pH依赖型冠心苏合缓释微丸的研究
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摘要
冠心苏合丸为中国药典2000年版一部收载品种，由苏合香、冰片、
青木香、檀香、乳香等五味药组成，具有理气宽胸，散瘀化浊，通窍止
痛的功效，临床上主要用于以气滞为主要病变之心绞痛，胸闷等症。本
文选用该药作为复方中药制剂的模型药物，设计并研制了pH依赖型缓
释胶囊，其目的是使中药中的复杂成分在体内同时按比例释放，从而发
挥中药的综合治疗作用，保持中药治疗的特色。
采用TLC法对方中的苏合香、乳香进行定性鉴别；采用HPLC法进
行了指标性成分桂皮酸的含量测定，并建立了人体血浆中桂皮酸血药浓
度的测定方法；采用GC法进行了冰片的含量测定。
为制备该复方的新剂型，研究了原处方中各药材有效部位的科学制
备工艺。以药效学试验为指标，分别对原药材进行了多种处理工艺的比
较：（1）采用β-环糊精对处方药材中的苏合香、冰片进行了包合，对青
木香采用醇提法，并通过喷雾干燥技术制备了青木香醇提物的固体粉
末；檀香油的提取采用水蒸汽蒸馏法；乳香提取挥发油后，残渣继续提
取得到浸膏；（2）苏合香、冰片、青木香、檀香的处理同前，乳香不经
提取，而在超低温下粉碎，直接入药；（3）苏合香、冰片的处理同前，
青木香、檀香、乳香混合提取挥发油，提取液制成浸膏。结果表明，第
三种工艺制得的精制中间品药效最强。对乳香挥发油的β-环糊精最佳包
结工艺进行研究，通过均匀设计法进行了工艺优化。包合物对原材料的
性质有不同程度的改善，不仅使液体药物粉末化，而且对溶解度、溶出
速度也有提高，从而为下一步的制剂工艺提供了基础。
以淀粉为填充剂，3％HPMC水溶液作为粘合剂，采用离心造粒法制
备了冠心苏合微丸，结果发现主机转盘转速、粘合剂的加入速度和加入
量以及供粉速率对成丸过程影响较大，通过对各因素的考察，确定制备
工艺，可制得表面较为光滑，圆整度较高的中药微丸，其18～20目粒
径的微丸收率可达80％以上。
以LE包衣材料、pH依赖型包衣材料HPMCP55和丙烯酸树脂Ⅱ号
沈阳药科大学硕士学位论文 摘 要
对微丸进行包衣，制备了3种包衣微丸，通过对溶出度的考察，发现包
衣增重量、阻滞剂（EC）的加入量对微丸的释放影响较大，采用正交设
计对含HPMCP55及丙烯酸树脂11号的处方进行了优化。将3种微丸混
合装入胶囊，服用后，随着胃肠道pH的变化，可分别在胃、十二指肠
和小肠中末端溶解释药，达到速效、长效、高效的目的。
以桂皮酸和冰片的含量变化为指标，对冠心苏合pH依赖型梯度释
药微丸进行了稳定性考察，结果发现，微丸中桂皮酸和冰片具有很高的
稳定性。可见我们采用的制备工艺基本上解决了药材中易挥发性成分不
稳定的问题。
健康志愿者口服“冠心苏合丸”、“冠心苏合缓释胶囊”后，桂皮酸
的血药浓度测定结果表明，桂皮酸体内过程呈双隔室模型，“冠心苏合
缓释胶囊”的 Cm删 Tm。分别为 88．20 ＂g／thl、0．25 hr，与市售“冠，O苏
合丸”相比，其达峰时间Tin。稍快，Cm。明显降低，非隔室模型分析的
统计矩参数也表明，其在体内的平均滞留时间（AlU’）比“冠心苏合丸”
延长，缓释效果好。药时曲线表明，“冠心苏合缓释胶囊”能在体内呈
现出梯度释药特征。
Guanxin Suhe Wan, listed in first section of the 2000's edition of
"Pharmacopeia of the People's Republic of China" consists of Styrax,
Borneolum, Olbanum, Radix aristolochiae and Lignum santali albi. It is
primarily applied to the treatment of chest distress, angina pectoris and
myocardial infarction caused by coronary heart. In this thesis, Guanxin Suhe
Wan was selected as the model drug of Traditional Chinese medicinal
compound recipe (TCMCR). In order to make it possible that various
components with great different properties in TCMCR are released
synchronously, Guanxin Suhe delayed-release capsules, which consists of
three kinds of pH-dependent gradient-release pellets were investigated.
TLC methods were used to identify Styrax, Olibanum. HPLC method
for cinnamic acid, GC method for bomeol were developed to determine their
contents in preparations. The concentration of cinnamic acid in human
plasma was assayed by HPLC method with IJV detector.
