DE102012111077A1 - Optimization of fogging properties of a solution or a colloid - Google Patents

Abstract

Inhalation, for example, is one of the most important forms of application of active ingredients in the treatment of respiratory diseases or in anesthesia. A disadvantage in the prior art is that not every solution or suspension can be nebulized with a conventional nebulizer in such a way that one for inhalation therapy results in a suitable particle size distribution of the aerosol produced. The invention therefore relates to a process for nebulizing a solution or a colloid to form aerosol particles, the solution or the colloid containing at least one additive, the additive being a low molecular weight compound or a polyether or a polysorbate, and aerosol-physical parameters resulting from nebulizing the Solution or colloid formed particles can be adjusted via the concentration of the additive in the solution or colloid. The invention further relates to an aerosol obtainable by this method for pulmonary application to a patient for diagnosis or therapy of a disease.

Description

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. In contrast to other routes of administration, for example, 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. In addition, in case of an emergency, 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. Through inhalation, drugs can be administered both locally and systemically.

In general, the person skilled in the art understands by inhalation the inhalation of aerosols or gaseous active substances. 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.

Typically, 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 nebulizer atomises a solution or a suspension (or a colloid) with the therapeutically or diagnostically active agent into fine aerosol droplets. The terms suspension and colloid are used synonymously below, unless explicitly stated otherwise. In piezoelectric nebulizers, aerosol droplets are generated from a solution or suspension using vibrating hole membranes.

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 μm are generally produced for inhalation application.

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.

Preference is given to aerosols prepared from a solution or a suspension with or without a therapeutically or diagnostically active ingredient, used whose particle size distribution is suitable for the highest possible deposition in the respiratory tract. Particles with an aerodynamic diameter smaller than 5 microns, for example, are suitable to reach even deeper areas of the airways

A disadvantage of the current state of the art is that not every solution or suspension with and without at least one medicinal agent can be so nebulised with a common nebulizer that results in a suitable inhalative therapy particle size distribution of the aerosol generated.

In particular, the aerodynamic properties of generated aerosols can hitherto essentially only be changed with the aid of constructional adaptations of the nebulizers and adapted to the therapeutic requirements. These limited adaptation options prevent the use of predetermined nebulizers for the production of different types of aerosols.

Object of the invention

Object of the present invention is therefore to eliminate the disadvantages of the prior art and to provide a method with which a broad spectrum of solutions or suspensions or colloids with or without medicinal active in a nebulizable form, which is suitable for common nebulizers , can be brought. The aerodynamic properties of the generated aerosols, in particular, the VMD (Volume Median Diameter or median volume diameter) and / or the FPF (Fine Particle Fraction or Fine Particle Fraction), be adjustable without having to adjust the intended nebulizer structurally.

Solution of the task

• – die Lösung oder das Kolloid mindestens einen Zusatz enthält, wobei der Zusatz eine niedermolekulare Verbindung oder ein Polyether oder ein Polysorbat ist, und
• – die aerosolphysikalischen Parameter VMD (Volume Median Diameter) und/oder FPF (Fine Particle Fraction) der durch Vernebelung der Lösung oder des Kolloids gebildeten Partikel über die Konzentration des Zusatzes in der Lösung oder des Kolloids eingestellt werden.

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 a low molecular weight compound or a polyether or a polysorbate, 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 of the colloid are adjusted via the concentration of the additive in the solution or the colloid.

In fact, it has surprisingly been found that the addition of various low-molecular-weight substances or of a polyether or of a polysorbate to a solution or a colloid enables the nebulizing properties, that is to say the aerosol-physical parameters of the particles formed, to be set in a targeted manner. Thus, via the level of the concentration of the additive, the aerosol physical parameters VMD (Volume Median Diameter) and / or FPF (Fine Particle Fraction) can be set without the need for a structural change of the nebulizer. Apart from the concentration of the low molecular weight compound, of the polyether or of the polysorbate, additional components of the solution or of the colloid that may be present need not necessarily be modified in order to adapt the desired aerosol physical parameters of the particles formed.

According to the invention, its properties for the required specific application can be individually adapted via the abovementioned aerosol-physical parameters of the aerosol produced.

According to an advantageous embodiment of the method, 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 Na-lauryl sulfate.

