WO2014076243A1 - Optimisation des propriétés de nébulisation d'une solution ou d'un colloïde - Google Patents

Optimisation des propriétés de nébulisation d'une solution ou d'un colloïde Download PDF

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Publication number
WO2014076243A1
WO2014076243A1 PCT/EP2013/073960 EP2013073960W WO2014076243A1 WO 2014076243 A1 WO2014076243 A1 WO 2014076243A1 EP 2013073960 W EP2013073960 W EP 2013073960W WO 2014076243 A1 WO2014076243 A1 WO 2014076243A1
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solution
colloid
aerosol
concentration
additive
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PCT/EP2013/073960
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German (de)
English (en)
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Moritz Beck-Broichsitter
Tobias Gessler
Thomas Schmehl
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Justus-Liebig-Universität Giessen
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Publication of WO2014076243A1 publication Critical patent/WO2014076243A1/fr

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    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the invention relates to a method for nebulizing a solution or a colloid to form aerosol particles, thereby obtained aerosols and their use for pulmonary administration in a patient for the diagnosis or therapy of a disease.
  • Inhalation for example, in the treatment of respiratory diseases, such as asthma and COPD, or in anesthesia one of the most important forms of application of therapeutically or diagnostically active agents.
  • the oral administration of drugs with the aid of tablets and Similarly, the drug passes through the inhalation directly into the respiratory tract of the patient.
  • the topical application usually requires less active ingredient and the side effects are often lower.
  • active ingredients administered with the help of inhalers act much more quickly in the desired target tissue of the respiratory tract. So u. a. the bioavailability increases as well as the onset of action are accelerated.
  • drugs can be administered both locally and systemically.
  • Aerosols are dispersions of liquid or solid particles in a gas phase. These particles in the aerosol are also referred to as aerosol particles or aerosol particles.
  • piezoelectric nebulizers for the generation of inhalable aerosols, piezoelectric nebulizers, nozzles, ultrasonic aerosol generators, soft mist inhalers, metered dose inhalers or dry powder inhalers are used, i. E. the application into the respiratory tract is carried out by inhalation of an aerosol generated by means of an aerosol generator from a solution, suspension or powder.
  • the separation behavior of particles of an aerosol in the respiratory tract is primarily determined by the diameter of the particles. Larger particles preferably deposit in the upper area of the respiratory tract, while smaller particles can reach the alveoli. Aerosols with a particle diameter of 2 to 6 ⁇ m are generally produced for inhalative administration. A prerequisite for the use of active ingredients in aerosol therapy, however, is that the active ingredients can be brought into a nebulizable form, so that they can be administered with conventional nebulizers.
  • a disadvantage of the current state of the art is that not every solution or suspension with and without at least one medicinal active ingredient can be so clouded with a common vernier that results in a suitable inhalative therapy particle size distribution of the aerosol generated.
  • the aerodynamic properties of generated aerosols can hitherto essentially only be changed with the aid of constructional adjustments of the nebulizers and adapted to the therapeutic requirements.
  • the particle size distribution of aerosols produced so far essentially can only be changed by means of structural adjustments of the vernebier.
  • the output has so far mainly been determined by the design of the vernier.
  • the limited adaptation options prevent the use of predetermined nebulizers for the production of different types of aerosols.
  • it is often insufficient to produce a sufficiently large proportion of fine particles for pulmonary deposition.
  • piezoelectric Vernebier be used, which using oscillating perforated membranes from Liquids generate droplets.
  • the properties of the aerosol droplets are essentially determined by the technical process of aerosol production and the construction of the respective Vernebiers and can not be adapted for a given Vernebier to the aerosol physical requirements for optimal pulmonary deposition, for. B. so the generation of the largest possible proportion of fine particles with an aerodynamic diameter less than 5 ⁇ .
  • the object of the present invention is therefore to eliminate the disadvantages in the prior art and to provide a method with which the widest possible spectrum of solutions or suspensions or colloids with or without medicinal active in a nebulizable form, which is suitable for common Vernebier , can be brought.
  • the aerodynamic properties of the aerosols produced in particular the VMD (Volume Median Diameter or median volume diameter) and / or the FPF (Fine Particle Fraction or Fine Particle Fraction), should be adjustable without having to adjust the intended nebulizer structurally.
  • the output of generated aerosols should also be adaptable to a nebulizer without the need for constructional changes to the nebuliser.
