剂量分散型肠道定位释药系统研究
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摘要
本课题属工业药剂学口服缓控释制剂研究范畴。目的是以膜控微丸为载体单元，建立能定位于小肠和结肠释药的剂量分散型给药体系，在剂型上探索微丸压片的可行性。
在研究方法上，首先以盐酸二甲双胍／美洛昔康为模型药物，以Eudragit~(?)L100-55／Eudragit~(?)FS 30 D为关键材料，以流化床液相层积包衣法为基本工艺，研究和建立涵盖载药层包衣、隔离层包衣和肠溶层包衣的膜控微丸的成型工艺路线。然后针对不同的定位目标，进行相应的小肠释药系统和结肠释药系统的体内外评价。最后以Eudragit~(?)FS30 D包衣的膜控微丸为药物单元，探索微丸压片的工艺可行性。
研究结果主要有：① 水溶性药物盐酸二甲双胍在水分散体肠溶包衣过程中，存在向肠溶层迁移扩散的现象，增加HPMC隔离层可有效克服这一现象。② β-环糊精能显著加速美洛昔康载药丸芯的药物溶出速率，并使其释药模式呈pH非依赖状态。③Eudragit~(?)FS 30 D的pH溶解临界值在7.2以上。④ 高浓度(0.2 M)的磷酸盐缓冲液可加快Eudragit~(?)FS 30 D包衣的膜控微丸的释药速率。⑤ 15％包衣水平的Eudragit~(?)FS 30D膜控微丸，在pH1.2的盐酸液中2小时释药低于1％，而在pH7.4的磷酸盐缓冲液中0.5小时即可释药完全。⑥ 15％包衣水平的Eudragit~(?)FS 30 D膜控微丸，在经五肽促胃酸激素处理的比格犬体内，药物被有效测出的初始时间是3.0±0.8h，和未包衣的载药丸芯(0.6±0.3h)相比，明显延迟。⑦ 70％(w／w)用量的微晶纤维素(Avicel~(?) PH 102)或复合乳糖(Cellactose~(?)80)，可使Eudragit~(?)FS 30 D膜控微丸在较低压力下形成片剂，而且片剂在pH1.2的盐酸液中2小时的释药量低于10％。
研究结论：本文研究和建立的用于肠道定位释药的膜控微丸的水分散体包衣工艺具有可重复性。释放介质中缓冲盐的种类和浓度，和pH值一样，决定肠溶包衣制剂的释药模式。Eudragit~(?)FS 30 D具有最高的pH溶解临界值，显示了理想的体内外结肠定位能力，该材料有望解决pH依赖型结肠给药系统提前释放药物的不足。在动物模型上，经五肽促胃酸激素处理的比格犬，在评价肠溶包衣制剂的体内行为上具有很大的优点和实用性。将Eudragit~(?)FS 30 D膜控微丸压制成片剂存在可行性，微晶纤维素是一种很理想的微丸压片赋型剂。
Abstract: BACKGROUND The present study is within the scheme of oral
controlled-release drug delivery systems, which is focused on industrial pharmacy research.
AIM The main objective of the present study was to develop the enteric-coated multi-unit
drug delivery systems for small intestinal or colonic targeting, respectively.The further
objective of the present study was to compress Eudragit FS 30 D-coated meloxicam pellets
into divisible rapidly disintegrating tablets. METHODS Metformin hydrochloride or
meloxicam-loaded pellets were prepared by layering the drug-binder solution onto
nonpareils using a fluidized bed coater with the Wurster insert and then coated with
Eudragit LI 00-55 or Eudragit FS 30 D to achieve a specific drug release in small intestine
or colon, respectively. To prevent the interaction between drugs and enteric polymers,
drug-loaded pellets were also seal coated with 3% w/w HPMC (6cps) prior to enteric coating.
