MXPA01008360A - Combinations of formoterol and fluticasone propionate for asthma - Google Patents

Abstract

A pharmaceutical composition comprising (A) formoterol or a pharmaceutically acceptable salt thereof or a solvate of formoterol or said salt and (B) fluticasone propionate, suitable for use in the treatment of inflammatory or obstructive airways diseases.

Description

COMBINATIONS OF FORMOTEROL AND FLUTICASONE PROPIONATE FOR ASTHMA Combinations of a beta-2 agonist and a steroid This invention relates to combinations of a beta-2 agonist and a steroid, and to its use for the treatment of inflammatory or obstructive diseases of the respiratory tract. Formoterol, N- [2-hydroxy-5- (l-hydroxy-2- ((2- (4-methoxyphenyl) -1-methylethyl) amino) ethyl) phenyl] formamide, particularly in the form of its fumarate salt , is a bronchodilator used in the treatment of inflammatory or obstructive diseases of the respiratory tract. Fluticasone propionate, 6a, 9a-difluoro-11β-hydroxy-16c-methyl-3-oxo-17a-propionyloxyandrosta-1,4-dien-17β-S-fluoromethyl carbonate, an anti-inflammatory corticosteroid, is described in the patent of the United States of North America number US4335121. Surprisingly, it has now been found that a significant unexpected therapeutic benefit, in particular a synergistic therapeutic benefit, can be obtained in the treatment of inflammatory or obstructive diseases of the respiratory tract by utilizing a composition containing formoterol. , or a salt or solvate thereof, and • fluticasone propionate. For example, it is possible to use this composition to significantly reduce the fluticasone propionate dosages required for a given therapeutic effect, compared to those required using the fluticasone propionate alone treatment, thereby possibly minimizing undesirable side effects. In particular, it has been found that compositions containing formoterol and fluticasone propionate induce an anti-inflammatory activity that is ~ significantly greater than that induced by formoterol or fluticasone propionate alone, and that it can be significantly reduced. amount of fluticasone propionate required for a given anti-inflammatory effect, when used mixed with formoterol, thereby reducing the risk of undesirable side effects from repeated exposure to the steroid involved in the treatment of inflammatory or obstructive airway diseases . In addition, using the compositions of the invention, drugs can be prepared that have a rapid establishment of action and a long duration of action. Furthermore, using the compositions of the invention, drugs can be prepared that result in a significant improvement in lung function. In another aspect, using the compositions of the invention, drugs can be prepared that provide better control of obstructive or inflammatory diseases of the respiratory tract, or a reduction in the exacerbation of such diseases. In a further aspect, using the compositions of the invention, drugs can be prepared that can be used on demand in the rescue treatment of obstructive or inflammatory diseases of the respiratory tract, or that reduce or eliminate the need for treatment with rescue medicines. - short-acting, such as salbutamol or terbutaline; therefore, drugs based on the compositions of the invention facilitate the treatment of an obstructive or inflammatory disease of the respiratory tract with a single medication. Accordingly, in one aspect, the present invention provides a pharmaceutical composition comprising: (A) formoterol or a pharmaceutically acceptable salt thereof, or a solvate of formoterol or said salt, and (B) fluticasone propionate. In another aspect, the present invention provides a method for the treatment of an inflammatory or obstructive disease of the respiratory tract, which comprises administering to a subject in need of such treatment, an effective amount of a pharmaceutical composition comprising (A) and ( B), as defined above in the present. In a further aspect, the present invention provides a pharmaceutical composition comprising a mixture of effective amounts of (A) and (B) as defined hereinbefore, together with a pharmaceutically acceptable carrier. In a still further aspect, the present invention provides a pharmaceutical composition for use in the treatment of an inflammatory or obstructive airway disease, which comprises (A) and (B) as defined hereinbefore. The invention still further provides the use of a pharmaceutical composition comprising (A) and (B) as defined hereinabove, for the preparation of a medicament for the treatment of