Franc Aleš, Kubová Kateřina, Elbl Jan, Muselík Jan, Vetchý David, Šaloun Jan, Opatřilová Radka
Department of Pharmaceutics, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic.
Department of Applied Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic.
Eur J Hosp Pharm. 2019 Jan;26(1):10-15. doi: 10.1136/ejhpharm-2016-001163. Epub 2017 Jul 24.
The abuse of benzodiazepines and Z-drugs reduces the quality of life of millions of addicted people worldwide. They cannot be discontinued abruptly due to harmful withdrawal symptoms. Detoxification is usually based on replacement of short/middle acting benzodiazepines or Z-drugs by diazepam and tapering the dose over time. In order to enhance patient adherence to an individual withdrawal plan, suitable diazepam dosage forms have to be available. Hard capsules containing an exact and uniform dose could be used for the relief of symptoms caused by altering the plasma level and overcoming psychogenic stress from the dose reduction.
This work demonstrates that capsules with a content of diazepam ranging from 2.125mg to 0.492 mg (dose decreasing always by 15%) cannot be easily prepared by standard mortar technology in a pharmacy. To meet mass and content uniformity European Pharmacopoeia criteria, capsules were prepared by improved technology based on the preparation of binary blends of calcium phosphate anhydrous and diazepam in descending concentrations in a high-speed mixer (time 30 s) and densification of about 10% during filling of the capsules.
All batches (n=20) prepared by improved technology met the requirement for content uniformity compared with only nine batches prepared by standard mortar blender technology. Based on the process capability index, none of the samples prepared by standard technology fitted pharmacopeia limits at the statistically acceptable level. On the other hand, all batches prepared by improved technology exhibited acceptable process capability index.
We have shown that at least 99.73% of batches prepared by our improved technology would meet the pharmacopoeia limits for content uniformity and are suitable for treatment of this type of addiction.
苯二氮䓬类药物和Z类药物的滥用降低了全球数百万成瘾者的生活质量。由于有害的戒断症状，这些药物不能突然停用。戒毒通常基于用 diazepam 替代短效/中效苯二氮䓬类药物或Z类药物，并随着时间逐渐减少剂量。为了提高患者对个体化戒断计划的依从性，必须有合适的 diazepam 剂型。含有精确且均匀剂量的硬胶囊可用于缓解因改变血浆水平和克服剂量减少引起的心理压力而导致的症状。
这项研究表明，药房采用标准研钵技术难以轻松制备 diazepam 含量在2.125mg至0.492mg之间（剂量每次减少15%）的胶囊。为满足欧洲药典关于质量和含量均匀性的标准，采用改进技术制备胶囊，该技术基于在高速混合器中制备无水磷酸钙和 diazepam 的二元混合物，浓度递减（时间30秒），并在填充胶囊过程中压实约10%。
与仅用标准研钵搅拌技术制备的9批相比，采用改进技术制备的所有批次（n = 20）均符合含量均匀性要求。基于过程能力指数，标准技术制备的样品在统计学可接受水平上均未达到药典限度。另一方面，采用改进技术制备的所有批次均表现出可接受的过程能力指数。
我们已经表明，采用我们的改进技术制备的批次中至少99.73%符合药典含量均匀性限度，适用于治疗此类成瘾。
