CN106687138A - 包含双膦酸盐剂的细胞性免疫用疫苗药物组合物 - Google Patents
包含双膦酸盐剂的细胞性免疫用疫苗药物组合物 Download PDFInfo
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- CN106687138A CN106687138A CN201580047564.3A CN201580047564A CN106687138A CN 106687138 A CN106687138 A CN 106687138A CN 201580047564 A CN201580047564 A CN 201580047564A CN 106687138 A CN106687138 A CN 106687138A
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Abstract
本发明的目的在于,提供能够普遍用于对各种抗原进行细胞性免疫诱导的、发挥高的细胞性免疫诱导效果的疫苗药物组合物。本发明为一种疫苗药物组合物,其为用于细胞性免疫诱导的疫苗药物组合物,其包含抗原和作为双膦酸盐剂的第一细胞性免疫诱导促进剂。
Description
技术领域
本发明涉及用于细胞性免疫诱导的疫苗药物组合物。
背景技术
一般被广泛使用的疫苗为了诱导用于感染症预防的免疫而将微生物或病毒等病原体或其一部分进行给药。除此之外,还有:以使细胞性免疫机制识别癌细胞特异性抗原、诱导利用免疫体系对癌细胞的特异性攻击为目的的癌疫苗,作为癌治疗手段之一而被使用。
利用疫苗给药的免疫中,一般利用皮下或皮内注射、肌肉内注射等注射。特别是用于感染症预防的免疫的情况下,通常,微生物或病毒由于其尺寸而阻止通过皮肤向体内的侵入,因此,疫苗必须以侵入的方式向体内给药。
作为利用注射的免疫中使用的佐剂或免疫活化剂,氢氧化铝、磷酸铝、氯化铝等铝盐、MF59、AS03等包含角鲨烯的乳剂等被实用化,除此之外,还广泛研究了鞭毛成分、核酸、细胞因子、阳离子聚合物、多肽等。
然而,注射中,疼痛、恐怖心理、注射痕迹和紧随其的瘢痕化、重复进行给药时,从住院成为患者生活的负担等患者的QOL的观点出发存在问题,特别是给药次数多的癌疫苗的情况下,这些问题变显著。进一步,有如下问题:仅允许医疗从业者、免疫效果高的皮内注射的给药手法难、有医疗从业者的针刺感染事故的风险、产生注射针等需要特殊废弃的医疗废弃物等,因此,注射未必说是最佳的给药途径。
另外,利用注射的免疫中,迄今为止使用的佐剂或免疫活化剂的大部分是为了预防感染症而使抗体产生的物质。作为诱导细胞性免疫的物质(细胞性免疫诱导促进剂),研究了GM-CSF、IL-2、IL-12、IFN-γ等Th1细胞因子、利用抗原的缓释性而提高效果的油脂系佐剂即弗式佐剂、Montanide等,但在为受限的种类的基础上,无法达到实用化,安全性与效果的平衡性方面也存在问题。
作为除了注射之外的疫苗的给药途径,例如尝试了经皮给药(参照专利文献1和非专利文献1)、颊侧给药、鼻腔给药、舌下给药等(参照非专利文献2、专利文献2和3)。
特别是,皮肤上存在大量的作为抗原呈递细胞的朗格汉斯细胞,因此,作为解决涉及注射的各种问题的一个手段,研究了经皮给药或经粘膜给药。
作为利用经皮给药或经粘膜给药的免疫中研究的佐剂或免疫活化剂,可以举出:氢氧化铝、磷酸铝、氯化铝等铝盐、霍乱毒素、大肠杆菌非耐热性毒素等毒素类等。
然而,经皮给药或经粘膜给药中,迄今为止使用的佐剂或免疫活化剂的大部分是使体液免疫诱导的,作为细胞性免疫诱导促进剂,为霍乱毒素、大肠杆菌易热性毒素等毒素类、核酸类等有少量报道的程度。
另外,迄今为止,利用抗原的经皮给药的细胞性免疫诱导中能够使用的有效的免疫活化剂基本没有被报道,经皮给药中,与注射相比,大多情况下,无法得到充分的细胞性免疫诱导效果。
另一方面,近年来可知,作为骨质疏松症治疗药的双膦酸盐剂有如下作用:刺激树突状细胞或γδT细胞、使免疫应答活化,作为免疫活化剂的新的用途受到关注。
然而,γδT细胞在末梢血中仅存在1~5%,单纯地仅给予双膦酸盐剂时,无法期待充分的治疗效果。因此,进行了如下免疫细胞疗法:从患者末梢血分离γδT细胞,在invitro(生物体外)进行刺激,与其他免疫活性细胞进行共培养后,再次回到患者(参照专利文献4、5和6)。
另外,还报道了如下例子:在数天前注射双膦酸盐剂,刺激树突状细胞等,之后给予作为疫苗的病毒抗原,从而诱导充分的抗体产生(专参照利文献7)。
现有技术文献
专利文献
专利文献1:美国专利申请公开第2008/0193487号说明书
专利文献2:日本特表2002-531415号公报
专利文献3:美国专利申请公开第2008/0112974号说明书
专利文献4:国际公开第2006/006638号小册子
专利文献5:国际公开第2007/029689号小册子
专利文献6:日本特开2010-259373号公报
专利文献7:国际公开第2012/054807号小册子
非专利文献
非专利文献1:Hosoi Akihiro et al.,Cancer Research,68,3941-3949(2008)
非专利文献2:Zhengrong Cui et al.,Pharmaceutical Research,Vol.19,No.7,947-953(2002)
发明内容
发明要解决的问题
本发明的目的在于,提供能够普遍用于对各种抗原进行细胞性免疫诱导的、发挥高的细胞性免疫诱导效果的疫苗药物组合物。
用于解决问题的方案
本发明人等着眼于,作为骨质疏松症治疗药的双膦酸盐剂在体外(in vitro)刺激树突状细胞或γδT细胞,可以诱导有效的细胞性免疫。
γδT细胞具有通过抗原刺激而分泌IFN-γ、TNF-α等h1细胞因子而诱导细胞性免疫的作用。然而,γδT细胞在末梢血中仅存在1~5%,可以认为仅单纯地给药双膦酸盐剂时,无法诱导充分的细胞性免疫。
另一方面,在粘膜上皮层和真皮内存在大量的γδT细胞,对外敌的侵入立即进行反应,承担自然免疫那样的作用。
本发明人等着眼于该观点,发现:通过将作为双膦酸盐剂的第一细胞性免疫诱导促进剂与抗原一起,通过体表面上的给药(例如、经皮给药或经粘膜给药)直接给药至生物体,从而刺激树突状细胞或γδT细胞,可以有效果地诱导抗原特异性的细胞性免疫。另外,本发明人等发现:通过组合使用作为辅助肽的第二细胞性免疫诱导促进剂,从而可以进一步促进细胞性免疫。另外,本发明人等发现:通过组合使用抑制由双膦酸盐剂所导致的炎症的抗氧化剂和/或抗炎症剂,从而可以进一步促进细胞性免疫。
需要说明的是,体外(in vitro)中得到的见解未必预测体内(in vivo)中引起的生物体反应。
即,本发明为一种疫苗药物组合物,其为用于细胞性免疫诱导的疫苗药物组合物,其包含抗原和作为双膦酸盐剂的第一细胞性免疫诱导促进剂。
本发明的疫苗药物组合物优选还包含作为辅助肽的第二细胞性免疫诱导促进剂。
上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂优选为选自由依替膦酸盐(etidronate)、氯膦酸盐(clodronate)、替鲁膦酸盐(tiludronate)、帕米膦酸盐(pamidronate)、阿仑膦酸盐(alendronate)、伊班膦酸盐(ibandronate)、奈立膦酸盐(neridronate)、唑来膦酸盐(zoledronate)、利塞膦酸盐(risedronate)和米诺膦酸盐(minodronate)组成的组中的至少一种。
本发明的疫苗药物组合物优选还包含抗氧化剂和/或抗炎症剂。
本发明的疫苗药物组合物优选对体表面上给药。
以下,对本发明进行详述。
本发明的疫苗药物组合物是为了细胞性免疫诱导而使用的。
定量地测定细胞性免疫诱导效果的方法没有特别限定,开发了各种方法,例如可以通过使用免疫评价用模型动物的免疫诱导实验和ELISPOT方法(IFN-γ)来测定。作为用于ELISPOT方法的样品,例如可以举出:免疫评价用模型动物的脾脏。
本发明的疫苗药物组合物包含抗原和作为双膦酸盐剂的第一细胞性免疫诱导促进剂。
通过包含上述抗原和上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂,从而本发明的疫苗药物组合物可以有效地诱导抗原特异性的细胞性免疫。
