CN111184732B - 一种复合组合物制剂及其制备方法和皮肤炎症中的应用 - Google Patents
一种复合组合物制剂及其制备方法和皮肤炎症中的应用 Download PDFInfo
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- CN111184732B CN111184732B CN202010143602.8A CN202010143602A CN111184732B CN 111184732 B CN111184732 B CN 111184732B CN 202010143602 A CN202010143602 A CN 202010143602A CN 111184732 B CN111184732 B CN 111184732B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
本发明涉及一种基于皮肤屏障修复原理的复合营养组合物及其制备方法和应用。本发明的复合组合物在不抑制机体免疫的基础上，通过修复皮肤屏障发挥对皮肤疾患治疗作用，治疗效果好、治疗期短、安全性高。
Description
技术领域
本发明涉及一种复合组合物制剂及其制备方法和皮肤炎症中的应用。
背景技术
常见皮肤疾患主要有免疫激活，过度炎症导致。可导致诸多皮肤疾患，包括特应性皮炎、银屑病、毛细血管扩张症、激素依赖性皮炎、糖尿病足、艾滋病相关皮肤黏膜炎症等，给患者带来诸多的身体不适及心理障碍。目前这类疾病主要采用皮质激素及免疫抑制剂治疗(他克莫司、IL4抗体、IgM抗体等)，但复发率极高，由于抑制了免疫，破坏皮肤屏障，长期使用反而加重病情，使疾病反复发作，难以治愈。
2017年赛诺菲制药上市的“再生元——IL4抗体”，用于治疗中重度湿疹(特应性皮炎)，与激素联合应用，有效率仅为48％，且使用期内已出现2例因不良反应导致的死亡。可见，单一药物治疗的有效率低，且须长达半年的口服及外用治疗，副作用大于治疗获益。因此，研制一种安全有效的护理皮肤疾患的制剂具有重要意义。
本发明为了解决现有技术中皮肤疾患利用免疫抑制原理的单一治疗方案缺陷，提供了一种基于皮肤屏障修复原理的复合营养组合物及其制备方法和应用。本发明的复合组合物在不抑制机体免疫的基础上，通过修复皮肤屏障发挥对皮肤疾患治疗作用，治疗效果好、治疗期短、安全性高。
为了实现上述目的，本发明的发明人首创了“回归自然、防御性治疗”新理念，对免疫激活性疾病，不采用免疫抑制剂进行“杀伤性治疗”，而是利用身体内已有的物质或天然物质，恢复皮肤屏障，降低皮肤低外界刺激的敏感性，间接调节机体免疫激活状态，采用温和的方法，让机体免疫自我恢复到正常状态，而不是利用免疫抑制剂，强制性压制机体免疫，从而避免了停药反弹，也避免了免疫抑制剂对机体的产生的副作用。
发明内容
本发明采用如下技术方案：
一种复合组合物，其包括以下组分：1-50％的烟酰胺及其衍生物、1-50％的甘草酸及其甘草次酸衍生物、1-50％维生素C及其衍生物。
一种复合组合物，其包括以下组分：1-50％的烟酰胺及其衍生物、1-50％的甘草酸及其甘草次酸衍生物、1-50％维生素C及其衍生物、0.1％-5％环磷腺苷及其衍生物。
所述百分比为质量百分比。
烟酰胺及其衍生物：可由烟酰胺、烟酰胺核糖、烟酰胺单核苷酸、烟酰胺腺嘌呤二核苷酸、还原型烟酰胺腺嘌呤二核苷酸等提供。
甘草酸及其甘草次酸衍生物：可由甘草酸及其盐类：包括铵盐、镁盐、钠盐、钾盐、锌盐等提供；可由甘草次酸及其盐类：包括铵盐、镁盐、钠盐、钾盐、锌盐等提供。
维生素C及其衍生物：可由维生素C及其磷酸酯盐类：包括镁盐、钠盐、钾盐、锌盐等提供。
环磷腺苷及其衍生物：可由环磷腺苷、环磷腺苷葡胺等提供。
本发明复合组合物较佳地由以下组分组成：40％烟酰胺核糖、40％甘草酸单铵、15％维生素C磷酸酯镁、5％环磷腺苷，所述百分比为质量百分比。
本发明复合组合物较佳地由以下组分组成：30％烟酰胺单核苷酸、20％甘草酸二钠、49％维生素C磷酸酯钠、1％环磷腺苷，所述百分比为质量百分比。
