DE10145361A1 - Sterile liquid composition for pulmonary administration in aerosol form comprises a sparingly water-soluble drug in the form of suspended particles of defined size - Google Patents

Abstract

Sterile liquid composition for pulmonary administration in aerosol form comprises a sparingly water-soluble drug in the form of suspended particles with an average size of 0.5-2 microns. An Independent claim is also included for production of such a composition by preparing a surfactant-containing suspension of the drug in the form of particles with an average size above 1 micron, reducing the average particle size to less than 1 micron and heat-sterilizing the suspension.

Description

The invention relates to pharmaceutical preparations, especially aqueous ones Inhalation preparations as aerosol. It also relates to processes for the production of such Preparations in sterile form.

introduction

Aerosols are systems whose disperse phase is in one in the floating state gaseous medium and exemplary as dust aerosol (solid in air) or mist (liquid in air) can be described. The floating particles point Diameter from 0.001-100 microns and thus correspond in size z. B. Proteins until fog droplets. Scientific inhalation therapy was developed at the beginning of the 19th Century. Claude-Bernhard had already in 1857 on the good resorption capacity of the lungs pointed out for medication, and crucial basics of inhalation therapy The depth of penetration into the lungs was determined by Hommel in 1910 and by Höpfner in 1920 published. Finding iron for the first time in 1935 made it smaller in the air Particles in the human lungs breathing experimentally and mathematically and his tables on regional aerosol deposition in the bronchial tree essentially confirmed later. Dautrebande has 1952 anatomical and liquid aerosols characterized physiologically and thus the basis of the developed modern inhalation therapy; the one published in 2000 gives a good overview Book by D. Köhler and W. Fleischer: Theory and Practice of Inhalation Therapy, Arcis Verlag GmbH, Munich, ISBN 3-89075-140-7.

• 1. den biologisch-physiologischen Faktoren, die gekennzeichnet sind durch:
  • 1. die Art des Atemmanövers, wie Atemfrequenz, -fluss, -geschwindigkeit, und -volumen,
  • 2. der Anatomie des Respirationstraktes insbesondere der Glottisregion
  • 3. dem Alter und Gesundheits- bzw. Erkrankungszustand der Menschen bzw. Patienten
• 2. dem Tröpfchen bzw. Partikelspektrum, das beeinflusst wird durch:
  • 1. die Art und Konstruktion des Inhalationsgerätes
  • 2. die Zeit zwischen Erzeugung und Inhalation (Abtrocknungseigenschaften)
  • 3. der Modifikation des Tröpfchen- bzw. Partikelspektrums durch den Inhalationsfluss
  • 4. der Stabilität bzw. Integrität der erzeugten Aerosolwolke
• 3. dem Wirkstoff bzw. der Medikamentenformulierung, deren Eigenschaften beeinflusst werden durch:
  • 1. die Partikelgröße
  • 2. die Darreichungsform (z. B. Lösung, Suspension, Emulsion, Liposomendispersion)
  • 3. die Form und Oberflächeneigenschaften des Wirkstoffes bzw. der Formulierung (glatte Kugeln oder gefaltete poröse Strukturen)
  • 4. die Hygroskopie (beeinflusst Wachstum der Partikel)
  • 5. die Grenzflächeneigenschaften, wie Benetzbarkeit und Spreitbarkeit
  • 6. den Verdunstungs- bzw. Evaporationseigenschaften des Trägermediums

The treatment of lung diseases with aerosols allows targeted drug therapy, since the active ingredient can be brought directly to the target location using inhalation devices. The prerequisite is that the inhaled droplets or particles reach the target tissue and are deposited there. The influences on aerosol production and deposition are essentially influenced by 3 factors, which can be broken down as follows:

• 1. the biological-physiological factors, which are characterized by:
  • 1. the type of breathing maneuver, such as breathing frequency, flow, speed and volume,
  • 2. The anatomy of the respiratory tract, especially the glottic region
  • 3. the age and state of health or illness of people or patients
• 2. the droplet or particle spectrum, which is influenced by:
  • 1. the type and construction of the inhalation device
  • 2. the time between generation and inhalation (drying properties)
  • 3. the modification of the droplet or particle spectrum by the inhalation flow
  • 4. the stability or integrity of the aerosol cloud generated
• 3. the active ingredient or the drug formulation, the properties of which are influenced by:
  • 1. the particle size
  • 2. the dosage form (eg solution, suspension, emulsion, liposome dispersion)
  • 3. the shape and surface properties of the active ingredient or formulation (smooth spheres or folded porous structures)
  • 4. Hygroscopy (affects particle growth)
  • 5. the interface properties, such as wettability and spreadability
  • 6. the evaporation or evaporation properties of the carrier medium

Aerosols and their deposition behavior

The composition and shape of the aerosols are very varied. For practical purposes, it makes sense to standardize the description of a particle on its deposition behavior above diameters greater than 0.5 µm, since then essentially only the weight-dependent sedimentation and impaction are considered as separation mechanisms. For this purpose, the considered particle (diameter d _o ) of density p is compared with an equally fast sedimenting sphere of density water (ρ = 1 g / cm ³ ) and the sphere diameter is referred to as aerodynamic diameter (d _ae ): d _ae = d _o / ρ.