The index of pharmacodynamics was adopted to research three kinds of
preparation techniques of fine intermediate product: (1) Radix aristolochiae
was extracted with 80% alcohol, the spray drying technique was used to dry
extract of Radix aristolochiae in liquid state; Water steam distillation was
applied to extract the Santal oil and Olibanum oil; The beta-cyclodextrin
inclusion of Borneol and Styrax were formulated; (2) The preparation of
Styrax, Bomeol, Radix aristolochiae and Lignum santali albi were the same
as above, Olibanum was comminuted without extracting at super low
temperature; (3) The preparation of Styrax, Bomeol were the same as above,
Radix aristolochiae, Olibanum and Lignum santali albi were mixed and
extracted together. The results showed that the third technique was best.
The beta-cyclodextrin inclusion of Olibanum oil was formulated and
optimized by uniform design. Compared with mixture, the solubility and the
dissolution rate of inclusion complexes were remarkably increased.
The Guanxin Suhe pellets were prepared in a centrifugal granulator by
using starch as filler and 3% HPMC solution as adhesive agent. The added
speed of adhesive agent and powder feeding rate were found to have
significant influences on palletizing process. Under the optimum conditions,
the pellets prepared have perfect shape and surface characteristics and the
yield of 1 &"0 mesh pellets could reach to above 80%.
A self-designed mini-fluidized bed spray coater was made for the
coating pellets. A pH-dependent delayed-release pellet system was parepared
by coating with LE, HPMCP55 and Endragit II as coating material. The
above three kinds of coating pellets were designed to release drug in stomach,
duodenum and jejunum or ileum, respectively.
The results of stability experiments showed that cirmamic acid and
borneol in Guanxin Suhe pH-dependent delayed-release coated pellets
toward heat, humidity and light were stable. It was verified that the stability
problems of volatile components have been settled by the preparing
technology applied in formulations.
The plasma concentration of cinnamic acid in three healthy volunteers
after a single oral administration of "Guanxin Suhe delayed-release capsule"
was studied with "Guanxin Suhe Wan"as a reference preparation. The
concentration-time curves of cinnamic acid of "Guanxin Suhe Wan"fit in
two-compartment model. Cmax, Tmax of "Guanxin Suhe delayed-release
capsule"were 88.20 ng/nil, 0.25 hr, respectively. Compared with
青木香、檀香、乳香等五味药组成，具有理气宽胸，散瘀化浊，通窍止
痛的功效，临床上主要用于以气滞为主要病变之心绞痛，胸闷等症。本
文选用该药作为复方中药制剂的模型药物，设计并研制了pH依赖型缓
释胶囊，其目的是使中药中的复杂成分在体内同时按比例释放，从而发
挥中药的综合治疗作用，保持中药治疗的特色。
采用TLC法对方中的苏合香、乳香进行定性鉴别；采用HPLC法进
行了指标性成分桂皮酸的含量测定，并建立了人体血浆中桂皮酸血药浓
度的测定方法；采用GC法进行了冰片的含量测定。
为制备该复方的新剂型，研究了原处方中各药材有效部位的科学制
备工艺。以药效学试验为指标，分别对原药材进行了多种处理工艺的比
较：（1）采用β-环糊精对处方药材中的苏合香、冰片进行了包合，对青
木香采用醇提法，并通过喷雾干燥技术制备了青木香醇提物的固体粉
末；檀香油的提取采用水蒸汽蒸馏法；乳香提取挥发油后，残渣继续提
取得到浸膏；（2）苏合香、冰片、青木香、檀香的处理同前，乳香不经
提取，而在超低温下粉碎，直接入药；（3）苏合香、冰片的处理同前，
青木香、檀香、乳香混合提取挥发油，提取液制成浸膏。结果表明，第
三种工艺制得的精制中间品药效最强。对乳香挥发油的β-环糊精最佳包
结工艺进行研究，通过均匀设计法进行了工艺优化。包合物对原材料的
性质有不同程度的改善，不仅使液体药物粉末化，而且对溶解度、溶出
速度也有提高，从而为下一步的制剂工艺提供了基础。
以淀粉为填充剂，3％HPMC水溶液作为粘合剂，采用离心造粒法制
备了冠心苏合微丸，结果发现主机转盘转速、粘合剂的加入速度和加入
量以及供粉速率对成丸过程影响较大，通过对各因素的考察，确定制备
工艺，可制得表面较为光滑，圆整度较高的中药微丸，其18～20目粒
径的微丸收率可达80％以上。
以LE包衣材料、pH依赖型包衣材料HPMCP55和丙烯酸树脂Ⅱ号
沈阳药科大学硕士学位论文 摘 要
对微丸进行包衣，制备了3种包衣微丸，通过对溶出度的考察，发现包
衣增重量、阻滞剂（EC）的加入量对微丸的释放影响较大，采用正交设
计对含HPMCP55及丙烯酸树脂11号的处方进行了优化。将3种微丸混
合装入胶囊，服用后，随着胃肠道pH的变化，可分别在胃、十二指肠
和小肠中末端溶解释药，达到速效、长效、高效的目的。
以桂皮酸和冰片的含量变化为指标，对冠心苏合pH依赖型梯度释
药微丸进行了稳定性考察，结果发现，微丸中桂皮酸和冰片具有很高的
稳定性。可见我们采用的制备工艺基本上解决了药材中易挥发性成分不
稳定的问题。
健康志愿者口服“冠心苏合丸”、“冠心苏合缓释胶囊”后，桂皮酸
的血药浓度测定结果表明，桂皮酸体内过程呈双隔室模型，“冠心苏合
