CN105943595A - 一种治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物及其制备方法 - Google Patents
一种治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物及其制备方法 Download PDFInfo
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Abstract
本发明提供一种治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物,其包含5~60重量份黄芪和5~30重量份当归的水提物;5~30重量份老鹳草和5~30重量份紫草的70~80wt%乙醇水溶液的提取物;5~30重量份红花的45~55wt%乙醇水溶液的提取物。本发明的治疗化疗致手足综合征、靶向治疗所致手足皮肤反应的药物具有益气活血,解毒生肌的功能,能够达到有效治疗化疗致手足综合征、靶向治疗所致手足皮肤反应的满意效果。
Description
技术领域
本发明涉及一种治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物,特别是涉及一种以中草药为原料制成的治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物。
背景技术
恶性肿瘤发病率逐年升高,新化疗药物、靶向药物在肿瘤临床的应用日益广泛,提高了抗肿瘤疗效的同时也出现了许多新的不良反应,成为肿瘤临床难治的并发症。卡培他滨(capecitabine)、阿霉素脂质体(liposomal doxorubicin)和五氟尿嘧啶(5-Fu)为代表的化疗药物手足综合征(hand-foot syndrome,HFS),索拉非尼、舒尼替尼为代表的靶向药物所致手足皮肤反应(hand-foot syndrome skin reaction,HFSR)是目前肿瘤临床常见的不良反应,严重时影响肢体功能、导致痛性残疾,降低患者生活质量,还可能使有效的治疗被迫中断,间接影响患者的治疗获益。
手足综合征(HFS)又称为掌跖感觉丧失性红斑(palmoplantarerythrodysesthesia,PPE)或肢端红斑(acral erythema)。多种化疗药物都可诱导手足综合征的发生,其中最为常见的药物为卡培他滨(HFS发生率为50-60%)和阿霉素脂质体(HFS发生率为40-50%)。手足皮肤反应是MKI治疗后最常见的毒性反应,在接受索拉非尼或舒尼替尼治疗的患者中发生率为9%~62%。对索拉非尼皮肤副反应的双盲前瞻性3期临床试验表明,91%患者出现至少1次皮肤反应,60%患者出现HFSR,5%患者出现3级HFSR,导致治疗剂量减少。
HFS典型临床表现为掌跖感觉丧失和刺痛,多发生于化疗开始后2-12天。随着病情进展,3-4天后患者痛温度觉下降,但压力觉、轻触觉,本体觉保留。类似小神经纤维病变。神经系统症状出现后,伴发掌跖红斑水肿,边界明显,伴有紫色水肿。在手指侧面和远端脂肪垫最为显著。1-2周后,红斑可进展为水疱,而后出现脱皮、结痂、糜烂、溃疡和表皮坏死。HFS的病理学改变为非特异性,类似于细胞毒性反应。角质层角化过度,棘层海绵样水肿,基底层呈现局灶性空泡样变性,表皮血管周呈轻度淋巴细胞侵润和黑色素沉积。表皮层改变包括血管扩张,乳头样水肿,血管周的淋巴细胞浸润。严重者可见表皮全层坏死,与临床严重程度分级相一致。HFSR的临床特征为:手足部敏感、麻刺感、烧灼感、红斑肿胀、皮肤变硬、起茧、起疱、发干、皲裂、脱屑,通常为双侧性。以上症状多同时或连续发生,手足的受力区严重,多于治疗2~4周出现,在整个疗程中症状逐渐减轻。对HFSR的病理研究表明,58.3%活检标本显示水平层成角质细胞坏死。早期(治疗30d内)累及粒-棘层细胞改变;晚期(>30d)导致角质层病理改变。少数出现轻微汗腺毛囊改变,极少数出现鳞状上皮化生。
