CN109498698A - 一种靶向性抗甲真菌病的皮肤凝胶敷剂生产方法 - Google Patents
一种靶向性抗甲真菌病的皮肤凝胶敷剂生产方法 Download PDFInfo
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- CN109498698A CN109498698A CN201811505764.0A CN201811505764A CN109498698A CN 109498698 A CN109498698 A CN 109498698A CN 201811505764 A CN201811505764 A CN 201811505764A CN 109498698 A CN109498698 A CN 109498698A
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- onychomycosis
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Classifications
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Abstract
一种靶向性抗甲真菌病的皮肤凝胶敷剂生产方法,其特征在于:通过1)植物精油的制备:2)温敏性缓释羧化壳聚糖‑可德兰多糖复合凝胶的制备:3)抗真菌的皮肤凝胶敷剂的制备:再将以上各组分的质量配比为(w/%):复合凝胶30‑50,水10‑20,甘油1‑5,乙醇1‑5,植物精油20‑35,聚山梨酯80型1‑5,三乙醇胺1‑3。本发明以中成药植物精油作为甲癣治疗的主要成分,不含腐蚀性;致病菌敏感性强,渗透性好,多种杀菌成分有协同增效效应,疗效明显;其良好的粘滞性和亲水凝胶性使其具有较好的药物组分控缓释作用,药物组分可通过传输通道以均匀的速率向外扩散,以保证给药的持续性,可以满足甲癣类致病真菌需要长时间持续给药作用的要求。
Description
技术领域
本发明涉及治疗甲癣的外用药生产工艺,特别是涉及提取印度蒿、紫苏叶、黄花蒿、香鳞毛蕨、山苍子、川椒、香橼、丁香的精油提取物,并以羧化壳聚糖与可得兰多糖配制复合基质作为辅料制成温敏性凝胶敷剂的生产工艺,属抗真菌外用药生产技术领域。
背景技术
甲真菌病(俗称甲癣、灰指甲)是由皮肤甲真菌病癣菌、酵母菌及霉菌引起的甲板和甲下组织感染。据文献报道,导致甲真菌病的主要菌种分别是:皮肤癣菌(主要有红色毛癣菌、须癣毛癣菌、絮状毛癣菌等)占60-70%,酵母菌占 10-20 % , 霉菌占10-20%。甲真菌病导致指甲变形、增厚,易脱落、分离及颜色改变等,影响指甲美观,还具有很强的传染性。
医药界通过研究,推出了许多治疗甲真菌病药品。口服药品有灰黄霉素、疗霉舒、斯皮仁诺等,外用药有醋酸、水杨酸、苯甲酸、水合联氨等。口服药产生的不是直接对甲真菌病菌起作用,而是经口服吸收后经血液循环到达作用部位,但对身体有较多的副作用。外用药直接作用于患病部位,无副作用,但其药物组分渗入指甲内部较为困难,需要数月甚至数年的用药时间,而且对健康皮肤有很强的腐蚀性,患者往往疼痛难忍,无法坚持治疗。
这主要是因为这些药物对引起甲真菌病的癣菌、酵母菌及霉菌都有一定抑制作用,但针对性不强。如果使用的外用药中含有对癣菌、酵母菌及霉菌各自都有很强靶向性抑制作用的组分,则可以在短时间内破坏致病菌的微生物生态环境,达到治疗目的。
