粒是以水化还是以干燥状态提供、取决于颗粒吸收的水相的体积和所用的颗粒的量,并将根据具体情况确定。
在一些实施方案中,可能有利的是,匹配各个组分(油、水和/或颗粒)的比重以便改善组合物的稳定性。在一些实施方案中,使油相的比重与颗粒的比重匹配,在其它实施方案中,调整水相的比重以匹配油相(其最易满足并因此是优选的),或使颗粒的比重与水相的比重匹配。匹配意味着在20%,优选10%更优选5%以内。
Lipiodol具有1.28的比重。为了更好地匹配油相与水相或与颗粒的比重,可以制备lipiodol和其它药学上可接受的油的共混物,例如通过将大豆油(比重0.92-0.94)或棉籽油或蓖麻油(比重0.9-0.99)与Lipiodol混合。
为了匹配水性组分的比重与Lipiodol为1.28的比重,向水相添加比重调节组分以便使水相的比重接近该值,在此方法中,水相应具有介于1.15与1.35之间,尤其是介于1.2或1.25与1.3之间的比重。比重调节组分可以是适于此目的的任何药学上可接受的溶质。例如,右旋糖广泛用于调节注射液的比重,因为其为代谢中性的且易于溶解。便利地,已知比重的成像剂诸如含1-脱氧-1-(甲基氨基)-D-葡萄糖醇5-乙酰胺基-2,4,6-三碘-N-甲基异氨基甲酰苯甲酸盐(盐)的(Covidien Pharmaceuticals USA)、含(S)-N,N’-双[2-羟基-1-(羟甲基)-乙基]-2,4,6-三碘-5-内酰胺碘异酞酰胺(碘帕醇)的(BraccoDiagnostics Inc.USA)或含N,N′-双(2,3-二羟基丙基)-5-[N-(2,3-二羟基丙基)-乙酰胺基]-2,4,6-三碘异酞酰胺(碘海醇)的(GE Healthcare Inc.)可用于调节比重。这具有改善栓塞剂的原位成像的额外优点。Conray是Mallinckrodt,Inc.Corp.USA的商标;Isovue是Bracco Diagnostics Inc的商标;Omnipaque是GE Healthcare AS的商标。
在一个实施方案中,组合物将具有介于1.0与1.5之间的密度。尤其是介于1.1与1.35之间。注意,干燥颗粒(尤其是水凝胶)的密度在吸收Lipiodol时发生改变。因此,在又一个实施方案中,可使颗粒的密度更接近Lipiodol的密度,例如通过使用具有开放结构的颗粒,以使得它们吸收Lipiodol。这产生更均匀的颗粒悬浮液。
因此,步骤C可包括以下步骤中的一个或多个:
Ci)调节水相的体积以使得Lipiodol∶水相的比率大于1∶1vol/vol;以及
Cii)将水相的比重调节到介于1.15与1.35之间。
Ciii)使油的比重匹配颗粒的比重。
Civ)使油的比重匹配水相的比重以及
Cv)使颗粒的比重匹配水相的比重。
组合物的乳化通过以下方式实现:用力混合组合物的组分以提供足够的剪切而使组合物乳化。通常,这通过使组合物在两个20ml注射器之间快速传递,通常通过三通阀或旋阀20次而实现。所得的乳液包含水性不连续相的液滴,这些液滴包含悬浮在Lipiodol连续相中的药物活性物质。
在首先使栓塞颗粒与Lipiodol接触,再使颗粒-lipiodol混合物与包含药物活性物质的水性组合物接触的情况下,观察到活性物质快速载入颗粒中。该方法因此提供本发明的又一个方面,其为将药物活性物质载入栓塞颗粒中的方法,该方法包括以下步骤:
a).提供栓塞颗粒;
b).使栓塞颗粒与Lipiodol接触;以及
c).使颗粒:Lipiodol组合物与包含药物活性物质的水性组合物接触。
然后可以移除过量的Lipiodol和任何未结合的水相,或进一步添加水相以制备乳液制剂。过量的Lipiodol可通过例如洗涤或通过离心而移除。在一个实施方案中,对颗粒混合物离心,从而使过量的液体穿过网孔,而留住颗粒。
