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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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—Liposomes
• • 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

Definitions

• the invention relates to aqueous preparations for application as an aerosol.
• the preparations contain active ingredients and can be used pharmaceutically or to promote wellness.
• the invention relates in particular to sterile, aqueous preparations which are suitable for inhalation with a nebulizing system such as, for. B. a pump, nozzle, ultrasound, vibrating membrane nebulizer or other aerosol generation system are intended for aqueous preparations. It also relates to the nasal or pulmonary administration of physicochemically, organoleptically or physiologically problematic active substances. In further aspects, the invention relates to methods for producing such preparations and their uses.
• Medicinal therapy since the active ingredient can be brought directly to the pharmacological destination using inhalation devices [D. Köhler and W. Fleischer: Theory and practice of inhalation therapy, Arcis Verlag GmbH, Kunststoff, 2000, ISBN 3-89075-140-7].
• the prerequisite is that the inhaled droplets or particles reach the target tissue and are deposited there.
• diseases such as e.g. As asthma, chronic obstructive bronchitis (COPD) or a pulmonary emphysema quasi topically treat, but also active ingredients such.
• COPD chronic obstructive bronchitis
• pulmonary emphysema quasi topically treat, but also active ingredients such.
• B. Transfer insulin into the bloodstream using predominantly alveolar absorption.
• the type of breathing maneuver such as breathing frequency, flow, speed and volume
• the dosage form e.g. solution, suspension, emulsion, liposome dispersion
• the interface properties such as wettability and spreadability
• a bronchial deposition in the order of magnitude of about 5 - 28% has particles of 2 to 8 ⁇ m, while the oropharyngeal deposition increases in parallel.
• the deposition in the oropharynx is already 25 - 45% for particles of 6 ⁇ m and increases to 60 - 80%. for particles with a diameter of 10 ⁇ m. From this it is deduced that particle sizes of 1, 5 - 3 ⁇ m are favorable for optimal qualitative and quantitative alveolar deposition in adults if the oropharyngeal and bronchial deposition should be as low as possible.
• the bronchial deposition with about 18 - 28% for particles in the size range of 6 - 9 ⁇ m is relatively low and is always accompanied by a correspondingly higher oropharyngeal deposition.
• the deposition of the aerosol particles in the respiratory tract is essentially determined by the following four parameters: - the particle size,
• the geometrical and aerodynamic diameter is approximately the same for aqueous systems with a density of approximately 1 mg / cm 3 .
• aerosols are very varied. Depending on their composition, aerosols have a short or long life; their droplet or particle size is subject to changes which are influenced by the physicochemical properties of the formulation components. Small, aqueous droplets evaporate quickly depending on the air humidity to a solid core, so that the concentration of the dissolved substance (s) is 100% when completely evaporated.
• particles can grow in a moist environment, and this growth is particularly dependent on the hygroscopy of the active ingredient and / or excipient.
• a dry sodium chloride particle of 0.5 ⁇ m takes about 1 second to fully grow, with a 5 ⁇ m particle this takes about 10 seconds, which is proof that the speed with regard to particle growth is also size-dependent.
• Solid particles from powder nebulizers and metered dose aerosols can grow up to 4 - 5 times their original size, because the air humidity in the bronchial tree is 95 - 100%.
• Rodents and dogs are often used for toxicological studies. Rodents breathe through the nose in a similar way to toddlers, which is why the aerosol should be applied using a nasal mask in order to achieve high lung deposition.
• corticosteroids For the treatment of some lung diseases such as B. Asthma corticosteroids, beta-agonists and anticholinergics are predominantly used, which are brought directly to the site of action by means of metered dose inhalers, powder inhalers and jet or ultrasonic nebulizers.
• the pulmonary application of corticosteroids for the treatment of asthma has proven to be particularly advantageous compared to oral therapy because it is possible to effectively inhibit the underlying inflammatory process with much smaller doses of medication while significantly reducing the undesirable side effects.
• Active ingredients such as beclometasone dipropionate (BDP), budesonide (Bud), and fluticasone propionate (FP) are mainly used as pump sprays for the treatment of allergic diseases in the nasal area, while for pulmonary application metered dose inhalers (MDI), powder inhalers (DPI) and Jet nebulizers are used.
• BDP beclometasone dipropionate
• Bud budesonide
• FP fluticasone propionate
• MDI metered dose inhalers
• DPI powder inhalers
• Jet nebulizers Jet nebulizers
• Powder nebulisers are generally not suitable for the therapy of children under 5 years of age because the children are unable to generate the respiratory streams with which the powders can be reproducibly deagglomerated into respirable particles and deposited in the lungs with sufficient dosing accuracy .
• Metered aerosols in turn have the disadvantage that the aerosol is released at a speed of up to 100 km / h after actuation of the valve.
• more than 90% of the active ingredient impacted the throat, which can lead to undesirable side effects (hoarseness, voice changes, thrush, etc.).
• the evaporation of the propellant gas can cause a cold stimulus, which in hyper-reactive patients can lead to occlusion of the epiglottis or an asthma attack, which is why steroids should always be inhaled with ancillary chambers, so-called spacers with a volume of approx. 250 - 750 ml .
• spacers with a volume of approx. 250 - 750 ml
• There is nasal breathing for the application of steroids to small children who cannot carry out mouth breathing -specially spacer designs e.g. Babyhaler ® .
• the use of MDIs and spacers is very complex because active substances sediment during the inhalation process, adsorb on the spacer walls or can become electrostatically charged. This can lead to inadequate dosing accuracy and non-reproducible drug therapy.
• nebulization of aqueous preparations by means of jet, membrane or ultrasonic nebulizers is advantageous for pulmonary application of active substances in children and toddlers compared to metered dose inhalers and powder inhalers if sufficiently small droplets or particles are generated.
• the ideal prerequisite for therapy by means of nebulisation of an aqueous formulation is a drug which is sufficiently soluble and stable in water or isotonic saline solution and in which the chemical-physical characteristics do not change during the course of manufacture and storage.
• solubility of the drug is too low to produce an aqueous solution of sufficient concentration, nebulization in the form of a suspension can be considered.
