WO2008025560A1

WO2008025560A1 - Methods for taste masking of nebulised compositions for nasal and pulmonary inhalation therapy

Info

Publication number: WO2008025560A1
Application number: PCT/EP2007/007625
Authority: WO
Inventors: Manfred Keller; Aslihan Akkar
Original assignee: Pari Pharma Gmbh
Priority date: 2006-09-01
Filing date: 2007-08-31
Publication date: 2008-03-06

Abstract

The invention provides pharmaceutical aerosols suitable for inhalation. The aerosols comprise a water-soluble active ingredient exhibiting a poor taste and at least one taste-masking excipient. In a further aspect, the invention provides methods to produce solid and liquid compositions with improved stability in the dissolved state which are useful for preparing such aerosols. The aerosols can be administered to the upper or lower parts of the respiratory system using appropriate nebulisers to treat upper and lower respiratory tract diseases with distinct medications. Combination drug products comprising at least two active drugs may have an additive and/or synergistic effect.

Description

METHODS FOR TASTE MASKIlVG OF NEBULISED COMPOSITIONS FOR NASAL AND PULMONARY INHALATION THERAPY

DESCRIPTION

FIELD OF THE INVENTION

The invention relates to pharmaceutical aerosols which are useful for the prevention or treatment of diseases of the airways, such as the lungs, the bronchi, or the sinun- asal cavities. It is also related to solid or liquid pharmaceutical compositions for preparing such aerosols. In another aspect, the invention concerns methods for making pharmaceutical aerosols which are useful in the prevention and therapy of diseases and con- ditions of the respiratory system.

BACKGROUND OF THE INVENTION

- . The delivery of therapeutic compounds to the bronchi and lungs has been used primarily for the local treatment of diseases and conditions of the respiratory system, such as asthma, COPD, cystic fibrosis and bronchitis. More recently, the pulmonary administration of systemic drugs, such as insulin, has been proposed and actively pursued in product development programs, utilising the large surface area of the lungs for absorption.

In general, drug substances can be delivered to the respiratory system as aero- solised dry powders or liquids, the liquids representing either solutions or dispersions, such as drug suspensions. Various devices have been developed to convert a liquid or solid composition into an aerosol and to enable inhalation. Qne.of the most important requirements for any such device is that it is capable of achieving a particles size of the aerosol which will allow deposition at the target site, i.e. the designated site of action or of absorption. Depending on whether the drug should be delivered to the bronchi or to the deep lungs, the optimal droplet or particle size for typical formulations may vary from about 10 microns down to below one micron; larger particles may be useful if their density is very low. Metered-dose inhalers deliver a measured dose of the drug in the form of a suspension of small liquid or solid particles, which is dispensed from the inhaler by a pro- pellant under pressure. Such inhalers are placed into the mouth and activated to release drug as the individual takes a breath. This requires a certain amount of coordination and may therefore be unsuitable for children.

Spacers, or spacing devices, which are available for use with some aerosol inhalers, extend the space between the inhaler and the mouth. This reduces the speed at which the aerosol travels to the back of the mouth, allowing more time for the propel- lant to evaporate and therefore reducing the impact of the propellant on the back of the mouth- which can cause irritation-and enabling a higher proportion of the particles of the drug to be inhaled. There is also less need to coordinate breathing in with activation of the inhaler. Breath-activated inhalers deliver the drug, in the form of an aerosol or a dry powder, only when the user places his mouth over the outlet and breathes in. This obviates the need to coordinate breathing in with depressing the dispenser. The dose of drug will still be measured or metered, and is not dependent on the size of breath taken.

Dry powder inhalers, on the other hand, are loaded with portions of the drug substance in form of a powder formulation. The unit doses may be accommodated in small capsules. As the inhaler is activated by taking a breath, a capsule is punctured and a type of fan mechanism disperses the powder so that it can be inhaled, as e.g. in the commercially available devices known as "Spinhaler" and "Rotahaler". Another device known as "Turbohalers" is fitted with cartridges that contain measured doses of the powder formulation. In most cases, the droplet or particle distribution pattern are broad and consist of very small up to very large particles. The latter can cause undesired oropharyngeal deposition and particles / droplets < 3 μm have a high probability to be ei- ther systemically absorbed or exhaled. A parameter to describe the width of an aerosol cloud is the Geometric Standard Deviation (GSD) being typically about 2 or larger for pMDIs, DPIs and nebulised systems.

Aqueous-based solutions and suspensions are usually inhaled with nebulisers. Various types of nebulisers are commercially available or presently being developed. A traditional type is the jet nebulizer, which is still being used extensively. More recently, ultrasonic and vibrating membrane-type nebulizers were developed. Formulating aqueous compositions which are useful for nebulisation can be challenging, depending on the physical, chemical, and organoleptic properties of the active agent. Clearly, aqueous solutions are usually most preferred for nebulisation, but not often easily achievable. Poor aqueous solubility is a problem which is frequently en- countered with drug substances, such as in the case of several corticosteroids useful for inhalation therapy, including budesonide and fluticasone. To overcome poor solubility and achieve a sufficiently high drug concentration in the aqueous composition so that the volume of a single dose is not too high and allows convenient administration within an acceptable period of time, several formulation strategies have been suggested. For example, such poorly soluble drug substances may be solubilised with surfactants or surfactant combinations, as for example described in WO 2005/037246. According to another approach, the drug substances are solubilised in the form of water-soluble complexes with complexing agents such as cyclodextrins, as shown, for example, in WO 2005/065651, again for poorly soluble corticoids. A further formulation strategy is the development of lipid-based delivery vehicles such as liposomes, micelles, or mixed micelles, which may also be capable of solubilising compounds with low water solubility.

Another problem which has not been addressed very often in the context of inhalation therapy is the formulation of drug substances having a poor taste. Usually, active agents having poor organoleptic properties are thought of being problematic for oral delivery. In fact, most prior art relating to the improvement or masking of the poor taste of drug substances relates to standard oral dosage forms such as tablets and capsules. A simple and usually rather effective method of formulating such compounds is to coat the drug particles or the whole dosage form with a saliva-resistant coating.

Interestingly, several drug substances which have recently been suggested as be- ing potentially useful for inhalation therapy have a rather poor taste. Moreover, it has been found by the inventors that such poor taste may be as unpleasant when inhaling a nebulised solution of the respective compound as in the case of oral administration. The unpleasant taste results in the reduction of patient compliance, which influences the therapy. Therefore, taste masking is one of the crucial parameters in the pharmaceutical development. And of course, the use of coatings for taste-masking is not feasible for compositions for aerosolisation. While traditional inhalation therapies were primarily directed to the prevention and treatment of allergic and inflammatory diseases and conditions of the respiratory system including asthma and obstructive bronchitis, novel therapeutical approaches have been developed more recently. For instance, the local treatment of pulmonary in- fections with antibiotics has been suggested and, with tobramycin being the first antibiotic approved for this use, successfully introduced to the therapy of certain severe or even life-threatening types of infection. Tobramycin, which is supplied as Tobi^®, is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed air driven reusable nebuliser. It is approved for the treatment of cystic fibrosis patients infected with Pseudomonas aeruginosa.

Other pulmonary antibiotic therapies have been proposed in the scientific and patent literature. For instance, WO 02/03998 discloses inhalable formulations of macrolide antibiotics, such as erythromycylamine, for delivery by aerosolisation. The concentrated erythromycylamine formulations contain an amount of erythromycylamine effective to treat infections caused by susceptible bacteria. Unit dose devices having a container comprising a formulation of the macrolide antibiotic in a physiologically acceptable carrier are also described. The document further discloses methods for treatment of pulmonary infections by such formulations delivered as an aerosol having mass median aerodynamic diameter predominantly between 1 and 5 micrometers.

In WO 00/35461, a method for the treatment of severe chronic bronchitis (bronchiectasis) using a concentrated aminoglycoside antibiotic formulation is disclosed. The method includes delivering the antibiotic to the lungs endobronchial space including alveoli in an aerosol or dry powder having a mass medium diameter predominately be- tween 1 and 5 microns. The method comprises the administration of the antibiotic at a concentration one to ten thousand times higher than the minimal inhibitory concentration of the target organism. Preferably, the method comprises the endobronchial administration of aerosolized tobramycin to treat pseudomonal infections in severe chronic bronchitis patients.

A wide variety of gram-negative bacteria cause severe pulmonary infections, and many of these bacteria are or become resistant to commonly used or specialty antibiot- ics including tobramycin, and require treatment with new types of antibiotics. The pulmonary infections caused by gram-negative bacteria are particularly dangerous to patients who have decreased immunoprotective responses, such as cystic fibrosis (CF) and HIV patients, patients with chronic obstructive pulmonary disease (COPD) bronchiecta- sis or those on mechanical ventilation. Thus, bacterial respiratory infections caused by resistant bacteria remains a major problem, particularly in CF, COPD and HIV patients or those receiving immunosuppressive drugs. For example, chronic pulmonary infection with Pseudomonas aeruginosa in patients with cystic fibrosis is a major cause of their high mortality.

In order to address the continuous need for an effective therapy for treatment of acute and chronic pulmonary bacterial infections caused by gram-negative bacteria and particularly those caused, for example, by Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, and multidrug resistant Pseudomonas aeruginosa, WO 02/051356 proposes the local therapy of the respiratory system by delivering a concentrated formulation of the monobactam antibiotic aztreonam as an inhalable aerosol, or as a dry powder formulation. According to the document, about 1 to 250 mg of aztreonam may be dissolved in 1 to 5 ml of saline or another aqueous solution. The formulation is delivered to the lung endobronchial space as an aerosol having mass medium average diameter particles predominantly between 1 and 5 micrometers, using a nebulizer capable of atomizing the aztreonam solution into droplets or particles of the required sizes. Alternatively, for the delivery of a dry inhalable powder, aztreonam is milled or spray-dried to particle sizes of 1 to 5 micrometers.

Another anti -infective agent suggested for inhalation therapy is azithromycin. Azithromycin is a macrolide antibiotic with activity against common respiratory patho- gens such as S. pneumoniae and H. influenzae. It has potential anti-inflammatory effects in the management of chronic P. aeruginosa respiratory tract infection in CF patients. There is some evidence that short-term use in both adults and children with CF results in improved clinical and quality of life parameters. The impact of longer-term use is unknown. It may act synergistically with other agents against a range of CF pathogens, enhancing their in-vitro activity. It is not known if this will result in improved clinical efficacy. In general it has been well tolerated by CF patients. Azithromycin prevents bacteria from growing, by interfering with their protein synthesis. Azithromycin binds to the subunit 5OS of the bacterial ribosome, and thus inhibits the translocation of peptides. Azithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particu- larly Hemophilus influenzae. Furthermore, it has been discussed if the control of a Pseudomonas aeroginousa (PA) infection by orally administered azithromycin may be due to a Quorum Sensing System (QSS), sending signal to inhibit biofilm formation by reducing the virulence of PA. Another feature of azithromycin may be its inflammatory and immunomodulator potential.

It has been suggested, e.g. by A. J. Hickey et al., J. Aerosol Med. 19 (1), 2006, 54-

60, that azithromycin should be used in the local treatment of pulmonary infections. Hickey et al. further describe experiments in which aqueous solutions of this anti- infective agents having various drug concentrations have been more or less efficiently nebulised using three conventional jet nebulisers.

In clinical practice, however, it is not only aerosolisation efficiency which is needed for therapeutic success; in addition, the administration of the drug product must be acceptable to patients in order to achieve compliance. In the case of azithromycin, the acceptability of a simple - perhaps buffered - aqueous solution for inhalation is rather doubtful. For example, Hickey et al. used the commercially available azithromy- cin formulation which is approved for parenteral use. However, the poor taste of the drug substance severely compromises the usefulness of this formulation.

Other active compounds with potential or proven usefulness for inhalation therapy which are difficult to formulate appropriately not because of any solubility issues but because of poor taste include other macrolides, such as clarithromycin, tacrolimus- fluoroquinolones, such as levofloxacin, ciprofloxacin, moxifloxacin, gemifloxacin, xan- thin derivatives, such as theophylline, pentoxifylline, steroids, such as dehydro-epi- andosterone, (DHEA), and non steroidal anti-inflammatory drug (NSAID), such as ibu- profen-lysinate.

Thus, there is a need for further pharmaceutical compositions, aerosols and meth- ods of administration which are suitable for the prevention, management or treatment of airway diseases and conditions and which have improved acceptability for patients. One of the particular objects of the present invention is to provide acceptable aqueous formulations and aerosols comprising compounds having a poor taste and/or stability when being dissolved in aqueous solutions. Further objects will become clear on the basis of the following description and the patent claims.

SUMMARY OF THE INVENTION

The invention provides a pharmaceutical aerosol for nasal, sinunasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase. The dispersed liquid phase essentially consists of aqueous droplets having a mass median diameter from about 1.5 to about 6 μm. The droplets of the dispersed phase comprise an active compound having a poor taste and an aqueous solubility of at least about 5 mg/ml, preferably at least about 10 mg/ml, at 25 ⁰C and at a pH from about 3 to 9 and at least one taste-masking excipient.

The taste-masking agent is preferably a complexing agent, a surfactant, a polymer, a sweetener, a salt, an organic acid, an amino acid, a metal ion, or a combination of two or more of these. It has been surprisingly found that aerosols in which the poor taste of a water-soluble active compound is masked, covered or improved with particular effectiveness can be provided by including at least one complexing agent selected from the group of optionally derivatised α-, β-, and γ-cyclodextrins in the formulation. Surprisingly it was found, that in addition to taste masking, the chemical and physical stability of such drugs in aqueous systems can be improved, too, and that a combination of different cyclodextrin types can be very helpful to prevent a diffusion of some drugs out of the cyclodextrin complex.

