口服茶碱两次脉冲定时释药微丸的制备与评价
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摘要
随着时间生物学和时辰药理学研究的不断深入，逐渐认识到人体的许多生理现象如血压、心率、胃酸分泌、激素分泌以及某些疾病如心绞痛、高血压、哮喘、风湿性关节炎的发生发作均具有明显的节律性。以此为基础设计的脉冲释药系统根据疾病发作规律释放药物，通过按需给药达到最佳治疗。本文以茶碱为模型药制备一日口服1次的茶碱两次不等剂量脉冲释药微丸，两次释药时间分别是上午和晚上，剂量分别是35mg和65mg。
采用紫外分光光度法，建立了茶碱制剂的含量和体外释放度的测定方法。经方法学验证，适用于该品体外控制。采用高效液相色谱法，建立了犬体内茶碱血药浓度的测定方法，方法回收率为87.16％。此法简便、灵敏、准确，可以满足体内分析的要求。
本制剂由五部分组成：从内向外依次为载药丸芯、溶胀层、控释层、含药衣层、普通薄膜衣。载药丸芯通过挤出滚圆法制得。
用流化床包衣技术，以水溶胀性材料交联羧甲基纤维素钠(CCNa)为内包衣溶胀层，乙基纤维素水分散体(Surelease(?)E-7-19010)为外包衣控释层制备第二次脉冲释药微丸，并考察溶胀层种类、溶胀层和控释层包衣增重、溶出介质pH值和微丸粒径等对药物释放的影响。研究结果表明溶胀层和控释层包衣增重和微丸粒径等对第二剂量脉冲释药微丸的释药时滞和释药速率均具有显著影响，但不受溶出介质pH值的影响；随着溶胀层厚度的增加，释药时滞有一定程度的缩短；控释层厚度增加，可显著延长时滞。根据以上结果，最终选择交联羧甲基纤维素钠(CCNa)作为溶胀层材料，Surelease作为控释层材料，采用全面试验设计对处方进行优化，得最优处方为：CCNa增重为28％，Surelease增重为30％。此处方的时滞为8h，时滞后3h释药达80％以上。质量考察结果表明，第二次脉冲释药微丸对高温、高湿敏感。
对所制得的第二次脉冲释药微丸再进行包衣，即在其外层继续包上茶碱层和普通薄膜衣制备两次脉冲释药微丸。茶碱层含药量，即为第一次脉冲剂量，载药丸芯的含药量即为第二次脉冲剂量。考察了微丸中第一剂量茶碱的体外溶出度和含量均匀度及两次脉冲释药微丸体外溶出度。结果表明药层增重33.98％，薄膜衣增重3％，两次脉冲释药微丸中的第一脉冲释药在45min内能够达到理想的溶出度，其含量均匀度符合要求，第二剂量脉冲释药时滞为8.5h，时滞后3h释药达到80％以上。进一步的实验表明药层和普通薄膜衣对茶碱第二次脉冲释药速率几乎没有影响，只是时滞延长了0.5h。
采用自身交叉给药方案对茶碱两次脉冲释药微丸(受试制剂)和市售缓释片(参比制剂)进行了犬体内药动学考察，结果表明茶碱两次脉冲释药微丸，其第一和第二次脉冲释药在体内时滞分别为0.5h和10.0h；释药达峰时间分别是1.5h和14h。相对生物利用度为110％。
综上所述，制备茶碱两次脉冲定时释药微丸可行，且可以满足临床治疗的特殊需要。
With the continual development of chronobiology and chrono-pharmacology , it is realized that circadian rhythms exist in many physiological phenomena such as blood pressure, heart-beat rate, gastric acid secretion, hormone secretion and the occurrence of some diseases such as angina, hypertension, asthma, rheumatoid arthritis and so on. On the bases of it, pulsed release drag delivery system was designed to release drug according to the rhythms of occurrence of diseases and achieves an effective drug level at the required time so that optimum therapy can be obtain. Theophylline as the model drug was prepared the twice pulsed release pellets (PRP). Its doses were 35mg, and 65mg respectively.Ultraviolet spectrophotomatry method was developed for assay during the study of content and drug release. The method was monitored by methodology and was simple, accurate to be used in vitro. Precise and reliable High performance liquid chromatography (HPLC) method was was applied to quantify the drug plasma concentration of dogs. The extraction recovery of theophylline was 87.16%.The twice PRP consist of five laminar layers from the center to the outside: the core, the swelling agent layer ,the controlled layer, the drug layer and the normal coating materials. Theophylline-loaded core pellets were prepared by extrusion-spheronization technology. The second PRP were prepared with croscarmellose sodium (CCNa) as the inner swelling layer and ethylcellulose aqueous dispersion (Surelease) as the controlled layer. The influences of the coating material of the swelling layer, the coating level of the swelling layer, the controlled layer, the pH values of the media and the size of final pellets on the release of theophylline from the second PRP were investigated respectively. The results showed that the release behavior was influenced by the types and the amount of the swelling layer, the size of pellets and the amount of the controlled layer. For the pellets with the core pellet between 20 and 24 mesh , a 28% CCNa coating level and 30% Surelease coating level, the release in vitro was initiated after a lag time of 8h in water and the accumulative percent released more than 80% within the following 3h, which showed better pulsed release when compared to core pellets. The pellets were sensitive to high temperature and high humidity.
