CN101600417B - 用于神经递质的经鼻施用的控制释放递送*** - Google Patents
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Abstract
本发明涉及用于将神经递质例如多巴胺经鼻给药的盖仑凝胶制剂。本发明的具体的亲脂性或部分亲脂性的***产生活性成分在血浆和脑中的高的生物利用度,所述高的生物利用度是由持续的血清水平和/或从鼻子到脑的直接转运或部分直接转运引起的。
Description
发明领域
本发明一般地涉及用于在经鼻施用之后对***循环和/或脑控制释放神经递质的制剂。更具体地,本发明涉及通过经鼻给药对脑递送多巴胺。
发明背景
越来越多的证据认为作用于脑的化合物在控制受脑中受体影响的病症(例如,抑郁症、帕金森氏病、阿尔茨海默氏病、甚至是丧失***)的调节作用,所述作用于脑的化合物例如神经类固醇(例如,雄激素、孕激素)或神经递质(例如,多巴胺、3,4-二羟基苯基丙氨酸(左旋多巴,L-DOPA))。
神经类固醇作为几种神经递质的调节剂,作为***或抑制剂起作用。神经递质是接转、放大和调节神经元和另一个细胞之间的电信号的化学品。一些神经递质是兴奋性的,其它的主要是抑制性的。在很多情形里,正如多巴胺的情况一样,它是决定递质为兴奋性的还是抑制性的受体。
脑漂浮在大约150ml的脑脊液(CSF)中,所述脑脊液缓慢地向下循环通过四个脑室,向上通过蛛网膜下腔并且通过蛛网膜绒毛(arachnoid vili)排出到脑静脉中。因为脑没有淋巴***,CSF起到部分替代作用。尽管脑和CSF通过一定程度可渗透的软脑膜分开,但是血-脑脊液屏障和血脑屏障(BBB)代表着针对不合需要的血液物质的真正的保护。
BBB为脑产生受到保护的化学环境,其中某些分子可以执行与那些分子在身体的其余部分所执行的功能无关的功能。这对于例如神经递质多巴胺是特别重要的,所述多巴胺在作为输注施用时适合用于心脏病发作或肾衰竭,但是不适合于帕金森氏病的治疗,这是因为在通过这种途径(或经口给药)时,其不能通过BBB。
为了开发用于中枢神经***(CNS)的病症的有效药物,已经研究了经鼻递送。在经鼻施用之后,分子的摄取是通过血脑屏障、还是通过鼻腔与CSF之间的直接转运、还是通过所述两种途径仍是需要讨论的问题。在第一种情况中,分子在从鼻粘膜吸收之后必须从***循环跨过BBB。因为还有分子从脑外流,分子可能在不同的时期出现在脑中和血液中,具有不同的动力学或以不同的方法代谢。
经鼻药物递送提供许多优点,包括有可能直接进入脑、由于鼻中存在大量的毛细血管引起的迅速吸附、作用的快速起效、避免了肝脏的首过代谢、对于慢性药物的适用性、和容易给药。还已知的是,与大的和/或离子化的分子相反,具有充分低的分子量的亲脂性药物化合物一般是容易被鼻粘膜所吸收的。
因为药物进入到脑中的扩散似乎是主要取决于它们的物理化学性质,对于目前研究的大多数药物来说,在脑组织中检测到的总量通常只有经鼻给药剂量的2-3%。因此,关于制剂对这种摄取的影响的研究长久以来一直需要,以便确定可以增加脑利用度的制剂。
然而,长时间保持恒定的体内治疗药物浓度,特别是在脑中长时间保持恒定的体内治疗药物浓度是有问题的。治疗剂从沉积位置的快速经粘膜清除以及鼻腔中酶的存在(所述酶可以引起治疗剂的降解)产生短的用于吸收的时间跨度。另外,对调节为脑直接递送分子的机制以及必要条件的了解尚不充分。
在本领域中已经进行许多尝试,试图克服这些限制。GB1987000012176描述了使用生物粘性的微球体来增加在鼻腔中的停留时间。还发现使用增强剂改善鼻粘膜的渗透性,并且稳定剂阻止药物降解。PCT/GB98/01147(美国专利6,432,440)描述了使用原位凝胶化的果胶制剂。