In a further aspect, the invention provides liquid pharmaceutical compositions for preparing such an aerosol. The liquid compositions comprise an effective dose of the active compound dissolved in a volume of not more than about 10 ml, and preferably not more than about 5 ml with a most preferred range of 0.25 — 2.5 ml which can be nebulised in less than 5 minutes.

Moreover, the invention provides solid pharmaceutical compositions for preparing such liquid compositions. The solid compositions comprise an effective dose of the ac- tive compound and are dissolvable or dispersible in an aqueous liquid solvent having a volume of not more than about 10 ml, and preferably not more than about 5 ml.

The invention further provides a method of preparing and delivering an aerosol comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase essentially consists of aqueous droplets comprising an active compound having a poor taste and an aqueous solubility of at least about 5 mg/ml, preferably at least about 10 mg/ml, at 25 °C and at a pH from about 3 to 9. The method comprises the steps of (a) providing a liquid pharmaceutical composition comprising an effective dose of said active compound dissolved in a volume of not more than about 10 ml, and pref- erably not more than about 5 ml, and at least one taste-masking excipient; (b) providing a nebuliser capable of aerosolising said liquid pharmaceutical composition at a total output rate of at least 0.1 ml/min, the nebuliser further being adapted to emit an aerosol comprising a dispersed phase having a mass median diameter from about 1.5 to about 6 μm; a geometric standard deviation of 1.3 - 2.8 and (c) operating said nebuliser to aero- solise the liquid composition for the treatment and/or prevention of a disease.

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect, the invention provides a pharmaceutical aerosol for nasal, sinunasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase. The dispersed liquid phase essentially consists of aqueous drop- lets having a mass median diameter from about 1.5 to about 6 μm. The droplets of the dispersed phase comprise an active compound having a poor taste and an aqueous solubility of at least about 5 mg/ml, preferably at least about 10 mg/ml, at 25 °C and at a pH from about 3 to 9, and at least one taste-masking excipient.

According to the present invention, the aerosol comprises a dispersed liquid phase and a continuous gas phase. Such aerosols are sometimes referred to as "liquid aerosols" or, probably more appropriately, aerosolised liquids. It should be noted that the requirement of a dispersed liquid phase does not exclude the presence of a solid phase. In particular, the dispersed liquid phase may itself represent a dispersion, such as a suspension of solid particles in a liquid. The continuous gas phase may be selected from any gas or mixture of gases which is pharmaceutically acceptable. For example, the gas phase may simply be air or compressed air, which is most common in inhalation therapy using nebulisers as aerosol generators. Alternatively, other gases and gas mixtures, such as air enriched with oxy- gen, or mixtures of nitrogen and oxygen may be used (Helox). Most preferred is the use of air as continuous gas phase.

An active compound is a natural, biotechnology-derived or synthetic compound or mixture of compounds useful for the diagnosis, prevention, management, or treatment of a disease, condition, or symptom of an animal, in particular a human. Other terms which may be used as synonyms of active compound include, for example, active ingredient, active agent, active pharmaceutical ingredient, therapeutic compound, drug substance, drug, and the like.

According to the invention, the active compound is water soluble, i.e. it has a water solubility of at least about 5 mg/ml, preferably at least about 10 mg/ml, at 25 ⁰C and at a pH from about 3 to 9. As used herein, the water solubility or aqueous solubility is understood as solubility in an aqueous medium whose pH may be neutral or adjusted to a biocompatible value, such as from about pH 3 to pH 9, in the absence of any liquid solvents other than water, and in the absence of any surfactants. The pH range from about pH 3 to pH 9 takes into account thai some active compounds exhibit a pH- dependent solubility, and may not be soluble in pure water or in a neutral aqueous liquid, but become soluble at an increased or decreased pH within the given range. In other words, there should be at least one pH within the specified range at which the active compound has a solubility of at least about 5 mg/ml, preferably at least about 10 mg/ml, at 25 °C. In another embodiment, the aqueous solubility of the active compound is at least about 20 mg/ml, as defined herein. In further embodiments, the aqueous solubility is at least about 50 mg/ml and 100 mg/ml, respectively.

It should be noted that many active compounds are available in various forms, e.g. as salts or solvates. Some of the forms may be water soluble while others exhibit poor water solubility. In the context of the present invention, only the water solubility of the actually incorporated form of the compound is relevant. Consequently, the active compound does not have a problem with respect to insufficient solubility which could make the development of aqueous formulations for inhalation difficult. This is particularly true if the aqueous solubility of the drug substance is also sufficiently high in relation to its single therapeutic dose. Preferred active agents have a solubility which allows that a single dose can be dissolved in a volume of not more than about 10 ml of a pharmaceutically acceptable aqueous medium, and more preferably of not more than about 5 ml.

The active compound is also characterised by its poor taste. As used herein, a poor taste is a taste which could have a negative impact on the acceptability and patient com- pliance. According to another definition, the taste is poor if an aqueous - optionally buffered - solution of a single dose of the active compound in a volume of 0.5 up to 10 ml is regarded as poor. A poor tasting compound may be bitter, metallic, acrid, astringent, or otherwise unpleasant.

Examples of active compounds of interest for inhalation therapy which have a poor taste include many anti-infectives, such as azithromycin, clarithormycin, levoflox- acin, gemifloxacin, tobramycin or xanthin-derivatives, such as theophylline, pen- toxiphyllin or steroids such as dehydro-epi-androsterone (DHEA), synthetic corticosteroids such as mometasone or antifungals, such as amphotericin B and itraconazole. As used herein, a reference to the ΪNN name of a compound includes all potentially appli- cable forms of that substance, in particular the salts and solvates thereof.

According to one of the preferred embodiments, the active compound is an anti- infective agent, or a salt, solvate, isomer, conjugate, prodrug or derivative thereof. One of the particularly preferred anti-infective agents is azithromycin, including its salts and solvates, such as azithromycin dihydrate or azithromycin monohydrate ethanolate. The active compound, in particular the azithromycin or salt or solvate thereof, is preferebly used for the prophylaxis or treatment of acute or chronic sinusitis or rhinosinusitis, bronchitis, pneumonia, asthma, chronic obstructive pulmonary disease, bronchiectasis, HIV, pulmonary hypertension, prophylaxis to prevent graft rejection after lung, stem or bone marrow transplantation, bronchiolitis obliterans, Pneumocystis, diffuse bronchioli- tis, parenchymatic and/or fibrotic diseases or disorders including cystic fibrosis, any pulmonary infection with or without acute exacerbations, optionally due to Streptococ- cus pneumoniae, Haemophilus influenza or Moraxella catarrhalis; acute bacterial exacerbations in chronic bronchitis or in chronic obstructive pulmonary disease, optionally due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, Haemophilus parainfluenza or Moraxella catarrhalis; nosocomial pneumonia, optionally due to Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Buk- holderia cepacia, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenza or Streptococcus pneumoniae, Mycobacterium avium, kanasaii or chelonae abscessus; or community acquired pneumonia (CAP), or hospital acquired pneumonia (HAP), or ventilator associated pneumonia (VAP), optionally due to Staphylococcus aureus, Strepto- coccus pneumoniae, Haemophilus influenza, Haemophilus parainfluenza, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae or fungi, such as aspergillus or Candida.

The macrolides are lipophilic in nature and have a low degree of ionisation. This allows extensive penetration into tissues and fluids and results in a large volume of dis- tribution. Concentrations of macrolides and ketolides in respiratory tract tissues and fluids are, in most cases, higher than concurrent serum concentrations. This extensive distribution into respiratory tissues and fluids makes predictions of pharmacodynamic activity difficult as serum concentrations frequently used as predictors do not necessarily provide a good indication of macrolide activity. Azithromycin shows an excellent distribution into respiratory tissues, the concentration of azithromycin in lung tissue after single oral dose administration exceeds plasma concentration by about 10 to 20- fold, in bronchial mucosa by 29-fold, in alveolar macrophages by 170-fold, after multiple oral doses of azithromycin in sputum by 67-fold. It has been suggested that antibiotics that concentrate in polymorphonuclear neutrophils (eg, azithromycin, ciprofloxacin, levofloxacin, moxifloxacin) may be beneficial in the treatment of infections by bacteria that survive phagocytosis. Intracellular concentrations are important for defense against respiratory pathogens including L. pneumophila, C. pneumoniae, M. pneumoniae and U. urealyticum. The majority of the macrolides concentrate in the lysosomes. This is thought to occur as a result of trapping caused by the lower pH (4 to 5) found in the lysosomes compared with the cytoplasm (pH 7). The dibasic macrolides (e.g. azithromycin) display the highest concentrations in the lysosomes as the presence of two basic amine groups leads to greater ionisation and a subsequent increased ion trapping. These agents also display a much slower efflux from phagocytes.

The macrolides are able to exert their effects as lysosome fusion with the phagosomes is an essential event in the phagocytic killing process and, thus, high con- centrations of the agents are deposited in the compartment where the pathogens reside. The polymorphonuclear leukocytes are believed to act as carriers in the transport of azithromycin to the site of infection through chemotaxis. The release of this agent from polymorphonuclear leukocytes is enhanced by exposure to pathogens. Thus, neutrophils are vital in the delivery of azithromycin to sites of infection and play a dual role in the antibiotic infection cycle: neutrophils loaded with azithromycin target the site of infection and release the antibiotic into the interstitial space. The antibiotic then enhances the natural host defense mechanism by rendering the bacteria more susceptible to killing by the neutrophils.

Especially azithromycin is characterized by a remarkably long elimination half- life of about 60 h (up to 72 h). This feature makes the drug attractive for use in adults and children, since the regimen allows an once daily dosage. Compared to antibiotics with a distinct shorter half-life such as other macrolides, ketolides or most of antibiotics of different classes this property generally provides the possibility of considerably lower frequencies of drug application.

Azithromycin and clarithromycin serum concentrations do not reach the MIC for some pathogens (e.g. H. influenzae), however, they effectively inhibit their growth. This may be because of the high concentrations of these agents, which are achieved in tissues and fluids and which exceed the MIC. This underlines the fact that because of their unique pharmacokinetics, serum concentrations are not a good predictor of macrolide activity.

The macrolides exhibit antibacterial activity which persists after exposure. The post-antibiotic effect (PAE) of an agent is used to describe this type of persistent antibacterial activity and becomes important when the concentration of drug declines below the MIC. The existence of a long PAE of azithromycin against other gram-positive and gram-negative bacteria extends the pharmacokinetic advantages of the drug and strongly supports the application of this azalide in the therapy of respiratory infections. Azithromycin, ketolides, such as telithromycin (HMR 3647), streptogramins and fluoroquinolones exhibit concentration-dependent killing and have prolonged persistent effects, which correlates most closely with clinical efficacy. For these agents the aim is to maximize drug concentrations to which the target pathogen is exposed and this may require higher doses and hence enable longer dosing intervals to be used.

Macrolides generally have a low adverse effect profile and are considered to be one of the safest classes of antibacterials currently available. Adverse effects including GI disorders, allergic reactions, hepatotoxicity, ototoxicity and local irritation have been reported. Nausea and diarrhea were more common in those receiving chronic systemic azithromycin therapy. Macrolide-associated GI intolerance is the most common adverse effect and is dose related. GI intolerance has been reported to occur in 20 to 50% of patients receiving erythromycin but occurs less frequently with the newer macrolides (e.g. azithromycin, clarithromycin, roxithromycin). The effects of macrolides on the immune response have been described as being immunomodulatory, defined as sup- pressing hyperimmunity and inflammation without overt immunosuppression. These effects are thought to be independent of their antimicrobial action. Macrolides have been shown to decrease mucous hypersecretion by a number of mechanisms, including blocking mucin production and inhibiting water and chloride efflux. Macrolides have been shown to reduce biofilm formation by P. aeruginosa and have additional direct effects on P. aeruginosa, including inhibition of motility, cellular adherence and of the major stress protein Gro-EL. Macrolides can initially enhance host defence by increasing nitric oxide production and mediators such as IL-I and IL-2, IL-6 and granulocyte- macrophage colony-stimulating factor (GM-CSF). Long-term macrolide therapy then suppresses inflammatory mediators, including IL-8, eotaxin, tumour necrosis factor (TNF)-α and GM-CSF. They suppress T helper-2 cell (Th2) cytokines but not ThI cell cytokines, and decrease nuclear factor (NF)κβ. Macrolides reduce inflammatory cell infiltrate by decreasing adhesion molecule expression and enhancing apoptosis. A growing interest exists in exploiting their antiinflammatory and immunomodulatory properties for certain chronic inflammatory respiratory diseases such as diffuse panbronchioli- tis (DPB), asthma, cystic fibrosis (CF), chronic bronchitis, and chronic rhinosinusitis. An extensive body of in vitro and ex vivo evidence dating back over 40 years supports the anti-inflammatory properties of the macrolides. Furthermore, azitromycin is believed to be one of the most potent agents currently available for the treatment of nontuberculous mycobacterial disease. When administered as prophylaxis once weekly to patients with advanced human immunodeficiency virus (HFV) disease, it significantly reduced the incidence of disseminated Mycobacterium avium complex (MAC) infection in these patients, who are at very high risk to develop this infection. Azithromycin, both administered once or thrice weekly, has been useful as the cornerstone of therapy for pulmonary MAC infection. It has significant in vivo activity against many other nontuberculous mycobacteria as well.

