CN114376975A - 药物组合物醇质体、凝胶剂、水凝胶膏剂、贴剂及制备方法 - Google Patents
药物组合物醇质体、凝胶剂、水凝胶膏剂、贴剂及制备方法 Download PDFInfo
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- CN114376975A CN114376975A CN202210255100.3A CN202210255100A CN114376975A CN 114376975 A CN114376975 A CN 114376975A CN 202210255100 A CN202210255100 A CN 202210255100A CN 114376975 A CN114376975 A CN 114376975A
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Abstract
本发明提供一种药物组合物醇质体,包含以重量百分比计的如下组份:胸腺素β40.1‑0.2%,糖皮质激素0.5‑1%,低分子量醇30‑50%,磷脂3.0‑12.0%,胆固醇1.0‑2.5%,助剂0.51‑1.3%,其余为PBS缓冲液。本发明还提供了一种制备治疗瘢痕的药物组合物醇质体的方法。本发明的醇质体可降低激素的用量,减少副作用的产生,治疗效果更持久,除在用药过程中能使瘢痕萎缩,停止用药后,瘢痕也不易复发,达到1+1>2的功效。本发明的醇质体透皮能力强,包封率高,载药量大,稳定性好,易于储存和使用。此外,本发明的醇质体毒副作用,给药方便、安全、可控、顺应性良好,生物利用率更高。
Description
技术领域
本发明涉及药物制剂合成领域,特别涉及一种治疗效果好、副作用少、停药后不易复发且给药方便的治疗瘢痕的药物组合物醇质体、凝胶剂、水凝胶膏剂、贴剂及制备方法。
背景技术
瘢痕组织是指肉芽组织经改建成熟形成的老化阶段的纤维结缔组织。创伤等情况下,成纤维细胞分裂、增殖,向受损部位迁移,产生细胞外基质,形成瘢痕组织,从而修复创伤。瘢痕组织的形成是肉芽组织逐渐纤维化的过程,此时网状纤维及胶原纤维越来越多,网状纤维胶原化,胶原纤维变粗,与此同时纤维母细胞越来越少,少量剩下者转变为纤维细胞;间质中液体逐渐被吸收,中性粒细胞、巨噬细胞、淋巴细胞和浆细胞先后消失;毛细血管闭合、退化、消失,留下很少的小动脉及小静脉。这样,肉芽组织乃转变成主要由胶原纤维组成的血管稀少的瘢痕组织,肉眼呈白色,质地坚韧。
瘢痕是人体自卫体系的一个重要组成,它既是创伤的愈合过程,也是愈合的必然结果。但是,瘢痕生长超过一定的限度,就会发生各种并发症,诸如外形的破坏及功能活动障碍等,给患者带来巨大的肉体痛苦和精神痛苦,尤其是烧伤、烫伤、严重外伤后遗留的瘢痕。
糖皮质激素治疗瘢痕的原理主要是:减少胶原的合成和诱导胶原酶的生成,降解胶原。然而影响瘢痕不断生长的两大因素是:成纤维细胞和毛细血管。单纯使用糖皮质激素治疗瘢痕,当时可看到瘢痕吸收萎缩一些,一旦停止用药,瘢痕又会生长,甚至比之前更严重。这是因为糖皮质激素并不能降低成纤维细胞的活性,甚至注射部位可能出现毛细血管扩张,无法解决瘢痕形成的主要原因,因此,要想做到瘢痕治愈不复发,单单的激素治疗是没有实质作用的,必须配合其他治疗手段。且糖皮质激素治疗瘢痕一般采用注射给药,不仅增加了药物的毒副作用,使患者非常痛苦,而且很不方便,多次注射容易引起其他并发症和产生激素依赖。
