CN115006379B - 一种trpv1激动剂原位膜剂组合物,及其制备方法和用途 - Google Patents
一种trpv1激动剂原位膜剂组合物,及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一种TRPV1激动剂原位膜剂组合物,包括药学上的活性成分,成膜材料和溶剂体系。所述组合物,流动性好,给药方便、灵活性强,且可以从组合物和/或其干燥后形成的薄膜中快速释放辣椒素进入皮肤中的神经纤维末梢,通过短期大剂量的辣椒素刺激使表达TRPV1的神经末梢退化,从而达到单次使用即可长期缓解周围神经痛的作用,具有优于上市药品的皮肤递送能力。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种TRPV1激动剂原位膜剂组合物及其制备方法和用途。
背景技术
辣椒素是辣椒植物中的主要活性成分。David Julius利用辣椒素发现了皮肤神经末梢中的热觉感受器—瞬时受体电位香草酸亚型1(Transient receptor potentialvanilloid 1,TRPV1)的存在,并凭此发现获得2021年诺贝尔生理学或医学奖。TRPV1常被称为辣椒素受体,是一种非选择性阳离子通道受体,主要分布于中枢和外周的中、小型伤害性感觉神经元末端。辣椒素具有镇痛、抗炎消肿、防治风湿和调节食欲等作用。辣椒素的药效取决于递送部位的药物浓度,已知低浓度的辣椒素可与TRPV1受体结合导致钙离子内流产生短暂的灼烧感,痛觉过敏,异常疼痛和红斑,而长期低剂量或短期大剂量的辣椒素可使小直径感觉神经元退化,从而达到长效镇痛的作用。辣椒素对于神经元的作用是可逆的。
目前,高浓度的辣椒素贴剂(CN 100512806 C)已被开发上市,用于治疗带状疱疹后神经痛和糖尿病足周围神经病变神经痛。贴片使用前需要根据给药部位进行剪裁,并且对于不平整的区域(如脚踝、脚趾等部位)使用不便,黏附效果不好。专利CN104010635A公开了包含辣椒素类物质和止痛剂的局部用组合物和制备方法,以及使用这样的组合物来提供疼痛缓解和治疗多种疾病的方法,所述组合物为液体溶液,存在辣椒素扩散风险,可能刺激医护人员和患者的呼吸道及皮肤,导致咳嗽和灼烧感。专利101119713A公开了一种类辣椒素凝胶,用于治疗人类或动物中的外科手术后部位疼痛,包含基质,胶凝剂和其他赋形剂,但是该组合物在实施例中的浓度仅2mg/mL,且无法直接用于皮肤给药。
因此,需要提供一种给药方便灵活且有效的TRPV1激动剂(辣椒素及其类似物)制剂。
发明内容
为解决现有技术中存在的问题,本发明提供一种药物组合物,包括如下组分:
a.药学上的活性成分,所述活性成分选自式Ⅰ或式Ⅱ中的一种或几种:
所述式Ⅰ化合物为所述式Ⅱ化合物为/>
其中R选自饱和或不饱和脂肪烃基;
b.成膜材料;
c.溶剂体系;
根据本发明的实施方案,所述药物组合物还包含d.至少一种药学上可接受的抗氧化剂。
根据本发明的实施方案,所述药物组合物还可以包含e.至少一种药学上可接受的pH调节剂。
根据本发明的实施方案,所述a组分药学上的活性成分式Ⅰ或式Ⅱ中,R选自C6-20饱和或不饱和脂肪烃基,例如
在一些实施方案中,所述药学上的活性成分为辣椒素。
根据本发明的实施方案,所述成膜材料选自但不限于聚乙烯醇、聚乙烯吡咯烷酮、尤特奇、共聚维酮、乙基纤维素、羟丙纤维素、羟丙甲纤维素、羟丙甲纤维素酞酸酯、聚乙烯醇缩丁醛中的一种或多种组合。
根据本发明的实施方案,所述溶剂选自但不限于水、乙醇、异丙醇、丙酮、乙酸乙酯、二氯甲烷、甲醇、丙二醇、二乙二醇单乙醚、聚乙二醇、矿物油中的一种或多种组合。
根据本发明的实施方案,d组分所述药学上可接受的抗氧化剂包括但不限于亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、硫脲、半胱氨酸、二丁基羟基甲苯、丁基羟基茴香醚、酒石酸、枸橼酸、抗坏血酸、乙二胺四乙酸、乙二胺四乙酸或其盐、二巯基丙醇、维生素E、硫代甘油中的一种或多种组合。
根据本发明的实施方案,e组分所述药学上可接受的pH调节剂包括但不限于盐酸、硫酸、醋酸、磷酸、枸橼酸、酒石酸、马来酸、邻苯二甲酸、氨基酸类、苹果酸、乳酸、富马酸、琥珀酸、Mcllvaine缓冲液、磷酸盐缓冲液、醋酸盐缓冲液、枸橼酸盐缓冲液、碳酸盐缓冲体系、Tris(三羟甲基氨基甲烷)缓冲体系、硼酸盐缓冲体系、邻苯二甲酸盐缓冲液中的一种或多种组合。
根据本发明的实施方案,所述组合物可以是溶液、乳液、喷雾剂、乳膏、凝胶或软膏的形式,并且可以轻松地涂抹于皮肤表面,用于外周神经痛的治疗。所述组合物涂抹于病变部位后,随着溶剂的挥发形成完整的柔软的薄膜,给药完成后,可轻松揭除,分散在膜中的剩余的辣椒素可随膜一起清除,不会扩散,避免刺激患者和医生。
