CN100536851C - 丙戊酸的磷脂衍生物及其混合物 - Google Patents
丙戊酸的磷脂衍生物及其混合物 Download PDFInfo
- Publication number
- CN100536851C CN100536851C CNB018151736A CN01815173A CN100536851C CN 100536851 C CN100536851 C CN 100536851C CN B018151736 A CNB018151736 A CN B018151736A CN 01815173 A CN01815173 A CN 01815173A CN 100536851 C CN100536851 C CN 100536851C
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- Prior art keywords
- vpa
- valproic acid
- phospholipid moiety
- pharmaceutical composition
- covalent bonding
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Abstract
本发明涉及一种化合物,即,丙戊酸的磷脂衍生物,包含所述化合物的组合物及其用于治疗癫痫、偏头痛、两极细胞病和疼痛的应用。
Description
技术领域
本发明涉及一种化合物,即,丙戊酸的磷脂衍生物,包含所述化合物的组合物及其用于治疗癫痫、偏头痛、两极细胞病和疼痛的应用。
背景技术
癫痫是神经病学疾病,特征是阵发性脑电活性瞬时障碍。癫痫发作可以是局限于脑内特定病灶的局部或病灶发作,或者是可沿整个脑部造成异常活动的全面发作。癫痫发作期间的脑功能障碍可表现为精神和感觉的故障,例如,健忘症、幻觉症、似曾相识状态等,运动元异常现象,如痉挛或全身痉挛或意识的丧失。在极端情况下,癫痫可退化为可能危及生命的epilepticus状况(DeLorenzo等人,《J.Clin.Neurophysiol.(临床神经生理学杂志)》(1995)12:316~325)。
丙戊酸(VPA)及其钠盐(丙戊酸钠,NaVPA)是报道得最多的抗癫痫药。这些药对治疗两极细胞病和预防偏头痛也是有效的。
虽然丙戊酸的临床使用价值已充分确立,但该化合物存在着一些重大缺陷。采用VPA的治疗经常伴随出现副作用诸如胃-肠刺激、骨髓抑制(尤其表现为再生障碍性贫血和血小板减少症)以及肝功能障碍。VPA据报道还具有产生畸形的作用,并且以VPA治疗的患者可能遭遇到恶心、呕吐、晕眩、意识模糊或镇静。
丙戊酸的另一个缺点是,由于药物清除率快故其半衰期短。结果,在慢性病患者治疗期间VPA的血浆含量水平波动,因此即使作为缓释制剂服用每日仍需几次服药。另外,由于是液体,丙戊酸作为口服剂量形式不那么理想。另一方面,丙戊酸钠虽是固体,但由于吸湿故具有稳定性差的特征。
曾多方努力试图克服VPA-诱导的副作用以及该药物不利的物理和药代动力学性质。所采取的大多数方法涉及VPA分子的改性。但是,尽管某些改性后药物去掉了副作用,但大多数情况下它们也丧失了治疗效果或效力大打折扣。
Mergen等人(J.Pharm.Pharmacol.(药物及药理学杂志)》(1991),43:815~816)描述丙戊酸与1,3-二棕榈酰甘油、1,2-二棕榈酰甘油或1,3-二氨基棕榈酰-丙-2-醇的共轭物。按照Mergen等人的出版物,仅后一种化合物发现具有抗癫痫活性,而VPA与甘油二酯的两种共轭物则不具活性。
Hadad等人(《Biopharmaceutics & Drug Disposition(生物药剂学及配置)》(1993),14:51~59)研究了1,4-丁二醇的二丙戊酸酯、甘油基三丙戊酸酯和丙戊酰胺的抗惊阙活性并与丙戊酸做了比较。它们的研究显示,只有1,4-丁二醇的二丙戊酸酯在所试验的模型系统之一中具有比VPA好的保护指数值。
美国专利4,654,370,授予Marriott和Paris,公开了以一或二摩尔丙戊酸酯化的甘油酯。这些化合物据发现具有与单独丙戊酸一样有用的治疗效果但不引起胃刺激。
美国专利4,988,731和5,212,326,都授予Meade,公开一类丙戊酸钠与丙戊酸的摩尔比等于1:1的低聚物,其生理性质类似于丙戊酸或丙戊酸钠,但却显示超卓的稳定特性。
美国专利4,558,070,授予Bauer和Shada,公开一种丙戊酸与钾、铯或铷之间的稳定络合物,可由4mol丙戊酸与1mol碱金属离子的组合生成。该丙戊酸的碱金属盐据报道具有改进的稳定性。
尽管在该领域作出持续不断的努力,但迄今仍未满足对一种具有改进药代动力学性质和全面超卓疗效指数的抗癫痫药剂的长期需要。
发明概述