胸腺素β4(Thymosin beta 4,Tβ4)一种由43个氨基酸残基组成的大分子蛋白,广泛分布于人体内多种组织与细胞中。肌动蛋白在非肌肉细胞中约占总蛋白的10%,是创伤愈合所需的重要组分。胸腺素β4作为人体内主要的肌动蛋白调节分子之一,具有多重生物学功能,在组织再生、重塑、创伤愈合、维持肌动蛋白平衡、肿瘤发病与转移、细胞凋亡、炎症、血管生成、毛囊发育等生理、病理过程中扮演着极为重要的角色。有研究表明,Tβ4通过促进内皮细胞迁移和血管生成,可促进皮肤与角膜修复,表现出加速创伤修复的能力。胸腺素β4治疗瘢痕时采用口服给药方式,而口服给药时,胸腺素β4分子结构易被胃肠道破坏,生物利用率低。由于Tβ4的分子量远大于适合经皮给药系统给药的药物的分子量,单靠透皮给药无法很好的穿透皮肤发挥作用。
研究发现,糖皮质激素与Tβ4治疗瘢痕时,分别单独使用在治疗期间均可见一定程度的瘢痕吸收萎缩,而一旦停止用药,瘢痕又会生长出来,可见二者分别单独使用时,并不能对瘢痕起实质性的作用,无法阻止其复发,且糖皮质激素和胸腺素β4治疗瘢痕给药方式不同,二者药物联用还需克服同时给药的问题。
传统脂质体由于渗透能力有限,无法穿透角质层,只能将药物带到皮肤表面,无法达到深层治疗的效果。因此,为了克服脂质体在经皮给药系统中的局限性,研究人员发现了醇质体,即含高浓度乙醇(20%~50%)的含醇脂质体。醇质体的制备工艺简单,可以包载各种类型的药物,并能达到较高的包封率。与普通脂质体相比,醇质体可以携带药物到达皮肤深层,并提高其经皮吸收速率; 与传递体相比,醇质体更稳定; 醇质体还可制成凝胶、贴剂、乳膏等方便临床用药的制剂,因而在局部用药和药物经皮吸收方面具有很好的应用前景。
发明内容
本发明提供一种治疗瘢痕的药物组合物醇质体,以解决现有的治疗瘢痕的药物存在治疗效果不理想、停药后易复发及给药不方便等问题。
本发明实施例提供药物组合物醇质体,其中该醇质体包含以重量百分比计的如下组份:胸腺素β40.1-0.2%,糖皮质激素0.5-1%,低分子量醇30-50%,磷脂3.0-12.0%,胆固醇1.0-2.5%,助剂0.51-1.3%,其余为PBS缓冲液;其中所述低分子量醇为乙醇或丙二醇;所述糖皮质激素为氢化可的松、可的松、替可的松、强的松、莫米松、曲安奈德、安西缩松、布地奈德、倍他米松、地塞米松、氟可龙、氯倍他松、氯倍他索、氟泼尼定、卤贝他索、双氟拉松、醋酸氟轻松、哈西奈德、去羟米松、氟轻松、氟氢缩松、氟氢可的松、氟替卡松、羟泼尼缩松、双氟可龙、泼尼卡酯、甲泼尼松、泼尼松龙中的至少一种或其衍生物中的至少一种;所述磷脂为大豆卵磷脂、蛋黄卵磷脂、神经鞘磷脂、聚乙二醇化磷脂和磷脂酰肌醇中的至少一种;
所述助剂包括稳定剂0.3-0.7%,抗氧化剂0.2-0.5%及防腐剂0.01-0.1%,所述稳定剂为磷脂酰甘油、磷脂酸、磷脂酰丝氨酸、脱氧胆酸钠或壳聚糖中的至少一种;所述抗氧化剂为维生素E、维生素C、没食子酸丙酯、苹果酸、二叔丁基对甲酚或β-胡萝卜素中的至少一种;所述防腐剂为苯酚、间甲酚、氯甲酚、苄醇、对羟基苯甲酸丙酯或对羟基苯甲酸甲酯中的至少一种。通过加入稳定剂、抗氧化剂和防腐剂,使得制得的醇质体的稳定性好,易于储存和使用。