According to an alternative embodiment of the process, the polyether is in particular a polyethylene glycol (PEG), preferably PEG 10,000. A further modification relates to the process according to the invention, wherein the addition polysorbate is in particular polysorbate 20.

With the aid of the method according to the invention, the VMD can be between 9 and 1.5 μm, preferably between 5 and 1.5 μm, particularly preferably between 5 and 3 μm, and / or the FPF between 20 and 90%, preferably 50 to 90%, be set. For this purpose, only a slight adjustment of 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 method according to the invention when using an inorganic salt in a solution to be nebulized or in a suspension to be nebulized, when 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. Thus, the VMD continuously decreases in the stated range with increasing concentration of inorganic salt. 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 nebulized 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 is a direct relationship between the concentration of NaCl and the median diameter of the particles formed. Thus, the VMD decreases continuously in the mentioned range with increasing concentration of NaCl, and thus the FPF correspondingly too. In this area, therefore, a particularly simple adaptation of VMD and FPF can take place via the concentration of NaCl.

Even when CaCl _{2 is used} as an additive, the abovementioned aerosol physical parameters can be adjusted particularly well by the process according to the invention 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 via the concentration of CaCl ₂ can take place.

• – bei Vernebelung eines Kolloids zwischen 100 und 800 mM, vorzugsweise zwischen 150 und 725 mM gewählt ist oder
• – bei Vernebelung einer Lösung zwischen 100 und 1000 mM, vorzugsweise zwischen 150 und 900 mM gewählt ist.

When using a nonionic low molecular weight substance, preferably a disaccharide such as sucrose, as an additive, according to a further aspect of the method according to the invention said aerosol physical parameters can be adjusted particularly well if the concentration of the disaccharide such as sucrose

• When nebulizing a colloid is between 100 and 800 mM, preferably between 150 and 725 mM, or
• - Is selected in nebulization of a solution between 100 and 1000 mM, preferably between 150 and 900 mM.

It was found that, especially in the dynamic range between 150 and 725 mM sucrose or between 150 and 900 mM, there is a direct correlation between the concentration of sucrose and the median diameter of the particles formed. Thus, the VMD continuously decreases in the mentioned range with increasing concentration of sucrose and thus the FPF accordingly. In this area, therefore, a particularly simple adaptation of VMD and FPF can take place via the concentration of sucrose. Alternatively, in addition to sucrose, all other disaccharides can be used in the context of the invention.

• – bei Vernebelung eines Kolloids zwischen 0,1 und 5 mM, vorzugsweise zwischen 0,5 und 3 mM gewählt ist oder
• – bei Vernebelung einer Lösung zwischen 0,1 und 10 mM, vorzugsweise zwischen 0,5 und 5 mM gewählt ist.

When using polyether, preferably polyethylene glycol (PEG), as an additive, according to a further aspect of the process according to the invention, said aerosol-physical parameters can be adjusted particularly well if the concentration of polyether, in particular of PEG,

• - When nebulization of a colloid between 0.1 and 5 mM, preferably between 0.5 and 3 mM is selected or
• - When nebulization of a solution between 0.1 and 10 mM, preferably between 0.5 and 5 mM is selected.

It was found that, especially in the dynamic range of between 0.5 and 3 mM PEG or 0.5 and 5 mM PEG, there is a direct correlation between the concentration of PEG and the median diameter of the particles formed. Thus, as the concentration of PEG increases, the VMD in the named region decreases continuously and the FPF increases accordingly. In this area, therefore, a particularly simple adaptation of VMD and FPF can take place via the concentration of PEG.

The abovementioned aerosol-physical parameters can also be adjusted by the use of a surfactant as an additive according to the process of the invention. Embodiments containing nonionic surfactants, 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 Na lauryl sulfate, in a solution to be nebulized or in a suspension to be nebulised is between 0.001 and 100 mM, preferably between 0.01 and 20 mM. more preferably between 0.05 and 10 mM is chosen. Again, it was again found that, especially in the dynamic range of 0.01 to 20 mM sodium lauryl sulfate, there is a direct relationship between the concentration of Na lauryl sulfate and the median diameter of the particles formed. Thus, 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 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 methods 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 substance is in particular a therapeutically or diagnostically active medicinal active substance, preferably an active substance for the therapy of diseases of the respiratory tract such as, for example, pneumonia, asthma, COPD or pulmonary hypertension, for the therapy of systemic diseases, such as e.g. Diabetes mellitus, or for anesthesia.

