硝酸异山梨酯缓释微丸的研究
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摘要
硝酸异山梨酯(Isosorbide Dinitrate,ISDN)属于有机硝酸酯类药物,临床上主要用于预防和治疗心绞痛以及充血性心力衰竭。本品口服后吸收完全,但是有显著的肝脏首过效应,血浆半衰期为30～60min。因为显著的首过效应和短的半衰期,硝酸异山梨酯更适合制成缓释制剂,ISDN缓释制剂的吸收相显著延长,达峰时间推后,峰浓度较低,血浆中ISDN及其代谢物的浓度随时间变化平缓,其血液动力学效应表现较平稳,可避免普通制剂的“爆破性释放”引起的病人不适,而且ISDN缓释制剂可减少用药次数,使患者依从性更好。
建立高效液相色谱法测定硝酸异山梨酯的药物浓度,用于微丸中药物的含量测定及释放度测定,经方法学验证,适用于本品的体外质量控制。处方前研究表明:硝酸异山梨酯在水、pH1.2盐酸溶液、pH2.0盐酸溶液、pH 4.0、pH 5.8、pH 6.8、pH 7.8的溶液中溶解度分别为538.6、557.7、554.6、486.3、506.4、502.6、514.2μg·mL~(-1),微溶;在正辛醇/介质系统的表观油/水分配系数为8.12-11.98范围内,表明本品脂溶性较大。
用国产离心造粒机,采用粉末层积法制备硝酸异山梨酯微丸。通过处方筛选和工艺因素考察,优化了处方及操作参数,结果目标粒径24～28目的微丸收率90%以上,药物含量约9%,微丸收率和主药含量均达到预期目标。
分别采用Eudragit NE30D水分散体、Eudragit RS 30D和Eudragit RL 30D水分散体混合液作为包衣材料,以流化床悬浮包衣法对硝酸异山梨酯微丸(离心造粒法制备)进行缓释包衣。以释放度为指标,对包衣增重、抗静电剂、致孔剂、抗粘剂、增塑剂、包衣液浓度、热处理时间等因素进行考察。通过以上因素考察,确定了以Eudragit RS 30D和Eudragit RL 30D水分散体混合液作为包衣材料,其包衣处方为RS:RL配比为4:1,按增重5%包衣,表面活性剂SDS为0.5%,增塑剂柠檬酸三乙酯用量为20%,包衣液浓度为15%,40℃热处理24小时。结果表明,缓释微丸体外释药具有明显的缓释特征,释放机制接近Higuchi释药模型。
采用挤出滚圆法,以硬脂酸、十八醇、卡波姆、HPMC(K4M)为骨架材料制备了硝酸异山梨酯微丸,经处方筛选及工艺考察,都达不到理想释放。
建立了HPLC-UV法测定家犬体内血药浓度的方法,以市售普通片(规格:5mg)为参比,进行了缓释微丸在家犬体内的药动学和相对生物利用度研究,受试制剂(T)及参比制剂的Cmax分别为2.74mg·L~(-1)和4.21mg·L~(-1);Tmax为6h和3h,相对生物利用度为101.12%。结果表明,T有很好的缓释效果,生物等效性和参比制剂一致。
Isosorbide Dinitrate(ISDN)was organic nitrate drug,it was used to treat and prevent angina and congestive cardiac failure(CCF)in clinical.It was absorbed completely after oral administration,but there was obvious first pass effect.The half-life in plasma was about 30-60min, so it was suitable to be made sustained-release preparation.The absorption phase of ISDN was delayed and peak time was significantly prolonged.The peak concentration was lower.The concentration of ISDN and its metabolites in plasma changed gradually with the time elapse.
An HPLC method was set to assay the ISDN as well as to determine the release of ISDN in sustained release pellets.The preformulation results showed that ISDN was slightly soluble in pure water and various pH media(pH1.2,pH2.0,pH4.0,pH5.8,pH6.8 and pH7.8),the solubility was 538.6,557.7,554.6,486.3,506.4,502.6 and 514.2μg·mL~(-1),respectively.The apparent partition coefficiency in n-octanol/aqueous system was 8.12～11.98.It showed that ISDN was a high lipophilic drug.
ISDN pellets were prepared by powder superimpose with a domestic centrifugal granulation equipment.After the formulation screening and process evaluation,it was discovered that the yield of the objective pellets,24-28 mesh cut,was more than 90%and the average content of ISDN was about 9%.The results showed the preparation process and the content of ISDN pellets can reach the expected goals.
The coating formula composed of Eudragit NE30D,Eudragit RL 30D and Eudragit RS 30D mixture,respectively,were adopted for the coating of the pellets(powder layering method)by a fluid-bed.The coating level,anti-static agent,pore-forming agent,anti-tacking agent,plasticizers and curing time,as well as proportion of Eudragit RL 30D to Eudragit RS 30D were studied. Eudragit RL 30D and Eudragit RS 30D was selected for the excellent drug release character and convenient progress.Thus,the ISDN formulation was as follows:the solid copolymer in the coating suspension was 15%,the ratio of Eudragit RS 30D to Eudragit RL 30D was 4:1.The amount of SDS was 0.5%,the amount of TEC was 20%.The final product was underwent a 24 h curing period in a 40℃oven.The results demonstrated that the coated pellets showed obviously sustained-release effect,and the drug release profiles in vitro followed Higuchi kinetics.