进一步地,所述醇质体的平均粒径为90nm-170nm。
进一步地,所述醇质体的粒径分布为0.165PDI-0.355PDI。
进一步地,所述醇质体的粒径在80 ~ 160nm 所占百分比为52%-78%。
进一步地,所述醇质体的剂型为凝胶剂、水凝胶膏剂或水凝胶贴剂中的一种。该醇质体微微体外经皮给药制剂,与注射给药制剂相比,大大降低了其毒副作用,同时其给药方便、安全、可控、顺应性良好;与口服制剂相比,药物靶向性更强,药物结构不易被破坏,生物利用率更高。
本发明还提供一种制备上述的药物组合物醇质体的方法,该方法包括如下步骤:
(1)将所述重量份数的磷脂及胆固醇溶于低分子量醇中,得到醇相A;
(2)将所述重量份数的胸腺素β4、糖皮质激素及助剂溶于PBS缓冲液中,得到水相B;
(3)搅拌醇相A及水相B,并在温度为31-35℃条件下,将水相B加入到醇相A中,水合15-20分钟后过滤,即得到所述的治疗瘢痕的药物组合物醇质体;
(4)将步骤(3)中的治疗瘢痕的药物组合物醇质体进行整粒。
进一步地,步骤(3)中,以PBS缓冲液的总重量为100% 计,所述水相B加入的速度为3-8%/分钟。
进一步地,步骤(4)中,所述整粒方法为探头超声仪法或高速分散匀质机法。
本发明还提供一种制备上述的药物组合物醇质体凝胶剂的方法,该方法包括如下步骤:
(1)将卡波姆以1:40 (w/w)的比例缓慢加入烧杯中的蒸馏水中,然后以800rpm的速度混合2小时,形成均匀分散的凝胶基质;
(2)加入聚乙二醇1.0g、月桂氮卓酮1.2g,搅拌条件下缓慢加入三乙醇胺(0.54g)调节其pH至中性,充分混合均匀;
(3)将上述药物组合物醇质体与混合均匀的凝胶等重量混合,研制均匀,得到药物组合物醇质体凝胶剂。
本发明还提供一种制备药物组合物醇质体水凝胶膏剂的方法,该方法包括如下步骤:
(1)量取7ml的甘油,依次加入0.04g的甘羟铝,0.008g的EDTA,1.2g的聚丙烯酸钠NP-700和0.3g的聚乙烯吡咯烷酮K-90,搅拌均匀得C相;
(2)称取0.03g酒石酸溶解于1ml水作为D相;
(3)将D相分3次加入C相中,搅拌均匀,再加入等重量的上述药物组合物醇质体,混合均匀后涂布于水凝胶膏剂的支持层无纺布上,熟化,加盖保护层聚乙烯膜,得到药物组合物醇质体水凝胶膏剂。
本发明还提供一种制备药物组合物醇质体水凝胶贴剂的方法,该方法包括如下步骤:
(1)量取8ml的甘油,依次加入0.04g的甘羟铝,0.008g的EDTA,0.95g的聚丙烯酸钠NP-700和0.74g的聚乙烯吡咯烷酮K-90,搅拌均匀得C相;
(2)称取0.066g酒石酸溶解于2ml水作为D相;
(3)将C相加入D相中,搅拌均匀,再加入等重量的上述药物组合物醇质体,混合均匀后涂布于背衬材料上,熟化,加盖聚乙烯膜,得到药物组合物醇质体水凝胶贴剂。
本发明相较于现有技术,其有益效果为:本发明通过将糖皮质激素和胸腺素β4的组合物制成醇质体,不仅可以降低激素的用量,减少副作用的产生,而且使得治疗效果更持久,除了在用药过程中能使瘢痕萎缩,停止用药后,瘢痕也不易复发,达到1+1>2的功效。另一方面,本发明得到的醇质体透皮能力强,包封率高,载药量大,且助剂的加入使得醇质体的稳定性好,易于储存和使用。此外,本发明的醇质体为外用经皮给药制剂,与注射给药制剂相比,大大降低了其毒副作用,同时其给药方便、安全、可控、顺应性良好;与口服制剂相比,药物靶向性更强,药物结构不易被破坏,生物利用率更高。
