[go: up one dir, main page]

WO2008025560A1 - Procédés servant à masquer le goût de compositions nébulisées pour thérapie par inhalation nasale et pulmonaire - Google Patents

Procédés servant à masquer le goût de compositions nébulisées pour thérapie par inhalation nasale et pulmonaire Download PDF

Info

Publication number
WO2008025560A1
WO2008025560A1 PCT/EP2007/007625 EP2007007625W WO2008025560A1 WO 2008025560 A1 WO2008025560 A1 WO 2008025560A1 EP 2007007625 W EP2007007625 W EP 2007007625W WO 2008025560 A1 WO2008025560 A1 WO 2008025560A1
Authority
WO
WIPO (PCT)
Prior art keywords
aerosol
active compound
taste
azithromycin
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2007/007625
Other languages
English (en)
Inventor
Manfred Keller
Aslihan Akkar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PARI Pharma GmbH
Original Assignee
PARI Pharma GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by PARI Pharma GmbH filed Critical PARI Pharma GmbH
Publication of WO2008025560A1 publication Critical patent/WO2008025560A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • 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.
  • 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.
  • 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 are loaded with portions of the drug substance in form of a powder formulation.
  • the unit doses may be accommodated in small capsules.
  • 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.
  • GSD Geometric Standard Deviation
  • Aqueous-based solutions and suspensions are usually inhaled with nebulisers.
  • 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.
  • 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.
  • 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.
  • drug substances such as in the case of several corticosteroids useful for inhalation therapy, including budesonide and fluticasone.
  • 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.
  • such poorly soluble drug substances may be solubilised with surfactants or surfactant combinations, as for example described in WO 2005/037246.
  • 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.
  • complexing agents such as cyclodextrins
  • 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.
  • 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.
  • pulmonary antibiotic therapies have been proposed in the scientific and patent literature.
  • 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.
  • a method for the treatment of severe chronic bronchitis (bronchiectasis) using a concentrated aminoglycoside antibiotic formulation 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.
  • the method comprises the endobronchial administration of aerosolized tobramycin to treat pseudomonal infections in severe chronic bronchitis patients.
  • 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.
  • CF cystic fibrosis
  • COPD chronic obstructive pulmonary disease
  • bacterial respiratory infections caused by resistant bacteria remains a major problem, particularly in CF, COPD and HIV patients or those receiving immunosuppressive drugs.
  • chronic pulmonary infection with Pseudomonas aeruginosa in patients with cystic fibrosis is a major cause of their high mortality.
  • 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.
  • aztreonam is milled or spray-dried to particle sizes of 1 to 5 micrometers.
  • 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.
  • 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.
  • QSS Quorum Sensing System
  • 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.
  • DHEA dehydro-epi- andosterone
  • NSAID non steroidal anti-inflammatory drug
  • 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.
  • 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 ⁇ m.
  • 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 0 C 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 ⁇ -, ⁇ -, and ⁇ -cyclodextrins in the formulation.
  • 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.
  • 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 ⁇ m; 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.
  • 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 ⁇ m.
  • 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.
  • 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.
  • the requirement of a dispersed liquid phase does not exclude the presence of a solid phase.
  • 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.
  • the gas phase may simply be air or compressed air, which is most common in inhalation therapy using nebulisers as aerosol generators.
  • 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.
  • 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 0 C and at a pH from about 3 to 9.
  • 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.
  • the aqueous solubility of the active compound is at least about 20 mg/ml, as defined herein.
  • the aqueous solubility is at least about 50 mg/ml and 100 mg/ml, respectively.
  • 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.
  • 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.
  • 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.
  • a reference to the ⁇ NN name of a compound includes all potentially appli- cable forms of that substance, in particular the salts and solvates thereof.
  • 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, Hae
  • 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.
  • antibiotics that concentrate in polymorphonuclear neutrophils eg, azithromycin, ciprofloxacin, levofloxacin, moxifloxacin
  • 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
  • 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.
  • 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.
  • 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.
  • PAE post-antibiotic effect
  • 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.
  • 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.
  • immunomodulatory defined as sup- pressing hyperimmunity and inflammation without overt immunosuppression.
  • 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).
  • GM-CSF granulocyte- macrophage colony-stimulating factor
  • IL-8 IL-8
  • eotaxin tumour necrosis factor
  • GM-CSF GM-CSF
  • Th2 T helper-2 cell
  • NF nuclear factor
  • Macrolides reduce inflammatory cell infiltrate by decreasing adhesion molecule expression and enhancing apoptosis.
  • DPB diffuse panbronchioli- tis
  • CF cystic fibrosis
  • chronic bronchitis chronic rhinosinusitis.
  • azitromycin is believed to be one of the most potent agents currently available for the treatment of nontuberculous mycobacterial disease.
  • HBV human immunodeficiency virus
  • MAC avium complex
  • 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, such 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.
  • aminoglycosides such 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 anti
  • 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.
  • 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.
  • NSAIDs non steroidal anti-inflammatory drugs
  • the active drug compound will be selected as a pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative thereof.
  • 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.
  • 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 f ⁇ brotic 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.
  • 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.
  • a phosphodiesterase inhibitor such as sildenafil, vardenafil, or tadalafil
  • 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.
  • 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.
  • NSAID non steroidal anti-inflammatory drug
  • 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.
  • the active compound is poorly stable in an aqueous solution at 25 °C.
  • 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.
  • 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.
  • the dispersed phase of the aerosol exhibits a mass median diameter from about 1 to about 6 ⁇ m and more preferably from 2 - 4.5 ⁇ m.
  • mass median diameter 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.