从天然产物中寻找具有抗真菌活性的天然有效成分,并进一步开发应用,成为非常重要的研究方向。据不完全统计, 已报道有 300 多种中草药具有不同程度的抗真菌作用,但是目前开发的天然产物抗甲真菌病药物药效迟缓,主要是因为这些药物多是由数种中草药原料直接复配而成,未作有效成分提取浓缩,使其浓度不高,对病菌抑制和杀灭效果有限。此外,常见的传统外用涂搽药物挥发性强,在半小时内有效成分就挥发掉,大大降低了杀菌效果,因此需要在延长药效持续时间方面进一步研发。
发明内容
本发明的基本目的是:利用许多天然中草药分别对皮肤癣菌(红色毛癣菌、须癣毛癣菌等)、酵母菌及霉菌有各自的靶向性抑制及杀灭功效的特点,以多种中草药为原料,分别提取并收集其挥发性植物精油组分,并复配制成特定的混合精油制剂,再与特定的复合凝胶材料配成能长时间缓释给药、对皮肤癣菌、酵母菌及霉菌均有针对性靶向抑制及杀灭作用的、安全无痛的新型治疗甲真菌病高效外用敷药。
植物精油提取物化学成分复杂,可由 50-500 种不同的萜烯类、醛类、酯类、醇类等化学分子组成,在赋予不同的芳香气味的同时,具有抗真菌、霉菌、病毒等功能,提取物的抑菌作用和抑菌选择性很大程度上取决于其中的活性组分种类。
本发明用于抑制皮肤癣菌类微生物的主要原料是印度蒿、紫苏、山苍子、香鳞毛蕨,利用它们的精油提取物作为功效成分。植物精油的主要成分是萜烯、倍半萜烯及其氧化物,另外还有羰基化合物、酯、醇等,是具有强烈的气味和香味的挥发性液体。研究发现,植物精油成分具有抑制或杀死细菌等微生物的特性。
印度蒿又名麦蒿,半灌木,分布于我国东部、华南及中国台湾,日本、东南亚各国及印度也有。研究证明,印度蒿的叶片提取液对16种人体皮肤致病真菌有很强的抑制性,尤其是对红色毛癣菌和须癣毛癣菌有近乎100%的抑制性。另外有实验证实,紫苏、山苍子、香鳞毛蕨中的油类挥发性提取物对红色毛癣菌、须癣毛癣菌、絮状毛癣菌有很强的抑制效果。
本发明的第二类原材料为抑制霉菌而选择。多方研究证明,丁香、黄花蒿的植物精油对霉菌的杀灭功效十分明显,抑菌率都在 90% 以上。
本发明的第三类原材料为抑制酵母菌而选择。川椒、香橼的精油提取物对甲癣真菌中的酵母菌有很强的抑制作用,同时对须癣毛癣菌和红色毛癣菌有较强的抑制作用。
通常的甲癣敷剂是以羊毛脂和凡士林为基质,将药物研磨于其中,所得成品质地粗糙,易析出结晶,且油性软膏易污染衣物,涂展性差,使患者用药的依从性受到一定影响。而且传统的甲癣敷剂基质材料只是起到携带支撑药物成分的作用,其自身没有药效,这也大大降低了敷剂的药效功能。
此外,现有的部分液体基质的甲癣敷剂在携带有挥发性强、对热不稳定的植物精油类组分时,很难在体表形成黏附凝胶,致使药物对甲癣菌作用时间短。对部分固体基质甲癣敷剂产品而言,则凝胶剂本身的固体性质太强或贮藏条件或包装不严密,易出现干硬化,形成干胶团而不易涂展。因此需要寻找一种在涂抹之前主要呈液体状态,在涂抹之后主要呈固体状态的凝胶材料,以解决这种基质选择的困境。
本发明选用了羧化壳聚糖与可得兰多糖配制的新型水溶性基质作为辅料基质,克服了传统甲癣敷剂的以上多个缺点:产品均匀细腻,易涂展,对皮肤无刺激性;作为凝胶辅料基质的羧化壳聚糖本身又是一种真菌抑制剂,提高了产品药效;复合凝胶中的可德兰多糖有受热(人体温度即可)后自动生成固体状凝胶的特性,从而形成温度敏感性在体原位凝胶给药系统(温敏性凝胶),解决了前述的基质选择难题。