具体实施方式
下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
药物组合物醇质体的制备:
醇质体的组成:
醇质体制备方法:
(1)称取配方量的大豆卵磷脂和胆固醇溶于乙醇中,得到醇相A;
(2)称取配方量的胸腺素β4、曲安奈德、脱氧胆酸钠、维生素E和苯酚溶于PBS缓冲液中,得到水相B;
(3)磁力搅拌醇相A和水相B,并在温度为33°C条件下,将水相B加入到醇相A中;其中,以PBS缓冲液(磷酸缓冲盐溶液,phosphate buffered saline)的总重量为100% 计,水相B的加入速度为3%/分钟;
(4)相同条件下继续磁力搅拌,水合20分钟后过滤,得到药物组合物醇质体;
(5)利用高速分散匀质机法对所得到的药物组合物醇质体进行整粒。
醇质体凝胶剂制备方法:
(1)将卡波姆以1:40 (w/w)的比例缓慢加入烧杯中的蒸馏水中,然后以800rpm的速度混合2小时,形成均匀分散的凝胶基质;
(2)加入聚乙二醇1.0g、月桂氮卓酮1.2g,搅拌条件下缓慢加入三乙醇胺(0.54g)调节其pH至中性,充分混合均匀;
(3)将制备好的药物组合物醇质体与混合均匀的凝胶等重量混合,研制均匀,即得本实施例的药物组合物醇质体凝胶剂。
实施例2-8
实施例2-8的药物组合物醇质体胶凝剂的制备方法与实施例1的制备方法相同,不同之处在于醇质体中各组分的配方,具体如表1所示。
对比例1-2
对比例1-2的药物组合物醇质体胶凝剂的制备方法与实施例1的制备方法相同,不同之处在于醇质体中乙醇及PBS缓冲液的含量,具体如表1所示。
实施例9
包封率测定:
本实施例通过低温超速离心法测定实施例1-8所获得的药物组合物醇质体的包封率。
分别精密移取实施例1-8所获得的药物组合物醇质体2.0mL置于离心管中,在4℃的低温、14000rpm 条件下离心30min,移去上清液,并补足等量空白上清液(即配制的除不含药物组合物外,所有成份组成均同移去的上清液),同样条件下再离心30min,移去并合并上清液,HPLC(高效液相色谱法)测定上清液中药物组合物的量记为M;将离心沉降得到的药物组合物醇质体破乳(0.2mL甲醇破乳)后,用HPLC测定药物组合物的量,即为包封于醇质体的药物组合物的量,记为N;按下式计算药物组合物醇质体的包封率(EE%):
EE%= N/(M+N)×100%。测试结果见表2。
从表2可以看出,当药脂比(药脂比是指药物组合物同磷脂的质量比)相同时,药物组合物不同成分的含量对醇质体的包封率有影响。当药物组合物中胸腺素β4、糖皮质激素的含量过高或过低时均不利于药物的包载,优选的胸腺素β4浓度为0.1%-0.2%,优选的糖皮质激素浓度为0.5%-1%。
实施例10
粒径的测定:
本实施例使用Malvern nano ZS90 激光粒度分析仪测定实施例1-8、对比例1-2所获得的药物组合物醇质体的平均粒径、粒径分布PDI 及粒径在80 ~ 160nm 所占百分比,结果见表3。
