CN1195286A - 以延缓释放速度硬膜外给予治疗性化合物 - Google Patents
以延缓释放速度硬膜外给予治疗性化合物 Download PDFInfo
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- CN1195286A CN1195286A CN96196697A CN96196697A CN1195286A CN 1195286 A CN1195286 A CN 1195286A CN 96196697 A CN96196697 A CN 96196697A CN 96196697 A CN96196697 A CN 96196697A CN 1195286 A CN1195286 A CN 1195286A
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- epidural
- drug delivery
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- therapeutic compound
- morphine
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Abstract
药物传递系统提供缓释的硬膜外给予的治疗性生物活性化合物。在优选的实施例中,所述生物活性化合物为类鸦片,它被包封在多孔脂质体非同心的内部含水室中或双分子层中。当作为缓释止痛法以单独剂量硬膜外导入所述脂质体时,在延长的时间内所述类鸦片被释放。
Description
本发明的范围
本发明涉及自药物传递系统控制释放治疗性化合物。更具体地说,本发明涉及自脂质体制剂中以延缓释放速度硬膜外给予治疗性化合物。本发明还涉及在活的脊椎动物中安置硬膜外导管的方法。
背景
对于患者和医生(尤其是康复室的患者和医生)而言,当患者从麻醉中苏醒过来时,手术后疼痛控制是一个严重的问题。为控制疼痛全身性的给予大剂量的类鸦片可能会引起威胁生命的呼吸抑制。另一方面,过低或过迟剂量的手术后止痛药物疗法可以导致患者在不能忍受的剧痛期间苏醒。此外,已证明在腹部或胸手术后对术后疼痛较差地控制抑制胸壁、腹部和隔膜的换气运动导致肺膨胀不全(P.R.Bromage,Textbook of Pain,P.D.Wall,et al(Eds.):Churchill Livingstone,1989,pp744-753)。
在七十年代发现在脊髓中存在鸦片受体。在1979年最初的临床疗效报道(M.Behar et al.,Lancet 1:527-529,1979)后,硬膜外给予类鸦片对于术后疼痛控制已变得非常流行(T.I.Ionescu et al,Act.Anaesth.Belg.40:65-77,1989;C.Jayr et al.,Anesthesiology 78:666-676,1993;S.Lurie,et al. Euorpean Journal of Obstetrics and Gynecology andReproductive Biology 49:147-153,1993)。硬膜外给予类鸦片具有在脊柱水平达到良好的局部麻醉的优点,而不丧失运动或血管舒缩的控制或降低清醒的程度。
可注射的类鸦片在术后和产后硬膜外广泛使用。术后和产后的疼痛通常持续几天,然而,可注射的类鸦片具有较短的作用持续时间(W.G.Brose et al.,Pain 45:11-15,1991;R.H.Drost et al.,Arzneim-Forsch/Drug Res.38:1632-1634,1988;G.K. Gourlay et al.,Pain 31:297-305,1987)。从而,为了维持足够的疼痛控制需要连续输注或重复注射(J.W.Kwan,Am.J Hosp.Pharm.47(Suppl 1):S18-23,1990;J.S.Anulty,International Anesthesiology Clinics 28:17-24,1990;R.S.Sinatra,TheYale Journal of Biology and Medicine 64:351-374,1991)连续输注或重复注射还需要安置连接或不连接输注泵的导管系统,这一切需要昂贵的医生和精心护理和维持的时间。此外,重复大剂量注射(bolus injections)或连续输注可以导致呼吸抑制。
后期呼吸抑制和窒息的发作是早期研究中最使人关注的副作用(P.R.Bromage,Anesthesia and Analgesia 60:461-463,1981;E.M.Camporesi,et al,Anesthesia and Analgesea 62:633-640,1983;T.L.Yaksh,Pain 11:293-346,1981)。最近所作的在1085名经受胸、腹部或矫形手术患者中的前瞻性非随机研究估计硬膜外使用吗啡后的“呼吸抑制”率为0.9%(R.Stenseth et al.,Acta Anaesthesiol Scand.29:148-156,1985)。作为对比,在860名给予全身性吗啡(PO、IV、IM、SC)的患者中,“危及生命的呼吸抑制”的发生率为0.9%(R.R.Miller et al、DrugEffects in Hospitalized Patients.John Wiley & Sons,New York,1976)。对比在高危患者中硬膜外给予类鸦片和全身性给予类鸦片(IM或IV)的前瞻性、随机性研究已经显示采用硬膜外类鸦片的术后疼痛控制产生具有降低术后并发症的优越的止痛效果(N.Rawal et al.,Anesth.Analg63:583-592,1984;MP.Yeager,et al.Anesth.60:729-736,1987)。
