SK184799A3 - New combination of antiasthma medicaments - Google Patents

Abstract

The invention provides a composition or kit having as a first active ingredient formoterol, or a salt or solvate derivative thereof, and having as a second active ingredient ropfleponide, or a fatty acid ester thereof. Also disclosed are methods for treating respiratory disorders using this composition or kit.

Description

Disclosed is a composition or kit comprising, as a first active ingredient, formoterol or a salt thereof, or a solvate thereof, and as a second active ingredient, refleponide or a fatty acid ester thereof. Also disclosed are methods of treating respiratory distress using an uve, daily composition or kit.

A new combination of antiasthmatic drugs

Technical field

The invention relates to compositions and methods useful in the treatment of respiratory distress, particularly asthma; is based on the discovery that formoterol esters and rofleponide, or salts or solvates thereof, are effective when administered simultaneously or sequentially to a patient in the treatment of respiratory complaints, including inflammations such as asthma.

BACKGROUND OF THE INVENTION

Although advances in cognition of asthma and the introduction of very effective antiasthmatic drugs are known at present, asthma has so far been poorly investigated and often unsuccessfully treated. Further advances in the treatment of the disease arise as a result of the knowledge that asthma is a chronic inflammatory disease. The aim of therapy is not only to control symptoms, but also to reduce inflammation. Symptoms include uncontrolled airway inflammation, which may cause mucosal damage and structural changes that are likely to lead to irreversible airway constriction and lung fibrosis.

These symptoms can be controlled by β ₂ -adrenoreceptor agonists such as salbutamol, bambuterol, clenbuterol, phenoterol, prokaterol, bitolterol, broxaterol, salmeterol, terbutaline and formeterol.

Prophylactic therapy is typically provided by steroids such as beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone acetonide, dexamethasone, tipredan, ciclezonide, mometasone, RPR 106541 or fluticasone or propaneurate or fluticasone or fluticasone or fluticasone. salts of nedocromil.

Using sefadex-induced model edema (Källstrôm et al., Agents and Action 17: 355-377, (1985)), it has been found that the combination of active ingredients (i.e., formoterol and rofleponide) provides a significantly higher anti-inflammatory effect compared to the sum of individual the anti-inflammatory effects of both active ingredients, thereby achieving a visible advantage. SUMMARY OF THE INVENTION

The invention relates to a composition comprising (a) a first active ingredient which is formaterol, a pharmaceutically acceptable salt or solvate of formoterol or a solvate of said salt; and (b) a second active ingredient which is rofleponide or a rofleponide fatty acid ester.

It is preferred that the molar ratio of (a) to (b) is from 1: 1 to 1: 100, preferably from 1: 1 to 1:60, even more preferably from 1: 1 to 1:35 and most preferably 1:16.

For example, the first active ingredient (a) of the composition may be formoterol fumarate dihydrate and the second active ingredient (b) of the composition may be rofleponide palmitate.

The composition may be formulated as a dry powder whose particles have a mean diameter of less than 10 µm.

) t

The invention also includes a kit comprising: (a) a capsule with a first active ingredient which is formoterol, a pharmaceutically acceptable salt thereof, or a solvate thereof or a solvate of such a salt; (b) a shell comprising a second active ingredient, which is either rofleponide or a fatty acid ester of rofleponide; and (c) instructions for sequential or simultaneous administration of the first and second active ingredients to a patient in need thereof.

A patient suffering from respiratory distress such as asthma may be treated (e.g., by inhalation) by simultaneous or sequential administration of (a) a dose of a first active ingredient selected from the group consisting of formoterol, a pharmaceutically acceptable salt thereof, or a solvate thereof and a solvate of such a salt; and (b) a dose of a second active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide. The active ingredients may be formulated for inhalation as a dry powder.

When the active ingredients are administered sequentially, they may be administered in any order, and at an interval of two hours. For example, the first active ingredient may be administered to the patient up to about 30 minutes after the second active ingredient, or the second active ingredient may be administered to the patient up to about 30 minutes after the first active ingredient.

Other features and advantages of the invention will be apparent from the following description of preferred embodiments thereof and from the claims.

The combination of the invention has the advantage that the total dose of each active ingredient can be reduced, and it is likely that this is more convenient for the patient than would be expected from the properties of the individual active ingredients.

The invention provides a composition comprising (a) a first active ingredient selected from the group consisting of formoterol, a pharmaceutically acceptable salt thereof, or a solvate thereof and a solvate of such a salt; (b) a second active ingredient selected from the group consisting of rofleponide and a rofleponide fatty acid ester; and optionally (c) one or more pharmaceutically acceptable additives, diluents or carriers.

