JP2004503505A - Pharmaceutical anti-inflammatory aerosol formulation - Google Patents

Abstract

The present invention relates to fine particles of (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2- The present invention relates to a pharmaceutical aerosol formulation comprising a hydrofluoroalkane (HFA) propellant in which {[2- (2-methylphenoxy) acetyl] amino} pentanoyl) amino] propanoic acid or a salt or solvate thereof is dissolved. Methods and uses of the formulation and canisters and metered dose inhalers containing the formulation in the treatment of respiratory disorders have also been described.

Description

[0001]
The present invention relates to pharmaceutical formulations for use in administering drugs by inhalation. In particular, the present invention relates to pharmaceutical formulations for use in pressurized metered dose inhalers (MDI). The invention also relates to methods of their preparation and their therapeutic use.
[0002]
Inhalers are well-known devices for administering pharmaceutically active substances to the respiratory tract by inhalation. Such actives usually delivered by inhalation include bronchodilators such as β2 agonists and anticholinergics, corticosteroids, antiallergic drugs, and are effectively administered by inhalation to increase the therapeutic index and increase the activity Other substances can reduce the side effects of the substance.
[0003]
(2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- (2 -Methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid has recently been described in an international patent application (PCT / EP99 / 10,000) as a potent antagonist of both α4β1 and α4β7 integrins, It is disclosed to have.
[0004]
Metered dose inhalers (MDIs) are the most common of a wide range of inhaler types and utilize a liquefied propellant to deliver droplets containing a drug as an aerosol into the respiratory tract. MDI formulations are generally characterized as solution or suspension formulations.
[0005]
The most commonly used aerosol propellants for drugs were mixtures of Freon 11 (CCl ₃ F) and Freon 12 (CCl ₂ F ₂ ) and Freon 114 (CF ₂ Cl.CF ₂ Cl). However, these propellants are now thought to induce stratospheric ozone decomposition, and their use is now being phased out and the use of all CFC-containing aerosol propellants is disappearing. Thus, there is a need to provide aerosol formulations for drugs that use so-called "ozone-friendly" propellants.
[0006]
Hydrofluoroalkanes (HFAs; also known as hydrofluorocarbons or HFCs) have been proposed as alternatives to CFCs because they do not contain chlorine and are considered to be less ozone depleting. In particular, 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227) are the best candidate compounds as non-CFC propellants. Be recognized.
[0007]
The efficiency of an aerosol device, such as an MDI, correlates with the dose deposited at a suitable site in the lung. Deposition is affected by a number of factors, one of the most important being the aerodynamic particle size. The solid particles and / or droplets in an aerosol formulation can be characterized by their median aerodynamic particle size (MMAD, the particle size around which the aerodynamic particle size is equally distributed).
[0008]
Pulmonary particle deposition is driven by three physical mechanisms:
1. Intrusion, which is an action due to the inertia of the particles,
2. 2. sedimentation by gravity; and It relies heavily on the diffusion resulting from Brownian motion of fine, submicron (<1 μm) particles. The mass of the particle determines which of the three main mechanisms will dominate.
[0009]
Effective aerodynamic particle size is a function of particle size, shape and density and can affect the magnitude of force acting on the particles. For example, as the particle size and density increase, the effects of inertia and gravity increase, but the displacement caused by diffusion decreases. In practice, diffusion plays only a small role in the deposition of pharmaceutical aerosols. Inset and subsidence can be evaluated from measurements of MMAD, which determine displacement across streamlines under the influence of inertia and gravity, respectively.
[0010]
Aerosol particles with equivalent MMAD and GSD (geometric standard deviation) make similar deposits in the lungs regardless of their composition. GSD is a measure of aerodynamic particle size variability.
[0011]
For inhalation therapy, aerosols comprising particles for inhalation having a diameter of about 0.5-5 μm are preferred. Particles larger than 5 μm in diameter are deposited primarily in the pharyngeal orifice by inertial fit, particles 0.5 to 5 μm in diameter are ideal for deposition in the guiding airways, mainly under the influence of gravity, and 0.5-3 μm particles are desirable for aerosol delivery to the lung periphery. Particles smaller than 0.5 μm will be leached.