  • a MMD in the region of 2 to 4 ⁇ m is particularly suitable for sinus delivery.
  • 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.
  • 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.
  • the aerosol of the invention may have a mass median diameter of about 2.5 to 4.5 ⁇ m, in others from about 3 to about 4 ⁇ m, or from about 2 to about 3.5 ⁇ m, respectively.
  • the MMD is approximately ( ⁇ 0.25 ⁇ m) 2.0, 2.5 ⁇ m, 3.0 ⁇ m, 3.5 ⁇ m, 4.0 ⁇ m or 4.5 ⁇ m.
  • the geometric standard deviation of the MMD of the aerosol should preferably be larger than about 2, such as about 2.3 or more.
  • 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.
  • the aerosol if it is for pulmonary delivery, it may exhibit a MMD in the range from about 2.0 to about 4.5 ⁇ m 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.
  • the droplets of the aero- sol i.e. the dispersed liquid phase
  • 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.
  • 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.
  • the taste-masking agent is a complexing agent selected from pharmaceutically acceptable cyclodextrins, in particular ⁇ -, ⁇ -, and ⁇ - cyclodextrins or derivatives thereof.
  • Cyclodextrins are cyclic oligosaccharides composed of ( ⁇ -l,4)-linked ⁇ -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 ⁇ -, ⁇ -, and ⁇ -cyclodextrins with 6, 7, and 8 glucopyranose units, respectively.
  • the diameters of the cavities are approximately 4.7 to 5.3 A for ⁇ -cyclodextrins, 6.0 to 6.5 for ⁇ -cyclodextrins, and 7.5 to 8.3 for ⁇ - cyclodextrins.
  • the non-derivatised cyclodextrins exhibit aqueous solubilities of about 145 mg/ml ( ⁇ -cyclodextrin), 18.5 mg/ml ( ⁇ -cyclodextrin), and 232 mg/ml ( ⁇ - 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- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ - cyclodextrin, sulfobutyl- ⁇ -cyclodextrin, sulfobutyl- ⁇ -cyclodextrin, maltosyl- ⁇ - cyclodextrin, and methyl- ⁇ -cyclodextrin.
  • Particularly preferred at present are 2- hydroxypropyl- ⁇ -cyclodextrin, and sulfobutyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ - cyclodextrin, and ⁇ -cyclodextrin being essentially free from endotoxin contamination.
  • 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.
  • the cyclodextrin is selected from the group consisting of 2-hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
  • the dispersed phase of the aerosol comprises the active compound azithromycin and, as a taste-masking excipient, 2-hydroxypropyl- ⁇ - 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, ⁇ -cyclodextrin at a concentration in the range from about 1 to about 10 wt.-%, or from about 2.5 to about 7.5 wt.-%.
  • 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.
  • the taste-masking excipient is selected from the group of pharmaceutically acceptable sweeteners.
  • preferred sweeteners 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.
  • the respective salts and solvates of the compounds mentioned herein are always included, whether specifically mentioned or not.
  • 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.-%.
  • 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.
  • the dispersed phase of the aerosol comprises both, a cyclodextrin and a sweetener as taste-masking agents, such as ⁇ -cyclodextrin in combination with saccharin sodium, or 2-hydroxypropyl- ⁇ -cyclodextrin in combination with aspartame or xylitol.
  • a cyclodextrin and a sweetener as taste-masking agents, such as ⁇ -cyclodextrin in combination with saccharin sodium, or 2-hydroxypropyl- ⁇ -cyclodextrin in combination with aspartame or xylitol.
  • a sweetener as taste-masking agents, such as ⁇ -cyclodextrin in combination with saccharin sodium, or 2-hydroxypropyl- ⁇ -cyclodextrin in combination with aspartame or xylitol.
  • the latter is particularly preferred, since the antimicrobial efficiency of macrolides, such as azithromycin may be enhanced.
  • 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.
  • organic or amino acids such as arginine
  • water-soluble organic acids having a low molecular weight such as citric acid and lactic acid.
  • one of these compounds may be used in combination with a cyclodextrin and/or with a sweetener.
  • citric acid may be used in combination with ⁇ -cyclodextrin and saccharin sodium and/or xylitol.
  • 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.
  • 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.
  • macrolides e.g. azithromycin, clarithromycin or a combination thereof
  • metal ions e.g. divalent cations and combinations0 thereof.
  • 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 eFlowTM 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
  • an at least equimolar amount of ⁇ divalent cations is used (i.e., the molar ratio of divalent cations to macrolide is at least 1).
  • 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.
  • the aerosol of the invention may be generated with any conventional nebuliser.
  • nebulisers are devices capable of aerosolising liquids.
  • 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).
  • a piezoelectric, electro-hydrodynamic, and/or perforated membrane-type nebuliser is selected for generating the aerosol of the invention.
  • suitable nebulisers include the MysticTM, I-NebTM, MicroAirTM, MultisonicTM, RespimateTM, eFlowTM, AeroNebTM, AeroNeb ProTM, and Aero DoseTM device families.
  • 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.
  • the nebuliser is capable of emitting a pulsating (or vibrating) aerosol.
  • a pulsating aerosol or vibrating
  • 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.
  • 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.
  • 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.
  • the aerosol fraction deposited in the sinuses may be improved if the amplitude of the pulsation is also further increased.
  • 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.
  • 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.
  • an aerosol generator is a device or a combination of devices capable of generating and emitting an aerosol.
  • the device is capable of aerosolising a liquid material into a dispersed liquid phase.
  • a nebuliser typically, such device is referred to as a nebuliser.
  • the aerosol generator of the invention may require or include a compressor.
  • 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 SINUSTM compressor and a jet nebuliser or a modified eFlowTM electronic nebuliser making use of a perforated vibrating membrane to generate an aerosol.
  • an aerosol which is intended for sinus or sinunasal delivery is that it pulsates, or vibrates, with a selected frequency.
  • the pulsation of an aerosol is understood as a periodic change of pressure.
  • 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.
  • the pressure of the aerosol pulsates with a frequency in the range from about 10 Hz to about 90 Hz.
  • 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.
  • 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.
  • 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.
  • the output rate of the nebuliser should be selected to achieve a short nebulisation time of the liquid composition.
  • the nebulisation time will de- pend on the volume of the composition which is to be aerosolised and on the output rate.
  • 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.
  • 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.
  • 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.
  • 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.
  • it is an essential feature of the liquid composition that it comprises at least one taste-masking excipient as defined above.
  • 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.
  • the dynamic viscosity is selected in the range of about 1.0 to about 2.5 mPa-s.
  • 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.
  • 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.
  • an aerosol 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 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.
  • 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.