已有文件证明在体外和在动物体上经鞘内、皮下和腹膜内给药以及在患者身上经鞘内给药,可使加入脂质体(如多孔脂质体)后的各种治疗剂延缓地释放(S.Kim et al.,J.Clin.Oncol 11:2186-2193,1993;V.Russack et al.,Ann Neurol 34:108-112,1993;and M.C.Chamberlain etal.,Arch.Neurol.50:261-264,1993)。然而,延缓地释放硬膜外给予的化合物迄今在本领域内是未知的。
从而,需要新的和更好的以单独剂量硬膜外给予类鸦片和其它治疗化合物的方法,以便达到有效治疗水平的延缓释放速度。本发明通过提供治疗剂例如类鸦片的延缓释放制剂(它在硬膜外给予单独剂量后立即产生最大的镇痛效果并在其后的几天中镇痛效果逐渐降低)以显示出现有技术的局限性。
附图的介绍
图1为一组记录以剂量10、50、175、或250μg(从上方图片到下方图片)一次性硬膜外给予脂质体包封的硫酸吗啡(DTC401)(空心圆)或游离的硫酸吗啡(实心圆)后一定时间在大鼠身上的镇痛效果的四条曲线。镇痛强度用“最大的可能镇痛效果的百分数(%MPA)”表示。每个数据点代表5或6只动物的平均值和均值的标准误差(SEM)。
图2为显示在大鼠身上一次性硬膜外给予DTC401(空心圆)、游离的硫酸吗啡(实心圆)后或一次性皮下给予游离的硫酸吗啡(实心方块)后测定的镇痛峰值剂量-应答曲线的图形。由5或6只动物得到平均峰值%MPA±SEM。
图3为比较一次性硬膜外给予DTC401(空心圆)或游离的硫酸吗啡(实心圆)后在大鼠身上总的镇痛效果[通过镇痛-时间曲线(AUC)下面积测定]的图形。每个数据点代表5或6只动物的平均值和均值的标准误差(SEM)。
图4为一组比较以剂量10、50、175、1000或2000μg(从上方图片到下方图片)一次性硬膜外给予DTC401(空心圆)或游离的硫酸吗啡(实心圆)后一定时间在大鼠身上的血红蛋白的百分氧饱和(SpO2)的五条曲线。每个数据点代表5只动物的平均值和均值的标准误差(SEM),除了50μg剂量组中n=3。
图5为显示在一次性硬膜外给予DTC401(空心圆)或游离的硫酸吗啡(实心圆)后在大鼠身上的最大呼吸抑制剂量-应答曲线的图形。将所达到的最低SpO2对应硬膜外吗啡剂量作图。每个数据点代表5只动物的平均值和均值的标准误差(SEM),除了50μg剂量组中n=3。
图6显示比较硬膜外给予250μg的DTC401(空心圆)或游离的硫酸吗啡(实心圆)后在大鼠的脑脊液(上方图片)和血清(下方图片)中药物动力学的两条曲线。每个数据点代表由3或4只动物的平均值和均值的标准误差(SEM)。
本发明的概述
硬膜外给予以药物传递系统中的治疗性化合物与使用游离的治疗化合物相比产生惊人的、更大的延缓释放和持续的治疗效果。
从而,本发明的一个方面提供利用药物传递系统硬膜外给药到需要该治疗的脊椎动物,以便延缓释放治疗性化合物的方法。
所述脊椎动物优选为哺乳动物如人类。在不同的优选实施例中,所述药物传递系统为基于脂质的,尤其是多孔脂质体(multivesicularliposome)。
本发明的特征为能够使不同的治疗性化合物延缓释放(在优选的实施例中它们包括类鸦片或鸦片制剂的拮抗剂)以便调节镇痛效果,另外一些实施例可以传递如亲神经因子等的治疗性化合物。
此外,使用根据本发明方法的缓释制剂,通过省去连续输注、多次大剂量注射或安放导管简化并降低硬膜外镇痛的总体费用,并且也降低可能的感染。甚至在硬膜外导管存在下,降低注射次数也是非常有利的。
本发明的详细介绍
本发明提出用于硬膜外给予具有硬膜外效果的治疗性化合物例如类鸦片的基于脂质的缓释药物传递系统。通过硬膜外给药,将所述化合物释放到中枢神经系统和脑脊液中,而不刺伤硬脑膜并且以延缓速度释药。
术语“缓释”指的是当以脂质基制剂包封的大剂量给药时,所述治疗性化合物与以大剂量硬膜外注射给予的游离形式的同样药物相比可以在较长时间内释放。它不一定指的是在缓释期间所述治疗性化合物的浓度保持恒定。一般而言,在术后或产后,随着时间的推移,患者感觉疼痛的程度在下降。因而,一定时间后,患者对镇痛的要求也在减少。使用本发明的硬膜外给药的方法,可以在几天内,优选约2-约7天,维持所述治疗性化合物在脑脊液和/或血清中的治疗有效浓度。
在此所用术语“治疗性化合物”指的是具有调节生物学过程以便完成调节或治疗生物体中的不适症状所需作用的化合物。所述术语治疗性化合物包括化学的非蛋白质药物,例如抗生素和镇痛药以及蛋白质药物例如细胞活素、干扰素、生长因子等。
药物传递系统在本领域内是众所周知的。本发明关于任何缓释制剂例如以大分子复合物、毫微型胶囊、微球或小球形式的合成或天然的聚合物和脂质基体系包括水包油乳剂、胶团、混合胶团、合成膜囊(membrane vesicles)和再封的红细胞。这些体系统称为分散系。分散系是两相体系,其中一相以粒子或液滴的形式分布在第二相中。一般而言,包含在该体系中的粒子的直径约为20nm-50μm。该粒子大小范围使得其分散在药物溶液中并使用针或导管及注射器导入硬膜外腔中。
用于制备分散系的物质一般为无毒性和生物可降解的。例如在该方法中可以使用胶原、白蛋白、乙基纤维素、酪蛋白、明胶、卵磷脂、磷脂和豆油。通过类似于凝聚或微囊包封的过程可以制备聚合物分散体系。如需要,通过改变比重以使得所述分散液为高比重或低比重可以调节所述分散体系的密度。例如,通过加入iohexol、iodixanol、甲泛葡胺、蔗糖、海藻糖、葡萄糖或其它与高比重生物配伍的分子可以改变所述分散系的密度。