治疗HFS及HFSR的有效方法是降低剂量、延长给药周期,甚至停药。二者虽没有生命危险,但是一旦发生却严重影响患者生活质量,导致病人不能从事正常工作或日常活动,甚至导致治疗中断,从而影响治疗的效果。其他治疗措施包括局部冷却、维生素B6、皮质激素、DMSO以及支持疗法和病人教育,但尚未达到满意疗效。
因此,迫切需要一种能够有效治疗化疗性手足综合征及靶向治疗所致手足皮肤反应的药物。
发明内容
本发明的目的是提供一种有效治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物,其基于中医的“活血通络、解毒生肌”,外用治疗化疗性手足综合征患者,具有良好的临床疗效和安全性。
本发明的治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物,以重量份计,组成如下:
5~60重量份黄芪和5~30重量份当归的水提物;
5~30重量份老鹳草和5~30重量份紫草的70~80wt%乙醇水溶液的提取物;
5~30重量份红花的45~55wt%乙醇水溶液的提取物;
可药用辅料。
优选地,本发明的治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物,以重量份计,组成如下:
10~40重量份黄芪和5~20重量份当归的水提取物;
10~25重量份老鹳草和5~20重量份紫草的70~80wt%乙醇水溶液的提取物;
5~20重量份红花的45~55wt%乙醇水溶液的提取物;和
可药用辅料。
最优选地,本发明的治疗化疗性手足综合征的药物,以重量份计,组成如下:
10~15重量份黄芪和6~12重量份当归的水提取物;
10~15重量份老鹳草和5~10重量份紫草的70~80wt%乙醇水溶液的提取物;
5~10重量份红花的45~55wt%乙醇水溶液的提取物;和
可药用辅料。
本发明的治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物其特征在于所述药物是任何一种药剂学上所说的可外用的剂型,例如颗粒剂、散剂、溶液剂等。
本发明的治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物其特征在于所述药物是是散剂。
根据本发明的另一方面,本发明提供上述治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物的制备方法,其特征在于,
本发明的药物是采用如下重量配比的原料制成的:黄芪5~60重量份、红花5~30重量份、老鹳草5~30重量份、紫草5~30重量份、当归5~30重量份,
具体步骤如下:
取黄芪和当归用水煎煮1~3次,每次水量为黄芪和当归重量的8~10倍,合并提取液,减压浓缩,得到50±5℃相对密度为1.22~1.24的清膏1;
取老鹳草和紫草用70~80wt%乙醇水溶液提取1~3次,每次乙醇水溶液量为老鹳草和紫草重量的7~15倍量,温度为55~65℃,合并提取液,得到提取液1;
取红花用45~55wt%乙醇水溶液提取1~3次,每次乙醇水溶液量为红花重量的7~15倍量,温度为55~65℃,合并提取液,得到提取液2;
将上述得到的提取液1和提取液2合并,减压浓缩,得到50±5℃相对密度为1.22~1.24的清膏2;
将清膏1和清膏2混合,添加适量的可药用辅料,减压干燥,粉碎成细粉,按常规方法制成任何一种药剂学上的药剂。
所述制备步骤优选为:
取黄芪和当归用水煎煮1~3次,每次水量为黄芪和当归重量的8~10倍,每次煎煮1~1.5小时,合并提取液,减压浓缩,得到50±5℃相对密度为1.22~1.24的清膏1;
取老鹳草和紫草用70~80wt%乙醇水溶液提取1~3次,每次乙醇水溶液量为老鹳草和紫草重量的7~15倍量,温度为55~65℃,每次提取1~1.5小时,合并提取液,得到提取液1;
取红花用45~55wt%乙醇水溶液提取1~3次,每次乙醇水溶液量为红花重量的7~15倍量,温度为55~65℃,,提取1~1.5小时,合并提取液,得到提取液2;