• breath simulator With the aid of a breath simulator, different nebulization efficiencies can be demonstrated with regard to the selected drug form (suspension or solution) (dose applied, amount of drug remaining in the nebulizer, etc.).
• the respirable, ie respirable part of the generated aerosol can be calculated by determining the percentage of active substance-containing droplets with a geometric or aerodynamic diameter of less than 5 or 3 ⁇ m by means of laser diffraction or impactor measurement [N. Luangkhot et. al .; Characterization of salbutamol solution compared to budesonide suspensions consisting of submicron and micrometer particles in the PARI LC STAR and a new PARI Electronic Nebuliser (eFlowT). Drug delivery to the Lungs XI, 11 & 12. 12. 2000, p.14 - 17].
• suspensions containing budesonide in which the particle size of the suspended drug is significantly smaller than 1 ⁇ m, can be atomized as efficiently as a salbutamol sulfate solution, in contrast to a microsuspension.
• This finding is confirmed by Keller et al. [Nebulizer nanosuspensions. Important device and formulation interactions, Resp. Drug Delivery VIII, 2002, p. 197-206].
• microsuspensions should not be nebulized with an ultrasonic nebulizer. In the case of nebulization of a budesonide suspension (Pulmicort ® ), ultracentrifugation could be used to show that approx.
• budesonide 4.6% was dissolved or solubilized in Pulmicort ® in a molecularly dispersed manner and only this portion could be aerosolized by an ultrasonic nebulizer.
• the aqueous corticosteroid preparations previously available for nebulization are microsuspensions of beclomethasone dipropionate (Clenil ® ), budesonide (Pulmicort ® ) and fiuticasone propionate (Flixotide ® ), i.e. the micronized active ingredient (approx. 90% of the suspended drug particles are smaller 5 ⁇ m) is finely dispersed and stabilized in water.
• the sedimented particles or agglomerates must be finely dispersed again by shaking the packaging to ensure that as little active substance as possible remains in the container and that the nebuliser can be filled with the declared dose.
• a surfactant or wetting agent is usually added, but this must be harmless to inhalation toxicity in order to avoid undesirable side effects.
• Pulmicort ® should be used, which is available in two dosage strengths of 0.5 mg and 1 mg budesonide per 2 ml.
• the average particle size of 3 measured Pulmicort ® batches was larger than specified (approx. 2.8 - 3.2 ⁇ m) and spread between 3.7 and 4.4 ⁇ m.
• the differing finding may be due to the measurement method (laser diffraction), but also to particle growth or particle agglomeration.
• the publication DE 101 45 361 A1 describes methods for producing nanoparticulate systems and a method for producing a sterile submicron suspension.
• submicron suspensions represent an advance over conventional microsuspensions with particle diameters of approx. 1-6 ⁇ m for the reasons set out above, they still have certain disadvantages, because even in the presence of a stabilizing wetting agent the particle growth due to "Ostwald Ripening" during the Storage cannot be completely suppressed. Under certain storage conditions, dissolved particles can also precipitate and promote particle growth as seed crystals.
• particle size is fundamental to therapeutic efficiency, products are theirs Particle size cannot be kept constant during pharmaceutically usual storage times of 2-3 years, to be classified as critical.
• WO 00/27376 describes nanoparticulate aqueous active substance preparations for the production of aerosols, the active substance particles having sizes of less than 1000 nm, preferably less than 50 nm. These preparations are produced using surface-modifying agents which adsorb on the surface of the active substance particles. Vitamin E-TPGS is suggested as such an agent.
• the document RU 1280217 describes a propylene glycol-containing mixture as a solubilizer for the production of budesonide-containing aqueous preparations.
• preparations have a high viscosity and are hyperosmolar, which is why there is no irritation-free inhalation treatment, especially since the auxiliaries used have not yet been classified as harmless from an inhalation toxicological point of view.
• the use of propylene glycol leads to hyperosmolar solutions from a concentration of about 1%, which trigger a cough after inhalation.
• they have high viscosities, which is why formulations which have been produced using this auxiliary are unsuitable for inhalation therapy and, because of their physical properties alone, cannot be used with a vibrating membrane nebulizer.
• Another object is to provide processes for the preparation of such preparations.
• the preparations according to the invention are aqueous preparations.
• This generic term refers to liquid compositions in which the liquid carrier or solvent consists predominantly of water and which, in addition to the carrier, contain at least one further substance which serves as an active ingredient or auxiliary.
• the liquid state of matter means that it is either a liquid single-phase system or a multi-phase system with a liquid coherent phase.
• the preparations of the invention thus include aqueous solutions, colloidal solutions, suspensions and emulsions. Even if the liquid carrier consists predominantly of water, it can in individual cases contain portions of one or more liquids which are at least partially miscible with water, e.g. As ethanol, glycerol, propylene glycol or polyethylene glycol. Preparations which are largely free of such non-aqueous liquids are preferred according to the invention.
• sterility is to be understood in the usual pharmaceutical sense. It is understood as freedom from germs capable of reproduction, and is proven by means of suitable tests, which are bindingly laid down in the currently valid pharmacopoeia. According to today's state of science contamination rate (Sterility Assurance Level) of 10 -6 is considered acceptable for sterile preparations in general, that in a million units a unit may be contaminated. In practice, however, the contamination rate is likely to be higher. So you go z. B. assume that in aseptically prepared preparations the contamination rate should be around 10 "3.
• the scope of sterility tests for quality control of batches according to the pharmacopoeia is limited and, on the other hand, even contamination can be caused as artifacts when the tests are carried out, it is difficult to demand sterility in the absolute sense as a property or to prove it for a certain object. Therefore, the sterility of a preparation should be understood here in particular so that the preparation in question meets the requirements of the currently valid pharmacopoeia with regard to sterility.
• Aqueous preparations which can be converted into aerosols for use must - unlike e.g. B. organic solutions or suspensions in pressure-liquefied propellants - be aerosolized in special nebulizers.
• the preparations according to the invention are now characterized in that they contain an active ingredient and a combination of a nonionic surfactant and a phospholipid.
• An active ingredient is to be understood here as a substance or mixture of substances which can be used for therapeutic, diagnostic, prophylactic or other purposes serving the well-being.