本文所述的非乳化油性组合物适用于如本文所述的栓塞疗法,因此,本发明的又一个方面提供药物油组合物,其在Lipiodol中包含多个栓塞颗粒。
栓塞颗粒可以为本文所述的那些任何颗粒。优选的是,颗粒包含药物活性成分,然后可用于TACE。通过使Lipiodol的密度与悬浮的颗粒的密度匹配,可以改善乳液的稳定性,这同样适用于非乳化的油组合物。组合物可如上所述进行制备,或通过简单地将栓塞颗粒(其可以根据需要水化和/或预加载)再悬浮在Lipiodol中而制备。在使组合物中的颗粒水化的情况下,组合物可被视为具有不连续的水相和连续的油相,水相基本上在颗粒内,但少量的水相,优选地不超过总量的50%可作为液滴存在于颗粒外的油中;尤其是不超过40%、30%、20%、10%、5%或1%。由于组合物不含可存在于颗粒中的水相之外的水相,或仅含极少量的这种水相,所以其不是稳定的乳液,而是油组合物。颗粒可包含Lipiodol,尤其是在制剂中使用干燥的颗粒时,或者它们可以包含Lipiodol和活性物质或仅含活性物质,尤其是在预加载的情况下。
该组合物的制备与乳液相比非常简单,并可使用非常简单的设备临时制备并递送。因此,本发明的又一个方面提供用于制备栓塞油组合物的方法,该方法包括提供多个如本文所述的栓塞颗粒和Lipiodol,并将两者合并以提供栓塞油组合物。
在一个实施方案中,本发明提供了用于制备栓塞油组合物的方法,该方法包括以下步骤:
a)提供多个干燥的栓塞颗粒
b)使干燥的栓塞颗粒与Lipiodol接触以形成Lipiodol:栓塞颗粒混合物;
c)使Lipiodol:栓塞颗粒混合物与足够的药物活性物质的水溶液接触以至少部分地使栓塞颗粒再水化;以及
d)使栓塞颗粒吸收水溶液以提供栓塞组合物。
本发明还提供用于制备根据本发明的组合物的装置,并且在一个实施方案中,本发明提供用于制备油组合物的装置(1),该装置包括容纳干燥的栓塞颗粒(3)的容器(2),该容器具有引入Lipiodol的部件(8)、引入水性组合物的部件(8)、通过其递送油组合物的递送部件(8)和通过递送部件排出组合物的部件(9)。
容器可同时容纳颗粒和lipiodol,在此情况下,引入Lipiodol的部件可以不存在。容器通常密封以实现无菌。在一个简单的实施方案中,引入油的部件、引入水性溶液的部件和递送部件是朝容器敞开的通道。排出混合物的部件通常为柱塞,其操作以驱动混合物通过递送部件。通常,柱塞在容器内操作以驱动混合物通过递送部件。为简单起见,递送部件与用于引入Lipiodol或水溶液或两者的部件相同。虽然油组合物将被直接递送给患者,但递送部件可设有与连接到导管、适于将组合物递送给患者相适应的连接器。
用于引入Lipiodol、水溶液的部件和递送部件中的一个或多个可设有在引入或混合液体时防止颗粒损失的部件。便利地,存在可操作以引入液体但可以关闭以防止颗粒损失的阀。
在一种简单的方法中,装置(1)包括注射器(2),其在一端被密封(10)柱塞(9)并在另一端被附接到连接器(6)的密闭阀(5)密封。干燥的颗粒(3)设置在筒体(4)中。还可以的是单独提供Luer连接器(6)的无菌闭合件(11)并提供无菌阀,或提供阀的无菌闭合件。通常,装置以无菌包装的形式提供。在使用中,将针(7)连到阀(5),然后通过通道(8)将一定体积的足以覆盖颗粒的Lipiodol抽到注射器中。关闭阀,轻轻摇动注射器以进行混合。30分钟后,将注射器倒过来以防止Lipiodol损失,连接新的针头,并将足够的正好使颗粒再水化的药物活性物质水溶液通过通道(8)抽到注射器中,然后关闭阀(5)。摇晃混合物以彻底混合。药物活性物质和水被快速吸收到珠粒中。所得的组合物包含悬浮在Lipiodol中的水化水凝胶颗粒,该颗粒包含药物活性物质和Lipiodol。取下针头,将出口(6或12)连接到导管。然后可通过手动操作柱塞(9)来递送珠粒,或通过使用注射器驱动器以提供均匀的递送速率。
