左旋多巴漂浮型脉冲胶囊的研究
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摘要
定时脉冲释药系统又称智能给药系统,是一种在疾病发作前给药,经过预定的非释药时间(时滞)后,根据生理需要在很短的时间内迅速释放一定量药物的新型给药系统,该给药系统主要用于治疗和预防节律性发作的疾病。
帕金森病(PD)又称震颤麻痹,是继阿尔茨海默病之后中老年人常见的进行性中枢神经变性疾病,该病导致的运动功能障碍严重影响患者的生存质量,给社会和家庭生活带来了沉重负担。左旋多巴(L-dopa)是治疗帕金森病及其综合症最有效的一线药物,但长期服用传统左旋多巴类制剂的过程中伴随病程呈进行性发展会使患者在清晨出现严重的晨僵现象。目前的治疗方案由于没有考虑到晨僵现象发病的时间节律性,给药方式不符合时间药理学原理,给药剂量大,不良反应多,导致患者的顺从性差。因此,研制符合帕金森病发病时间节律性的给药系统是亟待解决的问题。
本课题根据帕金森病的时间生理学、时间药理学和时间治疗学的原理,以左旋多巴为模型药物,采用溶蚀塞型定时脉冲胶囊技术结合胃漂浮技术及静水压原理,研制符合帕金森病发病时间节律性的给药系统――左旋多巴漂浮型脉冲胶囊,使患者可在临睡前服用该胶囊,经7小时时滞后于次日清晨在胃内脉冲释药,迅速起效,改善患者的晨僵现象,同时还可提高生物利用度、减少左旋多巴用量,对治疗帕金森病及其综合症具有重要意义。
第一部分左旋多巴漂浮型脉冲胶囊的设计原理及处方前研究
1.根据帕金森病的时间生理学、时间药理学和时间治疗学的原理,采用溶蚀塞型定时脉冲胶囊技术结合胃漂浮技术及静水压原理,设计了具有定时、定位释药功能的新型给药系统――左旋多巴漂浮型脉冲胶囊。该给药系统由非渗透性胶囊体、溶蚀塞片、含药速释片、泡腾填充颗粒以及可溶性囊帽五部分组成。
2.经紫外扫描表明L-Dopa在0.1mol·L-1盐酸溶液、pH6.8磷酸盐缓冲液、超纯水中的最大吸收波长均为280nm。采用紫外分光光度法,建立了L-Dopa在0.1mol·L-1盐酸溶液、pH6.8磷酸盐缓冲液、超纯水三种介质中的含量测定方法,在1-60μg·ml-1的范围内浓度与吸收度均呈良好的线性关系,其回归方程分别为:A=0.0166+0.0140C(r=0.99992), A=0.0017+0.0158C(r=0.99965),A=0.0007+0.0136C(r=0.99990)。
第二部分左旋多巴漂浮型脉冲胶囊的制备
1.以乙基纤维素(EC45cp)为材料、二氯甲烷/无水乙醇/乙酸乙酯为溶剂,采用经优化的制备工艺,制备出囊体成形良好、囊口平整、透明、光洁、无异臭、硬度及韧性良好的非渗透性EC胶囊。
2.以L-Dopa为主药,乳糖为填充剂,分别以崩解时间、休止角、硬度、脆碎度等为评价指标,经单因素试验筛选出优选处方:主药(50%左旋多巴)、填充剂(25.75%乳糖)、粘合剂(20%微晶纤维素)、崩解剂(3%交联羧甲基纤维素钠)、润滑剂/助流剂(0.25%硬脂酸镁和1%微粉硅胶),经自制三维混合器混合,直接压片工艺制备得到左旋多巴速释片,其外观完整、光洁、色泽均匀、硬度、脆碎度、崩解时限、重量差异均符合《中国药典》要求。
3.以柠檬酸、乳糖、碳酸氢钠为原料,10%PVP乙醇溶液为粘合剂,采用非水制粒法,制备出颗粒均匀、外观干燥、色泽一致、无吸潮、无结块、无潮解的泡腾颗粒,经溶化性、外观检查均符合《中国药典》有关规定。
4.以HPMC-E50、乳糖为原料,经直接压片工艺制备出溶蚀塞片。以释药时滞(Tlag)为评价指标,考察了HPMC-E50的用量对释药时滞的影响,表明释药时滞随其用量增加而增大。并从中筛选出满足设计要求的4、5号处方纳入进一步研究。
第三部分左旋多巴漂浮型脉冲胶囊体外释放的研究
1.采用溶出度仪,以900ml人工胃液为释放介质、温度37℃±0.5℃,考察4、5号处方的溶蚀塞片在转速为50r/min和100r/min条件下的释药时滞。4号处方50r/min的释药时滞为389±20min、100r/min时为252±18min;5号处方50r/min的释药时滞为438±18min、100r/min时为281±15min。表明左旋多巴漂浮型脉冲胶囊的释药时滞随转速的增加而减小。
2.采用溶出度仪,以转速为50r/min、温度37℃±0.5℃,人工胃液900ml或1%HPMC-K4M人工胃液900ml为释放介质,考察粘度对释药时滞的影响。结果显示,4号处方在人工胃液中的释药时滞为389±20min、1%HPMC-K4M人工胃液的释药时滞为428±16min;5号处方在人工胃液的释药时滞为437±18min、1%HPMC-K4M人工胃液的释药时滞为491±24min。表明左旋多巴漂浮型脉冲胶囊的释药时滞随粘度的增加而增大;1%HPMC-K4M人工胃液中测定的释药时滞与体内的时滞接近。
3.采用溶出度仪,以1%HPMC-K4M人工胃液900ml为释放介质、转速为50r/min、温度37℃±0.5℃,建立了左旋多巴漂浮型脉冲胶囊释放度改良测定方法。
4.采用释放度测定法,分别考察了泡腾颗粒、乳糖颗粒作填充剂对时滞后的释药速率的影响。结果表明泡腾颗粒可显著提高左旋多巴漂浮型脉冲胶囊中主药片的释放速率。
5.采用溶出度仪,以人工胃液900ml为释放介质、转速为50r/min、温度37℃±0.5℃,考察左旋多巴漂浮型脉冲胶囊中的溶蚀塞片溶蚀行为,对其溶蚀残余百分率进行方程拟合,释放机制符合Peppas方程(0.45 采用γ-闪烁扫描技术考察标记99mTc的左旋多巴漂浮型脉冲胶囊与参比制剂(普通明胶胶囊)在Beagle犬体内的释药和滞留情况,结果表明参比制剂在胃中15min内即释放完毕,左旋多巴漂浮型脉冲胶囊在胃中释放时滞为(479±14)min,时滞后15min内释放完毕。表明左旋多巴漂浮型脉冲胶囊的释药时滞时间达到设计要求,释药速率与参比制剂基本一致,且重现性较好。
本课题根据帕金森病的时间生理学、时间药理学和时间治疗学的原理,采用溶蚀塞型定时脉冲胶囊技术结合胃漂浮技术及静水压原理,研制出符合帕金森病发病时间节律性的给药系统――左旋多巴漂浮型脉冲胶囊。该左旋多巴给药系统目前国内外尚未见报道。
Time-controlled pulsatile release system, which is called intelligent drug delivery system too, is capable of releasing drug after pre-determined time to address clinically therapeutic requirements. It is used to treat rhythm diseases.
