基于三维打印技术的新型口服控释给药系统研究
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摘要
三维打印技术是一种依据“逐层打印,层层叠加”的概念,通过计算机辅助绘图设计模型及计算机控制直接制备具有特殊外型或复杂内部结构物体的快速成形技术。该技术加工过程灵活、成形速度快、运行费用低且可靠性高。由于突破了传统制剂技术的一些局限性,三维打印能够为新型口服控释给药系统的研究提供新的策略与途径,这使得其在药剂学中的应用引起了越来越多的关注。根据“安全、有效、方便”的给药治疗原则,本文从给药系统的内部结构、局部成分与组成的差异、特殊几何外型、独特表面特征、控释材料(或药物)的梯度或离散分布、多药在同一系统中的准确定位与分布等方面出发,设计并制备了多种新型口服控释给药系统;通过常规分析、结构观察、药物体外释放特征研究等方面对所制备的给药系统进行性能评价;初步探讨了给药系统的粘结成形过程和机制、工艺条件选择与优化。具体完成的主要研究工作有:
(1)在分析传统口服控释给药系统制备技术的局限性基础上,综述了三维打印技术及其在药剂学中的应用现状,指出三维打印技术由于其突出的制造能力,能够为新型口服给药系统的研究与开发提供新的策略与思路。
(2)通过与传统粉末直接压片和湿法造粒压片技术相比较,反映三维打印成形技术的制备优势,如药片内部结构均匀、药物高度分散、载药量准确;药物释放稳定性高,重现性好;药片制备过程简单重复、自动化程度高,证明三维打印成形技术可以用于口服控释药片的研制。
(3)研究了三维打印制备工艺。通过体外溶出实验探究了不同工艺参数如控释粉末材料、粘结剂、粘结剂喷涂次数、粉末铺层厚度及药片中孔孔径等的变化对所制备控释片中药物释放的影响,证明了三维打印技术具有高度的制备灵活性。结合打印条件的选定,初步研究粘结成形机制及其对药片机械性能的影响。以羟丙基甲基纤维素、对乙酰基氨基酚、乳糖为混合粉末,以乙醇、水或混合液作打印液,研究不同粒径颗粒的溶解时间、不同打印液在粉末中的挥发速率,为选定合适的粉末粒径和打印层间隔时间提供了方法和依据。通过改变打印次数来调整粘结剂的喷涂量,测定不同喷涂量下药片的硬度与脆碎度的变化情况,并通过环境扫描电镜观察颗粒粘结状态,说明了机械性能变化的原因及相关粘结机制,为选定与喷涂量相关的工艺参数如打印次数、粉末层厚、打印线间距、滴间距等提供了合适的方法。
(4)利用三维打印技术制备了各种新型的零级控释给药系统,如:①具有药物梯度分布和部分表面阻释特征的零级控释给药系统。经过常规分析、结构分析和体外溶出试验,证明了该给药系统的各项指标符合相关片剂标准,轴向阻释层能够完全阻止药物释放,径向药物呈梯度向中心递增分布,药物能以零级方式恒速释放;②具有控释材料梯度及特殊表面特征的零级控释给药系统。通过药物预先与赋形剂混合,然后喷涂含控释材料打印液进行粘结成形的方式取代喷涂含药物打印液的方式来制备,并比较分析了不同材料如乙基纤维素、十二烷基硫酸钠、硬脂酸、丙烯酸树脂Eudragit RSPO在羟丙基甲基纤维素骨架片中的阻释性能;③部分包裹的馅饼型零级控释给药系统。系统中95%的对乙酰基氨基酚能够通过外周和内孔面的同时溶蚀以零级速率释放。径向两端的乙基纤维素阻释层与含药核心能较强地黏结在一起,在整个溶出期间提供持续的阻释效果。对乙酰基氨基酚的总释放时间能够通过馅饼片的环厚与含阻释材料粘结液的喷涂次数进行单独调整;对乙酰基氨基酚的剂量能够通过馅饼片的环高度进行单独调整。
(5)利用三维打印技术制备了各种新型的区位控制药物释放的给药系统,如:①片中心含有未粘结粉末的豆腐果苷速崩片。对所制备的速崩片进行常规分析、崩解时限、体外释药试验及结构观察,结果表明所制备速崩片的各项技术性能符合药典相关规定;载药量精准,片间药物含量差异为±1.1%;崩解快,仅为19.8 s,豆腐果苷溶出速度快,体外2 min内即可完全释放;②具有复杂结构和局部材料组成差异的盐酸二甲双胍漂浮控释片。该药片具有较好的初浮性,利用万分之一电子天平自制浮力计,结果显示药片在药物整个溶出过程中保持较大的持浮力,溶出结果表明药片能够控制盐酸二甲双胍在10h内以零级速率释放;③具有复杂结构的结肠靶向控释药片。体外释药试验表明,不同材料制备的控释片中,靶向效果丙烯酸树脂Eudragit S100 >Eudragit L100 >羟丙基甲基纤维素酚酞酸酯。不同药物制备控释片中,水难溶性药物双氯芬酸钠的靶向释药效果优于水易溶性药物马来酸氯苯那敏。
(6)利用三维打印技术制备了新型的按时间控制药物释放的给药系统。该系统片芯含药,片周控制药物初始释放时间,体外溶出试验结果表明药物释放具有较好的滞后效应,并可以通过致孔剂的粒径、含量,粘结剂的喷涂次数等参数调控滞后时间的长短。
利用三维打印技术制备了具有多层结构和层间材料组成差异的豆腐果苷多相控释片,将不同的释药方式结合在一起,控制药物以先脉冲后恒速的两相方式释放。体外溶出结果表明该药片在前两个小时的人工胃液中以脉冲方式释放51.64%的药物,随后在人工肠液中维持药物以恒定速率在11个小时内将药物释放完全。
Three-dimensional printing (3DP) is a solid freeform fabrication technique, which employs powder processing in the construction of parts in a layer-wise manner. It is capable of fabricating parts directly from CAD (computer-aided design) models, and can handle features such as special exterior shapes, complex inner structures and so on. It has the advantages of easy process, fast prototyping, and low cost and high reproducibility. Because of breaking through some limitations of conventional formulation techniques, 3DP can offer novel strategies and approaches for the research and development of novel oral controlled-release drug delivery systems (DDS). The applications of 3DP in pharmaceutics have drawn more and more attentions.
In this dissertation, many novel DDS have been conceived and fabricated using 3DP. The DDS have special design features to furnish the desired drug release profiles, which deliver the drug in a safe, efficient and convenient way. The features include special inner structures, local differences of materials and compositions, geometry, special surface texture, gradient or discrete distributions of the release-modulation materials (or active ingredients), accurate positioning and distribution of multi-drugs in the same DDS, and any combinations of these. The resulted DDS have been evaluated through routine analysis, observation of structure and surface characteristics, in vitro dissolution tests and so on. The prototyping process, the binding mechanisms of DDS, the selection and optimization of the process conditions have also been preliminary investigated.
(1) The limitations of conventional technologies for preparing oral controlled-release drug delivery systems have been summarized. 3DP and its application in pharmaceutics have been introduced. It is expected that 3DP can offer new strategies and approaches for the research and development of novel oral drug delivery systems because of its outstanding manufacturing capability.
(2) Compared with the tablets made by conventional direct compression method and wet granulation method, 3DP tablets showed some advantages, such as having uniform inner structure, highly drug dispersiblility, accurate dosage; reproducible and stable drug release profile, easy and highly automatic fabricating process and so on.
(3) The influence of different prototyping parameters such as release-modulation powder materials, binder liquid, printing passes of binder liquid, thickness of powder layer, the designed diameters of central holes on the drug release profiles were investigated by in vitro dissolution tests. The results demonstrated that 3DP had superior preparing flexibility.
The binder mechanism and its influence on the tablets’mechanical performance were investigated. Hydroxypropylmethylcellulose (HPMC), acetaminophen (ATP) and lactose were premixed and used as the layered powder, while ethanol, water, and their mixture were employed as binder liquids. The dissolution time of different powders and the volatilization rate of different binder solutions from the layered powder were determined, which were useful for the reasonable selection of particles’dimensions and interval times between two printing layers. The amount of dispensing binder liquid could be modulated by manipulating the printing passes. The values of tablets’hardness and friability under different amount of binder liquid were determined. Environmental scanning electron microscopy (ESEM) was employed to observe the binding state of particles. The reason for the alteration of mechanical performance and the relative binder mechanism was illustrated. These studies offered suitable methods for the selection of printing parameters related to the printing amount of binder solution, such as printing passes, layer thickness, line-to-line spacing, drop-todrop spacing and so on.
(4) Three kinds of novel oral zero-order controlled release DDS have been fabricated using 3DP:①DDS with gradient distributions of drug and partial release-retardation surface. Routine analysis, structure analysis and in vitro dissolution results showed that the pharmaceutical properties of the DDS met the relavent standards, drug release from the axial direction was totally retarded, drug distributed according to a radial gradient increasing manner from the circumference to the center.②DDS with with gradient distributions of release-retarded materials and special surface texture. The DDS were prepared by pre-mixing the drug with the excipients and then bound together by depositing the binder liquids containing release-retardation-materials instead of printing drug-contained binder solutions. The release-retardation capabilities in HPMC matrix tablets for ethyl cellulose (EC)、sodium lauryl sulfate (SLS)、stearic acid (SA)、Eudragit RSPO were also studied respectively.③DDS with partial-coating and donut-shape. Over 95% of the model drug ATP was released from the peripheral and inner hole surface in zero-order kinetics via erosion mechanism. The EC release-retarding layers on both sides in the axial direction were strongly bound with the drug-contained core, resulting in sustaining release-retardation effects in the whole dissolution process. The total release time of ATP could be modulated by the annular thickness and printing passes of release-retardation-material-contained binder liquids respectively. The dosage of ATP could be modulated by the annular height separately.