Azithromycin may also be of use in Pneumocystis jirvovecii (formerly Pneumo- cystis carinii) pneumonia (PCP) prophylaxis in patients with advanced HIV disease.

The antimicrobial effect of azithromycin and clarithromycin in the treatment of upper and lower respiratory tract infections can be enhanced in an additve or synergistic way by the addition of another anti-infective from the group of aminoglycosides, auch as tobramycin or amicacin, fluoroquinolones, such as levofloxacin, ciprofloxacin or gemifloxacin, peptide antibiotics, such as colistin, monobactams, such as aztreonam, penems, such as meropenem or antifungals, such as voriconazol, itraconazol or keto- conazol.

The immunmodulatory effect of azithromycin in the treatment of bronchiolitis obliterans and organ rejection after lung, bone marrow or stem cell transplantation can be enhanced in an additive or synergistic way by the preparation of a combination product comprising additionally of cyclosporin A or tacrolimus or sirolimus or everolimus or mycophenolat mofetil or rapamycin.

The anti-inflammatory effect of azithromycin in the treatment of upper and lower respiratory tract diseases can be enhanced in an additve or synergistic way by the addi- tion of other anti-inflammatory drugs from the group of steroids, such as budesonide, fluticasone, mometasone, ciclesonide or dehydroepiandrosteron-deriatives, such as DHEAS and non steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or indomethacin. In each case of the aforementioned combination products, the active drug compound will be selected as a pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative thereof.

In another embodiment, the active compound is a bronchodilator or a pharmaceu- tically acceptable salt, solvate, isomer, conjugate, prodrug or derivative thereof. Bron- chodilators are important drugs in the management of obstructive pulmonary disease and asthma. Sub-categories of bronchodilators are methylxanthines, betamimetics, and anticholinergics. In one of the preferred embodiments, the bronchodilator is selected from the class of methylxanthines, in particular theophylline for the treatment of asthma, chronic obtructive pulmonary disease or other pulmonary diseases associated with short breath or bronchoconstriction, such as fϊbrotic disorders, lung inflammation and/or infections and pulmonary hypertension.

Theophylline is frequently used in the therapy of chronic obstructive pulmonary disease (COPD) and bronchial asthma, but so far only as oral or parenteral medication. It is believed that it acts via a non-specific inhibition of phosphodiesterase enzymes, producing an increase in intracellular cyclic AMP. Moreover, theophylline inhibits TGF-beta mediated conversion of pulmonary fibroblasts into myofibroblasts via the cAMP-PKA pathway and suppresses COLl mRNA which codes for the biosynthesis of collagen fibers.

In another embodiment, the active compound is a phosphodiesterase inhibitor, such as sildenafil, vardenafil, or tadalafil, as a pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative thereof. These drugs are used in the management of erectile dysfunction in doses from 25 - 100 mg, but may be also be useful for the treatment of pulmonary hypertension. Sildenfil is a phosphosdiesterase type-5 in- hibitor given by mouth with a bioavailability of about 40%. The terminal half-lives of sildenafil and the N-desmethyl-sildenafil metabolite is about 4 hours. Since clearance in elderly and in patients with severe renal or hepatic impairment is reduced and variable, drug targeting by inhalation would offer advantages in the treatment of pulmonary hypertension.

In another embodiment, the active compound is a non steroidal anti-inflammatory drug (NSAID), such as ibuprofen, indomethacin, as a pharmaceutically water soluble acceptable salt, solvate, isomer, conjugate, prodrug or derivative thereof. These drugs are used in the management of pain in oral single doses up 800 mg, but may also be useful for the treatment of cystic fibrosis associated with pseudomonas infection, ductus arteriosus associated with respiratory distress syndrome and intraventricular haemor- rhage in infants and other respiratory inflammatory diseases. Since oral absorption in infants is poor and clearance in elderly and in patients with severe renal or hepatic impairment is reduced and variable, drug targeting by inhalation would offer advantages.

It appears desirable to make theophylline, or phosphdiesterase inhibitors, NSAID and other bronchodilators available for inhalation therapy. One of the problems which have made this unfeasible so far is the poor taste and to some extent an insufficient chemical stability of the compound in an aqueous system, which is overcome by the teachings of the present invention.

In another embodiment, the active compound is poorly stable in an aqueous solution at 25 °C. As used herein, poorly stable in an aqueous solution means that the con- tent of the drug compound decreases over a duration of 1 year by at least about 5 %, or even by at least about 10 %, when dissolved in an aqueous medium at 25 °C and at the same pH as the composition, but in the absence of any of the taste masking agents.

Optionally, the aerosol comprises two or more active compounds in combination, of which at least one exhibits the aqueous solubility and the poor taste as defined herein.

According to another feature of the invention, the dispersed phase of the aerosol exhibits a mass median diameter from about 1 to about 6 μm and more preferably from 2 - 4.5 μm. These values should be understood as mass median diameter values as determined by laser diffraction. Various appropriate analytical apparatuses to determine the mass median diameter are known and commercially available, such as the Malvern MasterSizer X or Malvern Spray Tec. The geometric distribution of the aerosolised liquid particles or droplets may be determined simultaneously with the mass median diameter. In some embodiments, also the geometrical standard deviation (GSD) which characterises the broadness of the size distribution of the aerosol particles is of significance. The selection of the precise mass median diameter (MMD) within this range should take into account the target region or tissue of the aerosol. For example, there are differences between the optimal droplet diameters depending on whether oral or nasal inhalation is intended, and whether bronchial, pulmonary, nasal, and/or paranasal sinus delivery is focussed upon. More importantly, the age group of patients is setting the requirement which particle size is most appropriate for drug delivery to the lungs. It is evident, that for the inhalation treatment of infants much smaller mean droplet sizes will be required (< 2.5 μm) than for adults (< 5 μm).

If the aerosol is for use in the prevention or treatment of a disease or condition of the upper airways, in particular the sinunasal mucosa, a MMD in the region of 2 to 4 μm is particularly suitable for sinus delivery. Furthermore, it is suggested that the MMD which will lead to the relatively largest aerosol deposition may also depend on individual factors, in particular on the geometry of the paranasal sinuses including the ostia through which the aerosol reaches the sinuses. For example, the volume of the sinuses and the diameter of the ostia differ substantially between individuals. A larger diameter of the ostia is believed to favour the entrance of larger aerosol droplets into the sinuses, even though the diameters of the ostia and of the droplets are of completely different magnitudes. If the individual sinunasal anatomy, or a parameter derived therefrom, of a person to be treated with an aerosol is at least partially known, it may even be possible to select a particular MMD for optimised sinunasal or sinus delivery. In some embodiments, the aerosol of the invention may have a mass median diameter of about 2.5 to 4.5 μm, in others from about 3 to about 4 μm, or from about 2 to about 3.5 μm, respectively. In further embodiments, the MMD is approximately (± 0.25 μm) 2.0, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm or 4.5 μm.

If the purpose is sinunasal delivery, the geometric standard deviation of the MMD of the aerosol should preferably be larger than about 2, such as about 2.3 or more. In other preferred embodiments, the geometric standard deviation is at least about 2.4, and at least about 2.5, and at least about 2.6, respectively. Other preferred geometric standard deviations range of about 2.4 to 2.7, and from about 2.5 to about 2.7, respectively.

On the other hand, if the aerosol is for pulmonary delivery, it may exhibit a MMD in the range from about 2.0 to about 4.5 μm and a GSD in the range from about 1.2 to about 1.8. More preferably, the aerosol of the invention, if adapted for pulmonary delivery, has a MMD in the range from about 2 to about 4.5 and a GSD in the range from about 1.4 to about 1.6. It has been found that each of these sets of combinations is particularly useful to achieve a high local drug concentration in the lungs, including the bronchi and bronchioli, relative to the amount of drug which is aerosolised. It must be considered in this context, that deep lung deposition requires smaller MMDs than deposition into the central airways and the younger the child the smaller the droplet size necessary.

It is a further essential feature of the present invention that the droplets of the aero- sol, i.e. the dispersed liquid phase, comprise at least one taste-masking excipient. As used herein, a taste-masking excipient is any pharmaceutically acceptable compound or mixture of compounds which is capable of improving the taste of an aqueous solution of a poor tasting active ingredient, regardless of the mechanism by which the improvement is brought about. For example, the taste-masking agent may cover the poor taste of the active compound, i.e. reduce the intensity in which it is perceived; or it may correct the taste by adding another - typically more pleasant - flavour to the composition so that the total organoleptic impression is improved.

In one of the embodiments, the taste-masking agent is a complexing agent selected from pharmaceutically acceptable cyclodextrins, in particular α-, β-, and γ- cyclodextrins or derivatives thereof.

Cyclodextrins (CDs) are cyclic oligosaccharides composed of (α-l,4)-linked α-D- glucopyranose units. They comprise a relatively hydrophobic central cavity and a hy- drophilic external region. Because the monomelic units cannot rotate freely at the cc- 1 ,4-linkages, the shape of the molecules is more conical than cylindrical, with the pri- mary hydroxyl groups located at the smaller part and the secondary hydroxyl groups at the larger part of the conus.

The most common cyclodextrins are α-, β-, and γ-cyclodextrins with 6, 7, and 8 glucopyranose units, respectively. The diameters of the cavities are approximately 4.7 to 5.3 A for α-cyclodextrins, 6.0 to 6.5 for β-cyclodextrins, and 7.5 to 8.3 for γ- cyclodextrins. The non-derivatised cyclodextrins exhibit aqueous solubilities of about 145 mg/ml (α-cyclodextrin), 18.5 mg/ml (β-cyclodextrin), and 232 mg/ml (γ- cyclodextrin) at 25 °C.

Cyclodextrins are known for their capability of forming inclusion complexes with smaller molecules. If the host molecules themselves are poorly water-soluble, they may become solubilised in the form of such cyclodextrin inclusion complexes. Several pharmaceutical agents have been successfully formulated into marketed drug products which incorporate cyclodextrins as solubility-enhancing agents.

Examples of potentially useful cyclodextrins include the non-derivatised cyclodextrins, but also derivatives whose hydroxyl groups are alkylated or hydroxyalkylated, esterified, or etherified, such as 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ- cyclodextrin, sulfobutyl-β-cyclodextrin, sulfobutyl-γ-cyclodextrin, maltosyl-β- cyclodextrin, and methyl-β-cyclodextrin. Particularly preferred at present are 2- hydroxypropyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin, α-cyclodextrin, β- cyclodextrin, and γ-cyclodextrin being essentially free from endotoxin contamination.

While cyclodextrins are usually considered as solubilising excipients for poorly soluble active agents, the inventors have found that they are surprisingly effective taste masking agents for poorly tasting active agents in aqueous solutions for inhalation, even though the active compounds are water soluble. Particularly effective is the use of one or two types of cyclodextrins in combination with a further taste-masking excipient which is not a member of the class of cyclodextrins.

In one of the further embodiments, the cyclodextrin is selected from the group consisting of 2-hydroxypropyl-β-cyclodextrin, γ-cyclodextrin, and α-cyclodextrin. According to further embodiments, the dispersed phase of the aerosol comprises the active compound azithromycin and, as a taste-masking excipient, 2-hydroxypropyl-β- cyclodextrin at a concentration in the range from about 1 to about 15 wt.-%, or from about 5 to about 10 wt.-%, respectively; or it comprises azithromycin and, as a taste- masking excipient, γ-cyclodextrin at a concentration in the range from about 1 to about 10 wt.-%, or from about 2.5 to about 7.5 wt.-%. If azithromycin is the active agent, its concentration in the dispersed phase of the aerosol is preferably in the range from about 0.5 to about 10 wt.-%, or from about 1 to about 5 wt.-%, such as about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 wt.-%, respectively.

In a further embodiment, the taste-masking excipient is selected from the group of pharmaceutically acceptable sweeteners. Among the preferred sweeteners according to the invention are saccharin, aspartame, cyclamate, sucralose, acesulfame, neotame, thaumatin, and neohesperidine, including the salts and solvates thereof, e.g. the dihy- drochalcone of neohesperidine, the sodium salt of saccharin, and the potassium salt of acesulfame. Again, the respective salts and solvates of the compounds mentioned herein are always included, whether specifically mentioned or not.

Particularly preferred sweeteners are aspartame at a concentration from about 0.1 to about 3 wt.-%, in particular from about 0.5 to about 2 wt.-%, and saccharin sodium at a concentration from about 0.1 to about 2 wt.-%, in particular from about 0.25 to about 1 wt.-%. Alternatively, sugars such as, sucrose, trehalose, fructose, lactose or sugar al- cohols, such as xylitol, mannitol, isomalt can be used in concentrations up to about 5% w/w.

According to another embodiment, the dispersed phase of the aerosol comprises both, a cyclodextrin and a sweetener as taste-masking agents, such as γ-cyclodextrin in combination with saccharin sodium, or 2-hydroxypropyl-β-cyclodextrin in combination with aspartame or xylitol. The latter is particularly preferred, since the antimicrobial efficiency of macrolides, such as azithromycin may be enhanced.

Further useful taste-masking agents include pharmaceutically acceptable surfactants, alkali or alkaline earth metal salts, and organic or amino acids, such as arginine, in particular water-soluble organic acids having a low molecular weight, such as citric acid and lactic acid. Optionally, one of these compounds may be used in combination with a cyclodextrin and/or with a sweetener. For example, citric acid may be used in combination with γ-cyclodextrin and saccharin sodium and/or xylitol.