Consequently, their in vitro and in vivo performances were evaluated, respectively. Finaly,
compression of Eudragit FS 30 D-coated meloxicam pellets were investigated using single
punch press. RESULTS The diffusion of highly water-soluble metformin hydrochloride
from the drug-loaded cores to the aqueous enteric film occurred during the polymer coating
process. 3% HPMC-sealed coat could prevent this phenomenon effectively, β-cyclodextrin
could evidently improve the aqueous solubility of meloxicam and most importantly make the
solubility pH-independent. The critical dissolution pH of Eudragit FS 30 D was 7.2 or
above in 0.2 M phosphate buffer. Buffer capacity of phosphate buffer influenced the
dissolution of enteric coating, and increasing the ionic strength or buffer capacity increased
meloxicam release form Eudragit FS 30 D-coated pellets. 15% coating level of Eudragit
FS 30 D allowed sufficient gastric resistance (no release for 2 hours at pH 1.2) and the total
release of meloxicam at pH 7.4 within 30 minutes. In vivo, the onset of meloxicam
在研究方法上，首先以盐酸二甲双胍／美洛昔康为模型药物，以Eudragit~(?)L100-55／Eudragit~(?)FS 30 D为关键材料，以流化床液相层积包衣法为基本工艺，研究和建立涵盖载药层包衣、隔离层包衣和肠溶层包衣的膜控微丸的成型工艺路线。然后针对不同的定位目标，进行相应的小肠释药系统和结肠释药系统的体内外评价。最后以Eudragit~(?)FS30 D包衣的膜控微丸为药物单元，探索微丸压片的工艺可行性。
研究结果主要有：① 水溶性药物盐酸二甲双胍在水分散体肠溶包衣过程中，存在向肠溶层迁移扩散的现象，增加HPMC隔离层可有效克服这一现象。② β-环糊精能显著加速美洛昔康载药丸芯的药物溶出速率，并使其释药模式呈pH非依赖状态。③Eudragit~(?)FS 30 D的pH溶解临界值在7.2以上。④ 高浓度(0.2 M)的磷酸盐缓冲液可加快Eudragit~(?)FS 30 D包衣的膜控微丸的释药速率。⑤ 15％包衣水平的Eudragit~(?)FS 30D膜控微丸，在pH1.2的盐酸液中2小时释药低于1％，而在pH7.4的磷酸盐缓冲液中0.5小时即可释药完全。⑥ 15％包衣水平的Eudragit~(?)FS 30 D膜控微丸，在经五肽促胃酸激素处理的比格犬体内，药物被有效测出的初始时间是3.0±0.8h，和未包衣的载药丸芯(0.6±0.3h)相比，明显延迟。⑦ 70％(w／w)用量的微晶纤维素(Avicel~(?) PH 102)或复合乳糖(Cellactose~(?)80)，可使Eudragit~(?)FS 30 D膜控微丸在较低压力下形成片剂，而且片剂在pH1.2的盐酸液中2小时的释药量低于10％。
研究结论：本文研究和建立的用于肠道定位释药的膜控微丸的水分散体包衣工艺具有可重复性。释放介质中缓冲盐的种类和浓度，和pH值一样，决定肠溶包衣制剂的释药模式。Eudragit~(?)FS 30 D具有最高的pH溶解临界值，显示了理想的体内外结肠定位能力，该材料有望解决pH依赖型结肠给药系统提前释放药物的不足。在动物模型上，经五肽促胃酸激素处理的比格犬，在评价肠溶包衣制剂的体内行为上具有很大的优点和实用性。将Eudragit~(?)FS 30 D膜控微丸压制成片剂存在可行性，微晶纤维素是一种很理想的微丸压片赋型剂。
Abstract: BACKGROUND The present study is within the scheme of oral
controlled-release drug delivery systems, which is focused on industrial pharmacy research.
AIM The main objective of the present study was to develop the enteric-coated multi-unit
drug delivery systems for small intestinal or colonic targeting, respectively.The further
objective of the present study was to compress Eudragit FS 30 D-coated meloxicam pellets
into divisible rapidly disintegrating tablets. METHODS Metformin hydrochloride or
meloxicam-loaded pellets were prepared by layering the drug-binder solution onto
nonpareils using a fluidized bed coater with the Wurster insert and then coated with
Eudragit LI 00-55 or Eudragit FS 30 D to achieve a specific drug release in small intestine
or colon, respectively. To prevent the interaction between drugs and enteric polymers,
drug-loaded pellets were also seal coated with 3% w/w HPMC (6cps) prior to enteric coating.
Consequently, their in vitro and in vivo performances were evaluated, respectively. Finaly,
compression of Eudragit FS 30 D-coated meloxicam pellets were investigated using single
punch press. RESULTS The diffusion of highly water-soluble metformin hydrochloride
from the drug-loaded cores to the aqueous enteric film occurred during the polymer coating
process. 3% HPMC-sealed coat could prevent this phenomenon effectively, β-cyclodextrin
could evidently improve the aqueous solubility of meloxicam and most importantly make the
solubility pH-independent. The critical dissolution pH of Eudragit FS 30 D was 7.2 or
above in 0.2 M phosphate buffer. Buffer capacity of phosphate buffer influenced the
dissolution of enteric coating, and increasing the ionic strength or buffer capacity increased
meloxicam release form Eudragit FS 30 D-coated pellets. 15% coating level of Eudragit
FS 30 D allowed sufficient gastric resistance (no release for 2 hours at pH 1.2) and the total
release of meloxicam at pH 7.4 within 30 minutes. In vivo, the onset of meloxicam
引文
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2 Debunnea A., Vervaet C., Mangelings D., et al., 2004. Compaction of enteric-coated pellets: influence of formulation and process parameters on tablet properties and in vivo evaluation. Eur. J. Pharm. Sci. 22 (4), 305-314.
3 Dashevsky A., Kolter K., Bodmeier R., 2004. Compression of pellets coated with various aqueous polymer dispersions. Int. J. Pharm. 279 (1/2), 19-26.
4 平其能主编．1998．现代药剂学[M]．北京：中国医药科技出版社．
5 梅兴国主编．2004．生物技术药物制剂：基础与应用[M]，北京：化工出版社．
6 Alvin KY, Deborah SC, Aleksandra B., 1996. Metformin; A new treatments option for non-insulin-dependent diabetes mellitus. J Family Practice 42, 612-617.
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