本说明书中使用时,术语“抗原”是指,能够诱导免疫应答的所有物质。上述抗原没有特别限定,例如可以举出:蛋白质、肽等。要求抗原的皮肤透过性的经皮给药中,优选使用分子量小的抗原,可以使用例如包含约8~12个氨基酸的肽。
上述抗原没有特别限定,例如可以举出:癌抗原肽、源自感染性病原体的抗原。
本说明书中使用时,术语“癌”是指,癌基因的异常表达。作为上述癌,例如可以举出:造血系统肿瘤、实体癌等伴随着过剩表达的癌。
本说明书中使用时,术语“基因的异常表达”是指,某个细胞中的其基因的表达水平与相同组织的其他细胞相比,以例如2倍以上、4倍以上等的倍率显著地上升或降低。
本说明书中使用时,术语“过剩表达”是指,异常表达为表达水平的上升。基因的表达水平可以利用该技术领域中公知的任意方法而容易地测定。
作为上述癌基因,例如可以举出:存活蛋白基因、GPC3基因、HER2/neu基因、MAGE3基因、MAGE A1基因、MAGE A3/A6基因、MAGE A4基因、MAGE12基因、蛋白酶-3基因、AFP基因、CA-125基因、CD44基因、CEA基因、c-Kit基因、c-met基因、c-myc基因、L-myc基因、COX2基因、Cyclin(细胞周期蛋白)D1基因、Cytokeratin(细胞角蛋白)-7基因、Cytokeratin-19基因、Cytokeratin-20基因、E2F1基因、E2F3基因、EGFR基因、Gli1基因、hCGβ基因、HIF-1α基因、HnRNP A2/B1基因、hTERT基因、MDM基因、MDR-1基因、MMP-2基因、MMP-9基因、Muc-1基因、Muc-4基因、Muc-7基因、NSE基因、ProGRP基因、PSA基因、RCAS1基因、SCC基因、热球蛋白基因、VEGF-A基因、VEGF-A基因等。
伴随着上述存活蛋白基因的异常表达的癌中包括恶性淋巴癌、膀胱癌、肺癌、大肠癌等,但不限定于这些。伴随着上述GPC3基因的异常表达的癌中包括肝癌、胆管癌、胃癌等,但不限定于这些。伴随着上述HER2/neu基因的异常表达的癌中包括乳腺癌、胃癌、卵巢癌、子宫癌、膀胱癌、非小细胞肺癌、前列腺癌等,但不限定于这些。伴随着上述MAGE3基因的异常表达的癌中包括黑色素瘤、肺癌、头颈部癌、膀胱癌、胃癌、食道癌、肝癌等,但不限定于这些。伴随着上述蛋白酶-3基因的异常表达的癌中包括急性骨髄性白血病、胰腺癌等,但不限定于这些。
本说明书中使用时,术语“癌抗原”是指,肿瘤细胞或癌细胞中特异性表达且能够诱导细胞性免疫应答的蛋白质、肽等物质。
本说明书中使用时,术语“癌抗原肽”是指,源自癌抗原蛋白质的部分肽、且能够诱导细胞性免疫应答。通常,癌抗原肽通过作为癌基因的产物的癌抗原蛋白质在癌细胞内被分解而产生,利用MHC I类分子呈递在癌细胞的表面。
上述癌抗原肽可以为从癌细胞分离和纯化的内源性的癌抗原肽,也可以为具有与内源性的癌抗原肽相同的氨基酸序列的合成肽。作为上述癌抗原肽,具体而言,优选存活蛋白2B肽、GPC3肽、HER2/neu_A24肽、MAGE3_A24肽、PR1肽、HER2/neu_A02肽、MAGE3_A02肽、HER2/neu_E75肽、MUC1肽、或它们的变异肽。
本说明书中使用时,术语“存活蛋白2B肽”是指由序列Ala Tyr Ala Cys Asn ThrSer Thr Leu(序列号1)组成的、源自癌基因产物存活蛋白的肽。
本说明书中使用时,术语“GPC3肽”是指由序列Glu Tyr Ile Leu Ser Leu GluGlu Leu(序列号2)组成的、源自癌基因产物GPC3的肽。
本说明书中使用时,术语“HER2/neu_A24肽”是指由序列Thr Tyr Leu Pro ThrAsn Ala Ser Leu(序列号3)组成的、源自癌基因产物HER2/neu的HLA-A24限制性肽。
本说明书中使用时,术语“MAGE3_A24肽”是指由序列Ile Met Pro Lys Ala GlyLeu Leu Ile(序列号4)组成的、源自癌基因产物MAGE3的HLA-A24限制性肽。
本说明书中使用时,术语“PR1肽”是指由序列Val Leu Gln Glu Leu Asn Val ThrVal(序列号5)组成的、源自癌基因产物蛋白酶-3的肽。
本说明书中使用时,术语“HER2/neu_A02肽”是指由序列Lys Val Phe Gly SerLeu Ala Phe Val(序列号6)组成的、源自癌基因产物HER2/neu的HLA-A02限制性肽。
本说明书中使用时,术语“MAGE3_A02肽”是指由序列Lys Val Ala Glu Ile ValHis Phe Leu(序列号7)组成的、源自癌基因产物MAGE3的HLA-A02限制性肽。
本说明书中使用时,术语“HER2/neu_E75肽”是指由序列Lys Ile Phe Gly SerLeu Ala Phe Leu(序列号8)组成的、源自癌基因HER2/neu的产物(HER2蛋白质)的肽。
本说明书中使用时,术语“MUC1肽”是指由序列Ser Thr Ala Pro Pro Val HisAsn Val(序列号9)组成的、源自在很多癌细胞上高表达的糖蛋白即MUC1蛋白的肽。
本说明书中使用时,术语“变异肽”是指,肽的全部或一部分氨基酸通过置换或修饰等而变异的肽。
对于上述变异肽没有特别限定,例如可以举出:(a)包含肽的氨基酸序列中置换、缺失或添加了1个至多个(例如1个、2个、3个、4个或5个)的氨基酸而成的氨基酸序列的肽;(b)包含肽的氨基酸序列中、全部或一部分的氨基酸(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个)的氨基酸进行了修饰而成的氨基酸序列的肽等。
上述变异肽能够具有的氨基酸的修饰没有特别限定,例如可以举出:乙酰化、甲基化等烷基化、糖基化、羟基化、羧基化、醛化、磷酸化、磺酰化、甲酰化、肉豆蔻酰化、棕榈酰化、硬脂酰化等脂肪链添加修饰、辛酰化、酯化、酰胺化、脱酰胺化、胱胺酸修饰、谷胱甘肽修饰、巯基乙酸修饰等二硫键形成修饰、糖化、泛素化、琥珀酰亚胺形成、谷酰胺化、异戊二烯化等。
上述变异肽也可以为包含1个以上氨基酸的置换、缺失或添加与1个以上的氨基酸的修饰组合的肽。
本说明书中使用时,术语“源自感染性病原体的抗原”是指,感染性病原体或其构成成分或源自它们的物质、且能够诱导细胞性免疫应答。因此,通过将上述源自感染性病原体的抗原与上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂一起向对象给予,从而可以对感染性疾病进行处置或预防。
作为上述源自感染性病原体的抗原,优选IPEP87肽、HBVenv肽、或它们的变异肽。
本说明书中使用时,术语“IPEP87肽”是指由序列Asp Leu Met Gly Tyr Ile ProAla Val(序列号10)组成的、源自丙型肝炎病毒(HCV)蛋白质的肽。
本说明书中使用时,术语“HBVenv肽”是指由序列Trp Leu Ser Leu Leu Val ProPhe Val(序列号11)组成的、源自B型肝炎病毒(HBV)蛋白质的肽。
本说明书中使用时,术语“感染性疾病”是指,由于感染性病原体的感染、增殖等而引起的疾病。
作为上述感染性疾病,没有特别限定,例如可以举出:腺病毒(例如,人腺病毒)、疱疹病毒(例如,单纯疱疹病毒、水痘/带状疱疹病毒、巨细胞病毒、人疱疹病毒、卡波西肉瘤相关疱疹病毒)、小核糖核酸病毒(例如,脊髓灰质炎病毒、感冒病毒、甲型肝炎病毒)、痘病毒(例如,天花病毒、痘苗病毒、传染性软疣病毒)、小核糖核酸病毒(例如,鼻病毒、肠道病毒)、正粘病毒(例如,流感病毒)、副粘病毒(例如,副流感病毒、腮腺炎病毒、麻疹病毒、呼吸道合胞体病毒(RSV)、新城疫病毒)、细小病毒(例如,腺随伴病毒)、外衣病毒(例如,风疹病毒)、冠状病毒(例如,SARS冠状病毒)、嗜肝DNA病毒(例如,乙型肝炎病毒)、黄病毒(例如,乙型脑炎病毒、黄热病病毒、登革热病毒、西尼罗热病毒、圣路易脑炎病毒、墨累山谷脑炎病毒、丙型肝炎病毒、庚型肝炎病毒)、肝炎病毒(例如,戊型肝炎病毒)、乳头瘤病毒(例如,人乳头瘤病毒)、杯状病毒(例如,诺如病毒)、弹状病毒(例如,狂犬病毒、水泡性口炎病毒)、纤丝病毒(例如,埃博拉出血热病毒)、沙粒病毒(例如,拉沙病毒、丁型肝炎病毒)、布尼亚病毒(例如,加里福尼亚脑炎病毒、裂谷热病毒)、呼肠孤病毒(例如,轮状病毒)、逆转录病毒(例如,人类免疫缺陷病毒(HIV)、成人T细胞白血病病毒)等由病毒感染患上的疾病等病毒疾病;埃希氏菌属、肠杆菌、沙门氏菌、葡萄球菌、志贺菌、李斯特菌、气杆菌、螺杆菌、克雷伯菌、变形杆菌、假单胞菌、链球菌、衣原体、支原体、肺炎球菌、淋球菌、梭菌、芽孢杆菌、棒状杆菌、分枝杆菌、弯曲杆菌、弧菌、沙雷氏菌、普罗威登斯菌、色杆菌、布鲁氏菌、耶尔森菌、嗜血杆菌、博德特杆菌等由细菌感染患上的疾病等细菌疾病;衣原体、念珠菌病、曲霉菌病、组织胞浆菌病、隐球菌性髓膜炎等真菌疾病;疟疾、肺孢子虫肺炎、利什曼病、隐孢子虫病、弓形虫病、锥虫感染等。
