WO1987000431A1

WO1987000431A1 - Use of gallopamil for treating bronchospastic airway diseases

Info

Publication number: WO1987000431A1
Application number: PCT/US1986/001443
Authority: WO
Inventors: Allyn Golub; Leslie Hendeles
Original assignee: Allyn Golub; Leslie Hendeles
Priority date: 1985-07-15
Filing date: 1986-07-14
Publication date: 1987-01-29
Also published as: US4689213A; DK127287D0; KR870700351A; FI871078A; EP0252088A1; AU6133186A; FI871078A0; DK127287A

Abstract

Bronchospastic diseases characterized by airway hyperreactivity are treated by administration of the calcium channel blocker gallopamil. Unlike other calcium channel blockers, the effective dose of gallopamil is small enough that undesirable side effects are not present.

Description

Use of gallopamil for treating bronchospastic airway diseases.

BACKGROUND OF THE INVENTION

1. Field of the Invention The present invention is directed to the treatment of bronchospastic airway diseases, especially reversible airway hyperreactivity, with a calcium channel blocker. More particularly, the invention is concerned with such treatment using the calcium channel blocker gallopamil.

2. Description of the Prior Art

The compound gallopamil is a known calcium channel blocker. Like other calcium channel blockers such as nifedipine, diltiazim, and verapamil, gallopamil is used in cardiovascular therapy. Verapamil, diltiazim and nifedipine have been tested for possible use as active therapeutic agents in treating reversible airway hyperreactivity. However, the dosages necessary to obtain the desired airway hyperreactivity reduction have resulted in undesirable side effects such as broncho spasm. Also, the dosages have been as high or higher than the dosages used in cardiovascular therapy.

SUMMARY OF THE INVENTION In a first aspect, the present invention is directed to a method for treating a bronchospastic disease characterized by airway hyperreactivity comprising administering to a subject an amount of gallopamil sufficient to reduce airway hyperreactivity, particularly via a pulmonary route.

A second aspect of the invention involves a composition for treating a bronchospastic disease characterized by airway hyperreactivity, comprising an amount of gallopamil effective to reduce airway hyperreactivity and a pharmaceutically acceptable carrier, adjuvant or excipient therefor, especially in a form suitable for aerosol administration. DETAILED DESCRIPTION OF THE INVENTION The present invention concerns treatment of bronchospastic airway diseases, especially reversible airway hyperreactivity, by administration of the calcium channel blocker gallopamil (5- [ [2-(3,4-dimethoxyphenyl) ethyl]methylamino]-2-isopropyl-2-[3,4,5-trimethoxy- phenyljpentanonitrile hydrochloride) . The term "gallopamil" is intended to cover useful derivatives such as other pharmaceutically acceptable salts, non-salt forms, etc. The term "reversible airway hyperreactivity" refers to conditions such as allergen and exercise-induced asthma, etc., which result in reversible blockage of the air. passages. So-called irreversible airway conditions such as emphysema also involve reversible aspects. It is expected that the present invention will be most useful in treatment of chronic conditions.

It is preferred that the gallopamil be administered in a pulmonary fashion, i.e., directly to the lungs in the form of an aerosol. Such aerosol administration can be in the form of a nebulized saline solution. Generally, the solution can include about -1% by weight gallopamil in 0.4% saline. Solubility of gallopamil in the solution is improved by addition of solubilizers such as ethanol and propylene glycol, both in amounts of about 4% by weight, for example. pH adjustment should be accomplished with sodium bicarbonate. . Alternatively, the gallopamil could be dispersed in freon and administered through a metered dose inhaler. It is particularly desirable to use a metered dose inhaler with an inhaling device such as that disclosed in Sackner et al. U.S. Patent 4,484,577, the disclosure of which is incorporated herein by reference. Oral administration in the form of tablets or capsules is possible, but may be disadvantageous because higher dosages are required, possibly leading to undesired cardiovascular effects. Parenteral and topical administration are also possible, although not preferred because of inconvenience and higher required dosage. Parenteral administration likely would be most useful in emergency situations, but it is contemplated that the present invention will be most useful in a preventative manner or for relief via self-administration.

When the gallopamil is delivered via a nebulized saline solution, enough solution should be used to provide a gallopamil dose of about 1-20 mg, preferably 1-10 mg. This dosage can be repeated up to three or four times per day. When a metered dose inhaler is used in place of the nebulization, the dose of gallopamil may be reduced to about one tenth of the nebulized dose, preferably about 0.1-1 mg of gallopamil.

As noted above, a nebulized aerosol composition can be made using 0.4% saline' as the carrier for gallopamil to be delivered in a nebulized manner. Suitable solubilizers and other presently known components for aerosol compositions can be used if necessary or desired. Carrier gases presently known for use in metered dose inhalers, such as freon, are suitable for administering gallopamil from a metered dose inhaler. EXAMPLE

Subjects documented to be susceptible to intermittent asthma attacks due to causes such as allergens, exercise, smoke, etc., are selected. The dose (PD__) of methacholine (an asthma inducer) necessary to produce a 20% decrease in forced expired volume in one second (FEV..) is determined for each subject, with each subject having a PD„- of less than 12 mg/ml. Administration of nebulized gallopamil (3 ml of a solution containing amounts of gallopamil varying from 1-20 mg, 4% ethanol and 4% propylene glycol in sterile saline, pH adjusted to 6 with sodium bicarbonate) increases the PD _u ^for methacholine by 2-3 fold, thus showing significant reduction in airway hyperreactivity. There is no significant cardiovascular activity and undesired side effects such as bronchospasms are not present. Approximately 10 times as much verapamil does not produce as large a D₂n increase, and bronchospasm results from higher dosages.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for treating a bronchospastic disease characterized by airway hyperreactivity comprising administering to a subject an amount of gallopamil sufficient to reduce airway hyperreactivity.

2. The method of claim 1, wherein the gallopamil is administered in aerosol form via a pulmonary route.

3. The method of claim 2, wherein the gallopamil is administered from a metered dose inhaler.

4. The method of claim 2, wherein the gallopamil is administered in a nebulized form.

5. The method of claim 3, wherein the amount of gallopamil administered is about 0.1-1 mg.

6. The method of claim 4, wherein the amount of gallopamil administered is about 1-20 mg.

7. A composition for treating bronchospastic disease characterized by airway hyperreactivity, comprising an amount of gallopamil effective to reduce airway hyperreactivity and a pharmaceutically acceptable carrier, adjuvant or excipient therefor.

8. The composition of claim 7, wherein the composition is in a form suitable for aerosol administration.

9. The composition of claim 8, wherein the composition is in a form suitable for administration through a metered dose inhaler.

10. The composition of claim 9, wherein the composition is in a form suitable for administration via nebulization.

11. The composition of claim 9, wherein about 0.1-1 mg of gallopamil is administered.

12. The composition of claim 10, wherein about 1-20 mg of gallopamil is administered.