For the purposes of the present invention, a colloid may be any liquid dispersion medium having droplets or particles dispersed therein. In particular, 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, particularly biodegradable polyesters, are used as drug carrier systems. The nanoparticles or microparticles are obtained in particular by the solvent extraction / evaporation method known to the person skilled in the art. Alternatively, 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.

For the purposes of the present invention, an emulsion can be a single or a multiple emulsion. For example, multiple emulsions may 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. These include, in particular, peptides and nucleic acid-based compounds, such as poly- and oligonucleotides.

In the present case, 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.

As 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 , Antiepileptics, antihemorrhagics, hemostats, antihypertensives, antihypoglycemics, antihypotonics, anticoagulants, antomycotics, antiparasitics, antiphlogistics, antitussives, expectorants, atherosclerosis agents, β-blockers, calcium channel blockers, inhibitors of the renin-angiotensin-aldosterone system, broncholytics, antiasthmatics , Cholagogues, bile ducts, cholinergics, corticosteroids, diagnostics and diagnostic preparations, diuretics, circulating agents, weaners, enzyme inhibitors, enzyme activators or stimulators, enzyme deficient preparations, receptor antagonists, transport proteins, F ibrinolytics, geriatrics, gout remedies, flu remedies, cold remedies, gynecologics, hepatics, hypnotics, sedatives, pituitary or hypothalamic hormones, regulatory peptides, hormones, peptide inhibitors, immunomodulators, cardiacs, coronary agents, laxatives, lipid-lowering agents, local anesthetics, neural therapeutics, gastric Intestinal, migraine, mineral supplements, muscle relaxants, anesthetics, neurotropic agents, osteoporosis agents, calcium / bone metabolism regulators, Antiparasitic agents, psychotropic drugs, sinusitis agents, roborantia, thyroid medicines, serums, immunoglobulins, vaccines, antibodies, sex hormones and their inhibitors, spasmolytics, anticholinergics, antiplatelet agents, tuberculosis agents, urologic agents, venous therapeutics, vitamins, cytostatics, antineoplastic agents, homeopathics, vascular active substances, gene therapeutics (DNA / RNA derivatives), transcription inhibitors, antivirals, nicotine, erectile dysfunction agents, nitric oxide and / or nitric oxide-liberating substances.

Magnetic particles may also be active substances in the sense of the present invention. Such particles can be used, for example, in diagnostic imaging methods, but also in therapy, e.g. in chemo- and radiotherapy and hyperthermia.

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.

• – Emulsionströpfchen einer organischen Phase enthaltend ein Lösungsmittel, die gegebenenfalls ein biokompatibles Polymer, ein Lipid und/oder einen Wirkstoff enthält, in eine wässrige Phase eingebracht werden, wobei die wässrige Phase einen Zusatz – also eine niedermolekulare Verbindung oder ein Polyether gemäß einem der oben genannten Ausführungsformen – enthält, und
• – das Lösungsmittel durch Evaporation über die wässrige Phase entfernt wird. In dieser vorteilhaften Ausgestaltung des erfindungsgemäßen Verfahrens wird der Zusatz also der wässrigen Phase zugesetzt. Die Einstellung der aerosolphysikalischen Parameter VMD und/oder FPF der durch Vernebelung des Kolloids gebildeten Partikel kann einfach über die Höhe der Konzentration des Zusatzes in der wässrigen Phase vor der Vernebelung erfolgen.

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 solvent is removed by evaporation over the aqueous phase. In this advantageous embodiment of the method according to the invention, therefore, 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.

In particular, 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. 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. The materials for the nanoparticles and microparticles are preferably suitable for pulmonary application.

For the purpose of coating and stabilizing the nanoparticles or microparticles, a stabilizer, preferably a polymer such as polyvinyl alcohol, may also be present in the aqueous phase, the concentration of which being chosen to be between 1 and 15 mg / ml.

In this case, 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. Preferably, the biocompatible polymer concentration for preparation is about 50 g / L and the stabilizer concentration is about 10 g / L.