将上述得到的提取液1和提取液2合并,减压浓缩,得到50±5℃相对密度为1.22~1.24的清膏2;
将清膏1和清膏2混合,添加清膏量1~3倍的可药用辅料,减压干燥,粉碎成细粉,按常规方法制成任何一种药剂学上的药剂。
经动物药效学和临床试验等试验证明,本发明的治疗化疗致手足综合征、靶向治疗所致手足皮肤反应的药物具有益气活血,解毒生肌的功能,能够达到有效治疗化疗致手足综合征、靶向治疗所致手足皮肤反应的满意效果。
具体实施方式
下面结合实施例对本发明进行进一步的描述。
制备实施例1:制备散剂
按下述重量配比称取原料:
黄芪15Kg红花10Kg老鹳草15Kg紫草10Kg当归12Kg
制备方法:
黄芪和当归用水煎煮两次,每次水量为黄芪和当归的10倍量,每次煎煮1.5小时,合并提取液,减压浓缩,得到50℃相对密度为1.24的清膏1。老鹳草和紫草用75wt%乙醇水溶液提取两次,每次乙醇水溶液量分别为老鹳草和紫草重量的15倍和12倍,温度为60℃,每次提取1.5小时,合并提取液,得到提取液1。红花用50wt%乙醇水溶液提取两次,每次乙醇水溶液量为红花重量的12倍和10倍,温度为60℃,每次提取1.5小时,合并提取液,得到提取液2。将上述得到的提取液1和提取液2合并,减压浓缩,得到50℃相对密度为1.24的清膏2。将清膏1和清膏2混合,减压干燥,粉碎成细粉。加入糊精,比例为干膏:糊精=1:1~3,混合均匀。
制备实施例2:制备颗粒剂
按下述重量配比称取原料:
黄芪10Kg 红花5Kg 当归10Kg
老鹳草10Kg 紫草10Kg
制备方法:
黄芪和当归用水煎煮两次,每次水量为黄芪和当归的10倍量,每次煎煮1小时,合并提取液,减压浓缩,得到55℃相对密度为1.22的清膏1。老鹳草和紫草用80wt%乙醇水溶液提取两次,每次乙醇水溶液量分别为老鹳草和紫草重量的15倍和12倍,温度为60℃,每次提取1小时,合并提取液,得到提取液1。红花用55wt%乙醇水溶液提取两次,每次乙醇水溶液量为红花重量的12倍和10倍,温度为60℃,每次提取1小时,合并提取液,得到提取液2。将上述得到的提取液1和提取液2合并,减压浓缩,得到55℃相对密度为1.22的清膏2。将清膏1和清膏2混合,减压干燥,粉碎成细粉。加入糊精,比例为干膏:糊精=1:1~3,制成颗粒剂。
本发明药物与治疗作用有关的主要药效学试验
材料和方法
1.实验动物及分组:动物实验均遵循《北京市实验动物管理条理》。雌性C57BL小鼠,8周龄,饲养于中日友好医院SPF动物房(许可证号SYXK(京)2008-0019),根据体重随机分为对照组、模型组、外用中药组。
2.手足综合征模型建立:参照Elbayoumi TA方法建立小鼠手足综合征模型(Elbayoumi TA,Torchilin VP.Tumor-specific antibody-mediated targeted deliveryof Doxil reduces the manifestation of auricular erythema side effect inmice.Int J Pharm.2008,357(1-2):272-9.)。盐酸阿霉素脂质体注射液(4mg/kg体重,q5d×4)尾静脉注射。
3.研究用药:制备实施例1制得的散剂。
4.给药方法:参照文献记载方法给药(娄彦妮,陈信义,田爱平,等.通络活血法外用治疗化疗性手足综合征临床研究[J].辽宁中医药大学学报,2013,15(4):68-70;柯丹丹,贾立群,邓博,等.温经通络散外用对奥沙利铂所致周围神经毒性大鼠坐骨神经传导的影响[J].中日友好医院学报.2014,28(3):165-168.)。将200g制备实施例1制得的散剂溶于1000ml去离子水,得到溶液(相当于临床常用浓度的10倍)。中药组从造模第1天起给予上述溶液,浸洗四肢及尾部,水温28-30℃,每次20min,每日给药2次。空白对照组和模型组按照与试验组相同的方法给予等量去离子水浸泡四肢及尾部。连续给药25日后,观测以下指标。