由表3可知,乙醇浓度对药物组合物醇质体的平均粒径、粒径分布均有显著影响,结果表明,优选的乙醇浓度范围为30%-50%。
实施例11
药物组合物醇质体水凝胶膏剂的制备:
醇质体的组成:
醇质体制备方法:
(1)称取配方量的PEG化磷脂和胆固醇溶于乙醇中,得到醇相A;
(2)称取配方量的胸腺素β4、氢化可的松、壳聚糖、没食子酸丙酯和苄醇溶于PBS缓冲液中,得到水相B;
(3)磁力搅拌醇相A和水相B,并在31°C条件下,将水相B加入醇相A中;其中,以PBS缓冲液的总重量为100% 计,水相B的加入速度为5%/分钟;
(4)相同条件下继续磁力搅拌,水合16min后过滤,得到药物组合物醇质体;
(5)利用探头超声仪法对所得到的药物组合物醇质体进行整粒。
采用激光散射仪测得本实施例制备的醇质体粒径为117nm;包封率为73.2%。
醇质体水凝胶膏剂制备方法:
(1)量取7ml的甘油,依次加入0.04g的甘羟铝,0.008g的EDTA,1.2g的聚丙烯酸钠NP-700和0.3g的聚乙烯吡咯烷酮K-90,搅拌均匀得C相;
(2)称取0.03g酒石酸溶解于1ml水作为D相;
(3)将D相分3次加入C相中,搅拌均匀,再加入等重量的制备好的药物组合物醇质体,混合均匀后涂布于水凝胶膏剂的支持层无纺布上,熟化,加盖保护层聚乙烯膜,即得本发明的药物组合物醇质体水凝胶膏剂。
实施例12
药物组合物醇质体水凝胶贴剂的制备:
醇质体的组成:
醇质体制备方法:
(1)称取配方量的神经鞘磷脂和胆固醇溶于丙二醇中,得到醇相A;
(2)称取配方量的胸腺素β4、地塞米松、磷脂酰甘油、苹果酸和对羟基苯甲酸丙酯溶于PBS缓冲液中,得到水相B;
(3)磁力搅拌醇相A和水相B,并在34°C条件下,将水相B加入醇相A中;其中,以PBS缓冲液的总重量为100% 计,水相B的加入速度为7%/分钟;
(4)相同条件下继续磁力搅拌,水合18min后过滤;
(5)利用探头超声仪法对所得到的药物组合物醇质体进行整粒。
采用激光散射仪测得本实施例制备的醇质体粒径为112.7nm;包封率为72.3%。
醇质体水凝胶贴剂制备方法:
(1)量取8ml的甘油,依次加入0.04g的甘羟铝,0.008g的EDTA,0.95g的聚丙烯酸钠NP-700和0.74g的聚乙烯吡咯烷酮K-90,搅拌均匀得C相;
(2)称取0.066g酒石酸溶解于2ml水作为D相;
(3)将C相加入D相中,搅拌均匀,再加入等重量的制备好的药物组合物醇质体,混合均匀后涂布于背衬材料上,熟化,加盖聚乙烯膜,即得本发明的药物组合物醇质体水凝胶贴剂。
对比例3
采用与实施例1相同的方法制备药物组合物凝胶剂,不同之处在于,在本实施例制备凝胶剂的过程中,将配方中的胆固醇和大豆卵磷脂均去除,除PBS之外的其它组分含量不变,最后用PBS补足量即可。
实施例13
离体经皮渗透特性的测定:
本实施例测定对比例1-3以及实施例1-8的离体经皮渗透特性。具体方法如下:
取合适大小(4cm2)的去除皮下组织的人体皮肤,用生理盐水洗净,将皮肤固定在TP-6型(天津精拓仪器科技有限公司)透皮扩散仪的扩散池上,在供给室内分别加入等量(以有效成分药物组合物计算为0.6mg)的制备好的各样品,接受介质为乙醇/PEG400/生理盐水的混合溶液;设定透皮扩散仪各参数,分别于特定时间点取样,并补充等量的空白接受介质。HPLC(高效液相色谱)各取样点接受介质中药物组合物的含量,计算其24小时内各取样点累计经皮透过量。
