Medicament comprising a highly potent long-lasting beta2-agonist in combination with other active ingredients

A technology of active ingredients and compositions, applied in the field of pharmaceutical compositions containing high-efficiency and long-acting β2-agonists and other active ingredients, can solve problems such as undetermined effective and safe doses

Inactive Publication Date: 2006-03-29
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A very large therapeutic window of 0.8-9.6 μg is therefore suggested, but no effective and safe dose has been established

Method used

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  • Medicament comprising a highly potent long-lasting beta2-agonist in combination with other active ingredients
  • Medicament comprising a highly potent long-lasting beta2-agonist in combination with other active ingredients
  • Medicament comprising a highly potent long-lasting beta2-agonist in combination with other active ingredients

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1 - In vitro test of the anti-inflammatory efficacy of the composition of the invention on a human U-937 derived macrophage cell line

[0070] U-937 cells were incubated with 10 ng / ml phorbol myristate acetate and subjected to macrophage differentiation for 48 hours.

[0071] Cells were then treated with 1 μg / ml lipopolysaccharide (LPS) or LPS and a concentration range of β 2 -Agonists, corticosteroids or combinations together. TNF[alpha] and IL-10 were assayed after different times of incubation. Media was collected and cells were lysed for cyclic adenosine 3',5'-monophosphate (cAMP) assay.

[0072] TNFα and IL-10 were measured in the medium by a commercially available ELISA assay, and simultaneously by a commercially available 3 The H-cAMP assay system measures cAMP.

[0073] in the absence and presence of 10 -10 and 10 -8 The concentrations of M provided by TA 2005 were used to determine the corticosteroid dose-response curve. Inhibition of TNFa and IL-...

Embodiment 2

[0075] Example 2 - In vivo test of the anti-inflammatory efficacy of the composition of the invention in a Sephadex-induced pulmonary edema model

[0076] Rat pulmonary edema induced by Sephadex is a model leading to inflammatory cell infiltration and persistent interstitial edema. Evaluation with another long-acting beta 2 Anti-inflammatory activity of TA 2005 alone and in combination with budesonide compared with the adrenoceptor agonist, formoterol.

[0077] Sephadex beads (5 mg / ml) were administered intratracheally to anesthetized rats (200-250 g) at a dose volume of 1 ml / kg. The control group received 1 ml / kg saline.

[0078] The test substances are suspended in saline and suitably diluted in Sephadex suspension for intratracheal administration.

[0079] Twenty-four hours after administration, the animals were sacrificed, and the lungs were removed and weighed. The percent inhibition of Sephadex-induced edema was then determined.

[0080] Intratracheal instillation...

Embodiment 3

[0082] Example 3 -Effect of TA 2005 and budesonide combination on acetaldehyde-induced bronchoconstriction in guinea pigs

[0083] Control of bronchoconstriction induced by acetaldehyde (AcCHO) by TA 2005 has been studied in anesthetized artificially ventilated guinea pigs according to the experimental animal model described by Berti et al., Arzneim-Forsch / Drug Res 1994;44:323-326 and neuroinflammatory capacity.

[0084] Intravenous injection of AcCHO resulted in dose-dependent bronchoconstriction accompanied by increased blood histamine and Evans blue extravasation in tracheal tissue, indicating altered vascular permeability.

[0085] The protective activity of TA 2005 (0.1-10 pmol), formoterol (0.3-30 pmol) or budesonide (31.25-500 nmol) was determined after intratracheal perfusion alone or in combination.

[0086] All effects of AcCHO were effectively antagonized by TA 2005 and formoterol. However, TA 2005 was almost twice as effective as formoterol in preventing bronch...

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PUM

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Abstract

The present invention relates to the use of a bronchodilator in combination with one or more further active ingredients for the treatment of respiratory disorders and especially asthma and chronic obstructive pulmonary disease (COPD), and to pharmaceutical compositions containing said active ingredients. In particular, the invention relates to the use of the long-acting beta2-agonist 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1methylethyl]amino]ethyl-2(1H)-quinolinone and / or physiologically acceptable salts and / or solvates thereof as a bronchodilator in combination with other active ingredients.

Description

Background of the invention [0001] Asthma is a disease that is becoming more common and is one of the most common childhood diseases. It can be identified by recurrent wheezing and intermittent airflow limitation. Despite many advances in its understanding, its pathology remains an underrecognized and often poorly treated disease. [0002] Previously, contraction of airway smooth muscle was considered the most important feature of asthma. There have been significant changes in the management of asthma due to the recognition that asthma is a chronic inflammatory disease. Uncontrolled airway inflammation may lead to mucosal damage and structural changes, leading to irreversible narrowing of the airways and fibrosis of lung tissue. The goal of treatment should therefore be to control symptoms to enable normal life while providing a basis for treating the underlying inflammation. [0003] Symptoms can be controlled by: First Generation Beta 2 - Adrenoceptor agonists such as a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/47A61P11/08A61K31/56
CPCA61K31/47A61K31/56A61P11/00A61P11/06A61P11/08A61P29/00A61K2300/00
Inventor R·拉泽蒂F·帕斯托雷
Owner CHIESI FARM SPA
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