根据本发明的实施方案,所述药学上的活性成分占组合物总量的约0.01%至16.0%(w/w),例如约0.01%、0.05%、0.1%、0.5%、1.0%、1.5%、2.0%、2.5%、3.0%、3.5%、4.0%、4.5%、5.0%、5.5%、6.0%、6.5%、7.0%、7.5%、8.0%、8.5%、9.0%、9.5%、10.0%、10.5%、11.0%、11.5%、12.0%、12.5%、13.0%、13.5%、14.0%、14.5%、15.0%、15.5%、16.0%(w/w)。在一些实施方案中,所述药学上的活性成分约为2%至16%(w/w)。
根据本发明的实施方案,所述成膜材料占组合物总量的约5%至约60%(w/w),例如约5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%。在一些实施方案中,所述成膜材料约为8%至50%(w/w)。
根据本发明的实施方案,所述药学上可接受的溶剂占组合物总量的约25%至约90%(w/w),例如约25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%。在一些实施方案中,所述药学上可接受的溶剂约为30%至90%(w/w)。
根据本发明的实施方案,所述抗氧化剂占组合物总量的约0.001%至2.0%(w/w),例如约0.001%、0.005%、0.01%、0.05%、0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1.0%、1.1%、1.2%、1.3%、1.4%、1.5%、1.6%、1.7%、1.8%、1.9%、2.0%。在一些实施方案中,所述抗氧化剂约为0.05%至1.0%(w/w)。
根据本发明的实施方案,所述组合物的pH范围为3.0~7.0。在一些实施方案中,所述组合物的pH范围为4.0~6.0,在一些实施方案中,所述组合物的pH范围为4.5~5.5。
根据本发明的实施方案,所述组合物还可以进一步包括其他药学领域常规的赋形剂,合适的药物赋形剂的实例在Handbook of Pharmaceutical ManufacturingFormulations Semisolid Products second edition第159-180页,Excipients andtheir use in injectable products.PDA J Pharm Sci Technol.第51卷,1997年7-8月,第166-171页和Excipient Selection In Parenteral Formulation Development,PharmaTimes,第45卷,第3期,2013年3月,第65-77页中描述,他们通过引用整体并入本发明中。
本发明提供了一种所述药物组合物的制备方法,包括如下步骤:
a1.将成膜材料和溶剂搅拌混合,必要时加热处理,得澄清溶液;
a2.将药学上的活性成分溶于溶剂中,得澄清溶液;
a3.将步骤a1和步骤a2中的溶液搅拌混合均匀;
a4.必要时加入抗氧化剂并调节组合物pH。
本发明还提供了一种用于制备所述组合物的方法,包括如下步骤:
b1.将成膜材料和溶剂搅拌混合,必要时加热处理,得澄清溶液;
b2.将药学上的活性成分加入步骤b1的溶液中,搅拌混合均匀;
b3.必要时加入抗氧化剂并调节组合物pH。
本发明还提供了另一种用于制备所述组合物的方法,包括如下步骤:
c1.将成膜材料、药学上的活性成分和溶剂搅拌混合,必要时加热处理,得澄清溶液;
c2.必要时加入抗氧化剂并调节组合物pH。
术语与缩写
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
本申请说明书和权利要求书记载的数值范围,当该数值范围被定义或其仅可为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“0~10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。
当该数值范围被定义为“数”或可以包括“整数”或“非整数”时,应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如,“0~10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