根据本发明可以使用的一类分散体系包括在聚合物基质中的治疗剂的分散液。所述治疗剂作为聚合物基质被释放并分解或生物降解成可溶性产物,排泄出体外。为此已经研究了几种类型的合成聚合物包括聚酯(Pitt,et al.In Controlled Release of Bioactive Materials,R.Baker,Ed.,Academic Press,New York,1980);聚酰胺(Sidman,et al.,Journal ofMembrane Science,7:227,1979);聚胺酯(Master,et al.,Journal ofPolymer Science,Polymer Symposium,66:259,1979);聚原酸酯(Heller,etal.,Polymer Engineering Science,21:727,1981);和聚酐(Leong,et al.,Biomaterials,7:364,1986)。对于PLA和PLA/PGA聚酯已经做了大量的研究工作。毫无疑问,这是出于方便和安全的考虑。这些聚合物容易得到,因为它们已经用作可生物降解的缝合线并且它们分解成为无毒性的乳酸和乙醇酸(见美国专利4578384和美国专利4785973,结合在本发明中作为参考)。
使用如本体聚合、界面聚合、溶液聚合及开环聚合的聚合方法可以合成固体聚合物分散系(Odian,G.,Principles of Polymerization,2nded,John Wiley & Sons,New York,1981)。使用这些方法中的任何一种方法,可以获得具有广泛的机械性能、化学性能和生物可降解的性能的各种不同的合成聚合物;通过改变参数:反应温度、反应物浓度、溶剂类型和反应时间来控制性质和特征上的差异。如需要,可以开始制备大块的固体聚合物分散系,然后使其粉碎或者加工成足以维持在适当的生理缓冲液中的分散液的小粒子(见例如美国专利4452025、美国专利4389330和美国专利4696258,结合在本发明中作为参考)。
如需要,可以将治疗性化合物掺入非分散结构中,通过手术或机械方法将该结构硬膜外植入。非分散结构为具有一定的外形例如板、圆柱或球形的结构。Hopfenberg已经介绍了由可生物降解的板形、圆柱形和球形结构释放治疗剂的机理(Controlled Release PolymericFormulations,pp. 26-32,Paul,D.R.and Harris,F.W.,Eds.,AmericanChemical Society,Washington,D.C.,1976)。描述添加物自这些装置中释放的简单的表达式为(其中释放主要通过基质降解来控制):
Mt/M∞=1-[1-k0t/C0α]n其中对于球形而言n=3,对于圆柱形而言n=2,对于板形而言n=1。所述符号α代表球形或圆柱形的半径或板形的一半厚度。Mt和M∞为分别在时间t和无限大释放药物的质量。
任何已知的脂质基的药物传递系统可以用于本发明的实施。例如,多孔脂质体(MVL)、多室脂质体(也称为多层囊或“MLV”)单室脂质体包括小单室脂质体(也称作单层囊或“SUV”)和大单室脂质体(也称作大单层囊或“LUV”)均可以使用,只要可以确定包封治疗化合物的延缓释放速度即可。然而,在优选的实施例中,脂质基的药物传递系统为多孔脂质体体系。制备控释多孔脂质体药物传递系统的方法在下列文献中全面介绍:美国专利申请登记号08/352342(于1994年12月7日申请)和08/393724(于1995年2月23日申请)以及PCT申请登记号US94/12957和US94/04490,在此全部结合在本发明中作为参考。
所述合成膜囊(membrane vesicle)的组成通常为为磷脂的组合物,一般与类固醇尤其胆固醇结合。也可以使用其它的磷脂或其它脂质。
用于合成膜囊制备中的脂质的实例包括磷脂酰甘油、磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺、鞘脂类、脑苷脂类和神经节苷酯。例证性的磷脂包括蛋磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二油酰磷脂酰胆碱、二棕榈酰磷脂酰甘油、和二油酰磷脂酰甘油。
在制备含有治疗剂的膜囊过程中,应该考虑如药物包封的效能、药物的不稳定性、所形成膜囊体的均一性和粒度大小、药物与脂质比例、渗透性、制剂的不稳定性和制剂的药学上的可接受性等变量(Szoka,et al.,Annual Reviews of Biophysics and Bioengineering,9:467,1980;Deamer,et al.,in Liposomes,Marcel Dekker,New York,1983,27;Hope,et al.,Chem.Phys.Lipids,40:89,1986)。
其它人已经进行了类鸦片的脂质基制剂的用途的研究只获得有限的进展并且没有人进行经硬膜外途径的研究。例如,已经进行了脂质体包封类鸦片的制备及体外活性的研究(F.Reig,et al.,J.Microencapsulation 6:277-283,1989),而未做任何体内的硬膜外研究。此外,已经研究了包封在脂质体制剂中并通过大鼠脊柱给药的四唑芬太尼的抗感受伤害作用(antinociception)和副作用(M.S.Wallace et al.,Anesth.Analg.79:778-786,1994;C.M.Bernards et al,Anesthesiology77:529-535,1992)。然而,这些化合物的药动力学和药效学与用来证明其在临床实践中的作用的标准类鸦片的药动力学和药效学没有足够的差异。这些研究没有探索经硬膜外途径给予类鸦片的缓释制剂。
加入治疗性化合物的脂质基药物传递系统可以以单独剂量给药,例如经硬膜外导管给药。然而,在优选的实施例中,使用小号(gauge)针头以单独剂量将所述脂质基药物传递系统注射到脊髓周围的硬膜外腔中,从而避免安置导管。优选使用18号-25号针头。