  • magnesium salts as complexing and taste masking agent improves the tolerability of azithromycin formulations upon inhala- tion via an eFlowTM 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).
  • 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).
  • an optimised aerosol osmolality may not be as critical as, for example, in the case of deep lung delivery of aerosols.
  • the intended use of the aerosol should be taken into account when selecting the osmolality of the liquid composition.
  • an osmolality in the range of up to 800 mOsmol/kg may be acceptable.
  • an osmolality in the range of about 200 up to about 600 mOsmol/kg is preferred.
  • the osmolality is even closer to the physiological value, i.e. from about 220 to about 450 mOsmol/kg.
  • 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.
  • 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
  • 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.
  • the composition comprises at least one excipient to adjust the pH.
  • the preparation according to the invention should be adjusted to a euhydric pH value.
  • 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.
  • 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.
  • physiologically acceptable acids for adjusting and, optionally, buffering the pH value
  • physiologically acceptable acids for adjusting and, optionally, buffering the pH value
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the taste- masking agent(s) may be incorporated in an aqueous solvent which is provided to reconstitute the solid composition.
  • one or more additional excipients may be useful.
  • 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.
  • 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.
  • kit preferably comprises the solid composition in sterile form.
  • 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.
  • contamination rates may be higher.
  • the contamination rate for aseptically manufactured preparations might amount to about 10 "3 .
  • 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.
  • 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.
  • 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 ⁇ m; and (c) operating said nebuliser to aerosolise the liquid composition.
  • 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.
  • 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;
  • the composition is administered using a regimen of repeated admini- stration over a course of at least about five days.
  • 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.
  • 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 solution was sterile filtered under laminar air flow (LAF) using a 0.22 ⁇ m sterile filter.
  • LAF laminar air flow
  • the sterile filtered clear solution was filled in Type I glass vials (USP) and stored under 5 0 C ⁇ 3 conditions as a sterile solution, ready-to-use.
  • the solution exhibited a dynamic viscosity of 1.22 mPa s, an osmolality of 396 m ⁇ smol/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.
  • 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 ⁇ m 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.
  • a sterile aqueous solution was prepared from azithromycin dihydrate (5.0 wt.-%), L-arginine (0.5 wt.-%), and ⁇ -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 m ⁇ smol/kg. The solution was sterile filtered under LAF. The sterile solution was filled into Type I glass vials.
  • 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 ⁇ -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.
  • USP type I glass
  • 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.
  • a sample of 2 ml of the azithromycin solution of Example 1 was tested for its suitability for nebulisation.
  • a PARI eFlowTM 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 MasterSizerXTM. The aerosol was measured at a flow rate of 20 1/min entrained air, conditioned to 23 °C and 50% r.h.
  • 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 ⁇ m, 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 ⁇ m, was 76 wt.-%.
  • Example 1 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).
  • 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.
  • 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.-%).
  • a sterile solution comprising 5 wt.-% pentoxifylline and 10 wt.-% 2- hydroxypropyl- ⁇ -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- ⁇ -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.
  • the resulting lipo- some dispersion was sterile filtered under LAF and 2 ml were filled into Type I brown glass vials (USP).
  • USP Type I brown glass vials
  • 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.
  • 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 eFlowTM electronic inhaler to treat acute exacerbations of COPD, bronchiectasis, pneumonia, bronchiolitis and cystic fibrosis
  • 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 18 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 m ⁇ smol/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 Example 18:
  • 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.
  • 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.
  • lactose monohydrate 2.5 wt %)
  • saccharin sodium 0.25 wt.-%)
  • L-menthol 0.25 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 2-6DTM freeze dryer according to a process as follows: freezing for 4 hours (-40 0 C and 0.010 mbar), followed by the primary drying (-10 0 C and 0.025 mbar), which was conducted for 18 hours followed by a secondary drying (+20°C and 0.025 mbar) for 18 hours.
  • 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.
  • tobramycin base was added to this solution and the weight was adjusted by the addition of water for injection to 100 g.
  • 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 m ⁇ smol/kg after being stored at 2 to 8 0 C 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 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.
  • 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.
  • 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.
  • 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.
  • the nebulization efficiency of the formulation as described in Example 28 with the eFlowTM nebulizer was investigated by breath simulation and laser diffraction. Breath simulation experiments were performed using a COMPASTM 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.
  • the aerosol produced by the eFlowTM nebulizer had a mass median diameter of 3.6 ⁇ m with 75% of the droplets being smaller than 5 ⁇ m.
  • 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.
  • 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.
  • the following lyophilisation programme was employed: freezing for 4 hours at -40 0 C 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 Example 32:
  • the solution was neutralised to a pH of about 7 by adding sodium hydroxide solution (1 M) in a dropwise manner.
  • sodium hydroxide solution (1 M)
  • 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 ⁇ m 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Nanotechnology (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des aérosols pharmaceutiques convenant pour l'inhalation. Les aérosols comprennent un ingrédient actif soluble dans l'eau ayant mauvais goût et au moins un excipient masquant le goût. Dans un autre aspect, l'invention concerne des procédés de production de compositions solides et liquides ayant une meilleure stabilité à l'état dissous et qui sont utiles pour préparer de tels aérosols. Les aérosols peuvent être administrés à la partie supérieure ou à la partie inférieure du système respiratoire au moyen de nébuliseurs appropriés pour traiter les maladies des voies respiratoires supérieures et inférieures avec des médicaments différents. Une combinaison de produits médicamenteux comprenant au moins deux médicaments actifs peut avoir un effet additif et/ou synergétique.
PCT/EP2007/007625 2006-09-01 2007-08-31 Procédés servant à masquer le goût de compositions nébulisées pour thérapie par inhalation nasale et pulmonaire Ceased WO2008025560A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06018357 2006-09-01
EP06018357.1 2006-09-01

