Stability study of 0.2% morphine mouthwashes for high dose chemotherapy induced mucositis

Marie Dubois 1, Kathleen Leger 1, Elina Wolff 1, Sophie Perriat 1, Anaïs Grand 1, Yann Cretu 1, Jean Marie Canonge 1, Coralie Guillemot 1, Florent Puisset 1 1 Pharmacie IUCT-Oncopole, Toulouse, France

Introduction and objective:
The treatment of pain of chemo-induced mucositis after high dose chemotherapy is still an unmet medical need. Various mouthwashes have been studied but none appears as a gold standard. Among them 0.2% morphine mouthwash has been proposed for pain relief and limiting systemic opioïd intake. Since this mouthwash nominal preparation has been implemented in our facility we observed a pain relief without increasing opioid intake in near than 50% of patients. Whereas encouraging, this result means that patients who are not relieved stop mouthwash use thus their prepared mouthwashes are to be destroyed. To avoid destruction, a serial preparation was considered, but the short stability published (7 days) was a limit. The objective of this study was to assess the physical, chemical and microbiological stability of 0.2% morphine mouthwashes to set up hospital preparations.

Method and materials:
A high performance liquid chromatography method (HPLC) using a photodiode array detector, a ProntoSIL® C18 column (150 x 4.6 mm, 5µm), a mobile phase with a mixture of 0.1% trifluoroacetic acid and acetonitrile in a 80:20 volumetric ratio, at a wavelength at 255 nm was developed to measure the concentration of morphine.
The chemical stability was assessed at baseline then at week 1-2-3-4-6-8-10 and 12 by the evolution of the concentration of morphine measured as triplicate on three samples (for stability concentration should remained between 95% and 105% of baseline without detectable degradation product. The physical stability was assessed by visual check and measure of pH.
At each defined time a sample was seeded to assess the microbiological stability.

Forced degradation of morphine led products of degradation (retention time [RT] = 3.2 min) well separated from morphine (RT =3.8min) by the HPLC method. The linearity of the HPLC method was validated within 0.5 and 3 mg/ml (correlation coefficient between 0.9993 and 0.9995). Inaccuracy and precision of the HPLC method were within -2.6% and +2.7% and within 0.05% and 0.39% respectively. Concentration of morphine remained between 96% and 103% of baseline whatever the temperature of storage during the 12 weeks. No product of degradation has been detected. No change of color has been observed, but a trend in elevation of pH (5.4 to 5.8) was seen from the 8th week. All preparations remained sterile for the duration of the study.

According to these results, the chemical and microbiological stability of 0.2% morphine mouthwashes stored at room temperature and between 2 and 8°C as well is proven for three months. Due to the physical stability, the shelf life of morphine mouthwash is capped to 2 months. Therefore, the stability is as long as enough to allow the preparation of morphine mouthwashes as serial preparation.

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