5.观测指标:
(1)手足综合征分级:参照Vail DM方法(Vail DM,Chun R,Thamm DH,etal.Efficacy of pyridoxine to ameliorate the cutaneous toxicity associatedwith doxorubicin containing pegylated(Stealth)liposomes:a randomized,double-blind clinical trial using a canine model[J].Clin Cancer Res.1998,4(6):1567-71.),对红斑、脱皮/结痂、脱毛/溃疡、水肿等临床体征进行评分,评分标准见表1。
表1手足综合征分级评分标准
(2)痛行为学观测:
机械性痛觉超敏:参照Zhao M(Zhao M,Isami K,Nakamura S,et al.Acute coldhypersensitivity characteristically induced by oxaliplatin is caused by theenhanced responsiveness of TRPA1 in mice.Mol Pain.2012,28,8:55.)方法,采用up-and-down法观测各组小鼠对von Fery纤维刺激的50%缩足域。
冷痛觉过敏:参照Meyer L(Meyer L,Patte-Mensah C,Taleb O,etal.Allopregnanolone prevents and suppresses oxaliplatin-evoked painfulneuropathy:multi-parametric assessment and direct evidence[J].Pain.2011,152(1):170-81.)及Zhao M方法,采用冷板仪观测各组小鼠对冷刺激的缩足反射潜伏期。
结果
1.手足综合征分级评分:空白对照组小鼠未见明显皮损。相对于空白对照组,模型组小鼠出现明显的红斑、脱毛等皮损,手足综合征分级评分明显升高(p<0.01)。相对于模型组,外用中药组皮损明显缓解,手足综合征评分明显下降(p<0.01)。(表2)
表2手足综合征分级评分
注:相对于空白对照组ΔP<0.05,ΔΔP<0.01;相对于模型组*P<0.05,**P<0.01。下同。
2.机械性痛觉超敏:空白对照组小鼠未见明显机械性痛觉超敏。相对于空白对照组,模型组小鼠对von Fery纤维刺激的50%缩足域明显下降,呈现机械性痛觉超敏状态(p<0.01)。相对于模型组,外用中药组机械性痛觉超敏明显缓解,50%缩足域明显下降(p<0.01)。(表3)
表3机械刺激50%缩足域
3.冷痛觉过敏:相对于空白对照组,模型组小鼠对冷刺激的缩足反射潜伏期明显下降,呈现冷痛觉过敏状态(p<0.05)。相对于模型组,外用中药组冷痛觉过敏明显缓解,冷缩足反射潜伏期明显下降(p<0.01)。(表4)
表4冷缩足反射潜伏期
上述试验结果表明本发明药物对小鼠化疗性手足综合征有显著的抑制作用,对机械性痛觉超敏和冷痛觉过敏有显著的缓解作用。
本发明药物治疗化疗性手足综合征的临床资料
资料与方法
1.研究设计
采用多中心、前瞻性、随机、双盲、安慰剂对照研究,观测本发明药物外用,治疗化疗致手足综合征及靶向治疗所致手足皮肤反应的临床疗效和安全性。采用分层随机区组设计,纳入120例,2:1随机分为试验组与对照组。
2.分级标准
参照NCI标准:①0级:无;②1级:轻微的皮肤改变或皮炎(如红斑、脱屑)伴感觉异常(如麻木感、针刺感、烧灼感),但不影响日常活动;③2级:如前皮肤改变伴疼痛,轻度影响日常活动,皮肤表面完整;④3级:溃疡性皮炎或皮肤改变伴剧烈疼痛,严重影响日常生活,明显组织破坏(如脱屑、水疱、出血、水肿)。
3.治疗方法