本发明提供一种药物组合物,它包含一种化合物作为活性成分,该化合物包含共价键合在磷脂部分上的丙戊酸或其药剂学可接受衍生物。在本发明的优选实施方案中,磷脂部分选自缩醛磷脂、磷脂酸和磷酸甘油酯。更优选的化合物中,所述磷脂部分是溶血磷脂酰-乙醇胺、该胺的N-单-(C1~4)-烷基、N,N-二(C1~4)-烷基和季铵衍生物。
按照本发明,最优选的实施方案是一种包含丙戊酸的磷脂衍生物(以下称DP-VPA)的组合物,其中丙戊酸以酯的形式共价键合在磷脂部分的sn-2位置上。
目前最优选的DP-VPA化合物是1-棕榈酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸,亦称作1-十六烷酰-sn-甘油基-3-磷酸胆碱(以下记做C16-DP-VPA)和1-硬脂酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸,亦称作1-十八烷酰-sn-甘油基-3-磷酸胆碱(以下记做C18-DP-VPA)。
按照本发明的优选实施方案,该药物组合物包含DP-VPA化合物的混合物,更优选C16-DP-VPA与C18-DP-VPA的混合物(以下记做C16/C18-DP-VPA)。
在一种优选的实施方案中,C16-DP-VPA与C18-DP-VPA在C16/C18-DP-VPA混合物中的比例介于约1:20~约1:2(重量)。最优选的是这样的混合物,其中C16-DP-VPA与C18-DP-VPA的比例介于约1:5~约1:7w/w(相当于15±5% C16-DP-VPA:85±5% C18-DP-VPA(w/w))。
本发明的化合物和组合物可用于治疗中枢神经系统疾病,包括但不限于,癫痫、偏头痛、慢性疼痛和两极细胞疾病。
于是,按照本发明另一种实施方案,提供一种治疗某对象的中枢神经系统疾病的方法,包括给需要它的患者服用治疗有效数量的本发明化合物或药物组合物。
本发明的目的在本领域技术人员进一步研读下面公开内容,包括本发明具体实施方案详述之后就明白了。
附图简述
图1画出C16/C18-DP-VPA组合物的典型HPLC(高压液相色谱)图,其中C16-DP-VPA与C18-DP-VPA的比例介于15:85(w/w)。
图2A~B给出在人体对象一次口服0.625g C16/C18-DP-VPA(C16/C18比例=13%:87%w/w)之后,在不同时刻测定的C16-DP-VPA(2A)和C18-DP-VPA(2B)的血浆浓度。
发明详述
本发明涉及丙戊酸的磷脂衍生物、包含此类化合物及其混合物的药物组合物,以及它们在治疗神经病学疾病方面的应用。
DP-VPA分子公开在美国专利申请08/479,959和国际专利公开WO94/22483中,在此将其公开内容收作参考。
具体公开在上述申请中的是一种被称作“TVA 16”的分子,它是丙戊酸与1-十六烷酰-sn-甘油基-3-磷酸胆碱的1:1酯。TVA 16已证明具有显著抗惊阙活性并且比丙戊酸钠的效力更强。在本申请中,丙戊酸与1-十六烷酰-sn-甘油基-3-磷酸胆碱的1:1酯,或其化学名称1-棕榈酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸,以下称作C16-DP-VPA。
本申请公开的另一种实施方案是丙戊酸与1-十八烷酰-sn-甘油基-3-磷酸胆碱的1:1酯,或其化学名称1-硬脂酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸。该分子以下称作C18-DP-VPA。
本发明的DP-VPA化合物包括丙戊酸,或其药剂学可接受衍生物,与任何磷脂,优选磷酸甘油酯的共轭物。合适的磷脂包括但不限于,缩醛磷脂、磷脂酸及其磷-酯衍生物。优选的磷脂部分,按照本发明,包括溶血磷脂酰-乙醇胺、该胺的N-单-(C1~4)-烷基、N,N-二(C1~4)-烷基和季铵衍生物。目前在本发明化合物中最优选的磷脂是磷脂酰胆碱。
下面,结合本发明优选化合物具体地讨论位于甘油基-磷脂部分的位置sn-1处的脂肪酸残基的选择。然而,要知道,VPA或其药剂学可接受衍生物可在位置sn-1、sn-2共价地连接磷脂部分,或者在位置sn-3连接磷脂端基基团。相应地,VPA或其衍生物有可能通过相应磷脂酶PLA1、PLA2、PLC和PLD的作用裂解而释放出来,正如下面的路线1所示。
X=H或极性端基基团。
在本发明优选的实施方案中,VPA或其药剂学可接受衍生物在位置sn-2通过酯键连接磷脂,因此能够在磷脂酶A2作用下释放出VPA。在特别优选的实施方案中,VPA由酯键共价地连接到磷脂酰胆碱的sn-2位置。
术语“VPA的药剂学可接受衍生物”在本说明书中被用来指具有类似治疗活性的丙戊酸药剂学可接受类似物。这包括VPA与具有一个或多个双键和/或三键的饱和/或不饱和碳链的衍生物。在该分子的碳原子上的药剂学可接受取代基也是允许的,可包括,例如,卤素原子或1~5个碳原子的低级烷基基团。VPA的酰胺及其类似物,如上所述,也包括在本发明范围内。另外,对于那些具有不对称手性中心的化合物,本发明化合物包括光学活性异构体、外消旋物或其优选的混合物。