The aerodynamic diameter is of the size, density, shape and orientation of the Particle dependent. Usually you have it in practice with a hetero- or to do polydisperse size distribution, d. H. with a mixture of different particles Size. If these are aerosols of the same structure (e.g. from a nebuliser), then the median aerodynamic mass diameter (MMAD) can be a number to be discribed. 50% of the aerosol mass is larger and 50% smaller than that MMAD. The width of the distribution is given by percentiles, e.g. B. 10% and 90% Percentile. These numbers indicate the particle size up to which less than 10% or less which particle size is only 10% of the mass. Symmetric distributions that are distributed almost normally, due to the geometric standard deviation (GSD = Geometric Standard Deviation). The GSD is dimensionless and greater than 1 and a measure of the symmetrical particle distribution of an aerosol cloud.

If one speaks of size distributions in an aerosol, it is imperative be specified whether it is the number of particles, the volume or the mass is. Since the mass depends on the third power of the diameter, calculate that a particle of 10 µm corresponds to the mass of 1000 particles of 1 µm. For The biological effect of drug aerosols is predominantly the aerodynamic Mass distribution of the aerosol spectrum essential, since a deposited aerosol particle immediately in the aqueous phase of the bronchial mucus (mucus and periciliary fluid or epithelium lining fluid) is dissolved and thus the entire substance is available. This also applies to water-soluble solid particles from powder nebulizers. Even bad water-soluble substances, such as. B. Beclomethasone because of the small particle size resolved within a few minutes. The situation is different for insoluble ones Particles or those whose solubility and release by pharmaceutical technological measures (e.g. liposomes) was modified.

It has recently become known that insoluble particles, such as. B. coal dust, which as ultrafine aerosols (diameter less than 0.1 µm) get into the lungs, the degree of Toxicity increases linearly with the total surface area of the particles as it causes inflammation lead in the bronchial wall and in the interstitium. It plays with larger insoluble particles Form a roll if it moves too far from a ball. An example of this is the Toxicology of asbestos fibers, which as a whole are no longer phagocytosed by macrophages can be.

Depending on the composition, aerosols have a short or long life and their particle size is subject to changes that are influenced by the chemical-physical properties of the formulation components. Depending on the air humidity, small aqueous particles evaporate quickly to a solid core, so that the concentration of the dissolved substance is 100% when completely evaporated. The resulting diameter (d ₂ ) starting from the original diameter (d ₁ ) corresponds to the third root from the concentration ratio before (c ₁ ) and after (c ₂ ) shrinkage (assuming density of 1 g / cm ³ for the dissolved substance) according to Formula: d ₂ = d ₁ ³ √ (c ₁ / c ₂ ). So z. B. the drying of surf aerosols by the wind with a sea water droplet (c ₁ = 3.6%) of 20 µm to a salt particle with a diameter of approx. 6.7 µm, which then made it respirable. This effect is such. B. used in liquid nebulizers to reduce the particle size by drying effects (z. B. heating by PARI Therm) or admixture of dry air.

Conversely, particles can grow in a humid environment, and this is growth particularly dependent on the hygroscopy of the active ingredient and / or auxiliary. For example a dry sodium chloride particle of 0.5 µm takes about 1 second to full growth, with a 5 µm particle this takes about 10 seconds what a Evidence of this is that the speed in terms of particle growth is also is size dependent. Solid particles from powder nebulizers and metered dose aerosols can up to grow to 4-5 times their original size, as there is one in the bronchial tree Humidity of 95-100% prevails.

impaction

Aerosol particles or droplets follow the streamlines of their carrier gas if they are not too large. The inertia of the aerosol particle becomes relevant from about 2-3 µm. It then endeavors to fly straight ahead when the gas changes direction. This increases the probability of deposition through impaction. The deposition probability (DE) is proportional to the square of the diameter (d) and the flow (V): DE ≍ d ² V.