Publications (1)

Publication Number Publication Date
WO2008025560A1 true WO2008025560A1 (fr) 2008-03-06

Family

ID=37698842

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/007625 Ceased WO2008025560A1 (fr) 2006-09-01 2007-08-31 Procédés servant à masquer le goût de compositions nébulisées pour thérapie par inhalation nasale et pulmonaire

Country Status (1)

Country Link
WO (1) WO2008025560A1 (fr)

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2098219A1 (fr) * 2008-03-05 2009-09-09 PARI Pharma GmbH Compositions de macrolide ayant un goût et une stabilité améliorés
ES2335334A1 (es) * 2008-09-23 2010-03-24 Laboratorio Jaer, S.A. Utilizacion del xilitol para el enmascaramiento gustativo de amargantes en alimentos para animales.
WO2010034853A1 (fr) * 2008-09-23 2010-04-01 Laboratorio Jaer, S.A. Utilisation de xylitol ou de ses dérivés pour le masquage du goût d'agents chimiothérapeutiques du groupe de l'acide quinolon-o-naphthyridoncarboxilique administrés dans des aliments destinés au bétail porcin
WO2010042553A1 (fr) * 2008-10-07 2010-04-15 Mpex Pharmaceuticals, Inc. Formulations à base de fluoroquinolone sous forme d'aérosol pour une pharmacocinétique améliorée
US7838532B2 (en) 2005-05-18 2010-11-23 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
ES2351643A1 (es) * 2009-07-27 2011-02-09 Laboratorio Jaer,S.A. Utilización de xilitol o sus derivados para el enmascaramiento gustativo de quimioterápicos del grupo del ácido quinolon-o-naftiridoncarboxílico administrados en alimentos destinados a ganado porcino.
US20120058198A1 (en) * 2009-03-26 2012-03-08 Pulmatrix, Inc. Methods for treating and preventing pneumonia and ventilator-associated tracheobronchitis
US20120083462A1 (en) * 2006-10-11 2012-04-05 Arthur Deboeck Pharmaceutical anti-infective composition for inhalation
EP2398462A4 (fr) * 2009-02-18 2012-07-25 Aradigm Corp Formulations modulées par le ph destinées à une administration pulmonaire
US8357696B2 (en) 2005-05-18 2013-01-22 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
EP2641477A1 (fr) * 2012-03-19 2013-09-25 Symrise AG Compositions de matière
US8629139B2 (en) 2008-10-07 2014-01-14 Mpex Pharmaceuticals, Inc. Topical use of Levofloxacin for reducing lung inflammation
ITRM20130268A1 (it) * 2013-05-06 2014-11-07 Medivis S R L Formulazioni oftalmiche acquose a base di azitromicina.
US8992983B2 (en) 2010-08-30 2015-03-31 Pulmatrix, Inc. Respirably dry powder comprising calcium lactate, sodium chloride and leucine
US9061352B2 (en) 2010-08-30 2015-06-23 Pulmatrix, Inc. Dry powder formulations and methods for treating pulmonary diseases
CN105073123A (zh) * 2013-03-15 2015-11-18 因赛特视觉公司 浓缩的氮杂内酯类水性制剂
WO2016050933A1 (fr) * 2014-10-03 2016-04-07 Xellia Pharmaceuticals Aps Dispositif d'inhalation
US9433576B2 (en) 2010-09-29 2016-09-06 Pulmatrix, Inc. Cationic dry powders
US9642798B2 (en) 2010-09-29 2017-05-09 Pulmatrix, Inc. Monovalent metal cation dry powders for inhalation
US9700564B2 (en) 2009-09-04 2017-07-11 Horizon Orphan Llc Use of aerosolized levofloxacin for treating cystic fibrosis
US9737518B2 (en) 2013-04-01 2017-08-22 Pulmatrix Operating Company, Inc. Tiotropium dry powders
WO2017207117A1 (fr) * 2016-05-31 2017-12-07 Polyphor Ag Peptidomimétique en épingle à cheveux bêta présentant une activité d'inhibition de l'élastase et formes pharmaceutiques aérosols correspondantes