Bayne的美国再公告专利RE29,892公开了通过给予包括多巴胺和一种肼化物的组合物来提高脑组织中的多巴胺浓度的方法。所公开的方法允许将组合物局部、经直肠、经口、或非肠道给药。优选的组合物包括肼化合物例如L-α-肼基-α-低级烷基-3,4-二羟基苯基丙酸和左旋多巴及其药学接受的盐。
Haffner等人的美国专利4,826,852公开了给予麦角碱基(ergolinyl)化合物来增加哺乳动物脑组织中的多巴胺浓度的方法。Haffner的特定目的是治疗精神病例如精神***症。
另外,Wenzel等人的美国专利5,624,960公开了通过口服给予包含左旋多巴和卡比多巴的组合物来治疗帕金森氏病。Mandel等人的美国专利6,319,905公开了通过基因治疗紧密地调节哺乳动物脑中的左旋多巴的产生。使用了调节剂例如四氢蝶呤(PH4)来控制多巴胺的生成。EP0160501A2公开了包含儿茶酚胺、乳化剂、分散剂和缓释剂。US6310089B1公开了用于鼻内给药多巴胺受体的部分或完全D1激动剂,其中在制备微粒的中间步骤使用水包油乳剂。
需要鉴定增加脑对神经递质(特别是多巴胺)的利用度的制剂。神经递质可以调节或控制情绪的管理以及相关的精神性障碍(例如抑郁症)。鉴定可以增加多巴胺的生物利用度的制剂为治疗与脑中多巴胺不足有关的疾病提供了可能性,所述疾病尤其是例如抑郁症、帕金森氏病、注意力缺乏活动过强病症(ADHD)、或毒瘾或酒瘾。
发明内容
本发明人出人意料地发现,将各种神经递质药物结合在具体的亲脂性或部分亲脂性的***中产生更高的生物利用度,其通常是由于血浆和CSF中的持续的血清水平引起的。
本发明包括用于经鼻施用的制剂,包括:(a)至少一种活性的神经递质药物;(b)至少一种亲脂性载体;和(c)至少一种表面活性剂,其量对于在制剂接触水时就地生成乳液是有效的,所述制剂还包括粘度调节剂。
在本发明的一个方面中,活性成分是神经递质药物。优选地,所述神经递质是多巴胺。优选多巴胺以0.2-6重量%、优选0.2-4重量%、更优选0.2-2重量%、最优选大约2重量%的量被包括在制剂中。
优选地,亲脂性载体包括油。更优选地,所述油是植物油。最优选地,所述油是蓖麻油。
本发明的优选实施方案包括占制剂的30-98重量%、优选60-98重量%、更优选75-95重量%、更优选85%-95重量%、最优选大约90重量%的量的油。
另一个实施方案的特征在于所述表面活性剂选自卵磷脂、多元醇的脂肪酸酯、山梨聚糖的脂肪酸酯、聚氧乙烯山梨聚糖的脂肪酸酯、聚氧化乙烯的脂肪酸酯、蔗糖的脂肪酸酯、聚甘油的脂肪酸酯,和/或至少一种湿润剂选自山梨醇、甘油、聚乙二醇、和聚乙二醇甘油脂肪酸酯。优选地,组分(c)包括油酰基聚乙二醇甘油酯或油酰基聚乙二醇甘油酯的混合物。
组分(c)以1-20重量%、优选1-10重量%、更优选1-5重量 %、最优选大约4重量%的量被包括在制剂中。
本发明的制剂还包括粘度调节剂。优选地,所述粘度调节剂包括选自以下的增稠剂或胶凝剂:纤维素和纤维素衍生物、聚糖、卡波姆、聚乙烯醇、聚维酮、胶体二氧化硅、鲸蜡醇、硬脂酸、蜂蜡、矿脂、甘油三酯和羊毛脂、或其混合物。更优选地,所述增粘剂是胶体二氧化硅。
所述粘度调节剂以0.5-10重量%、优选0.5-5重量%、更优选1-3重量%、最优选大约3重量%的量被包括在制剂中。
尽管不希望束缚于理论,但是认为本发明的盖仑制剂的经鼻给药能够恢复分子的选择性作用,这样又可以提供新的临床应用。认为这种作用是由于本发明的盖仑凝胶制剂使得有可能进入脑中。经鼻施用本发明的盖仑制剂产生出人意料的和与常规制剂相比不同的化合物对脑的作用。
附图简述
图1示出了经鼻给药的多巴胺凝胶剂对抑郁大鼠的不动性和攀爬的影响。
图2表示在将多巴胺经鼻给药之后在伏核和新纹状体中的多巴胺和代谢物的浓度。
发明详述