(5) Three kinds of novel oral site-specific DDS have been fabricated using 3DP:①Fast-disintegrating helicid tablets with unbound powder in the central core. Routine analysis, disintegrating time limit, structure observation and in vitro dissolution results showed that the tablet technical performance met the related ordainments of Chinese pharmacopoeia. The dosage of loaded drug was accurate with the content deviation among tablets of±1.1%. Helicid could be dissolved out very quickly with the disintegrating time of 19.8 s and the exhausting time in vitro of 2 minutes;②Metformin hydrochloride floating DDS with complex structure features and local material and composition difference. The tablets had good buoyancy when put into the dissolution medium. The results achieved by a self-made buoyancy meter, which was reconstructed from an electronic scale, showed that the tablets could keep enough buoyancy force in the whole dissolution process. Dissolution results in vitro indicated that metformin hydrochloride was released from the tablets in zero-order kinetics for 10 hours;③Colon-targeted DDS with complex structure features. Dissolution results in vitro indicated that the target effects had the following sequence: Eudragit S100 >Eudragit L100 >HPMCP (Hydroxypropylmethyl Cellulose phthalate), when these materials were employed in the fabrication of tablets. The target effect of water insoluble drug diclofenac sodium was better than that of the water freely soluble drug chlorphenamine maleate when they were incorporated into the tablets.
(6) Time-specific DDS with drug only in the center were prepared using 3DP. The initial release time was controlled by the peripheral region. Dissolution results in vitro showed that the drug release had good time-lag effect, and that the lag time could be modulated by the channeling agent’s diameter, content and the dispensing times of binder liquid.
Multi-phasic helicid DDS with multi-layer structure and difference of material and composition among layers were fabricated using 3DP. Different release profiles were combined together. The drug was released in a bi-phasic manner, i.e. first in pulse manner and then in zero-order manner. Dissolution results in vitro indicated that 51.64% of the drug was released in the mock gastric juice in pulse manner in the former 2 hours, and the left drug was completely released in the mock gut juice in zero-order manner in the later 11 hours.
(1)在分析传统口服控释给药系统制备技术的局限性基础上,综述了三维打印技术及其在药剂学中的应用现状,指出三维打印技术由于其突出的制造能力,能够为新型口服给药系统的研究与开发提供新的策略与思路。
(2)通过与传统粉末直接压片和湿法造粒压片技术相比较,反映三维打印成形技术的制备优势,如药片内部结构均匀、药物高度分散、载药量准确;药物释放稳定性高,重现性好;药片制备过程简单重复、自动化程度高,证明三维打印成形技术可以用于口服控释药片的研制。
(3)研究了三维打印制备工艺。通过体外溶出实验探究了不同工艺参数如控释粉末材料、粘结剂、粘结剂喷涂次数、粉末铺层厚度及药片中孔孔径等的变化对所制备控释片中药物释放的影响,证明了三维打印技术具有高度的制备灵活性。结合打印条件的选定,初步研究粘结成形机制及其对药片机械性能的影响。以羟丙基甲基纤维素、对乙酰基氨基酚、乳糖为混合粉末,以乙醇、水或混合液作打印液,研究不同粒径颗粒的溶解时间、不同打印液在粉末中的挥发速率,为选定合适的粉末粒径和打印层间隔时间提供了方法和依据。通过改变打印次数来调整粘结剂的喷涂量,测定不同喷涂量下药片的硬度与脆碎度的变化情况,并通过环境扫描电镜观察颗粒粘结状态,说明了机械性能变化的原因及相关粘结机制,为选定与喷涂量相关的工艺参数如打印次数、粉末层厚、打印线间距、滴间距等提供了合适的方法。
(4)利用三维打印技术制备了各种新型的零级控释给药系统,如:①具有药物梯度分布和部分表面阻释特征的零级控释给药系统。经过常规分析、结构分析和体外溶出试验,证明了该给药系统的各项指标符合相关片剂标准,轴向阻释层能够完全阻止药物释放,径向药物呈梯度向中心递增分布,药物能以零级方式恒速释放;②具有控释材料梯度及特殊表面特征的零级控释给药系统。通过药物预先与赋形剂混合,然后喷涂含控释材料打印液进行粘结成形的方式取代喷涂含药物打印液的方式来制备,并比较分析了不同材料如乙基纤维素、十二烷基硫酸钠、硬脂酸、丙烯酸树脂Eudragit RSPO在羟丙基甲基纤维素骨架片中的阻释性能;③部分包裹的馅饼型零级控释给药系统。系统中95%的对乙酰基氨基酚能够通过外周和内孔面的同时溶蚀以零级速率释放。径向两端的乙基纤维素阻释层与含药核心能较强地黏结在一起,在整个溶出期间提供持续的阻释效果。对乙酰基氨基酚的总释放时间能够通过馅饼片的环厚与含阻释材料粘结液的喷涂次数进行单独调整;对乙酰基氨基酚的剂量能够通过馅饼片的环高度进行单独调整。
(5)利用三维打印技术制备了各种新型的区位控制药物释放的给药系统,如:①片中心含有未粘结粉末的豆腐果苷速崩片。对所制备的速崩片进行常规分析、崩解时限、体外释药试验及结构观察,结果表明所制备速崩片的各项技术性能符合药典相关规定;载药量精准,片间药物含量差异为±1.1%;崩解快,仅为19.8 s,豆腐果苷溶出速度快,体外2 min内即可完全释放;②具有复杂结构和局部材料组成差异的盐酸二甲双胍漂浮控释片。该药片具有较好的初浮性,利用万分之一电子天平自制浮力计,结果显示药片在药物整个溶出过程中保持较大的持浮力,溶出结果表明药片能够控制盐酸二甲双胍在10h内以零级速率释放;③具有复杂结构的结肠靶向控释药片。体外释药试验表明,不同材料制备的控释片中,靶向效果丙烯酸树脂Eudragit S100 >Eudragit L100 >羟丙基甲基纤维素酚酞酸酯。不同药物制备控释片中,水难溶性药物双氯芬酸钠的靶向释药效果优于水易溶性药物马来酸氯苯那敏。
(6)利用三维打印技术制备了新型的按时间控制药物释放的给药系统。该系统片芯含药,片周控制药物初始释放时间,体外溶出试验结果表明药物释放具有较好的滞后效应,并可以通过致孔剂的粒径、含量,粘结剂的喷涂次数等参数调控滞后时间的长短。
利用三维打印技术制备了具有多层结构和层间材料组成差异的豆腐果苷多相控释片,将不同的释药方式结合在一起,控制药物以先脉冲后恒速的两相方式释放。体外溶出结果表明该药片在前两个小时的人工胃液中以脉冲方式释放51.64%的药物,随后在人工肠液中维持药物以恒定速率在11个小时内将药物释放完全。
Three-dimensional printing (3DP) is a solid freeform fabrication technique, which employs powder processing in the construction of parts in a layer-wise manner. It is capable of fabricating parts directly from CAD (computer-aided design) models, and can handle features such as special exterior shapes, complex inner structures and so on. It has the advantages of easy process, fast prototyping, and low cost and high reproducibility. Because of breaking through some limitations of conventional formulation techniques, 3DP can offer novel strategies and approaches for the research and development of novel oral controlled-release drug delivery systems (DDS). The applications of 3DP in pharmaceutics have drawn more and more attentions.
In this dissertation, many novel DDS have been conceived and fabricated using 3DP. The DDS have special design features to furnish the desired drug release profiles, which deliver the drug in a safe, efficient and convenient way. The features include special inner structures, local differences of materials and compositions, geometry, special surface texture, gradient or discrete distributions of the release-modulation materials (or active ingredients), accurate positioning and distribution of multi-drugs in the same DDS, and any combinations of these. The resulted DDS have been evaluated through routine analysis, observation of structure and surface characteristics, in vitro dissolution tests and so on. The prototyping process, the binding mechanisms of DDS, the selection and optimization of the process conditions have also been preliminary investigated.
(1) The limitations of conventional technologies for preparing oral controlled-release drug delivery systems have been summarized. 3DP and its application in pharmaceutics have been introduced. It is expected that 3DP can offer new strategies and approaches for the research and development of novel oral drug delivery systems because of its outstanding manufacturing capability.
(2) Compared with the tablets made by conventional direct compression method and wet granulation method, 3DP tablets showed some advantages, such as having uniform inner structure, highly drug dispersiblility, accurate dosage; reproducible and stable drug release profile, easy and highly automatic fabricating process and so on.
(3) The influence of different prototyping parameters such as release-modulation powder materials, binder liquid, printing passes of binder liquid, thickness of powder layer, the designed diameters of central holes on the drug release profiles were investigated by in vitro dissolution tests. The results demonstrated that 3DP had superior preparing flexibility.
The binder mechanism and its influence on the tablets’mechanical performance were investigated. Hydroxypropylmethylcellulose (HPMC), acetaminophen (ATP) and lactose were premixed and used as the layered powder, while ethanol, water, and their mixture were employed as binder liquids. The dissolution time of different powders and the volatilization rate of different binder solutions from the layered powder were determined, which were useful for the reasonable selection of particles’dimensions and interval times between two printing layers. The amount of dispensing binder liquid could be modulated by manipulating the printing passes. The values of tablets’hardness and friability under different amount of binder liquid were determined. Environmental scanning electron microscopy (ESEM) was employed to observe the binding state of particles. The reason for the alteration of mechanical performance and the relative binder mechanism was illustrated. These studies offered suitable methods for the selection of printing parameters related to the printing amount of binder solution, such as printing passes, layer thickness, line-to-line spacing, drop-todrop spacing and so on.