The second PRP were further coated to prepare the first PRP with the drug layer(the first dose) and the normal coating material, the twice PRP is 33.98%the drug coating level and 3% the normal coating level. The results showed that theophylline of the first dose could dissolute completely within 30 min in vitro and content uniformity of it was ideal. After the lag time of 8.5h, the drug of the second dose release from twice PRP was more than 80% within the following 3 h.
The behavior in vivo of the pellets was evaluated in three dogs after a oral administration of single dose of sustained-release tablet on sale(reference formulation) or the twice pulsed release pellets (test formulation). T_(max) of the first dose and second dose were 1.5h and 14.0h respectively relative bioavailability was 110%.
In conclusion, the preparation of the twice PRP of theophylline was feasible and could fulfill the specific needs of clinical therapy.
采用紫外分光光度法，建立了茶碱制剂的含量和体外释放度的测定方法。经方法学验证，适用于该品体外控制。采用高效液相色谱法，建立了犬体内茶碱血药浓度的测定方法，方法回收率为87.16％。此法简便、灵敏、准确，可以满足体内分析的要求。
本制剂由五部分组成：从内向外依次为载药丸芯、溶胀层、控释层、含药衣层、普通薄膜衣。载药丸芯通过挤出滚圆法制得。
用流化床包衣技术，以水溶胀性材料交联羧甲基纤维素钠(CCNa)为内包衣溶胀层，乙基纤维素水分散体(Surelease(?)E-7-19010)为外包衣控释层制备第二次脉冲释药微丸，并考察溶胀层种类、溶胀层和控释层包衣增重、溶出介质pH值和微丸粒径等对药物释放的影响。研究结果表明溶胀层和控释层包衣增重和微丸粒径等对第二剂量脉冲释药微丸的释药时滞和释药速率均具有显著影响，但不受溶出介质pH值的影响；随着溶胀层厚度的增加，释药时滞有一定程度的缩短；控释层厚度增加，可显著延长时滞。根据以上结果，最终选择交联羧甲基纤维素钠(CCNa)作为溶胀层材料，Surelease作为控释层材料，采用全面试验设计对处方进行优化，得最优处方为：CCNa增重为28％，Surelease增重为30％。此处方的时滞为8h，时滞后3h释药达80％以上。质量考察结果表明，第二次脉冲释药微丸对高温、高湿敏感。
对所制得的第二次脉冲释药微丸再进行包衣，即在其外层继续包上茶碱层和普通薄膜衣制备两次脉冲释药微丸。茶碱层含药量，即为第一次脉冲剂量，载药丸芯的含药量即为第二次脉冲剂量。考察了微丸中第一剂量茶碱的体外溶出度和含量均匀度及两次脉冲释药微丸体外溶出度。结果表明药层增重33.98％，薄膜衣增重3％，两次脉冲释药微丸中的第一脉冲释药在45min内能够达到理想的溶出度，其含量均匀度符合要求，第二剂量脉冲释药时滞为8.5h，时滞后3h释药达到80％以上。进一步的实验表明药层和普通薄膜衣对茶碱第二次脉冲释药速率几乎没有影响，只是时滞延长了0.5h。
采用自身交叉给药方案对茶碱两次脉冲释药微丸(受试制剂)和市售缓释片(参比制剂)进行了犬体内药动学考察，结果表明茶碱两次脉冲释药微丸，其第一和第二次脉冲释药在体内时滞分别为0.5h和10.0h；释药达峰时间分别是1.5h和14h。相对生物利用度为110％。
综上所述，制备茶碱两次脉冲定时释药微丸可行，且可以满足临床治疗的特殊需要。
With the continual development of chronobiology and chrono-pharmacology , it is realized that circadian rhythms exist in many physiological phenomena such as blood pressure, heart-beat rate, gastric acid secretion, hormone secretion and the occurrence of some diseases such as angina, hypertension, asthma, rheumatoid arthritis and so on. On the bases of it, pulsed release drag delivery system was designed to release drug according to the rhythms of occurrence of diseases and achieves an effective drug level at the required time so that optimum therapy can be obtain. Theophylline as the model drug was prepared the twice pulsed release pellets (PRP). Its doses were 35mg, and 65mg respectively.Ultraviolet spectrophotomatry method was developed for assay during the study of content and drug release. The method was monitored by methodology and was simple, accurate to be used in vitro. Precise and reliable High performance liquid chromatography (HPLC) method was was applied to quantify the drug plasma concentration of dogs. The extraction recovery of theophylline was 87.16%.The twice PRP consist of five laminar layers from the center to the outside: the core, the swelling agent layer ,the controlled layer, the drug layer and the normal coating materials. Theophylline-loaded core pellets were prepared by extrusion-spheronization technology. The second PRP were prepared with croscarmellose sodium (CCNa) as the inner swelling