试验组采用本发明制备实施例1中制得的散剂,每剂药13.5g,用温水溶解后稀释至1000mL,患者从入组第1天起外用洗/浸患部,使用恒温足浴盆温浴(水温约36~40),每次20min,每日2次,7天为1个观察周期。对照组采用安慰剂,外观、包装,规格、剂量与疗程均同试验组。
4.观察指标及评价标准
参照NCI标准结合问诊进行评估,在试验前及试验结束后进行评价。疗效评价标准:治愈(CR):分级降至0级;有效(PR):分级下降1级及以上;无效(NP):分级无下降。
结果
1.入组病例情况
共入组120例患者,其中试验组80例,对照组40例。
2.HFS分级变化及疗效分析
HFS分级变化及疗效分析总结于表5和表6。
表5手足综合征分级变化
表6手足综合征疗效分析
本发明上述临床试验采用多中心、前瞻性、随机、双盲、安慰剂对照研究设计,根据“通络活血法”,观察中医外治的方法对化疗性HFS的治疗作用。从结果可以看出,本发明药物能够有效降低分级,试验组总有效率为96.25%,明显优于对照组的27.50%(P<0.0001)。因此,本发明药物能够有效治疗化疗性HFS。
Claims (6)
1.一种治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物,以重量份计,组成如下:
5~60重量份黄芪和5~30重量份当归的水提物;
5~30重量份老鹳草和5~30重量份紫草的70~80wt%乙醇水溶液的提取物;
5~30重量份红花的45~55wt%乙醇水溶液的提取物;
可药用辅料。
2.根据权利要求1所述的药物,以重量份计,组成如下:
10~40重量份黄芪和5~20重量份当归的水提取物;
10~25重量份老鹳草和5~20重量份紫草的70~80wt%乙醇水溶液的提取物;
5~20重量份红花的45~55wt%乙醇水溶液的提取物;和
可药用辅料。
3.根据权利要求1所述的药物,以重量份计,组成如下:
10~15重量份黄芪和6~12重量份当归的水提取物;
10~15重量份老鹳草和5~10重量份紫草的70~80wt%乙醇水溶液的提取物;
5~10重量份红花的45~55wt%乙醇水溶液的提取物;和
可药用辅料。
4.根据权利要求1所述的药物,其中,所述药物为颗粒剂或散剂。
5.一种权利要求1所述的治疗化疗致手足综合征、靶向治疗致手足皮肤反应的药物的制备方法,包括以下步骤:
取黄芪和当归用水煎煮1~3次,每次水量为黄芪和当归重量的8~10倍,合并提取液,减压浓缩,得到50±5℃相对密度为1.22~1.24的清膏1;
取老鹳草和紫草用70~80wt%乙醇水溶液提取1~3次,每次乙醇水溶液量为老鹳草和紫草重量的7~15倍量,温度为55~65℃,合并提取液,得到提取液1;
取红花用45~55wt%乙醇水溶液提取1~3次,每次乙醇水溶液量为红花重量的7~15倍量,温度为55~65℃,合并提取液,得到提取液2;
将上述得到的提取液1和提取液2合并,减压浓缩,得到50±5℃相对密度为1.22~1.24的清膏2;
将清膏1和清膏2混合,添加适量的可药用辅料,减压干燥,粉碎成细粉,按常规方法制成任何一种药剂学上的药剂。
6.根据权利要求5所述的制备方法,包括以下步骤:
取黄芪和当归用水煎煮1~3次,每次水量为黄芪和当归重量的8~10倍,每次煎煮1~1.5小时,合并提取液,减压浓缩,得到50±5℃相对密度为1.22~1.24的清膏1;
取老鹳草和紫草用70~80wt%乙醇水溶液提取1~3次,每次乙醇水溶液量为老鹳草和紫草重量的7~15倍量,温度为55~65℃,每次提取1~1.5小时,合并提取液,得到提取液1;
取红花用45~55wt%乙醇水溶液提取1~3次,每次乙醇水溶液量为红花重量的7~15倍量,温度为55~65℃,,提取1~1.5小时,合并提取液,得到提取液2;
将上述得到的提取液1和提取液2合并,减压浓缩,得到50±5℃相对密度为1.22~1.24的清膏2;
将清膏1和清膏2混合,添加清膏量1~3倍的可药用辅料,减压干燥,粉碎成细粉,按常规方法制成任何一种药剂学上的药剂。
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