KR20020050254A - New Combination Comprising a Beta 2 (β2) Adreno Receptor Agonist and a Leukotriene Receptor Antagonist - Google Patents

Abstract

The present invention provides a pharmaceutical composition, medicament or kit comprising a first active ingredient that is a beta2 (β2) adrenergic receptor agonist and a second active ingredient that is a leukotriene receptor antagonist for use in the treatment of an inflammatory disease.

Description

New Combination Comprising a Beta 2 (β2) Adreno Receptor Agonist and a Leukotriene Receptor Antagonist}

Many different inflammatory mediators are involved in the pathogenesis of respiratory diseases such as asthma. However, drugs used for the treatment of respiratory diseases are not always highly discernible with respect to the etiological nature of these diseases. Therefore, although glucocorticosteroid therapy is known to be very effective in treating asthma, glucocorticosteroids act extensively and nonspecifically and can cause serious side effects when administered orally. On the other hand, inhaled glucocorticosteroids rarely cause serious side effects.

In view of the complexity of respiratory diseases such as asthma, it is difficult for any one parameter alone to satisfactorily treat the disease.

Therefore, it would be desirable to develop new pharmaceuticals that can more effectively treat inflammatory diseases.

The present invention relates to a combination of pharmaceutically active substances for use in the treatment of inflammatory diseases (diseases), in particular respiratory diseases.

Therefore, according to the present invention, the first active ingredient, which is a beta2 (β2) adrenergic receptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof, and zapirlukast, montelukast and pharmaceutically acceptable derivatives thereof A pharmaceutical composition is provided in a mixture comprising a second active ingredient which is a leukotriene receptor antagonist selected from.

In the present specification, unless otherwise stated, pharmaceutically acceptable derivatives of formoterol (also known as epoterolol) include pharmaceutically acceptable esters, salts or solvates of formoterol (eg, For example, formoterol fumarate) or a pharmaceutically acceptable solvate (eg, formoterol fumarate dihydrate) of said ester or salt. Pharmaceutically acceptable derivatives of zafirlukast or montelukast (eg montelukast sodium) should likewise be interpreted.

Examples of suitable esters are lower alkyl (C ₁ -C ₆ alkyl) esters.

Applicable pharmaceutically acceptable salts include chloride, bromide, sulfate, phosphate, maleate, fumarate, tartarate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate, methanesulfonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarvallate, hydroxynaphthalene-carboxylate or oleate Acid addition salts derived from pharmaceutically acceptable inorganic and organic acids such as acid salts; And salts prepared from pharmaceutically acceptable inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferrous, ferric iron, lithium, magnesium, manganese first, manganese second, potassium, sodium, zinc and bismuth salts. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of cyclic amines such as primary, secondary and tertiary amines, arginine, betaine, choline and the like.

Examples of pharmaceutically acceptable solvates are hydrates.

Certain active ingredients used in the present invention may exist in stereoisomeric forms. It is to be understood that the present invention encompasses all geometric and optical isomers of the active ingredients and mixtures thereof, including racemates. In addition, tautomers and mixtures thereof provide one aspect of the present invention.

The present invention also provides a formulation of a first active ingredient which is a beta2 (β2) adrenergic receptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof, for use simultaneously, successively or separately in therapy, and zafir Provided is a medicament comprising a combination of a formulation of a second active ingredient which is a leukotriene receptor antagonist selected from lucast, montelukast and pharmaceutically acceptable derivatives thereof.

In another aspect, the present invention provides a formulation of a first active ingredient, zafirlukast, montelukast and their pharmaceutically acceptable, which is a beta2 (β2) adrenergic receptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof. A kit is provided that includes a formulation of a second active ingredient that is a leukotriene receptor antagonist selected from derivatives, and instructions for simultaneous, continuous or individual administration to patients in need thereof.

It can be seen that it is advantageous to select the active ingredient according to the present invention because the active ingredient according to the present invention has a useful anti-inflammatory and bronchodilating effect; Asthma, such as bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma and dust asthma, especially chronic asthma or inveterate asthma (eg, late night asthma and airway high-sensitive asthma); It can be used to treat various acute and chronic inflammatory diseases (diseases) such as rhinitis and rheumatoid arthritis.

