Cantor Stuart L, Hoag Stephen W, Augsburger Larry L
School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.
Drug Dev Ind Pharm. 2009 Mar;35(3):337-51. doi: 10.1080/03639040802360502.
The aim of this study was to characterize and evaluate a modified release, multiparticulate tablet formulation consisting of placebo beads and drug-loaded beads. Acetaminophen (APAP) bead formulations containing ethylcellulose (EC) from 40-60% and placebo beads containing 30% calcium silicate and prepared using 0-20% alcohol were developed using extrusion-spheronization and studied using a central composite experimental design. Particle size and true density of beads were measured. Segregation testing was performed using the novel ASTM D6940-04 method on a 50:50 blend of uncoated APAP beads (60%EC) : calcium silicate placebo beads (10% alcohol). Tablets were prepared using an instrumented Stokes-B2 rotary tablet press and evaluated for crushing strength and dissolution rate. Compared with drug beads (60%EC), placebo beads (10% alcohol) were smaller but had higher true densities: 864.8 mum and 1.27 g/cm(3), and 787.1 mum and 1.73 g/cm(3), respectively. Segregation testing revealed that there was approximately a 20% difference in drug content (as measured by the coefficient of variation) between initial and final blend samples. Although calcium silicate-based placebo beads were shown to be ineffective cushioning agents in blends with Surelease(R)-coated APAP beads, they were found to be very compactibile when used alone and gave tablet crushing strength values between 14 and 17 kP. The EC in the APAP bead matrix minimally suppressed the drug release from uncoated beads (t(100%) = 2 h). However, while tablets containing placebo beads reformulated with glycerol monostearate (GMS) showed a slower release rate (t(60%)= 5 h) compared with calcium silicate-based placebos, some coating damage ( approximately 30%) still occurred on compression as release was faster than coated APAP beads alone. While tablets containing coated drug beads can be produced with practical crushing strengths (>8 kP) and low compression pressures (10-35 MPa), dissolution studies revealed that calcium silicate-based placebos are ineffective as cushioning agents. Blend segregation was likely observed due to the particle size and the density differences between APAP beads and calcium silicate-based placebo beads; placebo bead percolation can perhaps be minimized by increasing their size during the extrusion-spheronization process. The GMS- based placebos offer greater promise as cushioning agents for compacted, coated drug beads; however, this requires an optimized compression pressure range and drug bead : placebo bead ratio (i.e., 50:50).
本研究的目的是对一种由安慰剂微丸和载药微丸组成的缓释多颗粒片剂制剂进行表征和评估。采用挤出滚圆法制备了含40%-60%乙基纤维素（EC）的对乙酰氨基酚（APAP）微丸制剂以及含30%硅酸钙且使用0%-20%乙醇制备的安慰剂微丸，并采用中心复合实验设计进行研究。测量了微丸的粒径和真密度。使用新型ASTM D6940-04方法对未包衣的APAP微丸（60%EC）与硅酸钙安慰剂微丸（10%乙醇）按50:50混合的样品进行离析测试。使用仪器化的斯托克斯B2旋转压片机压制片剂，并对其抗压强度和溶出速率进行评估。与载药微丸（60%EC）相比，安慰剂微丸（10%乙醇）粒径较小但真密度较高，分别为864.8μm和1.27 g/cm³，以及787.1μm和1.73 g/cm³。离析测试表明，初始混合样品与最终混合样品之间的药物含量（以变异系数衡量）存在约20%的差异。尽管基于硅酸钙的安慰剂微丸在与Surelease®包衣的APAP微丸混合时被证明是无效的缓冲剂，但发现其单独使用时具有很好的可压性，片剂抗压强度值在14至17 kP之间。APAP微丸基质中的EC对未包衣微丸的药物释放抑制作用最小（t100% = 2小时）。然而，与基于硅酸钙的安慰剂相比，含有用单硬脂酸甘油酯（GMS）重新配制的安慰剂微丸的片剂释放速率较慢（t60% = 5小时），但在压片时仍出现了一些包衣破损（约30%），因为其释放速度比单独的包衣APAP微丸快。虽然含有包衣载药微丸的片剂可以在实际抗压强度（>8 kP）和低压缩压力（10-35 MPa）下生产，但溶出研究表明，基于硅酸钙的安慰剂作为缓冲剂是无效的。由于APAP微丸与基于硅酸钙的安慰剂微丸之间的粒径和密度差异，可能会观察到混合离析现象；也许可以通过在挤出滚圆过程中增加安慰剂微丸的尺寸来最小化安慰剂微丸的渗滤。基于GMS的安慰剂作为压实包衣载药微丸的缓冲剂更有前景；然而，这需要优化压缩压力范围和载药微丸与安慰剂微丸的比例（即50:50）。