(4) Three kinds of novel oral zero-order controlled release DDS have been fabricated using 3DP:①DDS with gradient distributions of drug and partial release-retardation surface. Routine analysis, structure analysis and in vitro dissolution results showed that the pharmaceutical properties of the DDS met the relavent standards, drug release from the axial direction was totally retarded, drug distributed according to a radial gradient increasing manner from the circumference to the center.②DDS with with gradient distributions of release-retarded materials and special surface texture. The DDS were prepared by pre-mixing the drug with the excipients and then bound together by depositing the binder liquids containing release-retardation-materials instead of printing drug-contained binder solutions. The release-retardation capabilities in HPMC matrix tablets for ethyl cellulose (EC)、sodium lauryl sulfate (SLS)、stearic acid (SA)、Eudragit RSPO were also studied respectively.③DDS with partial-coating and donut-shape. Over 95% of the model drug ATP was released from the peripheral and inner hole surface in zero-order kinetics via erosion mechanism. The EC release-retarding layers on both sides in the axial direction were strongly bound with the drug-contained core, resulting in sustaining release-retardation effects in the whole dissolution process. The total release time of ATP could be modulated by the annular thickness and printing passes of release-retardation-material-contained binder liquids respectively. The dosage of ATP could be modulated by the annular height separately.
(5) Three kinds of novel oral site-specific DDS have been fabricated using 3DP:①Fast-disintegrating helicid tablets with unbound powder in the central core. Routine analysis, disintegrating time limit, structure observation and in vitro dissolution results showed that the tablet technical performance met the related ordainments of Chinese pharmacopoeia. The dosage of loaded drug was accurate with the content deviation among tablets of±1.1%. Helicid could be dissolved out very quickly with the disintegrating time of 19.8 s and the exhausting time in vitro of 2 minutes;②Metformin hydrochloride floating DDS with complex structure features and local material and composition difference. The tablets had good buoyancy when put into the dissolution medium. The results achieved by a self-made buoyancy meter, which was reconstructed from an electronic scale, showed that the tablets could keep enough buoyancy force in the whole dissolution process. Dissolution results in vitro indicated that metformin hydrochloride was released from the tablets in zero-order kinetics for 10 hours;③Colon-targeted DDS with complex structure features. Dissolution results in vitro indicated that the target effects had the following sequence: Eudragit S100 >Eudragit L100 >HPMCP (Hydroxypropylmethyl Cellulose phthalate), when these materials were employed in the fabrication of tablets. The target effect of water insoluble drug diclofenac sodium was better than that of the water freely soluble drug chlorphenamine maleate when they were incorporated into the tablets.
(6) Time-specific DDS with drug only in the center were prepared using 3DP. The initial release time was controlled by the peripheral region. Dissolution results in vitro showed that the drug release had good time-lag effect, and that the lag time could be modulated by the channeling agent’s diameter, content and the dispensing times of binder liquid.
Multi-phasic helicid DDS with multi-layer structure and difference of material and composition among layers were fabricated using 3DP. Different release profiles were combined together. The drug was released in a bi-phasic manner, i.e. first in pulse manner and then in zero-order manner. Dissolution results in vitro indicated that 51.64% of the drug was released in the mock gastric juice in pulse manner in the former 2 hours, and the left drug was completely released in the mock gut juice in zero-order manner in the later 11 hours.
引文
[1]张志荣,何勤.药剂学研究进展[J].中国药学杂志, 2001, 36 (1): 10-13.
[2] Das NG, Das SK. Controlled-release of oral dosage forms [EB/OL]. Available at: http://www.pharmtech.com/pharmtech/data/articlestandard/pharmtech/232003/59302/article.pdf
[3] Suresh P. Development, characterization and evaluation of a pulsed-release tablet dosage form for low dose water soluble drugs [D]. PhD dissertation. Kingston: University of Rhode Island, 2000.
[4]余灯广,杨祥良,徐辉碧. pH-敏感型水凝胶在多肽和蛋白质药物给药系统研究中的应用[J].中国医院药学杂志, 2005,25(8): 762-764.
[5] Wu BM, Borland SW, Giordano RA, et al. Solid free-form fabrication of drug delivery devices [J]. J. Control Release, 1996, 40: 77-87.
[6] John BS. Controlled delivery oral dosage forms in the new millennium [EB/OL]. Available at: http://www.nutraceutix.com/pdf/PMPS_12_2000.pdf.
[7] Scahs EM, Haggerty JS, Cima MJ, et al. Three-dimensional printing technique [P]. US Patent NO.5204055, 1993.
[8]张曙,穆兰.快速原形技术的医学应用[J].机电一体化, 2000, 1/2: 22-25.
[9] Leong KF, Cheah CM, Chua CK. Solid freeform fabrication of three-dimensional scaffolds for engineering replacement tissues and organs [J]. Biomaterials, 2003, 24: 2363-2378.
[10] Anonymity. What is the 3DPTM process [EB/OL]. Available at: http://web.mit.edu/tdp/www/whatis3dp.html.
[11] Katsta WE, Palazzolo RD, Rowe CW, et al. Oral dosage forms fabricated by three-dimensional printing [J]. J Control Release, 2000, 66: 1-9.
[12] Rowe CW, Katstra WE, Palazzolo RD, et al. Multimechanism oral dosage forms fabricated by three-dimensional printing [J]. J control Release, 2000(66): 11-17.
[13] Wang CC, Yoo J, Bornancini E, et al. Diffusion-controlled dosage form and method of fabrication including three-dimensional printing [P]. US Patent NO. 005360, 2004.
[14] Pryce Lewis WE, Rowe CW, Cima MJ, et al. System for manufacturing controlled release dosage forms, such as a zero-order release profile dosage form manufactured by three-dimensional printing [P]. US Patent NO. 0198677, 2003.
[15] Rowe CW, Pryce Lewis WE, Cima MJ, et al. Printing of dispensing a suspension such as three-dimensional printing of dosage forms [P]. US Patent NO.0099708, 2003.
[16] Wu BJ, Cima MJ. Effects of solvent-particle interaction kinetics on Microstructure formation during three-dimensional printing [J]. Polymer Eng Sci, 1999, 39: 249-260.
[17]李晓燕,张曙.三维打印成形技术在制药工程中的应用[J].中国制造业信息化, 2004, 33 (4): 105-107.
[18] Sachs E, Cima M, Williams P, et al. Three-dimensional printing: Rapid tooling and prototypes directly from a CAD model [J]. J Eng Ind, 1992, 114(4): 481-488.
[19] Langer R.药物人体漫游记[J].科学, 2003, 6: 34-39.
[20] John T, Santini J, Cima M J, et al. A controlled-release microchip [J]. Nature, 1999, 397(28): 335-338.
[21] Cima LG, Chim MJ. Preparation of medical devices by solid free-form fabrication methods [P]. US Patent NO. 5490962, 1996.
[22] Low KH, Leong KF, Chua CK, et al. Characterization of SLS parts for drug delivery devices [J]. Rapid Prototyping J, 2001,7 (5): 262-267.
[23] Leong KF, Cheah CM, Chua CK. Solid freeform fabrication of three-dimensional scaffolds for engineering replacement tissues and organs. Biomaterials [J], 2003, 24 (13): 2363-2378.
[24] Petezold R, Zeilhfer HF, Kalender WA. Rapid prototyping technology in medicine-basics and applications [J]. Computerized Medical Imaging and Graphics,1999, 23(5): 277-284.
[25]余灯广,杨祥良,徐辉碧,等.三维打印技术在药剂学中的应用[J].中国新药杂志, 2005,14 (7): 843-848.
[26]国家药典委员会.中华人民共和国药典(二部) [S].北京:化学工业出版社, 2005.附录74-77.
[27] Monkhouse DC, Yao J, Sherwood MJ, et al. Dosage forms exhibiting multi-phasic release kinetics and methods of manufacture thereof [P]. US Patent NO. 6280771, 2001.
[28] Rigby SP, Van der Walle CF, Raistrick JH. Determining drug spatial distribution within controlled delivery tablets using MFX imaging [J]. J Control Release, 2004, 96(1): 97-100.
[29]侯鹏,潘卫三,吴学明.固体分散技术在药剂学中的研究进展[J].中国新药杂志, 2003, 12(4): 245-249.
[30] Monkhouse DC, Sandee PK, Rowe CW, et al. A complex-aided fabrication process for rapid designing, prototyping and manufacturing [P]. WO Patent NO. 29202, 2000.
[31] Payumo FC, Sherwood JK, Yoo J, et al. Method and form of a drug delivery device, such as encapsulating a toxic core within a non-toxic region in an oral dosage form [P]. US Pat: 0015728, 2002-02-07.
[32]陈炜,姚晚萍.神衰果素片的稳定性研究[J].中草药, 1998, 29(10): 669-670.
[33]袁筝.豆腐果苷的剂型开发与药动学研究[D].硕士论文,武汉:华中科技大学, 2005.
[34]平其能.现代药剂学[M].北京:中国医药科技出版社, 1998.
[35] Petezold R, Zeilhfer HF, Kalender WA. Rapid prototyping technology in medicine-basics and applications [J]. Computerized Medical Imaging and Graphics, 1999, 23 (5): 277-284.
