CN102014868B - 含有棕榈酰乙醇酰胺和硬脂酰乙醇酰胺的药物制剂 - Google Patents
含有棕榈酰乙醇酰胺和硬脂酰乙醇酰胺的药物制剂 Download PDFInfo
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Abstract
本发明涉及包含作为活性成分的棕榈酰乙醇酰胺或PEA和硬脂酰乙醇酰胺或SEA化合物的混合物的新药物制剂。所述制剂适于口服、肠胃外、局部、经皮、直肠、舌下、鼻腔、局部、经皮、直肠、鼻腔或舌下给药，其中所述制剂的剂型可以是贴剂、栓剂、卵形栓剂、阴道栓剂、气雾剂或喷雾剂、乳剂、混悬剂、溶液剂。所述药物制剂用于治疗或预防皮肤病、用于治疗或预防妇科病、用于治疗以脂肪酸非正常代谢为特征的病症或疾病以及用于治疗以炎性状态为特征的病症或疾病。
Description
大麻素(即δ-9-四氢大麻酚(THC))是大麻的主要活性成分，长期已知其除了精神活性作用之外，还在与其相关的多种不同疾病或症状的治疗方面具有值得关注的药用性质(Ameri A.，1999 Progress in Neurobiol.58：315-348)。
在前述内容之中，目前具体的实验证据表明大麻素(例如大麻酚或THC的其它衍生物)能够在发生在不同身体部位的与炎症和/或过敏状况(allergiccondition)有关的急性或慢性疾病(还可以是自身免疫型疾病)中发挥止痛和抗炎的作用，所述疾病例如关节炎(包括类风湿关节炎)、慢性疼痛、神经根病、哮喘、溃疡性大肠炎(ulcerous colitis)、皮炎(参考所引用的Ameri A.，1999)。
另外，最近的实验证据表明THC衍生物对目前的多种其它症状或疾病具有潜在医疗用途。以多发性硬化症为例，对于这种疾病，大麻素不仅能够潜在地发挥抗炎作用，还能够发挥解痉作用，从而表明对肌肉紧张度控制的药理学作用(参考所引用的Baker D.等人.2000，Nature 404，84-87；Ameri A.1999)。
涉及大麻素及其相关衍生物的神经保护和抗惊厥性质的其它有前景的领域包括猝发(ictus)或者脑和脊柱损伤治疗领域。此外，始终在CNS水平，已有的实验证据显示所关注的拟大麻素(cannabimimetic)衍生物能够与其它药物(例如阿片样物质)联合用于疼痛治疗(Mas-Nieto M.等人.2001，Brit.J.Pharmacol.132：1809-16)。
由于它们的支气管扩张和抗高血压性质，它们被认为在呼吸和/或心血管机能不全以及高血压治疗的领域中是有前景的(参考所引用的Ameri A.1999)，同时，考虑到它们在抑制癌细胞增长和促进癌细胞死亡(抗增殖和促凋亡(pro-apoptotic)作用)两方面的功效，它们还被认为在癌症治疗方面是有前景的(参考所引用的Ameri A.1999)。
另外，还有大量的证据(即使是轶事)涉及THC或其衍生物在刺激患有艾滋病消耗综合征的患者的食欲(参考所引用的Ameri A.1999)以及减少接受化疗的癌症患者的恶心和呕吐(止吐作用)(参考所引用的Ameri A.1999)两方面的有益实施，因此表明其对食欲控制的作用。
最后，内源性大麻素样(endocannabinoid-like)分子如棕榈酰乙醇酰胺(palmitoyl ethanolamide，PEA)已被描述为对于IgE介导的肥大细胞介质的释放具有抑制作用，从而表明所述分子在缓解过敏状况方面的可能的作用(Facci L.等人.1995 Proc.Natl.Acad.Sci.USA Vol.92：3376-80)。
