CN113143844B - 一种用于治疗痤疮的聚合物微针贴片及其制备方法 - Google Patents
一种用于治疗痤疮的聚合物微针贴片及其制备方法 Download PDFInfo
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Abstract
本发明属于生物医用材料领域,具体公开了一种用于治疗痤疮的聚合物微针贴片及其制备方法,所述聚合物微针贴片由基座和针尖构成,所述基座为长方体,所述针尖为圆锥体,均匀分布于基座之上,所述针尖包括生物活性高分子化合物、鱼腥草素钠和红霉素。通过药物与生物活性高分子化合物间的相互作用,能够有效地控制药物释放,鱼腥草素钠和红霉素联合使用能够有效防止痤疮丙酸杆菌耐药性的产生,增强痤疮的治疗效果,同时针尖和基座分离可以实现载药针尖留在皮肤内,药物可以实现药物的程序性释放,进一步提高治疗痤疮的效果。
Description
技术领域
本发明属于生物医用材料领域,具体涉及一种用于治疗痤疮的聚合物微针贴片及其制备方法。
背景技术
痤疮是毛囊皮脂腺单位的一种慢性炎症性皮肤病,好发于面部和上半身,形成黑头、丘疹、脓疱、结节等多形性皮损。本病常在青少年期发作,是影响全世界80-85%以上人口的最常见疾病之一,痤疮的高发率造成了抗生素的长期和广泛使用,导致细菌耐药性增加,给社会带来了经济负担。痤疮的病程长、易复发、时轻时重、一部分患者皮损消退后常常遗留有持久性的色素沉着斑、凹陷或肥厚性瘢痕、少数严重者最终形成瘢痕疙瘩,损害外貌形象,给患者造成不同程度的心理压力,甚至影响其学习、工作、社交。目前,对于引起痤疮的病因尚未明确,一般认为痤疮的产生与雄激素分泌紊乱、皮脂分泌较多、微生物定植等有关,其中,引起炎性痤疮的主要致病菌是痤疮丙酸杆菌。临床上对于痤疮的治疗主要有局部治疗(维A酸类/过氧苯甲酰/外用抗生素/壬二酸)、系统治疗(口服异维A酸/口服抗生素)、光疗等,其中抗生素治疗是常用的一种方法。但是在过去的十年里,痤疮丙酸杆菌对抗生素的耐药性不断增加,已造成世界各地的公共卫生危机。为了应对这种耐药性,迫切需要开发具有新的靶点的抗生素。然而,由于寻找新抗生素的成本非常高,也可能导致进一步的耐药性。因此,需要对抗生素与天然产品的联合治疗进行广泛的研究,以便有效和安全地进行痤疮治疗,解决痤疮丙酸杆菌的耐药性。
专利文献CN109701152A公开了一种装载药物的可溶性微针贴片及其制备方法,该发明的微针贴片包括针头和基底贴片,针头和基底贴片由不同质量分数的聚乙烯醇-葡聚糖溶液经离心、冷冻、解冻制备而成,将药物粉末置于针头与基体贴片之间形成装载药物的可溶性微针贴片,其针尖和基底中间的夹心层可以装载大量的固体粉末药物,大幅提高微针贴片的载药量,实现药物或疫苗透皮缓释的目的,同时该微针贴片安全性高、溶解性能好、力学性质良好且载药量大。
专利文献CN108837299A公开了一种智能调节血糖的微针贴片及其制备方法,该发明的微针部分填充有智能调节血糖的药物,该药物载体材料、葡萄糖响应的敏感开关因子、药物分子,利用抽真空和离心的方法,将含药物的水凝胶溶液填充到微针模板的微针中;并通过再次离心的方法,用不含药物的水凝胶溶液制备微针贴片的基底,通过合适的方法进行水凝胶材料的固化,干燥后,将微针贴片从模板中剥离得到智能调节血糖的微针贴片。该发明微针贴片能够穿刺皮肤,并在体内根据血糖浓度智能释放出所载胰岛素,智能调节血糖水平。
发明内容
本发明旨在提供一种可用于治疗痤疮的聚合物微针贴片,药物鱼腥草素钠和红霉素联合用药,可以防止痤疮丙酸杆菌耐药性的产生,增强痤疮的治疗效果,同时与生物活性高分子化合物间发生的交联反应,能够有效地控制药物释放,针尖和基座分离可以实现载药针尖留在皮肤内,药物可以实现药物的程序性释放,进一步提高治疗痤疮的效果。