[36] Siepmann J, Kranz H, Peppas NA, et al. Calculation of the required size and shape of hydroxypropyl methylcellulose matrices to achieve desired drug release profiles[J]. Int J Pharm, 2000, 201: 151-164.
[37] Mahaguna V, Talbert RL, Peters JI, et al. Influence of hydroxypropyl methylcellulose polymer on in vitro and in vivo performance of controlled release tablets containing alprazolam [J]. Eur J Pharm Biopharm, 2003, 56: 461-468.
[38] Thomas DR, Stevin HG, Ajaz SH, et al. Polymer erosion and drug release characterization of hydroxypropyl methylcellulose matrices [J]. J Pharm Sci, 1998, 87: 1115-1123.
[39] Otsuka M, Matsuda Y. Comparative evaluation of mean particle size of bulk drug powder in pharmaceutical preparations by fourier-transformed powder diffuse reflectance infrared spectroscopy and dissolution kinetics [J]. J Pharm Sci, 1996, 85:112-116.
[40] Devotta I, Ambeskar VD, Mandhare AB, et al. The lifetime of a dissolving polymeric particle [J]. Chem Eng Sci, 1994, 49: 645-654.
[41] Tailin F. Droplet-powder impact interaction in three-dimensional printing [D]. Cambridge: Massachusetts institute of technology, 1995.
[42] Fell JT, Newton JM. Determination of tablets’strength by the diameter-compression test [J]. J pharm Sci 1970, 59, 688-691.
[43] Streubel A, Siepmann J, Peppas N A, et al. Bimodal drug release achieved with multi-layer matrix tablets: transport mechanisms and device design [J]. J Control Release 2000, 69: 455-468.
[44] Abdul S, Poddar SS. A flexible technology for modified release of drug: multi layered tablets [J]. J Control Release, 2004, 97: 393-405.
[45]贾伟,高文远.药物控释新剂型[M].北京:化学工业出版社, 2005: 87.
[46] Pillai O, Panchagnula R. Polymers in drug delivery [J]. Current opinion in chemical biology, 2001,5: 447-451.
[47] Chopra SK, Nangia AK, Lee D, et al. Controlled-release devices [P]. US Patent NO. 5342627, 1994.
[48] LangerR. New methods of drug delivery [J]. Science, 1990, 249: 1527-1533.
[49] Paolo C, Antonio CC, Giorgio P. Multilayer matrix systems for the controlled-release of active principles [P]. Euro Patent NO. 0598309A2, 1993.
[50]林晓,陈济民.水溶性药物骨架片释放达零级的几种方法[J].中国药学杂志, 2002,37(3): 192-197.
[51] Zhang F. Hot-melt extrusion as a novel technology to prepare sustained- release dosage forms [D]. Austin, America: The university of Texas, 1999.
[52] Wu BM. Microstructural Control during three-dimensional printing of polymeric medical devices [D]. Massachusetts, America: Massachusetts Institute of Technology, 1998.
[53] Reddy KR, Mutalik S, Reddy S. Once-daily sustained-release matrix tablets of nicorandil: Formulation and in vitro evaluation [J]. AAPS Pharm Sci Tech 2003, 4(4): E61.
[54] Pryce Lewis WE, Rowe CW, Cima MJ, Materna PA. A system and method for uniaxial compression of an article, such as a three-dimensional printed dosage form [P]. WO Patent NO. 03037607, 2003.
[55] Rowe CW, Pryce Lewis WE, Cima MJ, et al. Printing or dispensing a suspension such as three-dimensional printing of dosage forms [P]. WO Patent NO. 03041690, 2003.
[56] Rekhi GS, Jambhekar SS. Ethylcellulose - a polymer review [J]. Drug Dev Ind Pharm 1995, 21: 61-77.
[57] Pollock DK, Sheskey PJ. Micronized ethyl cellulose: Opportunities in direct-compression controlled-release tablets [J]. Pharm Tech 1996, 20: 120-130.
[58] Shlieout G, Zessin G. Investigation of ethyl cellulose as a matrix former and a new method to regard and evaluate the compaction data [J]. Drug Dev Ind Pharm 1996, 22: 313-319.
[59] Crowley MM, Schroeder B, Fredersdorf A, et al. Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion [J]. Int J Pharm 2004, 269: 509-522.
[60] Dittgen M, Durrani M, Lehmann K. Acrylic polymer: a review of pharmaceutical applications [J]. STP Pharm Sci 1997, 7: 403-437.
[61] Filippis PD, Zingone G, Gibellini M, et al. Dissolution rates of different drugs from solid dispersions with Eudragit RS [J]. Eur J Pharm Sci 1995, 3: 265-271.
[62]刘善奎,钟延强,孙其荣,等.丙烯酸树脂系列辅料在药物新剂型中的应用[J].药学实践杂志, 2002, 20: 12-15.
[63] Belal Hossain M, Rashid M, Motahar Hossain AKM. Effect of waxy materials on the release kinetics of ibuprofen from HPMC based sustained release matrix tablet [J]. Pak J Bio Sci 2004, 7: 772-776.
[64] Grassi M, Voinovich D, Franceschinis E, et al. Theoretical and experimental studies on theophylline release from stearic acid cylindrical delivery systems [J]. J Control Release 2003, 92: 275-289.
[65] Dhananjaya A, Sanford B, Norman GG. Hydroxypropyl methylcellulose anionic surfactant interactions in aqueous systems [J]. J Appl Polym Sci 1991, 42: 947-956.
[66] Nokhodchi A, Norouzi-Sani S, Siahi-Shadbad MR, et al. The effect of various surfactants on the release rate of propranolol hydrochloride from hydroxypropylmethylcellulose (HPMC)-Eudragit matrices [J]. Eur J Pharm Biopharm 2002, 54: 349-356.
[67] Rajabi-Slahboomi AR, Leung WSW, Al-Suwailem A, et al. Effect of bile salts on drug release from HPMC matrices [J]. Eur J Pharm Sci 1996, 4: S157.
[68] Lee BJ, Cao QR, Choi YW. Oral controlled-release dosage forms containing acetaminophen [P]. WO Patent NO. 006904, 2004.
[69] Conte U, Maggi L. Modulation of the dissolution profiles from Geomatrix? multi-layer matrix tablets containing drugs of different solubility [J]. Biomaterials 1996, 17: 889-896.
[70] Kr?gel I, Bodmeier R. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder [J]. J Control Release, 1999, 61: 43-50.
[71] Tiwari SB, Murthy TK, Pai MR, et al. Controlled release formulation of tramadol hydrochloride using hydrophilic and hydrophobic matrix system [J]. AAPS Pharm Sci Tech 2003, 4(3): E31.
[72] Reza MS, Quadir MA, Haider SS. Comparative evalution of plastic, hydrophobic and hydrophilic polymers as matrices for controlled-release drug delivery [J]. J Pharm Pharmaceut Sci 2003, 6: 282-291.
[73] Mehuys E, Vervaet C, Remon JP. Hot-melt extruded ethylcellulose cylinders containing a HPMC-Gelucire? core for sustained drug delivery [J]. J Control Release 2004, 94: 273-280.
[74] Traconis N, Rodríguez R, Campos ME, et al. Influence of admixed polymers on the metronidazole release from hydroxypropyl methylcellulose matrix tablets [J]. Pharm Acta Helv 1997, 72: 131-138.
[75] J. P. Cleave. Some geometrical considerations concerning the design of tablets [J]. J Pharm Pharmacol 1965, 17: 698.
[76] Kim CJ. Compressed doughnut-shaped tablets with zero-order release kinetics [J]. Pharm Res 1995, 12:1045-1048.
[77] Kim CJ. Release kinetics of coated doughnut-shaped tablets for water soluble drugs [J]. Eur J Pharm Sci 1999, 7:237-242.
[78] Cheng K, Zhu J, Song X, et al. Zhang. Studies of hydroxypropyl methylcellulose doughnut-shaped tablets [J]. Drug Dev Ind Pharm 1999, 25:1067-1071.
[79] Sundy E and Danckwerts MP. A novel compression-coated doughnut-shaped tablet design for zero-order sustained release [J]. Eur J Pharm Sci 2004, 22:477-485.
[80] Dinesh SM and Samuel HY. A flat circular hole device for zero-order release of drugs: characterization of the moving dissolution boundary [J]. Pharm Res 1990, 7:1195-1197.
[81] Narasimhan B and Langer R. Zero-order release of micro-and macromolecules from polymeric devices: the role of the burst effect [J]. J Control Release, 1997, 47:13-19.
[82] Mohsen AB. Geometric approach for zero-order release of drugs dispersed in aninert matrix [J]. Pharm Res 1994, 11: 914-916.
[83] Danckwerts MP, vander Watt JG, Moodley I. Zero-order release of theophylline from a core-in-cup tablet in sequenced simulated gastric and intestinal fluid [J]. Drug Dev Ind Pharm 1998, 24:163 -174.
[84] Monkhouse DC, Sandeep K, Rowe CW, et al. A computer-aided fabrication process for rapid designing, prototyping and manufacturing [P]. WO Patent NO. 0029202, 2000.
[85] Conte U, Maggi L. Modulation of the dissolution profiles from Geomatrix? multi-layer matrix tablets containing drugs of different solubility [J]. Biomaterials 1996, 17:889-896.
[86] Sangalli ME, Maroni A, Zema L, et al. In viyro and in vivo evaluation of an oral system for time and/or site-specific drug delivery [J]. J Control Release, 2001, 73:103-110.
[87]刘梅,崔光华.口腔速释片的进展及前景[J].中国药学杂志. 2001, 36(9): 580-583.