Parkinson's disease(PD), which is called agitans paralysis too, is the most common neurodegenerative movement disorder beside Alzheimer disease in the meddle and old-aged. The motor dysfunction caused by PD has a great impact on the life quality of patients and bring heavy burden to society and family life. Levodopa (L-dopa) is the most active drug during the treatment of PD and PD syndrome. However, the PD patients always have serious morning stiffness with the progress of disease during using traditional L-dopa preparation. The existing therapeutic regimens are not fit for chronopharmacology due to failure of consideration of temporal rhythm of morning stiffness. The compliance of patients is bad because of the high dose and more adverse effects of these administrations. Therefore, it is necessary to develop a delivery system fitted for temporal rhythm of PD.
The study develop the L-dopa floating and pulsatile capsule connecting to erosion time-controlled pulsatile capsule technique, stomach floating technique and hydrostatic pressure principle on the basis of chronophysiology, chronopharmacology and chronotherapeutics. The L-dopa releases next morning after 7 hours and leads to effect quickly after the PD patients taking this capsule before sleep. This capsule is used to improve morning stiffness, raise bioavailability and reduce dose of L-dopa. It is important for treating PD and PD syndrome.
PartⅠThe principle of the L-dopa floating and pulsatile capsule and the work of preformulation
1. This study develops the L-dopa floating and pulsatile capsule connecting to erosion time-controlled pulsatile capsule technique, stomach floating technique and hydrostatic pressure principle on the basis of chronophysiology, chronopharmacology and chronotherapeutics. This capsule is composed of impermeable capsule body, erodible plugs, fast-released L-dopa tablets, effervesce filling granules and soluble gelatin cap.
2. The ultraviolet absorption maximum of L-Dopa was 280nm in 0.1mol·L-1 hydrochloric acid solution, PBS (pH6.8) and ultrapure water. Establishing the assaying methods in 0.1mol·L-1 hydrochloric acid solution, PBS(pH6.8), ultrapure water by ultraviolet spectrophotometry. The calibration curves were liner ranging from 1 to 60μg·ml-1. The regression equations were: A=0.0166+0.0140C (r=0.99992), A=0.0017 +0.0158C (r=0.99965), A=0.0007+0.0136C (r=0.99990).
PartⅡThe preparation of L-dopa floating and pulsatile capsule
1. This study used the optimized formulation to prepare EC capsule with ethylcellulose and solvent of dichlormethane/dehydrated alcohol/acetic ether. The EC capsule was well forming, regular, transparent, clean, no abnormal flavour, well hardness and tenacity.
2. L-Dopa is used as a model drug and lactose as bulking agent. The optimized formulation was selected by single factor experiment with evaluation index of disintegration time, angle of repose, hardness and friability. The fast-released L-dopa tablets were prepared by direct compression after mixing in self-made blender with optimized formulation which composed of drug(50% L-dopa), bulking agent(25.75% lactose), binding agent(20% MCC), disintegrating agent(3% cCMC-Na), lubricant/ glidant (0.25% magnesium stearate / 1% Silicon dioxide). The fast-released tablets were consistent with the requirement of CP on appearance, hardness, friability, disintegration time, weight variation.
3. The effervesce filling granules were prepared by nonaqueous granulating method with citric acid, lactose, NaHCO3 and binding agent(10%PVP ethyl alcohol solution). The tests of dissolubility and appearance were consistent with the requirement of CP.
4. The erodible plugs were prepared by direct compression with HPMC-E50 and lactose. The effect of HPMC dosage on the lag time of the floating and pulsatile capsule was investigated. The result indicates that the lag time was lengthened with the increase of HPMC dosage. Formula 4 and
5 were selected to enter next experiment.
PartⅢStudy on release of L-dopa floating and pulsatile capsule in vitro
1. The lag time of erodible plugs of formula 4 and 5 at different paddle speed (50 and 100r/min) were studied by dissolution method. The release medium was 900ml simulated gastric fluid and the temperature was 37℃±0.5℃. The lag time of formula 4 at 50 and 100r/min were (389±20) min and (252±18) min. The lag time of formula 5 was (438±18) min and (281±15) min. The result indicates that the lag time of L-dopa floating and pulsatile capsule was shortened with increase of paddle speed.
2. The effect of viscosity of the release medium on lag time was investigated by dissolution method. The release medium was 900mL simulated gastric fluid with 1%HPMC-K4M or not. The temperature was 37℃±0.5℃and the paddle speed was 50r/min. The result shows that the lag time of formula 4 and 5 in simulated gastric fluid and simulated gastric fluid with 1%HPMC-K4M was (389±20)、(428±16)、(437±18) and (491±24) min. This indicates that the lag time of L-dopa floating and pulsatile capsule was lengthened with increase of viscosity. The lag time in simulated gastric fluid with 1%HPMC-K4M approaches to time in vivo.
3. The improved release method of L-dopa floating and pulsatile capsule was established by dissolution apparatus. The release medium was 900mL simulated gastric fluid with 1%HPMC-K4M. The paddle speed was 50r/min and the temperature was 37℃±0.5℃.
4. The effects of effervesce filling granules and lactose filling granules on the lag time were investigated by release testing. The result indicates effervesce filling granules can elevate the release rate of fast-released L-dopa tablets significantly.
5. The erosion behavior of erodible plugs in L-dopa floating and pulsatile capsule was investigated using dissolution apparatus. The release medium was 900ml simulated gastric fluid with 1%HPMC-K4M. The paddle speed was 50r/min and the temperature was 37℃±0.5℃. The mathematical model by erosion remaining percentage was established as Peppas equations(0.45 PartⅣγ-Scintigraphic Evaluation of L-dopa floating and pulsatile capsule in Beagle dogs
γ-Scintigraphy was used to monitor in vivo the release and gastric retention performance of the test (99mTc-labeled L-dopa floating and pulsatile capsule) and reference (99mTc-labeled common gelatin capsule) in Beagle dogs. The result shows that the reference releases completely during 15minutes,and the lag time of the test was (479±14)min which release completely during 15minutes too. This indicates that the lag time of L-dopa floating and pulsatile capsule meet the requirement of design and release rate consist with the reference with good reproducibility.
This study develops the L-dopa floating and pulsatile capsule which is consistent with temporal rhythm of Parkinson's disease connecting to erosion time-controlled pulsatile capsule technique, stomach floating technique and hydrostatic pressure principle on the basis of chronophysiology, chronopharmacology and chronotherapeutics. This delivery system of L-dopa has never been reported at home and abroad.