研究结果表明:醇质体各剂型的经皮渗透效果均明显优于非醇质体的药物组合物凝胶剂,且醇在一定的浓度范围内可提高渗透效果。各制剂经皮渗透能力与醇质体的包封率和粒径都有一定的关系,包封率越高,粒径越均匀,药剂的经皮渗透效果越好。结果见表4。
实施例14
药物组合物凝胶剂的制备
采用与实施例8相同的方法制备药物组合物凝胶剂,不同之处在于,在本实施例制备凝胶剂的过程中,配方中胸腺素β4的百分含量为0.1%,糖皮质激素的百分含量为1.5%,除PBS之外的其它组分含量不变,最后用PBS补足量即可。
实施例15
兔耳瘢痕修复实验
A)建立动物模型
购自中山大学动物中心的若干只成年家兔,雌雄各半,体质量2.0~2.5kg,酒精常规消毒后,在兔耳腹侧中段沿长轴避开可见血管,在左右耳的耳部内侧分别制造3个1cm×1cm创面,创面间隔1cm以上距离,手术刀切除全层皮肤至软骨,并用刮勺彻底刮除软骨膜,止血后无菌纱布包扎或用0.1%苯扎氯铵溶液冲洗创面。让家兔恢复7天,然后再次麻醉,并从伤口处撕下痂以加速增殖过程。术后创面暴露,待其自行愈合。第21天形成增生性瘢痕模型。
B)实验分组
取实施例1、实施例5、实施例6作为第Ⅰ组,实施例2、实施例3、实施例8作为第Ⅱ组,实施例11作为第Ⅲ组,阳性对照邦臣作为第Ⅳ组,对比例1-对比例3作为第Ⅴ组,进行检测。
将造模成功的30只实验兔的60只兔耳一共分为实验组、阴性对照组、阳性对照组。其中兔左耳作为药物的实验组(A1),瘢痕处涂抹药物;右耳作为药物的阴性对照组(A0),不使用任何药物。另取3只兔子作为阳性对照组,组中各兔的左耳涂抹邦臣疤痕硅凝胶(邦臣公司,以下简称邦臣),右耳作为邦臣的阴性对照组,不使用任何药物。
各兔左耳的所有创伤处相应制剂的涂抹量以刚好能够全部覆盖瘢痕即可,按照上法每天早晚各涂抹1次,持续给药14天。每2天重新剃去兔子瘢痕处的毛,每次涂抹之前均先用湿棉花擦拭瘢痕处以去除上一次使用的制剂。
C)瘢痕修复评价
通过测量瘢痕闭合度进行修复评价,瘢痕闭合度由瘢痕宽度来评估,在第1、7、14、21和28天进行评价,每个瘢痕的宽度在最宽处由数显卡尺来测量,结果见表5。
由表5可知,在整个治疗时间内,与未涂抹制剂组所形成的瘢痕相比,涂抹制剂组所形成的瘢痕在测量时间点皆显示出更大的闭合度。在第14天涂抹了实施例1、3、11制剂的瘢痕闭合度更高,实施例1、2、3、5的结果对比显示,胸腺素β4的含量过高或过低均不利于伤口闭合,实施例3、8、14的结果对比显示,糖皮质激素的含量过高并不能很好的修复瘢痕。实施例1与对比例1、2、3相比,实施例1的瘢痕修复效果均明显高于对比例1和2,说明在涂抹制剂期间,当药物组合物中药物各组分含量相同时,醇的浓度对瘢痕闭合也有影响,可能是因为醇的浓度对经皮渗透效果有影响,醇的浓度在一定范围内,药物的经皮渗透效果强,因此,实施例1制得的制剂比对比例1、2的效果好。实施例1与对比例3相比,由于醇质体的整体透皮渗透效果均比非醇质体好,因此,实施例1的效果也显著高于对比例3制得的制剂。