The sustained-release pellets were also prepared by extrution-spheronization method.ISDN together with stearic acid,octadecyl alcohol,carbomer and HPMC(K4M)was investigated.The matrix pellets cannot reach the expected goals
An HPLC -UV method was established to monitor the plasma concentration in dogs.The plasma concentration of ISDN in dogs were tested after a single oral administration of sustained-release pellets(T)and commercial tablets(5mg/tablet)as a reference preparation.The C_(max),of T and commercial tablets were 2.74mg·L~(-1)and 4.21mg·L~(-1);The T_(max)of T and commercial tablets were 6 h and 3 h,respectively.Compared with commercial tablets,the relative bioavailability was 101.12%.The results showed that T and commercial tablets were bioequivalent.
建立高效液相色谱法测定硝酸异山梨酯的药物浓度,用于微丸中药物的含量测定及释放度测定,经方法学验证,适用于本品的体外质量控制。处方前研究表明:硝酸异山梨酯在水、pH1.2盐酸溶液、pH2.0盐酸溶液、pH 4.0、pH 5.8、pH 6.8、pH 7.8的溶液中溶解度分别为538.6、557.7、554.6、486.3、506.4、502.6、514.2μg·mL~(-1),微溶;在正辛醇/介质系统的表观油/水分配系数为8.12-11.98范围内,表明本品脂溶性较大。
用国产离心造粒机,采用粉末层积法制备硝酸异山梨酯微丸。通过处方筛选和工艺因素考察,优化了处方及操作参数,结果目标粒径24～28目的微丸收率90%以上,药物含量约9%,微丸收率和主药含量均达到预期目标。
分别采用Eudragit NE30D水分散体、Eudragit RS 30D和Eudragit RL 30D水分散体混合液作为包衣材料,以流化床悬浮包衣法对硝酸异山梨酯微丸(离心造粒法制备)进行缓释包衣。以释放度为指标,对包衣增重、抗静电剂、致孔剂、抗粘剂、增塑剂、包衣液浓度、热处理时间等因素进行考察。通过以上因素考察,确定了以Eudragit RS 30D和Eudragit RL 30D水分散体混合液作为包衣材料,其包衣处方为RS:RL配比为4:1,按增重5%包衣,表面活性剂SDS为0.5%,增塑剂柠檬酸三乙酯用量为20%,包衣液浓度为15%,40℃热处理24小时。结果表明,缓释微丸体外释药具有明显的缓释特征,释放机制接近Higuchi释药模型。
采用挤出滚圆法,以硬脂酸、十八醇、卡波姆、HPMC(K4M)为骨架材料制备了硝酸异山梨酯微丸,经处方筛选及工艺考察,都达不到理想释放。
建立了HPLC-UV法测定家犬体内血药浓度的方法,以市售普通片(规格:5mg)为参比,进行了缓释微丸在家犬体内的药动学和相对生物利用度研究,受试制剂(T)及参比制剂的Cmax分别为2.74mg·L~(-1)和4.21mg·L~(-1);Tmax为6h和3h,相对生物利用度为101.12%。结果表明,T有很好的缓释效果,生物等效性和参比制剂一致。
Isosorbide Dinitrate(ISDN)was organic nitrate drug,it was used to treat and prevent angina and congestive cardiac failure(CCF)in clinical.It was absorbed completely after oral administration,but there was obvious first pass effect.The half-life in plasma was about 30-60min, so it was suitable to be made sustained-release preparation.The absorption phase of ISDN was delayed and peak time was significantly prolonged.The peak concentration was lower.The concentration of ISDN and its metabolites in plasma changed gradually with the time elapse.
An HPLC method was set to assay the ISDN as well as to determine the release of ISDN in sustained release pellets.The preformulation results showed that ISDN was slightly soluble in pure water and various pH media(pH1.2,pH2.0,pH4.0,pH5.8,pH6.8 and pH7.8),the solubility was 538.6,557.7,554.6,486.3,506.4,502.6 and 514.2μg·mL~(-1),respectively.The apparent partition coefficiency in n-octanol/aqueous system was 8.12～11.98.It showed that ISDN was a high lipophilic drug.
ISDN pellets were prepared by powder superimpose with a domestic centrifugal granulation equipment.After the formulation screening and process evaluation,it was discovered that the yield of the objective pellets,24-28 mesh cut,was more than 90%and the average content of ISDN was about 9%.The results showed the preparation process and the content of ISDN pellets can reach the expected goals.