用于硬膜外给药的治疗性化合物的代表性化合物包括阿片吗啡、氢吗啡酮、可待因、二氢可待因酮、羟甲左吗啡、羟氢可待酮、羟氢吗啡酮、二乙酰基吗啡、叔丁啡、环丁甲羟氢吗啡、环丁羟吗喃、镇痛新、美散酮、芬太尼、噻哌苯胺(sufentanyl)和四唑芬太尼(alfentanyl)。此外,使用本发明的方法可以硬膜外给予鸦片拮抗剂例如纳洛酮和环丙甲羟二羟吗啡酮,以便逆转或拮抗鸦片的作用。
与一个或多个神经受体例如δ(delta)鸦片受体、μ(mu)鸦片受体、κ(kappa)鸦片受体和ε(episilon)鸦片受体结合的肽类和peptidomimetics被认为是类鸦片并可以根据本发明的方法给药用于治疗。这类化合物包括脑啡肽(enkephalins)、内啡肽(endorphins)、casomorphin、kyotorphin和其生物活性断片。在此术语“生物活性断片”指的是基本保持完整治疗分子生物活性的治疗性化合物的任何部分。本领域的技术熟练人员将懂得或可以容易地确定是否断片基本保持整个分子的生物活性。
除了类鸦片以外,许多以延缓速度硬膜外给药时具有治疗作用的化合物也可以用于本发明方法的实施中。这些化合物包括神经营养因子例如胰岛素样的生长因子、睫状神经营养因子和神经生长因子;神经递质和其拮抗剂例如多巴胺、肾上腺素、去甲肾上腺素和γ-氨基丁酸;局麻药例如丁卡因、利多卡因、丁哌卡因和甲哌卡因;P物质和相关的肽类;及α-2受体兴奋剂例如氯压定和dexmedetomidine。此外,辅助性局麻药例如利多卡因、丁哌卡因和丁卡因可以增加硬膜外类鸦片的效力。
在本发明中,加入类鸦片(例如硫酸吗啡)的脂质基药物传递系统与硬膜外给予游离药物相比,经测试由最大的血液氧饱和或给予所述药物前的基线值在血红蛋白氧饱和(SpO2)方面下降的百分率显示具有最低可能的呼吸抑制。本领域的技术人员将很乐于接受血氧量可以容易地使用市场上可以买到的装置例如脉搏血氧计来测定这一现实。
也显示在多孔脂质体组合物中配制并硬膜外给药的单独剂量的缓释类鸦片产生长期持久的镇痛作用,及在单独剂量硬膜外给药后60分钟内出现治疗性药物的峰值小脑延髓池CSF浓度,然后在其后的几天内(例如直到8天)逐渐下降。尽管与硬膜外给予游离硫酸吗啡后的情况相比,峰值CSF浓度下降,与硬膜外给予游离硫酸吗啡相比,产生的总的镇痛效果(例如图1、3和表1中通过所述曲线下的面积(AUC)所示)增加许多倍。例如,硬膜外给予包封在多孔脂质体中的250μg的硫酸吗啡(DTC401)后与给予相同剂量的未包封的硫酸吗啡相比在大鼠中所述峰值血浓度和CSF吗啡浓度分别降低17倍和3.1倍,然而CSF AUC增加2.8倍。
因为使用控释硬膜外给予吗啡在吗啡的峰值血浓度和CSF浓度上的降低,没有呼吸抑制;而硬膜外给予高剂量游离的吗啡确实引起呼吸抑制。
本发明的主要优点有三方面。首先,其优点为硬膜外给予单独剂量的缓释化合物的方法使患者经受较小的与剂量有关的副作用(例如一般与大剂量注射或输注治疗性化合物有关的呼吸抑制)的风险。其次,通过硬膜外给予治疗性化合物而不是直接给药到脑脊液中,所述治疗性化合物不在整个脑和脊髓中迁移并且经过较长的时间(例如直到8天)将治疗有效量的所述治疗性化合物局部释放到硬膜外腔中。最后,不需要多次注射或连续输注便可以获得长时间的镇痛作用。
本领域的技术人员将理解在本发明的实施中,保持释药速度的时间将根据治疗的疾病状况、治疗化合物的特性和缓释药物传递系统以及包封和给予患者的化合物的总量而变化。
术语“治疗有效的”当其涉及本发明的组合物时,指的是以足以达到治疗剂所要达到的特定的医疗效果的浓度,自所述药物传递系统释放的治疗性化合物。例如,如果所述治疗性化合物是类鸦片,那么所需要的治疗效果为镇痛而没有呼吸抑制作用。准确的剂量将根据例如特定的治疗性化合物和所需要的治疗效果等因素以及患者因素如年龄、性别、一般状况等而变化。本领域内的技术人员可以容易地考虑这些因素并利用它们确定有效的治疗浓度而不需要做更多的实验。
例如,适合于硬膜外给予硫酸吗啡到人体的剂量范围包括1mg-60mg。更有效力的化合物可以需要低至0.01mg的剂量,而较低效力的化合物可以需要5000mg的剂量。尽管除了上述剂量范围外可以给出其它的剂量,然而所述剂量范围包括了实际上期待经硬膜外途径给予的所有治疗性化合物的使用范围。
以前报道在大鼠中进行硬膜外操作的方法包括经腰椎骨钻孔并推入导管1cm到硬膜外腔。本发明使得从上方(即从颈部)放置导管,而没有手术过程的损伤。也可以将所述导管末端置于沿着脊柱的任何位置上而不是如现有技术中所述限制于腰部。上述放置导管的方法也可以应用到大鼠以外的动物身上,例如兔、狗以及人类。
下列实施例说明实施本发明的方法。然而,可以理解所述实施例是为了说明,不认为本发明被限制于其中的特定物质或条件。
实施例1
A.在盐酸盐的存在下,制备包封硫酸吗啡(DTC401)的多孔脂体
步骤1在清洁的1克玻璃管形瓶[1.3cm(内径)×4.5cm(高)]中加入包含9.3μM二油酰卵磷脂(Avanti Polar Lipids,Alabaster,AL)、2.1μM二棕榈酰磷脂酰甘油(Avanti Polar Lipids)、15μM胆固醇(Avanti PolarLipids)和1.8μM三油酸甘油酯(Sigma)的1毫升氯仿(Spectrum Corp.,Gardena,CA)溶液。该溶液称为脂质成分。
步骤2将包含20mg/ml硫酸吗啡(Sigma Chemical Co.,St.Louis,MO)和0.1N盐酸的1毫升水溶液加入上述含有所述脂质成分的1克玻璃管形瓶中。
步骤3为了制备油包水型乳剂,将含有“步骤2”的混合物的玻璃管形瓶封口并水平固定在涡动摇动器(Catalogue #S8223-1,AmericanScientific Products,McGaw Park,IL.)的头部并以最大速度振摇6分钟。