CN109771397A (zh) * 2019-02-24 2019-05-21 谭淞文 通过乳糖微粉预沉积改良肺部吸入用药的设备集成及方法
CN109843266A (zh) * 2016-08-02 2019-06-04 安巴知识产权有限公司 稳定的布洛芬注射组合物
US10532080B2 (en) 2014-10-03 2020-01-14 Xellia Pharmaceuticals Aps Sulfomethylated polymixin compositions
JP2020033285A (ja) * 2018-08-29 2020-03-05 日本食品化工株式会社 マクロライド化合物の苦味抑制剤
US10589039B2 (en) 2012-02-29 2020-03-17 Pulmatric Operating Company, Inc. Methods for producing respirable dry powders
US10640536B2 (en) 2013-01-11 2020-05-05 Xellia Pharmaceuticals Aps Polymyxins, compositions, methods of making and methods of use
EP2211617B1 (fr) * 2007-10-04 2020-07-08 Sun Pharma Global FZE Formulations aqueuses concentrées d'azalide
US10711040B2 (en) 2014-07-09 2020-07-14 Xellia Pharmaceuticals Aps Low substituted polymyxins and compositions thereof
WO2021030553A1 (fr) * 2019-08-13 2021-02-18 Matinas Biopharma Nanotechnologies, Inc. Méthodes de traitement d'infections à cryptococcus
US11123323B2 (en) 2008-09-04 2021-09-21 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Monoterpenes for treating respiratory disorders, in particular bronchopulmonary disorders
WO2021205074A1 (fr) * 2020-04-07 2021-10-14 Aalto University Foundation Sr Formulation inhalable
CN113679690A (zh) * 2021-09-06 2021-11-23 复旦大学附属中山医院 茶碱干粉制剂及其制备方法和用途
CN115287060A (zh) * 2022-03-24 2022-11-04 辽宁科技大学 蓝光碳点、荧光粉和白光发光二极管及其制备方法
CN115736321A (zh) * 2022-11-18 2023-03-07 深圳市真味生物科技有限公司 一种新型雾化液
CN116322604A (zh) * 2020-07-06 2023-06-23 森索里克劳德公司 鼻卫生组合物、抗微生物处理、装置以及用于将其递送至鼻、气管和主支气管的制品

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0605203A2 (fr) * 1992-12-25 1994-07-06 Senju Pharmaceutical Co., Ltd. Composition antiallergique pour l'utilisation ophtalmique ou nasale
EP0640344A1 (fr) * 1993-08-30 1995-03-01 Medichemie Ag Composition pharmaceutique sous forme de dosage liquide contenant l'acide ursodésoxycholique
EP1092430A1 (fr) * 1991-06-10 2001-04-18 Schering Corporation Formulations d' aérosols sans chlorofluorohydrocarbures
WO2002072102A1 (fr) * 2001-03-05 2002-09-19 Ortho-Mcneil Pharmaceutical, Inc. Compositions pharmaceutiques liquides a gout masque
US6518239B1 (en) * 1999-10-29 2003-02-11 Inhale Therapeutic Systems, Inc. Dry powder compositions having improved dispersivity
WO2006011051A1 (fr) * 2004-07-22 2006-02-02 Pfizer Products Inc. Formulation de masquage du gout comprenant un medicament a dissolution retardee et/ou de la cyclodextrine a dissolution amelioree

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1092430A1 (fr) * 1991-06-10 2001-04-18 Schering Corporation Formulations d' aérosols sans chlorofluorohydrocarbures
EP0605203A2 (fr) * 1992-12-25 1994-07-06 Senju Pharmaceutical Co., Ltd. Composition antiallergique pour l'utilisation ophtalmique ou nasale
EP0640344A1 (fr) * 1993-08-30 1995-03-01 Medichemie Ag Composition pharmaceutique sous forme de dosage liquide contenant l'acide ursodésoxycholique
US6518239B1 (en) * 1999-10-29 2003-02-11 Inhale Therapeutic Systems, Inc. Dry powder compositions having improved dispersivity
WO2002072102A1 (fr) * 2001-03-05 2002-09-19 Ortho-Mcneil Pharmaceutical, Inc. Compositions pharmaceutiques liquides a gout masque
WO2006011051A1 (fr) * 2004-07-22 2006-02-02 Pfizer Products Inc. Formulation de masquage du gout comprenant un medicament a dissolution retardee et/ou de la cyclodextrine a dissolution amelioree