帕金森病(PD)又称震颤麻痹,是继阿尔茨海默病之后中老年人常见的进行性中枢神经变性疾病,该病导致的运动功能障碍严重影响患者的生存质量,给社会和家庭生活带来了沉重负担。左旋多巴(L-dopa)是治疗帕金森病及其综合症最有效的一线药物,但长期服用传统左旋多巴类制剂的过程中伴随病程呈进行性发展会使患者在清晨出现严重的晨僵现象。目前的治疗方案由于没有考虑到晨僵现象发病的时间节律性,给药方式不符合时间药理学原理,给药剂量大,不良反应多,导致患者的顺从性差。因此,研制符合帕金森病发病时间节律性的给药系统是亟待解决的问题。
本课题根据帕金森病的时间生理学、时间药理学和时间治疗学的原理,以左旋多巴为模型药物,采用溶蚀塞型定时脉冲胶囊技术结合胃漂浮技术及静水压原理,研制符合帕金森病发病时间节律性的给药系统――左旋多巴漂浮型脉冲胶囊,使患者可在临睡前服用该胶囊,经7小时时滞后于次日清晨在胃内脉冲释药,迅速起效,改善患者的晨僵现象,同时还可提高生物利用度、减少左旋多巴用量,对治疗帕金森病及其综合症具有重要意义。
第一部分左旋多巴漂浮型脉冲胶囊的设计原理及处方前研究
1.根据帕金森病的时间生理学、时间药理学和时间治疗学的原理,采用溶蚀塞型定时脉冲胶囊技术结合胃漂浮技术及静水压原理,设计了具有定时、定位释药功能的新型给药系统――左旋多巴漂浮型脉冲胶囊。该给药系统由非渗透性胶囊体、溶蚀塞片、含药速释片、泡腾填充颗粒以及可溶性囊帽五部分组成。
2.经紫外扫描表明L-Dopa在0.1mol·L-1盐酸溶液、pH6.8磷酸盐缓冲液、超纯水中的最大吸收波长均为280nm。采用紫外分光光度法,建立了L-Dopa在0.1mol·L-1盐酸溶液、pH6.8磷酸盐缓冲液、超纯水三种介质中的含量测定方法,在1-60μg·ml-1的范围内浓度与吸收度均呈良好的线性关系,其回归方程分别为:A=0.0166+0.0140C(r=0.99992), A=0.0017+0.0158C(r=0.99965),A=0.0007+0.0136C(r=0.99990)。
第二部分左旋多巴漂浮型脉冲胶囊的制备
1.以乙基纤维素(EC45cp)为材料、二氯甲烷/无水乙醇/乙酸乙酯为溶剂,采用经优化的制备工艺,制备出囊体成形良好、囊口平整、透明、光洁、无异臭、硬度及韧性良好的非渗透性EC胶囊。
2.以L-Dopa为主药,乳糖为填充剂,分别以崩解时间、休止角、硬度、脆碎度等为评价指标,经单因素试验筛选出优选处方:主药(50%左旋多巴)、填充剂(25.75%乳糖)、粘合剂(20%微晶纤维素)、崩解剂(3%交联羧甲基纤维素钠)、润滑剂/助流剂(0.25%硬脂酸镁和1%微粉硅胶),经自制三维混合器混合,直接压片工艺制备得到左旋多巴速释片,其外观完整、光洁、色泽均匀、硬度、脆碎度、崩解时限、重量差异均符合《中国药典》要求。
3.以柠檬酸、乳糖、碳酸氢钠为原料,10%PVP乙醇溶液为粘合剂,采用非水制粒法,制备出颗粒均匀、外观干燥、色泽一致、无吸潮、无结块、无潮解的泡腾颗粒,经溶化性、外观检查均符合《中国药典》有关规定。
4.以HPMC-E50、乳糖为原料,经直接压片工艺制备出溶蚀塞片。以释药时滞(Tlag)为评价指标,考察了HPMC-E50的用量对释药时滞的影响,表明释药时滞随其用量增加而增大。并从中筛选出满足设计要求的4、5号处方纳入进一步研究。
第三部分左旋多巴漂浮型脉冲胶囊体外释放的研究
1.采用溶出度仪,以900ml人工胃液为释放介质、温度37℃±0.5℃,考察4、5号处方的溶蚀塞片在转速为50r/min和100r/min条件下的释药时滞。4号处方50r/min的释药时滞为389±20min、100r/min时为252±18min;5号处方50r/min的释药时滞为438±18min、100r/min时为281±15min。表明左旋多巴漂浮型脉冲胶囊的释药时滞随转速的增加而减小。
2.采用溶出度仪,以转速为50r/min、温度37℃±0.5℃,人工胃液900ml或1%HPMC-K4M人工胃液900ml为释放介质,考察粘度对释药时滞的影响。结果显示,4号处方在人工胃液中的释药时滞为389±20min、1%HPMC-K4M人工胃液的释药时滞为428±16min;5号处方在人工胃液的释药时滞为437±18min、1%HPMC-K4M人工胃液的释药时滞为491±24min。表明左旋多巴漂浮型脉冲胶囊的释药时滞随粘度的增加而增大;1%HPMC-K4M人工胃液中测定的释药时滞与体内的时滞接近。
3.采用溶出度仪,以1%HPMC-K4M人工胃液900ml为释放介质、转速为50r/min、温度37℃±0.5℃,建立了左旋多巴漂浮型脉冲胶囊释放度改良测定方法。
4.采用释放度测定法,分别考察了泡腾颗粒、乳糖颗粒作填充剂对时滞后的释药速率的影响。结果表明泡腾颗粒可显著提高左旋多巴漂浮型脉冲胶囊中主药片的释放速率。
5.采用溶出度仪,以人工胃液900ml为释放介质、转速为50r/min、温度37℃±0.5℃,考察左旋多巴漂浮型脉冲胶囊中的溶蚀塞片溶蚀行为,对其溶蚀残余百分率进行方程拟合,释放机制符合Peppas方程(0.45
本课题根据帕金森病的时间生理学、时间药理学和时间治疗学的原理,采用溶蚀塞型定时脉冲胶囊技术结合胃漂浮技术及静水压原理,研制出符合帕金森病发病时间节律性的给药系统――左旋多巴漂浮型脉冲胶囊。该左旋多巴给药系统目前国内外尚未见报道。
Time-controlled pulsatile release system, which is called intelligent drug delivery system too, is capable of releasing drug after pre-determined time to address clinically therapeutic requirements. It is used to treat rhythm diseases.
Parkinson's disease(PD), which is called agitans paralysis too, is the most common neurodegenerative movement disorder beside Alzheimer disease in the meddle and old-aged. The motor dysfunction caused by PD has a great impact on the life quality of patients and bring heavy burden to society and family life. Levodopa (L-dopa) is the most active drug during the treatment of PD and PD syndrome. However, the PD patients always have serious morning stiffness with the progress of disease during using traditional L-dopa preparation. The existing therapeutic regimens are not fit for chronopharmacology due to failure of consideration of temporal rhythm of morning stiffness. The compliance of patients is bad because of the high dose and more adverse effects of these administrations. Therefore, it is necessary to develop a delivery system fitted for temporal rhythm of PD.