要知道,在本发明范围内,还有DP-VPA化合物的药剂学可接受盐。术语“药剂学可接受盐”是指本发明化合物的非毒性盐,包括但不限于,钠、钾、钙、镁、铵、烷基铵或胺衍生的盐。
虽然C18-DP-VPA与C16-DP-VPA二者都是强力抗惊阙剂,具有类似作用,但现已出乎意料地发现,这两种化合物在其药代动力学曲线上不同。C16-DP-VPA化合物,在一次口服后于血浆中表现出比C18-DP-VPA的半衰期显著长的半衰期。然而,C18-DP-VPA的血浆浓度,据发现达到峰值水平的时间比C16-DP-VPA分子的峰值水平来得迟。
现在此首次公开,C16-DP-VPA与C18-DP-VPA的混合物(以下称C16/C18-DP-VPA),与包含单独的C16-DP-VPA或者C18-DP-VPA的组合物相比,提供一个优点,即,显示更高的神经保护值和延长的疗效。
按照本发明,优选的组合物是这样的,其中C16-DP-VPA与C18-DP-VPA在C16/C18-DP-VPA混合物中的比例介于约1:20~约1:2(重量)。最优选的是这样的混合物,其中C16-DP-VPA与C18-DP-VPA在C16/C18-DP-VPA混合物中的比例介于约15±5%:85±5%(w/w)。
不拟囿于一种机理或理论,但据认为,在磷脂的位置sn-1处酯化的烷基部分的长度可决定DP-VPA分子的亲油性,并因此也决定其跨过细胞膜的运输。
替代地,同样也不拟囿于某种单一机理或理论,位置sn-1处的脂肪酸残基可决定DP-VPA共轭物,作为磷脂酶的底物的性质,并影响丙戊酸的调节释放,例如,借助提高磷脂酶A2(PLA2)对染病部位的活性。磷脂酶A2是一族酯酶,它能水解磷酸甘油酯分子中的sn-2酯键。已证明,在诸如癫痫之类的疾病中,PLA2的激活与癫痫的发作恰好吻合(Flynn和Wecker(1987)《J.Neurochem.(神经化学杂志)》48:1178~84;Bazan等人(1986)《Adv.Neurol.(神经病学进展)》44:879~902)。
还与磷脂酶A2活性的升高相关联的是两极细胞疾病和与发炎过程相关联的某些类型疼痛及偏头痛(Horrobin和Bennett(1999)《Prostaglandins Leukot Essent Fatty Acids》60:141~167)。
本发明化合物,由于本质为疏水的,故可以渗透生物膜和壁垒,从而促使药物向细胞或器官,例如向需要其作用的脑内的运输。
可以想见,丙戊酸部分在病灶部位的调节释放还可进一步改善药物的治疗指数,因为在潜在副作用和毒性减少的同时药物的效力预计将增加。丙戊酸可通过DP-VPA化合物在磷脂的位置sn-2处在磷脂酶A2或任何其他脂酶或酯酶作用下的裂解而释放出来。然而,并不排除该活性药物可能不同于原来的母体药物分子VPA,原因在于,在从其细胞内运输辅助剂中释放出来的同时某种或某些化学基团可能从其结构上被去除或加入,或者因为生理磷脂代谢的缘故。
重要的是,本发明的共轭物,即,共价地连接到磷脂部分上的丙戊酸或其药剂学可接受衍生物可能本身就是活性的。替代地,该脂-药物共轭物的共价键可在某些环境下裂解而释放该药理学活性药物。在后一种情况下,本发明化合物可看作是前体药物,就是说,治疗剂是从其运输辅助剂中释放出来的。
不论其作用机理究竟如何,有一点是清楚的,本发明化合物具有改进的治疗特性并且与VPA相比至少在以下两个方面更有效:(i)效力提高,以及(ii)副作用减少。
DP-VPA化合物在与VPA目前使用的剂量相比低得多的当量摩尔剂量下具有效果。此种治疗剂量的降低进而又降低了毒理学危险、伴随的副作用,同时也降低了与其他药物之间不希望的相互作用的危险。另外,DP-VPA分子据发现具有比VPA显著改善的药代动力学性质(例如,大大延长的在血清和脑组织中的半衰期)。因此,DP-VPA分子代表一类优异抗癫痫药物。
再者,本发明优选的药物组合物,即,包含C16-DP-VPA和C18-DP-VPA二者混合物的组合物可方便地从天然来源制备。
若一种DP-VPA分子能够从按照比较简单的程序由天然来源衍生的原料制备,那将是非常有利的。此种轻易可以获得的原料就是从蛋类或大豆卵磷脂制取的溶血-卵磷脂。大豆,由于是非动物源,因而是制备人类用药的优选原料。在由大豆衍生的典型氢化制备物中,1-棕榈酰-溶血卵磷脂的含量为约8~18%;1-硬脂酰-溶血卵磷脂的含量是80~90%(重量)。
纯C16-DP-VPA和C18-DP-VPA分子原本可以是化学合成的。替代地,纯C16-DP-VPA和C18-DP-VPA化合物可采用从天然来源获得的原料制备,即,C16-溶血卵磷脂和C18-溶血卵磷脂可从例如蛋或大豆中离析并提纯,然后用VPA酰化(=半天然源制备物)。
C16-DP-VPA和C18-DP-VPA,尤其以符合本发明优选比例范围的混合物形式使用时,已证明具有显著改进的治疗性能。此种优越性能的例子是DP-VPA在血清中显著延长的半衰期以及药物的高疗效。在血清中存留时间的改进有利于稳态药物含量水平的获得,以及沿治疗血液水平值上下波动的减少,以及给药频率减少到每日一至二次。
