盐酸地尔硫缓释片的制备及体外释放度
作者：何仲贵 唐星 刘峰 高淑琴
单位：何仲贵 唐星 刘峰(沈阳药科大学药学系，沈阳 110015)；高淑琴(北京市门头沟区医院，北京 100230)
关键词：盐酸地尔硫；缓释；羟丙基甲基纤维素
沈阳药科大学学报000501 摘 要 以羟丙基甲基纤维素为凝胶骨架材料，以淀粉-糊精混合物及乳糖为填充剂，采用湿法制粒压片，制备了盐酸地尔硫缓释片，并对其释放度进行了测定.所制备的缓释片在释放90%之前的释放符合Higuchi方程.片剂中羟丙基甲基纤维素的含量及稀释剂的种类与含量对药物的释放速度有较大影响，而压片力对药物的释放速度无明显影响.改变缓释片中羟丙基甲基纤维素的含量及稀释剂的种类可改变药物的释放速度.
分类号 R944.4
The Preparation and in Vitro Release of Sustained-release Diltiazem Hydrochloride Tablets
, http://www.100md.com
He Zhonggui，Tang Xing，Liu Feng，Gao Shuqin
(Department of Pharmacy, Shenyang Pharmaceutical University，Shenyang 110015)
Abstract This article indroduces the preparation method of diltiazem hydrochloride sustained-release tablets. Hydroxypropylmethyl cellulose (HPMC) was used as hydrophilic matrix. Starch dextrin mixture and lactose were used as additives respectively. The tablets were prepared by the wetting granule method, and its release rates were detected. The drug release from the tablets fitted to the Higuchi equation. The content of HPMC and additives in the tablets and different additives had significant influence on release rates, but the compressing force had little influence on the release rate from the tablets. The drug release rate could be changed as the amount of HPMC and the variety of additives changed.
, 百拇医药
Key words diltiazem hydrochloride; sustained-release; hydroxypropylmethyl cellulose
盐酸地尔硫(diltiazem hydrochloride，DTZ)属于钙离子通道阻滞剂，临床上用于治疗心绞痛和高血压等心血管疾病.本品体内半衰期短，目前收入《中国药典》1995年版的盐酸地尔硫缓释片因药物释放速度较快，尚需每日服用3次.国外关于盐酸地尔硫缓释制剂的研究报道较多，并且有多种缓控释制剂上市〔1～3〕.作者以盐酸地尔硫为模型药物，以羟丙基甲基纤维素(HPMC)作为亲水凝胶骨架片的材料，探讨影响药物从片剂中释放的因素及药物释放机制.
1 药品与仪器
1.1 药品
盐酸地尔硫(石家庄制药集团)；羟丙基甲基纤维素(HPMC K15M，上海卡乐康辅料有限公司)；其它为普通药用辅料.
, http://www.100md.com
1.2 仪器
WFZ800—D2紫外可见分光光度计(北京第二光学仪器厂)，ZP19压片机(上海制药机械一厂)；ZRS-智能溶出试验仪(天津大学无线电厂).
2 方法与结果
2.1 盐酸地尔硫缓释片的制备
取盐酸地尔硫(过100目筛)，加入处方量的HPMC及其它稀释剂，混合均匀，用80%乙醇为润湿剂制软材，过16目筛整粒，50℃干燥，干颗粒加1%的硬脂酸镁，混匀后压片即得.每片含盐酸地尔硫60 mg.
2.2 体外释放试验
按《中国药典》1995年版二部转篮法，转速为50 r/min，以pH6.8磷酸盐缓冲液900 mL为释放介质.照分光光度法，加释放介质稀释成每1 mL中含盐酸地尔硫15 μg的溶液，在236 nm波长处测定吸收度.同法取盐酸地尔硫对照品适量，加释放介质定量稀释成每1 mL中约含15 μg的溶液，同法测定吸收度，计算出每片在不同时间的释放量.
, 百拇医药
2.3 片剂中HPMC含量对药物释放的影响
在保持片重为160 mg不变的情况下，研究片剂中含不同量的HPMC K15M对药物释放的影响，实验结果见表1、图1.
Tab.1 Preparation of diltiazem hydrochloride sustained-release tablets with different contents of HPMC Batch No.
DTZ/g
HPMC K15M/g
Additives(dextrin-
starch 11∶3 mixture)
, http://www.100md.com
Content of HPMC in
the preparation/%
1
30
8.0
122.0
5
2
30
16.0
114.0
10
3
, http://www.100md.com
30
24.0
106.0
15
4
30
32.0
98.0
20
5
30
40.0
90.0
, 百拇医药
25
6
30
48.0
82.0
30
Fig.1 The effect of the content of HPMC on the release rate of DTZ sustained-release tablets
1—Content of HPMC is 5%;2—Content of HPMC is 10%;3—Content of HPMC is 15%;4—Content of HPMC is 20%;5—Content of HPMC is 25%;6—Content of HPMC is 30%
, http://www.100md.com
2.4 稀释剂对药物释放的影响
选用不同的稀释剂，其释放曲线见图2.