The study develop the L-dopa floating and pulsatile capsule connecting to erosion time-controlled pulsatile capsule technique, stomach floating technique and hydrostatic pressure principle on the basis of chronophysiology, chronopharmacology and chronotherapeutics. The L-dopa releases next morning after 7 hours and leads to effect quickly after the PD patients taking this capsule before sleep. This capsule is used to improve morning stiffness, raise bioavailability and reduce dose of L-dopa. It is important for treating PD and PD syndrome.
PartⅠThe principle of the L-dopa floating and pulsatile capsule and the work of preformulation
1. This study develops the L-dopa floating and pulsatile capsule connecting to erosion time-controlled pulsatile capsule technique, stomach floating technique and hydrostatic pressure principle on the basis of chronophysiology, chronopharmacology and chronotherapeutics. This capsule is composed of impermeable capsule body, erodible plugs, fast-released L-dopa tablets, effervesce filling granules and soluble gelatin cap.
2. The ultraviolet absorption maximum of L-Dopa was 280nm in 0.1mol·L-1 hydrochloric acid solution, PBS (pH6.8) and ultrapure water. Establishing the assaying methods in 0.1mol·L-1 hydrochloric acid solution, PBS(pH6.8), ultrapure water by ultraviolet spectrophotometry. The calibration curves were liner ranging from 1 to 60μg·ml-1. The regression equations were: A=0.0166+0.0140C (r=0.99992), A=0.0017 +0.0158C (r=0.99965), A=0.0007+0.0136C (r=0.99990).
PartⅡThe preparation of L-dopa floating and pulsatile capsule
1. This study used the optimized formulation to prepare EC capsule with ethylcellulose and solvent of dichlormethane/dehydrated alcohol/acetic ether. The EC capsule was well forming, regular, transparent, clean, no abnormal flavour, well hardness and tenacity.
2. L-Dopa is used as a model drug and lactose as bulking agent. The optimized formulation was selected by single factor experiment with evaluation index of disintegration time, angle of repose, hardness and friability. The fast-released L-dopa tablets were prepared by direct compression after mixing in self-made blender with optimized formulation which composed of drug(50% L-dopa), bulking agent(25.75% lactose), binding agent(20% MCC), disintegrating agent(3% cCMC-Na), lubricant/ glidant (0.25% magnesium stearate / 1% Silicon dioxide). The fast-released tablets were consistent with the requirement of CP on appearance, hardness, friability, disintegration time, weight variation.
3. The effervesce filling granules were prepared by nonaqueous granulating method with citric acid, lactose, NaHCO3 and binding agent(10%PVP ethyl alcohol solution). The tests of dissolubility and appearance were consistent with the requirement of CP.
4. The erodible plugs were prepared by direct compression with HPMC-E50 and lactose. The effect of HPMC dosage on the lag time of the floating and pulsatile capsule was investigated. The result indicates that the lag time was lengthened with the increase of HPMC dosage. Formula 4 and
5 were selected to enter next experiment.
PartⅢStudy on release of L-dopa floating and pulsatile capsule in vitro
1. The lag time of erodible plugs of formula 4 and 5 at different paddle speed (50 and 100r/min) were studied by dissolution method. The release medium was 900ml simulated gastric fluid and the temperature was 37℃±0.5℃. The lag time of formula 4 at 50 and 100r/min were (389±20) min and (252±18) min. The lag time of formula 5 was (438±18) min and (281±15) min. The result indicates that the lag time of L-dopa floating and pulsatile capsule was shortened with increase of paddle speed.
2. The effect of viscosity of the release medium on lag time was investigated by dissolution method. The release medium was 900mL simulated gastric fluid with 1%HPMC-K4M or not. The temperature was 37℃±0.5℃and the paddle speed was 50r/min. The result shows that the lag time of formula 4 and 5 in simulated gastric fluid and simulated gastric fluid with 1%HPMC-K4M was (389±20)、(428±16)、(437±18) and (491±24) min. This indicates that the lag time of L-dopa floating and pulsatile capsule was lengthened with increase of viscosity. The lag time in simulated gastric fluid with 1%HPMC-K4M approaches to time in vivo.
3. The improved release method of L-dopa floating and pulsatile capsule was established by dissolution apparatus. The release medium was 900mL simulated gastric fluid with 1%HPMC-K4M. The paddle speed was 50r/min and the temperature was 37℃±0.5℃.
4. The effects of effervesce filling granules and lactose filling granules on the lag time were investigated by release testing. The result indicates effervesce filling granules can elevate the release rate of fast-released L-dopa tablets significantly.
5. The erosion behavior of erodible plugs in L-dopa floating and pulsatile capsule was investigated using dissolution apparatus. The release medium was 900ml simulated gastric fluid with 1%HPMC-K4M. The paddle speed was 50r/min and the temperature was 37℃±0.5℃. The mathematical model by erosion remaining percentage was established as Peppas equations(0.45
γ-Scintigraphy was used to monitor in vivo the release and gastric retention performance of the test (99mTc-labeled L-dopa floating and pulsatile capsule) and reference (99mTc-labeled common gelatin capsule) in Beagle dogs. The result shows that the reference releases completely during 15minutes,and the lag time of the test was (479±14)min which release completely during 15minutes too. This indicates that the lag time of L-dopa floating and pulsatile capsule meet the requirement of design and release rate consist with the reference with good reproducibility.
This study develops the L-dopa floating and pulsatile capsule which is consistent with temporal rhythm of Parkinson's disease connecting to erosion time-controlled pulsatile capsule technique, stomach floating technique and hydrostatic pressure principle on the basis of chronophysiology, chronopharmacology and chronotherapeutics. This delivery system of L-dopa has never been reported at home and abroad.