[88]何忠芳,陈岚,王亚娟.口腔速崩片的研究进展及应用前景[J].兰州医学院学报. 2003, 29(3): 89-91.
[89] Simone S, Peter CS. Fast dispersible ibuprofen tablets [J]. European Journal of Pharmaceutical Sciences, 2002, 3(15): 295-305.
[90] Ito A, Sugihar A. Development of oral dosage forms for elderly patients: use of agar as base of rapidly disintegrating oral tablets [J]. Chem Pham Bull, 1996, 44(11): 2132.
[91] Davis DW. Method of swallowing a pill [P]. US Patent NO. 3418999, 1968.
[92] Baumgartner S, Kristl J, Vrecer F, et a1.Optimization of floating matrix tablets and evaluation of their gastric residence time [J]. Int J Pharm, 2000, 195(1-2): 125-135.
[93]陆彬.药物新剂型与新技术[M].第1版.北京:人民卫生出版社,1998,314.
[94]任飞亮,裴元英.口服结肠定位释药系统的研究进展[J].中国药学杂志. 2005, 40(17): 1288-1291.
[95] Rubinstein A. Colonic drug delivery [J]. DDT: Tec, 2005, 2(1): 34-37.
[96]张正全,陆彬.口服结肠定位给药系统新进展[J].中国药学杂志,2000,35(4): 221-223.
[97]朱盛山主编.药物制剂新剂型[M].北京:化学工业出版社, 2003: 239-250.
[98]周宇,蒋雪涛.口服结肠定位给药系统[J].国外医学药学分册,1999,26(4): 225-228.
[99]邹梅娟,程刚.口服结肠定位给药系统[J].沈阳药科大学学报,2001,18(5): 378-379.
[100]沙静姝.毛洪奎.豆腐果苷(昆明神衰果素) [J].药学通报, 1987, 22 (1): 27.
[101]刘苹,李健,纳冬荃,等.母鼠妊娠期服用豆腐果甙对仔代的神经行为效应[J].中草药. 2002,33(3):238-242.
[102]罗国安,叶磊,王义明,等.一种神衰果素速释片剂及其制备方法[P].中国专利: 1454600A, 2003-11-12.
[103]高春生,崔光华.水渗透对速崩制剂崩解作用的研究[J].中国药学杂志2000, 35(5): 308-311.
[104] Sastry SV, Nyshadham JR, Fix JA. Recent technological advances in oral drug delivery– a review [J]. PSTT, 2000, 3 (4): 138-145.
[105]黄东坡,王远,陈军,等.盐酸二甲双胍胃漂浮缓释片的制备及体外释放[J].中国医药工业杂志, 2002, 33(10): 483-486.
[106] Peter T, Andrewb D, Kirena V. Biphasic controlled release delivery system for high solubility pharmaceuticals and method [P]. WO Patent NO. 9947128, 1999.
[107]史振祺,蒋新国.胃漂浮片的研究进展[J].中国医药工业杂志, 2003, 34(4): 199-202.
[108]侯惠民,朱金屏.胃漂浮缓释片研究I硝苯啶胃漂浮缓释片的制备与性质[J].中国医药工业杂志, 1991, 22(3): 106-109.
[109]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地尔硫蕈胃漂浮缓释片[J].中国医药工业杂志, 1991, 22(4): 156-158.
[110]朱金屏,余勇,侯惠民.胃漂浮缓释片研究Ⅲ核黄素胃漂浮缓释片[J].中国医药工业杂志, 1995, 26(6): 249-251.
[111]宋维红,卢勰炜,朱康杰.壳聚糖胃漂浮小丸的制备[J].中国医药工业杂志2003, 34(11): 558-560.
[112] Reddy LHV, Murhan RSR. Floating dosage systems in drug delivery [J]. Crit Rev Ther Drug Carr Syst, 2002, 19 (6): 553-585.
[113] Curatolo WJ, Lo J. Gastric retention system for controlled drug release [P]. US Patent NO.5443843, 1995.
[114] ?zdemir N, Ordu S, ?zkan Y. Studies of floating dosage forms of furosemide: in vitro and in vivo evaluations of bilayer tablet formulations [J]. Drug Dev Ind Pharm, 2000, 26(8): 857-866.
[115]邹豪,卢文芸,陈宙艳,等.漂浮型脉冲释放胶囊的设计和研制[J].中国医药工业杂志2004, 35(10): 595-599.
[116] Marvola M, Nykanen P, Rautio S, et al. Enteric polymers as binders and coating materials in multiple-unit site-specific drug delivery systems [J]. Eur J Pharm Sci, 1999, 7(3): 259-271.
[117] Ishibashi T, Pitcairn GR,Yoshino H, et al. Scintigraphic evaluation of a new capsule-type colon specific drug delivery system in healthy volunteers [J]. J Pharm Sci, 1998, 87(5): 531-535.
[118] Watts P, Smith A. Target technology: coated starch capsules for site-specific drug delivery into the lower gastrointestinal tract [J]. Expert Opinion on Drug Delivery, 2005, 2(1): 159-167.
[119] Turkoglu M, Ugurlu T. In vitro evaluation of pectin-HPMC compression coated 5-amino- salicylic acid tablets for colonic delivery [J]. Eur J Pharm Biopharm, 2002, 53(1): 65-73.
[120] Sinha VR, Mittal BR, Kumria R. In vivo evaluation of time and site of disintegration of polysaccharide tablet prepared for colon-specific drug delivery [J]. Int J Pharm 2005, 289(1-2): 79-85.
[121] Sinha VR, Kumria R. Polysaccharides in colon-specific drug deliver [J]. Int J Pharm2001, 224(1-2): 19-38.
[122] Chen LG, Liu ZL, Zhuo RX. Synthesis and properties of degradable hydrogels of konjac glucomannan grafted acrylic acid for colon-specific drug delivery [J]. Polymer 2005, 46(16): 6274-6281.
[123] El-Hag Ali Said, Amr. Radiation synthesis of interpolymer polyelectrolyte complex and its application as a carrier for colon-specific drug delivery system [J]. Biomaterials 2005, 26(15): 2733-2739.
[124] Nyk?nen P, Krogars K, S?kkinen M, et al. Organic acids as excipients in matrix granules for colon-specific drug delivery [J]. Int J Pharm 1999, 184(2): 251-261.
[125] Hovgaard L, Br?ndsted H. Dextran hydrogels for colon-specific drug delivery [J]. J Control Release 1995, 36(1-2): 159-166.
[126] Yamaoka T, Makita Y, Sasatani H, et al. Linear type azo-containing polyurethane as drug-coating material for colon-specific delivery: its properties, degration behavior, and utilization for drug formulation [J]. J Control Release, 2000, 66(2-3): 187-196.
[127] Leopold, CS. Coated dosage forms for colon-specific drug delivery [J]. Pharm Sci Tec Today 1999, 2(5): 197-204.
[128] Kannan V, Kandarapu R, Garg S. Optimization techniques for the design and development of novel drug delivery systems, part II. Pharm Tec 2003, 27: 102-118.
[129] Bussemer T, Otto I, Bodmeier R. Pulsatile Drug-Delivery Systems [J]. Crit Rev Thera Drug Carrier System. 2001, 18(5): 433-458.
[130] Pazzi F, Furlani P, Gazzaniga A, et al. The time clock system: a new oral dosage form for fast and complete release of drug after a predermined lag time [J]. J Control Release, 1994, 31(1): 99-108.
[131] Zhang Y, Zhang ZR, Wu F. A novel pulsed-release system based on swelling and osmotic pumping mechanism [J]. J Control Release, 2003, 89(1): 47-55.
[132]张彦,张志荣.硫酸沙丁胺醇脉冲控释片的研制[J].中国医院药学杂志, 2004, 24(11):665-667.
[133] Mituyuki M, Kazuhiko A, Chizuko M, et a1.Delayed release tablets usinghydroxyethylcellulose as a gel-forming matrix [J].Int J Pharm, 1996, 138:225-235.
[134] Ishino R, Yoshino H, Hirakawa Y, et a1.Design and preparation of pulsatile release tablet as a new oral drug delivery system [J].Chem Pharm Bull, 1992, 40(11): 3036-3041.
[135] Halsas M , Penttinen T, Veski P, et al.Time-controlled release pseudoephedrine tablets: bioavailability and in vitro in vivo correlations [J].Pharmazie, 2001, 56(9): 718-723.
[136] Takeuchi H, Yasuji T, Yamamoto H, et a1.Spray dried lactose composite particles containing an ion complex of alginate-chitosan for designing a dry-coated tablet having a time-controlled releasing function [J].Pharm Res, 2000,17(1): 94-99.
[137] Lin SY, Lin KH, Li MJ. Micronized ethylcellulose used for designing a directly compressed time-controlled disintegration tablet [J]. J Controlled Release, 2001, 70(3): 321-328.
[138]吴芳,张志荣.磷酸川芎嗪脉冲塞胶囊的制备与体外研究[J].药学学报, 2002, 37(9): 733-738.
[139] Borchardt John K. Self-rupturing microcapsules for pulsed drug delivery: Biomaterials [J]. Materials Today, 2005, 8(11): 20.
[140] Gr?ning R, Kuhland U. Pulsed releases of nitro-glycerin from transdermal drug delivery systems [J]. Int J Pharm, 1999, 193(1): 57-61.
[141] Kikuchi Akihiko, Okano Teruo. Pulsatile drug release control using hydrogels [J]. Adv Drug Del Rev, 2002, 54(1): 53-77.