本发明的盖仑凝胶制剂是化学上和物理上稳定的,并且可以为药理学活性物质的悬浮液或溶液。优选地,将本发明的盖仑凝胶制剂填充到即使在较高的粘度下也能够精确递送上述制剂剂量的不含防腐剂的设备中。
在将本发明的盖仑凝胶制剂经鼻施用之后,活性成分或活性成分粒子有效地被截留在沉积位置并且以可预测的速率被吸收通过患者的粘膜,从而限制可能的由代谢酶和/或蛋白结合引起的减活。
还应该理解,本文中使用的术语和措辞具有与其各自相应的调查和研究领域相对应的这种术语和措辞的普通含义,除非本文中规定了其具有特定的含义。
术语“更高的利用度”应该是指在施用神经递质之后,在延长的时间段保持显著的和恒定的体内,特别是在脑中的治疗药物浓度。
A.神经递质
神经递质例如肾上腺素和多巴胺包含典型地从氨基酸酪氨酸(tryosine)合成的儿茶酚部分。
多巴胺或左旋多巴通常是从氨基酪胺合成的。其它神经递质通常由突触前神经元的末梢中的突触小泡限定并且包含药物,其在适当时间响应于充分量的刺激而释放,以便诱导突触后细胞的应答;将所述药物离子电渗到突触间隙中诱导相同的应答;并且该物质迅速地降解,使得电位复位。
已知具有各种用途的其它儿茶酚胺类包括肾上腺素、去甲肾上腺素、血清素。
神经递质药物以0.2-6重量%、优选0.2-4重量%、更优选0.2-2重量%、最优选大约2重量%的量被包括在制剂中。
B.亲脂性载体
本发明的载体用于使本发明的各种组分乳化或支持本发明的各种组分。为此,所述载体具有亲脂性的性质或特征。适合的油类家族包括脂肪酸和例如无机油和植物油的油类。特别地,衍生自植物的脂肪酸和油类特别有用。直链和支链的酸类和油类都是有用的,包括具有各种水平饱和度和取代作用的那些油类和酸类。尤其是包括甲酸、乙酸、丙酸、丁酸、戊酸、己酸、庚酸(emanthic acid)、辛酸、壬酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸和硬脂酸的链长都是有用的油和酸部分的代表。
术语“亲脂性载体”应该包括但不限于植物油,例如蓖麻油、豆油、芝麻油、或花生油,脂肪酸酯例如油酸乙酯和油酸油酯、肉豆蔻酸异丙酯、中链甘油三酯、脂肪酸的甘油酯,或聚乙二醇,磷脂,白色软石蜡,或氢化蓖麻油,或其混合物。在一个方面中,还可 以将活性成分结合在油混合物中,在一个优选的方面中,所述植物油是蓖麻油。
构成有效量的亲脂性载体的特定量取决于在制剂中使用的特定的粘度调节剂。因此,列举用于本发明的具体制剂中的具体量是不实际的。然而,亲脂性载体通常以占制剂的30-98重量%、优选60-98重量%、更优选75-95重量%、更优选85%-95重量%、最优选大约90重量%的量存在。
C.表面活性剂
本发明的表面活性剂或表面活化剂用于降低本发明的组合物中的表面张力。表面活化剂通常被认为是同时具有亲水性和疏水性特征的那些组合物。表面活性剂的亲脂性特征倾向于采取悬垂部分的形式,所述悬垂部分即使有也是仅有很少的电荷。相反,表面活性剂的亲水性特征倾向于是带电的,并且还指示该表面活性剂的所属类别。例如,可用于本发明的表面活性剂包括非离子型表面活性剂、离子型表面活性剂、两性表面活性剂、和阳离子型表面活性剂。
组分(c)为具有降低表面张力活性的化合物或化合物的混合物,包括至少一种表面活性剂和/或至少一种湿润剂,所述表面活性剂例如但不限于卵磷脂、多元醇的脂肪酸酯、山梨聚糖的脂肪酸酯、聚氧乙烯山梨聚糖的脂肪酸酯、聚氧乙烯的脂肪酸酯、蔗糖的脂肪酸酯、聚甘油的脂肪酸酯,所述湿润剂例如山梨醇、甘油、聚乙二醇、或聚乙二醇甘油脂肪酸酯。然而,特别有用的是油酰基聚乙二醇甘油酯(例如 M 1944 CS,得自Gattefosse(Saint-Priest,France))。