本发明可用于一般性药物递送,但尤其可用于具有血管的组织中的组织栓塞,特别是用于治疗血管生成依赖性病症和富血管性病症,诸如瘤形成和增生(良性和恶性的)。该治疗尤其可用于肝细胞癌(HCC)、肝转移(例如,结直肠癌转移(mCRC))和神经内分泌肿瘤。该方法还可用于治疗疼痛,尤其是与肿瘤相关的疼痛。本发明因此还提供通过使具有血管的组织栓塞而对需要治疗的患者进行治疗的方法,该方法包括:
a).提供如本文所述的乳液或油组合物
b).向所述血管递送乳液或油组合物以使组织栓塞。
通常,本发明的组合物通过注射(通常穿过导管)而递送,以提供对下游部位的栓塞,然而,本发明还设想了组合物可通过直接注入组织而递送,例如,直接瘤内注射。这样的方法可以不提供栓塞疗法,而是产生储库。
本发明还提供了如本文所述的组合物用于组织栓塞方法,以及此类组合物在制造用于组织栓塞的药剂中的用途。
所述新方法使得可以提供商业试剂盒和制品以用于制备和/或递送本文所述的药物组合物。
在一个实施方案中,试剂盒在密封容器中包含灭菌制剂,该制剂包含多个如本文所述的干燥或水化栓塞颗粒。或者,容器可包含Lipiodol和一个或多个栓塞颗粒。优选的是,颗粒为干燥的栓塞颗粒,其在被1mM无菌磷酸盐缓冲生理盐水完全水化后占据介于1与5ml之间的填充体积。
通常,试剂盒还将包含关于如何使用试剂盒制备本发明的组合物的说明,并且还可以包含一种或多种药物活性物质,这些活性物质可掺入栓塞颗粒中或在单独的容器中单独提供或在相同的容器中分开提供。
容器可例如为密封小瓶,但还设想了容器为注射器或容器适于并入递送组合物的装置中的实施方案。
现在将进一步参照以下非限制性示例方案和附图描述本发明。鉴于此,落在本发明范围内的另外的实施方案将对本领域的技术人员显而易见。
附图说明
图1示出了在存在Lipiodol的情况下多柔比星吸收到PVA-AMPS水凝胶栓塞珠粒中。
图2示出了多柔比星从使用甘露糖醇-干燥PVA-AMPS水凝胶颗粒(100-300um)、作为水化的PVA-AMPS水凝胶珠粒的DC-珠粒(100-300um)制备的乳液和对照Lipiodol乳液中的洗脱。
图3示出了用于制备油性组合物的装置。
实施例
实施例1
制备干燥的栓塞珠粒:将市售PVA-AMPS水凝胶微珠( -BiocompatiblesUK Ltd,Farnham,UK-2ml珠粒填充体积(100-300um)在8ml 1mM生理磷酸盐缓冲盐水(PBS)中)从悬浮介质中移除并重悬在10%D-甘露糖醇中。平衡后,通过抽吸移除上清液,将珠粒冻干。如上,在无甘露糖醇的情况下冻干第二批珠粒。
实施例2
栓塞珠粒在Lipiodol中的悬浮液:
样品1.将根据实施例1制备的一小瓶冻干的甘露糖醇-干燥栓塞珠粒通过轻轻摇晃重悬在4ml Lipiodol Ultra Fluide(Guerbet(Lipiod01))中,并使之静置几分钟以吸收Lipiodol。
在显微镜检查后,观察到冻干的珠粒(样品1)为透明的,并均匀分散在Lipiodol中。据发现,得自样品2的珠粒几乎完全存在于水相中。
实施例3
珠粒加载:将2ml25mg/ml的多柔比星溶液加到得自实施例2的每个样品中,并轻轻搅拌。
甘露糖醇-干燥珠粒(样品1)快速吸收了几乎所有的多柔比星溶液,并形成了与Lipiodol层分离的浆液。珠粒相的样品显示出亮红色珠粒以及偶尔的小水滴。
然而,样品2的制剂分离出3层:下部油相、中间多柔比星珠粒层和贫多柔比星溶液顶层。
然后将得自样品1和2的珠粒的样品轻轻地用移液器吸取到一定体积的去离子水表面之下。许多样品2的珠粒在下沉时分散在水中,从而表明分散在血液中的趋势,而样品1的那些珠粒(由冻干珠粒制备)以油滴沉到水底且不分散。
实施例4