本发明组合物可通过口服给药、不经肠(例如,静脉点滴或腹腔内、皮下或肌肉注射)、局部(例如,经鼻施用或吸入)或者直肠给药。口服给药是目前较为优选的给药途径。
适合本发明化合物给药的制剂,不论化合物分开使用或作为混合物,包括但不限于,粉末、丸粒、乳剂、悬浮体或溶液,包括在水中或非水介质中的,片剂、胶囊、糖浆或溶液。
用于口服时,约0.5~20mg/kg体重每日的DP-VPA的数量是有用的,优选1~8mg/kg体重每日。剂量的确定取决于症状的严重程度以及对象对DP-VPA药物的响应。医师和本领域技术人员能够轻易地确定最佳剂量和剂量形式,以及服法和给药手段。
现在,通过下面的非限定性实例来说明本发明。
实施例:
实例1:DP-VPA的合成
该DP-VPA的合成是两段法。第一阶段的目标是制取丙戊酸酐,即,通过丙戊酸在乙酐溶液中在催化剂吡啶存在下加热。在第二阶段,借助丙戊酸酐与溶血卵磷脂之间的反应来制备DP-VPA。该反应在丙戊酸酐溶液中,借助4-二甲氨基吡啶的催化在90~100℃进行。
获得的产物的萃取和提纯分四步进行。第一阶段提纯包括未反应的丙戊酸酐、丙戊酸和催化剂(4-氨基吡啶)用丙酮进行萃取。获得的粗产物在第二阶段从溶液中沉淀并分离。获得的固体产物在第三阶段被洗去残留化合物。最后,产物数次从丙酮/乙醇溶液中重结晶,并在真空下除掉残留溶剂。产物收率为约80%。
C
18
-DP-VPA的合成路线
收率=85%
1-棕榈酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸(C16-DP-VPA)和1-硬脂酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸(C18-DP-VPA)化合物,分别利用溶血-硬脂酰-和溶血-棕榈酰-磷脂酰胆碱制成。
该溶血-硬脂酰-和溶血-棕榈酰-磷脂酰胆碱可利用本领域熟知的手段和程序从天然来源(例如,蛋类或大豆)中提纯出来(F.Gunstone(1999)《Fatty Acid and Lipid Chemistry(脂肪酸和油脂化学)》pp.87~99,Sapen出版社)。
替代地,这些原料可通过本领域已知的化学合成程序获得。
实例2:C16/C18-DP-VPA的合成
C16/C18-DP-VPA的混合物按照与实例1中描述的相同DP-VPA制备程序制成。区别在于,在混合物组合物的情况下,丙戊酸酐与溶血-卵磷脂的相互反应中,该溶血-卵磷脂是由大豆取得并通过氢化达到饱和的(S VPC-3,来自Lipoid公司,Ludwigshafen,德国)。
实例3:DP-VPA化合物的分析
对如上所述在实例2中合成的C16/C18-DP-VPA混合物进行分析化验以鉴定和证明其结构。含比例为13%:87%(重量)的1-棕榈酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸(C16-DP-VPA)和1-硬脂酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸(C18-DP-VPA)的产物的分析结果如下给出。
质谱
质子化DP-VPA分子按照ESI(+)测定的质量是C16-DP-VPA的为622.4~622.8;和C18-DP-VPA的为650.4~650.8。这与计算的分子量数值很好地吻合。
元素分析
按M.H2O计算的数值:C60.93%;H10.25%;N2.11%;P4.66%(M按照1-棕榈酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸的含量)。
测定的平均值是C60.72%;H10.58%;N2.09%;P4.56%。
这些数值与计算值很好地吻合。
薄层色谱(TLC)分析
TLC在硅胶60 F254上,后者又在铝片上,实施的,其中以氯仿:甲醇:水(65:35:5,v/v)作为洗脱液。探测用的喷雾试剂是4-甲氧基苯甲醛(5mL)、硫酸95~98%(5mL)、乙醇(100mL)和冰醋酸(1mL)的混合物。在片材上喷洒该试剂,然后以120~150℃的热空气加热。
TLC分析结果显示,在Rf介于0.58~0.60处有一个斑。
NMR分析数据
下面给出的典型NMR数据是对应于质子、碳-13和磷-31的。
1H NMR(CDCl3),δ(ppm):0.84-0.90(m,9H),1.24-1.27(宽s)+1.31-1.41(m)(都在34H),1.50-1.59(m,4H),2.21-2.28(t,2H),2.29-2.37(m,1H),3.35(s,9H),3.77-3.78(宽s,2H),3.88-3.96(m,2H),4.06-4.14(m,1H),4.30(宽s,2H),4.40-4.46(d,1H),5.18(m,1H).