上述肽可以采用游离形或药理学上允许的任意盐形的形态。
作为上述药理学上允许的任意盐,例如可以举出:酸盐(例如乙酸盐、TFA盐、盐酸盐、硫酸盐、磷酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、草酸盐、氢溴酸盐、琥珀酸盐、硝酸盐、苹果酸盐、柠檬酸盐、油酸盐、棕榈酸盐、丙酸盐、甲酸盐、苯甲酸盐、苦味酸盐、苯磺酸盐、十二烷基硫酸盐、甲磺酸盐、对甲苯磺酸盐、戊二酸盐、各种氨基酸盐)、金属盐(例如碱金属盐(例如钠盐、钾盐)、碱土金属盐(例如钙盐、镁盐)、铝盐)、胺盐(例如三乙胺盐、苄胺盐、二乙醇胺盐、叔丁胺盐、二环己胺盐、精氨酸盐、二甲基铵盐、铵盐等)等。其中,优选乙酸盐或TFA盐。
上述肽可以使用利用公知的方法合成或产生、分离和纯化而得到的物质。
对于上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂,例如可以举出:作为骨质疏松症治疗药一般使用的、具有双膦酸盐骨架、且体现出骨吸收抑制作用的物质。具体而言例如可以举出:依替膦酸盐、氯膦酸盐、替鲁膦酸盐、阿仑膦酸盐、伊班膦酸盐、帕米膦酸盐、奈立膦酸盐、奥帕膦酸盐、唑来膦酸盐、利塞膦酸盐、米诺膦酸盐、西玛膦酸盐(Cimadronate)、因卡膦酸盐等。从不易引起对给药部位的刺激、炎症等副作用的方面出发,优选侧链上不含氮原子的被称为第一代的依替膦酸盐、氯膦酸盐、替鲁膦酸盐。另外,从细胞性免疫诱导效果高的方面出发,优选侧链上包含氮原子的第二代(阿仑膦酸盐、伊班膦酸盐、帕米膦酸盐、奈立膦酸盐、奥帕膦酸盐)和第三代(唑来膦酸盐、利塞膦酸盐、米诺膦酸盐、西玛膦酸盐、因卡膦酸盐)。需要说明的是,这些化合物是采用盐的形态的化合物。
其中,对于上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂,更优选选自由依替膦酸盐、氯膦酸盐、替鲁膦酸盐、帕米膦酸盐、阿仑膦酸盐、伊班膦酸盐、奈立膦酸盐、唑来膦酸盐、利塞膦酸盐和米诺膦酸盐组成的组中的至少一种。
本说明书中使用时,术语“盐”可以是任意的有机酸或无机酸的盐、优选为药理学上允许的盐。
本说明书中使用时,术语“药理学上允许的盐”是指不对给药对象造成有害的作用且不使疫苗药物组合物中的配混成分的药理活性消失的盐,例如可以举出:无机酸盐(例如盐酸盐、磷酸盐)、有机酸盐(例如乙酸盐、邻苯二甲酸盐、TFA盐)、金属盐(例如碱金属盐(例如钠盐、钾盐)、碱土金属盐(例如钙盐、镁盐、铝盐)、胺盐(例如三乙胺盐、苄胺盐、二乙醇胺盐、叔丁胺盐、二环己胺盐、精氨酸盐、二甲基铵盐、铵盐)等。
本发明的疫苗药物组合物中的上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂的含量没有特别限定,相对于上述抗原1重量份,优选的下限为0.001重量份、优选的上限为1000重量份。上述含量低于0.001重量份时,有时无法充分得到细胞性免疫诱导效果。上述含量超过1000重量份时,安全性有时成为问题。上述含量的更优选的下限为0.005重量份、更优选的上限为500重量份、进一步优选的下限为0.01重量份、进一步优选的上限为100重量份。
本发明的疫苗药物组合物优选还包含作为辅助肽的第二细胞性免疫诱导促进剂。
通过组合使用上述作为辅助肽的第二细胞性免疫诱导促进剂,可以进一步促进细胞性免疫。
本说明书中使用时,术语“辅助肽”是指,使辅助性T细胞活化的所有肽。
对于上述作为辅助肽的第二细胞性免疫诱导促进剂,例如可以举出:源自结核杆菌的辅助肽、源自麻疹病毒的辅助肽、源自B型肝炎病毒的辅助肽、源自丙型肝炎病毒的辅助肽、源自沙眼衣原体的辅助肽、源自热带性疟疾原虫孢子体的辅助肽、源自钥孔戚血蓝蛋白(keyhole limpet haemocyanin)的辅助肽、源自破伤风毒素的辅助肽、源自百日咳毒素的辅助肽、源自白喉毒素的辅助肽、源自癌细胞的辅助肽(例如IMA-MMP-001辅助肽、CEA-006辅助肽、MMP-001辅助肽、TGFBI-004辅助肽、HER-2/neu(aa776-790)辅助肽、AE36辅助肽、AE37辅助肽、MET-005辅助肽、BIR-002辅助肽)、通用辅助类似物(例如PADRE)、它们的变异肽等。其中,优选Peptide(肽)-25、变构Peptide-25、PADRE。作为上述变构Peptide-25,例如可以举出Peptide-25B。
本说明书中使用时,术语“Peptide-25”是指与由人型结核杆菌(Mycobacteriumtuberculosis)分泌的主要蛋白质之一即Ag85B的氨基酸残基240~254对应的、由序列PheGln Asp Ala Tyr Asn Ala Ala Gly Gly His Asn Ala Val Phe(序列号12)组成的15氨基酸的肽。
本说明书中使用时,术语“Peptide-25B”是指为了提高免疫活化效果而将Peptide-25的一部分氨基酸变构而成且由序列Phe Gln Asp Ala Tyr Asn Ala Val HisAla Ala His Ala Val Phe(序列号13)组成的15氨基酸的肽。
本说明书中使用时,术语“PADRE”是指由序列D-Ala Lys cyclohexyl-Ala ValAla Ala Trp Thr Leu Lys Ala Ala D-Ala(序列号14)组成的13个氨基酸的肽。
本发明的疫苗药物组合物中的上述作为辅助肽的第二细胞性免疫诱导促进剂的含量没有特别限定,相对于上述抗原1重量份,优选的下限为0.01重量份、优选的上限为100重量份。上述含量低于0.01重量份时,细胞性免疫有时没有得到充分促进。上述含量超过100重量份时,安全性有时成为问题。上述含量的更优选的下限为0.1重量份、更优选的上限为10重量份。
本发明的疫苗药物组合物优选还包含抗氧化剂和/或抗炎症剂。
上述抗氧化剂和/或抗炎症剂中,由于有抑制由上述双膦酸盐剂所导致的炎症的效果,因此,通过组合使用上述抗氧化剂和/或抗炎症剂,从而可以进一步促进细胞性免疫。
本说明书中使用时,术语“抗氧化剂”是指,减弱或除去氧参与的有害的反应的物质。其中,可以依据药品添加物标准中记载的药品添加物而使用抗氧化剂。
上述抗氧化剂没有特别限定,优选选自由亚硝酸钠、抗坏血酸、亚硫酸氢钠、盐酸半胱氨酸、柠檬酸水合物、二丁基羟基甲苯(BHT)、大豆卵磷脂、生育酚、焦亚硝酸钠、二丁基羟基苯甲醚(BHA)、1,3-丁二醇、苯并三唑、没食子酸丙酯和2-巯基苯并咪唑组成的组中的至少一种。需要说明的是,上述抗氧化剂中,也可以包含这些抗氧化剂的衍生物和药理学上允许的盐。其中,从可以进一步促进细胞性免疫的方面出发,更优选亚硝酸钠、二丁基羟基甲苯、大豆卵磷脂、焦亚硝酸钠、二丁基羟基苯甲醚、2-巯基苯并咪唑。
本发明的疫苗药物组合物中的上述抗氧化剂的含量没有特别限定,相对于上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂1重量份,优选的下限为0.01重量份、优选的上限为100重量份。上述含量低于0.01重量份时,细胞性免疫有时没有得到充分促进。上述含量超过100重量份时,安全性有时成为问题。上述含量的更优选的下限为0.1重量份、更优选的上限为50重量份。
本说明书中使用时,术语“抗炎症剂”是指,抑制炎症的物质。