乳化:将Omnipaque 350(GE Healthcare-Omnipaque))与水按50∶50混合,然后将4ml该溶液加到得自实施例3的各小瓶中。然后将每个小瓶的内容物转移到20ml注射器中并移除所有空气。通过以下方式制备乳液:穿过三通不锈钢旋阀在两个20ml注射器(BD Luer-Tip)之间来回通过,直到乳化的特征性声音停止并形成光滑稳定的乳液。这需要大约20次通过。
通过针头轻轻地将一定体积的乳液分配到去离子水表面之下。珠粒开始在一到两分钟内从样品2(DC珠粒)制备的乳液中分散,但不从样品1制备的乳液中分散(通过甘露糖醇-干燥珠粒制备)。
实施例5:
Lipiodol对加载PVA-AMPS水凝胶栓塞珠粒的速率的影响的观察:将10mlLipiodol加到一小瓶根据实施例1制备的干燥珠粒(100-300um,甘露糖醇-干燥珠粒和非甘露糖醇-干燥珠粒)中。将小瓶放在一边10分钟。一旦将lipiodol载入干燥珠粒中后,即将2ml 25mg/ml盐酸多柔比星溶液加到小瓶中并轻轻短暂混合。定期移除5μl水相等分试样,并用水稀释到1ml。小心操作,不要移除Lipiodol。在不存在Lipiodol的情况下重复实验。
将上述干燥珠粒制剂与使用水化珠粒的类似制剂进行比较。通过抽吸从一小瓶DC珠粒(100-300um)中移除填充溶液。添加十毫升Lipiodol,与珠粒轻轻混合,然后将混合物放在一边10分钟。向小瓶中加入两毫升25mg/ml的多柔比星。如前,移除并测定5μl等分试样。在不存在Lipiodol的情况下重复实验。
测定483nm下的稀释样品的吸光度,并转化成珠粒最大吸收百分比。
实施例6
Lipiodol乳液的制备。
A.将10ml Lipiodol加到一小瓶根据实施例1制备的干燥珠粒(100-300um)中。在轻轻混合并平衡后,将2ml 25mg/ml的盐酸多柔比星溶液和6ml350加入(水相密度为1.27)。穿过三通旋塞在20ml注射器与5ml注射器之间快速经过20次,使组合物乳化。显微镜检查显示出油包水乳液,其中载有多柔比星的珠粒处于水相中。
B.从一小瓶DC珠粒中移除填充溶液,并更换为10ml Lipiodol。然后添加2ml25mg/ml的盐酸多柔比星。珠粒立即开始吸收药物。摇晃后,添加6ml Omnipaque 350,并如上在两个注射器之间用力混合组合物。显微镜检查显示出油包水乳液,其中载有多柔比星的珠粒处于水相中。
C.40-90um粒度范围的珠粒:根据US 7,442,385实施例1(高AMPS配方)制备了PVA-AMPS栓塞珠粒,并过筛以提供直径介于40与90um之间的珠粒。将珠粒等分,以提供在8ml1mM无菌磷酸盐缓冲生理盐水中的2ml珠粒填充体积,以便储存。对于使用,抽吸出PBS储存溶液,然后按原样使用珠粒,或用于根据实施例1制备甘露糖醇干燥珠粒。
D.使用40-90um的甘露糖醇干燥珠粒的乳液。将10ml Lipiodol加到一小瓶根据上文C制备的甘露糖醇-干燥珠粒(40-90um)中以提供均匀悬浮液。在平衡后,将2ml 25mg/ml的盐酸多柔比星溶液加入,然后添加6ml350。珠粒保持了几乎所有的多柔比星溶液。混合后观察到了均匀的悬浮液,2分钟后出现沉降。添加另外2ml水,并将混合物转移到20ml注射器中。如上对组合物进行乳化。乳液稳定7-8分钟(即,在此时最先注意到相分离)。
E.使用40-90um的水化珠粒的乳液。该乳液在不存在Omnipaque的情况下制备。从一小瓶根据上文C制备的40-90um珠粒移除填充溶液,并添加10ml Lipiodol。将珠粒与Lipiodol混合以形成均匀悬浮液并添加2ml 25mg/ml的多柔比星。如上制备乳液。4分钟后观察到相分离的发生。
实施例7
将Lipiodol乳液与包含栓塞颗粒的乳液进行比较。