  • the largest possible proportion of particles with an aerodynamic diameter smaller than approximately 5 ⁇ m is to be obtained during nebulization, so that even deeper areas of the respiratory tract can be reached.
  • the above object is achieved by a method for nebulizing a solution or a colloid to form particles, wherein
  • the solution or colloid contains at least one additive, the additive being selected from the group consisting of a low molecular weight compound, a polyether, a polysorbate and a modified polyvinyl alcohol (PVA), and
  • the aerosol physical parameters VMD (Volume Median Diameter) and / or FPF (Fine Particle Fraction) of the particles formed by atomization of the solution or the colloid can be adjusted via the concentration of the additive in the solution or the colloid.
  • VMD Volume Median Diameter
  • FPF Factor Particle Fraction
  • the addition of various low molecular weight substances or a polyether or a polysorbate or a modified polyvinyl alcohol (PVA) to a solution or a colloid allows the nebulization properties, ie the aerosol physical parameters of the particles formed, to be set in a targeted manner .
  • the height of the concentration of the additive can be used to adjust the aerosol physical parameters VMD (Volume Median Diameter) and / or FPF (Fine Particle Fraction), without the need for structural alteration of the vaporizer.
  • the low molecular weight compound is selected from a compound of the group consisting of an inorganic salt, preferably NaCl or CaCl 2 , an organic salt, preferably sodium citrate, a nonionic low molecular weight substance, preferably a disaccharide, in particular sucrose, or a surfactant , preferably sodium lauryl sulfate.
  • an inorganic salt preferably NaCl or CaCl 2
  • an organic salt preferably sodium citrate
  • a nonionic low molecular weight substance preferably a disaccharide, in particular sucrose, or a surfactant , preferably sodium lauryl sulfate.
  • the polyether is in particular a polyethylene glycol (PEG), preferably PEG 10,000.
  • PEG polyethylene glycol
  • Another modification concerns the process according to the invention, wherein the addition polysorbate is polysorbate 20 in particular.
  • a modified PVA to a liquid to be atomized or a colloid to be atomized can improve the aerosol physical parameters of the aerosol produced by piezoelectric vernier.
  • PVA may be modified in particular with primary, secondary and / or tertiary amines.
  • the nitrogen atoms of the amines can carry suitable organyl radicals, in particular alkyl radicals and / or aryl radicals.
  • a Diethylaminopropylamin-modified PVA diethylamino propylamine modified polyvinyl alcohol - DEAPA-PVA is used.
  • the aerosol physical parameters of a generated aerosol can be adjusted particularly well by adding the said modified PVA, in particular the DEAPA-PVA, in comparison with the use of non-modified PVA.
  • the aerosol physical parameters can be adjusted particularly advantageously in the case of an aerosol generated by piezoelectric vernier.
  • the VMD can be between 9 and 1.5 ⁇ , preferably between 5 and 1.5 ⁇ , particularly preferably between 5 and 3 ⁇ , and / or the FPF between 20 and 90%, preferably 50 to 90%, be set.
  • the concentration of said additives in the solution or the colloid to be nebulised is necessary. Basically, the highest possible FPF is desirable.
  • the nebulisation of the solutions or colloids can advantageously be carried out with piezoelectric, jet, ultrasonic aerosol generators or soft mist inhalers.
  • the said aerosol physical parameters can be adjusted particularly well by the process according to the invention when using an inorganic salt in a solution to be nebulised or in a suspension to be nebulised, if the concentration of the inorganic salt between 0.001 and 1000 mM, preferably between 0.01 and 10 mM. It was found that, especially in the dynamic range of 0.01 to 10 mM inorganic salt, there is a direct relationship between the concentration of the inorganic salt and the median diameter of the particles formed. So the VMD takes in the mentioned Range with increasing concentration of inorganic salt continuously. In this area, therefore, a particularly simple adaptation of VMD and thus also the FPF via the concentration of the inorganic salt can take place.
  • the inorganic salt may be NaCl, CaCl 2 , MgCl 2 , KCl or another salt or a suitable salt mixture.