上述抗炎症剂没有特别限定,优选选自由多酚、生物碱和磷脂酶A2抑制剂组成的组中的至少一种。
作为上述多酚,例如可以举出:柚皮素、表儿茶素、表没食子儿茶素、芹黄素、白杨素、杨梅黄酮、芸香苷、槲皮素、染料木素、川陈皮素、姜黄素、白藜芦醇、它们的衍生物和药理学上允许的盐。作为上述生物碱,例如可以举出:香豆素、黄连素、它们的衍生物和药理学上允许的盐。作为上述磷脂酶A2抑制剂,例如可以举出:甘草次酸、其衍生物和药理学上允许的盐。其中,从可以进一步促进细胞性免疫的方面出发,更优选表儿茶素、白杨素、杨梅黄酮、白藜芦醇、香豆素、黄连素、甘草次酸。
另外,作为上述抗炎症剂,还环优选氧酶抑制剂。本说明书中使用时,术语“环氧酶抑制剂”是指,抑制环氧酶(COX)的功能的物质。以下,也称为“COX抑制剂”。
上述COX抑制剂可以选择性地作用于特定的环氧酶(例如COX-1、COX-2),也可以没有选择性。上述COX抑制剂优选选自由环氧酶非选择性抑制剂、环氧酶1选择性抑制剂和环氧酶2选择性抑制剂组成的组中的至少一种。
作为上述COX抑制剂,具体而言例如可以举出:依托度酸、氯索洛芬、塞来昔布、伐地考昔、帕瑞考昔、罗美昔布、美洛昔康、替诺昔康、双氯芬酸钠、甲灭酸、托芬那酸、氟芬那酸、甲氯芬那酸、尼氟灭酸、苄达明、吲哚布芬、三氟醋铆酸、托美丁、非诺洛芬、噻洛芬酸、联苯乙酸、奈帕芬胺、氨芬酸、普拉多林(pravadoline)、扎托洛芬、舒林酸、萘丁美酮、二氟尼柳、吡罗昔康、布洛芬、萘普生、非诺洛芬、阿司匹林、水杨酸甲酯、水杨酰胺、双水杨酯、阿洛普令、托美丁、吲哚美辛、丙谷胺、阿西美辛、氟比洛芬、普拉洛芬、对乙酰氨基酚、夫洛非宁、氯诺昔康、替诺昔康、噻洛芬酸、奥沙普秦、酮洛芬、右酮洛芬、右旋布洛芬、阿明洛芬、酮咯酸、莫苯唑酸、苯基丁氮酮、氧苯基丁氮酮、酮苯基丁氮酮、非普拉宗、索菲布它宗(Sulfinbutazone)、乙水杨胺、噻拉米特、替诺立定、依匹唑、依莫法宗、它们的衍生物和药理学上允许的盐。其中,从可以进一步促进细胞性免疫的方面出发,优选氯索洛芬、吡罗昔康、阿司匹林、吲哚美辛。
本发明的疫苗药物组合物中的上述抗炎症剂的含量没有特别限定,相对于上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂1重量份,优选的下限为0.01重量份、优选的上限为100重量份。上述含量低于0.01重量份时,细胞性免疫有时没有得到充分促进。上述含量超过100重量份时,安全性有时成为问题。上述含量的更优选的下限为0.1重量份、更优选的上限为50重量份。
本发明的疫苗药物组合物根据需要也可以含有添加剂。上述添加剂可以根据基材的主要成分、与上述抗原和上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂的适合性、想要的给药疗程等而例如可以举出:等渗剂、防腐杀菌剂、抗氧化剂、溶解剂、溶解辅助剂、悬浮剂、填充剂、pH调节剂、稳定化剂、吸收促进剂、释放速度控制剂、着色剂、增塑剂、交联剂、粘合剂等。这些添加剂可以单独使用或组合2种以上使用。
本发明的疫苗药物组合物也可以对皮内、皮下或肌肉内给药,优选对体表面上给药,更优选经皮给药或经粘膜给药。即,本发明的疫苗药物组合物可以为皮内、皮下或肌肉内给药用疫苗药物组合物,优选为经皮给药用或经粘膜给药用疫苗药物组合物。通过将本发明的疫苗药物组合物利用经皮给药或经粘膜给药向对象给予,从而可以有效地诱导抗原特异性的细胞性免疫。经皮给药的情况下,可以为非侵入性的给药也可以为低侵入性的给药。
本说明书中使用时,术语“对象”是指能够在实用阶段中给予疫苗药物组合物而诱导免疫应答的任意动物,上述对象典型地为包含人的哺乳类(例如小鼠、大鼠、狗、猫、兔子、马、牛、羊、猪、山羊、猴子、黑猩猩)。特别优选的对象为人。
<经皮给药用疫苗药物组合物>
上述经皮给药用疫苗药物组合物的剂型例如可以为擦剂、露剂等外用液体制剂;气雾剂等外用喷雾剂;凝胶剂、贴剂、巴布剂等粘贴剂;软膏剂、硬膏剂、霜剂。这些组合物的划分、定义、性质、制法等在该技术领域中是公知的,例如可以参照日本药典第16版。另外,作为这些材料,没有特别限定,可以使用以往公知的材料
上述剂型中,优选霜剂、粘贴剂(贴剂、巴布剂等)。
上述经皮给药用疫苗药物组合物中(贴剂时,为粘合剂层中)的上述抗原和上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂的含量没有特别限定,上述抗原的含量优选为0.01~40重量%、更优选为0.1~30重量%。上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂的含量优选为0.001~30重量%、更优选为0.01~20重量%。
作为上述擦剂中使用的基材,可以举出:水、乙醇、脂肪油、硬石蜡、软石蜡、液体石蜡、甘油、石蜡油、蜜蜡、金属皂、粘液(mucilage)、天然油(例如杏仁油、玉米油、落生油、蓖麻油、橄榄油或它们的衍生物(例如蓖麻油聚烃氧酯))、羊油或其衍生物、脂肪酸和/或其酯(例如硬脂酸、油酸、肉豆蔻酸异丙酯)。
上述露剂是将配混成分(即上述抗原、上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂、根据需要的上述第二细胞性免疫诱导促进剂等)微细地均质分散于水性液体中而得到的制剂,包括悬浮性露剂和乳浊性露剂。作为悬浮化剂,可以举出:阿拉伯胶、藻酸钠、羧甲基纤维素钠、甲基纤维素、膨润土等。作为乳化剂,可以举出:月桂基硫酸钠、失水山梨醇脂肪酸酯等。
作为上述软膏剂中使用的基材,可以举出:油脂类、蜡、烃化合物等一般作为疏水性基材使用的物质。具体而言可以举出:黄色凡士林、白色凡士林、石蜡、液体石蜡、Plastibase、有机硅等矿物性基材;蜜蜡、动植物性油脂等动植物性基材等。
作为上述霜剂中使用的基材,可以举出:亲水软膏、雪花膏等水/油型基材;亲水凡士林、精制羊毛脂、阿夸弗尔、优塞林、那塞林(Neocerin)、含水羊毛脂、冷霜、亲水Plastibase等油/水型基材。
作为上述凝胶剂中使用的基材,没有特别限定,可以使用:羧基乙烯基聚合物、凝胶基质、无脂肪性软膏、聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、藻酸钠、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、他拉胶、枸子胶、车前子胶、琼脂、结冷胶、葡甘露聚糖、刺槐豆胶、瓜尔胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚糖、甲基丙烯酸氨基烷基酯共聚物E、甲基丙烯酸氨基烷基酯共聚物RS、甲基丙烯酸共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S、甲基丙烯酸酯-甲基丙烯酸-甲基丙烯酸甲酯共聚物、丙烯酸乙酯-甲基丙烯酸甲酯共聚物、聚乙烯醇缩二乙基氨基乙酸酯、酪蛋白、藻酸烷基酯、明胶、聚乙二醇等水凝胶基材等。从抗原的扩散·释放性良好的方面出发,优选聚丙烯酸钠那样的亲水性基材。
作为上述巴布剂中使用的基材,没有特别限定,可以举出:明胶、羧甲基纤维素钠、甲基纤维素、聚丙烯酸钠、高岭土、聚乙烯醇、聚乙烯基吡咯烷酮、甘油、丙二醇、水等。
上述贴剂优选具有含有配混成分(即上述抗原、上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂、根据需要的上述第二细胞性免疫诱导促进剂等)的粘合剂层、和支撑上述粘合剂层的支撑体。可以进一步具有使用前不使粘合剂层露出,使用时能够从粘合剂层容易地剥离的剥离衬垫。
形成上述粘合剂层的粘合剂没有特别限定,例如可以举出:含有丙烯酸类聚合物的丙烯酸类粘合剂;含有橡胶系弹性体的橡胶系粘合剂;有机硅橡胶、二甲基硅氧烷基质、二苯基硅氧烷基质等有机硅系粘合剂;聚乙烯基甲基醚、聚乙烯基乙基醚、聚乙烯基异丁基醚等乙烯基醚系粘合剂;乙酸乙烯酯-乙烯共聚物等乙烯基酯系粘合剂;由对苯二甲酸二甲酯、间苯二甲酸二甲酯、邻苯二甲酸二甲酯等羧酸成分与乙二醇等多元醇成分形成的聚酯系粘合剂等。其中,优选丙烯酸类粘合剂、橡胶系粘合剂、有机硅系粘合剂。