This correlation explains why metered dose aerosols and many Powder inhalers that have a high exit velocity of the aerosol cloud, despite small particle diameter in vivo a high percentage (70-90%) oropharyngeal is deposited.

sedimentation

The movement of the aerosol particles is also determined by gravity and is the relevant deposition mechanism, especially in a particle size range of 0.5-4 µm. The sink rate (v _s ) depends on the square of the particle diameter (d), the gravitational constant (g), the particle density (ρ) and the viscosity of the gas (η). If one neglects the sliding correction required for the particle areas under 1 µm due to the absence of continuity of the gas and the buoyancy, the following relationship results for the sinking velocity in air: v _s = d ² g ρ / 18η. The formula is to be illustrated by the following example: an aqueous particle with a diameter of 6 µm falls due to the force of gravity during normal breathing in the bronchial system about 0.44 mm if its residence time in the supplying airways (anatomical dead space) is about 0.4 seconds. Theoretically, this particle could reach the 16th bronchial generation, but will on average be deposited even more centrally in the 12th bronchial generation or due to impaction effects.

Regional deposition behavior taking into account the different factors

The question of where aerosol particles deposit in the bronchial tree has been an issue for years numerous investigations. These are supplemented by constantly improving ones Calculation models of lung deposition. The regional deposition pattern at Mouth breathing shows through the breathing maneuver and the different anatomy of the Bronchial tree shows a high variability. Often mentioned in the literature respirable size range of 0.5-6 µm does not take into account the overlapping Deposit areas still the quantitative or percentage deposition rates.

When breathing through the mouth, about 40-60% of the particles in the range of 2.5-4.5 µm are preferred deposited in the alveolar area. A bronchial deposition on the order of approximately 5-28% have particles from 2 to 8 µm, in parallel oropharyngeal deposition takes place to. The deposition in the oropharynx is already 25-45% and for particles of 6 µm increases to 60-80% for particles with a diameter of 10 µm. From this it is deduced that for a optimal qualitative and quantitative alveolar deposition particle sizes of 1.5-3 µm are favorable if the oropharyngeal and bronchial deposition are as low as possible should. The bronchial deposition with about 18-28% for particles in the size range of 6-9 µm is relatively small and always goes with a correspondingly higher oropharyngeal Deposition. This is actually a disadvantage, since this is the target area for the local one Inhalation therapy with beta agonists and anticholinergics lies.

The deposition of the aerosol particles in the respiratory tract is essentially determined by the following four parameters: the particle size, the particle speed, the geometry of the respiratory tract and the inhalation technique or respiratory maneuver. According to Stokes' law, it can be deduced that the flow velocity and density of the aerosol particles are important, which is why the aerodynamic and not the geometric particle diameter is used as a parameter for the deposition behavior in the respiratory tract. It is known from various studies that only droplet or particle sizes with an aerodynamic diameter of about 0.6-6 µm can be used for pulmonary therapy. Particles with an aerodynamic diameter of about 6 µm impact in the upper respiratory tract, those smaller than 0.6 µm are exhaled again after inhalation. This means that e.g. B. powder with very low density and an aerodynamic diameter of about 3 microns a geometric diameter of z. B. may have greater than 10 microns. In contrast, the geometrical and aerodynamic diameter is approximately the same for aqueous systems with a density of approximately 1 mg / cm ³ .

State of the art

For the application of active ingredients, propellants are predominantly used today MDIs, powder inhalers and liquid nebulizers are used. Convince the latter Liquids using nozzles or ultrasound in aerosols with different Droplet diameter. In general, droplets or particles between 3 and 6 µm are more suitable for topical or local therapy, e.g. B. to treat asthma while particles less than 3 µm are more systemically absorbed, d. H. the active ingredient arrives in the peripheral Lung area through a predominantly alveolar absorption into the blood circulation and from there to the destinations in the body. The pros and cons of the different inhalers and the Ways to compensate for the systemic disadvantages were developed by M. Keller in [Development and Trends in Pulmonary Drug Delivery, Chimica Oggi, Chemistry today, No. 11/12, 1998]. Of particular importance for an improvement of the Inhalation efficiency is the coordination and optimization of the inhalation device and Drug formulation. This presupposes that the deposition mechanisms and the Knows strengths or weaknesses of the different systems and then a corresponding one Optimization.