缓释胶囊”的 Cm删 Tm。分别为 88．20 ＂g／thl、0．25 hr，与市售“冠，O苏
合丸”相比，其达峰时间Tin。稍快，Cm。明显降低，非隔室模型分析的
统计矩参数也表明，其在体内的平均滞留时间（AlU’）比“冠心苏合丸”
延长，缓释效果好。药时曲线表明，“冠心苏合缓释胶囊”能在体内呈
现出梯度释药特征。
Guanxin Suhe Wan, listed in first section of the 2000's edition of
"Pharmacopeia of the People's Republic of China" consists of Styrax,
Borneolum, Olbanum, Radix aristolochiae and Lignum santali albi. It is
primarily applied to the treatment of chest distress, angina pectoris and
myocardial infarction caused by coronary heart. In this thesis, Guanxin Suhe
Wan was selected as the model drug of Traditional Chinese medicinal
compound recipe (TCMCR). In order to make it possible that various
components with great different properties in TCMCR are released
synchronously, Guanxin Suhe delayed-release capsules, which consists of
three kinds of pH-dependent gradient-release pellets were investigated.
TLC methods were used to identify Styrax, Olibanum. HPLC method
for cinnamic acid, GC method for bomeol were developed to determine their
contents in preparations. The concentration of cinnamic acid in human
plasma was assayed by HPLC method with IJV detector.
The index of pharmacodynamics was adopted to research three kinds of
preparation techniques of fine intermediate product: (1) Radix aristolochiae
was extracted with 80% alcohol, the spray drying technique was used to dry
extract of Radix aristolochiae in liquid state; Water steam distillation was
applied to extract the Santal oil and Olibanum oil; The beta-cyclodextrin
inclusion of Borneol and Styrax were formulated; (2) The preparation of
Styrax, Bomeol, Radix aristolochiae and Lignum santali albi were the same
as above, Olibanum was comminuted without extracting at super low
temperature; (3) The preparation of Styrax, Bomeol were the same as above,
Radix aristolochiae, Olibanum and Lignum santali albi were mixed and
extracted together. The results showed that the third technique was best.
The beta-cyclodextrin inclusion of Olibanum oil was formulated and
optimized by uniform design. Compared with mixture, the solubility and the
dissolution rate of inclusion complexes were remarkably increased.
The Guanxin Suhe pellets were prepared in a centrifugal granulator by
using starch as filler and 3% HPMC solution as adhesive agent. The added
speed of adhesive agent and powder feeding rate were found to have
significant influences on palletizing process. Under the optimum conditions,
the pellets prepared have perfect shape and surface characteristics and the
yield of 1 &"0 mesh pellets could reach to above 80%.
A self-designed mini-fluidized bed spray coater was made for the
coating pellets. A pH-dependent delayed-release pellet system was parepared
by coating with LE, HPMCP55 and Endragit II as coating material. The
above three kinds of coating pellets were designed to release drug in stomach,
duodenum and jejunum or ileum, respectively.
The results of stability experiments showed that cirmamic acid and
borneol in Guanxin Suhe pH-dependent delayed-release coated pellets
toward heat, humidity and light were stable. It was verified that the stability
problems of volatile components have been settled by the preparing
technology applied in formulations.
The plasma concentration of cinnamic acid in three healthy volunteers
after a single oral administration of "Guanxin Suhe delayed-release capsule"
was studied with "Guanxin Suhe Wan"as a reference preparation. The
concentration-time curves of cinnamic acid of "Guanxin Suhe Wan"fit in
two-compartment model. Cmax, Tmax of "Guanxin Suhe delayed-release
capsule"were 88.20 ng/nil, 0.25 hr, respectively. Compared with
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