尽管如此，虽然从实验观点来看，THC衍生物和THC本身看起来非常有前景，但其目前唯一被批准的临床应用是用于降低青光眼患者的眼内压(参考所引用的Ameri A.1999)。
相对于上述这些引出大麻素衍生物的多种不同的临床应用的假设的实验证据，随着1990年发现特异性THC受体(称为CB受体)的存在和1992年发现所述受体的内源性配体(称为内源性大麻素)的存在，最近几年对于这些分子可能的作用机制的研究已经历了突飞猛进的发展。
迄今为止，尽管最近已对一种表现出对于THC和PEA的纳摩尔亲和阵列(nano-mole affinity array)的称为GPR55的新的受体进行识别并表征(Ryberg E等人.Br J Pharmacol.2007年9月17日；印刷前的电子出版)，但被认为参与介导THC及相关合成衍生物的作用的受体为以下两种：普遍在神经系统以及一些周缘组织上表达的受体CB1(Piomelli D等人.2000，TIPS21：218-24)，以及主要存在于哺乳动物免疫系统细胞内并且仅在1993年被首次识别的受体CB2(参考所引用的Piomelli D.等人.2000)。此外，虽然识别了受体GRP55，但是还存在尚未表征的其它CB受体的证据(Wiley J.L.，Martin B.R.2002，Chem.Phys.Lipids 121：57-63)。
在发现受体CB1之后，1992年从猪脑中分离出第一个能够选择性地与所述受体结合的内源性化合物。所述化合物由动物细胞膜上普遍存在的两种成分即花生四烯酸和乙醇胺所形成的酰胺组成，被称为花生四烯酸乙醇酰胺(anandamide)，从而表明此类分子(即N-酰胺(N-acylamides))的拟大麻素类内源性介质的作用(Martin等人.1999，Life Sci.65，573-595)。随后分离出属于已知为单酰甘油的中间代谢产物类的另一类分子，即具有拟大麻素活性和高CB1及CB2受体亲和性的2-花生四烯酰甘油(2-arachidonylglycerol)(参考所引用的Martin等人，1999)。最后，最终分离和表征的内源性大麻素似乎非常类似于之前的2-花生四烯酰甘油，但是其具有与甘油的2位碳成醚性(ethereally)连接的花生四烯酸基团(arachidonic radical)(Hanus L.等人，2001 Proc.Natl.Acad.Sci.USA Vol 98，3662-5)。用所述分子进行的实验研究表明：虽然这三种经识别的内源性大麻素以不同的官能团为特征，但所有这三种均能够与CB1和CB2受体相互作用(尽管通过不同的亲和力)，并且具有能够与天然大麻素(如THC)及其合成衍生物的作用相叠加的作用(参考所引用的Martin等人，1999)。最后，近几年收集的实验证据指向一个假设，即这一类的分子(内源性大麻素)还与辣椒素受体(vanilloid receptor，TRPV)相互作用(De Petrocellis等人，2000，Chem.Phys Lipids；108，191-209)，然而，仅仅是不久前才得知可以归类于氨烷基吲哚类的拟大麻素分子(例如WIN 55.212)除了能够与CB受体相互作用之外，还能够与其它已知的受体(例如5-HT3a受体)相互作用(Barann M.等人，2002，Brit.J.Pharmacol.：137，589-96)。因此不可能排除内源性大麻素能够与许多其它受体或酶系统相互作用。最近几年的所述发现激励了对大麻素和内源性大麻素的大量科学研究，这不仅导致了对大麻素及其衍生物的潜在治疗作用的可观进展，还导致了各种不同化合物的合成和开发，这些化合物能够作为受体激动剂起作用，和/或能够通过干扰例如参与内源性大麻素的合成和降解的酶以及参与其释放和再摄取的细胞体系来增强内源性大麻素的作用。