The acceptance of nebulizers is compared to metered dose inhalers and powder inhalers a large part of the users less because the treatment time on average Is 5-10 minutes or longer. Another disadvantage is that z. B. at Jet nebulizers i. d. R, part of the medication used is not due to the system can be nebulized. However, studies show that the treatment duration of 9.1 min reduced to 1.3 min, and the filling volume in the nebulizer reduced from 3.5 ml to 1 ml can be if you z. B. uses an undiluted salbutamol solution. [N. Luangkhot et. al., Aerosols in Inhalation Therapy IV, 1999, pages 98-103]. This example shows that more concentrated solutions can advantageously be used without the aerosol properties change in vitro. This can be done in a laboratory test with a Breath simulator from the deposition behavior of the active ingredient on inhalation and Detect exhalation filters [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 (e-Flow). Drug delivery to the Lungs XI, 11 & 12. 12. 2000, p. 14-17]. Provided the drug has sufficient solubility and has stability in water or saline and the chemical physical Characteristics do not change, the therapy using a nebulizer can be simplified and thus also be improved.

The nebulization of water-insoluble substances, such as. B. Corticosteroids or substances that are unstable in aqueous solution. These will therefore preferably formulated as suspensions, d. H. the micronized active ingredient is fine dispersed in water. The smaller the particle size of the active ingredient and the smaller the difference in density between active ingredient and dispersing medium, the longer the active ingredient stays in limbo, d. H. the slower sedimentation generally takes place. In order to do better Wetting the lipophilic active substance surface with water usually becomes an amphiphilic surfactant added, which must however be harmless to inhalation to avoid undesirable Avoid side effects. Pulmicort® should be used as an example two dosage strengths of 0.5 mg and 1 mg budesonide per 2 ml is commercially available. Budesonid lies suspended in saline, which is buffered with citric acid and sodium citrate and contains polysorbate 80 (= Tween® 80) as a surfactant. The disadvantage is that the aerosol characteristics can change during nebulization. This can be done e.g. B. from increasing the budesonide concentration in the non-nebulized residual Derive suspension. This effect can a. thereby explaining that larger particles pass through Aerosol droplets with a smaller diameter cannot be transported can and therefore remain as a residue in the nebulizer.

As an alternative to solutions and suspensions, it was checked whether and to what extent the nebulization of liposomes loaded with hydrophilic or lipophilic substances offers advantages. Liposomes are spherical vesicles with self-contained membrane lamellae separate an aqueous interior from a continuous aqueous phase. The Membranes consist of at least one lipid bilayer of amphiphilic lipids, the hydrophilic parts of the molecule are directed to the aqueous side, and their lipophilic parts form the hydrophobic interior of the membrane. They are mostly made up of Phospholipids, cholesterol and glycolipids are made. The diameters vary between approx. 20 nm and several micrometers. The membranes have a thickness of approximately 5 nm, depending on the number of slats. By choosing the membrane lipids, the Size and membrane thickness can change the properties of the liposome respectively Requirements are adjusted. It is of particular interest to achieve one Depot effect and use in the area of drug targeting. For aerosol therapy this opens up the possibility of briefly inhaling active ingredients Reduce half-life and thus improve patient compliance. About that is also the increase in drug concentration in certain target cells of the lungs conceivable what should allow a reduction in the dose of the drug used.

The stability of the liposomes especially during storage and against the Nebulization is an important prerequisite for successful inhalation therapy active ingredients packaged in liposomes. Studies by Waschkowitz et al. (Aerosols in the Inhalation Therapy IV, 1999, pages 83-90) show that ultrasonic nebulizers have stability of liposomes, and depending on the type of nozzle nebulizer Lipid composition about 20-30% of the active ingredient are no longer packed liposomally.