本发明的复合凝胶材料由羧化壳聚糖与可德兰多糖复配而成。
羧化壳聚糖是重要的壳聚糖衍生物,水溶性好,有优良的乳化性、保湿性、成膜性和生物相溶性,广泛应用于医用敷料,也常作为药物靶向控释载体材料。羧化壳聚糖在作为敷料基质的同时,自身还具备有效抑制霉菌和真菌生长和繁殖的能力,对常见的皮肤癣菌、伤口感染菌等具有显著的抑制效果,并有促进伤口愈合和消炎、止血等功能。
可德兰多糖又称热凝胶多糖(Curdlan),是一种细菌产胞外多糖,安全无毒,性能优良,该多糖具有在受热条件下形成固态凝胶的独特性质,故被命名为热凝胶。其主要功能是增稠、悬浮、乳化等作用,在药剂学上可作为成胶剂、粘合剂、流变学改进剂(增湿剂、助悬剂、稳定剂)等。作为良好的凝胶基质,可德兰多糖具有水溶性基质的特点,释药快,无油腻性,易于涂铺,对皮肤及粘膜无刺激性,是局部药物转运系统的优良基质。
羧化壳聚糖与可德兰多糖复配的基质除具有水溶性基质的特点外,与凡士林、乳膏基质相比,具有操作简便,性质稳定,不污染衣物,不需明火加热等优点,尤其适合制备植物精油等挥发性强、对热不稳定药物的皮肤敷剂剂。在涂抹到皮肤上被体温37℃的加热作用后,自动形成半固体状凝胶层,形成温度敏感性在体原位凝胶给药系统(温敏性凝胶)。这种温敏性凝胶最大特点是以液体形态给药后,在药用部位因温度变化刺激( 体温 37℃ )而快速发生相转变,固化形成凝胶,从而控制药物的释放。
本发明中利用羧化壳聚糖与可德兰多糖发生交联反应,使其分子链弥散伸展呈极大的膨胀状态增稠而形成凝胶,由聚合物的链相互共价交联,形成网状结构,其良好的粘滞性和亲水凝胶性使其具有较好的药物组分控缓释作用。由于凝胶中加入甘油等保湿剂,凝固后的凝胶内部保持一定的含水量,该水凝胶内部的渗透压使其间形成了一定的传输通道,药物组分可通过传输通道以均匀的速率向外扩散,以保证给药的持续,而且使载入药物只在病变组织部位释放,不仅能有效利用药物获得最优治疗效果,而且不会在其它正常部位产生毒副作用。
本发明的技术方案是:
1.植物精油的制备:
将印度蒿叶、紫苏叶、黄花蒿叶、香鳞毛蕨、山苍子叶、川椒、香橼、丁香8种原料经自然风干后,采用高效植物样品粉碎机粉碎,过20-80目筛,按相同的质量比称取每种原料,充分混合均匀,形成混合原料。用水蒸气蒸馏法工艺处理混合原料,提取混合植物精油:
将混合原料与含有 5%氯化钠的蒸馏水溶液以 1∶5-15 的料液比(质量比)混合,静置浸泡 5-15h,置于圆底烧瓶中,连接冷凝装置,并自冷凝管向测定器的刻度部分添加蒸馏水至溢入蒸馏烧瓶为止,以电热套加热,保持微沸状态进行提取,从开始微沸时计时,提取 4-8 h后停止加热,用无水硫酸钠脱水干燥,收集精油,4℃保存于棕色瓶内待用。称取混合原料粉末和植物精油质量,计算植物精油提取率,提取率可达0.5-1.5%(质量比)。
温敏性缓释羧化壳聚糖-可德兰多糖复合凝胶的制备:
常温下称取一定量的羧化壳聚糖粉末溶于蒸馏水中,充分搅拌均匀,配成1.5-4.5%质量分数的羧化壳聚糖溶胶。同时在常温下取适量超纯水,均匀撒入可德兰多糖粉末,搅拌均匀后静置,自然溶胀 10-30 h,制得质量分数2.0-5.0%的溶胶,备用。取等体积的羧化壳聚糖溶胶与可德兰多糖溶胶,在电动搅拌下将羧化壳聚糖溶胶慢慢加入可德兰多糖溶胶中,混合均匀,使样品成透明粘稠状,研匀后制得羧化壳聚糖—可德兰多糖复合凝胶,备用。