Pharmaceutical compositions of the invention can be prepared by mixing the first active ingredient with the second active ingredient. Therefore, in a further aspect of the invention, a first active ingredient which is a beta2 (β2) adrenergic receptor agonist selected from formoterol and its pharmaceutically acceptable derivatives is selected from zapirlukast, montelukast and pharmaceutically acceptable salts thereof. Provided is a method of preparing a pharmaceutical composition comprising mixing with a second active ingredient a leukotriene receptor antagonist selected from the derivatives.

The first and second active ingredients may alternatively be co-administered (in addition to administration in a mixture as described above), continuous administration or separately to treat inflammatory diseases. Continuous administration refers to the administration of another immediately after administration of one of the first and second active ingredients. When they are administered separately, it is still desirable to administer about 4 hours, preferably about 2 hours, more preferably about 30 minutes apart.

The active ingredient is actually selected from one or more pharmaceutically acceptable ingredients, such as auxiliaries, carriers, binders, lubricants, diluents, stabilizers, buffers, emulsifiers, viscosity-adjusting agents, surfactants, preservatives, perfumes and coloring agents. It may be used in admixture with ingredients which may be used.

For use in the treatments mentioned above, of course the dosage administered varies depending on the first and second active ingredients used, the mode of administration, the method of treatment to be treated and the disease indicated. Generally, however, the total daily dose of the first active ingredient (s) for oral inhalation is 1-50 μg, in particular 1, 2, 3, 4 or 5 to 48, preferably 1, 2, 3, 4 or 5 to 40, more preferably in the range of 1, 2, 3, 4 or 5 to 24 μg, wherein the total daily dose of the second active ingredient (s) for oral inhalation is 1 to 800 μg, in particular 1, 2, 5, 10 Or satisfactory results when in the range of 20 to 400, preferably 1, 2, 5, 10 or 20 to 200 μg.

The pharmaceutical compositions, medicaments or kits according to the invention may be administered in dosages divided into 1 to 4 times daily, preferably 1 or 2 times daily.

The first and second active ingredients are conveniently administered topically (to the lungs and / or airways) in the form of solutions, suspensions, aerosols and dry powders.

For example, metered dose inhalation devices can be used to administer the active ingredient (s) dispersed in a suitable propellant in the presence or absence of additional excipients, surfactants, lubricants or stabilizers such as ethanol.

Suitable propellants include hydrocarbon, chlorofluorocarbons and hydrofluoroalkane (eg, heptafluoroalkanes) propellants or mixtures of any of the above propellants. P134a and P227 are particularly preferred propellants, each of which may be used alone or in admixture with other propellants and / or surfactants and / or other excipients.

In addition, the aqueous suspensions or preferably solutions sprayed into the nebulizer may be used in either unit dose or multiple dose formulations with or without suitable pH and / or muscle tone regulators.

Dry powder inhalers can be used to administer the active ingredient (s) alone or in combination with a pharmaceutically acceptable carrier, in the latter case it can be either a finely divided powder or a prescribed mixture. Dry powder inhalers may be for unit or combined administration, and dry powder or powder-containing capsules may be used.

Metered dose inhalers, nebulizers and dry powder inhalation devices are known and a variety of devices are available.

The invention also provides the use of a pharmaceutical composition, medicament or kit according to the invention in the manufacture of a medicament for the treatment of an inflammatory disease.

The invention also provides a method of treating an inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention.

In addition, the present invention

(a) a (therapeutically effective amount) dose of a first active ingredient which is a beta2 (β2) adrenergic receptor agonist selected from formoterol and its pharmaceutically acceptable derivatives; And

(b) Dose (in therapeutically effective amount) of a second active ingredient which is a leukotriene receptor antagonist selected from zafirlukast, montelukast and pharmaceutically acceptable derivatives thereof

It provides a method for the treatment of an inflammatory disease comprising simultaneous administration, continuous administration or separate administration to a patient in need thereof.

Also, in the context of the present specification, the term "treatment" includes "prevention" unless otherwise stated. The terms "therapeutic" and "therapeutic" should be interpreted accordingly.

Prevention is thought to be particularly related to treating a person who is prognostic of the disease or condition or, in other words, is believed to be at increased risk. A person at risk of developing a particular disease or condition generally refers to a person having a family history of the disease or condition, or a person identified as being particularly prone to progression by genetic testing or screening.

