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

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.

Results:
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.

Discussion-Conclusion:
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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