摘要
痤疮为常见的慢性毛囊皮脂腺炎症性皮肤病,发病率较高。加味枇杷清肺胶囊是以《医宗金鉴》收载的治疗肺风粉刺的经典名方枇杷清肺饮为基础,适当加味而成,其主药由枇杷叶(蜜炙),桑白皮,黄连,关黄柏,黄芩,栀子,山楂,石膏,甘草,党参等中药组成。方中枇杷叶与桑白皮共为君药,宣肺清热;黄连、关黄柏、黄芩、栀子四味为臣药,清热解毒;山楂、石膏为佐药,祛瘀化浊并增强清热之功;党参、甘草为使药,益气和中,顾护脾胃。
本论文系统地研究了加味枇杷清肺胶囊的制备工艺、质量标准、初步稳定性、初步药效学及急性毒性。主要内容和结果如下:
1.研究了加味枇杷清肺胶囊的制备工艺。将九味种植物药分成四组,分别对其药效成分进行提取、纯化,按一定的比例混合四种提取物粉末,石膏粉直接加入其中,选择乳糖为填充剂;采用正交试验对制粒的工艺条件进行了优选,确定了制粒工艺为石膏和乳糖的配比为1:1,润湿剂为50%乙醇,用量为12%(即100g药粉加入12mL50%乙醇);对助流剂进行了筛选,选择了微粉硅胶为胶囊的助流剂,其用量为0.4%。测定了制粒后颗粒的堆密度为0.56g/mL,临界相对湿度为60%。
2.制定了加味枇杷清肺胶囊的质量标准。对胶囊中枇杷叶、桑白皮、黄连、关黄柏、黄芩、栀子采用薄层色谱法进行定性鉴别;对其主要药效成分盐酸小檗碱,黄芩苷含量采用高效液相色谱法测定。规定每粒胶囊中盐酸小檗碱含量不低于5.0mg,黄芩苷含量不低于21mg。对胶囊的体外溶出度进行了测定,其主要药效成分盐酸小檗碱,黄芩苷在45分钟内相对累积溶出度超过了70%。按《中国药典》胶囊剂项下规定对胶囊的水分含量、装量差异及重金属含量进行了检查,结果符合《中国药典》2005版的规定。
3.进行初步稳定性考察。经过高温、高湿、强光照射试验以及三个月的加速试验,本品性状、鉴别、检查、含量测定等指标均合格,说明本品质量稳定。
4.对加味枇杷清肺胶囊进行了初步药效学和急性毒性试验研究。体外抑菌试验表明,加味枇杷清肺胶囊的对痤疮丙酸杆菌和金黄色葡萄球菌这两种致病菌的MIC分别为5mg/mL和40mg/mL,说明本品可以通过抑制痤疮的主要致病菌而发挥治疗作用;通过小鼠耳肿胀法试验表明,加味枇杷清肺胶囊能明显抑制二甲苯所致的小鼠耳廓肿胀,具有一定的抗炎作用;以金黄地鼠皮脂腺斑为模型,考察加味枇杷清肺胶囊对皮脂腺内雄激素水平的影响,试验表明,加味枇杷清肺胶囊可引起金黄地鼠皮脂腺斑面积非常显著的降低,说明加味枇杷清肺胶囊可影响皮脂腺内雄激素的水平。进行了初步的拆方研究,对经方枇杷清肺饮、加味组药物及胶囊的抗炎作用和对皮脂腺内雄激素水平影响作用进行了比较。抗炎试验结果表明,三组药物都具有一定的抗炎作用,在同等剂量下,由经方和加味组药物组成胶囊的抗炎作用强于两组药物单独使用,说明经方和加味组药物联用在抗炎作用方面有协同作用。对金黄地鼠皮脂腺斑面积影响的试验结果表明,三组药物均能使金黄地鼠皮脂腺斑面积减小,在同等剂量下,经方与胶囊的作用相当,说明经方与加味组药物联用对皮脂腺内雄激素水平的降低无协同作用。急性毒性试验表明加味枇杷清肺胶囊无明显毒性反应。
Acne is one of common chronic skin diseases, whose incidence is quite high, in sebaceous gland folliculitis. The medication, Jiawei Pipa Qingfei capsule aiming at treating acne, consists of Folium Eriobotryae (stir-frying with honey), Cortex Mori, Rhizoma Coptidis, Cortex Phellodendri, Radix Scutellariae, Fructus Gardeniae, Fructus crataegi, Gypsum Fibrosum, Radix Glycyrrhizae and Radix Codonopsis. This medication is based on the classical prescription of Pipa Qingfei decoction recorded in the traditional Chinese scripture,named as Yizong Jinjian. In the prescription, Folium Eriobotryae and Cortex Mori are principal drugs, which serve to open the inhibited lung-energy and clear away the heat-evil. Besides, Rhizoma Coptidis,Cortex Phellodendri, Radix Scutellariae, Fructus Gardeniae are assistant drugs, which help clear away the heat-evil and expel superficial evils. Fructus crataegi and Gypsum Fibrosum are adjuvant drug used to remove blood stasis and turbid as well as enhance the effect of heat-clearing. And finally, Radix Glycyrrhizae and Radix Codonopsis are guiding drugs, which benefit vital energy and regulate the middle warmer thus functioning to protect spleen and stomach.A preliminary study of Jiawei Pipa Qingfei capsule has been carried out in terms of preparation technics, quality control, stability, rudiment pharmacodynamics as well as its acute toxicity test. And the main contents and outcomes are to be demonstrated as follows.1. Preparation technics of the capsule has been studied: nine herbaceous elements from the prescription were divided into four groups, each of which was treated for extraction and purification separately. Then distilled power from each group was mixed to be the principal drug according to different ratio, then added with satis quantum gesso and lactin as supplement. The technical process of granulation