The production of particulate systems in the nano range and their use as Carriers for active substances and vaccines have been known for more than 20 years. [J. Kreuter: Nanoparticles and nanocapsules - new dosage forms in the nanometer size range; Pharm. Acta Helv. 53 (1978). p. 33-39; J. J. Marty et al .: Nanoparticles - a new colloidal drug delivery system; Pharm Acta Helv. 53 (1978) p. 17-23; J. Kreuter: Possibilities of using nanoparticles as carrier for drug and vaccines; J. Microencapsulation, 5 (1988) p. 101-114]. The Production of nanoparticulate systems using high-pressure homogenization processes, such as B. Microfluidization was also published more than 10 years ago [F. Koosha and R. Müller: Nanoparticle Production by Microfluidization; Archives of Pharmacy 321 (1988) 680; R. Bomeier, and H. Chen: Indomethacin Polymeric Nanosuspension prepared by Microfluidization; J. Contr. Rel. 12, (1990) p. 223-233]. It is known from the literature how one can manufacture submicron systems. A special embodiment for the production of nanosuspensions by means of high pressure homogenization, which was published in the previously Literature is already suggested can be found in WO 96/14830. Here's the use different surface-modifying auxiliary substance classes for the production of Nanosuspensions for the application of a large part of the known medical Active ingredients as claimed in the invention. An example of a nanosuspension containing 2% -3% of the active ingredient RMKP, 0.3% Tween® 80 and 16.7 g mannitol ad 100 ml sterilization by means of gamma radiation. The particle size increased after sterilization for formulation A from 890 to 1222 µm and for the formulation B from 60 to 165 µm. However, it was not checked whether and to what extent the stability of these Formulations changed after storage at different temperature conditions. It should also be noted that due to the high mannitol content, the formulation is hyperosmolar and therefore not suitable for nebulization. The one described Gamma sterilization is recognized and approved as a method, but it does great material and financial expenditure ahead. This procedure also applies to liquid Preparations are not the method of choice. Easier to use and the Regulatory aspects are heat sterilization using strained water vapor (121 ° C, 2 bar). Such a method is also described in WO 96/14830 (Example 12). According to this, there is a considerable dependence on the surfactant concentration Particle growth. The suspended particles reach diameters which make them inhalative Make application unusable. This can only be done at certain surfactant concentrations Particle size can be kept. However, this is only for formulations containing mannitol in WO 96/14830. Mannitol is known to be used as a suspension stabilizer [A. H. Kibbe, Handbook of pharmaceutical excipients, Pharmaceutical Press, 2000]. Also the use of mannitol for stabilization purposes according to the principle of "preferential exclusion "is well known [T. Rock, knowledge-based development of parenterals Peptide solutions and lyophilisates, Shaker Verlag, 1999]: this can make hydrophobic Interactions or aggregation processes are effectively prevented. Because such Processes in suspensions that can trigger particle growth is the Combination mannitol / Tween® 80, as described in the example, an effective agent, a To enable heat sterilization. However, a mannitol concentration of 16.7% due to the resulting hyperosmolality too high for an inhalation application of the Formulation that enables a reduction in the amount of surfactant used in this Connection insignificant. Also the increased viscosity of the Mannitz additive such suspensions can severely limit their possible uses. A successful Heat sterilization without the addition of mannitol is not described in WO 96/14830.

For the use of aqueous suspensions with particle sizes of 400-4000 nm, the As a medicine to be used for inhalation it is necessary that this are physically and chemically stable and none during storage Particle growth, e.g. B. as a result of "Ostwald Ripening". Suspensions and in particular those with particle sizes smaller than 4 µm are i. d. R. very sensitive to temperature, since the Solubility of the active ingredients increases with increasing temperature and it is first used for The very small and later also the larger particles dissolve. At the Cooling process can precipitate or crystallize out or as seed crystals lead to particle growth. Alternatively, it happens due to the heating and Cooling process leads to an increase in interparticle attractions, too Agglomerations and thus also leads to particle growth. Such processes too prevent and the particle size distribution despite heating and cooling in one Keeping a narrow spectrum poses an immense challenge in terms of formulation, that could not be managed so far. This is u. a. from claim No. 11c of US Patent 5,510,118 can be seen, from which a temperature limit of 40 ° C for one Shredding process using "microfluidization" to produce a nanosuspension is specified.

The pulmonary or nasal administration of an aqueous micro or nano suspension however, using a nebulizer presupposes that the product can be sterilized. A Sterile filtration through a 0.2 µm filter is not possible if the suspended Particles have a diameter that is greater than 200 nm. As a result, these Products by other common methods, such as. B. heat and / or pressure or Gamma sterilization can be made sterile. U.S. Patent 5,470,583 points to this problem out and describes a method as inventive in which a Nanosuspension in the presence of Tyloxapol and Phospholipen at 121 ° C for 20 min can be heat sterilized without causing agglomeration or change in the Particle size of the diagnostic agent WIN 8883 should come. The manufacture of the However, nanosuspension was carried out by means of a wet grinding process using ZrO and other substances, such as. B. magnesium silicate, glass as grinding aid, the Influence on the sterilization process has not been examined and presented. The Inhalation toxicity harmlessness of those used in US Pat. No. 5,470,583 However, substances and the 24-hour grinding process is not proves why its usability for the intended application is not given.

In the patent of Nanosystems (WO 00/27363), the production of a nanosuspension is used Inhalation with a non-aqueous solvent according to a wet milling process described, without giving instructions for sterilization and investigations or evidence of this will be presented. As already explained above, however aqueous preparations, such as solutions and suspensions due to pharmaceutical law Regulations and ethical reasons only in sterile form for inhalation using nebulizers be used.