an inflammatory or obstructive airway disease. Pharmaceutically acceptable salts of formoterol include, for example, salts of the inorganic acids, such as hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and of the organic acids, such as fumaric, maleic, acetic, lactic, citric, tartaric acids, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic, benzoic, p-ethoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic, and 3-hydroxy-2-naphthalenecarboxylic. The component (A) can be in any isomeric form or mixture of isomeric forms, for example a pure enantiomer, a mixture of enantiomers, a racemate, or a mixture thereof. It may be in the form of a solvate, for example a hydrate thereof, for example as described in U.S. Patent Nos. US3994974 or US5684199, and may be present in a particular crystalline form, for example as described in International Publication Number O95 / 05805. Preferably, component (A) is formoterol fumarate, especially in the dihydrate form. The administration of the pharmaceutical composition as described hereinabove is preferably by inhalation, in which case (A) and (B) are in an inhalable form. The inhalable form of the composition can be, for example, a sprayable composition, such as an aerosol comprising the active ingredients, ie (A) and (B), in solution or dispersion in a propellant, or a nebulizable composition that comprising a dispersion of the active ingredients in an aqueous, organic, or aqueous / organic medium. For example, the inhalable form of the pharmaceutical composition can be an aerosol comprising a mixture of (A) and (B) in solution or dispersion in a propellant. In another example, the inhalable form is a nebulizable composition comprising a dispersion of (A) and (B) in an aqueous, organic, or aqueous / organic medium. An aerosol composition suitable for use as the inhalable form of the composition of the invention may comprise the active ingredients in solution or dispersion in a propellant, which may be selected from any of the propellants known in the art. Suitable propellants include hydrocarbons, such as normal propane, normal butane, or isobutane, or mixtures of two or more of these hydrocarbons, and hydrocarbons substituted by halogen, for example methane, ethane, propane, butane, cyclopropane, or cyclobutane substituted by fluorine , in particular 1,1,1,2-tetrafluoroethane (HFA134a), and 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA227), or mixtures of two or more of these hydrocarbons substituted by halogen. When (A) and / or (B) are present in suspension in the propellant, that is, when they are present in a particulate form dispersed in the propellant, the aerosol composition may also contain a lubricant and a surfactant, which can be select from the lubricants and surfactants known in the art. Other suitable aerosol compositions include surfactant-free or substantially surfactant-free aerosol compositions. The aerosol composition may contain up to about 5 weight percent, for example from 0.002 to 5 percent, from 0.01 to 3 percent, from 0.015 to 2 percent, from 0.1 to 2 percent, from 0.5 to 2 percent, or from 0.5 to 1 percent by weight of the mixture of (A) and (B), based on the weight of the propellant. When present, the lubricant and the surfactant may be in an amount of up to 5 percent and 0.5 percent, respectively, by weight of the aerosol composition. The aerosol composition may also contain a co-solvent, such as ethanol, in an amount up to 30 weight percent of the composition, particularly for delivery from a pressurized metered dose inhalation device. In another embodiment of the invention, the inhalable form is a dry powder, ie, (A) and (B) are present in a dry powder comprising (A) and (B) finely divided, optionally together with a pharmaceutically acceptable carrier. finely divided, which is preferably present and may be one or more materials selected from the materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides, and sugar alcohols, such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, or mannitol. A particularly preferred carrier is lactose, in particular in the monohydrate form. The dry powder can be in gelatin or plastic capsules, or in ampoules, for use in a dry powder inhalation device, preferably in dosage units of the mixture of (A) and (B) together with the carrier, in quantities to bring the total weight of the powder in each capsule up to 5 milligrams to 50 milligrams. Alternatively, the dry powder may be contained in a reservoir of a multi-dose dry powder inhalation device.

