{
  "abstract": "Background and Importance Eye drops packaged in preservative-free multidose containers (MDC) eliminate the need to add antimicrobial preservatives, which is a significant advantage due to their local cytotoxicity. However, under certain conditions contact between MDC and the eye drops may lead to the release of compounds such as 2,4-di-tert-butylphenol (2,4 DTBP), thereby contaminating the patients. The potential local toxicity of 2,4 DTBP and the clinical consequences need to be assessed.Aim and Objectives The objectives were to determine if and how much 2,4 DTBP migrates into eye drops from the MDC and to assess its cytotoxicity threshold.Material and Methods Tests simulating the patient‘s use of eye drops were carried out on seven preparations (tacrolimus = TAC, ciclosporin = CsA, voriconazole = VCZ, atropin, vancomycin, ceftazidime and Costec) packaged in the same kind of MDC. The drops were collected twice a day for 1 month and then analysed by liquid chromatography to detect and quantify 2,4 DTBP. The in vitro cytotoxicity threshold of 2,4 DTBP was determined on L929 mouse fibroblasts, according to the 3- (4,5-dimethylthiazol-2-yl)-2,5-bromide (MTT) cytotoxicity test of ISO standard 10993-5.Results The average amount per drop (± standard deviation) varied between the first and last day of drop emission from 47 ± 13 to 20 ± 4 ng for TAC, 401 ± 102 to 32 ± 4 ng for CsA, and from 235 ± 45 to 101 ± 28 ng for VCZ, corresponding to calculated monthly cumulative doses of 1,687 ng, 4,939 ng, and 9,108 ng, respectively. After exposing the cells to various amounts of 2,4 DTBP for 24 hours, all doses above 1,200 ng led to cytotoxicity, as assessed by the morphological and metabolic assays.Conclusion and Relevance The nature of the formulation seems to influence the migration of 2,4 DTBP, as it was only found in eye drops composed of a hydrophobic active ingredient solubilised by a surfactant for TAC and CsA and cyclodextrin for VCZ. None of the daily amounts per drop exceeded the dose of 1,200 ng, but further studies are needed to determine its cumulative toxicity during chronic administration. Adapting the MTT assay to corneal cells would enable a more accurate evaluation of its ocular cytotoxicity.Conflict of Interest No conflict of interest",
  "authors": [
    {
      "affiliations": [
        "Université Clermont Auvergne- Chu Clermont Ferrand-Clermont Auvergne Inp- Cnrs- Iccf, Pharmacy, Clermont Ferrand, France"
      ],
      "name": "M Barrieu"
    },
    {
      "affiliations": [
        "Chu Clermont Ferrand, Pharmacy, Clermont Ferrand, France"
      ],
      "name": "O Allard"
    },
    {
      "affiliations": [
        "Université Clermont Auvergne- Chu Clermont Ferrand-Clermont Auvergne Inp- Cnrs- Iccf, Pharmacy, Clermont Ferrand, France"
      ],
      "name": "L Bernard"
    },
    {
      "affiliations": [
        "Université Clermont Auvergne- Chu Clermont Ferrand-Clermont Auvergne Inp- Cnrs- Iccf, Pharmacy, Clermont Ferrand, France"
      ],
      "name": "V Sautou"
    },
    {
      "affiliations": [
        "Université Clermont Auvergne- Chu Clermont Ferrand-Clermont Auvergne Inp- Cnrs- Iccf, Pharmacy, Clermont Ferrand, France"
      ],
      "name": "P Chennell"
    }
  ],
  "title": "3PC-017 Migration of leachable 2,4-di-tert-butylphenol from preservative-free multidose dropper systems into ophthalmic preparations and assessment of in vitro cytotoxicity",
  "uid": "487420ee-18ae-5771-bca3-5140549b5f9b"
}