术语“脂肪烃基”包括饱和或不饱和,直链或具有支链的链状烃基,所述脂肪烃基的类型可选自烷基(饱和脂肪烃基)、烯基、炔基等,所述脂肪烃基的碳原子数优选为6-20(例如为C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16,C17,C18,C19,C20),具体可包括但不限于如下基团:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基,1-丙炔基,2-丙炔基,1-丁炔基,1-甲基-2-丙炔基,3-丁炔基,1-戊炔基和1-己炔基;其他基团中所含“脂肪烃基”部分同上述解释。
本发明使用的缩写词具有如下定义:PVA为聚乙烯醇,PVP为聚氧乙烯吡咯烷酮,EC为乙基纤维素、HPMC为羟丙基甲基纤维素,PVP/VA为共聚维酮,Eudragit为丙烯酸树脂,二丁基羟基甲苯为BHT。
有益效果
1)本发明的组合物,流动性好,一方面可根据病变部位形状涂抹,给药方便、灵活性强,另一方面可以从组合物和/或其干燥后形成的薄膜中快速释放辣椒素进入皮肤中的神经纤维末梢,通过短期大剂量的辣椒素刺激使表达TRPV1的神经末梢退化,从而达到单次使用即可长期缓解周围神经痛的作用,具有优于上市药品的皮肤递送能力;
2)辣椒素及其类似物对呼吸道和粘膜刺激性强,可能导致咳嗽和灼烧感,本发明的组合物为粘稠流体,辣椒素不易扩散,溶剂挥发成膜后具有合适的拉伸强度(不会断裂形成碎屑)且容易揭除,皮肤表面无残留。
3)本发明的组合物稳定有效,通过合适的抗氧化剂和pH调节剂的加入可以进一步提高制剂稳定性,有效控制杂质增长。
附图说明
图1示意辣椒素、乙醇、PVA溶液三元相图;
图2示意实施例3的组合物的显微镜照片,A:透明组合物;B:半透明组合物;C:白色组合物;
图3示意组合物22和上市制剂中辣椒素在皮肤中的吸收量对比,n=4,*p<0.05;
图4示意组合物23的外用镇痛效果,n=6,*p<0.05;
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例1
不同成膜材料组合物制备
按表1处方制备含不同成膜材料(PVA、PVP、Eudragit、PVP/VA、EC和HPMC)的辣椒素原位膜剂。
表1 含不同成膜材料的辣椒素原位膜剂处方组成(wt%)
实施例2
膜的性能研究
对实施例1中的组合物的成膜性能、可揭性进行评价,对实施例1中的组合物形成的膜的拉伸强度和断裂伸长率进行评价。测定方法如下:
成膜性和可揭性评价:取0.1g组合物涂抹于1cm2的乳胶手套上,过夜后考察成膜性和可揭除性。
拉伸强度、断裂伸长率测定:画12*3cm的矩形区域,涂抹3.5g组合物,使膜厚度均匀,没有气泡,边缘无缺口,过夜后揭下的膜剪裁成相同大小用于拉伸强度和断裂伸长率检测。拉伸强度=断裂强力/横截面积,断裂伸长率=(断裂长度-初始长度)/初始长度×100%。
测定结果见表2。结果显示含PVA、PVP、Eudragit、PVP/VA、EC和HPMC的辣椒素原位膜剂涂抹后均可形成薄膜,可揭性评价中PVA、PVP、Eudragit、EC和HPMC形成的膜可完整揭除,共聚维酮形成的膜揭除过程中断裂成5片。膜的机械性能包括拉伸强度和断裂伸长率与成膜材料相关。
表2 含不同成膜材料的辣椒素原位膜剂的性能评价
实施例3
辣椒素原位膜剂相图研究
制备辣椒素、PVA、乙醇和水的原位膜剂组合物的相图。为了快速全面的了解四元组合物的相行为,将PVA和水合并配制成粘度合适的水溶液,即可利用三元相图进行研究。三元相图制备过程:将PVA加入水中,加热搅拌配制23%PVA溶液,称量PVA溶液、乙醇、辣椒素,混合均匀后,10000rpm离心3min后,观察外观和显微,相图见图1。
在制备过程中发现,辣椒素的载药量取决于组合物中乙醇的比例,乙醇比例越高溶解的辣椒素越多,但当乙醇比例过高会导致PVA凝胶化析出;随着辣椒素比例增加,组合物外观变化趋势为透明溶液、半透明溶液、白色溶液、沉淀分层,不同外观对应的显微照片见图2。从图中可以看出透明溶液中无液滴为均相体系。半透明溶液和白色溶液中分布着乳滴,为非均相体系。
实施例4
粘度研究
制备不同粘度的组合物,并对其粘度、挤出性能和涂布性能进行评价。处方组成见表3,性能评价结果见表4。组合物粘度在1700~43000cP之间均表现出较好的挤出性能和涂布性能。组合物7和组合物10粘度较大,涂布后即使在倾斜状态下也不流动,其他组合物在倾斜状态下会流动,干燥后的膜厚度不均匀。虽然粘度低的组合物表现出较大的流动趋势,但仍适用于平整的皮肤表面。
表3 不同粘度辣椒素原位膜剂处方组成(wt%)
表4 不同粘度辣椒素原位膜剂挤出和涂布性能评价
