复方防风颗粒制备工艺及制剂质量标准研究
摘要
药物脱毒治疗,目前国际通用的方法有阿片受体激动剂和非阿片受体激动剂对症处理,或用麻醉药品剥夺意识,取得较好效果。但也存在成瘾潜力大,副作用大,接受率、维持率及病人依从性低等诸多问题。因此,如何安全、有效地戒断阿片类成瘾是当前医学的一个急待解决的难题。中药复方制剂具有多系统、多靶点、安全有效、疗程短、见效快、副作用少、经济等优势,本课题选用临床实践经验中药处方,运用现代科学技术手段,制成一种较为理想的无毒副作用及依赖性反应的非成瘾性戒毒中药制剂。处方由防风、炮姜、陈皮、山楂(焦)、肉苁蓉(酒)、党参组成,具有解毒活血,息风止痛,补肾健脾的功效。阿片类成瘾的急性戒断期证属毒瘀互阻,脾肾不足,寒热错杂证。本课题根据中药传统用药方法,结合中药现代研究成果,采用正交试验法,对各提取工艺、精制工艺、制剂成型工艺进行了研究,确定了制剂制备工艺,并进行中试放大生产研究；根据《中国药典》要求,对制剂质量标准进行了研究；根据《中国药典》和“中药、天然药物稳定性研究技术指导原则”要求,对复方防风颗粒分别进行了加速稳定性试验研究及长期稳定性试验研究。为其开发成中药复方制剂新药奠定基础。
主要结论如下：
1.应用正交试验法,对制剂制备工艺进行了研究,确定防风、炮姜、陈皮加6倍量水浸泡2hr,水蒸气蒸馏法提取挥发油,提取8hr,收集挥发油；残渣继续加水煎煮2次,每次1hr,加水量4倍、4倍；肉苁蓉、山楂、党参加水浸泡4hr,煎煮2次,每次1.5hr,加水量台倍、6倍。挥发油采用β-环糊精包结技术,搅拌法包结,油：β-环糊精为1:4,包结时间为15 min,包结温度为30±1℃。成型工艺为滤液浓缩至相对密度1.04(6℃测)的清膏,高速离心,上清液浓缩至相对密度1.20(60℃测)的稠膏,以稠膏：挥发油β-环糊精包结物与糊精的混合物=4.3:1流化喷雾制粒。并进行中试研究,显示上述工艺简单异性,工艺重复性好,适合工业化大生产。
2.根据《中国药典》颗粒剂制剂通则,对复方防风颗粒检查项粒度、水分、溶化性、装量差异、微生物限度进行了研究及限定；采用薄层鉴别法,以升麻素苷和5-O-甲基维斯阿米醇苷为对照定性鉴别了防风,以党参对照药材为对照定性鉴别了党参,以干姜对照药材为对照定性鉴别了炮姜,以橙皮苷为对照定性鉴别了陈皮；采用高效液相色谱法对升麻素苷和5-O-甲基维斯阿米醇苷进行了测定并规定了含量限度,暂定本品含防风以升麻素苷及5-O-甲基维斯阿米醇苷的总量计每袋不得少于20mg。
3.对复方防风颗粒3批次成品进行了加速稳定性试验研究及长期稳定性试验研究,结果显示本品制剂在观察期内均符合本品质量标准草案各项规定。根据稳定性试验结果,对复方防风颗粒制剂贮存条件、包装材料、有效期进行了评定及确定。确定本品采用药品包装用塑料、镀铝复合膜为包装材料,在常温条件下密封,贮存暂定复方防风颗粒有效期为24个月。制剂
On the treatment of drug detoxification, the current internationally accepted the methods of opioid receptor agonists and non-opioid receptor agonist symptomatic treatment, or awareness deprivation of narcotic drugs. However, great potential for addiction, side effects, low acceptance rates, low maintain rates and low patient compliance is also the great problems. So, safe and effective opiate addiction withdrawal is currently a pressing medical problem to solve. Traditional Chinese medicine has a lot of advantages as multi-system, multi-target, safe and effective, short course, wok quickly, few side effects, economic. So the topic choose the clinical experience prescription, and use the modern scientific and technological means, to make an ideal non-side effects and non-dependence reaction drug of traditional Chinese medicine preparations. The preparation composed of Saposhnikoviae Radix, baked Rhizoma Zingiberis, Pericarpium Citri Reticulatae, Hawthorn Fruit (coke), Herba Cistanchis (wine). It can promote blood flow, neutralize poison, rest the wind, relieve pain, invigorate the kidney and spleen. Clinical use of acute withdrawal period of opioid addiction with appearance of poison congestion stasis, insufficient of kidney and spleen, cold-heat complicated syndrome. The researches used the method of treatment according to traditional Chinese medicine and combined with modern research results. To optimize the technology of manufacture of the praeparatum, use the method of orthogonal experiment, to formulate the quality standards of preparation according to the requirements of "The Chinese Pharmacopoeia". And we also carried out the research of accelerated stability tests and long-term stability tests.