was screened through orthogonal tests which determined that the optimum granulate conditions were: the ratio of gesso and lactin was 1:1, 50% alcohol as moistening agent whose dosage was 12%(that is 12mL50%Alcohol added to 100g medicine powder). The tests also selected Gum Acacia as the glidant of capsule whose dosage was 0.4%. The bulk density of particle was 0.56g/mL, relatively critical humidity was 60%.2. The quality standard of the capsule has also been established. The elements of Folium Eriobotryae, Cortex Mori, Rhizoma Coptidis, Cortex Phellodendri, Radix Scutellariae, Fructus Gardeniae were identified by means of TLC. Berberine and Baicalin were determined by HPLC. The content of Berberin hydrochloride and Baicalin should not be less than 5.50mg and 21mg per capsule. The dissolution of capsule was determined in vitro, relative accumulative dissolution of Berberin hydrochloride and Baicalin were more than 70% within 45 min. Moisture content, content uniformity, content of heavy metal were detected and the result was in accordance with the regulation set by Chinese Pharmacopeia(2005 edition).
3. The preliminary stability of Jiawei Pipa Qingfei Capsule was studied in the test with conditions of high temperature, high moisture and exposure to heavy light which lasted for 3 months with acceleration. The result indicated that the character, identification, detection, content determination and hygienic quality remained unchanged. It showed that the quality of Jiawei Pipa Qingfei Capsule was stable.
4. Rudimentary pharmacodynamics and acute toxicity test have been carried out. The preparation possesses antibacterial effects for Propionibacteria acnes and Staphylococcus aureus, the minimal inhibitory concentration on Propionibacteria acnes and Staphylococcus aureus were 5mg/mL and 40mg/mL respectively. Good anti-inflammatory effect on the edemas of the mice's ears induced by dimethyl benzene was observed. The Syrian Hamster Flank Organ was adopted as animal models to investigate the effect of the capsule on androgen in glandulae sebaceae. The results showed that it can decrease the area of the Syrian Hamster Flank Organ, which suggested that the capsule can inhibit androgen in glandulae sebaceae. The anti-inflammatory action and the inhibition action of androgen in glandulae sebaceae of the capsule were compared with the classical prescription and the additional drugs and test results are that they all have anti-inflammatory action to some extent, the effect of the capsule was better than the classical prescription and the additional drugs respectively, the combination of classical prescription and additional drugs has synergism effect on anti-inflammatory action. The classical prescription, the additional drugs and the capsule all can inhibit androgen in glandulae sebaceae, and the effect of the former was the same as that of the later. The combination of classical prescription and the additional drugs has no synergism effect on inhibition of androgen in glandulae sebaceae. Acute toxicity test showed that Jiawei Pipa Qingfei Capsule had no obvious toxic reaction.
引文
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