作为示例，以下提供一组可产生大麻素样(cannabinoid-like)活性的示例性化合物：a)THC衍生物(例如HU-210，CP55940)(Patel S.和Hillard C.J.2001，J.Pharmacol.Exp.Ther.297，629-37)；b)氨烷基吲哚衍生物(例如WIN55.212)(参考所引用的Patel S.和Hillard C.J.2001)；c)饱和及不饱和的内源性大麻素衍生物(例如油酰乙醇酰胺(oylethanolamide)OEA、棕榈酰乙醇酰胺PEA、甲基花生四烯酸乙醇酰胺(methanandamide)、奥伐尼(olvanil)、arvanil、NADA)(Calignano A等人，2001，Eur.J.Pharmacol.419，191-198)；d)FAAH抑制剂，脂肪酸酰氨基水解酶(例如AM 374)(Gifford A.N.等人，.1999，Eur.J.Pharmacol.383，9-14)；e)内源性大麻素再摄取抑制剂(例如AM404)(Giuffrida A.等人，2001，J.Pharmacol.Exp.Ther.，298，7-14)。迄今为止，已进一步合成和开发了针对已知受体(如CB1和CB2)的一些受体拮抗剂(例如SR141716和SR144528)(Francisco M.E.等人，2002，J.Med.Chem.45，2708-19)。
尽管为了获得对外周CB2受体(即作为参与外周炎性过程的控制的受体)具有特异性激动剂活性的化合物而合成分子，但迄今得到的结果可能并不突出，这是因为以下事实：在很多情况下所述衍生物与中枢受体CB1相互作用(尽管是通过微小但并非可以忽略不计的亲和力)，或者同样地，当将PEA或双键数量小于4的花生四烯酸乙醇酰胺衍生物以及低级同系物(inferior homologues)(例如硬酯酰乙醇酰胺(stearoyl ethanolamide)SEA、OEA)体内给药时，其表现出中枢型作用(central type effects)(Lambert D.M.Di Marzo V 1999，Curr.Med.Chem.6，757-73)。
在这种情形下，饱和N-乙酰基-乙醇酰胺(NAE)代表了一类脂质衍生物，尽管它们对已知的大麻素受体没有显示出明显的亲和力，但它们仍以明确具有药理学价值的大麻素样活性为特征。
在所述分子中，最有名且研究最多的当然是棕榈酰乙醇酰胺(PEA)。实际上在20世纪50年代就已知所述分子以各种不同的药理活性(参见上文)，特别是抗炎活性为特征(Ganley O.H：等人，1958；Perlik F.等人，1971)。以Impulsin名称制备的PEA的用途，在20世纪70年代广泛地应用于人类(Masek K.，等人，1974Europ.J.Clin.Pharmacol.7，415-419；Hurych J等人，1980 Czecoslovak Medicine，8，218-225)以预防和治疗初期呼吸道疾病。20世纪90年代，在发现花生四烯酸乙醇酰胺之后，由于经证实PEA在多种不同的实验模型中对降低肥大细胞脱颗粒有效，因此它再度为人所关注(参考所引用的Facci L.；Mazzari S.，1996，Eur J Pharmacol.300，227-36)。此外必须强调，最近的出版物(参考所引用的Ryberg E.)描述了PEA对最近识别的受体GPR55表现出纳摩尔亲和阵列。