本发明复合组合物较佳地由以下组分组成：5％烟酰胺单核苷酸、50％甘草酸二钠、15％维生素C磷酸酯钠、30％环磷腺苷葡胺，所述百分比为质量百分比。
本发明复合组合物较佳地由以下组分组成：30％酰胺腺嘌呤二核苷酸、30％甘草酸二钾、30％维生素C磷酸酯钠、10％环磷腺苷，所述百分比为质量百分比。
本发明提供了一种所述复合组合物的制备方法，其包括将各组分混合均匀即可。
本发明还提供一种皮肤护理制剂，其包含所述复合组合物。
该组合物不含化学添加剂(防腐剂、色素、香精、表面活性剂、乳化剂、增稠剂)、药用辅料，不能用于霜剂、乳剂的制备，会影响其“屏障修复治疗”效果。
本发明还提供了所述复合组合物或所述皮肤护理制剂在皮肤护理中的应用。所述皮肤护理可为治疗皮肤疾患，所述皮肤疾患优选为特应性皮炎、银屑病、毛细血管扩张症、激素依赖性皮炎、糖尿病足、艾滋病相关皮肤黏膜炎症的治疗及敏感性肌肤的护理。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明提供的复合组合物，基于皮肤疾患的发病机制，采取与当今治疗策略完全不同的治疗原理，从构建健康的皮肤屏障入手，精准进行“皮肤屏障重建性干预”，从源头干预皮肤疾患的发病过程。该复合营养组合物中各组分协同配合，发挥营养肌肤、调节免疫、重建健康皮肤屏障的作用，对皮肤疾患具有很好的治疗效果，治疗期短。
另外，该复合组合物利用机体内原生态物质及天然产物组成，不含激素，不添加任何添加剂(如乳化剂、表面活性剂、防腐剂等)，安全性高。
附图说明
图1为效果实施例1-4中各组小鼠的皮肤状态。
图2为效果实施例1-4中各组小鼠的皮肤血管炎症改变图。
图3为效果实施例4中1例湿疹患者康复图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1
将以下各组分混合均匀，得复合组合物1：40％烟酰胺核糖、40％甘草酸单铵、15％维生素C磷酸酯镁、5％环磷腺苷，所述百分比为质量百分比。
实施例2
将以下各组分混合均匀，得复合组合物2：30％烟酰胺单核苷酸、20％甘草酸二钠、49％维生素C磷酸酯钠、1％环磷腺苷，所述百分比为质量百分比。
实施例3
将以下各组分混合均匀，得复合营养组合物3：5％烟酰胺单核苷酸、50％甘草酸二钠、15％维生素C磷酸酯钠、30％环磷腺苷葡胺，所述百分比为质量百分比。
实施例4
将以下各组分混合均匀，得复合组合物4：30％酰胺腺嘌呤二核苷酸、30％甘草酸二钾、30％维生素C磷酸酯钠、10％环磷腺苷，所述百分比为质量百分比。
效果实施例1
采用KM小鼠，雌性70只，体重25±2g，由武汉大学A3动物实验中心提供，合格证编号：SCXK(鄂2016-0004)。将小鼠随机分为9组，每组10只。9组分别为：(1)正常对照组；(2)皮炎模型(M)组；(3)M+复合组合物1组；(4)M+复合组合物2组；(5)M+复合组合物3组；(6)M+复合营养组合物4组；(7)M+地塞米松组。
将0.03mL二甲苯注射入第(2)-(7)组的小鼠右耳前后叶，以诱导小鼠的右耳发生急性耳水肿，建立小鼠炎性模型。接着，对第(3)-(7)组的小鼠的右耳涂抹相应药物(例如，对第(3)组的小鼠涂抹复合营养组合物1，对第(9)组的小鼠涂抹地塞米松乳膏)，每只0.1g，每天一次，连续2周。给药结束后，取左右耳，打耳片，称取左右耳重量，计算耳肿胀度。耳肿胀度的计算公式为：(右耳重-左耳重)/左耳重*100％。
结果见表1，其中，第(3)-(6)组的耳肿胀度分别为26.72％、15.68％、32.11％和9.44％％，第(7)组的耳肿胀度为10.36％，可见，本发明实施例1-4的复合组合物1-4对炎性耳肿胀有很好的对抗作用，组合物4与皮质激素抗炎作用近似。
表1.复合组合物对耳肿胀炎性模型小鼠耳肿胀度的影响
| 序号 | 组别 | 耳肿胀度 |
| 1 | 正常对照组 | -1.22％ |
| 2 | 耳肿胀炎性模型(M)组 | 56.78％ |
| 3 | M+复合组合物1组 | 26.72％ |