上述粘合剂层中的上述粘合剂的含量没有特别限定,以固形成分计,优选为上述粘合剂层的总重量的10~90重量%、更优选为20~80重量%。
上述丙烯酸类粘合剂优选含有以包含(甲基)丙烯酸烷基酯作为第一单体的聚合物作为主要成分。
作为上述第一单体,可以举出:具有碳数1~18的直链状、支链状或环状烷基的(甲基)丙烯酸烷基酯等。其中,优选具有碳数4~18的直链状、支链状或环状烷基的(甲基)丙烯酸烷基酯。进一步,为了在常温赋予粘合性,降低聚合物的玻璃化转变温度的单体成分的使用是更适合的,因此,更优选具有碳数4~8的直链状、支链状或环状烷基(例如可以举出:丁基、戊基、己基、环己基、庚基、辛基、2-乙基己基等,优选丁基、2-乙基己基、环己基,特别优选2-乙基己基)的(甲基)丙烯酸烷基酯。
作为上述第一单体,具体而言优选丙烯酸丁酯、丙烯酸2-乙基己酯、甲基丙烯酸2-乙基己酯、丙烯酸环己酯、甲基丙烯酸环己酯,特别优选丙烯酸2-乙基己酯。这些第一单体可以单独使用或组合2种以上使用。
上述第一单体也可以与第二单体共聚,作为这样的第二单体,可以举出:具有使用交联剂时能够成为交联点的官能团的单体。作为能够参与交联反应的官能团,可以举出:羟基、羧基、乙烯基等,优选羟基、羧基。
作为上述第二单体,具体而言可以举出:(甲基)丙烯酸羟基乙酯、(甲基)丙烯酸羟基丙酯、N-羟基烷基(甲基)丙烯酰胺、(甲基)丙烯酸、衣康酸、马来酸、马来酸酐、中康酸、柠康酸、戊烯二酸等。其中,从获得的容易性的观点出发,优选丙烯酸、甲基丙烯酸、丙烯酸羟基乙酯(特别是丙烯酸2-羟基乙酯),特别优选丙烯酸。这些第二单体可以单独使用或组合2种以上使用。
上述第一单体和第二单体也可以进一步与第三单体共聚。
作为上述第三单体,例如可以举出:乙酸乙烯酯、丙酸乙烯酯等乙烯基酯类;甲基乙烯基醚、乙基乙烯基醚等乙烯基醚类;N-乙烯基-2-吡咯烷酮、N-乙烯基己内酰胺等乙烯基酰胺类;(甲基)丙烯酸甲氧基乙酯、(甲基)丙烯酸乙氧基乙酯、(甲基)丙烯酸四氢糠基酯等(甲基)丙烯酸烷氧基酯;(甲基)丙烯酸羟丙基酯、α-羟基甲基丙烯酸酯等含羟基单体(由于作为第三单体使用,所以不是交联点);(甲基)丙烯酰胺、二甲基(甲基)丙烯酰胺、N-丁基(甲基)丙烯酰胺、N-羟甲基(甲基)丙烯酰胺等具有酰胺基的(甲基)丙烯酸衍生物;(甲基)丙烯酸氨基乙酯、(甲基)丙烯酸二甲基氨基乙酯、(甲基)丙烯酸叔丁基氨基乙酯等(甲基)丙烯酸氨基烷基酯;(甲基)丙烯酸甲氧基乙二醇酯、(甲基)丙烯酸甲氧基二乙二醇酯、(甲基)丙烯酸甲氧基聚乙二醇酯、(甲基)丙烯酸甲氧基聚丙二醇酯等(甲基)丙烯酸烷氧基亚烷基二醇酯;(甲基)丙烯腈;苯乙烯磺酸、烯丙基磺酸、(甲基)丙烯酸磺基丙酯、(甲基)丙烯酰氧基萘磺酸、丙烯酰胺甲磺酸等具有磺酸的单体;乙烯基哌啶烷酮、乙烯基嘧啶、乙烯基哌嗪、乙烯基吡咯、乙烯基咪唑、乙烯基恶唑、乙烯基吗啉等含乙烯基的单体等。其中,优选乙烯基酯类、乙烯基酰胺类;乙烯基酯类优选乙酸乙烯酯,乙烯基酰胺类优选N-乙烯基-2-吡咯烷酮。这些第三单体可以单独使用或组合2种以上使用。
上述(甲基)丙烯酸烷基酯(第一单体)与具有能够参与上述交联反应的官能团的乙烯基单体(第二单体)的共聚物的情况下,上述(甲基)丙烯酸烷基酯与具有能够参与上述交联反应的官能团的乙烯基单体的重量比优选为99~85:1~15、更优选为99~90:1~10。
上述(甲基)丙烯酸烷基酯(第一单体)与具有能够参与上述交联反应的官能团的乙烯基单体(第二单体)与除了这些之外的其他单体(第三单体)的共聚物的情况下,上述(甲基)丙烯酸烷基酯与具有能够参与上述交联反应的官能团的乙烯基单体与除了这些之外的其他单体的重量比优选为40~94:1~15:5~50、更优选为50~89:1~10:10~40。
聚合反应没有特别限定,可以利用以往公知的方法进行,例如可以举出:添加聚合引发剂(例如过氧化苯甲酰、偶氮双异丁腈),在溶剂(例如乙酸乙酯)中使上述单体在50~70℃下反应5~48小时的方法。
上述丙烯酸类粘合剂更优选含有丙烯酸2-乙基己酯/丙烯酸/N-乙烯基-2-吡咯烷酮的共聚物、丙烯酸2-乙基己酯/N-(2-羟基乙基)丙烯酰胺/N-乙烯基-2-吡咯烷酮的共聚物、丙烯酸2-乙基己酯/丙烯酸2-羟基乙酯/乙酸乙烯酯的共聚物、丙烯酸2-乙基己酯/丙烯酸的共聚物,特别优选含有丙烯酸2-乙基己酯/丙烯酸/N-乙烯基-2-吡咯烷酮的共聚物。
可以对上述丙烯酸类粘合剂利用紫外线照射、电子束照射等辐射线照射实施物理交联处理,也可以实施利用三官能性异氰酸酯等异氰酸酯系化合物、有机过氧化物、有机金属盐、金属醇盐、金属螯合剂化合物、多官能性化合物(例如多官能性外部交联剂、二(甲基)丙烯酸酯等多官能性内部交联用单体)等交联剂的化学交联处理。
作为形成上述橡胶系粘合剂的橡胶系弹性体,没有特别限定,可以举出:聚异丁烯-聚丁烯系、苯乙烯-二烯-苯乙烯嵌段共聚物、苯乙烯-丁二烯系、腈系、氯丁二烯系、乙烯基吡啶系、聚异丁烯系、丁基系、异戊二烯-异丁烯系等。其中,从对上述配混成分的溶解性和皮肤粘接性的方面出发,优选聚异丁烯(PIB)、苯乙烯-二烯-苯乙烯嵌段共聚物(例如苯乙烯-丁二烯-苯乙烯嵌段共聚物(SBS)、苯乙烯-异戊二烯-苯乙烯嵌段共聚物(SIS))。这些橡胶系弹性体可以单独使用或组合2种以上使用。
上述橡胶系粘合剂中,为了得到适当的粘合力和对上述配混成分的溶解性,可以将同一成分或不同成分且平均分子量不同的橡胶系弹性体混合而使用。例如优选平均分子量15万~550万的高分子量的聚异丁烯与平均分子量1万~15万的中分子量的聚异丁烯和/或平均分子量500~4000的低分子量的聚异丁烯的混合物。相对于聚异丁烯的总体量,高分子量的聚异丁烯的配混量为10~80重量%、优选为20~70重量%。相对于聚异丁烯的总体量,中分子量的聚异丁烯的配混量为0~90重量%、优选为10~80重量%。相对于聚异丁烯的总体量,低分子量的聚异丁烯的配混量为0~80重量%、优选为10~60重量%。
本说明书中使用时,术语“平均分子量”是指,利用Flory的粘度式计算的粘均分子量,其是由20℃下的乌氏粘度计的毛细管1的流动时间利用Schulz-Blaschke式算出斯托丁格指数(Staudinger Index)(J0),使用该J0值通过下述式求出的。
(式)
J0=ηsp/c(1+0.31ηsp)(Schulz-Blaschke式)
ηsp=t/t0-1
t:溶液的流动时间(利用Hagenbach-couette校正公式)
t0:溶剂的流动时间(利用Hagenbach-couette校正公式)
c:溶液的浓度(g/cm3)
粘均分子量
上述橡胶系粘合剂中,为了赋于适度的粘合性,可以配混例如松香系树脂、聚萜烯树脂、香豆酮-茚树脂、石油系树脂、萜烯-酚醛树脂、二甲苯树脂、脂环族饱和烃树脂等增粘剂。这些增粘剂可以单独使用或组合2种以上使用。
对于上述增粘剂的含量,基于上述橡胶系粘合剂的总重量,优选为50重量%以下、更优选为5~40重量%。
作为上述有机硅系粘合剂,可以举出:包含有机聚硅氧烷系、聚二甲基硅氧烷系、聚二甲基二苯基硅氧烷系等的有机硅系粘合剂。其中,优选使用Dow Corning Corporation制造的BIO PSA这样的商业上能获得的有机硅系粘合剂。
上述粘合剂层可以还含有皮肤透过性增强剂。
本说明书中使用时,术语“皮肤透过性增强剂”是指,能够改善经皮给药的抗原透过皮肤的效率的所有物质。
作为上述皮肤透过性增强剂,优选在室温(25℃)下为液态(即,具有流动性)的物质。混合2种以上的皮肤透过性增强剂使用时,优选最终混合物在室温(25℃)下变为液态,具有皮肤透过促进效果。作为这样的有机液态成分,从上述粘合剂层中的相容性的观点出发,优选疏水性液态成分。
作为上述皮肤透过性增强剂,可以举出:高级醇、脂肪酸酯、多元醇脂肪酸酯。
作为上述高级醇,优选碳数8~18的高级醇、更优选碳数8~14的高级醇。作为上述脂肪酸酯,优选碳数8~18的脂肪酸与碳数1~18的一元醇的脂肪酸酯、更优选碳数12~16的脂肪酸与碳数1~18的一元醇的脂肪酸酯。其中,优选脂肪酸酯、特别优选肉豆蔻酸异丙酯、棕榈酸异丙酯、癸二酸二乙酯。