[0012]
In the case of suspension formulations, the particle size is in principle controlled during manufacture, usually by micronization, until the solid drug is reduced. However, if the drug to be suspended exhibits little solubility in the propellant, the particle size can be increased by a process known as Ostwald ripening. It is also possible that the particles may agglomerate or have a tendency to adhere to a portion of the MDI (eg, a canister or valve). The effect of Ostwald ripening, especially the effect of drug deposition, is particularly important for potent drugs that need to be formulated at low doses. Solution formulations do not have these disadvantages, but differ in that the particle size is a function of the rate at which the propellant evaporates from the formulation and the time between the release of the formulation from the canister and the moment of inhalation. Having. Thus, the particle size is quite variable and is usually difficult to control.
[0013]
According to the present invention, (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2- A pharmaceutical aerosol formulation is provided which comprises a hydrofluoroalkane (HFA) propellant in which {[2- (2-methylphenoxy) acetyl] amino} pentanoyl) amino] propanoic acid or a salt or solvate thereof is dissolved. .
[0014]
Examples of suitable salts include the physiologically acceptable salts, such as alkali metal salts, for example, calcium, sodium and potassium salts, and salts with (trishydroxymethyl) aminomethane.
[0015]
(2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- (2 -Methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid is preferably present as the potassium salt. Free acids are also important.
[0016]
The formulations of the present invention typically contain a solubilizing agent that helps solubilize the drug in the formulation. Suitable solubilizers include propylene glycol, glycerol and ethanol, especially propylene glycol and ethanol, preferably ethanol. Other suitable solubilizers include alkanes and ethers (eg, dimethyl ether). Important as a further solubilizer is dimethoxymethane, which has particularly good solubility properties.
[0017]
Examples of HFA propellants are 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) and mixtures thereof. No. A preferred propellant is 1,1,1,2-tetrafluoroethane (HFA134a). Of particular interest is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227).
[0018]
As specific embodiments of the present invention, the following (i) to (iv):
(I) (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-{[2 -(2-methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid or a salt or solvate thereof;
(Ii) hydrofluoroalkane (HFA) propellant;
(Iii) low volatile components that increase the median aerodynamic particle size (MMAD) of the aerosol particles upon operation of the inhaler; and (iv) a sufficient amount of a drug to solubilize the drug in the formulation. There is provided a pharmaceutical aerosol formulation comprising a solubilizer (particularly ethanol).
[0019]
The presence of the less volatile component in the solution formulation indicates that the contents of stages 3-5 of the Andersen Cascade Impactor during operation of the formulation, as compared to a solution formulation without this component. Increase the fine particle mass (FPM) defined by Solution formulations that do not contain more volatile components typically result in a particle size distribution that contains more fine particles.
[0020]
Suitable low volatility components are glycerol, propylene glycol or polyethylene glycol, especially glycerol, which is preferably present in an amount of 0.5 to 3% (w / w).
[0021]
A preferred solubilizing agent is ethanol. Preferably, the solubilizer is present in the formulation at a concentration of 35% (w / w) or less, most preferably at a concentration of 5-30% (w / w). [0022]
More specifically, the present invention provides the following (i) to (iv):
(I) (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-{[2 -(2-methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid or a salt or solvate thereof;
(Ii) 1,1,1,2-tetrafluoroethane (HFA134a);
(Iii) 0.5-3% (w / w) glycerol; and (iv) a sufficient amount of a solubilizer (especially ethanol) to solubilize the drug in the formulation.
Can be defined as a pharmaceutical aerosol formulation comprising
[0023]
In some cases, additional active ingredients suitable for inhalation therapy may be incorporated into the formulation, including, for example, corticosteroids (eg, fluticasone propionate) or bronchodilators (eg, salmeterol or albuterol or salts thereof). .
[0024]
The formulation according to the invention can be utilized with a suitable metering valve. The formulation is preferably actuated by a metered valve capable of delivering a volume of 50 μl to 100 μl, for example 50 μl or 63 μl or 100 μl.
