含羟丙基-β-环糊精的 1%苯巴比妥口服液的制剂及稳定性研究。
Formulation and stability study of an oral paediatric phenobarbital 1% solution containing hydroxypropyl-β-cyclodextrins.
机构信息
Department of Pharmacy, Armand Trousseau Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
Department of Pharmacy, Armand Trousseau Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.
出版信息
Eur J Hosp Pharm. 2024 Jun 21;31(4):363-368. doi: 10.1136/ejhpharm-2022-003487.
OBJECTIVES
Phenobarbital is a barbiturate, used to treat focal and generalised epilepsy. Since the end of marketing of the oral solution KANEURON in 2017, phenobarbital tablets remain the only available dosage form. Development of an oral phenobarbital solution for paediatric use is therefore essential to fulfil clinical needs. A new formulation of phenobarbital with hydroxypropyl-β-cyclodextrins (HPBCD) was developed, and the physicochemical stability of the solution was evaluated.
METHODS
Different excipients have been selected to formulate a solution of phenobarbital. Samples were dosed by High Performance Liquid Chromatography (HPLC) at 216 nm with a LiChroCART C18 endcapped column and mobile phase composed of phosphate buffer pH 3 and methanol (50:50 v/v). Linearity, accuracy, sensibility and specificity of the method were tested, and a forced degradation study was carried out. During stability study, content of phenobarbital, pH, osmolality of the phenobarbital solution and degradation products were followed up for 6 months in line with GERPAC guidelines.
RESULTS
The stability indicating the character of the assay method has been validated. The physicochemical stability study shows that the phenobarbital solution formulated is stable for 6 months, in line with International Conference of Harmonisation (ICH) recommendations Q1A and Q3B (R2) regarding the content of phenobarbital and levels of degradation products (no degradation products >0.01%). Phenobarbital concentration was 101.59±2.6% of initial concentration in refrigerated samples and 101.14±0.5% at 20±5°C. No phenobarbital degradation products (>0.01%) were observed throughout the 6 months. No significant variation of pH or osmolality was observed.
CONCLUSIONS
HPBCD solubilise phenobarbital and create a homogeneous solution. These stability data set the shelf life of this new phenobarbital solution at up to 6 months. A microbiological stability study will be carried out to ensure the possibility of using this solution in children.
目的
苯巴比妥是一种巴比妥类药物，用于治疗局灶性和全身性癫痫。自 2017 年 KANEURON 口服液停止销售以来，苯巴比妥片剂仍然是唯一可用的剂型。因此，开发一种用于儿科的口服苯巴比妥溶液对于满足临床需求至关重要。开发了一种新的含有羟丙基-β-环糊精（HPBCD）的苯巴比妥制剂，并对该溶液的物理化学稳定性进行了评估。
方法
选择了不同的赋形剂来配制苯巴比妥溶液。样品通过高效液相色谱法（HPLC）在 216nm 处进行测定，使用 LiChroCART C18 端封柱和由磷酸盐缓冲液 pH3 和甲醇（50:50v/v）组成的流动相。对该方法的线性、准确性、灵敏度和特异性进行了测试，并进行了强制降解研究。在稳定性研究中，根据 GERPAC 指南，在 6 个月内跟踪苯巴比妥溶液的含量、pH 值、渗透压和降解产物。
结果
该分析方法的稳定性指示特性已得到验证。物理化学稳定性研究表明，所配制的苯巴比妥溶液在 6 个月内稳定，符合国际人用药品注册技术协调会（ICH）关于苯巴比妥含量和降解产物水平（无降解产物>0.01%）的 Q1A 和 Q3B（R2）建议。冷藏样品中苯巴比妥浓度为初始浓度的 101.59±2.6%，20±5°C 时为 101.14±0.5%。在整个 6 个月内未观察到苯巴比妥降解产物（>0.01%）。pH 值或渗透压无明显变化。
结论
HPBCD 增溶苯巴比妥并形成均匀溶液。这些稳定性数据将这种新的苯巴比妥溶液的保质期设定为长达 6 个月。将进行微生物稳定性研究，以确保该溶液可用于儿童。
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