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Inhalable preparation containing indacaterol maleate and glycopyrronium bromide solution

A kind of technology of glycopyrronium bromide and solvent, applied in the field of inhalable preparations, can solve problems such as difficult administration

Active Publication Date: 2022-02-22
GUANGZHOU ANOVENT PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Dry powder inhalation is more difficult, especially for children and elderly patients

Method used

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  • Inhalable preparation containing indacaterol maleate and glycopyrronium bromide solution
  • Inhalable preparation containing indacaterol maleate and glycopyrronium bromide solution
  • Inhalable preparation containing indacaterol maleate and glycopyrronium bromide solution

Examples

Experimental program
Comparison scheme
Effect test

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] Components are listed in Table 1, according to Table 1, 50% benzalkonium chloride and 95% ethanol were dissolved in Table 1, and then transferred to a 100ml 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] Table ...

Embodiment 3

[0097] Preparation of different pH value inhalation solutions of sample 4, sample 5, sample 6 and sample 7:

[0098] 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.

[0099] 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.

[0100] ...

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Abstract

The present invention discloses a liquid, propellant-free pharmaceutical formulation and a method of administering the pharmaceutical formulation by nebulizing the pharmaceutical formulation in an inhaler. The liquid, propellant-free pharmaceutical preparation includes: (a) an active substance selected from glycopyrronium bromide and indacaterol maleate; (b) a solvent; (c) a pharmaceutically acceptable preservative, any Optionally include a pharmaceutically acceptable stabilizer, a pharmaceutically acceptable solubilizer, a pharmaceutically acceptable co-solvent or other pharmaceutically acceptable additives.

Description

[0001] priority statement [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 856,707, filed June 3, 2019, which is hereby incorporated by reference in its entirety. Background technique [0003] Indacaterol (Indacaterol), the chemical name is 5-[(R)-2-(5,6-diethylindol-2-ylamino)-1-hydroxyethyl]-8-hydroxy-(1H )-quinolin-2-one. The preparation of indacaterol has been disclosed in WO 00 / 75114 and WO 2004 / 076422. Indacaterol can exist as the maleate salt, indacaterol maleate, which has the following chemical structure: [0004] [0005] Indacaterol maleate is a beta-selective adrenoceptor agonist with strong bronchodilatory activity. Indacaterol maleate is especially useful in the treatment of asthma and chronic obstructive pulmonary disease (COPD). [0006] Glycopyrronium bromide (also known as glycopyrrolate) acts as a long-acting antimuscarinic (LAMA) and anticholinergic agent with the following chemical structure: [0007] [0...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/40A61K9/12A61K47/12
CPCA61K31/40A61K31/4704A61K9/0078A61K47/10A61K47/183A61K47/186A61K47/12
Inventor 黄才古许英爱赵悦张璐璐
Owner GUANGZHOU ANOVENT PHARM CO LTD
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