Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations

Abstract

A method is provided for improving lung function in COPD by administering a muscarinic antagonist with a high efficiency nebulizer.

Description

[0001]This application claims priority under 35 U.S.C. §120 from U.S. nonprovisional patent application Ser. No. 12 / 393,709, filed Feb. 26, 2009, and claims priority under 35 U.S.C. §119(e) from U.S. provisional patent application 61 / 031,639, filed Feb. 26, 2008, and from U.S. provisional patent application 61 / 080,184, filed Jul. 11, 2008, each of which applications is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Chronic obstructive airway disease (COPD) is a pulmonary (lung) disease characterized by chronic obstruction of the airways. COPD encompasses emphysema and chronic bronchitis. Chronic bronchitis is diagnosed where a patient suffers from chronic cough, mucus production, or both, for at least three months in at least two successive years where other causes of chronic cough have been excluded. In chronic bronchitis, airway obstruction is caused by chronic and excessive secretion of abnormal airway mucus, inflammation, and bronchospasm. Ofte...

AI Technical Summary

Benefits of technology

[0011]Furthermore, previous published reports of delivery of a glycopyrrolate solution formulation by nebulizer were at concentrations of no more than 0.2 mg / ml and contained a preservative, benzyl alcohol, that is a known lung irritant. Without wishing to be bound by theory, it is believed that a higher concentration of glycopyrrolate at the muscarinic receptor level and a more selective targeting of the muscarinic receptors (higher quantity of receptor binding) in the airways will contribute to a faster onset and / or greater magnitude of therapeutic effect and / or a greater duration of therapeutic effect. Additionally, eliminating the preservative enables higher or more concentrated doses of glycopyrrolate to be delivered in a better-tolerated manner.

[0016]Some embodiments described herein provide a method of treating a patient having chronic obstructive pulmonary disease (COPD), comprising administering to the patient, with a nebulizer, a dose of glycopyrrolate, wherein the administration produces in the patient an area under the plasma concentration curve of glycopyrrolate (AUC) of at least about 100 pg / mL·hr. In some embodiments, the administration of the dose of glycopyrrolate achieves in the patient a ratio of AUC to maximum plasma concentration of glycopyrrolate (Cmax) of at least about 0.6 hr, at least about 0.75 hr, at least about 1.0 hr, at least about 1.25 hr, or at least about 1.5 hr. In some embodiments, the method results in a therapeutic effect for at least about 24 hours after administering the glycopyrrolate. In some embodiments, the glycopyrrolate dose is about 25 μg to about 1000 μg of glycopyrrolate. In some embodiments, the glycopyrrolate dose is about 25 μg to about 400 μg of glycopyrrolate. In some embodiments, the therapeutic effect comprises an improvement of FEV1 of at least about 100 mL above baseline when adjusted for placebo or at least about 10% above baseline when adjusted for placebo 24 hours after the glycopyrrolate is administered with the nebulizer. In some embodiments, the nebulizer is a high efficiency nebulizer.

Problems solved by technology

Emphysema involves the destruction of elastin in terminal bronchioles, which leads to remodeling, destruction and ultimate collapse of the airway walls.

Patients with emphysema gradually lose the ability to exhale, causing a rise in blood waste gasses (such as carbon dioxide), a drop in blood oxygen, and a general degradation of patient stamina and overall health.

While most patients respond to treatment with metered dose inhalers or dry powder inhalers, there is a subset of patients for whom such options are not well-suited.

Older and sicker COPD patients, for example, often find it difficult to use, or do not experience therapeutic benefit from the use of, metered dose inhalers or dry powder inhalers.

Patients whose motor skills are impaired or not fully developed will often have trouble activating the device, coordinating their breathing, and generally using metered dose inhalers.

Patients who also have poor inhalation capacity and control find dry powder inhalers to be difficult to operate as well.

The '607 patent distinguishes this methodology from administration of a solution formulation of glycopyrrolate, which is characterized as being unable to achieve effective treatment of COPD for longer than 12 hours.

Although the bronchoprotective effect in response to a bronchial challenge test is considered a useful surrogate test for treatment of lung diseases with airway hyperresponsiveness, such as asthma, a positive bronchoprotective test is not considered a predictive tool and useful test in patients with COPD, because of the different disease pathology and mechanisms involved in COPD.

As outlined in the literature and international guidelines, the airway hyperresponsiveness test is not considered a suitable test for use in COPD, therefore the data in asthma patients presented by Hansel et al. cannot be extrapolated for COPD.

Nevertheless none of the treated patients in Hansel, et al were identified as suffering from COPD, and no study has demonstrated a clinically meaningful bronchodilator response in COPD, asthma, or any other respiratory disease with nebulized glycopyrrolate for greater than 12 hours at any dose.

However, the treatment options for these patients are limited.

Ipratropium bromide is the only muscarinic antagonist approved for nebulizer delivery in COPD (monotherapy or in combination with albuterol), however ipratropium + / −albuterol is indicated for administration four times per day (QID); and QID dosing and long nebulization times of this short-acting agent is inconvenient, leading to poor compliance and thus sub-optimal clinical outcomes.

Heretofore, no method, device or system has been suggested that satisfies these needs.

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