Alternatively, organic solvents, such as ethanol, dexpanthenol and/or of aromatic natures, such as the ingredients of essential oils (menthol, thymol) may be added to im- prove both the taste and tolerability of these formulations. In addition to the above mentioned taste masking agents and concepts, it was found that the addition of polymers, such as dextranes, hydroxypropylmethylcellulose (HPMC), chitosan, modified starches, etc. may be useful to improve the tolerability of the formulation including taste and the adherence of the drug product to the surface cell 5 layer, e.g. mucosa. Chitosan is preferred since the antimicrobial efficiency of mac- rolides, such as azithromycin or clarithromycin alone or in combination may be enhanced.

In another embodiment, macrolides, e.g. azithromycin, clarithromycin or a combination thereof, are formulated with metal ions, e.g. divalent cations and combinations0 thereof. Especially, water soluble magnesium and calcium salts can be employed for this purpose and surprisingly it was found, that water soluble magnesium salts will improve substantially the taste of dissolved azithromycin formulations for inhalation when aerosolized for instance with an eFlow™ electronic nebulizer. Surprisingly it was found, that the solubility and stability upon storage of aqueous azithromycin solutions 5 comprising water soluble magnesium or calcium salts are improved compared to formulations without magnesium and calcium salts. The molar ratio of the divalent cations, e.g. magnesium or calcium cations, to the macrolide, e.g. azithromycin or clarithromycin, is generally in the range of from about 0.1 : 1 to about 10 : 1, for example 0.1 : 1, 0.5 : 1, 1 : 1, 1.5 : 1, 2 : 1, 5 : 1 or 10 : 1. Preferably, an at least equimolar amount ofυ divalent cations (relative to the amount of macrolide) is used (i.e., the molar ratio of divalent cations to macrolide is at least 1). hi many cases an at least equimolar amount of divalent cations (relative to the amount of macrolide) is most advantageous to achieve the desired effect of taste masking.

It is not fully clear why exactly the combination of two or more taste-masking ex-5 cipients from different chemical classes is so effective in improving both the organoleptic and in case of azithromycin the antimicrobial properties of an aerosol; however, the inventors have found a surprising degree of synergy between these excipients.

The aerosol of the invention may be generated with any conventional nebuliser.

As used herein, nebulisers are devices capable of aerosolising liquids. Preferably, the0 nebuliser is selected from jet, ultrasonic, piezoelectric, jet collision, electrohydrody- namic, capillary force, perforated membrane, or perforated vibrating membrane nebulis- ers as described in more detail by Knoch and Keller (Expert Opin. Drug Deliv., 2005, 2 (2), 377-390). If the intended use is the delivery of the active agent to an affected (or potentially affected) site of the lower airways such as the bronchi or the deep lungs, it is particularly preferred that a piezoelectric, electro-hydrodynamic, and/or perforated membrane-type nebuliser is selected for generating the aerosol of the invention. Examples of suitable nebulisers include the Mystic™, I-Neb™, MicroAir™, Multisonic™, Respimate™, eFlow™, AeroNeb™, AeroNeb Pro™, and Aero Dose™ device families.

According to a further preference, the nebuliser is adapted to deliver the major fraction of the loaded dose of liquid composition as aerosol, such as at least about 40 wt.-% of the loaded liquid composition. More preferably, at least 60 wt.-% of the liquid composition filled into the nebuliser are actually emitted from the device, which is best achieved by using a modern, optionally customised electronic nebuliser based on the vibrating perforated membrane design. According to another embodiment, at least about 40 wt. -% of the composition charged into the medication reservoir is aerosolised, or even at least about 50 wt.-% or up to 95 wt.-%, when breath actuated or controlled breathing modes are applied.

On the other hand, if the aerosol is to be delivered to the nasal or sinunasal cavities or regions, it is preferred that the nebuliser is capable of emitting a pulsating (or vibrating) aerosol. Such modified jet or electronic nebulisers can reach sinunasal or paranasal cavities much better than applying an aerosol in a continuous mode. These nebulisers have a nose piece for directing the aerosol flow into the nose. If only one nostril is used for inhalation of the aerosol, the other nostril must be closed by a suitable restrictor. Furthermore, these nebulisers are characterized in that they release an aerosol with pulsating pressure. The pulsating pressure waves achieve a more intensive ventila- tion of the sinuses so that a concomitantly inhaled aerosol can spread better into these cavities. Examples for such nebulisation devices are disclosed in DE 102 39 321 B3.

For sinunasal delivery, the nebuliser or aerosol generator is preferably selected or adapted to produce and emit a pulsating aerosol and to maintain an amplitude of pressure pulsation of the emitted aerosol of at least about 5 mbar. It has been found that, depending on the individual sinunasal anatomy of a human person, the pressure amplitude of a pulsating aerosol may be attenuated substantially, such as by large sinus vol- umes. According to this preferred embodiment, however, the aerosol generator is adapted or selected to maintain a pressure amplitude of at least 5 mbar, measured at aerosol flow in the nasal cavity, irrespective of the individual anatomy of the patient.

As the delivery of aerosol to the sinuses is driven by the pressure gradient between the nasal cavity and the sinuses created by the pressure pulses of the vibrating aerosol, the aerosol fraction deposited in the sinuses may be improved if the amplitude of the pulsation is also further increased. Thus, further embodiments of the invention are characterised in that the aerosol generator is adapted to maintain a pressure pulsation amplitude of at least about 10 mbar, or at least about 15 mbar, or at least about 20 mbar, or at least about 25 mbar. Further examples of useful amplitudes maintained by the device are from about 20 to about 50 mbar, or from about 30 to about 50 mbar, such as about 40 mbar. Even higher amplitudes than 50 mbar might be useful for certain patients and indications in which some degree of discomfort to the patients may be found acceptable, such as serious diseases and affections of the sinus mucosae.

As used herein, an aerosol generator is a device or a combination of devices capable of generating and emitting an aerosol. According to the present invention, the device is capable of aerosolising a liquid material into a dispersed liquid phase. Typically, such device is referred to as a nebuliser. Depending on the type and model of the device, the aerosol generator of the invention may require or include a compressor. In other words, the term aerosol generator is used for the complete apparatus or assembly required to produce and emit an aerosol and to administer the aerosol to an animal, such as to a human patient. A particularly preferred aerosol generator is the PARI SINUS combination of the PARI SINUS™ compressor and a jet nebuliser or a modified eFlow™ electronic nebuliser making use of a perforated vibrating membrane to generate an aerosol.

One of the preferred features of an aerosol which is intended for sinus or sinunasal delivery is that it pulsates, or vibrates, with a selected frequency. As used herein, the pulsation of an aerosol is understood as a periodic change of pressure. Preferably, the pulsation is regular, i.e. the time interval between pressure peaks is approximately constant. The amplitude of pressure pulsation may also be relatively constant, at least with regard to the generation and emission of the pulsating aerosol from the aerosol generator. According to the one embodiment of the invention, the pressure of the aerosol pulsates with a frequency in the range from about 10 Hz to about 90 Hz. According to some further embodiments, the pressure may also pulsate at a frequency in the range from about 10 to about 60 Hz, or from 10 to about 55 Hz, or from about 30 to about 60 Hz. In a further embodiment, the aerosol vibrates at a frequency of about 30 to about 55 Hz, such as from about 40 to about 50 Hz, for example about 44 Hz.

It has been found that a vibrating aerosol enters the paranasal sinuses after nasal inhalation to a much larger extent than a conventional aerosol having a substantially constant pressure, provided that the appropriate particles sizes are selected as outlined above. Larger particle sizes will lead to little sinus deposition, but to a large deposition on the nasal mucosa, whereas very small particle sizes allow the aerosol droplets to enter the sinuses following the pressure gradient of a pressure pulse, but also their exit from the sinuses without them being deposited therein.

Whether adapted for pulmonary or sinunasal delivery, the nebuliser should pref- erably be selected or adapted to be capable of aerosolising a unit dose, i.e. a volume of the liquid composition comprising the effective amount of active compound which is designated to be admim^'stered during a single administration, at a rate of at least about 0.1 ml/min or, assuming that the relative density of the composition will normally be around 1, at a rate of at least about 100 mg/min. More preferably, the nebuliser is capa- ble of an output rate of at least about 0.15 ml/min or 150 mg/min, respectively. In further embodiments, the output rates of the nebuliser are at least about 0.2, 0.3, 0.4, 0.5, 0.6 or 0.7 ml/min, respectively.

Furthermore, the output rate of the nebuliser should be selected to achieve a short nebulisation time of the liquid composition. Obviously, the nebulisation time will de- pend on the volume of the composition which is to be aerosolised and on the output rate. Preferably, the nebuliser should be selected or adapted to be capable of aerosolising a volume of the liquid composition comprising an effective dose of the active compound within not more than about 20 minutes. More preferably, the nebulisation time for a unit dose is not more than about 10 minutes. In further embodiment, the nebuliser is selected or adapted to enable a nebulisation time per dose unit of not more than about 6 minutes, or not more than about 3 minutes. Presently most preferred is a nebulisation time in the range from about 1 to about 5 minutes.

According to a further aspect, the invention provides a liquid pharmaceutical composition for preparing an aerosol as defined herein. The liquid composition comprises an effective dose of the active compound dissolved in a volume of not more than about 10 ml, and preferably not more than about 5 ml and most preferably between 0.25 and 2.5 ml.

As will be understood by a person skilled in the art, some of the features and preferences with respect to the dispersed phase, as disclosed herein-above, may also be ap- plied to the liquid composition which is used to generate the aerosol. In particular, the liquid composition comprises - like the dispersed phase of the aerosol - an active compound having a poor taste and an aqueous solubility of at least about 5 mg/ml, preferably at least about 10 mg/ml. Similarly, it is an essential feature of the liquid composition that it comprises at least one taste-masking excipient as defined above.

In a further embodiment, the liquid composition exhibits a dynamic viscosity in the range from about 0.8 to about 3 mPa s. The dynamic viscosity of the liquid composition has an influence on the particle size distribution of the aerosol formed by nebulisation and on the efficiency of nebulisation. According to another preferred embodiment, the dynamic viscosity is selected in the range of about 1.0 to about 2.5 mPa-s.

To obtain an aerosol which is highly suitable for the preferred uses described herein, the surface tension of the liquid composition should preferably be adjusted to the range of about 25 to 80 mN/m, and more preferably to the range of about 30 to 75 mN/m. In this context, it is to be taken into consideration that, in the lowest part of this range, a particularly good adhesion and spreadability of the preparation on the mucous membranes may be expected, but that the quality of the aerosol and the efficiency of the nebulisation could be adversely affected.

On the other hand, if the incorporation of a surfactant appears necessary, e.g. for taste-masking reasons, it can hardly be avoided that the surface tension is reduced fairly markedly below that of water or physiological buffer solution. Thus, a compromise may have to be found in each case depending on the active compound and the intended application.

In order to be well-tolerated, an aerosol should, as far as possible, have a physiologic tonicity or osmolality. Thus, it may be desirable to incorporate an osmotically ac- tive excipient to control the osmolality of the aerosol. The content of this excipient (or excipients, if a combination of substances is used) should be selected to yield an osmolality of the aerosol which does not deviate too much from that of physiological fluids, i.e., from about 290 mOsmol/kg. However, in individual cases, a compromise has again to be found between the physical-chemical or pharmaceutical needs on one hand and the physiological requirements on the other hand. Hence, osmolality values of the inventive formulations may range from about 150 to about 1200 mOsmol/kg, preferably from abaout 150 to abaout 800 mOsmol/kg.

Surprisingly it was found that the addition of magnesium salts as complexing and taste masking agent improves the tolerability of azithromycin formulations upon inhala- tion via an eFlow™ nebuliser even when these formulations have an osmoloality of up to 1200 mOsmol/kg. The better tolerability may be attributable to a bronchodilatatory effect of magnesium ions as described by Hughes et al. (The Lancet, 2003, 361, 2114- 17). Alternatively, since acidification was usually achieved by the addition of 1 N hydrochloric acid the permanent chloride ion concentration did exceed 31 mmolar as claimed helpful by Weber et al. (Ped. Pulmonology 23: 249-260, 1997).

It is further believed that for sinunasal delivery, an optimised aerosol osmolality may not be as critical as, for example, in the case of deep lung delivery of aerosols. Thus, the intended use of the aerosol should be taken into account when selecting the osmolality of the liquid composition. In general, an osmolality in the range of up to 800 mOsmol/kg may be acceptable. In particular, an osmolality in the range of about 200 up to about 600 mOsmol/kg is preferred. In further embodiments, the osmolality is even closer to the physiological value, i.e. from about 220 to about 450 mOsmol/kg.

Optionally, the liquid composition may comprise further pharmaceutically acceptable excipients, such as osmotic agents, in particular inorganic salts; excipients for ad- justing or buffering the pH, such as organic or inorganic salts, acids, and bases; bulking agents and lyophilisation aids, such as sucrose, lactose, trehalose, mannitol, sorbitol, xylitol, and other sugar alcohols; stabilisers and antioxidants, such as vitamin E or vitamin E derivatives, such as Vitamin E-TPGS, Lycopene and its derivatives, ascorbic acid, sulphites, hydrogen sulphites, gallic acid esters, butyl hydroxyanisole, and butyl hydroxytoluene.

