Ciavarella Anthony B, Khan Mansoor A, Gupta Abhay, Faustino Patrick J
Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Food and Drug Administration, Life Science Building 64, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Food and Drug Administration, Life Science Building 64, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
PDA J Pharm Sci Technol. 2016;70(6):523-532. doi: 10.5731/pdajpst.2016.006411.
This U.S. Food and Drug Administration (FDA) laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs.
Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product, and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance.
All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5 to 2.1 standard deviation (SD) of the percent label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3 to 9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation.
Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting can have an effect on the amount of drug present in a split tablet and available for absorption.
Tablet splitting has become a very common practice in the United States and throughout the world. Tablets are often split to modify dose strength, make swallowing easier, and reduce cost to the consumer. To better address product quality for this widely used practice, the U.S. Food and Drug Administration (FDA) published a Guidance for Industry that addresses tablet splitting. The guidance provides testing criteria for scored tablets, which is a part of the FDA review process for drugs. The model drugs selected for this study were amlodipine and gabapentin, which have different sizes, shapes, and tablet scores. Whole and split amlodipine tablets were tested for drug content because of a concern that the low-dose strength may cause greater variability. Whole and split gabapentin tablets were tested for weight variation because of their higher dosage strength of 600 mg. All whole tablets met the acceptance criteria for the Uniformity of Dosage Units based on the guidance recommendations. When unscored amlodipine tablets were split by a splitter, all formulations did not meet the acceptance criteria. When fully scored gabapentin tablets were split by hand and by splitter, they met the acceptance criteria. The findings of this FDA study indicated physical characteristics such as size, shape, and tablet score can affect the uniformity of split tablets.
本美国食品药品监督管理局（FDA）实验室研究考察了片剂掰开的影响、片剂分割器的作用以及片剂刻痕对两种模型药物剂量均匀性的影响。
从五家生产商购买氨氯地平整片，从六家生产商购买加巴喷丁整片。每种药品使用两种分割器，加巴喷丁片剂也进行手工掰开。按照美国药典（USP）<905>剂量单位均匀度通则对氨氯地平整片和掰开片进行含量均匀度测试，这是FDA新药片刻痕行业指南的一项要求。根据指南建议，对加巴喷丁掰开片采用USP重量差异法。
所有整片均符合USP剂量单位均匀度的验收标准。整片含量的变异范围为标示量百分比的0.5至2.1标准偏差（SD）。与整片相比，未刻痕的氨氯地平片剂掰开后剂量变异性显著增加，达到6.5 - 25.4 SD。所有氨氯地平药品的掰开片均不符合USP含量均匀度的验收标准。加巴喷丁掰开片的重量变异大于整片，范围为1.3至9.3 SD。所有完全刻痕的加巴喷丁产品均符合USP重量差异的验收标准。
尺寸、形状以及片剂是否有刻痕会影响氨氯地平片和加巴喷丁片的含量均匀度和重量差异。片剂掰开产生的变异性更高。观察到片剂分割器掰开和手工掰开在剂量变异性和裂片方面存在差异。这些结果与FDA对片剂掰开可能影响掰开片中药物含量及吸收量的担忧一致。
片剂掰开在美国乃至全世界都已成为一种非常普遍的做法。片剂常被掰开以调整剂量强度、便于吞咽并降低消费者成本。为更好地解决这种广泛使用做法的产品质量问题，美国食品药品监督管理局（FDA）发布了一份关于片剂掰开的行业指南。该指南提供了刻痕片剂的测试标准，这是FDA药品审评过程的一部分。本研究选用的模型药物为氨氯地平和加巴喷丁，它们具有不同的尺寸、形状和片剂刻痕。由于担心低剂量强度可能导致更大变异性，对氨氯地平整片和掰开片进行了药物含量测试。由于加巴喷丁的较高剂量强度为600 mg，对加巴喷丁整片和掰开片进行了重量差异测试。根据指南建议，所有整片均符合剂量单位均匀度的验收标准。当用分割器掰开未刻痕的氨氯地平片剂时，所有制剂均不符合验收标准。当完全刻痕的加巴喷丁片剂进行手工掰开和用分割器掰开时，它们符合验收标准。FDA这项研究的结果表明，尺寸、形状和片剂刻痕等物理特性会影响掰开片均匀度。