上述皮肤透过性增强剂具体而言可以举出:油醇、辛基十二烷醇等高级醇;甘油、乙二醇、聚丙二醇等多元醇;油酸、辛酸等高级脂肪酸;肉豆蔻酸异丙酯、棕榈酸异丙酯、油酸乙酯等脂肪酸酯;癸二酸二乙酯、己二酸二异丙酯等多元酸酯;三异硬脂酸二甘油酯、单油酸失水山梨醇酯、二辛酸丙二醇酯、聚乙二醇单月桂酸酯、四油酸聚氧乙烯山梨醇酯等多元醇脂肪酸酯;聚氧乙烯月桂基醚等聚氧乙烯烷基醚;角鲨烷、液体石蜡等烃;橄榄油、蓖麻油等植物油;硅油;N-甲基吡咯烷酮、N-十二烷基吡咯烷酮等吡咯烷酮类;癸基甲基亚砜等亚砜。这些皮肤透过性增强剂可以单独使用或组合2种以上使用。
使用上述丙烯酸类粘合剂或上述橡胶系粘合剂时,作为上述皮肤透过性增强剂,例如可以使用:聚乙烯基吡咯烷酮、交联聚维酮、聚丙二醇、聚乙烯醇、羧基乙烯基聚合物、羟丙基纤维素或者它们的混合物。其中,优选聚乙烯基吡咯烷酮、交联聚维酮、聚丙二醇。
上述粘合剂层中的上述皮肤透过性增强剂的含量没有特别限定,优选为上述粘合剂层的总重量的0.1~70重量%、更优选为1~65重量%、进一步优选为5~60重量%。上述皮肤透过性增强剂的含量为0.1重量%以上时,可以得到高的皮肤透过促进效果。上述皮肤透过性增强剂的含量为70重量%以下时,抑制上述粘合剂层整体的粘合力、聚集力的降低、且得到高的皮肤透过促进效果。
上述粘合剂层的厚度没有特别限定,优选为10~1000μm。通过设为上述范围的厚度,从而在上述粘合剂层中含有有效量的上述配混成分、发挥充分的粘合力、形成上述粘合剂层等变容易。
上述支撑体没有特别限定,优选实质上对上述配混成分具有不透过性的支撑体,即,上述粘合剂层中所含的上述抗原、上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂、根据需要的上述第二细胞性免疫诱导促进剂等通过支撑体从背面消失而不会引起含量的降低的支撑体。
作为上述支撑体,例如可以举出:聚酯、聚酰胺、聚偏氯乙烯、聚乙烯、聚丙烯、聚氯乙烯、乙烯-丙烯酸乙酯共聚物、聚四氟乙烯、离聚物树脂、金属箔等单独的薄膜或它们的层叠薄膜等。其中,对于上述支撑体,为了提高与上述粘合剂层的粘接性(锚固性),优选为由上述材质形成的无孔的塑料薄膜与多孔薄膜的层叠薄膜。上述情况下,优选上述粘合剂层形成于多孔薄膜侧。
作为上述多孔薄膜,只要提高与上述粘合剂层的锚固性就没有特别限定,例如可以举出:纸、织布、无纺布、针织物、实施了机械穿孔处理的片等。其中,从操作性等的观点考虑,优选为纸、织布、无纺布。上述多孔薄膜的厚度从锚固性提高、贴剂的柔软性及贴附操作性等方面考虑,优选1~200μm。另外,织布或无纺布的情况下,上述多孔薄膜的单位面积重量优选为5~30g/m2,更优选为6~15g/m2。
作为上述支撑体,特别优选的是,厚度1.5~6μm的聚酯薄膜(优选聚对苯二甲酸乙二醇酯薄膜)与单位面积重量6~15g/m2的聚酯(优选聚对苯二甲酸乙二醇酯)制无纺布的层叠薄膜。
作为上述剥离衬垫,只要能够实施剥离处理、确保充分轻的剥离力就没有特别限定,例如可以举出:通过在与上述粘合剂层的接触面涂布有机硅树脂、氟树脂等而实施了剥离处理的聚酯、聚氯乙烯、聚偏氯乙烯、聚对苯二甲酸乙二醇酯等的薄膜、优质纸、玻璃纸等纸;优质纸或玻璃纸等与聚烯烃的层压薄膜等。
上述剥离衬垫的厚度优选为10~200μm、更优选为25~100μm。
作为上述剥离衬垫,从阻隔性、价格等方面出发,特别优选由聚酯(特别是、聚对苯二甲酸乙二醇酯)树脂形成的剥离衬垫。上述情况下,从操作性的方面出发,厚度优选为25~100μm左右。
<经粘膜给药用疫苗药物组合物>
作为上述经粘膜给药,例如可以举出:舌下给药、鼻腔给药、颊侧给药、直肠给药、阴道给药等。
上述经粘膜给药用疫苗药物组合物的剂型例如可以为凝胶剂(啫喱剂)、霜剂、软膏剂、硬膏剂等半固体制剂;液体制剂;散剂、细粒剂、颗粒剂、膜剂、片剂、口腔内崩解片等固体制剂;气雾剂等粘膜用喷雾剂;吸入剂等。这些组合物的划分、定义、性质、制法等在该技术领域中是公知的,例如可以参照日本药典第16版。另外,作为这些材料,没有特别限定,可以使用以往公知的材料。
上述经粘膜给药用疫苗药物组合物中的上述抗原和上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂的含量没有特别限定,上述抗原的含量优选为0.01~40重量%、更优选为0.1~30重量%。上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂的含量优选为0.001~30重量%、更优选为0.01~20重量%。
作为上述液体制剂中使用的溶剂,可以举出:适量的水、乙醇、甘油、丙二醇等。通过使上述配混成分分散或溶解于这些溶剂,从而可以制备液体制剂。
作为上述凝胶剂(啫喱剂)中使用的基材,没有特别限定,可以举出:羧基乙烯基聚合物、凝胶基质、无脂肪性软膏、聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、藻酸钠、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、他拉胶、枸子胶、车前子胶、琼脂、结冷胶、葡甘露聚糖、刺槐豆胶、瓜尔胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚糖、EUDRAGIT、酪蛋白、藻酸烷基酯、明胶、聚乙二醇等水凝胶基材等。可以将这些基材溶解于溶剂并配混上述配混成分来制备具有流动性的凝胶剂或具有成形性的凝胶剂。作为溶剂,优选为水,也可以使用甘油、丙二醇等。另外,从抗原的扩散·释放性良好的方面出发,优选聚丙烯酸钠那样的亲水性基材。
作为上述霜剂中使用的基材,可以举出:亲水软膏、雪花膏等水/油型基材;亲水凡士林、精制羊毛脂、阿夸弗尔、优塞林、那塞林(Neocerin)、含水羊毛脂、冷霜、亲水Plastibase等油/水型基材。将这些基材加入油脂系溶剂或水中,利用均化器等进行高速搅拌并配混上述配混成分,从而可以制备霜剂。
作为上述膜剂中使用的基材,没有特别限定,可以举出:聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、藻酸钠、甲基纤维素、羧基乙烯基聚合物、琼脂、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、刺槐豆胶、瓜尔胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚糖、甲基丙烯酸氨基烷酯共聚物E、甲基丙烯酸氨基烷酯共聚物RS、甲基丙烯酸共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S、丙烯酸甲酯-甲基丙烯酸-甲基丙烯酸甲酯共聚物、丙烯酸乙酯-甲基丙烯酸甲酯共聚物、聚乙烯醇缩二乙基氨基乙酸酯、酪蛋白、藻酸烷基酯等。将这些基材溶解于水或乙醇等极性有机溶剂,配混上述配混成分,薄膜涂覆后,使其干燥,从而可以制备膜剂。
另外,从抗原的扩散·释放性良好的方面出发,优选聚丙烯酸钠那样的亲水性基材。
作为上述散剂、细粒剂、颗粒剂、片剂等中使用的添加剂,可以举出:乳糖、玉米淀粉、结晶纤维素等赋形剂、羟丙基纤维素、阿拉伯胶等粘合剂。将这些添加剂添加至适量的水或乙醇等溶剂中,配混上述配混成分,混合搅拌后,组合造粒、干燥、压片等工序,从而可以制备上述散剂、细粒剂、颗粒剂、片剂等。根据需要,也可以添加硬脂酸镁等润滑剂、羟丙基纤维素、蔗糖等包衣剂。
作为上述口腔内崩解片(冻干型)中使用的基材,可以举出:明胶、普鲁兰多糖等多糖类。另外,可以使用甘露糖醇、海藻糖、山梨糖醇、甘氨酸等成形剂。将这些基材和成形剂溶解于水,配混上述配混成分,分注后使其冻干,从而可以制备口腔内崩解片(冻干型)。
作为上述气雾剂,作为内容物的液体制剂、流动性高的凝胶剂、霜剂、散剂等细粉末。使用喷雾设备,将这些内容物以固体或液体的微粒的形式分散于气体中,从而可以效率良好地对口腔粘膜、鼻腔粘膜等给药部位进行给药。
<皮内、皮下或肌肉内给药用疫苗药物组合物>
上述皮内、皮下或肌肉内给药用疫苗药物组合物的剂型例如只要为液体制剂、水溶性或疏水性的悬浮剂、霜剂等具有能够注射给药的程度的流动性的剂型即可。这些组合物的划分、定义、性质、制法等在该技术领域中是公知的,例如可以参照日本药典第16版。另外,作为这些材料,没有特别限定,可以使用以往公知的材料。