  • the mentioned aerosol physical parameters can be adjusted particularly well by the method according to the invention using NaCl as an additive, if the concentration of NaCl in a solution to be nebulised or in a suspension to be nebulised between 0.01 and 1000 mM, preferably between 0.01 and 10 mM is chosen. It was found that, especially in the dynamic range of 0.01 to 10 mM, preferably 0.01 to 5 mM, NaCl has a direct relationship between the concentration of NaCl and the median diameter of the particles formed. Thus, the VMD decreases continuously in the range mentioned with increasing concentration of NaCl, and thus the FPF correspondingly. In this area, therefore, a particularly simple adaptation of VMD and FPF can take place via the concentration of NaCl.
  • the abovementioned aerosol-physical parameters can be adjusted particularly well if the concentration of CaCl 2 in a solution to be nebulised or in a suspension to be nebulised is between 0.01 mM and 1000 mM, preferably between 0.01 mM and 1 mM is selected. It was found that, especially in the dynamic range of 0.01 to 10 mM, preferably 0.01 to 1 mM, CaCl 2 is a direct relationship between the concentration of CaCl 2 and the median diameter of the particles formed. Thus, the VMD decreases continuously in the mentioned range with increasing concentration of CaCl 2 and thus the FPF accordingly. In this area, therefore, a particularly simple adaptation of VMD and FPF can take place via the concentration of CaCl 2 .
  • the aerosol physical parameters can be adjusted particularly well if the concentration of the disaccharide such as sucrose - when nebulizing a colloid between 100 and 800 mM, according to a further aspect of the method according to the invention preferably between 150 and 725 mM or when nebulizing a solution between 100 and 1000 mM, preferably between 150 and 900 mM is selected.
  • said aerosol-physical parameters can be adjusted particularly well if the concentration of polyether, in particular of PEG,
  • nebulizing a colloid between 0.1 and 5 mM, preferably between 0.5 and 3 mM is selected or
  • aerosol-physical parameters can also be adjusted by the use of a surfactant as an additive according to the process of the invention.
  • a surfactant such as polysorbate, anionic surfactants, such as sodium lauryl sulfate, cationic surfactants, such as benzalkonium chloride, or amphoteric surfactants, such as betaines, are conceivable.
  • the aerosol physical parameters can be adjusted particularly well by the process according to the invention if the concentration of surfactant, in particular sodium lauryl sulfate, in a solution to be nebulised or in a suspension to be nebulised is between 0.001 and 100 mM, preferably between 0.01 and 20 mM.
  • the VMD continuously decreases in the stated range with increasing concentration of Na lauryl sulfate and thus the FPF accordingly. In this area, therefore, a particularly simple adaptation of VMD and FPF can take place via the concentration of Na lauryl sulfate.
  • the abovementioned aerosol-physical parameters can also be adjusted by the use of a modified PVA as additive according to the method according to the invention.
  • modified PVA in particular PVA modified with primary, secondary and / or tertiary amines
  • the nitrogen atoms of the amines can carry suitable organyl radicals, in particular alkyl radicals and / or aryl radicals.
  • suitable organyl radicals in particular alkyl radicals and / or aryl radicals.
  • a Diethylaminopropylamin-modified PVA diethylamino propylamine modified polyvinyl alcohol - DEAPA-PVA is used.
  • the aerosol physical parameters can be adjusted particularly well by the method according to the invention if the concentration of modified PVA in a solution to be nebulised or in a suspension to be nebulised is between 0.001 and 10 mg / ml, preferably between 0.01 and 10 mg / ml preferably between 0.05 and 5 mg / ml is selected.
  • concentration of modified PVA in a solution to be nebulised or in a suspension to be nebulised is between 0.001 and 10 mg / ml, preferably between 0.01 and 10 mg / ml preferably between 0.05 and 5 mg / ml is selected.
  • the concentration of modified PVA in the mentioned range decreases particularly strongly with increasing concentration of modified PVA and thus the FPF accordingly. In this area, therefore, a particularly simple and efficient adaptation of VMD and FPF can take place via the concentration of modified PVA.
  • the process according to the invention can be carried out for atomizing any solutions or colloids to form aerosol particles.
  • a solution according to the present invention may optionally contain an active ingredient.
  • the solution is used as a carrier solution for an active ingredient.
  • the invention thus also encompasses processes for atomizing a solution or a colloid to form aerosol particles according to at least one of the abovementioned Embodiments, wherein the solution to be nebulized or the colloid to be nebulised contains an active substance.