为了达到上述目的,本发明采用以下技术方案:一种用于痤疮治疗的聚合物微针贴片,由基座和针尖构成,所述基座为长方体,长为5~15cm,宽为5~15cm,高为1~5cm;所述针尖为圆锥体,均匀分布于所述基座之上,直径为200~400μm,高度为500~700μm,针尖间距为500~700μm。
优选地,所述针尖包括生物活性高分子化合物、鱼腥草素钠和红霉素。
优选地,所述生物活性高分子化合物、鱼腥草素钠和红霉素的质量比为(6~10):(1~4):(2~6)。
优选地,所述生物活性高分子化合物为含有氨基基团的羧甲基壳聚糖,所述鱼腥草素钠在水溶液下会水解成具有羰基的癸酰乙醛。
优选地,所述基座由透明质酸制成。
此外,本发明还提供了上述微针贴片的制备方法,具体包括以下步骤:
S1、合成羧甲基壳聚糖:将壳聚糖悬浮在异丙醇中,在20~30℃每隔5min加入5mL碱性溶液,边加边搅拌;然后将反应物加热至50~70℃,并在此温度下搅拌2~5h,制得反应混合物;然后取反应混合物离心5~15min,留下残余固体产物,最后真空干燥制得羧甲基壳聚糖;
S2、合成席夫碱聚合物:称取配方量的鱼腥草素钠,加入甘油、吐温80,将鱼腥草素钠润湿,再加入纯化水至2~6mL,在50~70℃水浴至完全溶解,然后加入红霉素,最后加入羧甲基壳聚糖,并在70~90℃反应至溶液呈黄色粘稠液体,即得席夫碱聚合物;
S3、合成聚合物微针贴片:将步骤S2制备得到的席夫碱聚合物倾倒在微针模具上,2~6℃3000~5000rpm离心1~20min,使步骤S2得到的席夫碱聚合物充分进入微针模具中,形成针头,用棉拭子擦去模具表面多余的聚合物,放入干燥箱在35~40℃烘0.5~2h后取出,在模具表面再加入透明质酸,2~6℃2000~4000rpm离心10~30min,形成微针贴片的基座,并置于干燥箱中干燥至微针脱落,用镊子取出即得微针贴片。
优选地,所述步骤S1的碱性溶液为10mg/mL的NaOH溶液。
优选地,所述步骤S2中加入甘油的浓度为5%(m/V),加入吐温80的浓度为0.05%(m/V)。
优选地,所述步骤S1中壳聚糖和异丙醇的用量比为10g:65~85mL。
优选地,所述步骤S3中选用的透明质酸浓度为8%(m/V)。
与现有技术相比,本发明具有以下有益效果:
(1)本发明药物与生物活性高分子化合物发生交联反应获得响应基团,具有响应性的聚合物在炎症区域弱酸性环境下解交联,从而控制药物释放,针尖和基座分离可以实现载药针尖留在皮肤内,药物可以实现药物的程序性释放,提高治疗痤疮的效果。
(2)本发明鱼腥草素钠和红霉素联合用药,可以防止痤疮丙酸杆菌耐药性的产生,增强痤疮的治疗效果,此外本发明采用两步离心法制备微针贴片,制备成型后的针尖和基座在使用时容易分离,使得针尖更容易插入皮肤,进入组织液,进一步提高痤疮的治疗效果。
(3)本发明微针的制备方法简单合理,性价比高,而且针尖所采用的生物活性高分子材料是生物相容性材料,在生物体内发生降解不会对身体机能产生较大的影响,具有广阔的市场应用前景。
附图说明
图1为本发明用于治疗痤疮的聚合物微针贴片的结构示意图。
图2为本发明用于治疗痤疮的聚合物微针贴片的工艺流程示意图。
图3为本发明用于治疗痤疮的聚合物微针贴片的治疗机理示意图。
图4为本发明用于治疗痤疮的聚合物微针贴片的细胞毒性测试结果示意图。
图5为本发明用于治疗痤疮的聚合物微针贴片的体内药效实验结果示意图。
附图标记说明:1-基座,2-针尖。
具体实施方式
下面结合说明书附图和具体实施例对本发明作出进一步地详细阐述,所述实施例只用于解释本发明,并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