The main conclusions are as follows:
1. Saposhnikoviae radix, baked Rhizoma Zingiberis, pericarpium citri reticulatae were extracted by wet distillation for 8hrs, with 6 times the weight of water soaked 2hr. Collecte the volatile oil. The residues continue extracted by boiling water for 2 times, each time lhr, and each with water volume of 4 times the weight. Herba Cistanchis, Fructus Crataegi, Radix Codonopsitis, etc. were extracted with boiling water for 4hrs, and two times, each time 1.5hrs, 8 times and 6 times the weighy of water. The volatile oil was wraped withβ-CD bying stiring, with the ratio of the volatile oil:β-CD=1:4, stiring 15min, at 30±1℃. The filtrate was concentrated to the relative density of 1.04 (60℃), high-speed centrifugation, the supernatant was concentrated to the relative density of 1.20 (60℃). At the ratio of Thick paste : wraped volatile oilβ-CD and dextrine mixture=4.3:1, fluidized spray granulation.
2. According to "Chinese Pharmacopoeia" General granule preparation, checking items on the compound particle size wind, water, melting resistance, load difference, microbial limit has been studied and qualified; using TLC method to Cimicifuga glycosides and 4'-O-beta-Glucopyranosyl-5-O-Methylvisamminol qualitative identification of the wind were to Codonopsis control medicines to control the qualitative identification of Codonopsis, ginger ale, medicine to control the qualitative identification of the Baojiang to Orange glycosides for the qualitative identification of Citrus control; using HPLC to determine the Cimicifuga glycosides and 4'-O-beta-Glucopyranosyl-5-O-Methylvisamminol, and tentatively the total amount was not less than 20mg per bag.
3. The research of 3 batches of finished compound accelerated stability test and long-term stability test shows that the preparation packaging products in plastic, aluminum composite film for packaging materials, sealing under normal temperature conditions, will be valid for 24 months.
主要结论如下：
1.应用正交试验法,对制剂制备工艺进行了研究,确定防风、炮姜、陈皮加6倍量水浸泡2hr,水蒸气蒸馏法提取挥发油,提取8hr,收集挥发油；残渣继续加水煎煮2次,每次1hr,加水量4倍、4倍；肉苁蓉、山楂、党参加水浸泡4hr,煎煮2次,每次1.5hr,加水量台倍、6倍。挥发油采用β-环糊精包结技术,搅拌法包结,油：β-环糊精为1:4,包结时间为15 min,包结温度为30±1℃。成型工艺为滤液浓缩至相对密度1.04(6℃测)的清膏,高速离心,上清液浓缩至相对密度1.20(60℃测)的稠膏,以稠膏：挥发油β-环糊精包结物与糊精的混合物=4.3:1流化喷雾制粒。并进行中试研究,显示上述工艺简单异性,工艺重复性好,适合工业化大生产。
2.根据《中国药典》颗粒剂制剂通则,对复方防风颗粒检查项粒度、水分、溶化性、装量差异、微生物限度进行了研究及限定；采用薄层鉴别法,以升麻素苷和5-O-甲基维斯阿米醇苷为对照定性鉴别了防风,以党参对照药材为对照定性鉴别了党参,以干姜对照药材为对照定性鉴别了炮姜,以橙皮苷为对照定性鉴别了陈皮；采用高效液相色谱法对升麻素苷和5-O-甲基维斯阿米醇苷进行了测定并规定了含量限度,暂定本品含防风以升麻素苷及5-O-甲基维斯阿米醇苷的总量计每袋不得少于20mg。
3.对复方防风颗粒3批次成品进行了加速稳定性试验研究及长期稳定性试验研究,结果显示本品制剂在观察期内均符合本品质量标准草案各项规定。根据稳定性试验结果,对复方防风颗粒制剂贮存条件、包装材料、有效期进行了评定及确定。确定本品采用药品包装用塑料、镀铝复合膜为包装材料,在常温条件下密封,贮存暂定复方防风颗粒有效期为24个月。制剂
On the treatment of drug detoxification, the current internationally accepted the methods of opioid receptor agonists and non-opioid receptor agonist symptomatic treatment, or awareness deprivation of narcotic drugs. However, great potential for addiction, side effects, low acceptance rates, low maintain rates and low patient compliance is also the great problems. So, safe and effective opiate addiction withdrawal is currently a pressing medical problem to solve. Traditional Chinese medicine has a lot of advantages as multi-system, multi-target, safe and effective, short course, wok quickly, few side effects, economic. So the topic choose the clinical experience prescription, and use the modern scientific