In one of the preferred embodiments, one or more osmotic agents such as sodium chloride are incorporated in the composition to adjust the osmolality to a value in the preferred range as outlined herein-above.

According to another preference, the composition comprises at least one excipient to adjust the pH. In order to provide a well tolerated aerosol, the preparation according to the invention should be adjusted to a euhydric pH value. The term "euhydric" already implies that there may be a difference between pharmaceutical and physiological requirements so that a compromise has to be found which, for example, guarantees that the preparation is, from an economical point of view, just sufficiently stable during storage but, on the other hand, largely well tolerated. Preferably, the pH value lies in the slightly acidic to neutral region, i.e., between pH values of about 4 to 8. It is to be noted that deviations towards a weakly acidic environment can be tolerated better than shifts of the pH value into the alkaline region. A pH value in the range of about 4.5 to about 7.5 is particularly preferred.

For adjusting and, optionally, buffering the pH value, physiologically acceptable acids, bases, salts, and combinations of these may be used. Suitable excipients for lowering the pH value or as acidic components of a buffer system are strong mineral acids, in particular, sulphuric acid and hydrochloric acid. Moreover, inorganic and organic acids of medium strength as well as acidic salts may be used, for example, phosphoric acid, citric acid, tartaric acid, succinic acid, fumaric acid, methionine, acidic hydrogen phosphates with sodium or potassium, lactic acid, glucuronic acid etc. However, sulphuric acid and hydrochloric acid are most preferred. Suitable for raising the pH value or as basic component for buffer system are, in particular, mineral bases such as sodium hydroxide or other alkali and alkaline earth hydroxides and oxides such as, in particular, magnesium hydroxide and calcium hydroxide, ammonium hydroxide and basic ammo- nium salts such as ammonium acetate, as well as basic amino acids such as lysine, car- bonates such as sodium or magnesium carbonate, sodium hydrogen carbonate, citrates such as sodium citrate etc.

In one of the embodiments, the liquid composition of the invention contains a buffer system consisting of two components, and one of the particularly preferred buffer systems contains citric acid and sodium citrate. Nevertheless, other buffering systems may also be suitable.

Not primarily for physiological, but for pharmaceutical reasons the chemical stabilisation of the composition by further additives may be indicated. This depends mainly on the kind of the active agent contained therein. The most common degradation reac- tions of chemically defined active agents in aqueous preparations comprise, in particular, hydrolysis reactions, which may be limited, primarily, by optimal pH adjustment, as well as oxidation reactions. Examples for active agents which may be subject to oxidative attack are those agents that have olefinic, aldehyde, primary or secondary hydroxyl, ether, thioether, endiol, keto or amino groups. Therefore, in the case of such oxidation- sensitive active agents, the addition of an antioxidant, optionally in combination with a synergist, may be advisable or necessary.

Antioxidants are natural or synthetic substances which prevent or interrupt the oxidation of the active agents. These are primarily adjuvants which are oxidisable themselves or act as reducing agents, such as, for example, tocopherol acetate, retinolderiva- tives, such as vitamin A, lycopene, reduced glutathione, catalase, peroxide dismutase, selenoic acid. Synergistic substances are, for example, those which do not directly act as reactance in oxidation processes, but which counteract in oxidation by an indirect mechanism such as the complexation of metal ions which act catalytically in the oxidation, which is the case, for example, for EDTA derivatives (EDTA: ethyl enediamine tetraacetic acid). Further suitable antioxidants are ascorbic acid, sodium ascorbate and other salts and esters of ascorbic acid (for example, ascorbyl palmitate), fumaric acid and its salts, malic acid and its salts, selenoic acid and its salts, butyl hydroxy anisole, propyl gallate, as well as sulphites such as sodium metabisulfite. Apart from EDTA and its salts, citric acid and citrates, malic acid and its salts and maltol (3 -hydroxy-2 -methyl - 4H-pyran-4-one) may also act as chelating agents. In another embodiment, the aerosol of the invention comprises an active ingredient which is not sufficiently stable in aqueous solution to provide for a commercially acceptable shelf life. In such as case, it may be possible to extend the shelf life by making provision that the aqueous liquid composition is stored under refrigeration. Alterna- tively, a suitable market formulation may be designed as a solid composition which is reconstituted prior to use. Typically, a solid composition of a chemically unstable active compound has the potential for a longer shelf life.

The dry solid composition preferably comprises the active compound and at least one excipient. In general, the same excipients may be selected as described above. It is preferred, however, that the taste-masking excipient or, in the case that the aerosol comprises more than one taste-masking excipients, that at least one of these taste- masking agents, is also incorporated in the solid composition. Alternatively, the taste- masking agent(s) may be incorporated in an aqueous solvent which is provided to reconstitute the solid composition.

Depending on the manufacturing method of the solid composition, one or more additional excipients may be useful. For example, if the composition is prepared by freeze drying (lyophilisation), which is one of the particularly preferred methods of preparing such solid composition according to the invention, it may be useful to incorporate at least one bulking agent and/or lyophilisation aid, such as a sugar or a sugar alco- hoi, in particular sucrose, fructose, glucose, mannitol, sorbitol, trehalose, isomalt, or xylitol.

The solid composition is further characterised in that the portion of it which comprises an effective amount of the active compound, or a unit dose, is dissolvable or dis- persible in an aqueous solvent having a volume of not more than about 10 ml. In an- other embodiment, it is dissolvable or dispersible in an aqueous liquid volume of not more than about 5 ml, or not more than about 4 or even 2 ml, respectively. In addition nebulisation or inhalation takes less than 15 min and more preferably less than 8 minutes.

As defined herein, "dissolvable" means that the solid composition and the aqueous liquid solvent can be combined to form a solution or colloidal solution, whereas the term "dispersible" should be interpreted to also include the formation of liquid dispersions such as micro-suspensions.

The solid composition for reconstitution may be part of a pharmaceutical kit. Such kit preferably comprises the solid composition in sterile form. As used herein, the term "sterility" is to be defined according to the usual pharmaceutical meaning. It is understood as the absence of germs which are capable of reproduction. Sterility is determined with suitable tests which are defined in the relevant pharmacopoeias. According to current scientific standards, a sterility assurance level of 10^~6 is generally regarded as acceptable for sterile preparations, i.e., one unit in a million might be contaminated.

In practice, however, contamination rates may be higher. For example, it is generally assumed that the contamination rate for aseptically manufactured preparations might amount to about 10^"3. Since, on one hand, the extent of sterility tests for quality control of lots according to the pharmacopeias is limited and, on the other hand, contaminations may be caused as artefacts while carrying out the test itself, it is difficult to demand sterility in an absolute sense or to test a particular product for it. Therefore, the sterility of the composition should be understood herein such that the composition meets the requirements with respect to sterility of the relevant pharmacopeia. The same applies to the liquid formulations which are ready to use.

As mentioned above, the solid composition may be prepared by providing a liquid composition which is similar to the liquid composition to be aerosolised, and subsequently drying it, such as by lyophilisation. Similar means that the liquid composition from which the solid composition is prepared by drying may not comprise all solid ingredients of the ready-to-use liquid composition, for example in the case that the liquid carrier for reconstitution is designed to comprise one or more of the excipients. Also, it is not necessary that the concentrations of the ingredients are identical for these two liquid compositions. Alternatively, the solid composition for reconstitution may be prepared by providing the active ingredient and, optionally, at least one excipient, in powder form and subsequently mixing these to form a powder mixture.

The invention further provides a method of preparing and delivering an aerosol comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase essentially consists of aqueous droplets comprising an active compound having a poor taste and an aqueous solubility of at least about 5 mg/ml, preferably at least about 10 mg/ml, at 25 °C and at a pH in the range from about 3 to 9. The method comprises the steps of (a) providing a liquid pharmaceutical composition comprising an effective dose of said active compound dissolved in a volume of not more than about 10 ml, and preferably not more than about 5 ml, and at least one taste-masking excipient; (b) providing a nebuliser capable of aerosolising said liquid pharmaceutical composition at a total output rate of at least 0.1 ml/min, the nebuliser further being adapted to emit an aerosol comprising a dispersed phase having a mass median diameter from about 1.5 to about 6 μm; and (c) operating said nebuliser to aerosolise the liquid composition.

It will be understood by a person skilled in the art that the same guidance and preferences as disclosed herein-above with respect to the selection of the active agent, excipients, concentrations, volumes, the physical properties of the liquid composition which is nebulised, the nebulisers etc. should also be applied to the method and its practice.

The method, as well as the aerosol itself and the liquid and solid composition from which the aerosol is prepared, are preferably used in the design and manufacture of a medicament. Depending on the nature of the selected active compound, the medicament may be useful for the prophylaxis or treatment of a variety of diseases and conditions of the lower and upper respiratory tract, such as nontubercuious mycobacterial pulmonary diseases, pneumocstis jirovecii, pulmonary nocardia infections, acute or chronic sinusitis or rhinosinusitis, bronchitis, pneumonia, chronic obstructive pulmonary disease, HIV, pulmonary hypertension, prophylaxis to prevent graft rejection after lung or stem or bone marrow cell transplantation, parenchymatic and/or fibrotic diseases or disorders including cystic fibrosis, sarcoidosis, Bronchitis Obliterans (BO) with or without acute exacerbations, optionally due to Streptococcus pneumoniae, Haemophilus influenza or Moraxella catarrhalis; acute bacterial exacerbations in chronic bronchitis or in chronic obstructive pulmonary disease, optionally due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, Haemophilus parainfluenza or Moraxella catarrhalis; nosocomial pneumonia, optionally due to Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Bukholderia cepacia, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenza or Streptococcus pneumoniae; or community acquired pneumonia (CAP), or hospital acquired pneumonia (HAP), or ventilator associ- ated pneumonia (VAP), optionally due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, Haemophilus parainfluenza, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae or fungal infections of the respiratory tract or bone marrow due to Aspergillosis, Candida, etc. The different sensitivity of microorganisms against anti- infective drugs supports the use of combinations having different specificity and sensitivity and belonging to a different mode of action as known for the different classes of antibiotics.

Preferably, the composition is administered using a regimen of repeated admini- stration over a course of at least about five days. Optionally, the duration of the regimen is at least about one week, or about 10 days or about 2 weeks. In further embodiments, the duration is in the range of months or years. Furthermore, the regimen preferably comprises once, twice or thrice daily inhalation; most preferred is once or twice daily administration over the course of therapy. Other preferred regimen are once or twice a week.

The following examples serve to illustrate the invention; however, these are not to be understood as restricting the scope of the invention.

EXAMPLES

Example 1 :

The following procedures were conducted under aseptic conditions using sterile raw materials. Azithromycin dihydrate (1.5 g) was dissolved in water for injection. Hydrochloric acid (1 M) was added dropwise to obtain a clear solution of about pH 5.5. γ- cyclodextrin (5.0 g) was added, and the mixture was stirred for 5 min at 700 rpm, again yielding a clear solution. Water-free citric acid (0.5 g) and saccharin sodium (0.5 g) were added, and the mixture was stirred for 2 min at 700 rpm. Subsequently, the solution was neutralised to a pH of about 7 by adding sodium hydroxide solution (1 M) in a dropwise manner. The total weight of the resulting solution was approximately 100 g. the solution was sterile filtered under laminar air flow (LAF) using a 0.22 μm sterile filter. The sterile filtered clear solution was filled in Type I glass vials (USP) and stored under 5⁰C ± 3 conditions as a sterile solution, ready-to-use. The solution exhibited a dynamic viscosity of 1.22 mPa s, an osmolality of 396 mθsmol/kg, and a surface tension of 63.1 mN/m. It was found to have a sweet taste, and the bitter taste of the active ingredient was masked to a substantial degree.

Without wishing to be bound by theory, it is believed that not only the cyclodex- trin contributes to the taste masking, but also the water-free citric acid.

Example 2:

The procedure of Example 1 was repeated except that azithromycin monohydrate ethanolate was used instead of azithromycin dihydrate. Again, a clear, sweet, and taste- masked solution was obtained. The solution was sterile filtered under LAF using a 0.22 μm sterile filter.

The following table presents the stability data for a period of 9 months for the formulation with azithromycin monohydrate. The formulation was chemically stable when stored under 5°C ± 3 conditions.

Example 3:

Under aseptic conditions, a sterile aqueous solution was prepared from azithromycin dihydrate (5.0 wt.-%), L-arginine (0.5 wt.-%), and γ-cyclodextrin (5.0 wt.-%). Small amounts of hydrochloric acid (1 M) and sodium hydroxide solution (1 M) were used for pH adjustment. The resulting solution had a pH of approx. 6.5. The osmolality was 247 mθsmol/kg. The solution was sterile filtered under LAF. The sterile solution was filled into Type I glass vials.

Example 4:

Under aseptic conditions, a sterile aqueous solution was prepared from azithromycin dihydrate (4.0 wt.-%), tobramycin (6.0 wt.-%), L-arginine (0.5 wt.-%), L-lysine (0.5 wt.-%), and γ-cyclodextrin (5.0 wt.-%) and sucrose (3.0 wt.-%). Small amounts of hydrochloric acid (1 M) and sodium hydroxide solution (1 M) were used for pH adjust- ment. The resulting solution had a pH of approx. 6.5. The osmolality was 300 mOs- mol/kg. The solution was sterile filtered under LAF. 1 ml of the sterile solution was filled into type I glass (USP) vials.