Fig.2 The effect of additives on the release rate of DTZ from sustained-release tablets
1—Lactose as diluent；2—Dextrin-starch(11∶3) mixture as diluent
2.5 压片力对盐酸地尔硫缓释片释放度的影响
对同一组处方，采用不同压力压成片剂，其释放度试验结果见图3.
2.6 片剂中药物含量对释放速率的影响
, 百拇医药
固定每片中盐酸地尔硫的含量为30 mg，调整稀释剂(糊精-淀粉混合物)的量，使片剂中含有盐酸地尔硫的量不同，其释放结果见图4.
2.7 释药机制
盐酸地尔硫在片剂中的释药机制可能存在药物的扩散，骨架溶蚀及扩散和骨架溶蚀的共同作用.将Peppas经验方程：Mt/M∞=Ktn演化成下列形式：
logMt/M∞=logk+nlogt.
对表1中用不同量HPMC制成的盐酸地尔硫缓释片的释放度数据，按上式进行拟合，求出k、n及相关系数r.列于表2. 采用不同稀释剂压制成片剂的盐酸地尔硫缓释片按上式拟合结果见表3.
Fig.3 The effect of compression force on the release
, http://www.100md.com
rate of DTZ from tablets
1—4～5 kg；2—6～7 kg；3—9～10 kg
Fig.4 The effect of drug concentration in the tablets on the release rate of DTZ from tablets
1—DTZ concentration in tablet is 12.5%；2—DTZ concentration in tablet is 8.0%；3—DTZ concentration in tablet is 6.0%
Peppas方程中的n是表示释放机制的特征参数，参数与制剂骨架的形状有关，对于圆柱形制剂，当n<0.45时，药物的释放机制为Fick扩散；当n>0.89时，为骨架溶蚀机制；当0.45〔4〕.
, 百拇医药
Tab.2 The effect of HPMC content on n,k and td of Peppas Equation HPMC/%
n
k
td/h
r
5
0.560 2
40.02
2.26
0.979 2
10
, 百拇医药
0.522 6
30.96
3.92
0.996 4
15
0.536 3
27.91
4.59
0.994 1
20
0.568 4
26.55
4.42
, 百拇医药
0.998 8
25
0.555 6
25.80
5.01
0.999 3
30
0.557 4
24.18
5.66
0.998 2
Tab.3 The effect of different additives on n, k and td of Peppas Equation
, 百拇医药
Additives
n
k
td/h
r
Lactose
0.537 8
45.54
1.84
0.999 3
Starch-dextrin mixture
0.591 0
, 百拇医药
24.20
5.08
0.999 4
从表2可以看出，随着处方中HPMC的含量增加，药物的释放速度参数k不断减少，药物溶出63.2%的时间td亦呈不断增加趋势.不同含量的HPMC压成片剂的药物释放度数据求出n值均在0.5～0.6之间，表明药物的释放机制为扩散及溶蚀的共同作用.
3 讨论
a.片剂处方中含有HPMC的量不同，对药物释放速度有较大影响，但当处方中HPMC含量超过25%时，HPMC的量对释放度影响不大，而且随着HPMC的用量增加，片剂的可压性降低.
b.片剂中稀释剂的不同对药物的释放速率有较大影响，水溶性好的稀释剂促进药物的释放.
, 百拇医药
c.压片压力在一定范围内对HPMC骨架缓释片的释放速率影响不大.
d.增加稀释剂的用量以增加片重的办法，是降低水溶性药物在HPMC骨架缓释片中释放速率的有效办法.