  • the active ingredient is in particular a therapeutically or diagnostically active medicinal active substance, preferably an active ingredient for the treatment of respiratory diseases such as pneumonia, asthma, COPD or pulmonary hypertension, for the treatment of systemic diseases such as diabetes mellitus, or for anesthetics.
  • a colloid may be any liquid dispersion medium having droplets or particles dispersed therein.
  • these are suspensions or emulsions of droplets or particles in a liquid.
  • the particles are, for example, nanoparticles or microparticles of biocompatible polymers, of biocompatible polymers with active substances or of active substances in suspension.
  • the method according to the invention can be applied to suspensions with active ingredients known to the person skilled in the art.
  • Such polymers are used as drug carrier systems.
  • the nano- or microparticles are obtained in particular by the solvent extraction / evaporation method known to the person skilled in the art.
  • biocompatible nanoparticles and microparticles are also produced by means of nanoprecipitation, spray drying, salting out, and polymerization. These mentioned production methods are known to the person skilled in the art.
  • an emulsion can be a single or a multiple emulsion.
  • multiple emulsions can be multiple water-in-oil-in-water (W / O / W) emulsions, which are complex systems having an outer water phase and a water-in-oil emulsion dispersed therein Overall, both a water-in-oil and an oil-in-water emulsion is present. Because of the associated properties, multiple emulsions are suitable for the application of pharmaceutical or cosmetic active ingredients, it being possible for particularly sensitive active substances to be included in the inner aqueous phase of a multiple emulsion. In this way, the active ingredients can on the one hand be protected against external influences and degradation, and on the other hand be released with a time delay.
  • W / O / W water-in-oil-in-water
  • peptides and nucleic acid-based compounds such as poly- and oligonucleotides.
  • a colloid may also affect liposomes. These are generally known to the person skilled in the art. These are colloidal particles which form spontaneously when mixing lipids, in particular phospholipids, with an aqueous medium.
  • Solutions, nano- or microparticles in suspension, emulsions are aerosolized and can be inhaled by the patient. All said solutions or colloids may optionally contain an active ingredient.
  • active ingredients those selected from the group of appetite suppressants / antiadipositas, azidoether therapeutics, analeptics / antihypoxaemics, analgesics, antirheumatics, anthelmintics, antiallergics, antianemics, antiarrhythmics, antibiotics, antiinfectives, antidiabetic agents, antidiabetics, antidotes, antiemetics, antivertiginosa can be used with advantage .
  • the diagnostics can be both in vitro and in vivo diagnostics.
  • a diagnostic agent to be used according to the invention can be, for example, imaging and / or radioactive and / or a contrast agent.
  • a colloid, in particular a suspension with nano- or microparticles, can be provided by means of the solvent extraction / evaporation method, wherein
  • Emulsion droplets of an organic phase containing a solvent which optionally contains a biocompatible polymer, a lipid and / or an active ingredient are introduced into an aqueous phase, wherein the aqueous phase an additive - that is a low molecular weight compound or a polyether according to one of the above embodiments - contains, and
  • the additive is added to the aqueous phase.
  • the adjustment of the aerosol physical parameters VMD and / or FPF of the particles formed by nebulisation of the colloid can be carried out simply by way of the level of the concentration of the additive in the aqueous phase before the nebulization.
  • the biocompatible polymer may comprise a polyester such as polylactic acid (PLA) or poly (D, L-lactide-co-glycolide) copolymer (PLGA), a protein, a polysaccharide or polyethylene carbonate.
  • PLA polylactic acid
  • PLGA poly (D, L-lactide-co-glycolide) copolymer
  • Other suitable biocompatible water-insoluble polymers are known to the person skilled in the art, such as polyanhydride, polyorthoesters, polyphosphoric esters, polycarbonate, polyketal, polyurea, polyurethane, block copolymer (PEG-PLGA), star polymer or comb polymer.
  • PEG-PLGA block copolymer
  • the materials for the nanoparticles and microparticles are preferably suitable for pulmonary application.
  • a stabilizer preferably a polymer such as polyvinyl alcohol
  • the concentration of which being chosen to be between 1 and 15 mg / ml may be between 1 and 15 mg / ml.
  • a biocompatible polymer is used between 1 to 100 g / l and stabilizer between 0.1 to 25 g / l for the preparation of biocompatible nano- and microparticles.
  • the biocompatible polymer concentration for preparation is about 50 g / L and the stabilizer concentration is about 10 g / L.