The coating formula composed of Eudragit NE30D,Eudragit RL 30D and Eudragit RS 30D mixture,respectively,were adopted for the coating of the pellets(powder layering method)by a fluid-bed.The coating level,anti-static agent,pore-forming agent,anti-tacking agent,plasticizers and curing time,as well as proportion of Eudragit RL 30D to Eudragit RS 30D were studied. Eudragit RL 30D and Eudragit RS 30D was selected for the excellent drug release character and convenient progress.Thus,the ISDN formulation was as follows:the solid copolymer in the coating suspension was 15%,the ratio of Eudragit RS 30D to Eudragit RL 30D was 4:1.The amount of SDS was 0.5%,the amount of TEC was 20%.The final product was underwent a 24 h curing period in a 40℃oven.The results demonstrated that the coated pellets showed obviously sustained-release effect,and the drug release profiles in vitro followed Higuchi kinetics.
The sustained-release pellets were also prepared by extrution-spheronization method.ISDN together with stearic acid,octadecyl alcohol,carbomer and HPMC(K4M)was investigated.The matrix pellets cannot reach the expected goals
An HPLC -UV method was established to monitor the plasma concentration in dogs.The plasma concentration of ISDN in dogs were tested after a single oral administration of sustained-release pellets(T)and commercial tablets(5mg/tablet)as a reference preparation.The C_(max),of T and commercial tablets were 2.74mg·L~(-1)and 4.21mg·L~(-1);The T_(max)of T and commercial tablets were 6 h and 3 h,respectively.Compared with commercial tablets,the relative bioavailability was 101.12%.The results showed that T and commercial tablets were bioequivalent.
引文
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[3]赵胜乾,吴敏.冠心病的药物治疗与进展.现代诊断与治疗,2003,Jan 14(1):26-27.
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[6]姜晓梅,王一尘.硝酸酯药物临床应用新进展.中国综合临床,2005,21(9):859-860.
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[2]刘旭杰,张兴华.青年冠心病进展.心血管病学进展,2006,27(6):756-759.
[3]赵胜乾,吴敏.冠心病的药物治疗与进展.现代诊断与治疗,2003,Jan 14(1):26-27.
[4]徐炽度.冠心病心绞痛治疗的进展.现代诊断与治疗,1997,Jan 8(1):1-3.
[5]孙宝贵,陈雄.硝酸酯临床应用的新进展.国外医学·心血管疾病分册,2002,29(4):245-248.
[6]姜晓梅,王一尘.硝酸酯药物临床应用新进展.中国综合临床,2005,21(9):859-860.
[7]李静,程务本.硝酸异山梨酯缓释剂的作用机制、耐药性及临床应用.中国临床药学杂志,1998,7(2):93-98.
[8]陈在嘉,高润霖主编.冠心病.北京:人民卫生出版社,2002年第1版.
[9]中华人民共和国药典委员会.中国药典2005版二部.北京:化学工业出版社,2005:709.
[10]陈盛君,朱家壁.缓控释微丸制剂的研究进展.国外医学药学分册,2004,31(3):177-181.
[11]崔福德主编.药物的新剂型(2002年第1版).中国医药科技出版社,532-535.
[12]平其能主编.现代药剂学(第一版).中国医药科技出版社,1998,13.
[13]郑俊民主编.经皮给药新剂型.北京人民卫生出版社,1997,255.
[14]常翠,杨宏图,董淳等.缓释控释制剂的释放度测定方法的研究进展.广东药学,2003,13(2):16-18
[15]屠锡德主编.生物药剂学.中国医药科技出版社,1998,21-22.
[16]Isaac Ghebre-Sellassie.Pharmaceutical Pelletization Technology M.New York:Marcel Dekker Inc,1989.101-143
[17]Nesbitt R.U,Mahijour Mas jid,Nancy L mills,et al.Effect of substract on mass release from ethylcellulose latex coated pellest J.J Control Release,1994,32(1):71-77
[18]朴尤奎.离心造粒机的半自动论.中国药学杂志,1990,25(4):34-37
[19]Isaac Ghebre-Sellassie.Pharmaceutical Pelletization Technology M.New York:Marcel Dekker Inc,1989.145-185
[20]王文刚,崔光华,傅宏义等.离心制粒工艺制备微晶纤维素空白丸的研究.解放军药学学报,2002,18(5):268-271,320
[21]于巧玲,唐星,孙欣等.离心造粒法制备微晶纤维素空白丸核的工艺研究,沈阳药科大学学报,2002,19(6):398-402.
[22]陆斌主编.药物新剂型与新技术.人民卫生出版社,1998.
[23]汪芸,姜洪芳,王国华.微丸的成型性研究进展.江西中医学院学报,2002,14(1):59-60.
[24]Isaac Ghebre-Sellassie.Pharmaceutical Pelletization Technology M.New York:Marcel Dekker Inc,1989.130-133.
[25]罗姆公司.药用聚合物尤特奇(Eudragit).P2-7,17-26.
[26]Jeffrey WM,Henry HF.Mathematical comparison of dissolution profiles.Pharm Tech,1996,20(6):64-74.
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