在另一个方面中,可以将活性成分结合在表面活性剂混合物中。构成有效量的表面活性剂的特定量取决于在制剂中使用的特定 的油或油混合物。因此,列举用于本发明的具体制剂中的具体量是不实际的。然而,表面活性剂通常以1-20重量%、优选1-10重量%、更优选1-5重量%、最优选大约4重量%的量存在于制剂中。D.粘度调节剂
术语“粘度调节剂”是指增稠剂或胶凝剂。其实例包括但不限于纤维素及其衍生物、聚糖、卡波姆、聚乙烯醇、聚维酮、胶体二氧化硅、鲸蜡醇、硬脂酸、蜂蜡、矿脂、甘油三酯、羊毛脂等。优选的粘度调节剂是胶体二氧化硅(例如ACROSEL 得自Degussa)。
还有可能将活性成分结合在增稠剂或胶凝剂的混合物中。构成有效量的增稠剂/胶凝剂的特定量取决于在制剂中使用的特定的油或油混合物。因此,列举用于本发明的具体制剂中的具体量是不实际的。然而,增稠剂/胶凝剂通常以0.5-10重量%、优选0.5-5重量%、更优选1-3重量%、最优选大约3重量%的量存在于制剂中。表重量%
可用的 | 优选的 | 更优选的 | |
神经递质 | 0.5-6 | 2-4 | 0.5-2 |
亲脂性载体 | 30-98 | 60-98 | 85-95 |
表面活性剂 | 1-20 | 1-10 | 1-5 |
粘度调节剂 | 0.5-10 | 0.5-5 | 1-3 |
制剂
通常,可以通过以下常规方法非常容易地制备本发明的盖仑制剂:
将亲脂性载体和乳化剂填充到搅拌器容器中并且混入大约75%的粘度调节剂。在搅拌下加入活性成分,得到活性成分的均质分散 体。然后,用其余的粘度调节剂将制剂调节到必要的粘度。
优选将制剂填充到不含防腐剂的容器中。
因为神经递质可能在水中具有低的溶解度水平,其从制剂中的释放是吸附的限速步骤。已经出人意料地发现,将活性剂结合在本发明的包含适合的表面活性剂的含油制剂中产生生理学的血清水平并且产生随时间为稳态的、持续的激素作用。
由于神经递质药物在含油载体中的溶解度以及因为制剂的粘度使其长时间保持在粘膜上,神经递质药物的释放是持续的。
在制剂接触粘膜的湿度时,活性成分的沉淀被表面活性剂形成包含活性成分的油滴的能力所阻碍。因此,通过向制剂中加入适合的表面活性剂,活性成分的溶出模式变得更有利和更有效,因为在溶出方面没有大的变化性,这样确保了生物等效性。
还可以将本发明的活性成分以经过处理的形式,例如尤其是微球体、脂质体的形式引入到制剂中。
还可以将本发明的制剂加工为粉末形式,例如通过冷冻干燥或喷雾干燥。表1.最优选的制剂
化合物 | 每个容器的量 | 每次喷雾的递送量 |
多巴胺 | 2% | ≈2.8mg |
胶体二氧化硅 | 3% | ≈4.2mg |
油酰基聚乙二醇-甘油酯 | 4% | ≈5.6mg |
蓖麻油 | 91% | ≈127.4mg |
具体实施方式
以下实施例意在进一步说明而不是用于限制本发明的实施方案。
实施例1:对大鼠经鼻给药多巴胺
将本发明制剂的多巴胺(DA)凝胶经鼻给药大鼠,将所述大鼠用于验证的“强迫游泳试验”。如图1所示,多巴胺的给药产生抗抑郁样作用。如图2所示,在通过本发明的制剂经鼻给药多巴胺之后,观察到在新纹状体和复侧纹状体(伏核)中的强烈的多巴胺能活性。
通常,在观察到抗抑郁作用之前,抗抑郁药必须服用较长的时间。出人意料的是,在对大鼠经鼻施用多巴胺凝胶制剂之后,在数小时内出现抗抑郁作用并且没有任何副作用,例如已知在使用地昔帕明(冷漠)或氟西汀(体重损失)时已知的那些副作用。