  • Emulsion and subsequent evaporation are therefore the steps
  • the nebulization can take place, wherein the aerosol physical parameters VMD and / or FPF of the particles of the aerosol for the respective application is set.
  • the additive according to the invention a low molecular weight compound or a polyether or a polysorbate or a modified PVA - can either be added during the preparation of the solution or the colloid or, alternatively, can be added subsequently before the nebulisation.
  • the present invention relates to an aerosol which is obtainable according to at least one of the abovementioned embodiments of the method according to the invention, wherein the aerosol is suitable in particular for pulmonary application in a patient for the diagnosis or therapy of a disease.
  • An aerosol according to the invention can be used in particular for the therapy of diseases of the respiratory tract or for the treatment of systemic diseases or for anesthetics.
  • Another aspect of the invention relates to an embodiment of the aerosol for the treatment of pneumonia, asthma, COPD or pulmonary hypertension.
  • a further aspect of the present invention relates to a nebulizer for nebulizing a solution or a colloid to form particles, wherein the aerosol physical parameters VMD and / or FPF of the nebulization of the solution or the colloid formed particles on the level of the concentration of the additive in the solution or the colloid according to a method according to one of the said embodiments are adjustable. This means that these parameters can be changed without adjusting the vernier.
  • the nebulizer may according to an advantageous embodiment have an additional reservoir in which an additive according to the invention is contained. Thus, a metered addition of the additive from the reservoir into the solution or the colloid to be atomized is possible.
  • the aerosol physical parameters VMD and / or FPF of the aerosol for the respective application can be set on the atomizer itself.
  • FIG. 1
  • Embodiment 1 wherein NaCl solutions as a carrier solution with different concentrations c Na ci were aerosolized with Aeroneb® Professional and eFlow®rapid according to the manufacturer.
  • the squares represent the VMD values in ⁇ for the Aeroneb® Professional and the circles the values for the eFlow®rapid nebulizer.
  • the dependence of the VMD in ⁇ on the concentration of NaCl can be seen.
  • Embodiment 2 wherein CaCI 2 solutions as a carrier solution with different concentrations c Ca ci2 were aerosolized with the aerosol Aeroneb® Professional and eFlow®rapid according to the manufacturer.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • the dependence of the VMD in ⁇ on the concentration of CaCl 2 can be seen.
  • Embodiment 3 with sucrose (sucrose) solutions were aerosolized as a carrier solution with different concentrations c Su crose with the nebulizer Aeroneb® Professional and eFlow®rapid according to manufacturer's instructions.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • the dependence of the VMD in ⁇ on the concentration of sucrose can be seen.
  • Embodiment 4 wherein PEG 10,000 (PEGI OkDa) solutions as a carrier solution with different concentrations c PE Gi okDa were aerosolized with the aerosol Aeroneb® Professional and eFlow®rapid according to the manufacturer.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • the dependence of the VMD in ⁇ on the concentration of sucrose can be seen.
  • Embodiment 5 wherein Na-lauryl sulfate (NLS) solutions as a carrier solution with different concentrations of C N LS were aerosolized with the aerosol Aeroneb® Professional and eFlow®rapid according to the manufacturer.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • the dependence of the VMD in ⁇ and the FPF in% of the concentration of Na-lauryl sulfate can be seen.
  • Embodiment 6 in which suspensions were sprayed with Pluronic® F127-coated PLGA nanoparticles (gray symbols, FIG. 6a) and with Mowiol® 4-88-coated PLGA nanoparticles (black symbols, FIG. 6b).
  • c Na ci was added to the suspensions as an addition of NaCl in various concentrations.
  • the dependence of the VMD in ⁇ on the concentration of NaCl can be seen.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • Embodiment 7 wherein suspensions were sprayed with Pluronic® F127 coated PLGA nanoparticles (gray symbols, Fig. 6a) and with Mowiol® 4-88 coated PLGA nanoparticles (black symbols, Fig. 6b).
  • the suspensions were each added as an additive CaCl 2 in various concentrations c C aci2.
  • the dependence of the VMD in ⁇ on the concentration of CaCl 2 can be seen.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier. Fig.
  • Embodiment 8 wherein suspensions were sprayed with Pluronic® F127-coated PLGA nanoparticles (gray symbols, Fig. 6a) and with Mowiol® 4-88 coated PLGA nanoparticles (black symbols, Fig. 6b).