[142]郝钦,岗艳云,朱家壁.硝酸异山梨酯脉冲控释微丸的研制[J].中国医药工业杂志, 1999, 30(3): 109-112.
[143] Medlicott Natalie J, Tucker Ian G. Pulsatile release from subcutaneous implants [J]. Adv Drug Del Rev, 1999, 38(2): 139-149.
[144]罗国安,叶磊,王义明,等.一种神衰果素速释片剂及其制备方法[P].中国专利: CN1454600A, 2003-11-12.
[145]袁筝.豆腐果苷的剂型开发与药动学研究[D].硕士论文,武汉:华中科技大学,2005.
[146]郑育平,林志绣,陈华土.神衰果素亲水凝胶缓释骨架片的制备及释药机理的研究[J].中南药学, 2004, 2(2): 92-94.
[147]吴明,蒋学华,唐宝书,等.豆腐果素的缓控释制剂[P].中国专利: 1478482A, 2004-03-03.
[148] Palmieri GF, Lovato D, Martelli S. New controlled-release ibuprofen tablets [J]. Drug Dev Ind Pharm, 1999,25(5): 671-677.
[149] Maggi L, Machiste EO, Torre ML. Fomulation of biphasic release tablets containing slightly soluble drugs [J]. Eur J Pharm Biopharm, 1999,48(1): 37-42.
[150] Lee BJ, Ryu SG, Cui JH. Controlled release of dual drug-loaded hydroxypropyl methylcellulose matrix tablet using drug-containing polymeric coating [J]. Int J Pharm, 1999, 188(1): 71-80.
[151] Kwabena OK, John TF. Biphasic drug release from film-coated tablets [J]. Int J Pharm, 2003, 250(3): 431-440.
[152] Murakami H, Kobayashi M, Takeuchi H, et al. Evaluation of poly (DL-Lactido-co-glycolide) nanoparticles as matrix material for direct compression [J]. Advanced Power Technol, 2000, 11(3): 311-322.
[2] Das NG, Das SK. Controlled-release of oral dosage forms [EB/OL]. Available at: http://www.pharmtech.com/pharmtech/data/articlestandard/pharmtech/232003/59302/article.pdf
[3] Suresh P. Development, characterization and evaluation of a pulsed-release tablet dosage form for low dose water soluble drugs [D]. PhD dissertation. Kingston: University of Rhode Island, 2000.
[4]余灯广,杨祥良,徐辉碧. pH-敏感型水凝胶在多肽和蛋白质药物给药系统研究中的应用[J].中国医院药学杂志, 2005,25(8): 762-764.
[5] Wu BM, Borland SW, Giordano RA, et al. Solid free-form fabrication of drug delivery devices [J]. J. Control Release, 1996, 40: 77-87.
[6] John BS. Controlled delivery oral dosage forms in the new millennium [EB/OL]. Available at: http://www.nutraceutix.com/pdf/PMPS_12_2000.pdf.
[7] Scahs EM, Haggerty JS, Cima MJ, et al. Three-dimensional printing technique [P]. US Patent NO.5204055, 1993.
[8]张曙,穆兰.快速原形技术的医学应用[J].机电一体化, 2000, 1/2: 22-25.
[9] Leong KF, Cheah CM, Chua CK. Solid freeform fabrication of three-dimensional scaffolds for engineering replacement tissues and organs [J]. Biomaterials, 2003, 24: 2363-2378.
[10] Anonymity. What is the 3DPTM process [EB/OL]. Available at: http://web.mit.edu/tdp/www/whatis3dp.html.
[11] Katsta WE, Palazzolo RD, Rowe CW, et al. Oral dosage forms fabricated by three-dimensional printing [J]. J Control Release, 2000, 66: 1-9.
[12] Rowe CW, Katstra WE, Palazzolo RD, et al. Multimechanism oral dosage forms fabricated by three-dimensional printing [J]. J control Release, 2000(66): 11-17.
[13] Wang CC, Yoo J, Bornancini E, et al. Diffusion-controlled dosage form and method of fabrication including three-dimensional printing [P]. US Patent NO. 005360, 2004.
[14] Pryce Lewis WE, Rowe CW, Cima MJ, et al. System for manufacturing controlled release dosage forms, such as a zero-order release profile dosage form manufactured by three-dimensional printing [P]. US Patent NO. 0198677, 2003.
[15] Rowe CW, Pryce Lewis WE, Cima MJ, et al. Printing of dispensing a suspension such as three-dimensional printing of dosage forms [P]. US Patent NO.0099708, 2003.
[16] Wu BJ, Cima MJ. Effects of solvent-particle interaction kinetics on Microstructure formation during three-dimensional printing [J]. Polymer Eng Sci, 1999, 39: 249-260.
[17]李晓燕,张曙.三维打印成形技术在制药工程中的应用[J].中国制造业信息化, 2004, 33 (4): 105-107.
[18] Sachs E, Cima M, Williams P, et al. Three-dimensional printing: Rapid tooling and prototypes directly from a CAD model [J]. J Eng Ind, 1992, 114(4): 481-488.
[19] Langer R.药物人体漫游记[J].科学, 2003, 6: 34-39.
[20] John T, Santini J, Cima M J, et al. A controlled-release microchip [J]. Nature, 1999, 397(28): 335-338.
[21] Cima LG, Chim MJ. Preparation of medical devices by solid free-form fabrication methods [P]. US Patent NO. 5490962, 1996.
[22] Low KH, Leong KF, Chua CK, et al. Characterization of SLS parts for drug delivery devices [J]. Rapid Prototyping J, 2001,7 (5): 262-267.
[23] Leong KF, Cheah CM, Chua CK. Solid freeform fabrication of three-dimensional scaffolds for engineering replacement tissues and organs. Biomaterials [J], 2003, 24 (13): 2363-2378.
[24] Petezold R, Zeilhfer HF, Kalender WA. Rapid prototyping technology in medicine-basics and applications [J]. Computerized Medical Imaging and Graphics,1999, 23(5): 277-284.
[25]余灯广,杨祥良,徐辉碧,等.三维打印技术在药剂学中的应用[J].中国新药杂志, 2005,14 (7): 843-848.
[26]国家药典委员会.中华人民共和国药典(二部) [S].北京:化学工业出版社, 2005.附录74-77.
[27] Monkhouse DC, Yao J, Sherwood MJ, et al. Dosage forms exhibiting multi-phasic release kinetics and methods of manufacture thereof [P]. US Patent NO. 6280771, 2001.
[28] Rigby SP, Van der Walle CF, Raistrick JH. Determining drug spatial distribution within controlled delivery tablets using MFX imaging [J]. J Control Release, 2004, 96(1): 97-100.
[29]侯鹏,潘卫三,吴学明.固体分散技术在药剂学中的研究进展[J].中国新药杂志, 2003, 12(4): 245-249.
[30] Monkhouse DC, Sandee PK, Rowe CW, et al. A complex-aided fabrication process for rapid designing, prototyping and manufacturing [P]. WO Patent NO. 29202, 2000.
[31] Payumo FC, Sherwood JK, Yoo J, et al. Method and form of a drug delivery device, such as encapsulating a toxic core within a non-toxic region in an oral dosage form [P]. US Pat: 0015728, 2002-02-07.
[32]陈炜,姚晚萍.神衰果素片的稳定性研究[J].中草药, 1998, 29(10): 669-670.
[33]袁筝.豆腐果苷的剂型开发与药动学研究[D].硕士论文,武汉:华中科技大学, 2005.
[34]平其能.现代药剂学[M].北京:中国医药科技出版社, 1998.
[35] Petezold R, Zeilhfer HF, Kalender WA. Rapid prototyping technology in medicine-basics and applications [J]. Computerized Medical Imaging and Graphics, 1999, 23 (5): 277-284.
[36] Siepmann J, Kranz H, Peppas NA, et al. Calculation of the required size and shape of hydroxypropyl methylcellulose matrices to achieve desired drug release profiles[J]. Int J Pharm, 2000, 201: 151-164.
[37] Mahaguna V, Talbert RL, Peters JI, et al. Influence of hydroxypropyl methylcellulose polymer on in vitro and in vivo performance of controlled release tablets containing alprazolam [J]. Eur J Pharm Biopharm, 2003, 56: 461-468.
[38] Thomas DR, Stevin HG, Ajaz SH, et al. Polymer erosion and drug release characterization of hydroxypropyl methylcellulose matrices [J]. J Pharm Sci, 1998, 87: 1115-1123.
[39] Otsuka M, Matsuda Y. Comparative evaluation of mean particle size of bulk drug powder in pharmaceutical preparations by fourier-transformed powder diffuse reflectance infrared spectroscopy and dissolution kinetics [J]. J Pharm Sci, 1996, 85:112-116.
[40] Devotta I, Ambeskar VD, Mandhare AB, et al. The lifetime of a dissolving polymeric particle [J]. Chem Eng Sci, 1994, 49: 645-654.
[41] Tailin F. Droplet-powder impact interaction in three-dimensional printing [D]. Cambridge: Massachusetts institute of technology, 1995.
[42] Fell JT, Newton JM. Determination of tablets’strength by the diameter-compression test [J]. J pharm Sci 1970, 59, 688-691.
[43] Streubel A, Siepmann J, Peppas N A, et al. Bimodal drug release achieved with multi-layer matrix tablets: transport mechanisms and device design [J]. J Control Release 2000, 69: 455-468.
[44] Abdul S, Poddar SS. A flexible technology for modified release of drug: multi layered tablets [J]. J Control Release, 2004, 97: 393-405.
[45]贾伟,高文远.药物控释新剂型[M].北京:化学工业出版社, 2005: 87.