步骤4为了使所述氯仿小球体悬浮在水中,将自“步骤3”得到的油包水型乳剂分成等体积并迅速用小直径尖的Pasteur移液管加入两个各1克的玻璃管形瓶[1.3cm(内径)×4.5cm(高)]中,其中各瓶中含有2.5ml水、葡萄糖(32mg/ml)和游离碱性赖氨酸(40mM)(Sigma)。然后,密封每个管形瓶,固定在如“步骤3”中所用的同一个涡动摇动器的头部并以最大速度振摇3秒钟以便形成氯仿小球体。
步骤5为了得到所述多孔脂质体,将在“步骤4”的两个管形瓶中制备的氯仿小球体悬浮液倒入含有5ml水、葡萄糖(32mg/ml)和游离碱性赖氨酸(40mM)的250ml Erlenmeyer烧瓶的底部。在振动的水浴中将所述烧瓶在37℃保温,用10-15分钟,以7L/min将氮气流通入所述烧瓶中,以便缓慢蒸发氯仿。然后以600×g离心5分钟分离该脂质体并用0.9%氯化钠溶液洗涤三次。
B.制备制剂
在硬膜外注射以前,调整所述DTC401制剂和对照的未包封(“游离”)的硫酸吗啡,以便50μl含有10、50、175、250或1000μg剂量。此外,将含有用于研究呼吸抑制的2000μg剂量的硫酸吗啡的MVLs制剂配制成75μl注射液。通过将50μl的每种制剂用1ml异丙醇溶解,然后在水中稀释来测定不同脂质体制剂中吗啡的浓度。使用已经公开的方法(S.P.Joel et al.,Journal of Chromatography 430:394-399,1988)经HPLC测定吗啡的浓度。就空白对照而言,用葡萄糖代替硫酸吗啡制备空白多孔脂质体组合物。
实施例2
A.动物的准备
饲养6-8周龄,体重为205-254g的雄性Sprague-Dawley大鼠(Harlan Sprague-Dawley,San diego,CA),每笼1或2只,在温度控制的环境下,明暗12小时轮换并容许自由觅食和饮水。在每个研究以前,使动物适应所述环境。每只动物仅研究一次。所有的动物均按照theCommittee on Care and Use of Laboratory Animals of the Institute ofLaboratory Animal Resources,National Research Council的指导方针饲养。
B.硬膜外插导管
大鼠尾部硬膜外插导管按如下进行:诱导氟烷麻醉并将动物定向性躺着放置,高度7cm。使其头弯曲,注意保持动物正常呼吸。将略成斜角的19号针头在正好向枕骨嵴的尾侧以与针头弯曲所对的中心线以约170°插入脊柱中。所述针头向着C1椎骨向前推进直到针尖接触棘状突起或C1的后层为止。将所述针尖小心地移动到所述后层的腹侧边缘。在这一点上,留下一点弹性并使针头再向前1-2mm。注意不使针头穿透硬脑膜。通过经针套或经皮下放置的导管脑脊液(CSF)的溢出可以确定硬脑膜的意外的妨碍。使聚乙烯导管[PE-10;长度12cm,内径0.28mm;体积7.4μl(Becton Dickinson,Sparks,MD)]经所述针头进入背侧的硬膜外腔中。使所述导管缓慢地推进通过针头并在距C18cm在约L1水平停止。将所述导管的暴露部分在头皮下皮下挖沟并用结扎3-0丝缝合线的袋固定。最后,用10μl的生理盐水冲洗所述导管并用不锈钢丝塞住。从开始麻醉到缝合过程持续约10-15分钟。使动物苏醒并观察60分钟。只有那些由上述过程完全恢复的动物才用于下列研究中。
C.抗伤害感受作用
按照M.S.Wallace等人所述的试验方法(Anesth.Analg.79:778-786,1994)通过将所述动物置于标准热板上(52.5±0.5℃)测定安置硬膜外导管后的感受伤害的基线值。测定自动物被置于热板上时起到它们或者舔其后爪或者跳下时止对感受伤害的应答潜伏期(以秒表示)。将每只试验动物的基线(处理前)应答潜伏期值规定为最大可能镇痛(MPA)作用的0%。然后,每只动物硬膜外注射50μl或者含有硬膜外吗啡剂量范围在10-250μg的DTC401,未包封硫酸吗啡溶液或者对照MVL空白液。也测定以剂量250μg-1mg皮下给予硫酸吗啡的抗感受伤害作用。经如上述埋入(emplant)的导管硬膜外给予所述试验溶液后,用10μl0.9%的氯化钠冲洗所述硬膜外导管。
然后,使所述动物再次经受热板试验以便测定在特定时点:在给予未包封的硫酸吗啡后0.5、1、2、3、4、6、12和24小时和给予DTC401和MVL空白液后0.5、1、6小时和1、2、3、4、5、6、7和8天测定抗感受伤害作用。对于每个剂量和每种药物在5或6只动物中测定抗感受伤害作用。为防止对脚垫(footpads)的组织损伤,使用60秒钟的截止时间。因此,100%MPA规定为抗感受伤害作用持续≥60秒钟。相应于0%-100%的MPA的分别为10±2-60秒钟的潜伏期间隔对于显示在研究剂量范围内的剂量-应答是敏感的。
使用RSTRIP计算机程序[Micromath,Salt Lake City,UT],通过不规则四边形法则到最后一个数据点计算各曲线下的所有面积。
使用单向(one-way)方差分析(ANOVA)以便分别确定对于不同药物制剂和给药途径的剂量依赖性;而使用双向(two-way)ANOVA以比较相同剂量的不同制剂。对所有的ANOVA分析进行Newman-Keuls检验以便确定统计学的显著性;P<0.05被认为对所有试验统计学上显著。所有数据表示为均值±均值的标准差(SEM)。
如图1中数据所示,硬膜外给予DTC401产生等位发作(equivalentonset)的镇痛作用,然而,镇痛的持续时间与硬膜外给予游离硫酸吗啡相比显著延长。硬膜外注射对照MLV空白液未显示可证明的抗感受伤害作用(未显示数据)。如图2所示,硬膜外DTC401和硬膜外及皮下硫酸吗啡的峰值镇痛作用为剂量依赖性的,且硬膜外游离硫酸吗啡的峰值镇痛潜伏期大于硬膜外DTC401的峰值镇痛潜伏期,它显著大于皮下给予游离硫酸吗啡的峰值镇痛潜伏期(就每一个比较而言,P<0.05)。