Example 5:

2.54 g of azithromycin dihydrate and 2.5 g of levofloxacin hemihydrate were weighed into a flask. 100 g of water for injection were added, and the suspension was acidified with hydrochloric acid (1 M) until all of the azithromycin was dissolved. Subsequently, 8 g of 2-hydroxypropyl-β-cyclodextrin and 0.2 g of chitosan were added. The pH was then adjusted to 9 by adding sodium hydroxide solution. The resulting liquid was filtered through a 0.45 μm membrane filter. To the filtrate, 2 g of 2-hydroxypropyl- β-cyclodextrin and xylitol, each were added. Finally, the pH was adjusted to approx. 7. The final solution had a concentration of about 17 mg/ml of azithromycin and 19 mg/ml of levofloxacin. The solution was sterile filtered under a laminar airflow hood and 1 ml of the sterile solution was filled into 2 ml brown glass vials. The formulation is intended to be used for pulmonary and nasal administration to treat upper and lower respiratory tract infections caused by gram positive and negative bacteria.

Example 6:

A sample of 2 ml of the azithromycin solution of Example 1 was tested for its suitability for nebulisation. A PARI eFlow™ nebuliser was connected to a PARI breath simulator via a Y-piece with attached inhalation and exhalation filters. The breath simulator settings were 15 breath/min and a tidal volume of 500 ml. The inhalation/exhalation ratio was 1 , mimicking an adult breathing pattern. Assessment of the geometric droplet size distribution of the aerosol was conducted by laser diffraction using a Malvern MasterSizerX™. The aerosol was measured at a flow rate of 20 1/min entrained air, conditioned to 23 °C and 50% r.h.

In result, the nebulisation time was about 3.4 min, during which a dose of 20 mg of the active compound or 67 % of the loaded dose were delivered ex mouthpiece. The mass median diameter of the aerosol was 3.9 μm, with a geometric standard deviation of 1.6. The respirable fraction, defined as the fraction of the aerosol having a droplet size of less than 5 μm, was 76 wt.-%. Example 7:

In another nebulisation experiment, a sample of 2 ml of the azithromycin solution of Example 1 was tested for its sinunasal aerosol delivery efficiency using a PARI Sinus nebuliser (based on an LC Sprint model) and Sinus compressor (providing pressurised air which pulsates at a frequency of 44 Hz) combination and an in-vitro sinunasal cast model based on anatomical dimensions. The cast model is equipped with two cavities (representing the sinuses) in frontal, maxillary and sphenoid position. Cavities as well as orifices (ostia) are exchangeable, allowing variation of the sinus volume (7.5, 13 and 23 ml) and ostium diameter (0.5, 1.0 and 2.0 mm).

In this experiment, the model was equipped with 0.5 mm / 7.5 ml cavities in frontal, 1.0 mm / 13 ml cavities in sphenoid and 2.0 mm / 23 ml sinuses in maxillary position. Ostium length was 10 mm for all diameters. Filter pad liners were inserted into the sinus flasks in order to improve reproducibility of deposition.

The sample was nebulised for 8 minutes, i.e. 4 minutes in each nostril. After the experiment, all parts of the experimental set-up that were in contact with the inhalation solution, the cavities with ostia, the model, the nebulizer and the expiratory filter, were extracted with a defined volume of solvent. The nebuliser was weighed before and after the experiment for the gravimetric determination of the aerosol output.

In result, the total sinus deposition of azithromycin was found to be 2.1 mg (7 wt.- %), and the nasal cavity deposition was 3.0 mg (10 wt.-%). The emitted drug dose was 8.1 mg (26 wt.-%).

Example 8:

A sterile solution comprising 5 wt.-% pentoxifylline and 10 wt.-% 2- hydroxypropyl-β-cyclodextrin was prepared by first dissolving the appropriate amount of pentoxifylline in water for injection, followed by sonication until a clear solution was obtained. Subsequently, the weighed amount of 2-hydroxypropyl-β-cyclodextrin was added, and the mixture was again sonicated until a clear solution was formed, which was then stirred overnight. The final solution showed a substantial degree of taste masking compared to a cyclodextrin-free aqueous solution of pentoxifylline. Its osmolality was 161 mθs- mol/kg, its viscosity 1.64 mPa-s, and its surface tension was 57 mN/m. The final solution was sterile filtered under LAF and 0.5 ml were filled under nitrogen protection into polyethylene blow fill seal vials.

Example 9:

2 g of azithromycin dihydrate were weighed into a flask. 100 g of water for injection were added, and the suspension was acidified with hydrochloric acid (1 M) until all of the azithromycin was dissolved. Subsequently, 1O g of 2-hydroxypropyl-β- cyclodextrin and 2 g of xylitol were added. The pH was then adjusted to 7.0 by adding sodium hydroxide solution. To this clear solution 40 g of colistimethate sodium was added. The resulting liquid was filtered through a 0.22 μm membrane filter. The final solution had an azithromycin concentration of 20 mg/ml and 500.000 IU colistimethate sodium (colistin). 3 ml each of the sterile solution were filled under a laminar airflow hood into 6 ml Type I glass vials (USP) and lyophilised thereafter. The dry lyophilisate cake was reconstituted with 2 ml of sodium chloride solution (0.9%), resulting in an inhalation solution containing about 60 mg of azithromycin and 1.5 million I.E. colistin. The formulation is intended to be used for pulmonary and nasal administration to treat upper and lower respiratory tract infections caused by gram positive and negative bacte- ria.

Example 10:

4 g of azithromycin dihydrate were weighed into a flask. 100 g of water for injection were added, and the suspension was acidified with hydrochloric acid (1 M) until all of the azithromycin was dissolved. The pH was then adjusted to 7.0 by adding sodium hydroxide solution. 4.5 g of phospholipid (soy lecithin) was added and the dispersion was let to stir for one hour at room temperature. 0.35 g of Tween 80 and 0.35 g of vitamin E TPGS was added and the solution was stirred. To this clear solution 0.5 g of ci- closporin A was added and stirred for one hour. The resulting dispersion was homogenised at 1500 bar, room temperature for 20 homogenisation cycles. The resulting lipo- some dispersion was sterile filtered under LAF and 2 ml were filled into Type I brown glass vials (USP). The formulation is intended to be used to prevent and treat bronchio- litis obliterans after lung and stem cell transplantation, idiopathic pulmonary fibrosis, sarcoidosis, COPD and autoimmune diseases of the upper and lower respiratory tract.

Example 11 :

1.5 g of azithromycin dihydrate was weighed into a flask. 100 g of water for injection were added, and the suspension was acidified with hydrochloric acid (1 M) until all of the azithromycin was dissolved. Subsequently, 10 g of 2-hydroxypropyl-β-cyclodextrin were added and thereafter 2.5 g ibuprofen-lysinate and 0.5 g sodium chloride and xyli- tol, each. The pH was then adjusted to 7.0 and mixed until a clear solution was obtained. The solution was sterile filtered under LAF and filled into Type I glass vials (USP). The solution was lyophilised, each vial containing 5 ml of the 15 mg/ml concentrated azithromycin solution. The lyophilisate was reconstituted with 1.25 ml of tobramycin solution, having a drug concentration of 100 mg/ml providing an inhalation solution with a total content of about 75 mg of azithromycin, and about 125 mg each of ibuprofen-lysinate and tobramycin. The solution is intended to be used upon nebulization via an eFlow™ electronic inhaler to treat acute exacerbations of COPD, bronchiectasis, pneumonia, bronchiolitis and cystic fibrosis

Example 12:

5.0 g of 2-hydroxypropyl-β-cyclodextrin, 0.03 g of citric acid, 0.09 g of sodium citrate dihydrate and 0.71 g of sodium chloride were weighed into a flask. 94.16 g of water for injection was added and the mixture was stirred until a clear solution was obtained. 12 μg/ml of formoterol fumarate dihydrate and 500 μg/ml of theophylline were added and the mixture was stirred until complete dissolution. The pH was adjusted to pH 5.0 by use of 0.1 M HCl or 0.1 M NaOH, respectively, and the solution afterwards sterile filtered under a LAF. 1 ml of the sterile solution was filled under a LAF hood and nitro- gen gassing into blow fill seal vials. The solution is intended for inhalation via the eFlow™ electronic nebulizer to treat asthma and COPD.

Example 13:

7.5 g of 2-hydroxypropyl-β-cyclodextrin was dissolved in 92.5 g of water for injection by use of stirring. 3.85 g of dehydro-epiandrosterone-sulfate (DHEAS) was added and the mixture was stirred until a homogeneous dispersion was obtained. Afterwards 0.2 g of hydroxypropylmethylcellulose and 0.5 g of vitamin E tocopheryl-polyethyleneglycol- succinate (Vit E-TPGS) were added and dispersed by use of sonification and stirring. Subsequently, 3.0 g of gamma-cyclodextrin, 0.25 g of sodium saccharin and 4.0 g of lactose were added and the mixture was stirred until a clear solution was obtained. The pH was adjusted to pH 7.5 by adding 1 N sodium hydroxide and the solution was afterwards sterile filtered; 2 ml were filled under laminar airflow in an aseptic process and under nitrogen gas protection into nitrogen gassed blow fill seal vials which were subsequently overpouched with an aluminium laminate foil. The solution is intended for use to treat asthma and COPD.

Example 14:

5.0 g of 2-hydroxypropyl-β-cyclodextrin, 0.03 g of citric acid, 0.09 g of sodium citrate dihydrate, 0.02g of hydroxyl-propyl-methyl-cellulose (HPMC) and 0.71 g of sodium chloride were weighed into a flask. 94.16 g of water for injection was added and the mixture was stirred until a clear solution was obtained. 2.5 g of ibuprofen-lysinate were added and the mixture was stirred until complete dissolution. The pH was adjusted to pH 6.5 by use of 0.1 M HCl or 0.1 M NaOH, respectively, and the solution afterwards sterile filtered under a LAF. After sterile filtration 1 ml of the solution was filled into Type I glass vials (USP). The final solution contained about 25 mg/ml of ibuprofen- lysinate. The solution is intended for use as an anti-inflammatory product to treat asthma, COPD and cystic fibrosis.

Example 15:

5.0 g of 2-hydroxypropyl-β-cyclodextrin, 1.0 g xylitol, 0.03 g of citric acid, 0.09 g of sodium citrate dihydrate and 0.3 g of sodium chloride were weighed into a flask. 94.16 g of water for injection was added and the mixture was stirred until a clear solution was obtained. 2 g of sildenafil citrate and 0.5 g of L-arginine were added and the mixture was stirred until complete dissolution. The pH was adjusted to pH 6.5 by use of 0.1 M HCl or 0.1 M NaOH, respectively, and the solution afterwards sterile filtered under a laminar airflow hood. 0.5 ml of the sterile solution was filled into Type I glass vials (USP). The solution is intended for use upon pulmonary administration via the eFlow™ nebulizer to treat pulmonary hypertension and COPD, Example 16:

1.5 g of azithromycin dihydrate was dissolved in water for injection. Hydrochloric acid (1 M) was added dropwise to obtain a clear solution of pH 5.5. An amount of 5 g of 2-hydroxypropyl-γ-cyclodextrin and 5 g of 2-hydroxypropyl-β-cyclodextrin was added, and the mixture was stirred for 5 min at 700 rpm, again yielding a clear solution. Water- free citric acid (0.5 g) and saccharin sodium (0.5 g) were added, and the mixture was stirred for 2 min at 700 rpm. Subsequently, the solution was neutralised to a pH of about 7 by adding sodium hydroxide solution (1 M) in a dropwise manner. Subsequently, 20 mg of mometasone fuorate and a sufficient amount of water for injection to yield a total weight of 100 g were added. The solution was sterile filtered under LAF using a 0.22 μm sterile filter. The liquid was stirred at room temperature for about 5 hours and filtered through a sterile filter having a pore size of 0.22 μm. The clear solution was filled in Type I glass vials (USP) and stored under 5°C ± 3 conditions as a sterile solution, ready-to-use. Later the entire content of a vial was transferred into the medication cup of the electronic inhaler eFlow™ for oral inhalation, intended for the treatment of asthma, COPD, bronchiolitis obliterans, panbronchiolitis, pneumonia, and via nasal administration to treat acute and chronic rhinosinusitis, nasal polyps and other inflammatory diseases.

Example 17:

5.0 g of azithromycin monohydrate ethanolate was dissolved with an equimolar amount of magnesium chloride hexahydrate (about 1.4 g) in about 91 g of water for injection, acidified with HCl (1 M) and stirred until completely dissolved. The pH of the clear solution at this stage was about 6.0. Thereafter, mannitol (2.0 wt.-%), saccharin sodium (0.025 wt.-%) and L-menthol (0.025 wt.-%) were dissolved under stirring and the pH of the clear solution was adjusted to 6.3 and the weight adjusted with water for injection to 100 g. After sterile filtration of the solution under laminar air flow about 5 ml of the solution was filled into sterile amber glass vials and stored at three temperature conditions. The osmolality of the solution was 598 mθsmol/kg. The solution is intended for use as an anti-inflammatory product to treat asthma, COPD, bronchiectasis, bronchioli- tis, panbronchiolitis, bronchiolitis obliterans and cystic fibrosis. Example 18:

5.O g of azithromycin dihydrate was dissolved with an equimolar amount of magnesium aspartate (about 2.2 g) in about 80.8 g of water for injection and the pH adjusted employing about 1O g of HCl (1 M) to about 6. The solution was stirred until com- pletely dissolved. After having dissolved the other taste masking agents xylitol (2.0 wt- %), saccharin sodium (0.025 wt.-%) and L-menthol (0.025 wt.-%) were added and dissolved under stirring. The pH of the resulting clear solution was adjusted to 6.3 and the weight made up to 100 g by addition of water for injection. Upon sterile filtration of the solution under LAF, 2 ml each were filled into presterilized polyethylene blow fill and seal vials containing sterile nitrogen gas. The osmolality of the solution was 640 mθsmol/kg. The solution is intended to be used to treat upper and lower respiratory tract inflammations and infections and autoimmune diseases.