参考文献
1，Peppas NA, Colombo P. Analysis of drug release behavior from swellable polymer carriers using the dimensionality index. J Control Rel, 1997, 45:35
2，Colombo P, Conte U, Gazzaniga A, et al. Drugs release modulation by physical restrictions of matrix swelling. Int J Pharm, 1990, 63:43
3，侯惠民，朱金屏，熊全美，等. PVP、PVA为辅料的胃漂浮缓释片研究Ⅱ地尔硫胃漂浮缓释片. 中国医药工业杂志，1991，22(4)：156
4，Salsa T, Veiga F, Pina ME. Oral controlled-release dosage forms. Ⅰ. Cellulose ether polymers in hydrophilic matrices. Drug Dev Ind Pharm, 1997, 23(9):929
收稿日期:2000-03-17, http://www.100md.com
单位：何仲贵 唐星 刘峰(沈阳药科大学药学系，沈阳 110015)；高淑琴(北京市门头沟区医院，北京 100230)
关键词：盐酸地尔硫；缓释；羟丙基甲基纤维素
沈阳药科大学学报000501 摘 要 以羟丙基甲基纤维素为凝胶骨架材料，以淀粉-糊精混合物及乳糖为填充剂，采用湿法制粒压片，制备了盐酸地尔硫缓释片，并对其释放度进行了测定.所制备的缓释片在释放90%之前的释放符合Higuchi方程.片剂中羟丙基甲基纤维素的含量及稀释剂的种类与含量对药物的释放速度有较大影响，而压片力对药物的释放速度无明显影响.改变缓释片中羟丙基甲基纤维素的含量及稀释剂的种类可改变药物的释放速度.
分类号 R944.4
The Preparation and in Vitro Release of Sustained-release Diltiazem Hydrochloride Tablets
, http://www.100md.com
He Zhonggui，Tang Xing，Liu Feng，Gao Shuqin
(Department of Pharmacy, Shenyang Pharmaceutical University，Shenyang 110015)
Abstract This article indroduces the preparation method of diltiazem hydrochloride sustained-release tablets. Hydroxypropylmethyl cellulose (HPMC) was used as hydrophilic matrix. Starch dextrin mixture and lactose were used as additives respectively. The tablets were prepared by the wetting granule method, and its release rates were detected. The drug release from the tablets fitted to the Higuchi equation. The content of HPMC and additives in the tablets and different additives had significant influence on release rates, but the compressing force had little influence on the release rate from the tablets. The drug release rate could be changed as the amount of HPMC and the variety of additives changed.
, 百拇医药
Key words diltiazem hydrochloride; sustained-release; hydroxypropylmethyl cellulose
盐酸地尔硫(diltiazem hydrochloride，DTZ)属于钙离子通道阻滞剂，临床上用于治疗心绞痛和高血压等心血管疾病.本品体内半衰期短，目前收入《中国药典》1995年版的盐酸地尔硫缓释片因药物释放速度较快，尚需每日服用3次.国外关于盐酸地尔硫缓释制剂的研究报道较多，并且有多种缓控释制剂上市〔1～3〕.作者以盐酸地尔硫为模型药物，以羟丙基甲基纤维素(HPMC)作为亲水凝胶骨架片的材料，探讨影响药物从片剂中释放的因素及药物释放机制.
1 药品与仪器
1.1 药品
盐酸地尔硫(石家庄制药集团)；羟丙基甲基纤维素(HPMC K15M，上海卡乐康辅料有限公司)；其它为普通药用辅料.
, http://www.100md.com
1.2 仪器
WFZ800—D2紫外可见分光光度计(北京第二光学仪器厂)，ZP19压片机(上海制药机械一厂)；ZRS-智能溶出试验仪(天津大学无线电厂).
2 方法与结果
2.1 盐酸地尔硫缓释片的制备
取盐酸地尔硫(过100目筛)，加入处方量的HPMC及其它稀释剂，混合均匀，用80%乙醇为润湿剂制软材，过16目筛整粒，50℃干燥，干颗粒加1%的硬脂酸镁，混匀后压片即得.每片含盐酸地尔硫60 mg.
2.2 体外释放试验
按《中国药典》1995年版二部转篮法，转速为50 r/min，以pH6.8磷酸盐缓冲液900 mL为释放介质.照分光光度法，加释放介质稀释成每1 mL中含盐酸地尔硫15 μg的溶液，在236 nm波长处测定吸收度.同法取盐酸地尔硫对照品适量，加释放介质定量稀释成每1 mL中约含15 μg的溶液，同法测定吸收度，计算出每片在不同时间的释放量.
, 百拇医药
2.3 片剂中HPMC含量对药物释放的影响
在保持片重为160 mg不变的情况下，研究片剂中含不同量的HPMC K15M对药物释放的影响，实验结果见表1、图1.
Tab.1 Preparation of diltiazem hydrochloride sustained-release tablets with different contents of HPMC Batch No.
DTZ/g
HPMC K15M/g
Additives(dextrin-
starch 11∶3 mixture)
, http://www.100md.com
Content of HPMC in
the preparation/%
1
30
8.0
122.0
5
2
30
16.0
114.0
10
3
, http://www.100md.com
30
24.0
106.0
15
4
30
32.0
98.0
20
5
30
40.0
90.0
, 百拇医药
25
6
30
48.0
82.0
30
Fig.1 The effect of the content of HPMC on the release rate of DTZ sustained-release tablets
1—Content of HPMC is 5%;2—Content of HPMC is 10%;3—Content of HPMC is 15%;4—Content of HPMC is 20%;5—Content of HPMC is 25%;6—Content of HPMC is 30%
, http://www.100md.com
2.4 稀释剂对药物释放的影响
选用不同的稀释剂，其释放曲线见图2.