| 4 | M+复合组合物2组 | 15.68％ |
| 5 | M+复合组合物3组 | 32.11％ |
| 6 | M+复合组合物4组 | 9.44％ |
| 7 | M+地塞米松组 | 10.36％ |
效果实施例2
采用KM小鼠，雌性70只，体重25±2g，由武汉大学A3动物实验中心提供，合格证编号：SCXK(鄂2016-0004)。将小鼠随机分为7组，每组10只，7组分别为：(1)正常对照组；(2)湿疹模型(M)组；(3)M+复合组合物1组；(4)M+复合组合物2组；(5)M+复合组合物3组；(6)M+复合组合物4组；(7)M+地塞米松乳膏组。
用电推剪对小鼠背部进行剃毛，面积约为4cm2。对第(2)-(7)组的小鼠在脱毛区域涂抹质量分数为1.0％的DNFB溶液(溶剂为丙酮：橄榄油＝3:1)100μL进行致敏，第3天再涂抹上述溶液300μL以加强致敏，第7、11、14天，在小鼠背部外涂质量分数为0.5％的DNFB溶液50μL诱发皮炎，建立小鼠湿疹模型。对第(1)组的小鼠在脱毛区域涂抹等体积的溶剂(丙酮：橄榄油＝3:1)，作为空白对照。
接着，对第(3)-(7)组的小鼠涂抹相应药物(例如，对第(3)组的小鼠涂抹复合营养组合物1，对第(7)组的小鼠涂抹阳性对照药品地塞米松乳膏)。每只0.1g，每天一次，连续2周。14天后，各组小鼠的皮肤状态如图1所示。测定各组小鼠的皮肤的经皮失水率、皮炎程度、皮肤pH值、皮肤含水量、皮肤水肿度、皮肤密度，结果见表2，由表2可知：
第(2)组小鼠的皮肤经皮失水率与第(1)组相比高达6.3倍，第(3)-(6)组小鼠的经皮失水率明显下降，其中第(6)组经皮失水率接近正常组。第(2)组小鼠的皮炎程度评分为9.85分，由第(3)-(6)组小鼠的皮炎程度可知，本发明实施例的复合营养组合物1-4可显著改善皮炎程度评分，其中第(6)组(复合营养组合物4)的皮炎程度评分下降至1.84分。第(2)组小鼠的皮肤pH值与第(1)组相比显著升高，由第(3)-(6)组小鼠的皮肤pH值可知，本发明实施例的复合营养组合物1-4可明显降低皮肤pH值。第(2)组小鼠的皮肤含水量显著降低，仅为第(1)组的48.8％，由第(3)-(6)组小鼠的皮肤含水量可知，本发明实施例的复合营养组合物1-4可显著提高皮肤含水量。第(2)组小鼠的皮肤出现明显水肿，皮肤水肿度为第(1)组小鼠的73.3％，由第(3)-(6)组小鼠的皮肤水肿度可知，本发明实施例的复合营养组合物1-4可显著降低皮肤水肿度。第(2)组小鼠的皮肤密度显著降低，仅为第(1)组小鼠的26％，由第(3)-(6)组小鼠的皮肤密度可知，本发明实施例的复合营养组合物1-4可显著提升皮肤密度，其中第(2)组小鼠的皮肤密度基本恢复正常。
由第(7)和(8)组小鼠的测试结果可知，对比例1和2的复合营养组合物5、6对皮肤炎症各指标无明显改善。可见，当组合物的组分组成比例不在本发明的范围内时，可失去疗效，组分组成比例对湿疹的治疗至关重要。由第(9)组小鼠的测试结果可知，地塞米松乳膏虽然可降低经皮失水率、降低皮肤炎症程度，降低pH值，提升皮肤含水量，降低皮肤水肿度，但作用较弱，疗效不及本发明实施例的复合营养组合物1-4；并且，地塞米松乳膏对皮肤密度无改善作用。
表2.复合营养组合物对湿疹模型小鼠皮肤炎症各指标的影响
效果实施例3
采用实施例4的复合组合物4对10例湿疹患者进行护理，疗程6个月，有效率90％，治愈率30％。图3为其中1例湿疹患者康复图。由图3可见，经约6个月的护理，该患者湿疹完全治愈。
Claims (2)
1.一种复合组合物，其特征在于，由30～40％的烟酰胺核糖或烟酰胺单核苷酸、20～40％的甘草酸盐、15～49％维生素C磷酸酯盐、1％～5％环磷腺苷组合而成，以上百分比为重量百分比
所述的甘草酸盐，选自铵盐、钠盐；
所述维生素C磷酸酯盐，选自镁盐、钠盐。
2.一种复合组合物的制备方法，其特征在于，将权利要求1所述的各组分混合均匀即可。
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