• the active ingredient can be a chemically defined ("small") molecule or a peptide, protein or polysaccharide derived from nature.
• the active ingredient is not a surfactant and preferably not another substance, which is also usually used as a pharmaceutical excipient and the effect of which is predominantly based on its physicochemical properties.
• Surfactants are to be understood as amphiphilic, surface or surface-active substances. Such compounds have at least one more hydrophilic and at least one more hydrophobic or lipophilic molecular region. They accumulate in phase boundaries and lower the interfacial tension. Among other things, surfactants are used to stabilize multiphase systems. Non-ionic surfactants are surfactants that do not have a real ionic charge in aqueous media at largely neutral pH values (e.g. between pH 4 and 10), but at most partial charges. Phospholipids are defined as amphiphilic lipids that contain phosphorus. Also known as phosphatides, they play an important role in nature, particularly as double-layer-forming components of biological membranes.
• Phospholipids which are chemically derived from phosphatidic acid are widespread and frequently used for pharmaceutical purposes. This is a (mostly double) acylated glycerol-3-phosphate, in which the fatty acid residues can be of different lengths.
• the descendants of phosphatidic acid are e.g. B. the phosphocholines or phosphatidylcholines, in which the phosphate group is additionally esterified with choline, phosphatidylethanolamines, phosphatidylinosites, etc.
• lecithins are natural mixtures of various phospholipids, which generally have a high proportion of phosphatidylcholines.
• Suitable nonionic surfactants are, above all, those that are considered safe for inhalation. These primarily include tyloxapol, polysorbates, especially polysorbate 80, and vitamin E TPGS. The most preferred nonionic surfactant currently by the inventors is tyloxapol.
• Suitable phospholipids are also those that are suitable for inhalation administration due to their physiological properties. These include, above all, phospholipid mixtures which are extracted in the form of lecithin from natural sources such as soybeans or chicken egg yolk, preferably in hydrogenated form and / or freed from lysolecithins, and purified, enriched or partially synthetically obtained phospholipids, preferably with saturated fatty acid residues. Purified, enriched or partially synthetically obtained medium to long-chain zwitterionic phospholipids are particularly preferred which are largely free of unsaturation in the acyl chains and free of lysolecithins and peroxides. Of the phospholipid mixtures, lecithin is particularly preferred. Examples of enriched or pure compounds are dimyristoylphosphatidylcholine (DMPC),
• DMPC dimyristoylphosphatidylcholine
• DSPC Distearoylphosphatidylcholine
• DPPC Dipalmitoylphosphatidylcholine
• DMPC Distearoylphosphatidylcholine
• DPPC Dipalmitoylphosphatidylcholine
• phospholipids with oleyl residues and phosphatidylglycerols without choline residues are suitable for some configurations and applications of the invention.
• the preparation contains tyloxapol as a nonionic surfactant and lecithin as a phospholipid, and in a further preferred embodiment, tyloxapol as a nonionic surfactant and DMPC as a phospholipid.
• a further surfactant in addition to the nonionic surfactant and the phospholipid.
• This can be another nonionic surfactant, another phospholipid or an ionic surfactant without phosphorus. However, it is preferably a nonionic surfactant.
• the nonionic surfactants already mentioned are particularly suitable.
• the surfactant to be used according to the invention and the phospholipid to be used according to the invention can fulfill different functions.
• one of the remarkable effects of the combination is its ability to solubilize poorly soluble active ingredients colloidally, better than is possible with a single surfactant - even with a correspondingly increased concentration within the physiologically acceptable limits (see also Example 1).
• the preparation is therefore a single-phase system, i.e. H. as an aqueous solution.
• Single-phase and “solution” also mean, in particular, colloidal solutions in which the solutes or some of them are present in a colloidal dispersion rather than in a molecularly dispersed manner.
• the position of the molecules that are solubilized in such micelles or mixed micelles depends on the structure of these molecules and the surfactants used. For example, it can be assumed that particularly non-polar molecules are primarily located inside the colloidal structures, while polar substances are more likely to be found on the surface.
• the colloidal systems as the single-phase preparations can present themselves, therefore contain particles that are on average in the colloidal size range, i.e. below about 1 ⁇ m according to the generally customary definition, or between 1 and about 500 nm, as described by other sources (H. Stricker, Physikalische Pharmazie, 3. Edition, p. 440). They are therefore practically invisible with a light microscope and do not lead to a pronounced clouding of the solution, but at most to an opalescence.
• the single-phase, colloidal preparations of the invention preferably contain association colloids with an average particle size of less than 500 nm (measured by photon correlation spectroscopy). Colloids with medium ones are particularly preferred
• colloids up to about 200 nm, and in further preferred embodiments, colloids with average particle sizes up to about 100 nm and up to about 50 nm are included.
• colloids appear mainly as liposomes.
• Methods for the production and characterization of liposomes and liposomal preparations are known per se to the person skilled in the art.
• those are preferred according to the invention which have a predominantly colloidal size, i. H. whose average particle size is below about 1 ⁇ m, better still at a maximum of about 500 nm or even at a maximum of about 200 nm.
• An average particle size of up to about 200 nm generally allows sterile filtration through a filter with a pore size of 0.22 ⁇ m.
• the weight ratio between the nonionic surfactant and the phospholipid must be determined or optimized, taking into account the selection of the surfactants. According to the invention, a weight ratio of about 5: 1 to about 1: 2 is preferred. Particularly good solubilization is usually achieved with ratios of about 3: 1 to 1.5: 1, that is to say with a slight excess of the nonionic surfactant, for example about 2: 1 This is particularly true if the preferred tyloxapol is selected as the nonionic surfactant and the preferred DMPC (or DPPC or DSPC) as the phospholipid. In particular, poorly soluble corticoids such as budesonide can be surprisingly well solubilized.
• the total content of surfactant in the preparation should be limited to a maximum value of approximately 3% by weight, especially for physiological reasons, if pulmonary application is provided. With a nasal application, higher amounts of surfactant can also be considered, e.g. B. up to about 10 wt .-%. To avoid irritation of the mucous membrane, it would be advantageous to limit the surfactant content to as little as possible not more than about 5% by weight.