Cited By (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8357696B2 (en) 2005-05-18 2013-01-22 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US10987357B2 (en) 2005-05-18 2021-04-27 Horizon Orphan, LLC Aerosolized fluoroquinolones and uses thereof
US8546423B2 (en) 2005-05-18 2013-10-01 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US8524735B2 (en) 2005-05-18 2013-09-03 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US8524734B2 (en) 2005-05-18 2013-09-03 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US7838532B2 (en) 2005-05-18 2010-11-23 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US10709723B2 (en) 2006-10-11 2020-07-14 Galephar Pharmaceutical Research, Inc. Pharmaceutical anti-infective composition for inhalation
US20120083462A1 (en) * 2006-10-11 2012-04-05 Arthur Deboeck Pharmaceutical anti-infective composition for inhalation
EP2211617B1 (fr) * 2007-10-04 2020-07-08 Sun Pharma Global FZE Formulations aqueuses concentrées d'azalide
WO2009109390A1 (fr) * 2008-03-05 2009-09-11 Pari Pharma Gmbh Compositions de macrolide ayant un goût et une stabilité améliorés
EP2098219A1 (fr) * 2008-03-05 2009-09-09 PARI Pharma GmbH Compositions de macrolide ayant un goût et une stabilité améliorés
US11123323B2 (en) 2008-09-04 2021-09-21 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Monoterpenes for treating respiratory disorders, in particular bronchopulmonary disorders
US11135194B2 (en) 2008-09-04 2021-10-05 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Monoterpenes for treating respiratory diseases, in particular bronchopulmonary diseases
ES2335334B1 (es) * 2008-09-23 2011-02-09 Laboratorio Jaer, S.A. Utilizacion del xilitol para el enmascaramiento gustativo de amargantes en alimentos para animales.
WO2010034853A1 (fr) * 2008-09-23 2010-04-01 Laboratorio Jaer, S.A. Utilisation de xylitol ou de ses dérivés pour le masquage du goût d'agents chimiothérapeutiques du groupe de l'acide quinolon-o-naphthyridoncarboxilique administrés dans des aliments destinés au bétail porcin
ES2335334A1 (es) * 2008-09-23 2010-03-24 Laboratorio Jaer, S.A. Utilizacion del xilitol para el enmascaramiento gustativo de amargantes en alimentos para animales.
CN105520922A (zh) * 2008-10-07 2016-04-27 拉普特制药有限公司 用于改进的药物动力学的氟喹诺酮气雾剂制剂
US10149854B2 (en) 2008-10-07 2018-12-11 Horizon Orphan Llc Aerosol fluoroquinolone formulations for improved pharmacokinetics
US8629139B2 (en) 2008-10-07 2014-01-14 Mpex Pharmaceuticals, Inc. Topical use of Levofloxacin for reducing lung inflammation
US9717738B2 (en) 2008-10-07 2017-08-01 Horizon Orphan Llc Aerosol fluoroquinolone formulations for improved pharmacokinetics
US10722519B2 (en) 2008-10-07 2020-07-28 Horizon Orphan Llc Aerosol fluoroquinolone formulations for improved pharmacokinetics
US8815838B2 (en) 2008-10-07 2014-08-26 David C. Griffith Aerosol fluoroquinolone formulations for improved pharmacokinetics
US11020481B2 (en) 2008-10-07 2021-06-01 Horizon Orphan Llc Topical use of levofloxacin for reducing lung inflammation
WO2010042553A1 (fr) * 2008-10-07 2010-04-15 Mpex Pharmaceuticals, Inc. Formulations à base de fluoroquinolone sous forme d'aérosol pour une pharmacocinétique améliorée
AU2009302478B2 (en) * 2008-10-07 2015-09-03 Horizon Orphan Llc Aerosol fluoroquinolone formulations for improved pharmacokinetics
US9326936B2 (en) 2008-10-07 2016-05-03 Raptor Pharmaceuticals, Inc. Aerosol fluoroquinolone formulations for improved pharmacokinetics
AU2010216348B2 (en) * 2009-02-18 2015-01-22 Aradigm Corporation pH-modulated formulations for pulmonary delivery
EP2398462A4 (fr) * 2009-02-18 2012-07-25 Aradigm Corp Formulations modulées par le ph destinées à une administration pulmonaire
US20120058198A1 (en) * 2009-03-26 2012-03-08 Pulmatrix, Inc. Methods for treating and preventing pneumonia and ventilator-associated tracheobronchitis