可能是由于PEA的高级同系物硬酯酰乙醇酰胺(SEA)在水性环境中的溶解度极低，所以尽管其多年来在化妆品制剂中用作通常称为ComperlanHS的珠光剂(pearlising agent)，但就其生物学活性而言却很少进行研究。就抗炎活性而言，在三个专利(US5,990,170；US5,679,667和US5,506,224)中公开了关于SEA的生物学活性的可获得的少量数据，其中SEA始终表现出较低级同系物PEA低得多的活性。此外，还报道了SEA干扰内源性大麻素系统(Maccarrone等人，2002 Biochem J.366：137-44.Maccarrone M.等人，2002 Mol Cell Neurosci.21：126-40)以及酶SCD-1的表达(Terrazzino S.等人，2004 FASEB J.18：1580-2)。
由于为了获得不具有任何不期望的大麻素样作用的活性化合物而长期关注衍生自内源性大麻素类的分子的开发，申请人惊奇地发现该两种PEA和SEA衍生物的联合发挥协同作用，在免疫原性体外炎症模型中所产生的抗炎效果优于由单一衍生物所产生的抗炎效果。
因此，本发明的主题涉及PEA和SEA化合物在制备用于预防性治疗或辅助性治疗(paramedic treatment)能够得益于所述化合物的内源性大麻素样活性的病状(pathologic conditions)的组合物中的用途。
实际上，申请人惊奇地发现，用本发明的化合物的混合溶液进行体外治疗所产生的拟大麻素药理活性优于由单一成分所产生的拟大麻素药理活性。事实上，在用于治疗能够得益于大麻素/内源性大麻素的预防性医疗用途、治疗性用途和辅助性用途的病状的药物制剂中通常可使用混合溶液。
通过以下详细说明会最好地理解所述与乙醇胺缩合的饱和酰基衍生物的化合物在大麻素和内源性大麻素或本发明的类似分子能够控制的病状中的医疗用途、治疗性用途或辅助性用途的目的和优点。
实际上，申请人发现，在体外治疗之后，本发明的混合溶液使得能够观察到经免疫原性刺激所刺激的肥大细胞的炎性介质释放发生明显且高度显著的减少，这表明本发明的混合溶液产生强效的抗炎活性。
更具体地，使用RBL-2H3肥大细胞系表达对IgE免疫球蛋白具有高亲和性的受体。抗原和存在于细胞表面的IgE分子之间的相互作用刺激所述细胞分泌它们胞质内颗粒的促炎内容物，其中有有效量(significant quantities)的组胺、白三烯、前列腺素和TNFα。因而，RBL-2H3代表一种用于研究炎性介质的胞吐作用和释放以及相关调节(视情况而定)的机制的优秀细胞模型(cell module)。具体而言，进行β-己糖胺酶的活性测量，其释放与极强的促炎介质(如组胺和TNFα)的分泌正相关。
就其整体而言先前从未记载过的所述结果证实了饱和酰基衍生物具有大麻素/内源性大麻素样作用。考虑到由于它们的联合所产生的协同效应，所述作用可能是由不同的受体系统所实现的。
体外评价在下文中详细描述。
a.大麻素抗炎作用的体外测定
如已经指出的，使用RBL-2H3肥大细胞系表达对IgE免疫球蛋白具有高亲和性的受体，同时通过MTT方法记录细胞活力的评价。以总计20,000个细胞/孔(96孔)的密度开始RBL-2H3细胞培养，并且用IgE-抗-DNP孵育。在约1个小时之后，向培养物中引入抗原(DNP)，然后在另外30分钟之后，收集培养基。对收集的细胞进行β-氨基己糖苷酶的活性测量，其释放与极强的促炎介质(如组胺和TNFα)的分泌正相关。培养基中的酶活性的降低表明细胞脱颗粒较少，因此抗炎活性较低。将本发明的分子溶解在DMSO中，并在引入抗原之前1个小时时将二者以不同的浓度添加到细胞培养基中。
b.结果
在下表1中列举了按时记录的β-氨基己糖苷酶释放减少的结果。
表1-在源自受激RBL-2H3细胞的培养基中的β-氨基己糖苷酶释放的抑制
| 化合物 | β-氨基己糖苷酶释放的抑制(测定时的％) |