[0025]
The pharmaceutical composition according to the present invention can be filled in a canister suitable for delivering a pharmaceutical aerosol formulation.
[0026]
The canister is generally a plastic or plastic-coated glass bottle or a metal can, preferably anodized, lacquered and / or plastic-coated, which can withstand the vapor pressure of the HFA propellant, It comprises a container, for example an aluminum can, which is sealed with a metering valve. The canister is preferably coated with a fluorocarbon polymer as described in WO 96/32151, for example a copolymer of polyethersulfone (PES) and polytetrafluoroethylene (PTFE). Another coating polymer that may be contemplated is FEP (fluorinated ethylene propylene). The metering valve is designed to deliver a metered amount of formulation per actuation and incorporates a gasket to prevent propellant leakage through the valve. The gasket may comprise any suitable elastomeric material such as low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubber, butyl rubber and neoprene. The thermoplastic elastomer valves described in WO 92/11190 and the valves containing EPDM rubber described in WO 95/02651 are particularly suitable. Suitable valves are well known manufacturers in the aerosol industry, such as Valois, France (eg, DF10, DF30, DF60), Bespaq plc, United Kingdom (eg, BK300, BK356, BK357) and 3M-Neotechnic Ltd, United Kingdom (eg, , Spraymiser ^™ ). Valois, French DF31 valves are also suitable.
[0027]
It is preferred that the valve seal, especially the gasket seal, be made of a material that is inert to the formulation contents and resistant to extraction, especially when the contents contain ethanol.
[0028]
It is preferred that the valve material, especially the material of manufacture of the metering chamber, be made of a material that is inert to the formulation content and resistant to extraction, especially when the content contains ethanol. Particularly suitable materials for the production of metering chambers include polyesters, such as polybutylene terephthalate (PBT) and acetals, especially PBT.
[0029]
The material of manufacture of the metering chamber and / or valve stem is desirably fluorinated, partially fluorinated, or impregnated with a fluorine-containing substance so as not to deposit the drug.
[0030]
Larger batches for commercial production of full canisters can be manufactured using conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture. Thus, for example, in one bulk manufacturing method, a metering valve is attached to an aluminum can to form an empty canister. The drug is added to the fill container, and the mixture of ethanol, low volatility components and liquefied propellant is pressurized through the fill container and into a production container. An aliquot of the formulation is then filled into the canister through a metered valve. Typically, pharmaceutical manufactured batches check the weight of each full canister, code the batch number, and pack into storage trays prior to release testing.
[0031]
In an alternative process, an aliquot of the liquefied formulation is added to the open canister under conditions that are cold enough so that the formulation does not evaporate, and then a metering valve is mounted on the canister.
[0032]
Typically, for pharmaceutical manufactured batches, check the weight of each full canister, code the batch number, and pack into storage trays prior to the release test.
[0033]
Each fill canister is conveniently fitted with a suitable channeling device to assemble a metered dose inhaler prior to use, and administer the drug into the lungs or nasal passages of the patient. Suitable channeling devices include, for example, a valve actuator and a cylindrical or conical passageway, eg, a mouthpiece actuator, through which the drug is delivered from the fill canister via a metering valve to the nasal or oral cavity of the patient. Metered dose inhalers are designed to deliver a fixed unit dose of drug per actuation or "puff", e.g., 10-5000 [mu] g of drug per puff.
[0034]
In a typical arrangement, the valve stem is located in a nozzle block having an orifice leading to the expansion chamber. The outlet orifice of the expansion chamber extends into the mouthpiece. Actuator (outlet) orifice diameters of 0.1 to 0.45 mm are generally suitable, for example 0.15, 0.22, 0.25, 0.30, 0.33 or 0.42 mm. We have found that it is advantageous to use smaller diameters (eg, less than 0.25 mm, especially 0.22 mm), which results in higher FPM and lower throat deposition. . 0.15 mm is also suitable. The size of the orifice should not be so small that the jet will be obstructed.
[0035]
The length of the actuator jet is typically between 0.30 and 1.7 mm, for example 0.30, 0.65 or 1.50 mm.