13C NMR(CDCl3),δ(ppm):8.62(CH3),22.65(CH3),62.99[(CH3)3N],29.17,30.93,33.15,39.92,43.07,53.86,67.97,71.89,74.99,78.91(CH2和CH),182.21(CO),184.43(CO).
31P NMR(CDCl3),δ(pPm):-0.29(分别是D2O中的H3PO4).
HPLC分析
DP-VPA在下面的条件下接受HPLC分析:
仪器: 配备积分装置的液相色谱仪
柱: Zorbax Eclipse XDB C18,5μ,4.6 x 250mm
移动相: 甲醇-乙腈-水(85:15:5 v/v)
流速: 1.0mL/min
探测 UV@220nm
注射体积: 20μL
典型存留时间在下表中给出:
化合物名称 典型存留时间,min
1-棕榈酰-溶血卵磷脂(潜在杂质) 6
1-硬脂酰-溶血卵磷脂(潜在杂质) 8
1-棕榈酰-DP-VPA 12
1-硬脂酰-DP-VPA 18
所分析的上述比例为15%:85%(重量)的C16-DP-VPA/C18-DP-VPA混合物的典型HPLC色谱图载于图1中。
实例4:人体毒理学和安全性研究
进行了阶段I的安全性和耐受性临床试验,其中采用(比例为15%:85%w/w的C16-DP-VPA/C18-DP-VPA)C16-DP-VPA/C18-DP-VPA混合物在5%Poloxamer F-127+0.5%Tween-80中的溶液,以及口服给药路线。
该研究的设计方案为双盲法、安慰剂随机化。将它分为一次给药的部分,和每日重复,连服7日的部分。在每一部分中,剂量每7日递增一挡,倘若以前的剂量能很好地耐受的话。
在研究的第一部分中,从0.3125g到5gDP-VPA的5种剂量作为一次剂量给药,而在研究的第二部分中服用3种剂量作为重复剂量(0.3125g、0.625g和1.25g)。总共56个对象参加了这次研究:29个在第一部分;27个在第二部分。
在第一部分中,恶心和呕吐是报告得最普遍的副作用,在最高剂量(DP-VPA 5g)组中发病率最高的是,6个研究对象中有3个报告此情况。在次最高剂量组(DP-VPA 2.5g)中,6个研究对象中有2个报告恶心和呕吐。头痛、腹泻、腹痛和眩晕也有报告但根据调查者的意见,这些现象可能不是与所研究药物有关的。至于实验室结果、生命体征和ECG参数未发现任何趋势,并且所有对象的所有结果都维持在可接受的参数范围内。
在第二部分中,出现的副作用较少,仅有3个(胃灼热和腹痛)认为可能与药物有关,因为在服用后立即出现。24h内没有恶心的发病率;出现呕吐的有1例,且与研究的药物无关。
从生命体征、ECG、实验室试验、尿分析和体检的观点来看,耐受性非常好。
结论:在本研究的一次或重复给药部分中,临床和生理耐受性据发现在DP-VPA剂量最高至2.5g都非常好。可以得出这样的结论,DP-VPA的毒理学特性比母体药物VPA有显著改善。
实例5:人体药代动力学研究
为评估C16-DP-VPA和C18-DP-VPA化合物的药代动力学性质,对这些药物在人体对象内的血浆水平进行监测。
健康男性志愿者,18~40岁(每种试验剂量7个人)采用一次口服法接受0.3125g、0.625g或1.25g C16/C18-DP-VPA按C16/C18=13%:87%(w/w)比例的混合物。血样,每份10mL,在服药后的所示时刻从每个对象中抽取。样品收集后立即在4℃以1100g离心10min。C16-DP-VPA和C18-DP-VPA的血浆水平采用LC-MS/MS技术进行测定。一次口服0.625g C16/C18-DP-VPA之后24h内,监测C16-DP-VPA和C18-DP-VPA的血浆浓度曲线,分别示于图2A和2B中。
从人体研究的结果可以看出,C16-DP-VPA和C18-DP-VPA化合物具有不同的动力学曲线。虽然C16-DP-VPA在血浆中的峰值浓度在服药后6h的时刻达到,然而C18-DP-VPA的峰值却要迟2h才达到,即在服用后8h的时刻达到。
根据C16-DP-VPA和C18-DP-VPA化合物的血浆浓度-时间曲线计算出它们的终末血浆半衰期(t1/2)。发现这两种化合物的计算t1/2数值显著不同;C16-DP-VPA的t1/2是14.0±0.6h,而C18-DP-VPA的是8.3±1.3h。
总DP-VPA的t1/2测定值是10.6±1.2h,该数值综合了C16-DP-VPA和C18-DP-VPA两种化合物的药代动力学曲线。
在一次口服0.625g C16/C18-DP-VPA后各种不同时刻收集的样品中测定的C16-DP-VPA和C18-DP-VPA的血浆浓度(μg/mL)总括在表1中。
表1:在一次口服C16/C18-DP-VPA后人体血浆中的C16-DP-VPA和C18-DP-VPA浓度
时间(小时) | C<sub>16</sub>-DP-VPA(μg/ml) | C<sub>18</sub>-DP-VPA(μg/ml) | 比值C<sub>18</sub>/C<sub>16</sub> |
1 | 0.013±0.034 | 0.000±0.000 | |