[46] Pillai O, Panchagnula R. Polymers in drug delivery [J]. Current opinion in chemical biology, 2001,5: 447-451.
[47] Chopra SK, Nangia AK, Lee D, et al. Controlled-release devices [P]. US Patent NO. 5342627, 1994.
[48] LangerR. New methods of drug delivery [J]. Science, 1990, 249: 1527-1533.
[49] Paolo C, Antonio CC, Giorgio P. Multilayer matrix systems for the controlled-release of active principles [P]. Euro Patent NO. 0598309A2, 1993.
[50]林晓,陈济民.水溶性药物骨架片释放达零级的几种方法[J].中国药学杂志, 2002,37(3): 192-197.
[51] Zhang F. Hot-melt extrusion as a novel technology to prepare sustained- release dosage forms [D]. Austin, America: The university of Texas, 1999.
[52] Wu BM. Microstructural Control during three-dimensional printing of polymeric medical devices [D]. Massachusetts, America: Massachusetts Institute of Technology, 1998.
[53] Reddy KR, Mutalik S, Reddy S. Once-daily sustained-release matrix tablets of nicorandil: Formulation and in vitro evaluation [J]. AAPS Pharm Sci Tech 2003, 4(4): E61.
[54] Pryce Lewis WE, Rowe CW, Cima MJ, Materna PA. A system and method for uniaxial compression of an article, such as a three-dimensional printed dosage form [P]. WO Patent NO. 03037607, 2003.
[55] Rowe CW, Pryce Lewis WE, Cima MJ, et al. Printing or dispensing a suspension such as three-dimensional printing of dosage forms [P]. WO Patent NO. 03041690, 2003.
[56] Rekhi GS, Jambhekar SS. Ethylcellulose - a polymer review [J]. Drug Dev Ind Pharm 1995, 21: 61-77.
[57] Pollock DK, Sheskey PJ. Micronized ethyl cellulose: Opportunities in direct-compression controlled-release tablets [J]. Pharm Tech 1996, 20: 120-130.
[58] Shlieout G, Zessin G. Investigation of ethyl cellulose as a matrix former and a new method to regard and evaluate the compaction data [J]. Drug Dev Ind Pharm 1996, 22: 313-319.
[59] Crowley MM, Schroeder B, Fredersdorf A, et al. Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion [J]. Int J Pharm 2004, 269: 509-522.
[60] Dittgen M, Durrani M, Lehmann K. Acrylic polymer: a review of pharmaceutical applications [J]. STP Pharm Sci 1997, 7: 403-437.
[61] Filippis PD, Zingone G, Gibellini M, et al. Dissolution rates of different drugs from solid dispersions with Eudragit RS [J]. Eur J Pharm Sci 1995, 3: 265-271.
[62]刘善奎,钟延强,孙其荣,等.丙烯酸树脂系列辅料在药物新剂型中的应用[J].药学实践杂志, 2002, 20: 12-15.
[63] Belal Hossain M, Rashid M, Motahar Hossain AKM. Effect of waxy materials on the release kinetics of ibuprofen from HPMC based sustained release matrix tablet [J]. Pak J Bio Sci 2004, 7: 772-776.
[64] Grassi M, Voinovich D, Franceschinis E, et al. Theoretical and experimental studies on theophylline release from stearic acid cylindrical delivery systems [J]. J Control Release 2003, 92: 275-289.
[65] Dhananjaya A, Sanford B, Norman GG. Hydroxypropyl methylcellulose anionic surfactant interactions in aqueous systems [J]. J Appl Polym Sci 1991, 42: 947-956.
[66] Nokhodchi A, Norouzi-Sani S, Siahi-Shadbad MR, et al. The effect of various surfactants on the release rate of propranolol hydrochloride from hydroxypropylmethylcellulose (HPMC)-Eudragit matrices [J]. Eur J Pharm Biopharm 2002, 54: 349-356.
[67] Rajabi-Slahboomi AR, Leung WSW, Al-Suwailem A, et al. Effect of bile salts on drug release from HPMC matrices [J]. Eur J Pharm Sci 1996, 4: S157.
[68] Lee BJ, Cao QR, Choi YW. Oral controlled-release dosage forms containing acetaminophen [P]. WO Patent NO. 006904, 2004.
[69] Conte U, Maggi L. Modulation of the dissolution profiles from Geomatrix? multi-layer matrix tablets containing drugs of different solubility [J]. Biomaterials 1996, 17: 889-896.
[70] Kr?gel I, Bodmeier R. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder [J]. J Control Release, 1999, 61: 43-50.
[71] Tiwari SB, Murthy TK, Pai MR, et al. Controlled release formulation of tramadol hydrochloride using hydrophilic and hydrophobic matrix system [J]. AAPS Pharm Sci Tech 2003, 4(3): E31.
[72] Reza MS, Quadir MA, Haider SS. Comparative evalution of plastic, hydrophobic and hydrophilic polymers as matrices for controlled-release drug delivery [J]. J Pharm Pharmaceut Sci 2003, 6: 282-291.
[73] Mehuys E, Vervaet C, Remon JP. Hot-melt extruded ethylcellulose cylinders containing a HPMC-Gelucire? core for sustained drug delivery [J]. J Control Release 2004, 94: 273-280.
[74] Traconis N, Rodríguez R, Campos ME, et al. Influence of admixed polymers on the metronidazole release from hydroxypropyl methylcellulose matrix tablets [J]. Pharm Acta Helv 1997, 72: 131-138.
[75] J. P. Cleave. Some geometrical considerations concerning the design of tablets [J]. J Pharm Pharmacol 1965, 17: 698.
[76] Kim CJ. Compressed doughnut-shaped tablets with zero-order release kinetics [J]. Pharm Res 1995, 12:1045-1048.
[77] Kim CJ. Release kinetics of coated doughnut-shaped tablets for water soluble drugs [J]. Eur J Pharm Sci 1999, 7:237-242.
[78] Cheng K, Zhu J, Song X, et al. Zhang. Studies of hydroxypropyl methylcellulose doughnut-shaped tablets [J]. Drug Dev Ind Pharm 1999, 25:1067-1071.
[79] Sundy E and Danckwerts MP. A novel compression-coated doughnut-shaped tablet design for zero-order sustained release [J]. Eur J Pharm Sci 2004, 22:477-485.
[80] Dinesh SM and Samuel HY. A flat circular hole device for zero-order release of drugs: characterization of the moving dissolution boundary [J]. Pharm Res 1990, 7:1195-1197.
[81] Narasimhan B and Langer R. Zero-order release of micro-and macromolecules from polymeric devices: the role of the burst effect [J]. J Control Release, 1997, 47:13-19.
[82] Mohsen AB. Geometric approach for zero-order release of drugs dispersed in aninert matrix [J]. Pharm Res 1994, 11: 914-916.
[83] Danckwerts MP, vander Watt JG, Moodley I. Zero-order release of theophylline from a core-in-cup tablet in sequenced simulated gastric and intestinal fluid [J]. Drug Dev Ind Pharm 1998, 24:163 -174.
[84] Monkhouse DC, Sandeep K, Rowe CW, et al. A computer-aided fabrication process for rapid designing, prototyping and manufacturing [P]. WO Patent NO. 0029202, 2000.
[85] Conte U, Maggi L. Modulation of the dissolution profiles from Geomatrix? multi-layer matrix tablets containing drugs of different solubility [J]. Biomaterials 1996, 17:889-896.
[86] Sangalli ME, Maroni A, Zema L, et al. In viyro and in vivo evaluation of an oral system for time and/or site-specific drug delivery [J]. J Control Release, 2001, 73:103-110.
[87]刘梅,崔光华.口腔速释片的进展及前景[J].中国药学杂志. 2001, 36(9): 580-583.
[88]何忠芳,陈岚,王亚娟.口腔速崩片的研究进展及应用前景[J].兰州医学院学报. 2003, 29(3): 89-91.
[89] Simone S, Peter CS. Fast dispersible ibuprofen tablets [J]. European Journal of Pharmaceutical Sciences, 2002, 3(15): 295-305.
[90] Ito A, Sugihar A. Development of oral dosage forms for elderly patients: use of agar as base of rapidly disintegrating oral tablets [J]. Chem Pham Bull, 1996, 44(11): 2132.
[91] Davis DW. Method of swallowing a pill [P]. US Patent NO. 3418999, 1968.
[92] Baumgartner S, Kristl J, Vrecer F, et a1.Optimization of floating matrix tablets and evaluation of their gastric residence time [J]. Int J Pharm, 2000, 195(1-2): 125-135.
[93]陆彬.药物新剂型与新技术[M].第1版.北京:人民卫生出版社,1998,314.
[94]任飞亮,裴元英.口服结肠定位释药系统的研究进展[J].中国药学杂志. 2005, 40(17): 1288-1291.
[95] Rubinstein A. Colonic drug delivery [J]. DDT: Tec, 2005, 2(1): 34-37.
[96]张正全,陆彬.口服结肠定位给药系统新进展[J].中国药学杂志,2000,35(4): 221-223.
[97]朱盛山主编.药物制剂新剂型[M].北京:化学工业出版社, 2003: 239-250.
[98]周宇,蒋雪涛.口服结肠定位给药系统[J].国外医学药学分册,1999,26(4): 225-228.
[99]邹梅娟,程刚.口服结肠定位给药系统[J].沈阳药科大学学报,2001,18(5): 378-379.
[100]沙静姝.毛洪奎.豆腐果苷(昆明神衰果素) [J].药学通报, 1987, 22 (1): 27.
