Inhalable formulation of a solution containing indacaterol maleate and glycopyrronium bromide
A technology of glycopyrronium and glycopyrronium, applied in the field of glycopyrronium bromide and indacaterol maleate, salt or solvate, in the treatment of asthma and chronic obstructive pulmonary disease, which can solve problems such as drug administration difficulties
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Embodiment 1
[0083] Synthesis of indacaterol maleate.
[0084] 8-Phenylmethoxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]- was obtained by the method disclosed in US7534890 1H-Quinolin-2-one benzoate (40.0 g, 66.2 mmol). 8-Phenylmethoxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2- Ketobenzoate (40.0 g, 66.2 mmol), methanol (320 ml) and palladium on carbon (5% (4 g)) were charged into a 1 L hydrogenation vessel, then stirred and reacted at 40° C. for 2 hours.
[0085] The reaction mixture was cooled to room temperature, filtered and washed with methanol. The filtrate was concentrated under vacuum at 40 °C. Add 400ml of ethanol, heat to 50-60°C to dissolve, and add maleic acid (11.5g, 99.3mmol). The product crystallizes after cooling slowly to 0~5℃. Filtration, washing and drying yielded indacaterol maleate as a white solid. The yield of indacaterol maleate was 82.0%, and the HPLC purity was 99.0%.
Embodiment 2
[0087] Inhalation solutions of Sample 1, Sample 2, and Sample 3 were prepared with different amounts of disodium EDTA dihydrate:
[0088] The ingredients are listed in Table 1. Dissolve 50% benzalkonium chloride and 95% ethanol in Table 1 according to Table 1, and then transfer to a 100 ml volumetric flask. Indacaterol maleate and glycopyrronium bromide were added to the solution according to Table 1 and then sonicated until completely dissolved. Disodium EDTA dihydrate was added to the solution according to Table 1, and then sonicated until completely dissolved. Finally, the flask was brought to volume with purified water, and the pH value was adjusted to 3.0 with 1N HCl. Sample 1, Sample 2 and Sample 3 solutions remained substantially clear.
[0089] The results are shown in Table 2 and Table 3, showing that both indacaterol maleate and glycopyrronium bromide were completely dissolved in the solution. Impurities are undetectable or in very low levels.
[0090] ...
Embodiment 3
[0095] Preparation of different pH value inhalation solutions of sample 4, sample 5, sample 6 and sample 7:
[0096] The ingredients are listed in Table 4. Dissolve 50% benzalkonium chloride according to Table 4 in 95% ethanol according to Table 4 and transfer to a 100 ml volumetric flask. Indacaterol maleate and glycopyrronium bromide were added to the solution according to Table 4 and then sonicated until completely dissolved. Disodium EDTA dihydrate was added to the solution according to Table 4, and then sonicated until completely dissolved. Finally, the volumetric flask was made to volume with pure water, and the pH value was adjusted to the target value with 1N HCl. Sample 4, Sample 5, Sample 6 and Sample 7 solutions remained substantially clear.
[0097] The results are shown in Table 5 and Table 6, showing that both indacaterol maleate and glycopyrronium bromide were completely dissolved in the solution. Impurities are undetectable or in very low levels.
[0098] ...
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