实施例、本发明用于治疗痤疮的聚合物微针贴片及其制备
如图1所示,本发明用于治疗痤疮的聚合物微针贴片,由基座1和针尖2构成,所述基座1为长方体,长为10cm,宽为10cm,高为2cm;所述针尖2为圆锥体,均匀分布于所述基座1之上,直径为300μm,高度为600μm,针尖间距为600μm。
所述针尖由生物活性高分子化合物、鱼腥草素钠和红霉素按照如下质量比制成。
组别 | 羧甲基壳聚糖(mg) | 鱼腥草素钠(mg) | 红霉素(mg) |
实施例1 | 600 | 75 | 150 |
实施例2 | 480 | 80 | 160 |
实施例3 | 600 | 60 | 180 |
制备方法:S1、合成羧甲基壳聚糖:将10g壳聚糖悬浮在75mL异丙醇中,在25℃每隔5min加入5mL 10mg/mL的NaOH溶液,边加边搅拌;然后将反应物加热至60℃,并在此温度下搅拌3h,制得反应混合物;然后取反应混合物离心10min,留下残余固体产物,80%的甲醇-水混合物冲洗3次,再用无水乙醇冲洗2次,最后真空干燥制得羧甲基壳聚糖;
S2、合成席夫碱聚合物:称取配方量的鱼腥草素钠,加入5%的甘油,再加入0.05%的吐温80,将鱼腥草素钠润湿,加入纯化水至4mL,60℃水浴至完全溶解;称取配方量的红霉素加入鱼腥草素钠溶液中溶解;最后加入配方量的羧甲基壳聚糖,并于80℃反应至溶液呈黄色粘稠液体,即得席夫碱聚合物;
S3、合成聚合物微针:将步骤S2制备得到的席夫碱聚合物倾倒在微针模具上,4℃4000rpm离心10min,使步骤S2制备得到的席夫碱聚合物充分进入微针模具中,形成针头,用棉拭子擦去模具表面多余的聚合物,放入干燥箱37℃烘1h后取出,在模具表面再加入30μL8%(m/V)透明质酸,4℃3000rpm离心20min,形成微针贴片的基座,置于干燥箱中干燥至微针脱落后用镊子取出微针贴片。
对比例1
与实施例1相比,本对比例的区别仅在于:不含有鱼腥草素钠,相应地将红霉素的含量提高至225mg。
制备方法参考实施例1。
对比例2
与实施例1相比,本对比例的区别仅在于:不含有红霉素,相应地将鱼腥草素钠的含量提高至225mg。
制备方法参考实施例1。
试验例一、微针贴片的细胞毒性测试
一、实验样品:实施例1制备得到的微针贴片
二、实验方法
在研究药物制剂对皮肤毒性的实验中我们通常使用HaCaT细胞作为模型细胞。采用MTT法测定鱼腥草素钠对HaCaT的细胞毒性,具体方法为:
采用含10%胎牛血清和100U/mL氨苄青霉素的DMEM完全培养基,放入37℃饱和湿度的恒温培养箱中,5%CO2环境下进行HaCaT细胞培养。当细胞生长至其能覆盖培养瓶面积约80~90%时,用胰蛋白酶消化10min后加入DMEM完全培养基制备成混悬液,并用细胞计数板计数。用上述完全培养基调整细胞浓度至104cell/孔,接种于96孔板中,每组三个平行孔。用DEME完全培养基溶解空白微针和鱼腥草素钠微针48h,分别配制含不同浓度微针浸提液。
经24h孵育后,吸取培养基,并用上述含药无血清培养基代替,另外,以不含药的无血清培养基代替作为对照组。继续孵育24h,吸取培养基加入80μL新鲜培养基和20μL MTT试剂。继续在相同条件下孵育4h后,取出96孔板,弃去上清,每孔加入150μL二甲基亚砜,将培养板振摇10min后通过酶标仪检测各孔OD值,并计算细胞存活率。
三、实验结果
如图4所示,在浓度为0.25mg/mL和0.5mg/mL的条件下,鱼腥草素钠红霉素微针贴片(SH+ERY-MN)对HaCaT细胞均无明显的增殖抑制作用;而在高浓度(1mg/mL)的条件下,SH+ERY-MN对HaCaT细胞有一定的毒性,细胞存活率下降至80%左右。结果表明,本发明的微针贴片在一定浓度范围内没有细胞毒性作用,且在细胞水平生物具有较好相容性。