• – Lösen des biokompatiblen Polymers oder eines Lipids und gegebenenfalls des Wirkstoffs in einem Lösungsmittel unter Bildung einer organischen Phase,
• – Emulgieren der organischen Phase in einer wässrigen Phase mit einem Zusatz gemäß einer der oben genannten Verbindungen mit bestimmter Konzentration, gegebenenfalls zusätzlich enthaltend einen Stabilisator,
• – Entfernen des Lösungsmittels und Erhalten der Nano- und Mikropartikel in Suspension ausgeführt. Anschließend kann die Vernebelung erfolgen, wobei die aerosolphysikalischen Parameter VMD und/oder FPF der Partikel des Aerosols für die jeweilige Anwendung eingestellt ist.

For the preparation of biocompatible nano- and microparticles in suspension by means of emulsion and subsequent evaporation so the steps

• Dissolving the biocompatible polymer or a lipid and optionally the active ingredient in a solvent to form an organic phase,
• Emulsifying the organic phase in an aqueous phase with an additive according to one of the abovementioned compounds of defined concentration, optionally additionally containing a stabilizer,
• - Removal of the solvent and obtaining the nano- and microparticles in suspension. Subsequently, 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.

It must be emphasized that the additive according to the invention-a low molecular weight compound or a polyether or a polysorbate-can either be added during the preparation of the solution or the colloid or, alternatively, can be added subsequently before the nebulisation.

According to a further aspect, 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 used in particular for pulmonary administration to a patient for diagnosis or therapy of a patient Disease is suitable. 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 nebuliser for nebulizing a solution or a colloid to form particles, wherein the aerosol physical parameters VMD and / or FPF of the particles formed by nebulization of the solution or of the colloid are determined by the level of the concentration of the additive in the solution or the colloid can be adjusted by a method according to one of the said embodiments. This means that these parameters can be changed without adjusting the nebulizer. The nebulizer may according to an advantageous embodiment have an additional reservoir in which an inventive additive is included. Thus, a metered addition of the additive from the reservoir into the solution or the colloid to be atomized is possible. Thus, the aerosol physical parameters VMD and / or FPF of the aerosol for the respective application can be set on the nebulizer itself.

Further features, details and advantages of the invention will become apparent from the wording of the claims and from the following description of embodiments in connection with figures. Showing:

1 Embodiment 1, wherein NaCl solutions were aerosolized as a carrier solution with different concentrations of _NaCl c with the nebulizer Aeroneb Professional ^® and eFlow ^® rapid according to manufacturer's instructions. The squares represent the VMD values in microns for the Aeroneb Professional ^® and the circles the values for the eFlow ^® rapid nebulizer. The dependence of the VMD in μm on the concentration of NaCl can be seen.

2 Embodiment 2, wherein CaCl ₂ solutions were nebulized as a carrier solution with different concentrations c _{CaCl 2} with the nebulizer 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 nebulizer. The dependence of the VMD in μm on the concentration of CaCl ₂ can be seen.

3 Example 3, wherein sucrose (sucrose) solutions as a carrier solution with different concentrations c _sucrose with nebulizer Aeroneb ^® Professional and eFlow ^® rapid according to the manufacturer were nebulized. The squares represent the values for the Aeroneb ^® Professional and the circles the values for the eFlow ^® rapid nebulizer. The dependence of the VMD in μm on the concentration of sucrose can be seen.

4 Embodiment 4, wherein PEG 10,000 (PEG10kDa) solutions as a carrier solution with different concentrations c _{PEG10kDa were aerosolized} with the nebulizer 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 nebulizer. The dependence of the VMD in μm on the concentration of sucrose can be seen.

5a , b the embodiment 5, wherein Na-lauryl sulfate (NLS) solutions were sprayed as a carrier solution with different concentrations c _NLS with Aeroneb ^® Professional nebulizer 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

Nebulizer. The dependence of the VMD in μm and the FPF in% of the concentration of Na lauryl sulfate can be seen.

6a , b the embodiment 6, wherein suspensions with Pluronic ^® F127-coated PLGA nanoparticles (gray symbols, 6a () And coated with Mowiol ^® 4-88 PLGA nanoparticles black symbols, 6b ) were fogged. In each case, c _{NaCl was} added to the suspensions as an addition of NaCl in various concentrations. The dependence of the VMD in μm 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 nebulizer.