• the preparation preferably contains a surfactant content of approximately 0.01 to 3.0% by weight. Contents of about 0.1 to 2.0% by weight are particularly preferred.
• the optimal amount of surfactants used also depends on the active ingredient, ie its physicochemical properties and its content in the preparation, as well as on the selection of the surfactants and the intended effects and
• the particularly preferred total surfactant content is about 1 to 2% by weight, in particular about 1.5% by weight. -%. If, on the other hand, an improvement in the organoleptic properties of the preparation is desired, u. U. a significantly lower surfactant content is sufficient and therefore pharmaceutically advantageous, e.g. B. a content of not more than about 1.0 wt .-%, and better still one of not more than about 0.5 wt .-%.
• the active ingredient content must of course also be taken into account. Very low-dose active ingredients tend to be both solubilized and masked in taste with lower surfactant contents. In addition, smaller amounts of surfactant are sufficient to alleviate the properties of active substances that are irritating to the mucous membranes, which cause cough and bronchospasm.
• a preferred weight ratio between the surfactant content (i.e. total content of surfactant and phospholipid) and active ingredient content is at least about 1: 1, particularly preferably at least about 5: 1. Ratios of more than 10: 1 may even be required for the solubilization of some poorly soluble active ingredients.
• a ratio of about 50: 1 to 100: 1 should be selected for the solubilization of the poorly soluble active ingredient budesonide.
• significantly lower surfactant-drug ratios can usually suffice if no colloidal solubilization of the drug is desired or necessary and the surfactant mixture is used primarily to mask undesirable organoleptic or physiological properties of the drug or to improve the spreading of the aerosol in the respiratory tract.
• the surfactants When selecting the surfactants, the surfactant content and the ratio of the same to the active ingredient content, the effects on the physicochemical properties of the preparation which are important for atomization into an aerosol that can be administered by inhalation must of course be considered. Above all, this includes surface tension and dynamic viscosity.
• the surface tension especially for pulmonary application, should be set so that it is approximately 25 to 80 mN / m, preferably approximately 30 to 75 mN / m. It is too Please note that a particularly good spread of the preparation in the respiratory tract is to be expected in the lowest area of this interval, but that the quality of the aerosol and the efficiency of the nebulization can suffer. On the other hand, with the use of surfactants, which is necessary for the colloidal solubilization of a poorly soluble active ingredient, it can hardly be avoided that the surface tension is lowered quite far below that of water or physiological buffer solution. In each case, a compromise can be found that has to be adjusted depending on the active ingredient and the intended use. Especially for the solubilization of poorly soluble active ingredients, a surface tension in the range from about 30 to 50 mN / m is particularly preferred.
• the dynamic viscosity also has a significant influence on the
• Particle size distribution of the aerosol generated during the nebulization and on the nebulization efficiency should be set in the range from about 1 to about 3 mPas.
• a dynamic viscosity in the range from approximately 1.0 to approximately 2.5 mPas is particularly preferred.
• aqueous preparations according to the invention are to be used for application as an aerosol which is used in situ. H. immediately during use - generated by a suitable device.
• nebulizers with which such preparations can be aerosolized have already been presented at the beginning.
• Nozzle nebulizers have been used in therapy for a long time, and for some time also ultrasound nebulizers.
• powerful nebulizers have been developed that are named after their piezoelectric, electrohydrodynamic and / or functional principle based on a vibrating membrane or with pores (e.g. eFlow TM, eFlow Baby TM, AeroNeb TM, AeroDose TM or AERx TM) are.
• the different mechanisms of aerosol production lead to differences in the nebulization quality for certain preparations.
• the preparations of the present invention are particularly geared to the requirements of nebulization by the nebulizers (vibrating membrane nebulizers) working with vibrating, porous membranes.
• a particularly preferred nebulizer for which the preparation is intended to be used is the eFlow TM from Pari GmbH.
• This nebulizer and the devices of a similar type are particularly suitable for modern aerosol therapy: they are small and nebulize relatively large volumes of liquid within a short period of time to generally high-quality aerosols.
• these nebulizers also have limitations or application problems, e.g. B. when it comes to the nebulization of suspensions of poorly soluble active ingredients.
• the inhalation liquid is extruded through the pores of a vibrating membrane, larger solid particles are either completely excluded from aerosolization (if their diameter is at least approximately as large as the pore diameter) or - with particle sizes in the lower micrometer range - at least lead to a more or less pronounced sieving effect.
• the present invention is particularly advantageous for the administration of poorly soluble active ingredients with such nebulizers: for example, these active ingredients can now be formulated and inhaled as a colloidal solution instead of as a microsuspension, which practically eliminates or at least significantly reduces the sieving effect through the pores of the membrane.
• the preparation for the treatment of the oral or nasal mucosa is e.g. B. in allergic rhinitis, vasomotor rhinitis, nasal polyps, or in inflammatory diseases of the oral mucosa.
• very simple devices for generating the aerosol can also be used for this application, e.g. B. mechanical atomizers, as are often used for oral or nasal sprays.
• nozzle, ultrasonic or piezoelectric ones can also be used
• Vibrating membrane nebulizers are used, which may need to be adapted accordingly in the case of nasal application.
• the preparation is intended for the treatment of the mucous membrane of the sinus, jaw or frontal sinus.
• These mucous membranes are basically accessible to aerosol therapy.
• the efficient application of an aerosol is difficult due to the low ventilation of these cavities and can hardly be carried out with the usual nebulizers.
• the simple nasal inhalation of an aerosolized active ingredient preparation leads it close to the sinuses, but the aerosol flow predominantly passes through the openings (ostia) to the sinuses without a significant proportion of the aerosol entering the sinuses.
• the frontal and paranasal sinuses are very often the site of inflammatory processes that can be treated with budesonide.
• these nebulizers have a nose piece for directing the aerosol flow into the nose. If only one nostril is used to inhale the aerosol, the other must be closed using a suitable device.
• These nebulizers are also characterized by the fact that they release an aerosol with pulsating pressure. The pulsating pressure zones ensure intensive ventilation of the sinuses, so that an aerosol inhaled at the same time can be better distributed in these cavities. Examples of corresponding nebulizer devices are disclosed in DE 102 39 321 B3.
