Venkatesh G M
Pharmaceutical Development, SB Pharmaceuticals, Collegeville, Pennsylvania 19426-0989, USA.
Pharm Dev Technol. 1998 Nov;3(4):477-85. doi: 10.3109/10837459809028629.
The purpose of this research was to design and develop a novel controlled-release bead formulation for oral administration with buffer crystals as a carrier for loading of fenoldopam mesylate, an intravenous antihypertensive agent, which provides an in vitro release rate of 30-50 mg/hr for 6-8 hr. Buffer crystals were coated in a fluid-bed granulator with a blend of gastrointestinal (GI) insoluble/enteric Eudragit polymers (such as RSPM/S100 polymer blend), drug was layered on these polymer-subcoated buffer beads by a slurry coating process, and the drug-layered beads were subsequently overcoated using a blend of GI insoluble/enteric polymers. The release of fenoldopam and tartaric acid was monitored by a two-stage dissolution procedure using USP Apparatus 2 (paddles at 50 rpm) and HPLC methodologies. The overcoating of drug-layered tartaric acid crystals with Eudragit polymers with different permeabilities significantly affected the release of fenoldopam. However, even the least permeable polymer, Eudragit RS, could not sustain the release of tartaric acid beyond 2 hr, suggesting the need to subcoat freely water-soluble tartaric acid crystals prior to drug layering. By varying the type/ratios of the GI insoluble/enteric polymers for subcoat and overcoat, capsule formulations were developed, which released fenoldopam and tartaric acid at different rates. The use of Eudragit polymer blends at the optimized ratios for both subcoat and overcoat resulted in a significant retardation in the release of tartaric acid; still, the tartaric acid release was faster than that of fenoldopam, suggesting the need to use a less water-soluble fumaric or succinic acid crystals as the buffer. However, the technology described using tartaric acid crystals as the buffer will be highly useful for weakly basic drug substances with less stringent pH-dependent solubility profiles.
本研究的目的是设计并开发一种新型口服控释微丸制剂，以缓冲晶体为载体负载静脉用抗高血压药物甲磺酸非诺多泮，该制剂在体外6 - 8小时内的释放速率为30 - 50毫克/小时。在流化床制粒机中，用胃肠道（GI）不溶性/肠溶型丙烯酸树脂聚合物（如RSPM/S100聚合物混合物）对缓冲晶体进行包衣，通过淤浆包衣工艺将药物层铺在这些聚合物预包衣的缓冲微丸上，随后使用GI不溶性/肠溶聚合物混合物对药物层铺微丸进行包衣。使用美国药典装置2（桨板转速为50转/分钟）和高效液相色谱法通过两阶段溶出程序监测非诺多泮和酒石酸的释放。用具有不同渗透性的丙烯酸树脂聚合物对药物层铺的酒石酸晶体进行包衣显著影响了非诺多泮的释放。然而，即使是渗透性最低的聚合物丙烯酸树脂RS，也无法使酒石酸的释放在2小时后仍持续，这表明在药物层铺之前需要对水溶性高的酒石酸晶体进行预包衣。通过改变用于预包衣和包衣的GI不溶性/肠溶聚合物的类型/比例，开发出了以不同速率释放非诺多泮和酒石酸的胶囊制剂。在预包衣和包衣中使用优化比例的丙烯酸树脂聚合物混合物导致酒石酸的释放显著延迟；尽管如此，酒石酸的释放仍比非诺多泮快，这表明需要使用水溶性较低的富马酸或琥珀酸晶体作为缓冲剂。然而，所描述的使用酒石酸晶体作为缓冲剂的技术对于pH依赖性溶解度曲线要求不太严格的弱碱性药物物质将非常有用。