The active ingredients of the composition, i.e., the first and second, may be administered simultaneously or sequentially to treat respiratory complaints. Simultaneous administration is understood to mean that the first and second components (a) and (b) are administered together, for example as a mixture. Sequential administration generally means administering one component immediately after the previous. This still has the desired effect even if the ingredients are administered alone, but not later than two hours in a row, for example not longer than 30 minutes and preferably not longer than 5 minutes in a row.

Preferably, the composition is administered so as to provide a daily dose of from 0.5 to 200 nmol (preferably from 4 to 100 nmol) of component (a) and from 0.5 to 1140 nmol (preferably from 14 to 285 nmol and more preferably from 14 to 285 nmol). 285 nmol) of component (b) (provided that the molar ratio of (a) to (b) is from 1: 1 to 1: 100).

When component (a) is formoterol fumarate dihydrate, its preferred daily dose is from 0.2 to 84 µg (preferably from 2 to 42 mg); and from 0.4 to 800 M9 (preferably from 10 to 400 µg, more preferably from 10 to 200 gg) of component (b). when (b) is rofleponide palmitate (with the proviso that the molar ratio of (a) to (b) ranges from 1: 1 to 1: 100).

Suitable physiologically acceptable salts of formoterol include addition salts derived from inorganic and organic acids, for example chlorides, bromides, sulfates, phosphates, maleates, fumarates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2 or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluenesulfone , methanesulfonates, ascorbates, acetates, succinates, lactates, glutarates, gluconates, tricarbalylates, hydroxynaphthalenecarboxylates or olates or solvates thereof. The active ingredient (a) is preferably formoterol fumarate, in particular as a dihydrate.

The rofleponide is preferably esterified with a palmitoyl group.

Each of the active ingredients preferably comprises one or more pharmaceutically acceptable additives, diluents or carriers, more preferably in an amount of from 50 to 2000 pg per daily dose, most preferably in an amount of from 100 to 1000 pg. Examples of suitable diluents or carriers include lactose, dextran, mannitol and glucose. Lactose is preferably used.

Since the active ingredient (b) is preferably a fatty acid ester, the formulations containing it are expediently liposomal or proliposomal when they are dry powder formulations.

Suitable proliposomal fatty acid ester formulations of rofleponide are described in WO 96/19199. To improve stability, the composition may comprise tocopherol, in particular α-tocopherol.

Optionally, the active ingredients (a) and (b) may be mixed together for simultaneous administration. For example, they may be formulated as a proliposomal powder, for example of the conventional type described in WO 96/19199 (preferably comprising tocopherol as a stabilizer) or as a perfect mixture (a) in the form of a dry powder and a proliposomal dry powder containing (b). ).

One or both of the active ingredients of the invention are preferably in the form of a dry powder, more preferably in the form of a micronized dry powder, for example having a mean value of less than 10 μχα, e.g. Alternatively, the active ingredient (a) may take the form of an ordered mixture with ingredient (c). The components used in the present invention can be obtained in the preferred forms indicated using methods known to those skilled in the art.

The invention further relates to a method of treating respiratory distress, particularly asthma, chronic obstructive pulmonary disease (COPD) and / or rhinitis, which method comprises administering to a patient suffering from or susceptible to such conditions by administering a therapeutically effective amount of a combination of the invention .

The invention further relates to the use of the composition or kit of the invention in the manufacture of a medicament for simultaneous, divided or sequential use in therapy, preferably in the treatment of respiratory complaints such as asthma, chronic obstructive pulmonary disease and / or rhinitis.

Administration can be by oral or intranasal inhalation. The ingredients should conveniently be adapted for administration from a dry powder inhaler.

Optionally, the combination may be administered in divided doses of 1 to 4 times, and preferably once or twice daily, which means unit doses of 0.05 gg to 84 gg, preferably 0.5 gg to 42 gg, formothelium fumarate dihydrate and 0.1 gg. up to 800 gg, preferably from

2.5 gg to 400 gg, rofleponide palmitate.

The invention has been described in detail and it is understood that the purpose of this description is merely to illustrate, but not to limit the scope of the invention, which is defined by the scope of the appended claims. Other alternatives, advantages and modifications are within the scope of these claims.