ES2351643A1 (es) * 2009-07-27 2011-02-09 Laboratorio Jaer,S.A. Utilización de xilitol o sus derivados para el enmascaramiento gustativo de quimioterápicos del grupo del ácido quinolon-o-naftiridoncarboxílico administrados en alimentos destinados a ganado porcino.
US10792289B2 (en) 2009-09-04 2020-10-06 Horizon Orphan Llc Use of aerosolized levofloxacin for treating cystic fibrosis
US10231975B2 (en) 2009-09-04 2019-03-19 Horizon Orphan Llc Use of aerosolized levofloxacin for treating cystic fibrosis
US9700564B2 (en) 2009-09-04 2017-07-11 Horizon Orphan Llc Use of aerosolized levofloxacin for treating cystic fibrosis
US9233158B2 (en) 2010-08-30 2016-01-12 Pulmatrix, Inc. Dry powder formulations and methods for treating pulmonary diseases
US9061352B2 (en) 2010-08-30 2015-06-23 Pulmatrix, Inc. Dry powder formulations and methods for treating pulmonary diseases
US8992983B2 (en) 2010-08-30 2015-03-31 Pulmatrix, Inc. Respirably dry powder comprising calcium lactate, sodium chloride and leucine
US11173115B2 (en) 2010-09-29 2021-11-16 Pulmatrix Operating Company, Inc. Monovalent metal cation dry powders for inhalation
US10376465B2 (en) 2010-09-29 2019-08-13 Pulmatrix Operating Company, Inc. Monovalent metal cation dry powders for inhalation
US9744130B2 (en) 2010-09-29 2017-08-29 Pulmatrix Operating Company, Inc. Cationic dry powders
US9433576B2 (en) 2010-09-29 2016-09-06 Pulmatrix, Inc. Cationic dry powders
US9642798B2 (en) 2010-09-29 2017-05-09 Pulmatrix, Inc. Monovalent metal cation dry powders for inhalation
US10806871B2 (en) 2012-02-29 2020-10-20 Pulmatrix Operating Company, Inc. Inhalable dry powders
US10589039B2 (en) 2012-02-29 2020-03-17 Pulmatric Operating Company, Inc. Methods for producing respirable dry powders
US8828473B2 (en) 2012-03-19 2014-09-09 Symrise Ag Substance mixtures
EP2641477A1 (fr) * 2012-03-19 2013-09-25 Symrise AG Compositions de matière
US10640536B2 (en) 2013-01-11 2020-05-05 Xellia Pharmaceuticals Aps Polymyxins, compositions, methods of making and methods of use
EP2968383A4 (fr) * 2013-03-15 2016-08-24 Insite Vision Inc Formulations aqueuses concentrées d'azalide
CN105073123B (zh) * 2013-03-15 2019-05-28 太阳药业国际公司 浓缩的氮杂内酯类水性制剂
CN105073123A (zh) * 2013-03-15 2015-11-18 因赛特视觉公司 浓缩的氮杂内酯类水性制剂
JP2016512819A (ja) * 2013-03-15 2016-05-09 インサイト ヴィジョン インコーポレイテッド 濃縮水性アザライド製剤
US9737518B2 (en) 2013-04-01 2017-08-22 Pulmatrix Operating Company, Inc. Tiotropium dry powders
ITRM20130268A1 (it) * 2013-05-06 2014-11-07 Medivis S R L Formulazioni oftalmiche acquose a base di azitromicina.
WO2014181368A1 (fr) * 2013-05-06 2014-11-13 Medivis S.R.L. Formulations ophtalmiques aqueuses à base d'azithromycine
US10342816B2 (en) 2013-05-06 2019-07-09 Medivis S.R.L. Aqueous ophthalmic formulations based on azithromycin
US10711040B2 (en) 2014-07-09 2020-07-14 Xellia Pharmaceuticals Aps Low substituted polymyxins and compositions thereof
CN106999542B (zh) * 2014-10-03 2021-02-02 埃克斯利亚制药有限公司 吸入装置
AU2015326847B2 (en) * 2014-10-03 2018-11-29 Xellia Pharmaceuticals Aps Inhalation device
RU2702335C2 (ru) * 2014-10-03 2019-10-08 Кселлия Фармасьютикалз Апс Ингаляционное устройство
US10532080B2 (en) 2014-10-03 2020-01-14 Xellia Pharmaceuticals Aps Sulfomethylated polymixin compositions
RU2712276C2 (ru) * 2014-10-03 2020-01-28 Кселлия Фармасьютикалз Апс Композиции
KR102494511B1 (ko) * 2014-10-03 2023-01-31 셀리아 파마슈티칼즈 에이피에스 흡입 장치
WO2016050933A1 (fr) * 2014-10-03 2016-04-07 Xellia Pharmaceuticals Aps Dispositif d'inhalation
EP3520777A1 (fr) * 2014-10-03 2019-08-07 Xellia Pharmaceuticals ApS Dispositif d'inhalation
KR20170062521A (ko) * 2014-10-03 2017-06-07 셀리아 파마슈티칼즈 에이피에스 흡입 장치
CN106999542A (zh) * 2014-10-03 2017-08-01 埃克斯利亚制药有限公司 吸入装置
US11033602B2 (en) 2014-10-03 2021-06-15 Xellia Pharmaceuticals Aps Inhalation device