| 测定(TEST) | 0.00 |
| 棕榈酰乙醇酰胺(PEA)(10μM) | 23.6 |
| 硬脂酰乙醇酰胺(SEA)(10μM) | 25.3 |
| 地塞米松(Desametazone)(10μM) | 40.2 |
| PEA/SEA(5μM/5μM) | 58.5 |
| PEA/SEA(3μM/7μM) | 57.2 |
| PEA/SEA(2μM/8μM) | 52.3 |
| PEA/SEA(1μM/9μM) | 54.2 |
| PEA/SEA(7μM/3μM) | 53.2 |
| PEA/SEA(8μM/2μM) | 51.5 |
| PEA/SEA(9μM/1μM) | 51.0 |
因此，由于这些分子在体外所表现出的拟大麻素作用，本发明的PEA和SEA化合物因而可以有效地用于制备药物制剂，所述药物制剂单独或与用于特定病状的其它任选治疗剂联合用于可以得益于拟大麻素作用的病状的治疗性治疗，所述其它任选治疗剂例如抗癫痫药、神经安定药、非典型神经安定药(atypical neuroleptic)、抗抑郁药、多巴胺能药、多巴胺激动药、gaba激动剂、芬氟拉明超重(ponderal overweight)、记忆改善及抗炎/止痛药物(例如阿片样物质、水杨酸类(salicylics)、吡唑酸类(pyrazolics)、吲哚乙酸类(indolacetics)、灭酸类(fenamics)、芳基丙酸类(arylpropionics)、芳基乙酸类(arylacetics)、昔康类(oxycams)、吡喃羧酸类(pyrancarboxylics)、糖皮质激素、抗COX-2(anti-COX-2)、尼美舒利和对乙酰氨基酚)，所述拟大麻素作用例如：
●它们在慢性炎性疾病(无论其是否是自身免疫型)中的抗炎作用，所述慢性炎性疾病发生在包括皮肤在内的不同身体部位；
●它们在缓解过敏状况中所具有的抑制肥大细胞脱颗粒的能力。
可以为了预防性或治疗性治疗本发明的病状而实施的给药方法可以是通过口服、肠胃外、肌内、皮下、静脉内、局部、经皮、直肠、舌下和鼻腔给药。根据所述治疗用途的化合物可以以药物制剂的形式给药，所述药物制剂与已知的或新的符合制药用途的赋形剂、分散剂和稀释剂相混合，旨在实现活性成分向活性位点的最佳递送，以便可以快速、持续或延迟起效。因此，为了该目的，也可使用快速释放、持续释放或缓释的药物制剂。相对剂量取决于疾病的严重性和已经选择的给药方法，以及患者的目前状况(年龄、体重、一般健康状况)。为了描述本发明而非对其进行限制的目的，所讨论的剂量可以包括每日给药(per die administrations)1mg/kg体重至50mg/kg体重，重复2-16周。合适的口服给药可以通过分散粉状化合物、片剂、丸剂、硬胶囊剂或软胶囊剂以及混悬剂而实现；合适的肠胃外给药形式可以是肌内、皮下、静脉内和硬膜外给药，其是通过缓冲水溶液形式的化合物、油混悬剂或可在给药之前分散在合适的溶剂溶液(solvent solution)中的冻干化合物而实现的；合适的局部或经皮给药可以是直肠、鼻腔或舌下给药，其是通过形式为贴剂、栓剂、卵形栓剂(ovules)、阴道栓剂(pessaries)、气雾剂或喷雾剂的在合适的赋形剂或分散剂中的化合物而实现的。