Example 19:

5.0 g of azithromycin monohydrate ethanolate and about 1.7 g of magnesium sul- phate were dissolved in about 90 g of water for injection adjusting the pH to 5 by addition of 1 molar HCl to the solution and it was stirred until completely dissolved. After dissolution of the other taste masking agents trehalose (2.0 wt.-%), aspartame (0.025 wt.-%) and L-menthol (0.025 wt.-%), the pH was adjusted to 6.3 with 0.1 N NaOH and the weight was made up to 100 g by the addition of water for injection. The resulting clear solution was sterile filtered under LAF. Subsequently, 3 ml of the solution was filled into sterile nitrogen gassed amber glass vials and stored under three temperature conditions. The solution is intended to be used to treat upper and lower respiratory tract inflammations and infections.

Example 20:

5.Og of azithromycin monohydrate was dissolved with an equimolar amount of magnesium gluconate anhydrous (about 2.8 g) in about 88 g of water for injection. The pH of the solution was adjusted to about 5.5 employing 1 N HCl and the solution was stirred until completely dissolved. After addition and dissolution of the other excipients lactose monohydrate (2.5 wt %), saccharin sodium (0.025 wt.-%) and L-menthol (0.025 wt.-%), the pH was adjusted to 6.3 and the total weight was made up to 100 g by adding water for injection. The clear solution was used to dissolve about 3 g of colistimethate under gentle stirring. The resulting solution was sterile filtered under a LAF and 3 ml each containing about 150 mg of azithromycin and 1 million units of colistin were filled into 6 ml glass vials and lyophilised using a Christ Eypsilon 2-6D™ freeze dryer according to a process as follows: freezing for 4 hours (-40⁰C and 0.010 mbar), followed by the primary drying (-10⁰C and 0.025 mbar), which was conducted for 18 hours followed by a secondary drying (+20°C and 0.025 mbar) for 18 hours.

Instead of lactose, 2.5 wt.-% each of trehalose and sucrose were used for the other freeze drying experiments.

Example 21 :

Other examples for taste masked azithromycin formulations are summarized in the following table, all being sterile filtered under LAF and filled into amber glass vials. The formulations were prepared as outlined in the previous examples.

Example 22:

9.5 g of azithromycin and about 2.6 g of magnesium chloride hexahydrate were weighed into a glass beaker and dissolved under stirring in about 88 g of water for injection by dropwise addition of 1 molar HCl until a pH of 5 was obtained. The pH was than adjusted with 1 N NaOH to pH 6.3 and a citrate buffer was added to maintain this pH. As additional taste masking excipients 1% xylitol, 0.03% saccharin sodium and 0.02% levomenthol, each., were added and dissolved. The resulting clear solution was sterile filtered under LAF and 1.5 ml were filled into presterilized nitrogen gassed polypropylene vials. The solution is intended to be used to treat upper and lower respiratory tract inflammations and infections, acute pneumonia, HAP, VAP, cystic fibrosis and HIV.

Example 23:

A combination product of azithromycin monohydrate ethanolate with tobramycin was formulated as follows: 5.0 g of azithromycin was dissolved in about 82 g of water for injection, acidified by 1 M HCl to pH 5.5. An equimolar amount of magnesium chloride hexahydrate (about 1.4 g) and 10 mMol calcium chloride was added to the solution and stirred until completely dissolved. The additional excipients having taste masking properties mannitol (2.0 wt.-%), saccharin sodium (0.025 wt.-%) and L-menthol (0.025 wt- %) were added and dissolved by stirring. Thereafter, 10.0 g of tobramycin base was added to this solution and the weight was adjusted by the addition of water for injection to 100 g. After dissolution of the drug, the pH of the solution was adjusted to pH 6.3 and the final solution was sterile filtered under LAF. 1.5 ml were filled into presterilized polypropylene blow fill seal vials. The product was stored at two temperature condi- tions. The osmolality of this formulation was measured to be 748 mθsmol/kg after being stored at 2 to 8⁰C for three weeks. The solution is intended to be used to treat upper and lower respiratory tract inflammations and infections, acute pneumonia, HAP, VAP, cystic fibrosis and HIV.

The following table presents the pH values of the examples above. One can see a tem- perature dependent decrease in pH values, i.e. the pH values decrease as the storage temperature increases from 5°C to 40°C.

The following table demonstrates the osmolality values of the above described formulations, being stored at three different temperatures. In general, the osmolality of the formulation does not change.

Example 24:

17. Ig of azithromycin monohydrate ethanolate was dissolved with equimolar amount of magnesium chloride hexahydrate (about 4.7 g) in about 78 g of water for injection, acidified by 1 M HCl and stirred until completely dissolved. The pH of the clear solution was adjusted to pH 6.3 with NaOH after addition pf 0.05% saccharin sodium. The resulting solution was sterile filtered under LAF and 0.5 ml were filled into pre- sterilized polypropylene blow fill and seal vials. The solution is intended to be used to treat upper and lower respiratory tract inflammations and infections, acute pneumonia, HAP, VAP, cystic fibrosis and HIV.

Example 25:

1O g of azithromycin monohydrate ethanolate and about 4.3 g of magnesium aspartate are dissolved under stirring by the dropwise addition of 1 molar HCl. After addition and dissolution of the other taste masking agents xylitol (1.0 wt.-%) and saccharin sodium (0.04 wt.-%) and levomenthol (0.25% wt%) the pH of the solution was adjusted to 6.3, the buffer solution added and the weight adjusted to 100 g by the addition of water for injection. The resulting clear solution was sterile filtered under LAF and 1.5 ml of the solution was filled into sterile nitrogen gassed amber glass vials. The solution is in- tended to be used to treat upper and lower respiratory tract inflammations and infections, acute pneumonia, nontuberculous mycobacterial pulmonary diseases, pneumoc- stis jirovecii, pulmonary nocardia infections, HAP, VAP, cystic fibrosis, panbronchioli- tis, HIV, as well as acute and chrome sinusitis.

Example 26:

About 7.6 g of azithromycin monohydrate ethanolate and about 3g of levofloxacin HCl were dissolved in about 90 g of water for injection employing HCl (1 M) for acidification. An equimolar amount of magnesium chloride hexahydrate (about 3.8 g), 2 g of trehalose and 0.02% levomenthol was added and stirred until completely dissolved. The pH was adjusted to pH 6.3 with NaOH and the volume was made up to 100 ml. The solution was sterile filtered under LAF and 1.5 ml each were filled into pre-sterilized nitrogen gassed polypropylene blow fill seal vials for nebulization with the eFlow™ nebulizer. The solution is intended to be used to treat upper and lower respiratory tract inflammations and infections, acute pneumonia, HAP, VAP, cystic fibrosis, HIV as well as acute and chronic sinusitis.

Example 27:

10. Og of clarithromycin lactobionate was dissolved in about 86 g of water for injection employing a magnetic stirrer. An equimolar amount of magnesium chloride hexahydrate (about 1.9 g) and 5 mMol of calcium chloride was added to the solution and stirred until completely dissolved. The other taste masking agents mannitol (2.0 wt.-%), saccharin sodium (0.025 wt.-%) and L-menthol (0.025 wt.-%) were added and dissolved under stirring. The pH was adjusted to 6.4, the volume made up to 100 ml with water for injection and the resulting clear solution sterile filtered under LAF. Subsequently, 8 ml of the solution was filled into sterile amber glass vials (USP Type I) and stored at three temperature conditions. The solution is intended to be used to treat upper and lower respiratory tract inflammations and infections, including acute and chronic sinusitis.

Example 28:

4.7 g of azithromycin monohydrate ethanolate was dissolved with an equimolar amount of magnesium chloride hexahydrate (about 1.4 g) in about 92 g of water for injection employing 8 g HCl (1 M) and stirred until completely dissolved. The pH of the clear solution at this stage was 6.0 and was adjusted to pH 6.3 with NaOH after having dissolved the sweetening agents. The other taste masking agents xylitol (2.0 wt.-%), saccharin sodium (0.025 wt.-%) and L-menthol (0.025 wt.-%) were added and subse- quently stirred. The pH of the solution was adjusted to 6.3 to give a clear solution. The total volume was made up to 100 ml and the solution was sterile filtered under LAF. Subsequently, the solution was filled into sterile amber glass vials and stored at three temperature conditions. The dynamic viscosity was measured to be 1.33 ± 0.02 mPa-s and the surface tension was determined as 52.03 ± 0.19 mN/m. The solution is intended to be used to treat upper and lower respiratory tract inflammations and infections, acute pneumonia, HAP, VAP, cystic fibrosis, nontuberculous mycobacterial pulmonary diseases, pneumocstis jirovecii, pulmonary nocardia infections, HIV as well as acute and chronic sinusitis.

Example 29:

The nebulization efficiency of the formulation as described in Example 28 with the eFlow™ nebulizer was investigated by breath simulation and laser diffraction. Breath simulation experiments were performed using a COMPAS™ breathing simulator (PARI GmbH, Starnberg, Germany). A standard adult sinusoidal breathing pattern with 500 ml tidal volume, 15 breaths per minute and an inspiration to expiration ratio of 1 :1 was applied. The device was filled with 1 ml of formulation and connected via a filter to the breath simulator. The nebulizer was operated until it switched off automatically. Azithromycin collected on the inhalation filter was recovered and analyzed by a validated HPLC method and UV detection to quantify the delivered dose.

Results: The aerosol produced by the eFlow™ nebulizer had a mass median diameter of 3.6 μm with 75% of the droplets being smaller than 5 μm. Upon nebulization experiments, 35.2 mg of azithromycin corresponding to 72% of the initially charged drug amount were found on the inspiratory filter. The nebulization time was between 2.4 and 2.5 min. Example 30:

About 7.5g of azithromycin monohydrate ethanolate, 2.5 g of levofloxacin and an equimolar amount of magnesium chloride hexahydrate (about 2.8 g) were dissolved under stirring in about 85 g of water for injection employing dropwise 1 M HCl to ad- just the pH to about 6.0. The other taste masking agents xylitol (2.0 wt.-%), saccharin sodium (0.025 wt.-%) and L-menthol (0.025 wt.-%) were added and dissolved under stirring. The pH of the solution was adjusted to 6.3 and the volume made up to 100 ml by addition of water for injection. The resulting clear solution was sterile filtered under LAF. Subsequently, 2 ml of the solution was filled into pre-sterilized nitrogen gassed blow fill and seal vials. The solution is intended to be used to treat upper and lower respiratory tract inflammations and infections, acute pneumonia, bronchiectasis, acute COPD, HAP, VAP, cystic fibrosis, HIV as well as acute and chronic sinusitis.

Example 31 :

5.O g of azithromycin dihydrate was dissolved with an equimolar amount of magnesium gluconate anhydrous (2.77 g) in 75.18 g of water for injection employing 1Og HCl (1 M) and stirred until completely dissolved. The pH of the clear solution at this stage was 6.0 and was adjusted to pH 6.3 with NaOH after having dissolved the sweetening agents. The taste masking agents saccharin sodium (0.025 wt-%) and L-menthol (0.025 wt.-%) were added and subsequently stirred. 5.0 g of ceftazidime sodium is added to the solution. 2.0 g of lactose monohydrate was added to the formulation as cryoprotectant. The pH of the solution was adjusted to 6.3, the volume made up to 100 ml with water for injection and 2 ml of the solution was filled in to 10 ml flasks and subsequently, the solution was lyophilised.

The following lyophilisation programme was employed: freezing for 4 hours at -40⁰C and 1000 mbar, followed by primary drying for 18 hours at -10°C and 0.250 mbar. The final step of the lyophilisation was the secondary drying at +20°C and 0.04 mbar. The product is intended to be used to treat upper and lower respiratory tract inflammations and infections, acute pneumonia, bronchiectasis, acute COPD, HAP, VAP, cystic fibrosis, HIV as well as acute and chronic sinusitis. Example 32:

2.5 g of azithromycin dihydrate and 0.68 g of magnesium chloride hexahydrate was dissolved in 80.7 g water for injection. About 5.0 g of hydrochloric acid (1 M) was added dropwise to obtain a clear solution of pH 4.5. An amount of 5 g of 2- hydroxypropyl-g-cyclodextrin and 5 g of 2-hydroxypropyl-β-cyclodextrin was added, and the mixture was stirred for 5 min at 700 rpm, again yielding a clear solution. Water- free citric acid (0.5 g) and saccharin sodium (0.5 g) were added, and the mixture was stirred for 2 min at 700 rpm. Subsequently, the solution was neutralised to a pH of about 7 by adding sodium hydroxide solution (1 M) in a dropwise manner. Subsequently, 125 mg of mometasone fuorate and a sufficient amount of water for injection to yield a total weight of 100 g were added. The solution was sterile filtered under LAF using a 0.22 μm sterile filter. 2 ml of the clear solution was filled in Type I glass vials (USP) and stored under 5°C ± 3 conditions as a sterile solution, ready-to-use. The product is intended to be used to treat upper and lower respiratory tract inflammations, such as asthma, COPD, bronchiolitis obliterans, idiopathic pulmonary and parenchymatic fibrosis, sarcoidosis, autoimmune diseases, chronic and acute rhinosinusitis, and nasal polyps.