如下制备lipiodol乳液:将10ml Lipiodol吸到20ml注射器中。然后吸入2ml盐酸多柔比星溶液(25mg/ml),再吸入6ml Omnipaque。来回穿过三通连接器(BD Connecta)进入5ml注射器而将所有三种组分混合均匀(20次),以产生光滑乳液。
采用根据实施例1制备的甘露糖醇-干燥珠粒或水化DC-珠粒重复实验。
向一小瓶根据实施例1制备的干燥珠粒(100-300um)中,添加10ml lipiodol并混合均匀以提供珠粒在Lipiodol中的悬浮液。将小瓶放在一边10分钟。一旦将Lipiodol载入珠粒中后,即将2ml盐酸多柔比星(25mg/ml)加入,然后将小瓶放在一边5分钟以加载药物。在加载药物之后,将6ml Omnipaque加入小瓶中。然后将小瓶的所有组分转移到20ml注射器中,并如前进行乳化以得到光滑乳液。
在从一小瓶DC珠粒(100-300um)完全移除填充溶液后,添加10ml Lipiodol并混合均匀以提供珠粒在lipiodol中的溶液。然后将小瓶放在一边10分钟。DC珠粒为水凝胶,其包含大约95%的水。在包含2ml填充体积的珠粒的小瓶中,当移除间隙填充溶液后,水的体积为约0.9ml。
10分钟后,添加2ml25mg/ml的盐酸多柔比星溶液。然后将小瓶的内容物转移到20ml注射器中,向注射器加入6ml Omnipaque,并如前对内容物进行乳化。
乳化后,然后使每个注射器直立过夜,使顶端向上,并在接下来的50分钟中进行观察。
Lipiodol乳液在50分钟中保持稳定,未观察到相分离。
在容纳通过干燥珠粒制备的乳液的注射器中,在15分钟后仅在制剂的顶部和底部可见相分离,在20分钟后澄清,而在通过水化珠粒制备的小瓶中,在7分钟后即开始明显的相分离。表1对观察结果进行了汇总。
通过Terumo 2.4Fr导管,将得自每一者的初始样品引入到一定体积的磷酸盐缓冲盐水(pH7.4)表面之下。标准Lipiodol乳液快速消散,将多柔比星释放到溶液中。使用甘露糖醇-干燥珠粒制备的乳液仍作为液面之下的液滴存在,极少的珠粒与液滴分离。使用DC珠粒制备的乳液也仍作为液滴存在,但明显更多的珠粒分散在盐水中。
实施例8
比较多柔比星从乳液中的洗脱
在室温下将烧杯装上400ml磷酸盐缓冲盐水(pH7.4)(PBS)和磁力搅拌棒。将烧杯置于磁力搅拌器上。根据实施例7制备乳液,立即将完整的样品轻轻引入盐水表面之下,并开始轻轻搅拌。定期移除5ml PBS样品,并更换为新鲜的PBS。将样品离心以分离任何Lipiodol污染,在483nm处通过吸光度测定样品中的多柔比星浓度。图2示出了在前2小时中多柔比星的洗脱。
所存在的几乎所有的多柔比星均非常快地从标准Lipiodol乳液中洗脱出来。在相同的时间段中,从含有珠粒的乳液中洗脱出来的多柔比星少得多。
表1:对在具有和不具有栓塞颗粒的情况下制备的Lipiodol乳液的观察结果。
实施例9
将十毫升Lipiodol与2.2-2.3ml干燥的PVA-AMPS珠粒(无甘露糖醇-尺寸70-150um)混合并转移到注射器中。将多柔比星溶液(25mg/ml)和造影剂(Omnipaque 350-比重1.406)与该组合物混合以提供各种lipiodol与水相比率和水相比重。首先将多柔比星溶液加到珠粒/lipiodol组合物中,轻轻混合直到大部分多柔比星被吸入珠粒中(在40分钟的时间段中,约80%的多柔比星已被吸入珠粒中)。
如上所述在两个注射器之间用力混合后,将注射器保持直立以测定25%的lipiodol相沉降出来的时间(稳定性测量)。将得自每一者的样品通过Terumo 2.4Fr导管引入一定体积的磷酸盐缓冲盐水(pH7.4)表面之下,并对乳液行为进行观察,且根据以下方案评分。
表2:实施例9的评分检索表
表3:对得自实施例9的乳液的观察结果