7a , b the embodiment 7, wherein suspensions with Pluronic ^® F127-coated PLGA nanoparticles (gray symbols, 6a ) And coated with Mowiol ^® 4-88 PLGA nanoparticles (black symbols, 6b ) were fogged. In each case, c _{CaCl 2 was} added to the suspensions as CaCl ₂ additive in various concentrations. The dependence of the VMD in μm 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 nebulizer.

8a , b the embodiment 8, wherein suspensions with Pluronic ^® F127-coated PLGA nanoparticles (gray symbols, 6a ) And coated with Mowiol ^® 4-88 PLGA nanoparticles (black symbols, 6b ) were fogged. In each case, _{sucrose was} added to the suspensions as sucrose (sucrose) at various concentrations. The dependence of the VMD in μm 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 nebulizer.

9a , b, the embodiment 9, wherein suspensions with Pluronic ^® F127-coated PLGA nanoparticles (gray symbols, 6a ) And coated with Mowiol ^® 4-88 PLGA nanoparticles (black symbols, 6b ) were fogged. In each case, PEG 10,000 (PEG 10 kDa) in various concentrations c _{PEG10kDa was} added to the suspensions. The dependence of the VMD in μm 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 nebulizer.

embodiments

In the following embodiments, aerosols using the piezoelectric nebuliser Aeroneb Pro ^® and eFlow ^® rapid from solutions and colloidal suspensions are produced.

Comparative example

The nanoparticles are synthesized by nanoprecipitation with subsequent solvent evaporation at room temperature. First, this is between 1 to 100 g / l Poly (D, L-lactide-co-glycolide) copolymer (PLGA), which is commercially available and ^® for example, as Resomer RG502H from Boehringer Ingelheim (Ingelheim, Germany) can be obtained, in a water-miscible solvent, such as acetone. Then, 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 is here, for example polyvinyl alcohol (PVA), Mowiol 4-88 ^® commercially available as from Sigma-Aldrich (Steinheim, Germany) can be obtained. Furthermore, as a stabilizer Poloxamer 407, which is commercially available as Pluronic ^® F127, is used.

The nanoparticles (NP) are used directly after production. The nebulizer Aeroneb ^® Professional Aerogen (Dangan, Galway, Ireland) and eFlow ^® rapid Fa. Pari (Star Mountain, Germany) were used according to manufacturer's instructions.

In the comparative example, first a solution and various nanoparticles were nebulized in suspension. Thus, according to Table 1, a 0.9% (m / v) NaCl solution, one with Pluronic ^® F127-coated PLGA-NP suspension (2 mg / ml) (in distilled water) and a surface coated with Mowiol ^® 4-88 PLGA-NP suspension (2 mg / ml) ^® (in distilled water), both with an Aeroneb Pro and an eFlow ^® rapid nebulized.

The aerosols were analyzed for VMD (Volume Median Diameter), GSD (Geometric Standard Deviation or Geometric Standard Deviation), FPF (Fine Particle Fraction = Particle Size <5.25 μm) and Release Rate (Table 1). The parameters mentioned were determined by means of laser diffractometry and weighing. Table 1: nebulizer compound to be atomized VMD [μm] GSD FPF [%] Release rate [g / min] Aeroneb Pro ^® NaCl 0.9% (m / v) 5.0 ± 0.2 1.97 ± 0.03 53.8 ± 1.9 0.47 ± 0.02 Pluronic ^® F127-coated PLGA-NP (2 mg / ml) 7.0 ± 0.2 1.90 ± 0.09 28.5 ± 3.6 0.23 ± 0.02 Mowiol ^® 4-88-coated PLGA-NP (2 mg / ml) 7.4 ± 0.3 1.87 ± 0.04 31.3 ± 2.2 0.23 ± 0.03 eFlow ^® rapid NaCl 0.9% (m / v) 4.8 ± 0.2 1.81 ± 0.02 56.1 ± 2.3 0.83 ± 0.03 Pluronic ^® F127-coated PLGA-NP (2 mg / ml) 7.2 ± 0.4 1.74 ± 0.04 28.7 ± 3.0 0.33 ± 0.04 Mowiol ^® 4-88-coated PLGA-NP (2 mg / ml) 6.9 ± 0.2 1.73 ± 0.01 29.3 ± 1.8 0.37 ± 0.05 The values are given as mean ± standard deviation (SD) (n = 4).