• the preparation of the invention is used to produce a medicament for application with the aid of one of the devices described there for the treatment of infections of the upper respiratory tract, in particular with a device of the PARI Sinus type.
• the preparation In the sense of a compatible aerosol, the preparation should be adjusted to the most physiological tonicity or osmolality possible. It is therefore desirable to have an osmolality that is not too strongly different from that of physiological liquids, ie. H. deviates from about 290 mOsmol / kg. However, here too, compromises have to be made in individual cases between the physicochemical or pharmaceutical requirements on the one hand and the physiological requirements on the other. In general there is an osmolality in the
• Range of about 200 to 550 mOsmol / kg and in particular in the range of about 230 to about 350 mOsmol / kg are preferred for the preparations according to the invention.
• auxiliaries are above all harmless mineral salts that react largely neutrally (unless, such auxiliaries should adjust or buffer the pH at the same time), such as.
• One of the particularly preferred adjuvants is sodium chloride.
• Magnesium and calcium sulfate and chloride are further preferred auxiliaries for this purpose.
• physiologically acceptable organic auxiliaries can also be used as isotonizing agents.
• auxiliaries are sugar and sugar alcohols, in particular trehalose, mannitol, sorbitol and isomalt.
• the preparation according to the invention should be adjusted to an euhydric pH.
• euhydrisch already includes that in turn, a tension can exist between pharmaceutical and physiological requirements, so that a compromise must be found, e.g. B. just guaranteed in the economic sense sufficient stability of the preparation during storage, on the other hand is largely compatible.
• the pH value is preferably in the slightly acidic to neutral range, that is between pH values of approximately pH 4 to pH 8. It should be noted that deviations from the weakly acidic environment can be tolerated rather than shifts in the pH value in the alkaline area. A pH in the range from about 4.5 to about 7.5 is particularly preferred.
• auxiliaries for lowering the pH or as acidic components of a buffer system are strong mineral acids, especially sulfuric acid and hydrochloric acid.
• medium-strong inorganic or organic acids and acid salts are also possible, for.
• phosphoric acid citric acid, tartaric acid, succinic acid, fumaric acid, methionine, acidic hydrogen phosphates with sodium or potassium, lactic acid, glucuronic acid, etc.
• sulfuric acid and hydrochloric acid are preferred.
• Mineral bases such as sodium hydroxide or other alkali and alkaline earth metal hydroxides and oxides such as in particular magnesium hydroxide and calcium hydroxide, ammonium hydroxide and basic ammonium salts such as ammonium acetate and basic amino acids such as lysine are particularly suitable for raising the pH or as basic components of a buffer system , Carbonates such as sodium or magnesium carbonate, sodium hydrogen carbonate, citrates such as sodium citrate etc.
• the preparation according to the invention contains a buffer system consisting of two components, and one of the particularly preferred buffer systems contains citric acid and sodium citrate.
• the chemical stabilization of the preparation by additional additives may be indicated not primarily from physiological, but from pharmaceutical considerations. This mainly depends on the type of active ingredient contained.
• the most common degradation reactions of chemically defined active substances in aqueous preparations include, above all, hydrolysis reactions, which are primarily limited by an optimal pH setting, as well as oxidation reactions.
• Examples of active substances which are susceptible to oxidation are those which have olefinic, aldehyde, primary or secondary hydroxyl, ether, thioether, endiol, keto or amino groups.
• an antioxidant or an auxiliary which is synergistic with an antioxidant may therefore be recommended or necessary.
• Antioxidants are natural or synthetic substances that can prevent or interrupt the oxidation of the active ingredients. These are primarily auxiliaries that can themselves be oxidized or occur as reducing agents, such as tocopherol acetate, reduced glutathione, catalase peroxide bismuthase. Synergistic substances are e.g. B. Those that do not appear directly as reactants in oxidation processes, but which counteract oxidation by an indirect mechanism such as the complexation of metal ions that have a catalytic effect on oxidation, as is the case, for example, with EDTA derivatives (EDTA: ethylene ediaminetetraacetic acid ) the case is.
• EDTA ethylene ediaminetetraacetic acid
• antioxidants are ascorbic acid, sodium ascorbate and other salts and esters of ascorbic acid (e.g. ascorbyl palmitate), fumaric acid and its salts, malic acid and its salts, butylated hydroxyanisole, propyl gallate and sulfites such as sodium metabisulphite.
• ascorbic acid sodium ascorbate and other salts and esters of ascorbic acid (e.g. ascorbyl palmitate)
• fumaric acid and its salts e.g. ascorbyl palmitate
• malic acid and its salts e.g. butylated hydroxyanisole
• propyl gallate and sulfites such as sodium metabisulphite.
• citric acid and citrates, malic acid and its salts and maltol (3-hydroxy-2-methyl-4H-pyran-4-one) may also act as chelating agents.
• the preparation contains at least one antioxidant. In a further embodiment, it contains both an antioxidant and a chelating agent.
• a vitamin E derivative in particular vitamin E acetate
• an EDTA derivative in particular sodium edetate
• this combination has proven to be particularly advantageous for achieving a high chemical stability and durability of the preparation.
• This combination of excipients is particularly preferred in combination with the active ingredient budesonide.
• the combination of a nonionic surfactant and a phospholipid according to the invention has a markedly high ability to collubilize poorly soluble active ingredients. It can be assumed that micelles or mixed micelles with a lipophilic core and a hydrophilic outer region form. A particular advantage of colloidal solutions like these is that they are better (i.e. without high
• Loss of active ingredient in the nebulizer can be aerosolized and that aerosols with finer droplet sizes can be produced than this, for. B. is the case in the case of microsuspensions.
• An aerosol with a small average particle size or with a high proportion of droplets in the lower micrometer range is particularly important if inhalation is to reach the deeper regions of the respiratory tract, ie the fine branches of the bronchioles or even the alveoli. It is also particularly important and advantageous if the patients are children whose anatomical structures are significantly smaller than those of adults. In one of the preferred embodiments, the preparation is therefore intended for use on children, with which infants, toddlers, Children and adolescents are meant. In particular, the determination for use on infants and young children is preferred.