试验例二、微针贴片皮肤刺激性试验
一、药物与试剂:实施例1~3制备得到的微针贴片和生理盐水
二、实验方法
取符合要求的健康成年新西兰兔16只,随机分为4组,每组4只,在新西兰兔背部脊柱两侧各选取两块对称区域,于试验前24h进行脊背部脱毛处理,去毛范围为3×3cm,去毛区皮肤无损伤者留作完整皮肤试验;去毛区皮肤用刀片作多处“#”字形划破至渗血为度,留作损伤皮肤试验。左侧正常皮肤及破损皮肤脱毛区均涂以0.5ml生理盐水作为空白对照,右侧分别用2×2cm实施例1~3微针贴片直接刺入皮肤,用1层纱布和一层蜡纸覆盖,再用无纺布空贴及无刺激性胶布加以固定。4h后去除覆盖物,用温水清除残留受试样品。每天同一方法,同一时间给药1次,持续给药7d。在每次去除受试物后1h及再次贴敷前观察、记录皮肤是否有红斑、水肿、出血点等情况及其发生和消退时间。末次贴敷后,在去除受试物后1、24、48、72h观察并记录受试部位有无红斑和水肿,根据表1中的评分标准对皮肤红斑和水肿进行评分。
表1皮肤刺激反应评分标准
皮肤刺激反应评分均值=(红斑和焦痂总分+水肿总分)/实验动物总数,每组的评分以不同观察时间的最高值计。皮肤刺激强度分级标准:评分<0.5,无刺激性;评分0.5~<2.0,轻度刺激性;评分2.0~6.0,中度刺激性;评分>6.0,强刺激性。
三、实验结果
表2微针贴片皮肤刺激反应实验评分结果
由表2中的数据可以得到本发明空白对照组未对新西兰兔皮肤产生红斑、水肿等的刺激,实施例1~3在1h时具有勉强可见的轻度红斑,但在24h内恢复正常,平均反应刺激强度分值均为0.25<0.5,不具有刺激性。
因此可以得知,本发明实施例1~3的微针贴片给药时微针穿透角质层仅产生轻微刺激,且很快恢复,具有较好的使用安全性。
试验例三、药敏试验
一、实验样品:实施例1~3微针贴片和对比例1~2微针贴片。
二、实验方法:
测定痤疮丙酸杆菌对本发明实施例1~3样品、对比例1~2样品的敏感性,常见测试方法为纸片扩散法。取无菌干燥的滤纸片,每片加20μl实施例1~3、红霉素软膏溶解后的溶液,使滤纸片浸湿,阴性对照纸片加20μl无菌蒸馏水,37℃干燥30min备用。用无菌棉拭子蘸取实验菌悬液,在营养琼脂培养基平板表面均匀涂抹,室温干燥5min,制成染菌平板。将实验样品滤纸片贴放于染菌平板表面,每个平板贴4片实验样品片和1个对照样品片。将对照样品片贴在中央。置于37℃培养18h后,用游标尺测量抑菌环直径。待试验结束后观察抑菌圈并测定其大小,在此基础上判定敏感性的高低。
判定标准如表3所示。
表3敏感性程度
三、实验结果
表4痤疮丙酸杆菌的药敏试验
由表4的数据中可以得知本发明实施例1~3制备得到的微针贴片对于痤疮丙酸杆菌具有高度的敏感性,即具有显著抑制痤疮丙酸杆菌的作用,同时由实施例1~3与对比例1~2的数据可以得知本发明鱼腥草素钠和红霉素的联合使用能够有效地提高对于痤疮丙酸杆菌的敏感性,即有效地防止降低痤疮丙酸杆菌耐药性的产生,进一步增强对于痤疮的治疗效果。
试验例四、体内药效实验
一、实验样品:实施例1、对比例1~2制备得到的微针贴片、红霉素软膏
二、实验方法:
将Balb/c小白鼠随机分为7组(n=6),其中6组通过皮内注射感染P.acnes构建小鼠痤疮炎症模型,1组注射PBS溶液作为空白对照组(标记为正常),在PBS注射的小鼠中没有发现肿胀,而在P.acnes皮内注射感染后4天观察到痤疮出现。然后用不同的微针贴片对感染P.acnes的小鼠进行治疗,以评价治疗效果。选择一组为阴性对照,不加治疗(对照),另一组为红霉素软膏(ERY),其他4组分别用空白微针贴片(MN)、对比例2组(SH-MN)、对比例1组(ERY-MN)和实施例1组(SH+ERY-MN)。在治疗期间第一天和最后一天监测肿胀皮肤的体积大小。