The invention will now be more readily understood by reference to the examples illustrated below. These examples describe certain pharmaceutical compositions that can be formulated into dry powder formulations for oral inhalation.

Example 1

4.5 μg formoterol fumarate dihydrate

Zafirlukast 100 ㎍

Lactose Monohydrate 200-2000 ㎍

Example 2

9.0 μg formoterol fumarate dihydrate

Zafirlukast 100 ㎍

Lactose Monohydrate 200-2000 ㎍

Example 3

4.5 μg formoterol fumarate dihydrate

Zafirlukast 200 ㎍

Lactose Monohydrate300-2000 ㎍

Example 4

9.0 μg formoterol fumarate dihydrate

Zafirlukast 200 ㎍

Lactose Monohydrate300-2000 ㎍

Example 5

4.5 μg formoterol fumarate dihydrate

Montelukast Sodium 50 μg

Lactose Monohydrate 200-2000 ㎍

Example 6

4.5 μg formoterol fumarate dihydrate

Montelukast Sodium 100 ㎍

Lactose Monohydrate 200-2000 ㎍

Claims (23)

A first active ingredient which is a beta2 (β2) adrenergic receptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof, and a leukotriene receptor antagonist selected from zapyrucaste, montelukast and pharmaceutically acceptable derivatives thereof A pharmaceutical composition comprising two active ingredients in a mixture. The composition of claim 1 wherein the first or second active ingredient is in the form of a pharmaceutically acceptable salt, ester, solvate, or solvate of this ester or salt. The composition of claim 1 or 2, wherein the first active ingredient is formoterol fumarate dihydrate. The composition of claim 1, wherein the second active ingredient is zafirlukast. The composition of claim 1 wherein the second active ingredient is montelukast sodium. The composition of any one of claims 1 to 5 formulated for oral inhalation administration. Use of the composition of claim 1 in the manufacture of a medicament for the treatment of an inflammatory disease. A method of making the pharmaceutical composition of claim 1 comprising mixing the first active ingredient with the second active ingredient. A method of treating an inflammatory disease comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 1 to a patient in need thereof. The method of claim 9, wherein the inflammatory disease is asthma or chronic obstructive pulmonary disease. Preparations of a first active ingredient which is a beta2 (β2) adrenergic receptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof for use simultaneously, successively or separately in therapy, and zafirlukast, montelukast and A pharmaceutical product comprising a combination of agents of a second active ingredient which is a leukotriene receptor antagonist selected from their pharmaceutically acceptable derivatives. The pharmaceutical product of claim 11, wherein the first or second active ingredient is in the form of a pharmaceutically acceptable salt, ester, solvate, or solvate of this ester or salt. 13. The pharmaceutical product according to claim 11 or 12, wherein the first active ingredient is formoterol fumarate dihydrate. The pharmaceutical product according to claim 11, wherein the second active ingredient is zafirlukast. The pharmaceutical product according to claim 11, wherein the second active ingredient is montelukast sodium. Use of the medicament of claim 11 in the manufacture of a medicament for the treatment of an inflammatory disease. A leukotriene receptor antagonist selected from a formulation of a first active ingredient, zafirlukast, montelukast and pharmaceutically acceptable derivatives thereof, which is a beta2 (β2) adrenergic receptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof. A kit comprising a formulation of a second active ingredient and instructions for simultaneous, continuous or separate administration of these to a patient in need thereof. 18. The kit of claim 17, wherein the first or second active ingredient is in the form of a pharmaceutically acceptable salt, ester, solvate, or solvate of this ester or salt. 19. The kit of claim 17 or 18, wherein the first active ingredient is formoterol fumarate dihydrate. 18. The kit of claim 17, wherein the second active ingredient is zafirlukast. 18. The kit of claim 17, wherein the second active ingredient is montelukast sodium. Use of a kit according to claim 17 in the manufacture of a medicament for the treatment of an inflammatory disease. (a) a dose of a first active ingredient which is a beta2 (β2) adrenergic receptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof; And (b) Dosage of a second active ingredient which is a leukotriene receptor antagonist selected from zafirlukast, montelukast and pharmaceutically acceptable derivatives thereof A method of treating an inflammatory disease comprising simultaneous administration, continuous administration or separate administration to a patient in need thereof.