• micellar and mixed micellar solutions can be filtered through membrane filters with a pore size of 0.22 ⁇ m to remove any germs (sterile filtration). This method of sterilization is particularly important whenever heat or radiation sterilization does not seem possible or is not favorable for chemical or physicochemical reasons.
• the active ingredient is a poorly water-soluble active ingredient.
• Active substances that are sparingly soluble in water are substances that are used in aqueous media at room temperature and largely neutral pH, eg. B. at pH 4 to pH 10, but especially at pH 5 to 8 are sparingly soluble.
• sparingly soluble means that the solubility of an active ingredient is so low that at least 30 parts of water are required to dissolve one part of the active ingredient.
• it is a poorly soluble active ingredient which belongs to the group of corticoids, betamimetics, anticholinergics, anesthetics,
• Immunomodulators and anti-infectives including antibiotics, antivirals and antifungals is selected.
• a particularly preferred poorly soluble active ingredient is budesonide.
• the content of the sparingly soluble active ingredient is generally not more than about 2% by weight, preferably in the range from about 0.01 to 1.0% by weight.
• a colloidal solution with an active ingredient content of approximately 0.15 to 0.35 mg / ml is particularly preferred, and very particularly with a content of approximately 0.2 mg / ml.
• a physiologically well-tolerated preparation is provided which, in contrast to the previously known budesonide preparations for inhalation with modern nebulizers, also with Those that work with a porous, vibrating membrane can be nebulized quickly, efficiently and without major loss of active ingredient, and that to fine, high-quality aerosols that are also suitable for pediatric use.
• the inventors found in test trials that preparations with a combination of a nonionic surfactant and a phospholipid are surprisingly able to mask the bad taste of active ingredients during inhalation.
• a pronounced bad taste is extremely unpleasant and annoying when inhaling aerosols, and it can lead to non-compliance and thus to therapy failure.
• the bad taste is perceived by the patient through the proportion of the aerosol, which is reflected in the inhalation in the mouth and throat.
• the preparation according to the invention contains a bad-tasting active ingredient.
• a bad taste can have different forms, all of which are included here, e.g. B. acidic, sharp, metallic, biting, bad, spoiled, anesthetic, etc.
• the active ingredient with bad taste - in contrast to other embodiments of the invention - can have any water solubility.
• the active ingredient preferably belongs to the group of corticoids, betamimetics, anticholinergics, anesthetics and anti-infectives.
• a preferred active ingredient in this context is the antibiotic tobramycin, including its salts and other derivatives.
• the preparation accordingly contains an active ingredient which irritates the mucous membrane or causes cough or bronchoconstrictions.
• This active ingredient can have any water solubility.
• preference is again given to those active ingredients which come from the group of corticoids, betamimetics, anticholinergics, anesthetics and anti-infectives.
• a particularly preferred active ingredient is the antibiotic tobramycin, including its salts and derivatives. This ingredient is known to be coughing and
• compositions contained in the preparation are selected from the group consisting of corticosteroids, beta-sympathomimetics, anticholinergics, local anesthetics, immunomodulators, anti-infectives, angiotension converting enzyme (ACE) inhibitors, cytostatics, in particular Budesonide, ciclesonide, fluticasone, mometasone, beclomethasone, flunisolide; Formoterol, salmeterol, levalbuterol; Thiotropium, oxitropium, ipratropium; Lidocaine, prilocaine, mepivacaine, bupivacaine, articaine, ciclosporin, tacrolimus, sirolimus, rapamycin, azathioprine; Ciprofloxacin, moxifloxacin, azithromycin, clarithromycin, erythromycin, metronidazole, ketoconazole, itraconazole
• the preparation contains at least one further active ingredient.
• active ingredients in this context are e.g. B. (a) a betamimetic and a parasympatholytic, (b) a betamimetic and a corticoid, and (c) a parasympatholytic and a corticoid.
• mast cell stabilizers such as cromoglicic acid or nedocromil including their therapeutically usable salts.
• Combinations of antibiotics and bronchodilators as well as a mucolytic agent can also be useful.
• physiologically safe and well-tolerated antioxidants such as. B. tocopherols, catalase, peroxide bismuthase, since these can trap or reduce radical oxygen, which is responsible for many inflammatory processes.
• agents can also be selected which are primarily intended for diagnostic, prophylactic or well-being purposes.
• a preparation according to the invention can accordingly be intended for therapeutic, diagnostic and prophylactic applications. The determination for therapeutic use is particularly preferred.
• the active ingredient can be administered in the form of the preparation according to the invention in order to have its effect locally (e.g. in the nose, throat or bronchial tubes) at or near the Mucous membrane of the respiratory tract to develop, or it can have a systemic effect after absorption into the bloodstream.
• a more local effect will be the focus of therapy for respiratory diseases of the upper and lower respiratory tract.
• the use of the preparation of the invention is particularly advantageous for the production of medicaments which are used for the prophylaxis or treatment of bronchial or pulmonary diseases or symptoms, e.g. B. bronchial asthma or chronic obstructive bronchitis.
• the preparation is preferably intended for inhalation with a nozzle, ultrasound or piezoelectric vibrating membrane nebulizer, e.g. B. with a PARI eFlow TM or - in the case of a pediatric application - an eFlow Baby TM.
• the preparation of the invention can also be used for the production of medicaments which are to be used for the prophylaxis or treatment of diseases or symptoms of the mucous membrane of the forehead, jaw or paranasal sinuses, e.g. B. from acute and chronic sinusitis or from polyps.
• a nozzle nebuliser such as. B. happens the PARI Sinus, which is specially adapted for this application.
• suitable nebulizers have on the one hand a nose piece for directing the aeroso stream into the nose. If only one nostril is used to inhale the aerosol, the other must be closed using a suitable device.
• these nebulizers are characterized in that they let out an aerosol with pulsating pressure.
• the pulsating pressure waves ensure intensive ventilation of the sinuses, so that an aerosol inhaled at the same time can be better distributed in these cavities.
• Examples of corresponding nebulizer devices are disclosed in DE 102 39 321 B3.
• the use of the preparation of the invention for the manufacture of medicaments intended for the prophylaxis or treatment of diseases or symptoms of the mucous membrane of the oral and / or nasal cavity e.g. B. from stomatitis, aphthae, allergic rhinitis, vasomotor rhinitis, chronic rhinitis, or polyps.