举例来说，本发明特别地用于制备在妇科病(gynaecological pathologies)的治疗中用于缓解和预防的药物制剂，所述妇科病例如：非传染性外阴阴道炎、硬化性苔癣、iperplasia squamosa、慢性单纯性苔癣、扁平苔癣、银屑病、慢性湿疹性皮炎、外阴炎、刺激性外阴疾病(irritative vulvar pathology)、外阴痛、外阴萎缩(vulvar craurosis)、炎性阴道疾病(inflammatory vaginalpathology)、阴道炎、结节性阴道炎(nodular vaginitis)、乳突状阴道炎(papillaryvaginitis)、囊性阴道炎(cystic vaginitis)、萎缩性阴道炎、外阴前庭炎、前庭红斑(vestibular erythema)、子宫附件炎、salpingovariolysis、子宫内膜炎、慢性阴道炎、子宫炎、子宫旁组织炎。所述组合物可以是按照下述给定比例的配方的阴道凝胶剂的形式：
-丁二醇 10-50％
-水 50-90％
-丙烯酸丙酯钠(sodium propyl acrylate)或羟丙基纤维素 0.1-0.5％
本发明的组合物还特别地适用于制备用于缓解和预防皮肤病(skinpathology)的药物制剂，所述皮肤病例如：皮炎、特应性皮炎、接触性皮炎、疱疹样皮炎、变应性皮炎、脂溢性皮炎、棘层松解性皮炎或格罗弗病、penfigo buloso、银屑病、良性苔癣样角化病、过敏性紫癜(Henoch-Schonleinpurpura)、红斑狼疮、糖尿病脂性渐进性坏死、寻常性天疱疮(penfigo vulgar)、嗜酸细胞性筋膜炎、结节性红斑、瘙痒症、荨麻疹、色素性荨麻疹、丘疹性荨麻疹、黄瘤病、系统性硬化症、Sweet综合征、干燥综合征、结节病、湿疹、盘状或钱币状湿疹(discoid or mummular eczema)、擦烂、盘状红斑狼疮、单纯性苔藓、扁平苔癣、静脉曲张性湿疹、汗疱湿疹、干性皮肤、原发性刺激性皮炎、尿布皮炎(nappy Dermatitis)、光照性皮炎、结节性痒疹和皮肤淋巴瘤(skin lymphoma)。所述药物制剂优选为护肤霜(protective skincream)的形式，其包含按照下列给定比例存在于所述制剂中的下列化合物：
-丙二醇 40-50％
-水 40-50％
-聚山梨酯60 1-5％
-肉豆蔻酸异丙酯 1-5％
-单硬脂酸甘油酯 1-10％
-丙烯酸丙酯钠 0.1-0.5％
此外，所述组合物也可以特别地以凝胶乳剂(gel emulsion)的形式使用，其中下列化合物以下列给定比例存在于所述制剂中：
-丙二醇 40-50％
-水 40-50％
-单硬脂酸甘油酯 1-10％
-聚丙烯酸钠 0.1-0.5％。
Claims (8)
1.棕榈酰乙醇酰胺或PEA和硬脂酰乙醇酰胺或SEA化合物的组合在制备用于缓解或预防皮肤病的药物制剂中的用途，所述皮肤病为：皮炎、红斑狼疮、荨麻疹或湿疹，其中PEA和SEA的组合发挥协同作用，在免疫原性体外炎症模型中所产生的抗炎效果优于由单一化合物所产生的抗炎效果。
2.根据权利要求1的用途，其中所述制剂适于局部或经皮给药。
3.根据权利要求1的用途，其中所述制剂适于局部、经皮给药，并且其中所述制剂是贴剂、气雾剂或喷雾剂、乳剂、混悬剂、溶液剂的形式。
4.根据权利要求1的用途，其中所述制剂适于口服给药，并且其中所述制剂是混悬剂、乳剂和溶液剂的形式。
5.根据权利要求1的用途，其中所述制剂是缓冲水溶液剂或油溶液剂、油混悬剂、或可在给药之前直接分散在合适的溶剂溶液中的冻干粉剂的形式。
6.根据权利要求1的用途，其中所述制剂是护肤霜的形式。
7.棕榈酰乙醇酰胺或PEA和硬脂酰乙醇酰胺或SEA化合物的组合在制备在变应性皮炎、特应性皮炎和脂溢性皮炎或痤疮的治疗中用于缓解或预防的药物制剂中的用途。
8.根据权利要求1-7中任一项的用途，其特征在于所述制剂是凝胶乳剂的形式。
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