Embodiment 1

According to embodiment 1 ( 1 ) Was nebulized with the nebulizer Aeroneb Professional ^® and eFlow ^® rapid according to manufacturer's instructions a NaCl solution as a carrier solution with different concentrations of _NaCl c. The values are given as mean ± standard deviation (SD) (n = 4). The squares represent the values for the Aeroneb ^® Professional and the circles the values for the eFlow ^® rapid nebulizer. The dependence of the VMD (volume median diameter or mean volume diameter) in μm on the concentration of NaCl is off 1 to recognize.

Embodiment 2

According to Embodiment 2, a CaCl ₂ solution was nebulized as the carrier solution at different concentrations c _CaCl2 with the nebulizer Aeroneb Professional ^® and eFlow ^® rapid according to manufacturer's instructions. The values are given as mean ± standard deviation (SD) (n = 4). The dependence of the VMD in μm on the concentration of CaCl ₂ is out 2 to recognize. The squares represent the values for the Aeroneb ^® Professional and the circles the values for the eFlow ^® rapid nebulizer.

Embodiment 3

According to exemplary embodiment 3 ( 3 ) sucrose solution (sucrose) as a carrier solution with different concentrations c _{sucrose was} aerosolized with the nebulizer 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 nebulizer. The values are given as mean ± standard deviation (SD) (n = 4). The dependence of the VMD in μm on the concentration of sucrose is out 3 to recognize.

Embodiment 4

According to Embodiment 4, a PEG (PEG10kDa) nebulised solution as a carrier solution with different concentrations c _PEG10kDa with the nebulizer Aeroneb Professional ^® and eFlow ^® rapid according to manufacturer's instructions. The values are given as mean ± standard deviation (SD) (n = 4). The dependence of the VMD in μm on the concentration of sucrose is out 4 to recognize. The squares represent the values for the Aeroneb ^® Professional and the circles the values for the eFlow ^® rapid nebulizer.

Embodiment 5

According to embodiment 5 ( 5a , B) was nebulized with the nebulizer Aeroneb Professional ^® and eFlow ^® rapid according to manufacturer's instructions a sodium lauryl sulfate solution as a carrier solution having different concentrations. The squares represent the values for the Aeroneb ^® Professional and the circles the values for theeFlow ^® rapid nebulizer. The values are given as mean ± standard deviation (SD) (n = 4). The dependence of the VMD in μm and the FPF in% of the concentration of Na lauryl sulfate (NLS) is out 5a and to recognize b.

Embodiment 6

In 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 represent in the 5 to 8th the values for the Aeroneb ^® Professional and the circles for the eFlow ^® rapid nebuliser.

In embodiment 6 ( 6a B) suspensions were with Pluronic ^® F127-coated PLGA-NP (gray symbols, 6a ) As well as (with Mowiol ^® 4-88 coated PLGA-NP black symbols, 6b ) fogged. In each case, c _{NaCl was} added to the suspensions as an addition of NaCl in various concentrations. The values are given as mean ± standard deviation (SD) (n = 4). The dependence of the VMD in μm on the concentration of NaCl is over 6a and to recognize b.

Embodiment 7

In embodiment 7 ( 7a B) suspensions were with Pluronic ^® F127-coated PLGA-NP (gray symbols, 7a ) As well as (with Mowiol ^® 4-88 coated PLGA-NP black symbols, 7b ) fogged. In each case, c _{CaCl 2 was} added to the suspensions as CaCl ₂ additive in various concentrations. The values are given as mean ± standard deviation (SD) (n = 4). The dependence of the VMD in μm on the concentration of CaCl ₂ is out 7a and to recognize b.

Embodiment 8

In embodiment 8 ( 8a B) suspensions were with Pluronic ^® F127-coated PLGA-NP (gray symbols, 8a ) As well as (with Mowiol ^® 4-88 coated PLGA-NP black symbols, 8b ) fogged. In each case, _{sucrose was} added to the suspensions as sucrose (sucrose) at various concentrations. The values are given as mean ± standard deviation (SD) (n = 4). The dependence of the VMD in μm on the concentration of sucrose is out 8a and to recognize b.