• the application can be carried out by a device with a mechanical atomizer, as is often used in nasal or mouth sprays, or with the aid of a possibly adapted nozzle, ultrasound or vibrating membrane nebulizer.
• the preparation is produced using a combination of process steps known per se, each of which must be selected and, if necessary, adapted in view of the special requirements of the active ingredient and the desired product properties.
• the special requirements for preparations for inhalation must also be taken into account.
• the preparations must be sterile, that is to say they must be free of any reproductive elements, which must be ensured by careful selection and execution of the process steps. Additional requirements may arise from special application regulations. If e.g. B. the preparation for inhalation with a nebulizer of the type that works with porous, vibrating membranes is intended, must by the manufacturing process u. a. ensure that the size of the active ingredient particles - if present - are actually below the limit above which an undesirable sieving effect occurs.
• the preparation is an aqueous solution, which includes colloidal, e.g. B. micellar or mixed micellar solutions are to be understood, and if heat sterilization in the final container is not possible due to the physical or chemical thermolability of the preparation or individual components thereof, sterile filtration is a suitable sterilization process. Even if the preparation is an aqueous suspension, such as a microsuspension, final sterilization can be critical, since it can change the particle size distribution of the suspension particles considerably and thereby influence important properties of the preparation.
• one of the preferred manufacturing processes can include the following process steps:
• step (c) sterile filtration of the preparation prepared in step (a);
• step (d) filling the sterile-filtered preparation in step (b) into sterile containers under aseptic conditions.
• the ingredients in process step (a) are provided in a sterile state in order to limit the initial germ load of the preparation. If not all of the starting materials can be provided in a sterile state, at least those should be pre-sterilized for which this is possible without compromising quality.
• the aqueous preparation from the intended ingredients or starting materials after step (b) can be produced in several substeps.
• So z. B. first of all, the preparation of an aqueous solution (possibly colloidal solution) of the nonionic surfactant and the phospholipid and possibly other auxiliary substances.
• a process step with a relatively high energy input e.g. B. a homogenization step under increased pressure (high pressure homogenization), sonication or heating to about 45 ° C, to about 50-70 ° C or even higher temperatures.
• sterilized or low-germ starting materials should be used, if possible, and if possible under aseptic conditions. Furthermore, it might be appropriate to subject this colloidal auxiliary solution produced in a first sub-step of process step (b) to a heat sterilization process.
• the active ingredient would then have to be dissolved in the colloidal solution thus produced, if possible again under aseptic conditions.
• This is preferably done without any application of comminution processes in which solid active ingredient particles are mechanically broken up. Rather, it is preferred that energy input at this process stage - if necessary - be carried out by supplying heat or possibly by ultrasound.
• the active ingredients can be incorporated solely by stirring, even the colloidal distribution of poorly soluble active substances into micelles or mixed micelles.
• the previously prepared, active ingredient-containing solution or colloidal solution is sterile filtered, i. H. through a filter - e.g. B. a membrane filter - filtered with a pore size of about 0.22 microns, possibly using pressure to remove the germs and particles contained in the solution.
• a filter - e.g. B. a membrane filter - filtered with a pore size of about 0.22 microns, possibly using pressure to remove the germs and particles contained in the solution.
• Suitable sterile filtration methods are known in principle to the person skilled in the art in various variants together with the devices that can be used for them.
• the primary packaging can be glass containers (e.g. vials) with sealing devices made of elastomers and metal safety caps, alternatively plastic ials or blister-like primary packaging systems.
• a single primary packaging can contain a single dose or multiple of them. In all cases, however, in which heat sterilization of the preparation is possible and does not lead to a significant loss in quality, a method is preferred which, instead of sterile filtration, includes the final sterilization of the preparation by a medication-compliant heat sterilization process after it has been filled into the primary packaging.
• Suitable primary packaging made of plastic are e.g. B. polypropylene or polyethylene vials (PP / PE vials) and cycloolefin copolymer blister (COC blister).
• Sealed plastic containers such as PP or PE vials can, for example, be advantageously molded, filled and sealed using the blow-fill-seal process in an integrated process.
• the containers produced in this way are particularly suitable for liquid filling goods with a volume of approximately 0.2 ml or more.
• Particularly patient-friendly they can be formed with a closure that can be removed by twisting or kinking.
• the opening thereby created, through which the liquid content can be removed, can be designed in such a way that it fits onto a Luer connection or Luer lock connection.
• the opening can be round and have a diameter that largely corresponds to the outside diameter of a male Luer connector.
• a conventional syringe with a Luer connection could be connected to the container in a coherent manner, for example around the contents of the container and transfer to a nebulizer, or to mix the contents of the container with the contents of the syringe and then add them to a nebulizer.
• the plastic container is designed in such a way that after removal of the closure element, it can be largely conclusively connected to a connector provided for the supply of liquid of a correspondingly adapted nebulizer, which enables the preparation to be filled directly into the reservoir of the inhaler is.
• Plastic containers of this type are also advantageous because they can be easily embossed.
• important information can also be made accessible to visually impaired patients through such an imprint.
• the embossing can contain various information, e.g. B. a batch name, an expiry date, a product name, instructions for use, or one or more volume or dose brands.
• a plurality of volume marks can be used to facilitate the removal of the desired dose without further aids, which can reduce the risk of dosing errors.
• the preparations according to the invention described above may be advantageous to subject them to freeze drying in order to store them in the solid state.
• the liquid form required for atomization can be restored from it shortly before use by mixing with sterile water.
• a solid composition which can be obtained by freeze-drying the preparations according to the invention described above.
• the methods of freeze drying are known per se to those skilled in the art.
• Example 1 Solubilization of budesonide with tyloxapol and DMPC
• Buffered aqueous solutions of Tyloxapol, DMPC, and Tyloxapol mixed with DMPC were prepared.
• the saturation solubility of budesonide was measured by adding an excess of budesonide and treating the respective batch with heat and ultrasound and then allowing it to stand for equilibration.
• the equilibrated batches were filtered through a membrane filter with a pore size of 0.22 ⁇ m and the budesonide content in the filtrate was determined. Selected results from these experiments are shown in Table 1.