In the form of finely divided particles of the composition of the invention, (A) and (B) can each have an average particle diameter of up to about 10 microns, for example from 0.1 to 5 microns, preferably from 1 to 5 microns. mieras In the aerosol composition wherein (A) and / or (B) are present in a particulate form, (A) and / or (B) may have an average particle diameter of up to about 10 microns, for example 0.1 at 5 microns, preferably from 1 to 5 microns. The solid carrier, when present, generally has a maximum particle diameter of 300 microns, preferably 212 microns, and conveniently has an average particle diameter of 40 to 100 microns, preferably 50 to 50 microns. 75 microns. The particle size of the active ingredients (A) and (B), and that of the solid carrier when present in the dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an air jet mill, ball mill, or vibrating mill, microprecipitation, spray drying, lyophilization, or recrystallization from supercritical media. The inhalable pharmaceutical composition of the invention can be administered using an inhalation device suitable for the inhalable form, these devices being well known in the art. Accordingly, the invention also provides a pharmaceutical product comprising a pharmaceutical composition comprising (A) and (B) as described hereinabove, in an inhalable form as described hereinabove, in association with one or more inhalation devices. In a further aspect, the invention provides an inhalation device containing a pharmaceutical composition comprising (A) and (B) as described hereinabove, in an inhalable form as described hereinabove. When the inhalable form of the composition of the invention is an aerosol composition, the inhalation device can be an aerosol vial provided with a valve adapted to deliver a metered dose, such as from 10 to 100 microliters, for example 25 to 50 microliters of the composition, i.e., a device known as a metered dose inhaler. Aerosol vials and methods suitable for containing aerosol compositions under pressure in them are well known to those skilled in the art of inhalation therapy. For example, an aerosol composition can be administered from a coated can, for example as described in European Patent Number EP-A-0642992. When the inhalable form of the composition of the invention is an aqueous, organic, or aqueous / nebulizable organic dispersion, the inhalation device can be a known nebulizer, for example a conventional pneumatic nebulizer, such as an air jet nebulizer. , or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 milliliters, commonly from 1 to 10 milliliters of the dispersion; or a manual nebulizer, for example an electronically controlled device, such as an AERx (ex Aradigm, USA), or a mechanical device, such as a RESPIMAT nebulizer (Boehringer Ingeiheim), which allows much smaller nebulized volumes, for example from 10 to 100 microliters, than conventional nebulizers. When the inhalable form of the composition of the invention is the finely divided particulate form, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or ampoule containing a dosing of the dry powder, or a multi-dose dry powder inhalation device (MDPI) adapted to deliver, for example, 5 to 25 milligrams of dry powder per drive. Suitable dry powder inhalation devices are well known. For example, a suitable device for delivering dry powder in an encapsulated form, is that described in US Pat. No. US3991761, while a suitable multi-dose dry powder inhalation device is that described in International Publication Number WO97 / 20589. The weight ratio of formoterol, or the salt or solvate thereof, to fluticasone propionate, can be, in general, from 3: 1 to 1: 3000, for example from 2: 1 to 1: 2000, of 1: 1 to 1: 1000, from 1: 2 to 1: 500, or from 1: 5 to 1:50. More usually, this ratio is from 1:10 to 1 to 1:25, for example from 1:10 to 1:20. Specific examples of this proportion, up to the nearest whole number, include 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18 , 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, and 1:25. The above weight proportions apply in particular when (A) is formoterol fumarate dihydrate. Accordingly, because the molecular weights of formoterol fumarate dihydrate and fluticasone propionate are 840.9 and 500.6, respectively, the corresponding molar proportions of (A) to (B) can be, in general, 1.79: 1 a 1: 5017, for example from 1.2: 1 to 1: 3345, from 0.6: 1 to 1: 1672, from 1: 3.34 to 1: 836, or from 1: 8.36 to 1: 83.6; more usually from 1: 16.7 to 1: 41.8, for example from 1: 16.7 to 1: 33.4; the specific examples being the molar ratio of 1: 16.7, 1: 18.4, 1: 20.1, 1: 21.7, 1: 23.4, 1: 25.1, 1: 26.8, 1: 28.4, 1: 30.1, 1: 31.8, 1 : 33.4, 1: 35.1, 1: 36.8, 1: 38.5, 1: 40.1, and 1: 41.8. An appropriate daily dose of formoterol, or salt or solvate thereof, in particular as formoterol fumarate dihydrate, for inhalation in a composition of the invention, may be from 1 to 72 micrograms, for example from 1 to 60 micrograms, in general from 3 to 50 micrograms, preferably 6 to 48 micrograms, for example 6 to 24 micrograms. A suitable daily dose of fluticasone propionate for inhalation in a composition of the invention can