引文
[1] Lemmer B. Circadian rhythms and drug delivery[J].J Control Release, 1991,16:63-74
[2] 何绍雄.时间药理学与时间治疗学[M].天津科学技术出版社, 1993,46-201
[3] 邹豪.口服脉冲和定时释药系统[J]. 国外医学药学分册,1999,26(1):33-38
[4] 吴芳,张志荣.定时脉冲释药系统[J]. 药学进展,2001,25(5):279-283
[5] Andres M.lozano ,Suneil K.Kalia. New Movement in Pakinson’s[J], Science, 2005,6:58-65
[6] Z.Zhang, G.Roman, Z.Hong, et al. Parkinson’s disease in China:Prevalence in Beijing,xian,and Shanghai[J]. Lancet,2005, 365(9459):595-597
[7] Anthony H.V.Schapir, DSc, C.Warren Olanow. Neuroprotection in Parkinson Disease Mysteries,Myths and Misconceptions[J]. JAMA. 2004,291: 358-364
[8] 陆 彬 . 药 物 新 剂 型 与 新 技 术 [M]. 第 二 版 , 北 京 : 人 民 卫 生 出 版社.2005,466-506
[9] Junginger HE. Oral Applications of Pulsatile Delivery [A].Pulsatile Drug Delivery-Current Application and Futures Trends[C].Stuttgart: Wissenschaftliche Verlagsgesellschaft, 1993.113-134
[10] Ueda S, Hata T, Asakura S et al. Development of a novel drug release system time-controlled explosion system(TES) Concept and design[J]. J Drug Target. 1994,2(1):35-44
[11] Kikuchi A, Okano T. Pulsatile drug release control using hydrogels[J]. Adv Drug delivRev,2002,54:53-77
[12] HNE Stevens, Chronopharmaceutical drug delivery[J].J Pharm Pharmacol,1998,50:5
[13] Poli IND Chimica SPA(IT). Methods for treating morning pathologies[P]. USP:5788987. 1998-08-04
[14] 王晓维,金方.脉冲给药系统的释药机理及研究进展[J]. 中国医药工业杂志2003, 34(7):361-365
[15] 吴芳,张志荣,何伟玲等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[16] 邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598
[17] 莫良佩,杜青,廖娟. 茶碱盖塞控制型脉冲胶囊的制备及影响因素考察[J]. 中国医药工业杂志,2005,36(10):613-616
[18] Mcneill ME, Rashid A, Stevens HNE. Dispensing device[P]. US5342624. 1994-08-30
[19] Takada K. Controlled-release preparations[P]. US:5637319. 1997-06-10
[20] Ina Kr?gel,Roland Bodmerier.Pulsatile Drug Release from an Insoluble Capsule Body Controlled by an Erodible Plug[J].Pharmaceutical Research, 1998,15:474-481
[21] Ina Kr?gel, Roland Bodmerier. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder[J].Journal of Controlled Release,1999, (61):43-50
[22] 陆彬.药物新剂型与新技术[M].第二版,北京:人民卫生出版社.2005,395-404
[1] Junginger HE. Oral Applications of Pulsatile Delivery[A]. Pulsatile Drug Delivery-Current Application and Futures Trends[C].Stuttgart: Wissenschaftliche Verlagsgesellschaft, 1993.113-134
[2] Ueda S, Hata T, Asakura S, et al. Development of a novel drug release system time-controlled explosion system(TES) Concept and design[J]. J Drug Target. 1994,2(1):35-44
[3] Ina Kr?gel, Roland Bodmerier. Pulsatile Drug Release from an Insoluble Capsle Body Controlled by an Erodible Plug[J]. Pharmaceutical Research, 1998,15: 474-481
[4] Ina Kr?gel, Roland Bodmerier. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder[J].Journal of Controlled Release,1999, (61):43-50
[5] 吴芳,张志荣,何伟玲,等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[6] 邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598
[7] 莫良佩,杜青,廖娟. 茶碱盖塞控制型脉冲胶囊的制备及影响因素考察[J].中国医药工业杂志,2005,36(10):613-616
[8] Mcneill ME, Rashid A, Stevens HNE. Dispensing device[P]. US5342624. 1994-08-30
[9] 国家药典委员会编. 中华人民共和国药典 2005 版(二部)[S].北京:化学工业出版社,2005,85-86
[10] 陈新谦主编.新编药物学[M].第 16 版,北京:人民卫生出版社,2003,229-230
[1] M.E.McNeil, A.Rashid, H.N.E Stevens. WO90/09618, Dispensing device, Aug.23,1990
[2] Takadai K. Controlled-release preparations. US Patent:563719,1997-06-10
[3] Ina Krogel,Roland Bodmeier. Floating or pulsatile drug delivery systems based on coated effervescent cores[J]. International Journal of Pharmaceutics. 1999,187:175-184
[4] 吴芳,张志荣.灌注法制备脉冲给药装置的新型非渗透胶囊体[J].华西药学杂志,2006,21(1):005-007
[5] 车坷科,朱照静,李欣宇.口服溶蚀塞型脉冲胶囊体的研制[J].重庆医科大学学报,2008,33(7):871-874
[6] 邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598
[7] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006,869-870
[8] 程能林主编.溶剂手册[M].北京:化学工业出版社,1994,141-542
[9] 姚方耀,刘欢,刘衡,等.口腔崩解片体外崩解评价方法探讨[J].中国药学杂志,2007,42(4):276-279
[10] 陆彬主编.药剂学实验[M].北京:人民卫生出版社. 1994:19-21
[11] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006,743-745
[12] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006,198-206
[13] Record of the conference on the character and quality control of orally disintegrating tables[EB/OL].www.cde.org.cn,2003-08
[14] HISAKADZU S,YUNXIA B. Preparation,evaluation and optimization of rapidly disintegrating tables[J]. Powder Technolo,2002,122(3):188-198
[15] SR IKONDA V S, JANAKIRN, JOSEPHAN. Recent technology advances in oral drug delivery[J].Pharm Sci Technolo Today,2000,3(4):138-145
[16] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006:802-804
[17] 庄越主编.实用药物制剂技术[M].北京:人民卫生出版社,1999: 114-120
[18] 国家药典委员会编.中华人民共和国药典 2005 版(二部)[S].北京:化学工业出版社,2005:附录 14
[19] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006,500-501
[20] Ross AC, Macrae RJ, Walther M,et al. Chronopharmaceutical drug delivery from a pulsatile capsule device based on programmable erosion. J Pharm Pharmacol,2000,52(8):903-909
[21] Matsuo M, Nakamura C, Arimori K, et al. Evaluation of hydroxyethylcellulose as a hydrophilic swellable material for delayed-release tables. Chem Pharm Bull,1995,43(2):311-314