• the saturation concentration of budesonide in DMPC solution could also not be increased by a further increase in the DMPC content.
• Tyloxapol [wt%] DMPC [wt%] budesonide [ ⁇ g / ml] 0 1 20 1, 5 0 204 1 0.5 268
• Budesonide is an example of a poorly water-soluble active ingredient which can advantageously be formulated as a colloidal aqueous solution by the combination of surfactants according to the invention.
• the starting materials designated in Table 2 were provided in the amounts indicated.
• the specified starting materials apart from budesonide were first dissolved or dispersed by stirring with a magnetic stirrer. The mixture was then homogenized with a high-pressure homogenizer over 10 min at 1500 bar. This gave an opalescent, colloidal solution with a pH of about 4.5.
• the characterization of the filled preparation showed a budesonide content of 202.34 ⁇ g / ml, a surface tension of 38.8 mN / m, a dynamic viscosity of 1.07 mPas, an osmolality of 0.282 osmol / kg and a pH value of 4. 25 at 21.8 ° C.
• Two different nebulizers were used in these investigations, namely the nozzle nebulizer PARI LC PLUS ® and the piezoelectric nebulizer PARI eFlow TM baby.
• the legend also shows the active ingredient doses used for the nebulization. Percentage deposition information can be found in Table 3. In-vivo examinations with radiolabelled budesonide confirmed the better deposition of the colloidal budesonide solution according to the invention compared to the suspension.
• the colloidal solution obtained can also be in the form of a preservative-free nasal spray or with other application devices, such as, for example, a nozzle nebulizer working with a pulsating compressor, such as, for. B. the PARI SINUS TM, are used therapeutically and also for nasal treatment of sinus and / or sinus infections or allergic rhinitis.
• Example 3 Preparation of a budesonide formulation for nasal use 3.75 g of tyloxapol were weighed into a 1000 ml beaker. For this purpose, 486.0 g of water were added for injection purposes and the mixture was stirred at room temperature (20 ° C. stirred) until the tyloxapole had completely dissolved. 4.23 g of sodium chloride, 0.2 g of citric acid and 0.25 g of sodium citrate were added to the resulting solution. After all components had dissolved, the pH of the solution was adjusted to 4.3 by adding sodium citrate.
• Lipoid PC 14:14 (dimyristoylphosphatidylcholine) were added to the solution and homogenized using an Ultra-Turrax at 11,000 rpm (5 minutes). The formulation was then homogenized by means of high pressure homogenization (Microfluidies M100EH) at 1500 bar for 20 minutes. The resulting solution showed slight opalescence, which almost disappeared after 12 hours on a magnetic stirrer.
• the formulation was homogenized again (Ultra Turrax followed by high pressure homogenization). After standing for a further 12 hours on a magnetic stirrer, the now slightly opalescent preparation could be sterile filtered through a 0.22 ⁇ m membrane filter under aseptic conditions and placed in pump atomizer bottles (100 ⁇ l / Stroke).
• the finished budesonide-containing formulation showed the following physicochemical properties: pH value of 4.3 at 22.7 ° C, a dynamic viscosity of 1.16 mPas, a surface tension of 40.6 mN / m and an osmolality of 0.262 osmol / kg.
• Tobramycin is an example of a bad taste ingredient that can cause cough and bronchoconstriction.
• the characterization of the filled preparation showed a pH value of 6.23 at 21.8 ° C, a dynamic viscosity of 2.07 mPas, a surface tension of 36.5 mN / m and an osmolality of 0.229 osmol / kg.
• Example 5 Preparation of a sterile solution of lidocaine 0.55% (w / v) lidocaine base was incorporated into a solution of the components listed in Table 2 (without budesonide). After sterile filtration, the colloidal solution was filled into pre-sterilized single-dose containers (0.5-3 ml) made of glass and polypropylene. Inhalation experiments showed that the undesirable local anesthetic effect of lidocaine was reduced.
• Example 6 Preparation of a sterile solution of cyclosporin
• This example describes the possibility of solubilizing the water-insoluble immunomodulator cyclosporin according to the invention.
• Cyclosporin is first suspended or dissolved in propylene glycol. This mixture is mixed with aqueous buffer solution, which contains the amounts of tyloxapol, DMPC and NaCl mentioned in Table 4, and made up to 100 ml with water for injections. High pressure homogenization, as described above, creates a colloidal solution, which after sterile filtration through a 0.22 ⁇ m filter is filled into pre-sterilized 0.5 - 3 ml single-dose containers made of glass or polypropylene. The cyclosporin content of the formulation obtained is 570 ⁇ g / ml.
• the mean particle size (z-average) of this colloidal dispersion determined by photocorrelation spectroscopy is 9.7 nm.
• Combinations of steroids such as B. budesonide with water-insoluble or water-soluble substances from the group of betamimetics (such as salbutamol, formoterol) and / or anticholinergics (such as ipratropium, thiotropium) are therapeutically preferred due to a synergistic effect and improved patient compliance.
• Formoterol (20 ⁇ / ml) was incorporated in a first batch and ipratropium bromide (100 ⁇ g / ml) in a colloidal budesonide solution (200 ⁇ g / ml) prepared according to Example 2.
• the resulting colloidal solutions were sterile filtered and filled into pre-sterilized 0.5 - 5 ml single dose containers made of glass or polypropylene.
• Example 8 Preparation of a freeze-dried combination product with vitamin E acetate and reduced glutation
• Antioxidants such as B. reduced glutathione and tocopherols (vitamin E derivatives) can reduce inflammation processes induced by radical oxygen.
• the following example illustrates the possibility of solubilizing the water-insoluble tocopherol acetate with the water-soluble but storage-unstable glutanate with the aid of the surfactant combination according to the invention and stabilizing it by a subsequent freeze-drying process.
• 2 g of Tyloxapol, 2 g of DMPC, and 20 mg of tocopherol acetate are mixed in 200 ml of water for injection and pre-homogenized with an Ultra-Turrax.
• the dispersion is homogenized in a high-pressure homogenizer at 1500 bar for about 15 minutes.
• the lyophilisate dissolves completely within 10 seconds with shaking.

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