上述皮内、皮下或肌肉内给药用疫苗药物组合物中的上述抗原和上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂的含量没有特别限定,上述抗原的含量优选为0.01~40重量%、更优选为0.1~30重量%。上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂的含量优选为0.001~30重量%、更优选为0.01~20重量%。
作为上述液体制剂中使用的溶剂,可以举出:适量的水、生理盐水、乙醇、甘油、丙二醇等。通过使上述配混成分分散或溶解于这些溶剂,从而可以制备液体制剂。
作为上述水溶性悬浮剂中使用的基材,没有特别限定,可以举出:羧基乙烯基聚合物、凝胶基质、无脂肪性软膏、聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、藻酸钠、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、他拉胶、罗望子胶、车前子胶、琼脂、结冷胶、葡甘露聚糖、刺槐豆胶、瓜尔胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚糖、EUDRAGIT、酪蛋白、藻酸烷基酯、明胶、聚乙二醇等水凝胶基材等。通过将这些基材溶解于溶剂,配混上述配混成分,从而可以制备具有流动性的悬浮剂。作为溶剂,优选为生理盐水,也可以使用甘油、丙二醇等。
另外,从抗原的扩散·释放性良好的方面出发,优选聚丙烯酸钠那样的亲水性基材。
作为上述疏水性悬浮剂中使用的基材,可以举出:亲水软膏、雪花膏等水/油型基材;亲水凡士林、精制羊毛脂、阿夸弗尔、优塞林、那塞林(Neocerin)、含水羊毛脂、冷霜、亲水Plastibase等油/水型基材。通过将这些基材加入到油脂系溶剂或水中用均化器等使其高速搅拌,配混上述配混成分,从而可以制备油脂系悬浮剂。
将本发明的疫苗药物组合物对对象进行给药时,上述抗原的治疗上有效量依赖于疾病的重程症度、对象的年龄和相对健康、其他已知的因素等而可以在广泛范围内变化,一般来说,以1天用量约0.1μg~1g/kg体重可以得到满意的结果。上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂与上述抗原同时或依次地、优选同时地给药。
上述作为双膦酸盐剂的第一细胞性免疫诱导促进剂的治疗上有效量依赖于使用的具体的双膦酸盐剂、其他细胞性免疫诱导促进剂的有无等而可以在广泛范围内变化,一般来说,以1天用量约0.01μg~1g/kg体重可以得到满意的结果。
需要说明的是,可以将1天用量以1次给药,也可以分2次以上(例如2次、3次、4次、5次等)的多次进行给药。每1次的连续给药时间优选在1分钟~7天中适当选择。给药间隔优选根据患者的状态、疾病的重程症度、治疗目的或预防目的而从每天~1年1次(例如1天1次、2天1次、3天1次、1周1次、2周1次、1月1次、3月1次、6月1次、1年1次)或更长期的给药间隔中适当选择。一般来说,在现实中具有重度的疾病的患者的治疗目的下,优选的是,以更高频率和/或高用量给药本发明的疫苗药物组合物,在不患有疾病的患者的预防目的下,优选的是,以更低频率和/或低用量给药本发明的疫苗药物组合物。
发明的效果
本发明的疫苗药物组合物可以进行非侵入性体表面上的给药(例如经皮给药或经粘膜给药),因此,具有如下优点:优异的应变性,例如非侵入的给药(例如,经皮给药或经粘膜给药)或者低侵入的皮肤表面上的给药(例如,胶带剥离等角质剥离处理、微针、电穿孔等角质穿孔处理),无痛,从注射的恐惧心理解放,给药简便,因此,患者自己可以给药,也可以避免医疗从业者的针刺感染事故的风险,可以降低进行重复给药时的往返医院频率,可以对患者的生活品质提高作出贡献,不会产生注射针那样的需要特殊废弃的医疗废弃物。
本发明的疫苗药物组合物如果为贴剂、巴布剂等粘贴剂的形态,则具有如下优点:能够切实地给药规定的给药量,能够任意地控制药物释放速度,另外,在给药时不会附着于其他部位。进而,贴剂还有如下优点:由于能够容易地拆卸,所以在副作用产生的情况等通过由施用部位去除贴剂,能够由患者自己即时终止给药。
通过给予本发明的疫苗药物组合物,与抗原的单独给药相比,细胞性免疫诱导效果显著提高。进一步,通过将本发明的疫苗药物组合物用于非侵入性体表面上的给药(例如、经皮给药或经粘膜给药),从而与注射给药相比,可以诱导强的免疫。进一步,本发明的疫苗药物组合物通过进一步含有抗氧化剂和/或抗炎症剂,从而细胞性免疫诱导效果协同地增强。
附图说明
图1为示出将实施例1~10、比较例2中得到的经皮给药用霜剂进行经皮给药时的细胞性免疫诱导效果的图。
具体实施方式
以下示出实施例更详细且具体地说明本发明,但本发明不限定于这些实施例。
(实施例1~64、比较例1~51)
(经皮给药用霜剂的制备)
制备具有下述表1~4和6的组成的经皮给药用霜剂。具体而言,以下述表1~4和6中所示的配混量,将下述所示的抗原肽、作为双膦酸盐剂的第一细胞性免疫诱导促进剂、根据需要个作为辅助肽的第二细胞性免疫诱导促进剂、抗氧化剂、抗炎症剂(包含COX抑制剂)、二甲基亚砜(DMSO)15重量%配混,向其中加入基材(基质霜),使其总量为100重量%,进行混和,得到经皮给药用霜剂。使用的基质霜是以表5中记载的组成配混材料,进行混和而制备的。白色凡士林、失水山梨醇单硬脂酸酯、异硬脂酸、苄醇、硬脂醇、吐温60、浓甘油、二甲基亚砜(DMSO)购自和光纯药工业。鲸蜡醇购自东京化成工业。
准备将PET薄膜/PET无纺布层叠品(面积0.7cm2)与固定用粘合带的中央部以PET薄膜侧作为带侧贴合而成的复合基材。在该复合基材的无纺布部分涂布经皮给药用霜剂4mg,将其作为免疫试验的给药样品。
(作为双膦酸盐剂的第一细胞性免疫诱导促进剂)
依替膦酸盐(LKT Laboratories,Inc.制)
氯膦酸盐(LKT Laboratories,Inc.制)
替鲁膦酸盐(Sigma-Aldrich公司制)
帕米膦酸盐(东京化成工业株式会社制)
阿仑膦酸盐(medichem公司制)
伊班膦酸盐(URQUIMA S.A.公司制)
奈立膦酸盐(Sigma-Aldrich公司制)
唑来膦酸盐(甲南化工株式会社制)
利塞膦酸盐(Propharma S.A.公司制)
米诺膦酸盐(Ava Chem Scientific公司制)
(抗氧化剂)
亚硝酸钠(和光纯药工业株式会社制)
抗坏血酸(和光纯药工业株式会社制)
亚硫酸氢钠(和光纯药工业株式会社制)
盐酸半胱氨酸(KYOWA HAKKO BIO CO.,Ltd.制)
柠檬酸水合物(小松屋株式会社制)
BHT(二丁基羟基甲苯、和光纯药工业株式会社制)
大豆卵磷脂(和光纯药工业株式会社制)
生育酚(关东化学株式会社制)
焦亚硫酸钠(和光纯药工业株式会社制)
BHA(二丁基羟基苯甲醚、关东化学株式会社制)
1,3-丁二醇(1,3-butanediol、和光纯药工业株式会社制)
苯并三唑(和光纯药工业株式会社制)
没食子酸丙酯(DSP Gokyo Food&Chemical Co.,Ltd.制)
2-MBI(2-巯基苯并咪唑、和光纯药工业株式会社制)
(抗炎症剂)
柚皮素(多酚、LKT Laboratories,Inc.制)
表儿茶素(多酚、和光纯药工业株式会社制)
芹黄素(多酚、和光纯药工业株式会社制)
白杨素(多酚、和光纯药工业株式会社制)
杨梅黄酮(多酚、和光纯药工业株式会社制)
芸香苷(多酚、和光纯药工业株式会社制)
染料木素(多酚、和光纯药工业株式会社制)
川陈皮素(多酚、和光纯药工业株式会社制)
姜黄素(多酚、和光纯药工业株式会社制)
白藜芦醇(多酚、和光纯药工业株式会社制)
香豆素(生物碱、和光纯药工业株式会社制)
黄连素(氯化黄连素n水合物、生物碱、和光纯药工业株式会社制)
甘草次酸(磷脂酶A2抑制剂、和光纯药工业株式会社制)
(COX抑制剂(抗炎症剂))
依托度酸(和光纯药工业株式会社制)
氯索洛芬(氯索洛芬钠、株式会社阳进堂制)
双氯芬酸(双氯芬酸钠、和光纯药工业株式会社制)
塞来昔布(SIGMA公司制)
伐地考昔(SIGMA公司制)
吡罗昔康(SIGMA公司制)