*不包括多柔比星的贡献
Claims (10)
1.一种包含卤化油和一个或多个栓塞颗粒的药物组合物,其呈包含水相和油相的乳液的形式。
3.根据权利要求1或权利要求2所述的药物组合物,其中所述栓塞颗粒包含药物活性物质。
4.根据权利要求1至3所述的药物组合物,其包含处于所述油相和/或所述水相中的药物活性物质。
5.根据权利要求4所述的药物组合物,其包含溶于所述油相的疏水性药物活性物质。
6.根据任一项前述权利要求所述的药物组合物,其呈油包水乳液的形式。
7.根据权利要求1至4中任一项所述的药物组合物,其中Lipiodol与水相的比率≥1(Lipiodol):1(水相)(V/V)。
8.根据任一项前述权利要求所述的药物组合物,其中所述水相的比重介于1.15与1.35之间。
9.根据任一项前述权利要求所述的药物组合物,其中所述颗粒的比重介于1.0与1.5之间。
10.根据任一项前述权利要求所述的药物组合物,其中所述栓塞颗粒为亲水的。
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KR101971672B1 (ko) * | 2016-11-18 | 2019-04-23 | 주식회사 삼양바이오팜 | 화학색전용 에멀전 조성물 및 그의 제조방법 |
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JP6925014B2 (ja) | 2017-02-15 | 2021-08-25 | ドリームメディカルパートナーズ株式会社 | 塞栓材の製造方法 |
WO2023014752A1 (en) * | 2021-08-02 | 2023-02-09 | Board Of Regents, The University Of Texas System | Lipid emulsion alginate microspheres |
CN115501378B (zh) * | 2022-09-23 | 2023-08-22 | 江南大学 | 一种改性聚乙烯醇栓塞微球及其制备方法 |
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EP1810698A1 (en) * | 2006-01-24 | 2007-07-25 | Biocompatibles UK Limited | Process for producing radiopaque embolic microspheres |
WO2012101455A1 (en) * | 2011-01-27 | 2012-08-02 | Biocompatibles Uk Limited | Drug delivery systems |
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KR20160055810A (ko) | 2016-05-18 |
KR102323637B1 (ko) | 2021-11-08 |
JP2017508491A (ja) | 2017-03-30 |
US10406257B2 (en) | 2019-09-10 |
US20160228597A1 (en) | 2016-08-11 |
EP3046539A1 (en) | 2016-07-27 |
CN105579030A (zh) | 2016-05-11 |
JP6700634B2 (ja) | 2020-05-27 |
WO2015036626A1 (en) | 2015-03-19 |
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