Object of the invention

• - die nach der Zerkleinerung einem stabilen physikalisch-chemischen Aggregatzustand aufweisen,
• - die Verwendung inhalationstoxikologisch unbedenklicher Hilfsstoffe erlauben,
• - in einem Autoklaven bei 110-121°C und 1-2 bar Überdruck sterilisiert werden können,
• - durch den nachfolgenden Sterilisationsprozess eine Partikelgrößenverteilung aufweisen, die nur unwesentlich beeinflusst wird,
• - deren resultierendes Partikelgrößenverteilungsmuster bei verschiedenen Lagerungsbedingungen und -zeiten im Vergleich zu einer nicht hitzesterilisierten Submikron Suspensionen möglichst unverändert bleibt, und
• - die sich ähnlich wie Lösungen auch in hohen Konzentrationen vernebeln lassen.

In order to overcome the disadvantages of the processes described in patents and literature, attempts were made to find solutions for comminuting and enveloping or wetting water-insoluble or lipophilic substances as far as possible using a technically well-controlled, established process in such a way that aqueous submicron suspensions (SMS ) receives:

• - which have a stable physical-chemical physical state after comminution,
• - allow the use of auxiliaries that are harmless to inhalation toxicity,
• - can be sterilized in an autoclave at 110-121 ° C and 1-2 bar overpressure,
• - have a particle size distribution due to the subsequent sterilization process that is only marginally influenced,
• - The resulting particle size distribution pattern remains as unchanged as possible under different storage conditions and times compared to a non-heat sterilized submicron suspensions, and
• - which, like solutions, can also be atomized in high concentrations.

The object was achieved by a process for the production of a sterile liquid preparation for pulmonary application of a poorly water-soluble active ingredient according to claim 1. According to the invention, aqueous active ingredient dispersions of budesonide in concentrations of 0.01%, 0.1% and 1% (w / v) after suspension with an Ultra-Turrax and subsequent homogenization by means of a high-pressure collision jet grinding process after 40-50 cycles, transfer to a budesonide submicron suspensions (BSS) with a very narrow particle distribution spectrum of 350-550 nm, as can be seen in Fig. 1 can. Fig. 1 shows that the particle size reduction process is more efficient in the presence of 0.5% tyloxapol than in the presence of 0.5% polysorbate 80. The influence of the different homogenization cycles at a pressure of 1500 bar is shown in Fig. 2 for three different budesonide concentrations ( 0.01%, 0.1% and 1%) using 0.5% polysorbate 80. The figure shows that for a budesonide concentration of 0.1% and 1%, no further particle size reduction can be achieved after only 40 cycles.

Surprisingly, it has now been found that after autoclaving the two BSS for 15 min at 121 ° C and 1 bar overpressure, only that suspension remains relatively unaffected with regard to the particle size distribution, which was stabilized with 0.5% polysorbate 80, while that with 0.5% tyloxapol was stabilized, after heat sterilization has up to 10 times larger particles, as can be seen in Fig. 3. The sterilization of the BSS containing polysorbate 80 could also be carried out successfully without the addition of mannitol. In this way, the amount of adjuvant can be reduced compared to suspensions already described, and the low viscosity resulting improves the atomisability.

Short-term stability tests under 3 conditions over 30 days of the heat-sterilized and non-sterilized formulation did not show any storage-dependent changes in particle size, as can be seen in Fig. 4. From this it can be concluded that the submicron particles obtained with the high-pressure homogenization process described are only stabilized using 0.5% polysorbate 80, but not with 0.5% tyloxapol, so that their particulate aggregation state is retained.

Surprisingly, it was further found that the average size of the suspended drug particles of these BSS stabilized with polysorbate 80 is only insignificantly influenced by shear forces due to nebulization. Similar particle size distributions are obtained as with the initial suspension, regardless of whether the aerosol is generated by atomization with a compressor nozzle nebulizer (PARI LC STAR®) or an electronic vibrating membrane nebulizer with pores of approx. 3 µm (e-FIow ™) , as can be seen in Fig. 5.

Surprisingly, it was also found that the atomization efficiency can be improved with the BSS according to the invention, as can be seen from FIG. 6. Compared to a Pulmicort® Budesonide microsuspension (average particle size approx. 4 µm), much larger amounts of active ingredient are found on an inhalation filter after nebulization. This leads to the conclusion that the BSS according to the invention can be atomized far more efficiently than conventional micro suspensions.