JP2017530138A (ja) * 2014-10-03 2017-10-12 クセリア ファーマシューティカルズ エーピーエスＸｅｌｌｉａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ ＡｐＳ 吸入用デバイス
KR20190011750A (ko) * 2016-05-31 2019-02-07 폴리포 리미티드 엘라스타제 억제 활성을 갖는 베타-헤어핀 펩티드 모방체 및 이의 에어로졸 투여 형태
CN109195580A (zh) * 2016-05-31 2019-01-11 波利弗尔股份公司 具有弹性蛋白酶抑制活性的β-发夹肽模拟物及其气雾剂剂量形式
WO2017207118A1 (fr) * 2016-05-31 2017-12-07 Polyphor Ag Peptidomimétique en épingle à cheveux bêta ayant une activité inhibitrice à l'encontre de l'élastase, et ses formes posologiques en aérosol
US11844823B2 (en) 2016-05-31 2023-12-19 Polyphor Ag Beta-hairpin peptidomimetic with elastase inhibitory activity and aerosol dosage forms thereof
WO2017207117A1 (fr) * 2016-05-31 2017-12-07 Polyphor Ag Peptidomimétique en épingle à cheveux bêta présentant une activité d'inhibition de l'élastase et formes pharmaceutiques aérosols correspondantes
CN109310613A (zh) * 2016-05-31 2019-02-05 波利弗尔股份公司 具有弹性蛋白酶抑制活性的β-发夹肽模拟物及其气雾剂剂量形式
JP2019523763A (ja) * 2016-05-31 2019-08-29 ポリフォー・アクチェンゲゼルシャフトＰｏｌｙｐｈｏｒ Ａｇ エラスターゼ阻害活性を有するベータヘアピンペプチド模倣体及びそのエアロゾル剤形
EA039603B1 (ru) * 2016-05-31 2022-02-16 Полифор Аг Бета-шпилечные пептидомиметики, обладающие ингибирующей активностью в отношении эластазы, и содержащие их лекарственные формы в виде аэрозоля
KR102511284B1 (ko) * 2016-05-31 2023-03-16 폴리포 리미티드 엘라스타제 억제 활성을 갖는 베타-헤어핀 펩티드 모방체 및 이의 에어로졸 투여 형태
US11235023B2 (en) 2016-05-31 2022-02-01 Polyphor Ag Beta-hairpin peptidomimetic with elastase inhibitory activity and aerosol dosage forms thereof
AU2017273507B2 (en) * 2016-05-31 2022-03-17 Polyphor Ag Beta-hairpin peptidomimetic with elastase inhibitory activity and aerosol dosage forms thereof
JP2019523222A (ja) * 2016-05-31 2019-08-22 ポリフォー・アクチェンゲゼルシャフトＰｏｌｙｐｈｏｒ Ａｇ エラスターゼ阻害活性を有するベータヘアピンペプチド模倣体及びそのエアロゾル剤形
AU2017273508B2 (en) * 2016-05-31 2022-07-28 Polyphor Ag Beta-hairpin peptidomimetic with elastase inhibitory activity and aerosol dosage forms thereof
US11235024B2 (en) 2016-05-31 2022-02-01 Polyphor Ag Beta-hairpin peptidomimetic with elastase inhibitory activity and aerosol dosage forms thereof
CN109843266A (zh) * 2016-08-02 2019-06-04 安巴知识产权有限公司 稳定的布洛芬注射组合物
CN109843266B (zh) * 2016-08-02 2023-08-11 安巴知识产权有限公司 稳定的布洛芬注射组合物
JP2020033285A (ja) * 2018-08-29 2020-03-05 日本食品化工株式会社 マクロライド化合物の苦味抑制剤
CN109771397B (zh) * 2019-02-24 2021-09-28 谭淞文 通过乳糖微粉预沉积改良肺部吸入用药的设备集成及方法
CN109771397A (zh) * 2019-02-24 2019-05-21 谭淞文 通过乳糖微粉预沉积改良肺部吸入用药的设备集成及方法
WO2021030553A1 (fr) * 2019-08-13 2021-02-18 Matinas Biopharma Nanotechnologies, Inc. Méthodes de traitement d'infections à cryptococcus
WO2021205074A1 (fr) * 2020-04-07 2021-10-14 Aalto University Foundation Sr Formulation inhalable
CN116322604A (zh) * 2020-07-06 2023-06-23 森索里克劳德公司 鼻卫生组合物、抗微生物处理、装置以及用于将其递送至鼻、气管和主支气管的制品
CN113679690A (zh) * 2021-09-06 2021-11-23 复旦大学附属中山医院 茶碱干粉制剂及其制备方法和用途
CN115287060A (zh) * 2022-03-24 2022-11-04 辽宁科技大学 蓝光碳点、荧光粉和白光发光二极管及其制备方法
CN115736321A (zh) * 2022-11-18 2023-03-07 深圳市真味生物科技有限公司 一种新型雾化液

Similar Documents

Publication Publication Date Title
WO2008025560A1 (fr) Procédés servant à masquer le goût de compositions nébulisées pour thérapie par inhalation nasale et pulmonaire
EP2259773B1 (fr) Compositions de macrolide ayant un goût et une stabilité améliorés
EP1991201B1 (fr) Antibiotiques nébulisés pour thérapie par inhalation
RU2363449C2 (ru) Водный аэрозольный препарат
ES2599313T3 (es) Fluoroquinolonas en aerosol y sus usos
EP2248517B1 (fr) Formules pharmaceutiques à stabilisation de membrane concentrée
JP5827802B2 (ja) 鼻洞薬物送達用エーロゾル剤
TW200301131A (en) Pulmonary delivery of aminoglycosides
AU2012307661B2 (en) Aqueous compositions comprising arbekacin
US20150034087A1 (en) Low Dose Pharmaceutical Composition Comprising Zanamivir

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07802042

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07802042

Country of ref document: EP

Kind code of ref document: A1