Saito Jumpei, Imaizumi Hitomi, Yamatani Akimasa
1Department of Pharmacy, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 175-8535 Japan.
2Division of Clinical Pharmacology and Oral Formulation Development, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 175-8535 Japan.
J Pharm Health Care Sci. 2019 Dec 5;5:25. doi: 10.1186/s40780-019-0154-2. eCollection 2019.
Atropine eye drops are indicated for juvenile myopia progression, cycloplegia, amblyopia, and strabismus. According to the package insert, 10 mg/mL atropine eye drops must be diluted for pediatric patients to prevent systemic adverse effects. Compounding units in hospital pharmaceutical departments or community pharmacies are compelled to prepare this essential medication; however, validated atropine stability data is limited and the shelf life after preparation is extremely short. As it is a long-term treatment, a longer shelf life is necessary to improve patient care. This study aimed to demonstrate the physical, chemical, and microbiological stability of diluted atropine eye drops over a period of six months.
Preparation consists of dilution of a 10 mg/mL atropine solution (Nitten Atropine Ophthalmic Solution 1%; Nitten Pharmaceutical Co., Ltd.) in 0.9% NaCl to concentrations of 0.1, 1.0, 2.5, and 5.0 mg/mL, followed by a sterilizing filtration procedure and then an aseptic filling process of 5 mL in 5 mL polyethylene eyedropper bottles. The entire process is carried out in an overpressure isolator. All concentration products were kept for six months at 25 °C or 5 °C. Visual inspection was conducted and pH, osmolality, and atropine concentration were measured at day 0, day 14, day 28, and every month until six months. Atropine concentration was measured using liquid chromatography tandem mass spectrometry. The sterility was monitored using a method adapted from the Japanese Pharmacopoeia sterility assay.
Atropine remained within ±5% of the target value in the six batches. Osmolality (285 mOsm/kg) as well as pH (5.88) were kept constant. No variations in solution characteristics (crystallization, discoloration) were noted. Sterility was maintained.
This study validated the physical, chemical, and microbiological stability of 0.1, 1.0, 2.5, and 5.0 mg/mL atropine sulfate eye drops conserved inside polyethylene eyedroppers for six months at 25 °C or 5 °C.
阿托品滴眼液适用于青少年近视进展、睫状肌麻痹、弱视和斜视。根据药品说明书，对于儿科患者，必须稀释10mg/mL的阿托品滴眼液以防止全身不良反应。医院药房或社区药房的配制单位必须配制这种基本药物；然而，经过验证的阿托品稳定性数据有限，配制后的保质期极短。由于这是一种长期治疗方法，需要更长的保质期来改善患者护理。本研究旨在证明稀释后的阿托品滴眼液在六个月内的物理、化学和微生物稳定性。
配制方法为将10mg/mL的阿托品溶液（参天阿托品眼药水1%；参天制药株式会社）用0.9%氯化钠稀释至浓度为0.1、1.0、2.5和5.0mg/mL，然后进行除菌过滤，接着在5mL聚乙烯滴管瓶中进行5mL的无菌灌装。整个过程在超压隔离器中进行。所有浓度的产品在25°C或5°C下保存六个月。在第0天、第14天、第28天以及直至六个月每月进行一次外观检查，并测量pH值、渗透压和阿托品浓度。使用液相色谱串联质谱法测量阿托品浓度。采用改编自日本药典无菌检测法的方法监测无菌性。
六批产品中阿托品含量保持在目标值的±5%以内。渗透压（285mOsm/kg）以及pH值（5.88）保持恒定。未观察到溶液特性（结晶、变色）的变化。无菌性得以维持。
本研究验证了0.1、1.0、2.5和5.0mg/mL硫酸阿托品滴眼液在25°C或5°C下保存在聚乙烯滴管中六个月的物理、化学和微生物稳定性。