and technological means, to make an ideal non-side effects and non-dependence reaction drug of traditional Chinese medicine preparations. The preparation composed of Saposhnikoviae Radix, baked Rhizoma Zingiberis, Pericarpium Citri Reticulatae, Hawthorn Fruit (coke), Herba Cistanchis (wine). It can promote blood flow, neutralize poison, rest the wind, relieve pain, invigorate the kidney and spleen. Clinical use of acute withdrawal period of opioid addiction with appearance of poison congestion stasis, insufficient of kidney and spleen, cold-heat complicated syndrome. The researches used the method of treatment according to traditional Chinese medicine and combined with modern research results. To optimize the technology of manufacture of the praeparatum, use the method of orthogonal experiment, to formulate the quality standards of preparation according to the requirements of "The Chinese Pharmacopoeia". And we also carried out the research of accelerated stability tests and long-term stability tests.
The main conclusions are as follows:
1. Saposhnikoviae radix, baked Rhizoma Zingiberis, pericarpium citri reticulatae were extracted by wet distillation for 8hrs, with 6 times the weight of water soaked 2hr. Collecte the volatile oil. The residues continue extracted by boiling water for 2 times, each time lhr, and each with water volume of 4 times the weight. Herba Cistanchis, Fructus Crataegi, Radix Codonopsitis, etc. were extracted with boiling water for 4hrs, and two times, each time 1.5hrs, 8 times and 6 times the weighy of water. The volatile oil was wraped withβ-CD bying stiring, with the ratio of the volatile oil:β-CD=1:4, stiring 15min, at 30±1℃. The filtrate was concentrated to the relative density of 1.04 (60℃), high-speed centrifugation, the supernatant was concentrated to the relative density of 1.20 (60℃). At the ratio of Thick paste : wraped volatile oilβ-CD and dextrine mixture=4.3:1, fluidized spray granulation.
2. According to "Chinese Pharmacopoeia" General granule preparation, checking items on the compound particle size wind, water, melting resistance, load difference, microbial limit has been studied and qualified; using TLC method to Cimicifuga glycosides and 4'-O-beta-Glucopyranosyl-5-O-Methylvisamminol qualitative identification of the wind were to Codonopsis control medicines to control the qualitative identification of Codonopsis, ginger ale, medicine to control the qualitative identification of the Baojiang to Orange glycosides for the qualitative identification of Citrus control; using HPLC to determine the Cimicifuga glycosides and 4'-O-beta-Glucopyranosyl-5-O-Methylvisamminol, and tentatively the total amount was not less than 20mg per bag.
3. The research of 3 batches of finished compound accelerated stability test and long-term stability test shows that the preparation packaging products in plastic, aluminum composite film for packaging materials, sealing under normal temperature conditions, will be valid for 24 months.
引文
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[2]刘志民.药物滥用与药物依赖性流行病学调查[J].中国科技成果,2010,23：27-30
[3]刘志民.关于加强我国药物滥用防治工作的思考与建议[J].中国药物滥用防治杂志,2007,13(5)：249-251
[4]连智,孙桂宽,刘锐克,等.四省市吸毒人群中丁丙诺啡药物滥用／使用的现况调查[J].中国药物依赖性杂志,2010,2：120-124
[5]易晟,廖海滨,曾小华.广东出所戒毒人员的特点及提高戒断率的对策和建议[J].犯罪与改造研究,2011,7：24-27
[6]黄平,吴刚,周平乐,等.益安回生口服液治疗海洛因依赖临床疗效观察[J].实用中西医结合临床,2005,5(3)：15-16
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