3 | 0.167±0.094 | 0.058±0.043 | 0.35 |
6 | 0.397±0.172 | 0.818±0.292 | 2.1 |
8 | 0.385±0.140 | 1.175±0.137 | 3.1 |
10 | 0.368±0.182 | 0.949±0.254 | 2.6 |
12 | 0.318±0.150 | 0.698±0.163 | 2.2 |
从表1结果可以看出,C18-DP-VPA/C16-DP-VPA观察到的比例不同于预期的比例6.7(C18-DP-VPA:C16-DP-VPA比例87%:13%(重量))。
令人惊奇的是,C16-DP-VPA化合物在血浆中的存在比例据发现高于其在服用的混合物中的比例。此种现象在较短的时刻更为明显,即在C16/C18-DP-VPA服用后6h内。
C18/C16的最高比例,即,3.1(它仍然低于预期比例6.7)在服用C16/C18-DP-VPA以后8h的时刻达到。在此时刻,C18-DP-VPA在血浆中的水平达到其峰值浓度。
这些观察结果表明,C16-DP-VPA和C18-DP-VPA化合物展示不同的药代动力学特性。
实例6:C16-DP-VPA;C18-DP-VPA和C16/C18-DP-VPA混合物的抗惊阙作用(药效研究)
C16-DP-VPA、C18-DP-VPA和包含C16-DP-VPA和C18-DP-VPA的混合物的抗癫痫效力在老鼠体内做了评估。化合物的保护作用在以亚戊基四唑(PTZ)诱导的化学发作之后的不同时刻做了比较。
亚戊基四唑(PTZ)在老鼠体内诱导的发作模型是一种成熟的动物癫痫模型体系。PTZ皮下注射到对照例动物体内导致以下事件顺序:1~2min内,肌阵挛反射,随后是阵挛和强直性癫痫发作,每次持续约5~10s,发作严重程度随时间递增,最长达30min。80%的第一次发作在5min内观察到,100%在20min内。第二次发作通常在随后的6~10min内,并且以后每6min发作一次(若有的话)。
CD-1老鼠(25~30g)通过C16-DP-VPA或C18-DP-VPA或其混合物皮下注射(s.c.)接受预处理。用量相当于40mg/kg VPA。在指出的1、2或4h的时间后,致痉挛剂量的亚戊基四唑(85~100mg/kg)皮下注射到老鼠体内。PTZ给药后对动物监测1h以观察持续至少5s的阵挛发作事件的出现。保护作用以未经历第二次发作的动物数目除以试验动物总数来计算。
在表2A~D中,给出如上所述PTZ-诱导发作试验的结果,其中试验的组合物如下:
表A-C16-DP-VPA100%
表B-C16-DP-VPA/C18-DP-VPA比例50/50(重量)
表C-C16-DP-VPA/C18-DP-VPA比例10/90(重量)
表D-C18-DP-VPA 100%
n=经历了发作的动物数目
N=试验中动物总数
表2A~D:PTz-诱导的老鼠发作试验
A)C16-DP-VPA-100%
时间(h) | 第二次发作(n/N) | %保护率 |
1 | 4/8 | 50 |
2 | 6/8 | 25 |
4 | 5/8 | 38 |
B)C16-DP-VPA/C18-DP-VPA:50/50
时间(h) | 第二次发作(n/N) | %保护率 |
1 | 6/7 | 14 |
2 | 6/7 | 14 |
4 | 5/8 | 38 |
C)C16-DP-VPA/C18-DP-VPA:10/90
时间(h) | 第二次发作(n/N) | %保护率 |
1 | 5/7 | 29 |
2 | 6/7 | 14 |
4 | 2/8 | 75 |
D)C18-DP-VPA-100%
时间(h) | 第二次发作(n/N) | %保护率 |
1 | 5/6 | 17 |
2 | 6/7 | 14 |
4 | 1/7 | 86 |
如表2所示,C18-DP-VPA化合物对防止第二次发作更有效,显示86%的保护率,相比之下从100% C16-DP-VPA获得的保护率最高为50%。
C16-DP-VPA/C18-DP-VPA混合物表现中等,而C16-DP-VPA/C18-DP-VPA按10/90比例的效果(表C)则接近纯C18-DP-VPA化合物。然而,10/90的混合物在1h的保护作用比100% C18-DP-VPA更明显。
同样也重要的是,这两种DP-VPA所提供的保护作用具有不同的动力学。C18-DP-VPA的峰值活性是在服用PTZ后4h的时刻获得的,而纯C16-DP-VPA则在1h内已达到其最大疗效。
结论:尽管C16-DP-VPA和C18-DP-VPA作为抗惊阙剂具有相近的能力(即,相近的ED50值),但它们的疗效曲线却不同。C16-DP-VPA化合物在通过皮下注射PTZ而引入癫痫发作之后的头1h内能更有效地防止发作。另一方面,C18-DP-VPA则稍迟显示其最大抗惊阙活性,即,在注入PTZ以后4h(比较表A与表D)。
重要的是,试验的C16-DP-VPA/C18-DP-VPA混合物,特别是比例为10:90的C16-DP-VPA/C18-DP-VPA混合物,表现得类似于100% C18-DP-VPA化合物,即,同样显示高的最大癫痫发作保护作用,但却可持续一段更长的时间。