[0036]
Preferably, (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-{[2 The dose of-(2-methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid or a salt or solvate thereof is 0.1 to 10 mg, most preferably 0.5 to 3 mg per day.
[0037]
Metered dose inhalers are designed to deliver a fixed unit dose per actuation or "puff", eg, 25-500 μg drug per actuation. Formulations suitable for delivering a therapeutic amount of drug in one or two actuations are preferred.
[0038]
Thus, the concentration of the drug in the formulation is typically in the range of 0.02-5% w / w.
[0039]
Typically, administration may be from 1 to 5 inhalations per day (eg, 1, 2, 3 or 4 inhalations).
[0040]
Administration of the drug can be indicated for the treatment of mild, moderate or severe, acute or chronic conditions or for prophylactic treatment. It will be appreciated that the exact dose to be administered will depend on the age and condition of the patient, and the amount and frequency of administration will ultimately be at the discretion of the clinician.
[0041]
The fill canister and metered dose inhaler described herein comprise a further aspect of the invention.
[0042]
Yet a further aspect of the invention comprises a method of treating a respiratory disorder comprising administering by inhalation an effective amount of a formulation described herein above.
[0043]
Preferably, the respiratory disorder is asthma. Allergic rhinitis is also important.
[0044]
It will be appreciated that if the respiratory disorder is allergic rhinitis, the formulations of the present invention may be delivered by the nasal route.
[0045]
A further aspect of the invention comprises the use of a formulation as described herein above in the manufacture of a medicament for treating a respiratory disorder, for example, asthma or allergic rhinitis.
[0046]
The present invention is further described by, but not limited to, the following examples.
[0047]
【Example】
Example A : (2S) -3- [4-({[4- ( aminocarbonyl ) -1- piperidinyl ] carbonyl } oxy ) phenyl ] -2-[((2S) -4- methyl - 2- } [ 2- (2- Methylphenoxy ) acetyl ] amino { pentanoyl ) amino ] propanoic acid Wang resin (50 g) was added to (2S) -3- [4- (allyloxy) phenyl] -2-[(tert-butoxycarbonyl) amino A solution of DMF (475 ml) containing propanoic acid (115.8 g) and 1-hydroxybenzotriazole (48.6 g) was added. After 15 minutes, 1,3-diisopropylcarbodiimide (56.5 ml) was added and the mixture was stirred at 45 ° C. for 24 hours. The resin was filtered and washed with DMF (3 x 360 ml), methanol (3 x 360 ml) and dichloromethane (3 x 700 ml). Pyridine (14.7 ml) was added to a slurry of the resin in dichloromethane (644 ml). Acetic anhydride (26.9 ml) was added and the mixture was stirred at 20 ° C. for 12 hours. The resin was filtered and washed with dichloromethane (3 x 550 ml), methanol (3 x 370 ml) and dichloromethane (3 x 550 ml).
[0048]
A slurry of dichloromethane (100 ml) containing 20 g of resin was cooled to 2-5 ° C. and treated with a solution of phenol (20 g) in dichloromethane (80 ml). Chlorotrimethylsilane (20 ml) was added dropwise and the mixture was stirred for 6 hours at 2-5 ° C. The resin was filtered and dichloromethane (3 × 200 ml), methanol (3 × 200 ml), DMF containing 10% water (2 × 200 ml), DMF containing 10% diisopropylethylamine (3 × 200 ml), DMF (200 ml), methanol (3 × 200 ml) and dichloromethane (3 × 200 ml).
[0049]
A slurry of resin-containing DMF (55 ml) was treated with a solution of Fmoc-leucine (32.7 g) and 1-hydroxybenzotriazole (12.5 g) in DMF (85 ml). After 5 minutes, 1,3-diisopropylcarbodiimide (19.3 ml) was added and the mixture was stirred at 20 ° C. for 15 hours. The resin was filtered and washed with DMF (3 × 150 ml), methanol (3 × 150 ml) and dichloromethane (3 × 150 ml).