在图1中及通过在图3中对于DTC401的曲线下大的面积值(AUC)容易地看出在硬膜外给予DTC401的动物中镇痛作用显著延长。以250μg剂量(对于DTC401和游离硫酸吗啡而言,它产生接近100%MPA的峰值作用),对于DTC401而言,降低到50%MPA的时间是3.4天,与之相比硫酸吗啡为0.17天。
D.呼吸抑制
使用脉搏血氧计对呼吸抑制定量。将动物由笼中转移出来,放置在聚苯乙烯大鼠约束室(restraints)内(Plas Labs,Lansing,MI)并使其适应环境5分钟。在基线及给予单独剂量硬膜外大剂量硫酸吗啡或DTC401后在特定时间点,将脉搏血氧计探头置于大鼠的右后爪上测定氧饱和(Ohmeta Medical Systems,model 3740,Madison,WI)。DTC401和游离硫酸吗啡的剂量范围在10-2000μg。在每一个数据点用脉搏血氧计测定5-6只动物,除了在50μg剂量使用3只动物。在实际一段时间内连续监测血红蛋白氧饱和(SpO2)的百分数的脉搏血氧计值。在3分钟的记录期内获得的最大值规定为氧饱和。
图4描述以不同剂量的DTC401和硫酸吗啡通过脉搏血氧计测定的血红蛋白的氧饱和(SpO2)百分数的时间过程。如图5所示随着硫酸吗啡剂量的增加,在呼吸抑制方面的剂量依赖性增加;其中由同样剂量的DTC401产生最小的呼吸抑制。另一方面,在硬膜外给予游离硫酸吗啡或DTC401后1小时内,观察到在SpO2方面最大的降低并且对于两种制剂中任何一种均未观察到延迟的呼吸抑制。在硫酸吗啡和DTC401间在峰值呼吸抑制上的差异为统计学上显著(P<0.01)。
E.药动力学
在硬膜外单独给予250μg剂量的DTC401或游离硫酸吗啡后在适当的时点通过测定在外周血和在CSF中吗啡的浓度,来进行药动力学研究。在硬膜外给予上述DTC401后0.5、1小时及1、3、5、8、天取样和在硬膜外给予游离硫酸吗啡后0.5、1、3、6、12、24小时取样。使用氟烷麻醉一组3-4只动物,通过小脑延髓池穿刺和心脏穿刺分别收集CSF样和血样。然后用过量氟烷处死所述动物。通过离心从血液中分离血清并与CSF样一起于-80℃储存,直到用放射免疫测定法(RIA)进一步分析。
使用如制造商所推荐的对吗啡高度特异性的市场上可以买到的RIA仪[Coat-A-CountTM Serum Morphine,Diagnostic Products Corp.,LosAngeles,CA]测定血清和CSF中的吗啡浓度。所有测定一式两份。
图6显示注射250μg游离硫酸吗啡或DTC401的动物中小脑延髓池CSF和血清吗啡浓度。表1归纳了药动力学参数。硬膜外给予DTC401后峰值CSF和血清吗啡浓度分别为给予硫酸吗啡后的32%和5.9%。DTC401的终点CSF半衰期(β)为82小时,而硫酸吗啡为2.6小时。对于DTC401而言,曲线下CSF面积(AUC)与硫酸吗啡相比增加2.7倍,而血浆AUC非常类似。通过拟合所述药动力学曲线为双指数函数计算半衰期。使用RSTRIP程序以便完成通过反复非线性回归拟合的曲线。
实施例3
较大规模地制备DTC401
步骤1将包含46.5μM二油酰磷脂酰胆碱(Avanti Polar Lipids)、10.5μM二棕榈酰磷脂酰甘油(Avanti Polar Lipids)、75μM胆固醇(Sigma Chemical Co.)和9.0μM三油酸甘油酯(Avanti Polar Lipids)的5毫升氯仿溶液加入50毫升清洁的不锈铜离心试管中。这种溶液称为脂质成分。
步骤2将包含20mg/ml硫酸吗啡五水合物(Mallinckrodt ChemicalInc.)和0.1N盐酸的5毫升水溶液加入上述含有所述脂质成分的不锈钢离心试管中。
步骤3为了制备油包水型乳剂,将“步骤2”的混合物用TK混合器(AutoHomoMixer,Model M,Tokushu Kika,Osaka,Japan)以每分钟9000转(rpm)的转速搅拌9分钟。
步骤4为了使所述氯仿小球体悬浮在水中,将含有4%葡萄糖和40mM赖氨酸的25毫升水溶液加入步骤3的油包水乳剂中,然后以3500rpm的转速混合120秒钟。
步骤5为了得到所述多孔脂质体,将在所述离心试管中的氯仿小球悬浮液倒入含有4%葡萄糖和40mM赖氨酸的25毫升水溶液的1000毫升Erlenmeyer烧瓶的底部。在振动的水浴中将所述烧瓶在37℃保温,用20分钟,以7L/min将氮气流通入所述烧瓶中,以便缓慢蒸发氯仿。然后通过用4倍生理盐水稀释所述悬浮液并以600×g离心所述悬浮液5分钟分离该脂质体;倾出其上清液,将所述脂质体颗粒悬浮在50ml生理盐水中。通过以600×g离心5分钟,再次分离该脂质体。再倾出其上清液并将所述脂质体颗粒悬浮在生理盐水中。
本发明的上述介绍是示范性的,为了说明和解释的目的。应该理解只要不违背本发明的范围和精神,可行各种改动。因此,下列权利要求书可以理解为包括了所有的这类改动。
表1
在硬膜外注射250μg后的药动力学参数
MS,硫酸吗啡;Cmax最大浓度;t1/2α,开始半衰期;t1/2β,终点半衰期;AUC,所述曲线下面积。
DTC401 | MS | |
Cmax(ng/ml),CSF | 1960±1280 | 6060±3590 |
Cmax(ng/ml),Serum | 86±20 | 1460±97 |
tα(hr),CSF | 5.0 | 0.85 |
tβ(hr),CSF | 82 | 2.6 |
tα(days),Serum | 0.48 | 0.68 |
tβ(hr),Serum | 49 | 5.0 |
AUC(ng*days*ml-1)CSF | 1170 | 432 |
