Limitations and Challenges in the Stability of Cysteamine Eye Drop Compounded Formulations.

Cristina Martín-Sabroso,Damián Córdoba-Díaz,Mario Alonso-González,Federico Navarro-García,Ana Torres-Suárez,Juan Aparicio-Blanco,Ana Fernández-Carballido,Manuel Córdoba-Díaz

doi:10.3390/ph15010002

Cristina Martín-Sabroso, Damián Córdoba-Díaz + Show 6 more

Open Access

https://doi.org/10.3390/ph15010002

Copy DOI

Abstract

Accumulation of cystine crystals in the cornea of patients suffering from cystinosis is considered pathognomonic and can lead to severe ocular complications. Cysteamine eye drop compounded formulations, commonly prepared by hospital pharmacy services, are meant to diminish the build-up of corneal cystine crystals. The objective of this work was to analyze whether the shelf life proposed for six formulations prepared following different protocols used in hospital pharmacies is adequate to guarantee the quality and efficacy of cysteamine eye drops. The long-term and in-use stabilities of these preparations were studied using different parameters: content of cysteamine and its main degradation product cystamine; appearance, color and odor; pH and viscosity; and microbiological analysis. The results obtained show that degradation of cysteamine was between 20% and 50% after one month of storage in the long-term stability study and between 35% and 60% in the in-use study. These data confirm that cysteamine is a very unstable molecule in aqueous solution, the presence of oxygen being the main degradation factor. Saturation with nitrogen gas of the solutions offers a means of reducing cysteamine degradation. Overall, all the formulae studied presented high instability at the end of their shelf life, suggesting that their clinical efficacy might be dramatically compromised.

Highlights

Cystinosis is a rare autosomal recessive disorder that affects the lysosomal storage of the amino acid cystine
Considering the risk that the instability of this molecule may imply for patient health, along with the published studies that indicate the high lability of cysteamine in aqueous solutions [34–36], it was decided to evaluate the physical, chemical and microbiological stability of six formulations described in the bibliography over the course of their proposed long-term shelf life and in-use shelf life
After the long-term and in-use stability studies carried out on six compounded formulations of cysteamine eye drops, we can conclude that cysteamine is a very unstable molecule in aqueous solution, undergoing a rapid oxidation even when preparations are stored in the refrigerator

Summary

Introduction

Cystinosis is a rare autosomal recessive disorder that affects the lysosomal storage of the amino acid cystine. Its prevalence is estimated at around 1/100,000–1/200,000 among live births. This systemic disease is characterized by mutations in the CTNS gene located on chromosome 17p13 that lead to the defective production of the ubiquitous lysosomal transmembrane cystinosin, which is responsible for the transport of cystine out of the lysosome [1]. Cystine builds up in lysosomes as crystals, which in turn leads to the progressive impairment and dysfunction of multiple organs and tissues, including the kidneys and the eyes [2–4]. The tear film is the main barrier of the eye followed by the cornea. In this structure three membranes are distinguished: the epithelium, stroma and endothelium.

Objectives

Methods

Results

Discussion

Conclusion