三、实验结果
结果如图5所示,由图5-A可以得到在第一天时各组均能看到明显的痤疮,第6天时,对照组和空白微针贴片组(MN)均能够清晰得看到痤疮,鱼腥草素钠微针贴片组(SH-MN)和红霉素微针贴片组(ERY-MN)的痤疮仍未完全消失,本发明实施例1鱼腥草素钠红霉素微针贴片组(SH+ERY-MN)小鼠上的痤疮已经消失只剩下轻微的红点,由此可以得知本发明的鱼腥草素钠红霉素微针贴片能够有效地抑制痤疮的生长,且从图5-B痤疮肿胀皮肤的体积大小数据可以得到本发明相比于单独给药的鱼腥草素钠微针贴片、红霉素微针贴片以及红霉素软膏具有更好的痤疮治疗效果,即本发明在鱼腥草素钠和红霉素的协同作用能够显著地增强对痤疮的治疗效果。
从以上试验可以得出本发明中鱼腥草素钠和红霉素的联合使用能够显著地增强对痤疮的治疗效果,同时与生物活性高分子化合物发生交联反应制备得到的微针贴片能够在炎症区域弱酸性环境下解交联,从而控制药物释放,针尖和基座分离可以实现载药针尖留在皮肤内,药物可以实现药物的程序性释放,进一步提高治疗痤疮的效果。此外,本发明微针的制备方法简单合理,性价比高,而且针尖所采用的生物活性高分子材料是生物相容性材料,在生物体内发生降解不会对身体机能产生较大的影响,具有广阔的市场应用前景。
上述实施例仅例示性说明本发明的原理及其功效,而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下,对上述实施例进行修饰或改变。因此,举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变,仍应由本发明的权利要求所涵盖。
Claims (2)
1.一种用于治疗痤疮的聚合物微针贴片,其特征在于,由基座和针尖构成,所述基座为长方体,长为5~15cm,宽为5~15cm,高为1~5cm;所述针尖为圆锥体,均匀分布于所述基座之上,直径为200~400μm,高度为500~700μm,针尖间距为500~700μm;
所述针尖主要由生物活性高分子化合物、鱼腥草素钠和红霉素制成;
所述生物活性高分子化合物、鱼腥草素钠和红霉素的质量比为(6~10):(1~4):(2~6);
所述生物活性高分子化合物为羧甲基壳聚糖;
所述基座由透明质酸制成。
2.一种根据权利要求1所述的用于治疗痤疮的聚合物微针贴片的制备方法,其特征在于,包括以下步骤:
S1、合成羧甲基壳聚糖:将10g壳聚糖悬浮在75mL异丙醇中,在25℃每隔5min加入5mL10mg/mL的NaOH溶液,边加边搅拌;然后将反应物加热至60℃,并在此温度下搅拌3h,制得反应混合物;然后取反应混合物离心10min,留下残余固体产物,80%的甲醇-水混合物冲洗3次,再用无水乙醇冲洗2次,最后真空干燥制得羧甲基壳聚糖;
S2、合成席夫碱聚合物:称取配方量的鱼腥草素钠,加入5%的甘油,再加入0.05%的吐温80,将鱼腥草素钠润湿,加入纯化水至4mL,60℃水浴至完全溶解;称取配方量的红霉素加入鱼腥草素钠溶液中溶解;最后加入配方量的羧甲基壳聚糖,并于80℃反应至溶液呈黄色粘稠液体,即得席夫碱聚合物;
S3、合成聚合物微针:将步骤S2制备得到的席夫碱聚合物倾倒在微针模具上,4℃4000rpm离心10min,使步骤S2制备得到的席夫碱聚合物充分进入微针模具中,形成针头,用棉拭子擦去模具表面多余的聚合物,放入干燥箱37℃烘1h后取出,在模具表面再加入30μL8%(m/V)透明质酸,4℃3000rpm离心20min,形成微针贴片的基座,置于干燥箱中干燥至微针脱落后用镊子取出微针贴片。
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