#涂布均匀性:按0.1g/cm2的用量将组合物均匀涂抹于平板上,倾斜45°,待干燥后观察膜涂布厚度是否均匀。
实施例5
成膜时间研究
组合物中的溶剂挥发后会形成一层膜,其成膜时间与组合物中溶剂用量和涂抹厚度有关。将组合物按0.08g/cm2的用量涂抹均匀后,测定指触干燥时间。实施例4中的组合物的成膜时间结果见表5。
表5 不同组合物的成膜时间研究
编号 | 10 | 11 | 12 |
成膜时间(min) | 35 | 40 | 70 |
实施例6
辣椒素pH-稳定性研究
用不同pH的Mcllvaine缓冲液和乙醇按体积比6:4混合配制一系列不同pH的辣椒素溶液(1mg/ml),通过高温破坏(121℃,1h)考察其降解情况,结果见表6。结果显示辣椒素的稳定性与溶液pH值相关。
表6 不同pH辣椒素溶液经高温破坏(121℃,1h)后的杂质情况
溶液pH | 二聚体杂质% | 总杂% |
pH3.8 | 0.53 | 2.21 |
pH4.1 | 0.17 | 1.65 |
pH4.7 | 0.14 | 1.55 |
pH5.4 | 0.13 | 1.66 |
pH5.8 | 0.14 | 1.54 |
pH6.5 | 0.24 | 1.85 |
pH7.0 | 0.29 | 1.92 |
pH8.0 | 0.75 | 2.43 |
pH9.0 | 0.83 | 2.45 |
pH9.6 | 0.98 | 2.64 |
实施例7
抗氧化剂研究
按表7中处方制备含不同抗氧化剂的制剂,对比不同抗氧化剂的效果。经高温121℃-1h处理后和经60℃-15d处理后的杂质结果见表8。
表7 含不同抗氧化剂的组合物处方(wt%)
备注:表中制剂用盐酸调节pH至4.9
表8 不同抗氧化剂处方经高温破坏后的杂质情况
编号 | 121℃-1h二聚体杂质% | 60℃-15d二聚体杂质% |
13 | 0.55 | 3.15 |
14 | 0.66 | 1.49 |
15 | 0.75 | 2.20 |
16 | 0.20 | 0.74 |
17 | 0.21 | 0.31 |
实施例8
抗氧化剂用量及pH调节剂研究
按表9中处方制备组合物并考察其稳定性,结果见表10。
表9 不同抗氧化剂用量和pH的组合物处方(wt%)
表10 不同处方组合物的经高温破坏后的杂质情况
编号 | 60℃-11d二聚体杂质% |
18 | 0.08 |
19 | 0.02 |
20 | 0.03 |
21 | 未检出 |
实施例9
辣椒素原位膜剂组合物的大鼠皮肤吸收研究
辣椒素用于治疗外周神经痛的作用靶点是分布于表皮中的感觉神经纤维末梢的TRPV1受体。本发明组合物需要递送足够量的辣椒素进入皮肤才能发挥药效。本实施例展示组合物22向大鼠皮肤递送辣椒素的能力,并与上市制剂进行对比。
按表11处方制备组合物22。将8只大鼠随机分为2组,每组4只,剃去大鼠背部毛发,圈出3.14cm2的圆形区域,分别给予组合物22和上市制剂给药1h后除去药物,测定给药区域皮肤含药量。辣椒素在皮肤中的吸收情况见图3,结果显示组合物22中辣椒素吸收量明显高于上市制剂/>表现出增强的辣椒素皮肤递送能力。
表11 组合物22的处方组成
组分 | wt% |
辣椒素 | 4 |
PVA 05-88 | 23.04 |
水 | 34.56 |
乙醇 | 38.4 |
合计 | 100 |
实施例10
辣椒素原位膜剂的药效研究
按表12处方制备组合物23并对其镇痛效果进行评价。建立小鼠坐骨神经慢性压迫性损伤(Chronic constriction injury,CCI)模型,评价辣椒素原位膜剂组合物23的外用镇痛效果。造模侧足底涂抹药物3h后揭除药物,在给药前,给药后4h/1天(24h)/2天/3天/5天/7天/9天/11天/13天/15天,分别采用热板法和von frey法检测足底痛阈值。图4结果显示,辣椒素原位膜剂组合物23给药后产生显著的镇痛效果,与模型组相比,热痛和机械痛阈值明显提升。
表12 组合物23的处方组成
组分 | wt% |
辣椒素 | 4 |
PVA(17-88) | 12 |
乙醇 | 42.9 |
水 | 40.9 |
BHT | 0.2 |
合计 | 100 |
备注 | 浓盐酸调节pH4.5~5.5 |
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (1)
1.一种药物组合物,其特征在于,所述药物组合物选自如下处方:
组合物22的处方
,
组合物23的处方
,
组合物7的处方
,
组合物10的处方
,
组合物17的处方
。
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