be from 25 to 3000 micrograms, for example from 25 to 2000 micrograms, from 50 to 2000 micrograms, preferably from 100 to 1000 micrograms, for example from 200 to 1000 micrograms, or 200 to 500 micrograms. The precise dose used, of course, will depend on the condition to be treated, the patient, and the efficiency of the inhalation device. The formulation of a composition of the invention and its frequency of administration can be selected according to the above. An appropriate unit dose of the formoterol component (A), in particular as formoterol fumarate dihydrate, in a composition of the invention, can be from 1 to 72 micrograms, for example from 1 to 60 micrograms, in general from 3 to 48 micrograms, preferably from 6 to 36 micrograms, especially from 12 to 24 micrograms. An appropriate unit dose of fluticasone propionate (B) in a composition of the invention can be from 25 micrograms to 500 micrograms, for example from 50 micrograms to 400 micrograms, preferably from 100 micrograms to 300 micrograms, especially from 150 to 250 micrograms . These unit doses may be administered appropriately once or twice a day according to the appropriate daily dose mentioned hereinabove. For use on demand, a dosage unit containing 6 micrograms or 12 micrograms of (A), and 50 micrograms or 100 micrograms of fluticasone propionate (B) is preferred. In a preferred embodiment of the invention, when the pharmaceutical composition of the invention is a dry powder in a capsule containing a unit dose of (A) and (B), for example for inhalation from a single-capsule inhaler, the capsule may contain adequately, when (A) is formoterol fumarate dihydrate, from 3 micrograms to 36 micrograms of (A), preferably from 6 micrograms to 24 micrograms of (A), especially from 12 micrograms to 24 micrograms of (A), and from 25 micrograms to 500 micrograms of (B), preferably from 50 micrograms to 250 micrograms of (B), especially from 100 to 250 micrograms of (B), together with a pharmaceutically acceptable carrier, as described hereinabove, in an amount to carry the weight total dry powder per capsule up to between 5 milligrams and 50 milligrams, for example up to 5 milligrams, 10 milligrams, 15 milligrams, 20 milligrams, 25 milligrams, 30 milligrams, 35 milligrams, 40 milligrams, 45 milligrams, or 50 milligrams, preferably 20 to 25 milligrams, especially 25 milligrams. In another preferred embodiment of the invention, the pharmaceutical composition of the invention is a dry powder to be administered from a reservoir of a dry powder inhaler in multiple doses, to deliver from 3 milligrams to 25 milligrams of powder containing a unit dose of ( A) and (B) by actuation, for example, when (A) is formoterol fumarate dihydrate, a powder comprising, by weight, from 3 to 36 parts, preferably from 6 to 24 parts, especially from 12 to 24 parts. of (A); from 25 to 500 parts, preferably from 50 to 400 parts, especially from 100 to 250 parts of (B); and from 2464 to 24972 parts, preferably from 4464 to 14972 parts, especially from 4464 to 9972 parts of a pharmaceutically acceptable carrier, as described hereinabove. The treatment of inflammatory or obstructive diseases of the respiratory tract according to the invention can be a symptomatic or prophylactic treatment. Inflammatory or obstructive airway diseases to which the present invention is applicable include asthma of any type or genesis, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma. It should also be understood that asthma treatment encompasses the treatment of subjects, for example less than 4 or 5 years old, who exhibit symptoms of wheezing, and are diagnosed or diagnosed as "panting babies," an established patient category of great medical concern, and now frequently identified as early stage or early stage asthmatics. (For convenience, this particular asthmatic condition is referred to as "panting baby syndrome"). The prophylactic efficacy in the treatment of asthma will be evidenced by a reduced frequency or severity of the symptomatic attack, for example of asthmatic attack or acute bronchoconstrictor, improvement in pulmonary function, or better airway hyperreactivity. In addition, it can be evidenced by a reduced requirement of another symptomatic therapy, that is, therapy for, or intended to, restrict or abort the symptomatic attack when present, for example anti-inflammatory (eg corticosteroid) or bronchodilator. The prophylactic benefit in asthma can be observed in particular in subjects susceptible to "morning drowning". "Morning drowning" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics, and characterized by asthma attack, for example between the hours of about 4 to 6 a.m., ie, in a time usually substantially distant from any previously administered symptomatic asthma therapy. Other diseases and inflammatory or obstructive airway conditions to which the present invention is applicable include acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, respiratory disease, or lung disease ( COPD, COAD, or COLD), including chronic bronchitis and emphysema, bronchiectasis, and exacerbation of airway hyperreactivity as a result of other drug therapy, in particular another therapy with an inhaled drug.