Embodiment 9

In embodiment 9 ( 9a B) suspensions were with Pluronic ^® F127-coated PLGA-NP (gray symbols, 9a ) As well as (with Mowiol ^® 4-88 coated PLGA-NP black symbols, 9b ) fogged. In each case, PEG 10,000 (PEG 10 kDa) in various concentrations c _{PEG10kDa was} added to the suspensions. The values are given as mean ± standard deviation (SD) (n = 4). The dependence of the VMD in μm on the concentration of PEG 10,000 is out 9 to recognize a and b.

The invention is not limited to one of the above-described embodiments, but can be modified in many ways.

All of the claims, the description and the drawing forth features and advantages, including constructive details and method steps may be essential to the invention both in itself and in various combinations.

Claims (15)

A method for nebulizing a solution or a colloid to form aerosol particles, characterized in that - the solution or the colloid contains at least one additive, wherein the additive is a low molecular weight compound or a polyether or a polysorbate, and - the aerosol physical parameters VMD (Volume Median diameter) and / or FPF (Fine Particle Fraction) of the particles formed by nebulization of the solution or colloid via the concentration of the additive in the solution or colloid. A method according to claim 1, characterized in that - the low molecular weight compound is selected from 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 such as sucrose, and a surfactant, preferably Na lauryl sulfate, or - the polyether is a polyethylene glycol (PEG), preferably PEG 10,000, or the polysorbate is the polysorbate 20. A method according to claim 1 or 2, characterized in that the VMD (Volume Median Diameter) between 9 and 1.5 microns and / or the FPF (Fine Particle Fraction) between 20 and 90%, preferably 50 to 90%, is set. Method according to one of claims 1 to 3, characterized in that the nebulization by means of a nebulizer, preferably with piezometric, nozzle, ultrasonic aerosol generators or soft-mist inhalers occurs. Method according to one of claims 2 to 4, characterized in that the concentration of inorganic salt is chosen between 0.001 and 1000 mM, preferably between 0.01 and 10 mM. Method according to one of claims 2 to 5, characterized in that the inorganic salt is NaCl, wherein its concentration between 0.01 and 1000 mM, preferably between 0.01 and 10 mM, is selected. Method according to one of claims 2 to 5, characterized in that the inorganic salt is CaCl ₂ , wherein its concentration between 0.01 and 1000 mM, preferably between 0.01 and 1 mM is selected. Method according to one of claims 2 to 4, characterized in that the concentration of the nonionic low molecular weight substance, in particular of sucrose, - in nebulization of a colloid between 100 and 800 mM, preferably between 150 and 725 mM, or - in nebulization of a solution between 100 and 1000 mM, preferably between 150 and 900 mM. Method according to one of claims 2 to 4, characterized in that the concentration of polyether, preferably of polyethylene glycol (PEG), - is selected in nebulization of a colloid between 0.1 and 5 mM, preferably between 0.5 and 3 mM or when nebulising a solution between 0.1 and 10 mM, preferably between 0.5 and 5 mM is chosen. Method according to one of claims 2 to 4, characterized in that the concentration of surfactant, preferably Na-lauryl sulfate, between 0.001 and 100 mM, preferably between 0.01 and 20 mM, more preferably selected between 0.05 and 10 mM , Method according to one of claims 1 to 10, characterized in that the solution to be nebulized or the colloid to be nebulised contains an active ingredient.  Aerosol obtainable by a method according to any one of claims 1 to 11 for pulmonary administration to a patient for the diagnosis or therapy of a disease.  Aerosol according to claim 12 for the treatment of diseases of the respiratory tract or for the treatment of systemic diseases or for anesthetics.  An aerosol according to claim 13 for the treatment of pneumonia, asthma, COPD or pulmonary hypertension. Nebulizer for nebulising a solution or a colloid to form particles, characterized in that the aerosol physical parameters VMD (Volume Median Diameter) and / or FPF (Fine Particle Fraction) of the particles formed by nebulization of the solution or colloid above the concentration of the Additive in the solution or the colloid according to a method according to one of claims 1 to 11 are adjustable.

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