[101]刘苹,李健,纳冬荃,等.母鼠妊娠期服用豆腐果甙对仔代的神经行为效应[J].中草药. 2002,33(3):238-242.
[102]罗国安,叶磊,王义明,等.一种神衰果素速释片剂及其制备方法[P].中国专利: 1454600A, 2003-11-12.
[103]高春生,崔光华.水渗透对速崩制剂崩解作用的研究[J].中国药学杂志2000, 35(5): 308-311.
[104] Sastry SV, Nyshadham JR, Fix JA. Recent technological advances in oral drug delivery– a review [J]. PSTT, 2000, 3 (4): 138-145.
[105]黄东坡,王远,陈军,等.盐酸二甲双胍胃漂浮缓释片的制备及体外释放[J].中国医药工业杂志, 2002, 33(10): 483-486.
[106] Peter T, Andrewb D, Kirena V. Biphasic controlled release delivery system for high solubility pharmaceuticals and method [P]. WO Patent NO. 9947128, 1999.
[107]史振祺,蒋新国.胃漂浮片的研究进展[J].中国医药工业杂志, 2003, 34(4): 199-202.
[108]侯惠民,朱金屏.胃漂浮缓释片研究I硝苯啶胃漂浮缓释片的制备与性质[J].中国医药工业杂志, 1991, 22(3): 106-109.
[109]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地尔硫蕈胃漂浮缓释片[J].中国医药工业杂志, 1991, 22(4): 156-158.
[110]朱金屏,余勇,侯惠民.胃漂浮缓释片研究Ⅲ核黄素胃漂浮缓释片[J].中国医药工业杂志, 1995, 26(6): 249-251.
[111]宋维红,卢勰炜,朱康杰.壳聚糖胃漂浮小丸的制备[J].中国医药工业杂志2003, 34(11): 558-560.
[112] Reddy LHV, Murhan RSR. Floating dosage systems in drug delivery [J]. Crit Rev Ther Drug Carr Syst, 2002, 19 (6): 553-585.
[113] Curatolo WJ, Lo J. Gastric retention system for controlled drug release [P]. US Patent NO.5443843, 1995.
[114] ?zdemir N, Ordu S, ?zkan Y. Studies of floating dosage forms of furosemide: in vitro and in vivo evaluations of bilayer tablet formulations [J]. Drug Dev Ind Pharm, 2000, 26(8): 857-866.
[115]邹豪,卢文芸,陈宙艳,等.漂浮型脉冲释放胶囊的设计和研制[J].中国医药工业杂志2004, 35(10): 595-599.
[116] Marvola M, Nykanen P, Rautio S, et al. Enteric polymers as binders and coating materials in multiple-unit site-specific drug delivery systems [J]. Eur J Pharm Sci, 1999, 7(3): 259-271.
[117] Ishibashi T, Pitcairn GR,Yoshino H, et al. Scintigraphic evaluation of a new capsule-type colon specific drug delivery system in healthy volunteers [J]. J Pharm Sci, 1998, 87(5): 531-535.
[118] Watts P, Smith A. Target technology: coated starch capsules for site-specific drug delivery into the lower gastrointestinal tract [J]. Expert Opinion on Drug Delivery, 2005, 2(1): 159-167.
[119] Turkoglu M, Ugurlu T. In vitro evaluation of pectin-HPMC compression coated 5-amino- salicylic acid tablets for colonic delivery [J]. Eur J Pharm Biopharm, 2002, 53(1): 65-73.
[120] Sinha VR, Mittal BR, Kumria R. In vivo evaluation of time and site of disintegration of polysaccharide tablet prepared for colon-specific drug delivery [J]. Int J Pharm 2005, 289(1-2): 79-85.
[121] Sinha VR, Kumria R. Polysaccharides in colon-specific drug deliver [J]. Int J Pharm2001, 224(1-2): 19-38.
[122] Chen LG, Liu ZL, Zhuo RX. Synthesis and properties of degradable hydrogels of konjac glucomannan grafted acrylic acid for colon-specific drug delivery [J]. Polymer 2005, 46(16): 6274-6281.
[123] El-Hag Ali Said, Amr. Radiation synthesis of interpolymer polyelectrolyte complex and its application as a carrier for colon-specific drug delivery system [J]. Biomaterials 2005, 26(15): 2733-2739.
[124] Nyk?nen P, Krogars K, S?kkinen M, et al. Organic acids as excipients in matrix granules for colon-specific drug delivery [J]. Int J Pharm 1999, 184(2): 251-261.
[125] Hovgaard L, Br?ndsted H. Dextran hydrogels for colon-specific drug delivery [J]. J Control Release 1995, 36(1-2): 159-166.
[126] Yamaoka T, Makita Y, Sasatani H, et al. Linear type azo-containing polyurethane as drug-coating material for colon-specific delivery: its properties, degration behavior, and utilization for drug formulation [J]. J Control Release, 2000, 66(2-3): 187-196.
[127] Leopold, CS. Coated dosage forms for colon-specific drug delivery [J]. Pharm Sci Tec Today 1999, 2(5): 197-204.
[128] Kannan V, Kandarapu R, Garg S. Optimization techniques for the design and development of novel drug delivery systems, part II. Pharm Tec 2003, 27: 102-118.
[129] Bussemer T, Otto I, Bodmeier R. Pulsatile Drug-Delivery Systems [J]. Crit Rev Thera Drug Carrier System. 2001, 18(5): 433-458.
[130] Pazzi F, Furlani P, Gazzaniga A, et al. The time clock system: a new oral dosage form for fast and complete release of drug after a predermined lag time [J]. J Control Release, 1994, 31(1): 99-108.
[131] Zhang Y, Zhang ZR, Wu F. A novel pulsed-release system based on swelling and osmotic pumping mechanism [J]. J Control Release, 2003, 89(1): 47-55.
[132]张彦,张志荣.硫酸沙丁胺醇脉冲控释片的研制[J].中国医院药学杂志, 2004, 24(11):665-667.
[133] Mituyuki M, Kazuhiko A, Chizuko M, et a1.Delayed release tablets usinghydroxyethylcellulose as a gel-forming matrix [J].Int J Pharm, 1996, 138:225-235.
[134] Ishino R, Yoshino H, Hirakawa Y, et a1.Design and preparation of pulsatile release tablet as a new oral drug delivery system [J].Chem Pharm Bull, 1992, 40(11): 3036-3041.
[135] Halsas M , Penttinen T, Veski P, et al.Time-controlled release pseudoephedrine tablets: bioavailability and in vitro in vivo correlations [J].Pharmazie, 2001, 56(9): 718-723.
[136] Takeuchi H, Yasuji T, Yamamoto H, et a1.Spray dried lactose composite particles containing an ion complex of alginate-chitosan for designing a dry-coated tablet having a time-controlled releasing function [J].Pharm Res, 2000,17(1): 94-99.
[137] Lin SY, Lin KH, Li MJ. Micronized ethylcellulose used for designing a directly compressed time-controlled disintegration tablet [J]. J Controlled Release, 2001, 70(3): 321-328.
[138]吴芳,张志荣.磷酸川芎嗪脉冲塞胶囊的制备与体外研究[J].药学学报, 2002, 37(9): 733-738.
[139] Borchardt John K. Self-rupturing microcapsules for pulsed drug delivery: Biomaterials [J]. Materials Today, 2005, 8(11): 20.
[140] Gr?ning R, Kuhland U. Pulsed releases of nitro-glycerin from transdermal drug delivery systems [J]. Int J Pharm, 1999, 193(1): 57-61.
[141] Kikuchi Akihiko, Okano Teruo. Pulsatile drug release control using hydrogels [J]. Adv Drug Del Rev, 2002, 54(1): 53-77.
[142]郝钦,岗艳云,朱家壁.硝酸异山梨酯脉冲控释微丸的研制[J].中国医药工业杂志, 1999, 30(3): 109-112.
[143] Medlicott Natalie J, Tucker Ian G. Pulsatile release from subcutaneous implants [J]. Adv Drug Del Rev, 1999, 38(2): 139-149.
[144]罗国安,叶磊,王义明,等.一种神衰果素速释片剂及其制备方法[P].中国专利: CN1454600A, 2003-11-12.
[145]袁筝.豆腐果苷的剂型开发与药动学研究[D].硕士论文,武汉:华中科技大学,2005.
[146]郑育平,林志绣,陈华土.神衰果素亲水凝胶缓释骨架片的制备及释药机理的研究[J].中南药学, 2004, 2(2): 92-94.
[147]吴明,蒋学华,唐宝书,等.豆腐果素的缓控释制剂[P].中国专利: 1478482A, 2004-03-03.
[148] Palmieri GF, Lovato D, Martelli S. New controlled-release ibuprofen tablets [J]. Drug Dev Ind Pharm, 1999,25(5): 671-677.
[149] Maggi L, Machiste EO, Torre ML. Fomulation of biphasic release tablets containing slightly soluble drugs [J]. Eur J Pharm Biopharm, 1999,48(1): 37-42.
[150] Lee BJ, Ryu SG, Cui JH. Controlled release of dual drug-loaded hydroxypropyl methylcellulose matrix tablet using drug-containing polymeric coating [J]. Int J Pharm, 1999, 188(1): 71-80.
[151] Kwabena OK, John TF. Biphasic drug release from film-coated tablets [J]. Int J Pharm, 2003, 250(3): 431-440.
[152] Murakami H, Kobayashi M, Takeuchi H, et al. Evaluation of poly (DL-Lactido-co-glycolide) nanoparticles as matrix material for direct compression [J]. Advanced Power Technol, 2000, 11(3): 311-322.