[22] Ina Kr?gel, Roland Bodmerier. Pulsatile Drug Release from an Insoluble Capsle Body Controlled by an Erodible Plug[J]. Pharmaceutical Research, 1998, 15:474-481
[23] Ina Kr?gel, Roland Bodmerier. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder[J].Controlled release,1999 (61):43-50
[24] 吴芳,张志荣,何伟玲等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[25] 罗明生主编等.中国药用辅料[M].北京:化学工业出版社,2006,712-715
[26] General Information/ In vitro and in vivo evaluation of dosage froms<1088>. USP 23:1925
[1] 吴芳,张志荣.灌注法制备脉冲给药装置的新型非渗透胶囊体[J].华西药学杂志,2006,21(1):005-007
[2] 邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598
[3] 齐美玲,王鹏,郑俊民,等.盐酸尼卡地平定时释放片研究药学学报[J].1999, 34(9):710-715
[4] 陆彬. 药物新剂型与新技术[M].第二版,北京:人民卫生出版社.2005:386-392
[5] Pozzi F., Furlani P., Gazzaniga A., et al. The time clock system: a new oral dosage form for the fast and complete release of drug after a predetermined lag time[M]. J. of Controlled Release,1994,31(1):99-108
[6] 吴芳,张志荣,何伟玲等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[1] Connor AL, Wray H, Cottrell J, et al. A scintigraphic study to investigate the potential of altered gut distribution of loperamide from a loperamide-simethicone formulation in man[J]. Eur J Pharm Sci,2001,13:369-374
[2] 邹豪,蒋雪涛,潘文舟等.盐酸维拉帕米脉冲释放片在人体内γ-闪烁扫描示踪研究[J]. 实用放射学杂志,2001,17(12):881-885
[3] 邹豪,孔令山,谢明萱. 漂浮型脉冲胶囊释放的人体内γ-闪烁扫描示踪研究[J].中国医药工业杂志, 2004,35(12):724-726
[4] 吴芳,丁洪,张志荣. 用γ射线显影法研究磷酸川芎嗪脉冲塞胶囊在犬胃肠道内的崩解释药和转运行为[J]. 生物医学工程杂志,2006,23(4):790-794
[5] 张洁,张纯,高申,等. 胸腺肽α1结肠释放片在人体γ-闪烁扫描示踪研究[J]. 第二军医大学学报,2005,26(9):1026-1028
[6] 齐美玲,王鹏,吴德政. γ-闪烁扫描法确定替硝唑结肠释放片人体内释药部位的研究[J].中国药学杂志,2003,38(2):114-116
[7] 刘卫卫,张纯,谭真. 阿莫西林胃滞留片人体内γ-闪烁扫描示踪研究[J].南京军医学院学报,2001,23(1):39-40
[8] 陈艳,邹豪,蒋学涛.药物制剂体内示踪技术—γ-闪烁扫描的应用[J].药学实践杂志,2003,21(4):198-201
[1] Anthony H.V.Schapir, DSc, C.Warren Olanow. Neuroprotection in Parkinson Disease Mysteries, Myths and Misconceptions[J]. JAMA. 2004,291: 358-364
[2] Z.Zhang, G.Roman, Z.Hong et al. Parkinson’s disease in China: Prevalence in Beijing,xian,and Shanghai[J]. Lancet,2005, 365(9459):595-597
[3] 吴浩翔,刘玉玲.帕金森治疗药物研究进展[J].中国药学杂志,2004,39(6): 409-412
[4] 何绍雄.间药理学与时间治疗学[M]. 天津:天津科学技术出版社,1993,46-201
[5] 邹豪.口服脉冲和定时释药系统[J]. 国外医学药学分册,1999,26(1):33-38
[6] Lemmer B, Implications of chronopharmacokinetics for drug delivery: an antiasthmatics, H2-blockers and cardiovascular active drugs[J], Adv Drug Deliv Rev ,1991,6(1):83
[7] 吴芳,张志荣.定时脉冲释药系统[J].药学进展,2001,25(5):279-283
[8] Shinji N, Minako N, Y oshiyuki H. An organic acid-induced sigmoidal release system for oral controlled-release preparations. III. Elucidation of the anomalous drug release behavior through osmotic pumping mechanism[J]. Inter J Pharm, 1997,148:85-91
[9] 郝钦,岗艳云,朱家壁.硝酸异山梨酷脉冲控释微丸的研制[J].中国医药工业杂志,1999,30(3):109-111
[10]Poli IND Chimica SPA (IT). Methods for treating morning pathologies. US:5788987. 1998-08-04
[11]Ryuzo I, Hiroyuki Y, Y oshiyuki H. Absorption of Diltiazem in Beagle dog from pulsatile release tablet[J]. Chem Pharm Bull, 1992, 40(11):3094-3096
[12]Soberer DDS develops“alarm clock” dose formulation[J]. Pharm J,l991,247: 138
[13]齐美玲,王鹏,郑俊民,等.盐酸尼卡地平定时释放片研究[J]. 药学学报,1999, 34(9):710-71
[14]陈燕忠,岗艳云,金志忠,等.法莫替丁脉冲控释胶囊剂的研究[J].中国药科大学学报,1997,28(3):150-154
[15]Soni V, Singh R, Srinivasan R, et al. Pulsatile insulin delivery through the ocular route[J]. Drug Delivery,1998,5(1):47-51
[16]Michael C, Shari AL, Jane CL, et al. In vitro testing of a pulsatile delivery system and its in vivo application for immunisation against tetanus toxoid[J]. Journal of Controlled Release,1997,47:205-219
[17]Satoshi U, Rinta I, Sumihisa K,et al. Development of a novel drug release system, time-controlled explosion system (TES) Ⅲ.Relation between lag time and membrane thickness[J]. Chem Pharm Bull,1994,42(2):364-367
[18]Satoshi U, Hisami Y, MasateruK. Development of a novel drug release system, time-controlled explosion system (TES)Ⅱ. Design of multiparticulate TES and invitro drug release properties[J]. Chem Pharm Bull,1994,42(2):359-363
[19]T Ishibashi, G R P Itcairn, H Yoshino,et al. Scintigraphic evaluation of a new capsule-type colon specific drug delivery system in healthy volunteers[J]. J Pharm Sci,1998,87(5):531-53
[20]Scrip,1996,(2138):17
[21]S eiyaK, Tatsuki S, Y utakaK,et al. Electroresponsive pulsatile depot delivery of insulin from poly(dimethylaminopropylacrylamide) gel in rats[J]. J Pharm Sci,1997,86(1I):1273-1277
[22]Yoshida R, Sakai K, Okano T, et al. "On-Off' switching mechanism of pulsatile drug release poly(N-idopropylacrylamide-co-alkyl methacrylate) gels[J]. Proc Conf Intell Mater,1993:393-396
[23]Mcneill ME, Rashid A, Stevens HNE. Dispensing device. US5342624. 1994-08-30
[24]Takada K. Controlled-release preparations. US:563719. 1997-06-10
[25]Krogel I, Bodmeier R. Evaluation of an enzyme-containing capsular shaped pulsatile drug delivery system[J]. Pharm Res,1999,16(9):1424-1429
[26]Ina Kr?gel, Roland Bodmerier. Pulsatile Drug Release from an Insoluble Capsle Body Controlled by an Erodible Plug[J]. Pharmaceutical Research, 1998,15:474-481
[27]Ina Kr?gel, Roland Bodmerier. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder[J]. Journal of Controlled Release,1999, (61):43-50
[28]吴芳,张志荣,何伟玲,等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[29]邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598