Additional inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory disease), commonly occupational, of the lungs, often accompanied by airway obstruction, either chronic or acute, and caused by repeated inhalation of dust) of any type or genesis, including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptilosis , siderosis, silicosis, tabacosis, and byssinosis.

The invention is illustrated by the following Examples, in which the parts are by weight, unless otherwise reported.

Example 1 Composition in Aerosol for Dose Inhaler Measure Ingredient% by weight Formoterol fumarate dihydrate 0.012 Fluticasone propionate 0.250 Ethanol (absolute) 2,500 HFA 227 60,768 HFA 134a 36,470 Example 2 - Dry Powder Ingredient% by weight formoterol fumarate dihydrate 0.048 fluticasone propionate 1000 Lactose monohydrate 98,952 Example 3 A suitable dry powder is prepared to be delivered from the multi-dose inhaler reservoir described in International Publication Number WO97 / 20589, mixing 12 parts of formoterol fumarate dihydrate that has been milled to an average particle diameter of 1 to 5 microns in an air jet mill, 250 parts of fluticasone propionate that has been ground in a similar manner to an average particle diameter from 1 to 5 microns, and 4738 parts of lactose monohydrate having a particle diameter of less than 212 microns.

E-Examples 4 - 92 Example 3 is repeated, but using the amounts of the ingredients shown in the following table instead of the amounts used in that Example: Example 93 Gelatin capsules suitable for use in a capsule inhaler are prepared, such as that described in US Pat. No. US3991761, each capsule containing a dry powder obtained by mixing 12 micrograms of formoterol fumarate dihydrate which has been milled to an average particle diameter of 1 to 5 microns in an air jet mill, 250 micrograms of fluticasone propionate which has been ground in a similar manner to an average particle diameter of 1 to 5 microns, and 24738 micrograms of lactose monohydrate having a particle diameter of less than 212 microns.

Examples 94-152 Example 93 is repeated, but using the amounts of the ingredients shown in the following table instead of the amounts used in that Example: Examples 153-176 Example 3 is repeated, but using the amounts of the ingredients shown in the following table instead of the amounts used in that Example: Examples 177-216 Example 93 is repeated, but using the amounts of the ingredients shown in the following table instead of the amounts used in that Example:

Claims (20)

2é CLAIMS

1. A pharmaceutical composition comprising (A) formoterol or a pharmaceutically acceptable salt thereof, or a solvate of formoterol or said salt, and (B) fluticasone propionate.

2. A composition according to claim 1, which comprises a mixture of effective amounts of (A) and (B), together with a pharmaceutically acceptable carrier.

3. A composition according to the claim 1 or 2, wherein (A) is formoterol fumarate.

4. A composition according to claim 3, wherein the formoterol fumarate is in the form of its dihydrate.

5. A composition according to any of the preceding claims, which is in an inhalable form.

6. A composition according to the claim 5, which is a sprayable composition.

7. A composition according to the claim 6, which is an aerosol comprising a mixture of (A) and (B) in solution or dispersion in a propellant.

8. A composition according to the claim 6, which is a nebulizable composition comprising a dispersion of (A) and (B) in an aqueous, organic, or aqueous / organic medium.

9. A composition according to claim 5, which is a dry powder comprising (A) and (B) finely divided, optionally together with a pharmaceutically acceptable carrier in a finely divided form.

10. A composition according to the claim 9, where the vehicle is present and is a saccharide.

11. A composition according to the claim 10, where the vehicle is lactose.

12. A composition according to any of claims 9 to 11, wherein (A) and / or (B) have an average particle diameter of up to 10 microns.

13. A composition according to any of the preceding claims, wherein the weight ratio of (A) to (B) is from 3: 1 to 1: 3000.

14. A composition according to claim 13, wherein the ratio is from 1: 5 to 1:50.

15. A composition according to claim 13, wherein the ratio is from 1:10 to 1:25.

16. A composition according to the claim 1, which is a dry powder in a capsule, the capsule containing from 3 to 36 micrograms of (A) as formoterol fumarate dihydrate, from 25 to 500 micrograms of (B), and a pharmaceutically acceptable carrier in a quantity to be carried the total weight of the dry powder up to between 5 milligrams and 50 milligrams.

17. A composition according to claim 1, which is a dry powder comprising, by weight, from 3 to 36 parts of (A) as formoterol fumarate dihydrate, from 25 to 500 parts of (B), and from 4464 to 24,972 parts of a pharmaceutically acceptable vehicle.

18. A composition according to any of the preceding claims, for use in the treatment of an inflammatory or obstructive airway disease.

19. The use of a composition according to any of claims 1 to 17, for the preparation of a medicament for the treatment of an inflammatory or obstructive airway disease.

20. A method for the treatment of an inflammatory or obstructive airway disease, which comprises administering to a subject in need of such treatment, an effective amount of a composition according to any of claims 1 to 17.