阿司匹林(乙酰水杨酸、和光纯药工业株式会社制)
吲哚美辛(和光纯药工业株式会社制)
酮洛芬(和光纯药工业株式会社制)
布洛芬(和光纯药工业株式会社制)
萘普生(和光纯药工业株式会社制)
(抗原肽)
OVAp(OVA肽、序列Ser Ile Ile Asn Phe Glu Lys Leu(序列号16)的8氨基酸的肽)
Survivin-2B(存活蛋白2B肽、癌抗原肽)
GPC3(GPC3肽、癌抗原肽)
HER2/neu_A24(HER2/neu_A24肽、癌抗原肽)
MAGE-A3_A24(MAGE3_A24肽、癌抗原肽)
IPEP87(IPEP87肽、源自感染性病原体的抗原)
PR1(PR1肽、癌抗原肽)
HER2_A02(HER2/neu_A02肽、癌抗原肽)
MAGE-A3_A02(MAGE3_A02肽、癌抗原肽)
HBVenv(HBVenv肽、源自感染性病原体的抗原)
HER2/neu_E75(HER2/neu_E75肽、癌抗原肽)
MUC1(MUC1肽、癌抗原肽)
(辅助肽)
Peptide-25(Pep25)
Peptide-25B(Pep25B)
PADRE
<评价1>
对于实施例、比较例中得到的经皮给药用霜剂进行以下评价。
(细胞性免疫诱导效果的评价)
按照以下的步骤,使用经皮给药用霜剂,进行使用免疫评价用模型动物的小鼠免疫试验。之后,利用ELISPOT法,评价抗原特异性的细胞性免疫的诱导水平。
(1)免疫评价用模型动物
此处所谓“免疫评价用模型动物”是指,用于评价疫苗药物组合物(此处经皮给药用霜剂)的免疫诱导特性的模型动物,具体而言是指,用于评价经皮给药用霜剂的细胞性免疫诱导水平的模型动物。
作为免疫评价用模型动物,考虑经皮给药用霜剂中的抗原与动物的MHC类1分子的适合性,使用利用经皮给药用霜剂中的抗原能够评价细胞性免疫诱导的动物。
即,抗原为HLA-A*24型MHC限制性class1肽时,使用BALB/c小鼠进行评价。抗原为HLA-A*02型MHC限制性肽时,使用利用HLA-A*02型MHC限制性肽能够评价细胞性免疫诱导的基因变异小鼠进行评价。抗原为其他HLA型的MHC限制性肽时,使用利用该HLA型的MHC限制性肽能够评价细胞性免疫诱导的动物进行评价。蛋白抗原的情况下,使用具备与蛋白抗原的氨基酸序列中所含的类1表位中、想要进行细胞性免疫诱导的类1表位具有适合性的MHC的动物进行评价。
(2)经皮给药用霜剂的小鼠免疫试验
(实施例1~64、比较例1~51)
将下述表1~4和6中所示的小鼠的背部进行剃毛,设置用于使由剃毛导致的皮肤损伤恢复的饲养期间,然后对小鼠的背部皮肤给予经皮给药用霜剂4mg 24小时并除去,进行6天饲养。从给药起经过6天后摘除脾脏,制备脾细胞悬浮液。向固定化有抗小鼠IFN-γ抗体的ELISPOT板的孔中,将脾细胞(5×105个细胞/孔)和抗原肽(100μM)与培养液一起注入,在37℃、5%CO2的培养条件下进行20小时共培养,利用ELISPOT法评价IFN-γ产生细胞点数。将IFN-γ产生细胞点数作为“免疫结果”示于下述表1~4和6。另外,图1中示出比较例2(w/o佐剂)和实施例1~10的免疫结果。
[表1]
[表2]
[表3]
[表4]
[表5]
[表6]
(3)经皮给药用贴剂的小鼠免疫试验
(实施例65~76、比较例52~57)
(经皮给药用贴剂的制备)
制备具有下述表7的组成的经皮给药用贴剂。具体而言,以下述表7中所示的配混量,将上述所示的抗原肽、作为双膦酸盐剂的第一细胞性免疫诱导促进剂、根据需要的作为辅助肽的第二细胞性免疫诱导促进剂配混,向其中以有机溶剂干燥后的各成分与粘合剂的总计成为100重量%的方式配混下述表7中所示的粘合剂和有机溶剂(粘合剂为丙烯酸的情况下为乙酸乙酯,粘合剂为PIB的情况下为甲苯)并混和,制备粘合剂溶液。将所得粘合剂溶液以干燥后的厚度变为约80μm的方式在剥离衬垫上展延,通过干燥除去有机溶剂,形成粘合剂层。剥离衬垫使用实施了有机硅剥离处理的聚对苯二甲酸乙二醇酯(PET)制衬垫(厚度75μm)。使支撑体贴合于所得粘合剂层,得到经皮给药用贴剂。作为支撑体使用聚对苯二甲酸乙二醇酯(PET)薄膜(厚度25μm)。
将该经皮给药用贴剂以面积0.7cm2的方式切割,将其作为免疫实验的给药样品。给药时剥离剥离衬垫进行给予。
(粘合剂)
丙烯酸(在非活性气体气氛下,以60℃,使丙烯酸2-乙基己酯75份、N-乙烯基-2-吡咯烷酮22份、丙烯酸3份和偶氮双异丁腈0.2份在乙酸乙酯中进行溶液聚合而得到的丙烯酸类粘合剂溶液)
PIB(将聚异丁烯(Oppanol B200、BASF株式会社制)24份、聚异丁烯(Oppanol B12、BASF株式会社制)36份和脂环族系石油树脂(Alcon P-100、荒川化学工业株式会社制)40份溶解于甲苯而得到的PIB粘合剂溶液)
<评价2>
对于实施例、比较例中得到的经皮给药用贴剂进行以下评价。
(细胞性免疫诱导效果的评价)
利用与经皮给药用霜剂的评价同样的操作,对抗原特异性的细胞性免疫的诱导水平进行评价。将评价结果作为“免疫结果”示于下述表7。
[表7]
(4)经皮给药用霜剂的小鼠免疫试验(低侵入给药)
(实施例77~91、比较例58~59)
以与表1的经皮给药用霜剂相同的要领,制备具有表8的组成的经皮给药用霜剂。将小鼠的右背部剃毛,对利用日东电工制OPP胶带(EZ Dunplon No.3301EZ)实施了角质剥离处理5次的皮肤给药霜剂(低侵入给药)。24小时后除去右背部的经皮给药用霜剂,进行6天饲养。从给药起经过6天后摘除脾脏,利用ELISPOT法测定抗原特异性的IFN-γ产生细胞。
利用下述表8所示的基于低侵入给药的免疫方法,对给药抗原也可以诱导特异性的细胞性免疫。
[表8]
产业上的可利用性
本发明的疫苗药物组合物能够普遍用于对各种抗原进行细胞性免疫诱导,发挥高的细胞性免疫诱导效果,适合用于经皮给药或经粘膜给药。
序列表
<110> 日东电工株式会社(NITTO DENKO CORPORATION)
<120> 包含双膦酸盐剂的细胞性免疫用疫苗药物组合物
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Claims (9)
1.一种疫苗药物组合物,其特征在于,其为用于细胞性免疫诱导的疫苗药物组合物,
其包含抗原和作为双膦酸盐剂的第一细胞性免疫诱导促进剂。
2.根据权利要求1所述的疫苗药物组合物,其还包含作为辅助肽的第二细胞性免疫诱导促进剂。
3.根据权利要求1或2所述的疫苗药物组合物,其中,作为双膦酸盐剂的第一细胞性免疫诱导促进剂为选自由依替膦酸盐、氯膦酸盐、替鲁膦酸盐、帕米膦酸盐、阿仑膦酸盐、伊班膦酸盐、奈立膦酸盐、唑来膦酸盐、利塞膦酸盐和米诺膦酸盐组成的组中的至少一种。
4.根据权利要求3所述的疫苗药物组合物,其还包含抗氧化剂和/或抗炎症剂。
5.根据权利要求4所述的疫苗药物组合物,其中,抗氧化剂为选自由亚硝酸钠、抗坏血酸、亚硫酸氢钠、盐酸半胱氨酸、柠檬酸水合物、二丁基羟基甲苯、大豆卵磷脂、生育酚、焦亚硝酸钠、二丁基羟基苯甲醚、1,3-丁二醇、苯并三唑、没食子酸丙酯和2-巯基苯并咪唑组成的组中的至少一种。
6.根据权利要求4所述的疫苗药物组合物,其中,抗炎症剂为选自由多酚、生物碱和磷脂酶A2抑制剂组成的组中的至少一种。
7.根据权利要求4所述的疫苗药物组合物,其中,抗炎症剂为环氧酶抑制剂。
8.根据权利要求7所述的疫苗药物组合物,其中,环氧酶抑制剂为选自由环氧酶非选择性抑制剂、环氧酶1选择性抑制剂和环氧酶2选择性抑制剂组成的组中的至少一种。
9.根据权利要求1、2、3、4、5、6、7或8所述的疫苗药物组合物,其对体表面上给药。
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EP3189854A4 (en) | 2018-02-21 |
US20170360908A1 (en) | 2017-12-21 |
JP6577795B2 (ja) | 2019-09-18 |
US10925936B2 (en) | 2021-02-23 |
EP3189854A1 (en) | 2017-07-12 |
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