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Inhalable formulation of a solution containing formoterol fumarate and aclidinium bromide

A solvent and inhaler technology, applied in the field of salt or solvate, treatment of asthma and chronic obstructive pulmonary disease, aclidinium bromide and formoterol fumarate, can solve problems such as difficulty in administration

Active Publication Date: 2021-05-14
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 formulation of a solution containing formoterol fumarate and aclidinium bromide
  • Inhalable formulation of a solution containing formoterol fumarate and aclidinium bromide
  • Inhalable formulation of a solution containing formoterol fumarate and aclidinium bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Synthesis of aclidinium bromide:

[0082] To acetonitrile (100 mL) was added (R)-quinuclidin-3-yl-2-hydroxy-2,2-bis(thiophen-2-yl)acetate (10 g, 28.7 mmol) and (3-bromopropane oxy)benzene (12.3 g, 57.4 mmol). The reaction mixture was heated to 80-90°C and stirred for 8 hours before a white solid formed. The mixture was cooled to 20-25°C, filtered and washed with ice-cold acetonitrile (10 mL), repeated filtration and washing three times, and dried under vacuum at 50°C to obtain a white solid (15.4 g, 27.4 mmol). The yield of aclidinium bromide was 95%, and the HPLC purity was 99.8%.

Embodiment 2

[0084] Inhalation solutions of Sample 1, Sample 2, and Sample 3 were prepared with different amounts of disodium EDTA dihydrate:

[0085] The ingredients are listed in Table 1. According to Table 1, 50% benzalkonium chloride was dissolved in purified water three times, and then transferred to a 100ml volumetric flask. Add disodium edetate dihydrate and anhydrous citric acid to the solution according to Table 1, and sonicate until completely dissolved; then, add formoterol fumarate and aclidinium bromide to the solution according to Table 1 and sonicated until completely dissolved. Disodium EDTA dihydrate was added to the solution according to Table 1, and then sonicated until completely dissolved. Finally, the volumetric flask was adjusted 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. The results are shown in Table 2.

[0086] Table 1. Ingredient content of inhalatio...

Embodiment 3

[0091] Preparation of sample 4, sample 5, sample 6, sample 7 and sample 8 different pH value inhalation solution:

[0092] The ingredients are listed in Table 3. According to Table 3, 50% benzalkonium chloride was dissolved in purified water three times, and then transferred to a 100ml volumetric flask. Add disodium EDTA dihydrate and anhydrous citric acid to the solution according to Table 3, and sonicate until completely dissolved; then, add formoterol fumarate and aclidinium bromide to the solution according to Table 3 and 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. Samples 4-8 solutions remained essentially clear. The results are shown in Table 4.

[0093] Table 3. Ingredient content of inhalation preparation samples 4-8

[0094] components Sample 4 Sample 5 Sample 6 Sample 7 Sample 8 Aclidinium bromide 20mg 20mg 20m...

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Abstract

The present invention discloses a liquid, propellant-free pharmaceutical formulation and a method for administering a pharmaceutical preparation by nebulizing the pharmaceutical preparation in an inhaler. The propellant-free pharmaceutical formulation comprising: (a) active substances selected from aclidinium bromide and formoterol fumarate; (b) a solvent; and (c) a pharmacologically acceptable preservative, optionally including a pharmacologically acceptable stabilizer, a pharmacologically acceptable solubilizing agent, or other pharmacologically acceptable additives.

Description

[0001] priority statement [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 867,838, filed June 27, 2019, which is hereby incorporated by reference in its entirety. Background technique [0003] Aclidinium and its synthesis methods have been disclosed in WO 01 / 04118 and WO2008 / 009397. Aclidinium can be in the form of a bromide salt, such as aclidinium bromide, with the chemical name 3(R)–(2-hydroxy-2,2-dithio-2-ylacetoxy)-1-(3-phenoxy propyl)-1-azonium bicyclo[2.2.2]octane bromide, which has the following chemical structure: [0004] [0005] Aclidinium bromide is a white to off-white crystalline powder. Aclidinium bromide is a muscarinic antagonist that is commercially available. Aclidinium bromide is a long-acting anticholinergic approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. [0006] Formoterol, chemical na...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/12A61K31/135A61K31/439A61P11/08C07C215/76C07D453/02
CPCA61K31/138A61K31/439A61K9/0078A61K47/12A61K47/183A61K47/186A61M15/009A61M15/007A61M15/0073A61K47/22
Inventor 黄才古张海龙
Owner GUANGZHOU ANOVENT PHARM CO LTD
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