[2] 何绍雄.时间药理学与时间治疗学[M].天津科学技术出版社, 1993,46-201
[3] 邹豪.口服脉冲和定时释药系统[J]. 国外医学药学分册,1999,26(1):33-38
[4] 吴芳,张志荣.定时脉冲释药系统[J]. 药学进展,2001,25(5):279-283
[5] Andres M.lozano ,Suneil K.Kalia. New Movement in Pakinson’s[J], Science, 2005,6:58-65
[6] Z.Zhang, G.Roman, Z.Hong, et al. Parkinson’s disease in China:Prevalence in Beijing,xian,and Shanghai[J]. Lancet,2005, 365(9459):595-597
[7] Anthony H.V.Schapir, DSc, C.Warren Olanow. Neuroprotection in Parkinson Disease Mysteries,Myths and Misconceptions[J]. JAMA. 2004,291: 358-364
[8] 陆 彬 . 药 物 新 剂 型 与 新 技 术 [M]. 第 二 版 , 北 京 : 人 民 卫 生 出 版社.2005,466-506
[9] Junginger HE. Oral Applications of Pulsatile Delivery [A].Pulsatile Drug Delivery-Current Application and Futures Trends[C].Stuttgart: Wissenschaftliche Verlagsgesellschaft, 1993.113-134
[10] Ueda S, Hata T, Asakura S et al. Development of a novel drug release system time-controlled explosion system(TES) Concept and design[J]. J Drug Target. 1994,2(1):35-44
[11] Kikuchi A, Okano T. Pulsatile drug release control using hydrogels[J]. Adv Drug delivRev,2002,54:53-77
[12] HNE Stevens, Chronopharmaceutical drug delivery[J].J Pharm Pharmacol,1998,50:5
[13] Poli IND Chimica SPA(IT). Methods for treating morning pathologies[P]. USP:5788987. 1998-08-04
[14] 王晓维,金方.脉冲给药系统的释药机理及研究进展[J]. 中国医药工业杂志2003, 34(7):361-365
[15] 吴芳,张志荣,何伟玲等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[16] 邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598
[17] 莫良佩,杜青,廖娟. 茶碱盖塞控制型脉冲胶囊的制备及影响因素考察[J]. 中国医药工业杂志,2005,36(10):613-616
[18] Mcneill ME, Rashid A, Stevens HNE. Dispensing device[P]. US5342624. 1994-08-30
[19] Takada K. Controlled-release preparations[P]. US:5637319. 1997-06-10
[20] Ina Kr?gel,Roland Bodmerier.Pulsatile Drug Release from an Insoluble Capsule Body Controlled by an Erodible Plug[J].Pharmaceutical Research, 1998,15:474-481
[21] Ina Kr?gel, Roland Bodmerier. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder[J].Journal of Controlled Release,1999, (61):43-50
[22] 陆彬.药物新剂型与新技术[M].第二版,北京:人民卫生出版社.2005,395-404
[1] Junginger HE. Oral Applications of Pulsatile Delivery[A]. Pulsatile Drug Delivery-Current Application and Futures Trends[C].Stuttgart: Wissenschaftliche Verlagsgesellschaft, 1993.113-134
[2] Ueda S, Hata T, Asakura S, et al. Development of a novel drug release system time-controlled explosion system(TES) Concept and design[J]. J Drug Target. 1994,2(1):35-44
[3] Ina Kr?gel, Roland Bodmerier. Pulsatile Drug Release from an Insoluble Capsle Body Controlled by an Erodible Plug[J]. Pharmaceutical Research, 1998,15: 474-481
[4] Ina Kr?gel, Roland Bodmerier. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder[J].Journal of Controlled Release,1999, (61):43-50
[5] 吴芳,张志荣,何伟玲,等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[6] 邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598
[7] 莫良佩,杜青,廖娟. 茶碱盖塞控制型脉冲胶囊的制备及影响因素考察[J].中国医药工业杂志,2005,36(10):613-616
[8] Mcneill ME, Rashid A, Stevens HNE. Dispensing device[P]. US5342624. 1994-08-30
[9] 国家药典委员会编. 中华人民共和国药典 2005 版(二部)[S].北京:化学工业出版社,2005,85-86
[10] 陈新谦主编.新编药物学[M].第 16 版,北京:人民卫生出版社,2003,229-230
[1] M.E.McNeil, A.Rashid, H.N.E Stevens. WO90/09618, Dispensing device, Aug.23,1990
[2] Takadai K. Controlled-release preparations. US Patent:563719,1997-06-10
[3] Ina Krogel,Roland Bodmeier. Floating or pulsatile drug delivery systems based on coated effervescent cores[J]. International Journal of Pharmaceutics. 1999,187:175-184
[4] 吴芳,张志荣.灌注法制备脉冲给药装置的新型非渗透胶囊体[J].华西药学杂志,2006,21(1):005-007
[5] 车坷科,朱照静,李欣宇.口服溶蚀塞型脉冲胶囊体的研制[J].重庆医科大学学报,2008,33(7):871-874
[6] 邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598
[7] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006,869-870
[8] 程能林主编.溶剂手册[M].北京:化学工业出版社,1994,141-542
[9] 姚方耀,刘欢,刘衡,等.口腔崩解片体外崩解评价方法探讨[J].中国药学杂志,2007,42(4):276-279
[10] 陆彬主编.药剂学实验[M].北京:人民卫生出版社. 1994:19-21
[11] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006,743-745
[12] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006,198-206
[13] Record of the conference on the character and quality control of orally disintegrating tables[EB/OL].www.cde.org.cn,2003-08
[14] HISAKADZU S,YUNXIA B. Preparation,evaluation and optimization of rapidly disintegrating tables[J]. Powder Technolo,2002,122(3):188-198
[15] SR IKONDA V S, JANAKIRN, JOSEPHAN. Recent technology advances in oral drug delivery[J].Pharm Sci Technolo Today,2000,3(4):138-145
[16] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006:802-804
[17] 庄越主编.实用药物制剂技术[M].北京:人民卫生出版社,1999: 114-120
[18] 国家药典委员会编.中华人民共和国药典 2005 版(二部)[S].北京:化学工业出版社,2005:附录 14
[19] 罗明生主编.中国药用辅料[M].北京:化学工业出版社,2006,500-501
[20] Ross AC, Macrae RJ, Walther M,et al. Chronopharmaceutical drug delivery from a pulsatile capsule device based on programmable erosion. J Pharm Pharmacol,2000,52(8):903-909
[21] Matsuo M, Nakamura C, Arimori K, et al. Evaluation of hydroxyethylcellulose as a hydrophilic swellable material for delayed-release tables. Chem Pharm Bull,1995,43(2):311-314
[22] Ina Kr?gel, Roland Bodmerier. Pulsatile Drug Release from an Insoluble Capsle Body Controlled by an Erodible Plug[J]. Pharmaceutical Research, 1998, 15:474-481