Furthermore, it was found that, in contrast to the teaching of nanosystems (WO 00/27363), when aerosolizing aqueous formulations with a jet nebulizer, an aerosol is generated whose aerodynamic deposition behavior and MMAD and inhalable fraction (= fine particle fraction = FPF), primarily from depends on the droplet size of the aerosol and less on the particle size. This is shown in Table 1 for the BSS according to the invention in comparison to the commercial products Pulmicort® (micro-suspension) and Sultanol® (salbutamol sulfate solution) after atomization of 2 ml each with the PARI LC STAR®. There are clear differences only with regard to the amount of active ingredient found on the inhalation filter, which is due to the higher active ingredient concentration of the BSS. Table 1

• - Wasserunlösliche oder schlecht wasserlösliche Wirkstoffe lassen sich in wässrige Formulierungen überführen, die schneller und mit höherer Effizienz als handelsübliche Suspensionen vernebelt werden können.
• - Die Wirkstoffdepositionsraten der erfindungsgemäßen Formulierungen auf dem Inspirationsfilter sind deutlich höher als bei handelsüblichen Formulierungen.
• - Der Rückstand im Vernebler ist deutlich geringer als bei handelsüblichen Formulierungen, was eine bessere Verwertbarkeit ermöglicht.
• - Die Beladungsdichte und -homogenität der Tröpfchen wird im Vergleich zu einer handelsüblichen Suspension verbessert.
• - Die aerodynamischen Parameter werden durch die Teilchengröße nicht in dem Umfang beeinflusst, wie dies in der PCT US 99/26799 beschrieben ist, denn der MMAD wird nicht wesentlich erniedrigt.
• - Das Depositionsverhalten und damit Partikelgrößenverteilungsmuster wird überwiegend durch die Eigenschaften des Verneblers und weniger durch die Formulierung bestimmt, wie dies in der PCT US 99/26799 beschrieben ist, denn der MMAD und die respirable Fraktion korrelieren nicht direkt mit der Teilchengröße der BSS-Partikel.

The results also allow the conclusion that these BSS behave more like a solution in a concentration up to 20 times higher than that of Pulmicort®. This has the following advantages over both a solution and conventional suspensions:

• - Water-insoluble or poorly water-soluble active ingredients can be converted into aqueous formulations, which can be atomized more quickly and with greater efficiency than commercially available suspensions.
• The active substance deposition rates of the formulations according to the invention on the inspiration filter are significantly higher than in the case of commercially available formulations.
• - The residue in the nebuliser is significantly less than with commercially available formulations, which enables better usability.
• - The loading density and homogeneity of the droplets is improved compared to a commercially available suspension.
• - The aerodynamic parameters are not influenced by the particle size to the extent described in PCT US 99/26799, because the MMAD is not significantly reduced.
• - The deposition behavior and thus particle size distribution pattern is mainly determined by the properties of the nebulizer and less by the formulation, as described in PCT US 99/26799, because the MMAD and the respirable fraction do not correlate directly with the particle size of the BSS particles.

With the preparation according to the invention, the amount of active ingredient can be applied to inhalation filters increase, which indicates that the loading density and homogeneity of the droplets in the Compared to a commercially available suspension is improved. This effect depends probably with the surface-modifying properties of the used Auxiliary and the manufacturing process together and is not per se solely by the Particle size determined. In summary it can be said that contrary for the teaching of PCT / US 99/26799 the aerodynamic aerosol parameters predominantly is determined by the droplet size generated by the nebulizer. A more efficient and faster nebulization and less residue in the nebulizer is achieved, that a droplet can transport several smaller particles and these through the Surface modification with Polysorbate 80 reduces adhesion to walls exhibit.

Examples of the preparation of BSS and other formulations are listed below.

example 1

1 g of budesonide in 100 ml of isotonic saline in 0.5% polysorbate 80 are suspended using an Ultra-Turrax for 1 min at 10,000 revolutions / min. The Suspension is placed in a microfluidizer M110EH at a pressure of 1500 bar up to 50 × approximately pumped. 0.5 ml each after 10, 20, 30, 40 and 50 homogenization cycles removed and the particle size using 3 × 100 ul aliquots of the samples with a Malvern MasterSizer 2000 and a Malvern ZetaSizer 3000HSa. The resulting budesonide submicron suspension (BSS) is then closed Glass jar heat sterilized for 15 min at 121 ° C and 1 bar overpressure. After cooling down 2 ml each with a sterile pipette in a sterile bank in previously sterilized blow fill seal ampoules filled and sealed. The particle size of three 100 µl aliquots each is determined as described above.