实例7:适合DP-VPA给药的制剂
本发明DP-VPA化合物和组合物可按多种方式给药,都是技术上熟知的。例如,给药可按照口服、不经肠(例如,静脉点滴或腹腔内、皮下或肌肉注射)、局部(例如,经鼻施用或吸入)或者直肠给药来实施。
局部给药的制剂可包括但不限于,滴剂、液体、喷雾、粉末、栓剂、乳剂、凝胶和软膏。传统药剂学载体、水性、粉末或油性基,增稠剂之类可能是需要或理想的。
不经肠给药的制剂可包括但不限于,无菌水溶液,还可包含缓冲剂、稀释剂或其他适当添加剂。
口服给药的组合物可配制成粉末或丸粒、水或非水介质中的悬浮体或溶液、片剂、胶囊、糖浆或溶液等剂量形式。制剂可设计成能够对活性剂的受控释放进行调节。胶囊和片剂可包衣以便能够向胃肠道不同部分指定部位递送。增稠剂、稀释剂、香料、分散助剂、乳化剂或粘结剂可能是需要的。
可包括在该制剂中的合适的药剂学赋形剂包括但不限于,磷脂、甘油三酯、丙二醇、聚乙二醇、聚氧乙烯聚氧丙烯嵌段共聚物、表面活性剂和助表面活性剂。
配量取决于症状的严重程度以及对象对DP-VPA药物的响应。本领域技术人员能轻易地确定最佳剂量和剂量形式以及服法和给药手段。
虽然已对本发明做了具体描述,但本领域技术人员懂得,还可做出许多变化和修改。因此,本发明不应视为局限于这些具体描述的实施方案,而本发明的范围、精神和概念通过参考下面的权利要求将更容易理解。
Claims (10)
1.一种药物组合物,它包含:治疗有效数量共价键合在第一磷脂部分上的丙戊酸和治疗有效数量共价键合在第二磷脂部分上的丙戊酸;以及药剂学可接受载体;其中共价键合在所述第一磷脂部分上的所述丙戊酸是1-棕榈酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸,而共价键合在所述第二磷脂部分上的所述丙戊酸是1-硬脂酰-2-丙戊酰-sn-甘油基-3-胆碱磷酸,两者的比例介于1∶20~1∶2,以重量计。
2.权利要求1的药物组合物,其中所述共价键合在所述第一磷脂部分上的丙戊酸与所述共价键合在所述第二磷脂部分上的丙戊酸之间的比例介于1∶5~1∶7,以重量计。
3.权利要求1-2任一项的药物组合物,它适合口服给药、静脉内给药或直肠给药。
4.权利要求1-2任一项的药物组合物,其中所述组合物呈溶液、悬浮体、乳剂、糖浆、胶囊、片剂和栓剂的形式。
5.权利要求1的药物组合物,其中共价键合在所述第一磷脂部分上的所述丙戊酸,与共价键合在所述第二磷脂部分上的所述丙戊酸的总量,介于35mg~2500mg。
6.权利要求1的药物组合物,其中共价键合在所述第一磷脂部分上的所述丙戊酸,与共价键合在所述第二磷脂部分上的所述丙戊酸的总量,介于70mg~560mg。
7.权利要求1-6任一项的药物组合物在制备用于治疗哺乳类动物中枢神经系统疾病的药物中的应用。
8.权利要求7的应用,其中中枢神经系统疾病选自癫痫、两极细胞疾病和疼痛。
9.权利要求8的应用,其中所述疼痛是偏头痛。
10.权利要求7的应用,其中中枢神经系统疾病是癫痫。
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US09/614,271 US6313106B1 (en) | 1995-06-07 | 2000-07-12 | Phospholipid derivatives of valproic acid and mixtures thereof |
US09/614,271 | 2000-07-12 |
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EP (1) | EP1315506B1 (zh) |
JP (1) | JP5140224B2 (zh) |
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CA (1) | CA2415354C (zh) |
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IL (1) | IL153147A0 (zh) |
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WO2003086475A1 (en) * | 2002-04-12 | 2003-10-23 | A & D Bioscience, Inc. | Conjugates comprising cancer cell specific ligands, a sugar and diagnostic agents, and uses thereof |
WO2003094842A2 (en) * | 2002-05-07 | 2003-11-20 | A & D Bioscience, Inc. | Conjugates comprising central nervous system active drug |
US20050215487A1 (en) * | 2002-06-27 | 2005-09-29 | Holick Michael F | Conjugates comprising an nsaid and a sugar and uses thereof |