[23] Ina Kr?gel, Roland Bodmerier. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder[J].Controlled release,1999 (61):43-50
[24] 吴芳,张志荣,何伟玲等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[25] 罗明生主编等.中国药用辅料[M].北京:化学工业出版社,2006,712-715
[26] General Information/ In vitro and in vivo evaluation of dosage froms<1088>. USP 23:1925
[1] 吴芳,张志荣.灌注法制备脉冲给药装置的新型非渗透胶囊体[J].华西药学杂志,2006,21(1):005-007
[2] 邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598
[3] 齐美玲,王鹏,郑俊民,等.盐酸尼卡地平定时释放片研究药学学报[J].1999, 34(9):710-715
[4] 陆彬. 药物新剂型与新技术[M].第二版,北京:人民卫生出版社.2005:386-392
[5] Pozzi F., Furlani P., Gazzaniga A., et al. The time clock system: a new oral dosage form for the fast and complete release of drug after a predetermined lag time[M]. J. of Controlled Release,1994,31(1):99-108
[6] 吴芳,张志荣,何伟玲等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[1] Connor AL, Wray H, Cottrell J, et al. A scintigraphic study to investigate the potential of altered gut distribution of loperamide from a loperamide-simethicone formulation in man[J]. Eur J Pharm Sci,2001,13:369-374
[2] 邹豪,蒋雪涛,潘文舟等.盐酸维拉帕米脉冲释放片在人体内γ-闪烁扫描示踪研究[J]. 实用放射学杂志,2001,17(12):881-885
[3] 邹豪,孔令山,谢明萱. 漂浮型脉冲胶囊释放的人体内γ-闪烁扫描示踪研究[J].中国医药工业杂志, 2004,35(12):724-726
[4] 吴芳,丁洪,张志荣. 用γ射线显影法研究磷酸川芎嗪脉冲塞胶囊在犬胃肠道内的崩解释药和转运行为[J]. 生物医学工程杂志,2006,23(4):790-794
[5] 张洁,张纯,高申,等. 胸腺肽α1结肠释放片在人体γ-闪烁扫描示踪研究[J]. 第二军医大学学报,2005,26(9):1026-1028
[6] 齐美玲,王鹏,吴德政. γ-闪烁扫描法确定替硝唑结肠释放片人体内释药部位的研究[J].中国药学杂志,2003,38(2):114-116
[7] 刘卫卫,张纯,谭真. 阿莫西林胃滞留片人体内γ-闪烁扫描示踪研究[J].南京军医学院学报,2001,23(1):39-40
[8] 陈艳,邹豪,蒋学涛.药物制剂体内示踪技术—γ-闪烁扫描的应用[J].药学实践杂志,2003,21(4):198-201
[1] Anthony H.V.Schapir, DSc, C.Warren Olanow. Neuroprotection in Parkinson Disease Mysteries, Myths and Misconceptions[J]. JAMA. 2004,291: 358-364
[2] Z.Zhang, G.Roman, Z.Hong et al. Parkinson’s disease in China: Prevalence in Beijing,xian,and Shanghai[J]. Lancet,2005, 365(9459):595-597
[3] 吴浩翔,刘玉玲.帕金森治疗药物研究进展[J].中国药学杂志,2004,39(6): 409-412
[4] 何绍雄.间药理学与时间治疗学[M]. 天津:天津科学技术出版社,1993,46-201
[5] 邹豪.口服脉冲和定时释药系统[J]. 国外医学药学分册,1999,26(1):33-38
[6] Lemmer B, Implications of chronopharmacokinetics for drug delivery: an antiasthmatics, H2-blockers and cardiovascular active drugs[J], Adv Drug Deliv Rev ,1991,6(1):83
[7] 吴芳,张志荣.定时脉冲释药系统[J].药学进展,2001,25(5):279-283
[8] Shinji N, Minako N, Y oshiyuki H. An organic acid-induced sigmoidal release system for oral controlled-release preparations. III. Elucidation of the anomalous drug release behavior through osmotic pumping mechanism[J]. Inter J Pharm, 1997,148:85-91
[9] 郝钦,岗艳云,朱家壁.硝酸异山梨酷脉冲控释微丸的研制[J].中国医药工业杂志,1999,30(3):109-111
[10]Poli IND Chimica SPA (IT). Methods for treating morning pathologies. US:5788987. 1998-08-04
[11]Ryuzo I, Hiroyuki Y, Y oshiyuki H. Absorption of Diltiazem in Beagle dog from pulsatile release tablet[J]. Chem Pharm Bull, 1992, 40(11):3094-3096
[12]Soberer DDS develops“alarm clock” dose formulation[J]. Pharm J,l991,247: 138
[13]齐美玲,王鹏,郑俊民,等.盐酸尼卡地平定时释放片研究[J]. 药学学报,1999, 34(9):710-71
[14]陈燕忠,岗艳云,金志忠,等.法莫替丁脉冲控释胶囊剂的研究[J].中国药科大学学报,1997,28(3):150-154
[15]Soni V, Singh R, Srinivasan R, et al. Pulsatile insulin delivery through the ocular route[J]. Drug Delivery,1998,5(1):47-51
[16]Michael C, Shari AL, Jane CL, et al. In vitro testing of a pulsatile delivery system and its in vivo application for immunisation against tetanus toxoid[J]. Journal of Controlled Release,1997,47:205-219
[17]Satoshi U, Rinta I, Sumihisa K,et al. Development of a novel drug release system, time-controlled explosion system (TES) Ⅲ.Relation between lag time and membrane thickness[J]. Chem Pharm Bull,1994,42(2):364-367
[18]Satoshi U, Hisami Y, MasateruK. Development of a novel drug release system, time-controlled explosion system (TES)Ⅱ. Design of multiparticulate TES and invitro drug release properties[J]. Chem Pharm Bull,1994,42(2):359-363
[19]T Ishibashi, G R P Itcairn, H Yoshino,et al. Scintigraphic evaluation of a new capsule-type colon specific drug delivery system in healthy volunteers[J]. J Pharm Sci,1998,87(5):531-53
[20]Scrip,1996,(2138):17
[21]S eiyaK, Tatsuki S, Y utakaK,et al. Electroresponsive pulsatile depot delivery of insulin from poly(dimethylaminopropylacrylamide) gel in rats[J]. J Pharm Sci,1997,86(1I):1273-1277
[22]Yoshida R, Sakai K, Okano T, et al. "On-Off' switching mechanism of pulsatile drug release poly(N-idopropylacrylamide-co-alkyl methacrylate) gels[J]. Proc Conf Intell Mater,1993:393-396
[23]Mcneill ME, Rashid A, Stevens HNE. Dispensing device. US5342624. 1994-08-30
[24]Takada K. Controlled-release preparations. US:563719. 1997-06-10
[25]Krogel I, Bodmeier R. Evaluation of an enzyme-containing capsular shaped pulsatile drug delivery system[J]. Pharm Res,1999,16(9):1424-1429
[26]Ina Kr?gel, Roland Bodmerier. Pulsatile Drug Release from an Insoluble Capsle Body Controlled by an Erodible Plug[J]. Pharmaceutical Research, 1998,15:474-481
[27]Ina Kr?gel, Roland Bodmerier. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder[J]. Journal of Controlled Release,1999, (61):43-50
[28]吴芳,张志荣,何伟玲,等.磷酸川芎嗪脉冲塞胶囊的制备与体外释放[J].药学学报,2002,37(9):733-738
[29]邹豪,卢文芸,陈宙艳,等.漂浮型脉冲胶囊的设计和研制[J].中国医药工业杂志,2004,35(10):595-598