3. 抗真菌的皮肤凝胶敷剂的制备:
以复合凝胶为凝胶基质,以水、甘油和乙醇为水相, 植物精油为油相,聚山梨酯80型为乳化剂, 三乙醇胺为中和剂,进行复配制备。具体制备工艺为:
将甘油加入复合凝胶中搅拌研磨均匀细腻后, 加入少量蒸馏水使充分溶涨得Ⅰ相;另取植物精油加入三乙醇胺并搅匀后得Ⅱ相;将Ⅱ相加入Ⅰ相搅拌研磨,再加入聚山梨酯80型继续搅拌研磨均匀(糊状),最后缓慢加入乙醇、蒸馏水至全量,并持续搅拌研磨成乳胶状,即制成乳剂型凝胶敷剂。此过程在常温下操作。
以上各组分的质量配比为(w/%):复合凝胶30-50,水10-20,甘油1-5,乙醇1-5,植物精油20-35,聚山梨酯80型1-5 ,三乙醇胺1-3。
本发明与类似产品相比,具有以下创新特点:
1.本发明以中成药植物精油作为甲癣治疗的主要成分,不含腐蚀性,对健康的皮肤没有伤害,使用无痛感。而传统的治疗甲癣外用药主要成分多为醋酸、水杨酸、苯甲酸、水合联氨等有强腐蚀性组分,在使用中对健康皮肤刺激大,痛感强烈,很难为患者接受。
2.传统的治疗甲癣外用药主要成分对各种微生物都有广谱抑制作用,但针对性不强,有一定抑制效果但不明显,难以完全杀灭甲癣致病微生物,甲癣复发率高。本发明针对三大类甲癣致病菌皮肤癣菌(主要是红色毛癣菌和须癣毛癣菌等)、酵母菌及霉菌,分别选用对每类致病菌各自有强力靶向性杀灭抑制作用的药物原料,根据其中挥发性组分为主要杀菌成分的特点,混合提取其植物精油作为主要药用组分,制成敷剂,给药浓度高,致病菌敏感性强,渗透性好,多种杀菌成分有协同增效效应,疗效明显。
3.本发明的敷料基质为羧化壳聚糖与可得兰多糖配制的新型温敏性凝胶,产品均匀细腻易涂展,对皮肤无刺激性;复合凝胶中的可德兰多糖有受热(人体温度即可)后自动生成固体状凝胶的特性,从而形成温度敏感性在体原位凝胶给药系统(温敏性凝胶),既避免了液体基质甲癣敷剂难以在体表形成黏附凝胶、致使药物对作用时间短的缺陷,又没有固体基质(如羊毛脂和凡士林)甲癣敷剂质地粗糙、易析出结晶、油性软膏易污染衣物、涂展性差等问题。
4.传统的甲癣治疗敷剂中的辅料基质仅有携带支撑药物成分的物理性功能,自身没有药效。本发明产品中敷剂基质里的羧化壳聚糖本身又是一种真菌抑制剂,大大提高了产品药效。
5.本发明中的凝胶基质中羧化壳聚糖与可德兰多糖发生交联反应,聚合物的链相互共价交联,形成网状结构,其良好的粘滞性和亲水凝胶性使其具有较好的药物组分控缓释作用,药物组分可通过传输通道以均匀的速率向外扩散,以保证给药的持续性,可以满足甲癣类致病真菌需要长时间持续给药作用的要求。
具体实施方式
植物精油的制备:
将印度蒿叶、紫苏叶、黄花蒿叶、香鳞毛蕨、山苍子叶、川椒、香橼、丁香8种原料经自然风干后,采用高效植物样品粉碎机粉碎,过50目筛,按相同的质量比称取每种原料,充分混合均匀,形成混合原料。用水蒸气蒸馏法工艺处理混合原料,提取混合植物精油:
将混合原料与含有 5%氯化钠的蒸馏水溶液以 1∶10 的料液比(质量比)混合,静置浸泡10h,置于圆底烧瓶中,连接冷凝装置,并自冷凝管向测定器的刻度部分添加蒸馏水至溢入蒸馏烧瓶为止,以电热套加热,保持微沸状态进行提取,从开始微沸时计时,提取6h后停止加热,用无水硫酸钠脱水干燥,收集精油,4℃保存于棕色瓶内待用。称取混合原料粉末和植物精油质量,计算植物精油提取率,提取率可达0.8%(质量比)。
温敏性缓释羧化壳聚糖-可德兰多糖复合凝胶的制备:
常温下称取一定量的羧化壳聚糖粉末溶于蒸馏水中,充分搅拌均匀,配成3.0%质量分数的羧化壳聚糖溶胶。同时在常温下取适量超纯水,均匀撒入可德兰多糖粉末,搅拌均匀后静置,自然溶胀 20 h,制得质量分数2.5%的溶胶,备用。取等体积的羧化壳聚糖溶胶与可德兰多糖溶胶,在电动搅拌下将羧化壳聚糖溶胶慢慢加入可德兰多糖溶胶中,混合均匀,使样品成透明粘稠状,研匀后制得羧化壳聚糖—可德兰多糖复合凝胶,备用。
4. 抗真菌的皮肤凝胶敷剂的制备:
以复合凝胶为凝胶基质,以水、甘油和乙醇为水相, 植物精油为油相,聚山梨酯80型为乳化剂, 三乙醇胺为中和剂,进行复配制备。具体制备工艺为:
将甘油加入复合凝胶中搅拌研磨均匀细腻后, 加入少量蒸馏水使充分溶涨得Ⅰ相;另取植物精油加入三乙醇胺并搅匀后得Ⅱ相;将Ⅱ相加入Ⅰ相搅拌研磨,再加入聚山梨酯80型继续搅拌研磨均匀(糊状),最后缓慢加入乙醇、蒸馏水至全量,并持续搅拌研磨成乳胶状,即制成乳剂型凝胶敷剂。此过程在常温下操作。
以上各组分的质量配比为(w/%):复合凝胶35,水12,甘油3,乙醇2,植物精油25,聚山梨酯80型3 ,三乙醇胺2。
Claims (1)
1.一种靶向性抗甲真菌病的皮肤凝胶敷剂生产方法,其特征在于:
1)植物精油的制备:
将印度蒿叶、紫苏叶、黄花蒿叶、香鳞毛蕨、山苍子叶、川椒、香橼、丁香8种原料经自然风干后,采用高效植物样品粉碎机粉碎,过20-80目筛,按相同的质量比称取每种原料,充分混合均匀,形成混合原料;用水蒸气蒸馏法工艺处理混合原料,提取混合植物精油:
将混合原料与含有 5%氯化钠的蒸馏水溶液以 1∶5-15 的料液比(质量比)混合,静置浸泡 5-15h,置于圆底烧瓶中,连接冷凝装置,并自冷凝管向测定器的刻度部分添加蒸馏水至溢入蒸馏烧瓶为止,以电热套加热,保持微沸状态进行提取,从开始微沸时计时,提取 4-8 h后停止加热,用无水硫酸钠脱水干燥,收集精油,4℃保存于棕色瓶内待用;称取混合原料粉末和植物精油质量,计算植物精油提取率,提取率可达0.5-1.5%(质量比);
2)温敏性缓释羧化壳聚糖-可德兰多糖复合凝胶的制备:
常温下称取一定量的羧化壳聚糖粉末溶于蒸馏水中,充分搅拌均匀,配成1.5-4.5%质量分数的羧化壳聚糖溶胶;同时在常温下取适量超纯水,均匀撒入可德兰多糖粉末,搅拌均匀后静置,自然溶胀 10-30 h,制得质量分数2.0-5.0%的溶胶,备用;取等体积的羧化壳聚糖溶胶与可德兰多糖溶胶,在电动搅拌下将羧化壳聚糖溶胶慢慢加入可德兰多糖溶胶中,混合均匀,使样品成透明粘稠状,研匀后制得羧化壳聚糖—可德兰多糖复合凝胶,备用;
3) 抗真菌的皮肤凝胶敷剂的制备:
以复合凝胶为凝胶基质,以水、甘油和乙醇为水相, 植物精油为油相,聚山梨酯80型为乳化剂, 三乙醇胺为中和剂,进行复配制备;具体制备工艺为:
将甘油加入复合凝胶中搅拌研磨均匀细腻后, 加入少量蒸馏水使充分溶涨得Ⅰ相;另取植物精油加入三乙醇胺并搅匀后得Ⅱ相;将Ⅱ相加入Ⅰ相搅拌研磨,再加入聚山梨酯80型继续搅拌研磨均匀(糊状),最后缓慢加入乙醇、蒸馏水至全量,并持续搅拌研磨成乳胶状,即制成乳剂型凝胶敷剂;此过程在常温下操作;
以上各组分的质量配比为(w/%):复合凝胶30-50,水10-20,甘油1-5,乙醇1-5,植物精油20-35,聚山梨酯80型1-5 ,三乙醇胺1-3。
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