Claims

1. A pharmaceutical aerosol for nasal, sinunasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase essentially consists of aqueous droplets, wherein said droplets:

(a) comprise an active compound having a poor taste and an aqueous solubility of at least about 5 mg/ml at 25 °C and at a pH from about 3 to 9;

(b) comprise at least one taste-masking excipient; and

(c) have a mass median diameter from about 1.5 to about 6 μm.

2. The aerosol of claim 1, wherein the active compound is poorly stable in aqueous solution at 25 °C.

3. The aerosol of claim 1 or 2, wherein the aqueous solubility of the active compound is at least about 10 mg/ml.

4. The aerosol of claim 3, wherein the aqueous solubility of the active compound is at least about 20 mg/ml.

5. The aerosol of any of the preceding claims, wherein the active compound is selected from the group consisting of water-soluble anti-infectives, anti- inflammatory drugs, xanthins, bronchodilators, phosphodiesterase inhibitors as well as their pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs and derivatives.

6. The aerosol of any of the preceding claims, wherein the active compound is a macrolide or a pharmaceutically acceptable salt thereof.

7. The aerosol of claim 6, wherein the macrolide is azithromycin or clarithromycin or a pharmaceutically acceptable salt thereof.

8. The aerosol of claim 6 or 7, wherein the liquid phase further comprises another drug.

9. The aerosol of claim 8, wherein the other drug is an aminoglycoside, a corticosteroid or a pharmaceutically acceptable salt thereof.

10. The aerosol of claim 8, wherein the other drug is mometasone or a pharmaceutically acceptable salt thereof.

11. The aerosol of any of claims 6 to 10, wherein the active compound is azithromycin and the liquid phase further comprises an acid to adjust the pH of the liquid phase to a value in the range from about 5 to about 7.5.

12. The aerosol of claim 7, wherein the pH of the liquid phase is adjusted to about 6.2 to 6.4.

13. The aerosol of any of claims 7 to 12, wherein the active compound is azithromycin or clarithromycin or a combination thereof and the total concentration of azithromycin and/or clarithromycin is in the range of about 10 to about 180 mg/ml.

14. The aerosol of claim 13, wherein the total concentration of azithromycin and/or clarithromycin is in the range of about 30 to about 150 mg/ml.

15. The aerosol of any of claims 1 to 4, wherein the active compound is selected from the group consisting of anti-infectives, non steroidal anti-inflammatory drugs, macrolides, steroidal drugs, vasoactive drugs, phosphodiesterase inhibitors and bonchodilatators, alone or in combination with other active compounds.

16. The aerosol of claim 15, wherein the active compound is selected from the group consisting of

- non steroidal anti-inflammatory drugs selected from indomethacin and ibu- profen;

- macrolides and aminoglycosides selected from azithromycin, clarithromycin, tobramycin and amicacin;

- dehydro-epi-androsterone; - vasoactive drugs selected from sildenafil, vardenafil and tadalafil; and

- phosphodiesesterase inhibitors and bonchodilatators selected from theophyl- Hn and pentoxiphyllin.

17. The aerosol of any of the preceding claims, wherein the taste-masking agent is selected from the group consisting of complexing agents, surfactants, polymers, sweeteners, salts, organic acids, amino acids, metal ions and combinations of any of these.

18. The aerosol of any of the preceding claims, wherein the taste -masking agent is selected from the group consisting of divalent metal cations.

19. The aerosol of any of the preceding claims, wherein the taste masking agent comprises a water soluble magnesium salt or a water soluble calcium salt or a combination thereof.

20. The aerosol of claim 19, wherein the ratio of the total molar concentration of the magnesium salt and/or the calcium salt to the molar concentration of the active compound is in the range of from about 0.1 : 1 to 10 : 1.

21. The aerosol of any of claims 18 to 20, wherein the active compound is a macrolide or ketolide.

22. The aerosol of any of claims 18 to 21, wherein the active compound is azithromycin or clarithromycin or a combination thereof with another drug.

23. The aerosol of claim 21, wherein the macrolide is azithromycin or clarithromycin alone or a combination with another drug from a different class.

24. The aerosol of claim 23, wherein the liquid phase further contains another drug selected from the group consisting of aminoglycosides, fluoroquinolones, antibiotic acting polypeptides, and cefalosporins, antifungals, immunmodulators, nonsteroidal anti-inflammatory drugs, and steroids.

25. The aerosol of claim 24, wherein the liquid phase further contains another drug selected from the group consisting of tobramycin, amicacin, levofloxacin, colistin and ceftazidim.

26. The aerosol of any of claims 18 to 25, wherein the taste masking agent further comprises a sugar, sugar alcohol, sweetener or aromatic.

27. The aerosol of any of claims 1 to 16, wherein the taste-masking agent is a com- plexing agent selected from the group consisting of optionally derivatised α-, β-, and γ-cyclodextrins.

28. The aerosol of any of claims 1 to 16, wherein the taste-masking agent is a sweet- ener, a sugar or a sugar alcohol.

29. The aerosol of claim 28, wherein the sweetener is selected from the group consisting of saccharin, saccharin sodium, aspartame, cyclamate, sucralose, acesulfame, acesulfame potassium, neotame, thaumatin, neohesperidine and neohesperidine dihydrochalcone.

30. The aerosol of claim 28 wherein the sugar is selected from the group consisting of sucrose, trehalose, lactose and fructose.

31. The aerosol of claim 28 wherein the sugar alcohol is selected from the group consisting of xylitol, mannitol and isomaltol.

32. The aerosol of claim 17, wherein the taste-masking agent is citric acid, lactic acid or levomenthol.

33. The aerosol of claim 17, wherein the taste masking agent is L-arginine or L-lysine.

34. The aerosol of any of claims 1 to 16, comprising a first taste-masking agent selected from optionally derivatised α-, β-, and γ-cyclodextrins and a second taste- masking agent selected from sweeteners, organic acids, salts and amino acids, sugars, sugar alcohols and combinations thereof.

35. The aerosol of any of the preceding claims, wherein the chloride concentration in the liquid phase is in the range from about 30 to about 600 mmol/1.

36. The aerosol of any of the preceding claims, wherein the mass median droplet diameter is from about 1.5 to about 4 μm.

37. The aerosol of any of the preceding claims, wherein the geometric standard deviation of the droplet diameter is below 2.

38. The aerosol of any of the preceding claims, wherein more than 60 % of the aerosol droplets have a diameter in the range from about 1.5 μm to about 5 μm.

39. The aerosol of any of the preceding claims, wherein the amount of active compound contained in droplets having a diameter of 5 μm or less is at least 50 % of the total amount of active compound.

40. The aerosol of any of the preceding claims, being emitted from an aerosol generator at a rate of at least about 0.1 ml of dispersed liquid phase per minute in a continuous, breath triggered or pulsating mode.

41. The aerosol of any of the preceding claims, characterised in that its pressure pul- sates with a frequency in the range from about 10 to about 90 Hz.

42. The aerosol of claim 41, wherein the amplitude of pressure pulsation is at least about 5 mbar.

43. The use of a liquid pharmaceutical composition comprising an effective dose of an active compound dissolved in a volume of not more than about 10 ml for prepar- ing the aerosol of any of claims 1 to 42.

44. The use of claim 43, wherein the effective dose of the active compound is dissolved in a volume of not more than about 5 ml.

45. The use of claim 44, wherein the effective dose of the active compound is dissolved in a volume of about 0.25 to about 2.5 ml.

46. The use of any of claims 43 to 45, wherein the dynamic viscosity of the liquid composition is in the range from about 0.8 to about 3 mPas.

47. The use of any of claims 43 to 46, wherein the surface tension of the liquid composition is in the range from about 25 to 80 mN/m.

48. The use of any of claims 43 to 47, wherein the osmolality of the liquid composi- tion is from about 200 to 1200 mθsmol/kg,

49. The use of claim 48, wherein the osmolality of the liquid composition is from about 200 to 800 mθsmol/kg.

50. The use of a solid pharmaceutical composition for preparing the liquid composition of any of claims 43 to 49, wherein the solid composition comprises an effective dose of the active compound, and wherein the solid composition is dissolvable or dispersible in an aqueous liquid solvent having a volume of not more than about 10 ml.

51. The use of claim 50, wherein the solid composition is dissolvable or dispersible in an aqueous liquid solvent having a volume of not more than about 5 ml.

52. The use of claim 51, wherein the solid composition is dissolvable or dispersible in an aqueous liquid solvent having a volume of about 0.25 to about 2.5 ml.

53. The use of the aerosol of any of claims 1 to 42 for the manufacture of a medicament for the prophylaxis or treatment of acute or chronic sinusitis or rhinosinusi- tis, bronchitis, pneumonia, asthma, chronic obstructive pulmonary disease, bronchiectasis, nontuberculous mycobacterial pulmonary diseases, Pneumocstis ji- rovecii, pulmonary nocardia infections, HIV, pulmonary hypertension, prophy- laxis to prevent graft rejection after lung, stem or bone marrow transplantation, bronchiolitis obliterans, Pneumocystis, diffuse panbronchiolitis, parenchymatic and/or fibrotic diseases or disorders including cystic fibrosis, any pulmonary infection with or without acute exacerbations, optionally due to Streptococcus pneumoniae, Haemophilus influenza or Moraxella catarrhalis; acute bacterial ex- acerbations in chronic bronchitis or in chronic obstructive pulmonary disease, optionally due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, Haemophilus parainfluenza or Moraxella catarrhalis; nosocomial pneumonia, optionally due to Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Bukholderia cepacia, Escherichia coli, Klebsiella pneumo- niae, Haemophilus influenza or Streptococcus pneumoniae, Mycobacterium avium, kanasaii or chelonae abscessus; or community acquired pneumonia (CAP), or hospital acquired pneumonia (HAP), or ventilator associated pneumonia (VAP), optionally due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, Haemophilus parainfluenza, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, or My- coplasma pneumoniae or fungi, such as aspergillus or Candida causing an upper or lower respiratory tract infections or inflammation.

54. The use of claim 53, wherein the medicament is administered once a day or twice a day or once or twice weekly.

55. A method of preparing and delivering an aerosol for inhalation comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase essentially consists of aqueous droplets comprising an active compound having a poor taste and an aqueous solubility of at least about 5 mg/ml at 25 °C and at a pH from about 3 to 9, said method comprising:

(a) providing a liquid pharmaceutical composition comprising an effective dose of said active compound dissolved in a volume of not more than about 10 ml and at least one taste-masking excipient;

(b) providing a nebuliser aerosolising said liquid pharmaceutical composition at a total output rate of at least 0.1 ml/min, the nebuliser further being adapted to emit an aerosol comprising a dispersed phase having a mass median diameter from about 1.5 to about 6 μm; and

(c) operating said nebuliser to aerosolise the liquid composition.

56. The method of claim 55, wherein step (c) is conducted to last not more than about 10 minutes.

57. The method of claim 55, wherein step (c) is conducted to last not more than about 5 minutes.

58. The method of claim 55, wherein the nebulization time of a 2 ml volume of the liquid composition is less than 5 minutes.

59. The method of any of claims 55 to 58, wherein more than 50 % of the nominal dose is emitted for inhalation.

60. The method of any of claims 55 to 59, wherein the mass median droplet diameter is from about 1.5 to about 4 μm.

61. The method of any of claims 55 to 60, wherein the geometric standard deviation of the droplet diameter is below 2.

62. The method of any of claims 55 to 61, wherein more than 60 % of the aerosol droplets have a diameter in the range from about 1 ,5 μm to about 5 μm.

63. The method of any of claims 55 to 62, wherein the amount of active compound contained in droplets having a diameter of 5 μm or less is at least 50 % of the total amount of active compound.

64. The method of any of claims 55 to 63, wherein the nebulizer is a vibrating membrane type nebulizer.

65. The method of any of claim 55 to 64, wherein the nebuliser is adapted for pulmonary administration via oral inhalation or nasal administration.

66. The method of any of claims 55 to 64, wherein the nebuliser is adapted to emit an aerosol whose pressure pulsates with a frequency in the range from about 10 to about 90 Hz.

67. The method of claim 66, wherein the nebuliser is adapted to maintain an amplitude of pressure pulsation of at least about 5 mbar.

68. The method of claim 66 or 67, wherein the nebuliser is adapted for nasal or sinu- nasal administration.

69. The method of any of claims 55 to 68, wherein the nebuliser is adapted for nasal or pulmonary administration.

70. The method of any of claims 55 to 69, wherein the active compound is selected from the group consisting of anti-infectives, non steroidal anti-inflammatory drugs, macrolides, steroidal drugs, vasoactive drugs, phosphodiesterase inhibitors and bonchodilatators, alone or in combination with other active compounds.

71. The method of any of claims 55 to 69, wherein the active compound is selected from the group consisting of indomethacin, ibuprofen, azithromycin, clarithromy- cin, dehydro-epi-androsterone, mometasone, sildenafil, vardenafil, tadalafil, theo- phyllin and pentoxiphyllin, alone or in combination with other active compounds.

The method of any of claims 55 to 71, wherein the active compound, the taste masking agent and/or the liquid phase is/are defined as in any one of claims 2 to 35.