[0050]
The resin was treated with DMF containing 180% piperidine (180 ml) and stirred for 1 hour at 20 ° C. The resin was filtered and washed with DMF (3 × 150 ml), dichloromethane (3 × 150 ml), DMF (3 × 150 ml), and dichloromethane (3 × 150 ml). To a slurry of DMF (50 ml) containing the resin was added a solution of (2-methylphenoxy) acetic acid (17.9 g) and DMF (100 ml) containing 1-hydroxybenzotriazole (14.6 g). After 5 minutes, 1,3-diisopropylcarbodiimide (16.9 ml) was added and the mixture was stirred at 20 ° C. for 65 hours. The resin was filtered and washed with DMF (2 × 150 ml), methanol (3 × 150 ml) and dichloromethane (3 × 150 ml).
[0051]
A slurry of the resin in dichloromethane (60 ml) was treated with a solution of tetrakis (triphenylphosphine) palladium (0) (5.21 g) in dichloromethane (140 ml) followed by morpholine (13 ml). The mixture was stirred for 2 hours at 20 ° C., then the resin was filtered and washed with dichloromethane (7 × 200 ml).
[0052]
A slurry of the resin in dichloromethane (160 ml) was treated with diisopropylethylamine (12.4 ml) and then treated with 4-nitrophenyl chloroformate (24.8 g) in three parts at 5 minute intervals. The mixture was stirred at 20 ° C. for 1 hour. The resin was filtered and washed with dichloromethane (3 × 200 ml). The resin was treated with a solution of isonipecotamide (15.8 g) in DMF (180 ml) and the mixture was stirred at 20 ° C. for 1.5 hours. The resin was filtered and washed with DMF (4 × 200 ml) and dichloromethane (2 × 200 ml).
[0053]
The resin was treated with dichloromethane containing 200% TFA. After stirring for 1 hour at 20 ° C., the resin was filtered and washed with dichloromethane (5 × 200 ml). The filtrate and washings were combined and evaporated in vacuo. The residue was azeotropically distilled with toluene (2 × 100 ml), then triturated with ether (50 ml) and the resulting white solid filtered. To this was added acetonitrile (150 ml) and the mixture was heated to reflux. The resulting suspension was cooled to 20 ° C. and stirred for 18 hours. The mixture was filtered to give the title compound as a white solid (4.9 g).
[0054]
Example B : (2S) -3- [4-({[4- ( aminocarbonyl ) -1- piperidinyl ] carbonyl } oxy ) phenyl ] -2-[((2S) -4- methyl - 2- } [ 2- (2- methylphenoxy ) acetyl ] amino { pentanoyl ) amino ] propanoic acid potassium salt (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl]- A suspension of methanol (150 ml) containing 2-[((2S) -4-methyl-2-{[2- (2-methylphenoxy) acetyl] amino} pentanoyl) amino] propanoic acid (10 g) is refluxed. Warmed until a clear solution was obtained. To this was added a solution of potassium carbonate (1.16 g) in water (7.5 ml). After heating at reflux for 2 minutes, the solvent was evaporated in vacuo to give a crisp foam. To this was added acetonitrile (100 ml) and the mixture was warmed to reflux, during which time the foam broke and crystallization began. After 10 minutes, the mixture was cooled to 20 ° C., then filtered under reduced pressure and washed with acetonitrile (25 ml) and ether (50 ml) to give the title compound as a white solid (10.65 g, 100%). Was.
[0055]
Example 1
Aluminum canister with the following formulation:
(2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- (2 -Methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid (prepared according to Example A): 1% w / w;
Ethanol: 10%;
1,1,1,2-tetrafluoroethane: 100% total amount
And the canister was fitted with a metering valve.
[0056]
Example 2
Aluminum canister with the following formulation:
(2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- (2 -Methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid potassium salt (prepared according to Example B): 1% w / w;
Ethanol: 10%;
1,1,1,2-tetrafluoroethane: 100% total amount
And the canister was fitted with a metering valve.
[0057]
Example 3
Aluminum canister with the following formulation:
(2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- (2 -Methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid (prepared according to Example A): 3% w / w;
Ethanol: 20%;
Glycerol: 1.3% w / w;
1,1,1,2-tetrafluoroethane: 100% total amount
And the canister was fitted with a metering valve.