US20050170063A1 (en) * | 2004-01-29 | 2005-08-04 | Lalit Chordia | Production of powder and viscous material |
WO2006102521A2 (en) * | 2005-03-24 | 2006-09-28 | Davis, John M. | Methods of determining compounds useful in the treatment of bipolar disorder and methods of treating such disorders |
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CN104230981B (zh) * | 2013-06-20 | 2016-05-18 | 江苏恩华药业股份有限公司 | 丙戊酸磷脂衍生物的制备方法 |
CA3017696A1 (en) * | 2016-03-16 | 2017-09-21 | Buzzelet Development And Technologies Ltd | Terpene-enriched cannabinoid composition |
CN108659038B (zh) * | 2017-03-31 | 2022-01-11 | 江苏恩华药业股份有限公司 | 1-硬脂酰-2-丙戊酰-sn-甘油-3-磷脂酰胆碱的多晶型物及制备方法 |
CN108659037B (zh) * | 2017-03-31 | 2022-01-11 | 江苏恩华药业股份有限公司 | 丙戊酸磷脂衍生物的多晶型物及制备方法 |
KR101864085B1 (ko) * | 2017-09-22 | 2018-06-01 | 동아대학교 산학협력단 | 발프로산 유도체, 이의 제조방법 및 이를 포함하는 항경련제 |
CN110407867A (zh) * | 2018-04-28 | 2019-11-05 | 江苏恩华药业股份有限公司 | 丙戊酸磷脂衍生物的新晶型及其制备方法 |
CN114344303B (zh) * | 2022-01-13 | 2023-05-09 | 江苏海洋大学 | 一种新型精神药物固体分散体及制备方法和应用 |
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WO2002007669A2 (en) | 2002-01-31 |
CZ200386A3 (cs) | 2003-06-18 |
ATE461697T1 (de) | 2010-04-15 |
HUP0302635A3 (en) | 2007-06-28 |
BR0112337A (pt) | 2004-06-08 |
NZ522788A (en) | 2005-04-29 |
AU2001270962B2 (en) | 2006-03-16 |
KR20030034099A (ko) | 2003-05-01 |
EP1315506A4 (en) | 2005-03-30 |
HU229320B1 (en) | 2013-10-28 |
DK1315506T3 (da) | 2010-05-31 |
CZ305745B6 (cs) | 2016-03-02 |
CY1110113T1 (el) | 2015-01-14 |
AU7096201A (en) | 2002-02-05 |
HUP0302635A2 (hu) | 2003-11-28 |
US6313106B1 (en) | 2001-11-06 |
US20040033987A1 (en) | 2004-02-19 |
CN1774252A (zh) | 2006-05-17 |
ES2343403T3 (es) | 2010-07-30 |
EP1315506B1 (en) | 2010-03-24 |
CA2415354C (en) | 2009-09-29 |
JP2004509854A (ja) | 2004-04-02 |
MXPA03000326A (es) | 2004-12-13 |
KR100801213B1 (ko) | 2008-02-05 |
EP1315506A2 (en) | 2003-06-04 |
IL153147A0 (en) | 2003-06-24 |
JP5140224B2 (ja) | 2013-02-06 |
DE60141636D1 (de) | 2010-05-06 |
PT1315506E (pt) | 2010-05-17 |
AU2001270962B8 (en) | 2006-08-10 |
CA2415354A1 (en) | 2002-01-31 |
WO2002007669A3 (en) | 2003-01-09 |
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