  • the suspensions in each case as additional sucrose (sucrose) in various concentrations c Su crose was added.
  • the dependence of the VMD in ⁇ on the concentration of sucrose can be seen.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • Embodiment 9 wherein suspensions were sprayed with Pluronic® F127-coated PLGA nanoparticles (gray symbols, Fig. 6a) and with Mowiol® 4-88 coated PLGA nanoparticles (black symbols, Fig. 6b).
  • the suspensions were added as an additive PEG 10,000 (PEG 10 kDa) in various concentrations c PE Gi okDa.
  • the dependence of the VMD in ⁇ on the concentration of PEG 10,000 can be seen.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier
  • Embodiment 10 wherein the influence of a modified PVA, namely here DEAPA (49) -PVA - diethylaminopropylamine-modified PVA or DEAPA-PVA, is shown on the aerophysical parameters.
  • a modified PVA namely here DEAPA (49) -PVA - diethylaminopropylamine-modified PVA or DEAPA-PVA
  • Fig. 10a shows the values for the Aeroneb® Professional Vernebier.
  • Fig. 10b shows the values for the eFlow®rapid Vernebier.
  • the reduction of the VMD Volume Median Diameter or mean volume diameter
  • VMD Volume Median Diameter or mean volume
  • aerosols are generated from solutions and colloidal suspensions using the Aeroneb® Pro and eFlow® rapid piezoelectric profilers. Comparative example
  • the nanoparticles are synthesized by nanoprecipitation with subsequent solvent evaporation at room temperature.
  • 1 ml of the organic phase (dispersed phase) is transferred into 5 ml of an aqueous phase (constant phase) containing 0.1 to 15 g / l, for example, 2 g / l, of a surface stabilizer.
  • the stabilizer here is, for example, polyvinyl alcohol (PVA), which is commercially available as Mowiol 4-88® from Sigma-Aldrich (Steinheim, Germany). Furthermore, Poloxamer 407, which is commercially available as Pluronic® F127, is used as the stabilizer.
  • PVA polyvinyl alcohol
  • Pluronic® F127 Pluronic® F127
  • the nanoparticles (NP) are used directly after production.
  • Aeroneb® Professional aerosol from Aerogen (Dangan, Galway, Ireland) and eFlow®rapid from Pari company (Starnberg, Germany) were used according to the manufacturer's instructions.
  • a NaCl solution as a carrier solution with different concentrations of c Na ci was aerosolized with the aerosol Aeroneb® Professional and eFlow®rapid according to the manufacturer's instructions.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • the dependence of the VMD (Volume Median Diameter or average volume diameter) in ⁇ on the concentration of NaCl is shown in FIG.
  • Embodiment 2 The dependence of the VMD (Volume Median Diameter or average volume diameter) in ⁇ on the concentration of NaCl is shown in FIG. Embodiment 2
  • a CaCl 2 solution as a carrier solution with different concentrations c Ca ci2 was aerosolized with the aerosol Aeroneb® Professional and eFlow®rapid according to the manufacturer.
  • SD standard deviation
  • the dependence of the VMD in ⁇ on the concentration of CaCl 2 can be seen from Fig. 2.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • Embodiment 3 was a sucrose (sucrose) nebulised solution as a carrier solution with different concentrations c Su crose with the nebulizer Aeroneb® Professional and eFlow®rapid according to manufacturer's instructions.
  • the squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • SD standard deviation
  • Embodiment 5 The dependence of the VMD in ⁇ on the concentration of sucrose can be seen from FIG. The squares represent the values for the Aeroneb® Professional and the circles the values for the eFlow®rapid Vernebier.
  • a solution of Na lauryl sulfate as a carrier solution with different concentrations was aerosolized with Aeroneb® Professional nebulizer and eFlow®rapid according to the manufacturer's instructions.
  • SD standard deviation
  • the dependence of the VMD in ⁇ and the FPF in% of the concentration of Na-lauryl sulfate (NLS) can be seen from Fig. 5a and b.
  • Embodiments 6 to 9 various polymer nanoparticles were nebulised in suspension, with the effects of concentrating various additives on the aerodynamic parameters VMD (Volume Median Diameter or Mean Volume Diameter) and FPF (Fine Particle Fraction) being analyzed.
  • the poly (D, L-lactide-co-glycolide) copolymer (PLGA) nanoparticles (NP) were prepared as described in the comparative example.