DETAILED DESCRIPTION OF THE INVENTION rofleponide palmitate, 63 parts dipalmitoylphosphatidylcholine, 24 parts dimyristoylphosphatidylcholine, 3 parts dipalmitoylphosphatidylglycerol sodium and 0.1 parts racemic α-tocopherol are dissolved in 1300 parts tert-butanol at 80 ° C. The solution is poured onto lyophilizer compartments, which are cooled to -30 ° C. The solution reaches this temperature after about 30 minutes, then the lyophilizer pressure is lowered to induce the sublimation of the solvent. While the sublimation rate can be controlled by reducing the pressure and increasing the temperature, the temperature during the process cannot exceed -10 ° C. Lyophilization is continued until the solvent is completely removed. The obtained powder is scraped off the lyophilizer compartments and sieved. This powder is micronized in an air jet mill to a powder with a particle size of less than 5 gm.

0.5 parts of formoterol fumarate dihydrate are mixed with

79.5 parts by weight of lactose monohydrate. The mixture is micronized using a high-pressure air jet mill and then conditioned using the procedure of EP-A-717 616. 80 parts of this mixture are added to 20 parts of the steroid-lipid powder mixture with stirring and homogenization in a low pressure jet mill. The mixture is then spheronized using the procedure of EP-A

-721 331 and filled into a blister, capsule or cartridge of an inhaler for use in a dry powder inhaler.

Industrial usability

The invention represents a technically simple measure by which a combination of known components is obtained by a medicament effective in the treatment of respiratory complaints, in particular asthma. The dosage of this formulation may be lower, with the effect achieved being higher.

/ / Ml -f f

Claims (16)

A therapeutic composition comprising as part of (a) a first active ingredient selected from the group consisting of formoterol, a pharmaceutically acceptable salt thereof, or a solvate thereof and a solvate of such a salt; and (b) a second active ingredient selected from the group consisting of rofleponide and rofleponide fatty acid ester, wherein the molar ratio of (a) to (b) in said composition is from 1: 1 to 1: 100. The therapeutic composition of claim 1, wherein the molar ratio of (a) to (b) in said composition is from 1: 1 to 1:60, preferably from 1: 1 to 1:35. The therapeutic composition of claim 1 or 2, wherein component (a) is formoterol fumarate dihydrate. The therapeutic composition of any one of claims 1 to 3, wherein component (b) is rofleponide palmitate. The therapeutic composition of any one of claims 1 to 4, further comprising a pharmaceutically acceptable additive, diluent or carrier suitable for inhalation. Therapeutic composition according to any one of claims 1 to 5, characterized in that it is in the form of a dry powder whose particles have a mean diameter of less than 10 gm. Ί. A kit comprising (a) a capsule with a first active ingredient selected from the group consisting of formoterol, a pharmaceutically acceptable salt thereof, or a solvate thereof and a solvate of such a salt; (b) a shell with a second active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide; and (c) instructions for sequential or simultaneous administration of the first and second active ingredients to a patient in need thereof, which instructions specify that the first and second active ingredients are to be administered in a molar ratio of from 1: 1 to 1: 100. Kit according to claim 7, characterized in that the first active ingredient is formoterol fumarate dihydrate. Kit according to claim 7 or 8, characterized in that the second active ingredient is palmitate rofleponide. Kit according to any one of claims 7 to 9, characterized in that the instructions specify that the first and second active ingredients are to be administered in a molar ratio of from 1: 1 to 1:60, preferably 1: 1 to 1:35. 11. A method of treating respiratory distress comprising administering to a patient in need thereof simultaneously or sequentially (a) doses of a first active ingredient selected from the group consisting of formoterol, a pharmaceutically acceptable salt thereof, or a solvate thereof and a solvate of such a salt; and (b) doses of a second active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide, wherein the molar ratio of component (a) to component (b) is from 1: 1 to 1: 100. Method according to claim 11, characterized in that the molar ratio of component (a) to component (b) is from 1: 1 to 1:60, preferably from 1: 1 to 1:35. Method according to claim 11 or 12, characterized in that the first active ingredient is formoterol fumarate dihydrate. Method according to one of Claims 11 to 13, characterized in that the second active ingredient is palmitate rofleponide. The method of any one of claims 11 to 14, wherein the first active ingredient is administered to the patient less than about 30 minutes before and after administration of the second active ingredient. Method according to any one of claims 11 to 15, characterized in that the doses are administered so as to force the patient to inhale them simultaneously. 17. The method of claim 16, wherein the first and second active ingredients are provided to the patient for inhalation in the form of a dry powder.