AUC(ng*days*ml-1)Serum | 53 | 58 |
Claims (33)
1.硬膜外给予脊椎动物治疗性化合物的方法包括在所述化合物的具有缓释速度的药物传递系统中包封所述化合物并将所述药物传递系统硬膜外导入所述脊椎动物中。
2.权利要求1的方法,其中所述脊椎动物为哺乳动物。
3.权利要求2的方法,其中所述哺乳动物为人类。
4.权利要求1的方法,其中以单独剂量给予所述传递系统。
5.权利要求1的方法,其中所述药物传递系统为分散体系。
6.权利要求5的方法,其中所述药物传递系统包括脂质基制剂。
7.权利要求5的方法,其中所述药物传递系统包括脂质体制剂。
8.权利要求5的方法,其中所述药物传递系统包括多孔脂质体制剂。
9.权利要求7或8的方法,其中所述治疗性化合物为类鸦片。
10.权利要求7或8的方法,其中所述治疗性化合物为肽或peptidomimetic。
11.权利要求9的方法,其中所述治疗性化合物为硫酸吗啡。
12.权利要求9的方法,其中所述治疗性化合物为氢吗啡酮。
13.权利要求7或8的方法,其中所述治疗性化合物选自可待因、二氢可待因酮、羟甲左吗喃、羟氢可待酮、羟氢吗啡酮、二乙酰基吗啡、叔丁啡、环丁甲羟氢吗啡、环丁羟吗喃、镇痛新、美散酮、芬太尼、噻哌苯胺(sufentanyl)和四唑芬太尼(alfentanyl)。
14.权利要求7或8的方法,其中所述治疗性化合物选自脑啡肽、内啡肽、casomorphin、kyotorphin和其生物活性断片。
15.权利要求7或8的方法,其中所述治疗性化合物为鸦片拮抗剂。
16.权利要求15的方法,其中所述鸦片拮抗剂选自纳洛酮和环丙甲羟二羟吗啡酮。
17.权利要求7或8的方法,其中所述治疗性化合物为神经营养因子。
18.权利要求17的方法,其中所述神经营养因子选自胰岛素样的生长因子、睫状神经营养因子、神经生长因子、多巴胺、肾上腺素、去甲肾上腺素、γ-氨基丁酸和新斯的明。
19.权利要求1的方法,其中经硬膜外导管导入所述药物传递系统。
20.权利要求19的方法,其中自颈部向下插入硬膜外导管。
21.权利要求1的方法,其中经插入硬膜外腔的皮下注射针头导入所述药物传递系统。
22.在给予镇痛化合物的患者中改善呼吸抑制的方法包括硬膜外给予该患者单独剂量的包封在缓释脂质体制剂中的镇痛化合物。
23.权利要求22的方法,其中所述脂质体制剂包括多孔脂质体。
24.权利要求23的方法,其中所述镇痛化合物为类鸦片。
25.权利要求24的方法,其中所述类鸦片为硫酸吗啡。
26.权利要求24的方法,其中所述类鸦片选自氢吗啡酮、可待因、二氢可待因酮、羟甲左吗喃、羟氢可待酮、羟氢吗啡酮、二乙酰基吗啡、叔丁啡、环丁甲羟氢吗啡、环丁羟吗喃、镇痛新、美散酮、芬太尼、噻哌苯胺和四唑芬太尼。
27.权利要求25的方法,其中所述剂量包含约1mg-60mg的硫酸吗啡。
28.权利要求1的方法,其中所述药物传递系统包含聚合物基质。
29.权利要求28的方法,其中所述药物传递系统为非分散性的。
30.权利要求28的方法,其中所述聚合物基质选自聚交酯、聚乙交酯、聚酯、聚胺酯、聚酰胺和其混合物。
31.权利要求29的方法,其中所述聚合物基质为选自球形、圆柱形和板形的形式。
32.权利要求28的方法,其中所述药物传递系统为分散体系。
33.权利要求32的方法,其中所述聚合物基质为微球形式。
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US08/502,569 | 1995-07-14 | ||
US08/502,569 US5931809A (en) | 1995-07-14 | 1995-07-14 | Epidural administration of therapeutic compounds with sustained rate of release |
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CN1195286A true CN1195286A (zh) | 1998-10-07 |
CN1085944C CN1085944C (zh) | 2002-06-05 |
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CN96196697A Expired - Lifetime CN1085944C (zh) | 1995-07-14 | 1996-07-12 | 以延缓释放速度硬膜外给予治疗性化合物 |
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US (2) | US5931809A (zh) |
EP (2) | EP0839027A4 (zh) |
JP (4) | JP4592119B2 (zh) |
KR (2) | KR20060012027A (zh) |
CN (1) | CN1085944C (zh) |
AU (1) | AU699177B2 (zh) |
BR (1) | BR9609717A (zh) |
CA (1) | CA2226870C (zh) |
HK (1) | HK1014881A1 (zh) |
NO (1) | NO326261B1 (zh) |
NZ (1) | NZ312963A (zh) |
RU (1) | RU2215522C2 (zh) |
WO (1) | WO1997003652A1 (zh) |
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- 1996-07-12 KR KR1020057023867A patent/KR20060012027A/ko not_active Application Discontinuation