同样,在第28天的结果显示,实施例1、3、11制得的制剂效果均显著高于其他制剂,说明停止用药后,实施例1、3、11制得的制剂仍然对瘢痕的愈合发挥作用,而涂抹了其他制剂对瘢痕的愈合效果并不特别理想,实施例2和实施例8甚至显示出了瘢痕复发的迹象,对比例中虽然瘢痕的愈合速度较慢,但是却未显示出复发的迹象,可能是因为药物组分没有变,均为曲安奈德和胸腺素β4的组合物,但因醇质体中其他成分含量不同或未制成醇质体,透皮效果不好,发挥作用较慢。
由以上结果可明显看出,药物组合物醇质体中药物组分含量对皮肤瘢痕修复影响较大,只有当胸腺素β的重量百分比为40.1-0.2%,糖皮质激素的重量百分比为0.5-1%时,药物组合物才能发挥除很好的瘢痕修复效果。
D)兔耳皮肤瘢痕模型皮肤体内实验
最后一次涂抹药后对家兔造模耳造模部位做肉眼观察,并取病理活检,以10%福尔马林固定,石蜡包埋、切片,苏木素-伊红(HE)染色,应用购买北京碧云天生产的苏木素-伊红染色试剂盒按照使用说明书进行,光学显微镜下观察组织学改变。
造模前兔耳颜色粉红、菲薄、柔软,病理分析其上可见清晰的毛细血管,毛囊口排列整齐,模型制备成功后,取模型处皮肤组织,镜检可见局部皮肤成纤维细胞增殖,胶原纤维增多增粗,致密并排列紊乱,期间有少量炎性细胞。具体兔耳瘢痕组织学变化见下表6。
注:皮肤瘢痕局部皮肤病理变化分级参考标准为“-”:皮肤组织正常,组织结构完整;“+”:成纤维细胞增殖,胶原纤维增多增粗,致密并排列紊乱,期间有少量炎性细胞;“++”:成纤维细胞明显增殖,胶原纤维明显增多增粗,致密并排列紊乱,期间有炎性细胞;“+++”:成纤维细胞大量增殖,胶原纤维明显增多增粗,十分致密并排列紊乱,期间有较多炎性细胞。
表6结果中本发明实施例1、3、11制备的制剂治疗兔耳瘢痕模型,在治疗第14天兔耳瘢痕出现一定的修复,即增生性瘢痕成纤维细胞增殖得到一定的控制,胶原纤维减少变细,组织中炎症细胞液明显减少。同时各组动物模型体内均未发现成瘤现象。停止用药后在第28天兔耳瘢痕出现很好的修复,即增生性瘢痕成纤维细胞增殖得到很好的抑制,胶原纤维显著减少变细,组织中炎症细胞液明显减少。而其他组中并未达到这样的效果。进一步证明停止用药后,实施例1、3、11制备的制剂仍然对瘢痕的愈合发挥作用,治疗的瘢痕不易复发。
综上所述,虽然本发明已以优选实施例揭露如上,但上述优选实施例并非用以限制本发明,本领域的普通技术人员,在不脱离本发明的精神和范围内,均可作各种更动与润饰,因此本发明的保护范围以权利要求界定的范围为准。
Claims (10)
1.一种药物组合物醇质体,其特征在于,该醇质体包含以重量百分比计的如下组份:胸腺素β40.1-0.2%,糖皮质激素0.5-1%,低分子量醇30-50%,磷脂3.0-12.0%,胆固醇1.0-2.5%,助剂0.51-1.3%,其余为PBS缓冲液;其中所述低分子量醇为乙醇或丙二醇;所述糖皮质激素为氢化可的松、可的松、替可的松、强的松、莫米松、曲安奈德、安西缩松、布地奈德、倍他米松、地塞米松、氟可龙、氯倍他松、氯倍他索、氟泼尼定、卤贝他索、双氟拉松、醋酸氟轻松、哈西奈德、去羟米松、氟轻松、氟氢缩松、氟氢可的松、氟替卡松、羟泼尼缩松、双氟可龙、泼尼卡酯、甲泼尼松、泼尼松龙中的至少一种或其衍生物中的至少一种;所述磷脂为大豆卵磷脂、蛋黄卵磷脂、神经鞘磷脂、聚乙二醇化磷脂和磷脂酰肌醇中的至少一种;