  • the squares in Figures 5 through 8 respectively represent the values for the Aeroneb® Professional and the circles represent the values for the eFlow®rapid Vernebier.
  • Example 6 ( Figure 6a, b) suspensions were fogged with Pluronic® F127 coated PLGA NP (gray symbols, Figure 6a) and Mowiol® 4-88 coated PLGA NP (black symbols, Figure 6b).
  • c Na ci was added to the suspensions as an addition of NaCl in various concentrations.
  • SD standard deviation
  • SD standard deviation
  • Example 8 ( Figure 8a, b) suspensions were fogged with Pluronic® F127 coated PLGA NP (gray symbols, Figure 8a) and Mowiol® 4-88 coated PLGA NP (black symbols, Figure 8b).
  • sucrose sucrose
  • c Su crose sucrose
  • SD standard deviation
  • Embodiment 10 Embodiment 10
  • Embodiment 10 shows the influence of a modified PVA, namely DEAPA (49) -PVA: diethylaminopropylamine-modified polyvinyl alcohol, on the aerophysical parameters.
  • DEAPA (49) -PVA diethylaminopropylamine-modified polyvinyl alcohol
  • the addition of conventional PVA is tested without modification.
  • Fig. 10a shows the values for the Aeroneb® Professional Vernebier.
  • Fig. 10a shows the values for the Aeroneb® Professional Vernebier.
  • FIG. 10b shows the values for the eFlow®rapid Vernebier.
  • the dependence of the VMD (volume median diameter or average volume diameter) in ⁇ on the concentration of DEAPA (49) -PVA can be seen from Fig. 10a and b.
  • VMD volume median diameter or average volume diameter
  • a significant reduction in VMD can be observed even at lower concentrations of additive compared to PVA.
  • a VMD of 5 ⁇ or less can be achieved, whereas with PVA higher concentrations are required.

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Abstract

L'invention concerne l'optimisation des propriétés de nébulisation d'une solution ou d'un colloïde. L'inhalation constitue une des formes les plus importantes d'administration de principes actifs, par exemple dans le traitement de maladies respiratoires ou pour des anesthésies. Dans l'état actuel de la technique, l'inconvénient réside dans le fait qu'il n'est pas possible de nébuliser avec un nébuliseur courant n'importe quelle solution ou suspension de manière à obtenir une distribution granulométrique de l'aérosol produit appropriée à l'inhalothérapie. L'invention concerne donc un procédé de nébulisation d'une solution ou d'un colloïde par la formation de particules d'aérosol. La solution ou le colloïde contient au moins un additif, l'additif étant un composé de faible poids moléculaire, un polyéther, un polysorbate ou un PVA modifié. Les paramètres physiques des particules d'aérosol formées par la nébulisation de la solution ou du colloïde sont ajustés par la concentration de l'additif dans la solution ou le colloïde. L'invention concerne par ailleurs un aérosol obtenu par ce procédé pour une administration pulmonaire à un patient pour le diagnostic ou le traitement d'une maladie.
PCT/EP2013/073960 2012-11-16 2013-11-15 Optimisation des propriétés de nébulisation d'une solution ou d'un colloïde WO2014076243A1 (fr)

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WO1995031964A1 (fr) * 1994-05-21 1995-11-30 Glaxo Wellcome Australia Limited Formulations a base de propionate de fluticasone

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Publication number Priority date Publication date Assignee Title
WO1995031964A1 (fr) * 1994-05-21 1995-11-30 Glaxo Wellcome Australia Limited Formulations a base de propionate de fluticasone

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GHAZANFARI ET AL: "The influence of fluid physicochemical properties on vibrating-mesh nebulization", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 339, no. 1-2, 28 June 2007 (2007-06-28), pages 103 - 111, XP022133360, ISSN: 0378-5173, DOI: 10.1016/J.IJPHARM.2007.02.035 *
MCCALLION O N M ET AL: "NEBULIZATION OF FLUIDS OF DIFFERENT PHYSICOCHEMICAL PROPERTIES WITHAIR-JET AND ULTRASONIC NEBULIZERS", PHARMACEUTICAL RESEARCH, THIEME, vol. 12, no. 11, 1 January 1995 (1995-01-01), pages 1682 - 1688, XP000974652, ISSN: 0724-8741, DOI: 10.1023/A:1016205520044 *
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