- 1996-07-12 AU AU64911/96A patent/AU699177B2/en not_active Ceased
- 1996-07-12 EP EP08017456.8A patent/EP2036542B1/en not_active Expired - Lifetime
- 1996-07-12 WO PCT/US1996/011642 patent/WO1997003652A1/en not_active Application Discontinuation
- 1996-07-12 CN CN96196697A patent/CN1085944C/zh not_active Expired - Lifetime
- 1996-07-12 JP JP50535497A patent/JP4592119B2/ja not_active Expired - Lifetime
- 1996-07-12 KR KR1019980700208A patent/KR100593722B1/ko not_active IP Right Cessation
- 1996-07-12 RU RU98102450/14A patent/RU2215522C2/ru not_active IP Right Cessation
-
1997
- 1997-09-16 US US08/931,867 patent/US6428529B1/en not_active Expired - Lifetime
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1998
- 1998-01-13 NO NO19980146A patent/NO326261B1/no not_active IP Right Cessation
-
1999
- 1999-01-15 HK HK99100207A patent/HK1014881A1/xx not_active IP Right Cessation
-
2008
- 2008-01-24 JP JP2008013960A patent/JP2008143911A/ja not_active Withdrawn
-
2009
- 2009-10-02 JP JP2009230418A patent/JP2010031030A/ja active Pending
- 2009-10-02 JP JP2009230419A patent/JP2010043104A/ja active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102462662A (zh) * | 2010-08-16 | 2012-05-23 | 重庆富进生物医药有限公司 | 脂质体包裹重组人睫状神经营养因子 |
CN114949220A (zh) * | 2022-01-30 | 2022-08-30 | 浙江大学 | 一种靶向损伤节段背根神经节的pH响应镇痛药及其应用 |
CN114949220B (zh) * | 2022-01-30 | 2023-09-22 | 浙江大学 | 一种靶向损伤节段背根神经节的pH响应镇痛药及其应用 |
Also Published As
Publication number | Publication date |
---|---|
AU699177B2 (en) | 1998-11-26 |
KR20060012027A (ko) | 2006-02-06 |
KR19990028906A (ko) | 1999-04-15 |
EP0839027A4 (en) | 2000-12-06 |
US20020065506A1 (en) | 2002-05-30 |
KR100593722B1 (ko) | 2007-04-25 |
CA2226870A1 (en) | 1997-02-06 |
CN1085944C (zh) | 2002-06-05 |
JP2008143911A (ja) | 2008-06-26 |
US5931809A (en) | 1999-08-03 |
CA2226870C (en) | 2005-05-17 |
NZ312963A (en) | 1999-06-29 |
EP0839027A1 (en) | 1998-05-06 |
BR9609717A (pt) | 1999-12-21 |
AU6491196A (en) | 1997-02-18 |
NO326261B1 (no) | 2008-10-27 |
US6428529B1 (en) | 2002-08-06 |
RU2215522C2 (ru) | 2003-11-10 |
NO980146D0 (no) | 1998-01-13 |
JP2010031030A (ja) | 2010-02-12 |
JP4592119B2 (ja) | 2010-12-01 |
HK1014881A1 (en) | 1999-10-08 |
WO1997003652A1 (en) | 1997-02-06 |
EP2036542A1 (en) | 2009-03-18 |
JPH11508900A (ja) | 1999-08-03 |
MX9800391A (es) | 1998-09-30 |
EP2036542B1 (en) | 2016-04-20 |
NO980146L (no) | 1998-03-13 |
JP2010043104A (ja) | 2010-02-25 |
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