在将多巴胺在本发明的凝胶制剂中经鼻施用之后,出人意料地发现,伏核和新纹状体中的多巴胺浓度非常迅速地增加超过1000%。这些结果与以前描述的那些不同。在将多巴胺水溶液对小鼠经鼻施用之后,Bjorn Jansson,Comprehensive Summaries of UppsalaDissertations from the Faculty of Pharmacy 305(2004),在嗅球中发现多巴胺,但是在四小时之后达峰值。在对大鼠经鼻施用多巴胺水溶液之后,Maria Dahlin,Comprehensive Summaries of UppsalaDissertations from the Faculty of Pharmacy 240(2000),在短时间之后在脑脊液(CSF)中发现多巴胺,但是化合物浓度从基线的增加比本发明的经鼻凝胶低得多。Ikeda等人,Chem.Pharm.Bull.40(8):2155-2158(1992)分别使用赋形剂羟基丙基纤维素(HPC)和氮酮(1-十二烷基氮杂环庚-2-酮)使经鼻给予的多巴胺的生物利用度有一定程度的提高。De Souza Silva等人,Synapse 27:294-302(1997)表明, 通过对大鼠经鼻施用左旋多巴甲酯水溶液(50mg/kg),新纹状体中的多巴胺水平可以增加约130%。代谢物3,4-二羟基苯基乙酸(DOPAC)和高香草酸(homovanillic acid,HVA)略有增加,与De Souza Silva等人,J.Neurochem.68(1):233-239(1997)中腹腔内给予左旋多巴甲酯的观察结果相反。
此外,多巴胺的代谢似乎是与以前的描述完全不同。非常出乎意料的是,如图2所示,脑脊液(CSF)中的多巴胺没有如通常所观察的那样被代谢为3,4-二羟基苯基乙酸(DOPAC)或高香草酸(HVA)。因此,这些结果证明,将多巴胺在本发明的凝胶制剂中经鼻施用可用于与脑中多巴胺不足有关的疾病的病因治疗,所述疾病例如帕金森氏病、注意力缺乏活动过强病症(ADHD)、或毒瘾和/或酒瘾。
在前述说明书、权利要求和/或附图中公开的特征可以分别地和以其任何组合作为用于实现本发明的多种形式的素材。
Claims (8)
1.用于经鼻施用的制剂,包括:(a)占制剂总量的0.2-6重量%的至少一种选自儿茶酚胺的神经递质;(b)占制剂总量30-98重量%的至少一种选自油的亲脂性载体;和(c)至少一种选自卵磷脂、多元醇的脂肪酸酯、山梨聚糖的脂肪酸酯、聚氧乙烯山梨聚糖的脂肪酸酯、聚氧化乙烯的脂肪酸酯、蔗糖的脂肪酸酯、聚甘油的脂肪酸酯的表面活性剂,和/或至少一种选自山梨醇、甘油、聚乙二醇、和聚乙二醇甘油脂肪酸酯或其混合物的湿润剂,其中组分(c)以1-20重量%的量被包括在制剂中,该量对于在制剂接触水时就地生成乳液是有效的,所述制剂还包括占制剂总量0.5-10重量%的为增稠剂或胶凝剂的粘度调节剂。
2.权利要求1的制剂,其中所述油是植物油。
3.权利要求2的制剂,其中所述油是蓖麻油。
4.权利要求1的制剂,其中组分(c)是油酰基聚乙二醇甘油酯的混合物。
5.权利要求1的制剂,其中所述粘度调节剂选自以下的增稠剂或胶凝剂:聚糖、卡波姆、聚乙烯醇、聚维酮、胶体二氧化硅、鲸蜡醇、硬脂酸、蜂蜡、矿脂、甘油三酯和羊毛脂、或其混合物。
6.权利要求1的制剂,其中所述粘度调节剂是纤维素。
7.权利要求5或6的制剂,其中所述粘度调节剂是胶体二氧化硅。
8.权利要求1的制剂,其中所述制剂由2%的多巴胺、3%的胶体二氧化硅、4%的油酰基聚乙二醇-甘油酯和91%的蓖麻油组成。
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- 2007-09-27 JP JP2009530783A patent/JP5248510B2/ja not_active Expired - Fee Related
- 2007-09-27 RU RU2009116609/15A patent/RU2480208C2/ru active
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2009
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