所述助剂包括稳定剂0.3-0.7%,抗氧化剂0.2-0.5%及防腐剂0.01-0.1%,所述稳定剂为磷脂酰甘油、磷脂酸、磷脂酰丝氨酸、脱氧胆酸钠或壳聚糖中的至少一种;所述抗氧化剂为维生素E、维生素C、没食子酸丙酯、苹果酸、二叔丁基对甲酚或β-胡萝卜素中的至少一种;所述防腐剂为苯酚、间甲酚、氯甲酚、苄醇、对羟基苯甲酸丙酯或对羟基苯甲酸甲酯中的至少一种。
2.如权利要求1所述的药物组合物醇质体,其特征在于,所述醇质体的剂型为凝胶剂、水凝胶膏剂或水凝胶贴剂中的一种。
3.如权利要求1所述的药物组合物醇质体,其特征在于,所述醇质体的平均粒径为90nm-170nm。
4.如权利要求1所述的药物组合物醇质体,其特征在于,所述醇质体的粒径分布为0.165PDI-0.355PDI。
5.如权利要求1所述的药物组合物醇质体,其特征在于,所述醇质体的粒径在80 ~160nm 所占百分比为52%-78%。
6.一种制备如权利要求1-5任一项所述的药物组合物醇质体的方法,其特征在于,该方法包括如下步骤:
(1)将所述重量份数的磷脂及胆固醇溶于低分子量醇中,得到醇相A;
(2)将所述重量份数的胸腺素β4、糖皮质激素及助剂溶于PBS缓冲液中,得到水相B;
(3)搅拌醇相A及水相B,并在温度为31-35℃条件下,将水相B加入到醇相A中,水合15-20分钟后过滤,即得到所述的治疗瘢痕的药物组合物醇质体;
(4)将步骤(3)中的治疗瘢痕的药物组合物醇质体进行整粒。
7.如权利要求6所述的方法,其特征在于,步骤(3)中,以PBS缓冲液的总重量为100%计,所述水相B加入的速度为3-8%/分钟。
8.一种制备药物组合物醇质体凝胶剂的方法,其特征在于,该方法包括如下步骤:
(1)将卡波姆以1:40 (w/w)的比例缓慢加入烧杯中的蒸馏水中,然后以800rpm的速度混合2小时,形成均匀分散的凝胶基质;
(2)加入聚乙二醇1.0g、月桂氮卓酮1.2g,搅拌条件下缓慢加入三乙醇胺(0.54g) 调节其pH至中性,充分混合均匀;
(3)将权利要求6或7中制备的药物组合物醇质体与混合均匀的凝胶等重量混合,研制均匀,得到药物组合物醇质体凝胶剂。
9.一种制备药物组合物醇质体水凝胶膏剂的方法,其特征在于,该方法包括如下步骤:
(1)量取7ml的甘油,依次加入0.04g的甘羟铝,0.008g的EDTA,1.2g的聚丙烯酸钠NP-700和0.3g的聚乙烯吡咯烷酮K-90,搅拌均匀得C相;
(2)称取0.03g酒石酸溶解于1ml水作为D相;
(3)将D相分3次加入C相中,搅拌均匀,再加入等重量的权利要求6或7中制备的药物组合物醇质体,混合均匀后涂布于水凝胶膏剂的支持层无纺布上,熟化,加盖保护层聚乙烯膜,得到药物组合物醇质体水凝胶膏剂。
10.一种制备药物组合物醇质体水凝胶贴剂的方法,其特征在于,该方法包括如下步骤:
(1)量取8ml的甘油,依次加入0.04g的甘羟铝,0.008g的EDTA,0.95g的聚丙烯酸钠NP-700和0.74g的聚乙烯吡咯烷酮K-90,搅拌均匀得C相;
(2)称取0.066g酒石酸溶解于2ml水作为D相;
(3)将C相加入D相中,搅拌均匀,再加入等重量的权利要求6或7中制备的药物组合物醇质体,混合均匀后涂布于背衬材料上,熟化,加盖聚乙烯膜,得到药物组合物醇质体水凝胶贴剂。
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