[0058]
Example 4
Aluminum canister with the following formulation:
(2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- (2 -Methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid potassium salt (prepared according to Example B): 3% w / w;
Ethanol: 20%;
Glycerol: 1.3% w / w;
1,1,1,2-tetrafluoroethane: 100% total amount
And the canister was fitted with a metering valve.
[0059]
Throughout this specification and the claims, unless the context demands otherwise, the terms "comprise" and "comprises" and "comprising" and the like Will be understood to mean the inclusion of the specified completeness or step or group of completenesses, but not the exclusion of the completeness or step or completeness group.
[0060]
The contents of the above-mentioned patent application are incorporated herein by reference.

Claims (21)

Particulate (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- A pharmaceutical aerosol formulation comprising a hydrofluoroalkane (HFA) propellant in which (2-methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid or a salt or solvate thereof is dissolved. (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- (2 Pharmaceutical aerosol formulation according to claim 1, characterized in that -methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid is present as a potassium salt. (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- (2 Pharmaceutical aerosol formulation according to claim 1, characterized in that -methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid is present as free acid. The pharmaceutical aerosol formulation according to claim 1, comprising a solubilizer. The formulation according to claim 4, characterized in that the solubilizer is selected from propylene glycol, glycerol, ethanol, alkanes, ethers (for example dimethyl ether) and dimethoxymethane. The formulation according to claim 4, wherein the solubilizing agent is ethanol. A formulation according to any one of claims 4 to 6, characterized in that the solubilizer is present at a concentration of 5 to 30% (w / w) in the formulation. The hydrofluoroalkane (HFA) propellant is 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or a mixture thereof. The preparation according to any one of claims 1 to 7, which is a mixture. The formulation according to claim 8, wherein the hydrofluoroalkane (HFA) propellant is 1,1,1,2-tetrafluoroethane (HFA134a). The following (i) to (iv):
(I) (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-{[2 -(2-methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid or a salt or solvate thereof;
(Ii) hydrofluoroalkane (HFA) propellant;
(Iii) low volatile components that increase the median aerodynamic particle size (MMAD) of the aerosol particles upon operation of the inhaler; and (iv) a sufficient amount of a drug to solubilize the drug in the formulation. A pharmaceutical aerosol formulation comprising a solubilizer. The formulation according to claim 10, wherein the low volatile component is glycerol, propylene glycol or polyethylene glycol. The formulation according to claim 11, wherein the low volatile component is glycerol. Formulation according to any one of claims 10 to 12, characterized in that the low volatile component is present in the formulation in an amount of 0.5-3% (w / w). The following (i) to (iv):
(I) (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-{[2 -(2-methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid or a salt or solvate thereof;
(Ii) 1,1,1,2-tetrafluoroethane (HFA134a);
(Iii) 0.5-3% (w / w) glycerol; and (iv) a sufficient amount of a solubilizer (especially ethanol) to solubilize the drug in the formulation.
A pharmaceutical aerosol formulation comprising: (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidinyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-} [2- (2 15. The method according to claim 1, wherein -methylphenoxy) acetyl] amino {pentanoyl) amino] propanoic acid or a salt thereof is present in the preparation in an amount of 0.02 to 5% (w / w). Or the preparation according to item 1. A canister comprising a metering valve and comprising the pharmaceutical aerosol formulation according to any one of claims 1 to 15. 17. A metered dose inhaler comprising a canister according to claim 16 fitted with a suitable channeling device. A method for treating a respiratory disorder, comprising administering an effective amount of the pharmaceutical aerosol formulation according to any one of claims 1 to 15 by inhalation. A method for treating asthma, comprising administering by inhalation an effective amount of the pharmaceutical aerosol formulation according to any one of claims 1 to 15. A method for treating allergic rhinitis, comprising intranasally administering an effective amount of the pharmaceutical aerosol formulation according to any one of claims 1 to 15. Use of a pharmaceutical aerosol formulation according to any one of claims 1 to 15 in the manufacture of a medicament for treating a respiratory disorder, for example asthma or allergic rhinitis.