Fig.2 The effect of additives on the release rate of DTZ from sustained-release tablets
1—Lactose as diluent；2—Dextrin-starch(11∶3) mixture as diluent
2.5 压片力对盐酸地尔硫缓释片释放度的影响
对同一组处方，采用不同压力压成片剂，其释放度试验结果见图3.
2.6 片剂中药物含量对释放速率的影响
, 百拇医药
固定每片中盐酸地尔硫的含量为30 mg，调整稀释剂(糊精-淀粉混合物)的量，使片剂中含有盐酸地尔硫的量不同，其释放结果见图4.
2.7 释药机制
盐酸地尔硫在片剂中的释药机制可能存在药物的扩散，骨架溶蚀及扩散和骨架溶蚀的共同作用.将Peppas经验方程：Mt/M∞=Ktn演化成下列形式：
logMt/M∞=logk+nlogt.
对表1中用不同量HPMC制成的盐酸地尔硫缓释片的释放度数据，按上式进行拟合，求出k、n及相关系数r.列于表2. 采用不同稀释剂压制成片剂的盐酸地尔硫缓释片按上式拟合结果见表3.
Fig.3 The effect of compression force on the release
, http://www.100md.com
rate of DTZ from tablets
1—4～5 kg；2—6～7 kg；3—9～10 kg
Fig.4 The effect of drug concentration in the tablets on the release rate of DTZ from tablets
1—DTZ concentration in tablet is 12.5%；2—DTZ concentration in tablet is 8.0%；3—DTZ concentration in tablet is 6.0%
Peppas方程中的n是表示释放机制的特征参数，参数与制剂骨架的形状有关，对于圆柱形制剂，当n<0.45时，药物的释放机制为Fick扩散；当n>0.89时，为骨架溶蚀机制；当0.45
, 百拇医药
Tab.2 The effect of HPMC content on n,k and td of Peppas Equation HPMC/%
n
k
td/h
r
5
0.560 2
40.02
2.26
0.979 2
10
, 百拇医药
0.522 6
30.96
3.92
0.996 4
15
0.536 3
27.91
4.59
0.994 1
20
0.568 4
26.55
4.42
, 百拇医药
0.998 8
25
0.555 6
25.80
5.01
0.999 3
30
0.557 4
24.18
5.66
0.998 2
Tab.3 The effect of different additives on n, k and td of Peppas Equation
, 百拇医药
Additives
n
k
td/h
r
Lactose
0.537 8
45.54
1.84
0.999 3
Starch-dextrin mixture
0.591 0
, 百拇医药
24.20
5.08
0.999 4
从表2可以看出，随着处方中HPMC的含量增加，药物的释放速度参数k不断减少，药物溶出63.2%的时间td亦呈不断增加趋势.不同含量的HPMC压成片剂的药物释放度数据求出n值均在0.5～0.6之间，表明药物的释放机制为扩散及溶蚀的共同作用.
3 讨论
a.片剂处方中含有HPMC的量不同，对药物释放速度有较大影响，但当处方中HPMC含量超过25%时，HPMC的量对释放度影响不大，而且随着HPMC的用量增加，片剂的可压性降低.
b.片剂中稀释剂的不同对药物的释放速率有较大影响，水溶性好的稀释剂促进药物的释放.
, 百拇医药
c.压片压力在一定范围内对HPMC骨架缓释片的释放速率影响不大.
d.增加稀释剂的用量以增加片重的办法，是降低水溶性药物在HPMC骨架缓释片中释放速率的有效办法.
参考文献
1，Peppas NA, Colombo P. Analysis of drug release behavior from swellable polymer carriers using the dimensionality index. J Control Rel, 1997, 45:35
2，Colombo P, Conte U, Gazzaniga A, et al. Drugs release modulation by physical restrictions of matrix swelling. Int J Pharm, 1990, 63:43
3，侯惠民，朱金屏，熊全美，等. PVP、PVA为辅料的胃漂浮缓释片研究Ⅱ地尔硫胃漂浮缓释片. 中国医药工业杂志，1991，22(4)：156
4，Salsa T, Veiga F, Pina ME. Oral controlled-release dosage forms. Ⅰ. Cellulose ether polymers in hydrophilic matrices. Drug Dev Ind Pharm, 1997, 23(9):929
收稿日期:2000-03-17, http://www.100md.com