layer and ethylcellulose aqueous dispersion (Surelease) as the controlled layer. The influences of the coating material of the swelling layer, the coating level of the swelling layer, the controlled layer, the pH values of the media and the size of final pellets on the release of theophylline from the second PRP were investigated respectively. The results showed that the release behavior was influenced by the types and the amount of the swelling layer, the size of pellets and the amount of the controlled layer. For the pellets with the core pellet between 20 and 24 mesh , a 28% CCNa coating level and 30% Surelease coating level, the release in vitro was initiated after a lag time of 8h in water and the accumulative percent released more than 80% within the following 3h, which showed better pulsed release when compared to core pellets. The pellets were sensitive to high temperature and high humidity.
The second PRP were further coated to prepare the first PRP with the drug layer(the first dose) and the normal coating material, the twice PRP is 33.98%the drug coating level and 3% the normal coating level. The results showed that theophylline of the first dose could dissolute completely within 30 min in vitro and content uniformity of it was ideal. After the lag time of 8.5h, the drug of the second dose release from twice PRP was more than 80% within the following 3 h.
The behavior in vivo of the pellets was evaluated in three dogs after a oral administration of single dose of sustained-release tablet on sale(reference formulation) or the twice pulsed release pellets (test formulation). T_(max) of the first dose and second dose were 1.5h and 14.0h respectively relative bioavailability was 110%.
In conclusion, the preparation of the twice PRP of theophylline was feasible and could fulfill the specific needs of clinical therapy.
引文
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[2] Lemmer B. Circadian rhythms and drug delivery [J]. J Controlled Release, 1991, 16(1-2): 63-67.
[3] Junginger HG. Oral Applications of Pulsatile Delivery [A]. Pulsatile Drug Delivery—Current Application and Futures Trends[C]. Stuttgart: Wissenschaftliche Verlagsgesellschaft, 1993, 113-134.
[4] Lemmer B. implication of chronopharmacokinetics for drug delivery antiasthmatics, H_2-blockers and cardiovascular active drug[J]. Adv Drug Delivery Rev, 1991, 6(1): 83-100.
[5] 刘强，朱红霞．脉冲释药系统研究进展[J]．第一军医大学学报，2001，21(3)228-229；231．
[6] Vyas SP, Sood A, Venugopalan P, et al. circadian rhythm and drug delivery design [J]. Pharmazie, 1997, 52(11): 815-820.
[7] Ueda S, Yamaguehi H, Kotani M, et al. Development of a Novel Drug Release System, Time-Controlled Explosion System (TES). Ⅱ. Design of Multiparticulate TES and in vitro Drug Release Properties [J]. Chem Pharm Bull, 1994, 42(2): 359-363.
[8] Nadsawa S, Nagata M, Hirakawa Y, et al. An organic acid-induced sigmoidal release systerm for oral controlled-release preparations. Ⅲ. Elucidation of the anomalous drug release behavior through osmotic pumping mechanism [J]. Int J Pharm, 1997, 148(1): 85-91.
[9] Bethke K K, Fischer W. Development of a multiple unit drug delivery system for positioned release in the gastrointestinal tract [J]. J Contr Rel, 1991, 15(2): 105.
[10] Barnes PJ. Jonsson B, Klim JB.The costs of asthma. Eur Respir [J]. 1996, 9: 636.
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