Example 2

0.1 g of fluticasone propionate and 0.025 g of salmeterol in 100 ml of water for Injection in which 0.25% Polysorbate 80 is dissolved using an Ultra-Turrax for 1 min suspended at 10,000 rpm. The suspension is placed in a microfluidizer M110EH pumped up to 40 × round at a pressure of 1500 bar. 0.5 ml each taken after 10, 20, 30 and 40 homogenization cycles and the particle size on hand 3 × 100 µl aliquots of the samples with a Malvern MasterSizer 2000 and a Malvern ZetaSizer 3000HSa determined. The resulting submicron suspension (SMS) will then appear Heat sterilized in a sealed glass vessel for 15 min at 121 ° C and 1 bar overpressure. After cooling, 2 ml of it are placed in a sterile pipette in a sterile bench previously sterilized blow fill seal ampoules filled and sealed. The particle size of three 100 µl aliquots each are determined as described above.

Example 3

0.1 g budesonide and 0.01 g formoterol are dissolved in 100 ml of water for injections 0.25% Polysorbate 80 are dissolved using an Ultra-Turrax for 1 min at 10,000 Revolutions / min suspended. The suspension is added to a M110EH Microfluidizer a pressure of 1500 bar pumped up to 40 times. 0.5 ml each time after 10, 20, 30 and 40 homogenization cycles and the particle size using 3 × 100 µl Aliquots of the samples with a Malvern MasterSizer 2000 and a Malvern ZetaSizer 3000HSa determined. The resulting budesonide submicron suspension (BSS) is then used Heat sterilized in a glass vessel at 121 ° C and 1 bar overpressure for 15 minutes. After this 2 ml of each are cooled with a sterile pipette in a sterile bench beforehand sterilized blow fill seal ampoules filled and sealed. The particle size of each three 100 µl aliquots are determined as described above.

Example 4

0.25 g mometasone furoate and 0.05 g thiotropium are 0.8% in 100 ml Saline solution adjusted to pH 7.4 with a citrate buffer and 0.25% polysorbate 80 dissolved contains suspended with an Ultra-Turrax for 1 min at 10,000 revolutions / min. The suspension is placed in a M110EH microfluidizer at a pressure of up to 1500 bar 30 × pumped round. 0.5 ml each after 10, 20 and 30 homogenization cycles removed and the particle size using 3 × 100 ul aliquots of the samples with a Malvern MasterSizer 2000 and a Malvern ZetaSizer 3000HSa. The resulting submicron suspension (SMS) is then sealed Glass jar heat-sterilized for 15 min at 121 ° C and 1 bar overpressure for 15 min. After cooling 2 ml of each are previously sterilized with a sterile pipette in a sterile bench blow fill seal ampoules filled and welded. The particle size of three 100 µl each Aliquots are determined as described above.

Example 5

2 g budesonide are dissolved in 100 ml isotonic saline in 0.5% polysorbate 80 are suspended using an Ultra-Turrax for 1 min at 10,000 revolutions / min. The Suspension is placed in a microfluidizer M110EH at a pressure of 1500 bar up to 50 × approximately pumped. 0.5 ml each after 10, 20, 30, 40 and 50 homogenization cycles removed and the particle size using 3 × 100 ul aliquots of the samples with a Malvern MasterSizer 2000 and a Malvern ZetaSizer 3000HSa. The resulting budesonide submicron suspension (BSS) is then in a sealed glass jar at 121 ° C and 1 bar overpressure for 15 minutes. After this 2 ml of each are cooled with a sterile pipette in a sterile bench beforehand sterilized blow fill seal ampoules filled and sealed. The particle size of each three 100 µl aliquots are determined as described above. Before using the Suspension using a 0.5% sterile Tween® 80 solution to a budesonide content of Diluted 10 mg / ml.

Example 6

1 g of Ciclosporin A in 100 ml of isotonic saline in 1% polysorbate 80 are suspended using an Ultra-Turrax for 1 min at 10,000 revolutions / min. The Suspension is placed in a microfluidizer M110EH at a pressure of 1500 bar up to 50 × approximately pumped. 0.5 ml each after 10, 20, 30, 40 and 50 homogenization cycles removed and the particle size using 3 × 100 ul aliquots of the samples with a Malvern MasterSizer 2000 and a Malvern ZetaSizer 3000HSa. The resulting submicron suspension (SMS) is then in a glass vessel at 121 ° C and 1 bar overpressure heat sterilized for 15 min. After cooling, 2 ml of it are added a sterile pipette in a sterile bank into previously sterilized blow fill seal ampoules and welded. The particle size of three 100 µl aliquots each is as above described determined.

Example 7

5 g of ketoconazole in 100 ml of isotonic saline in the 1% polysorbate 80 are suspended using an Ultra-Turrax for 1 min at 10,000 revolutions / min. The Suspension is placed in a microfluidizer M110EH at a pressure of 1500 bar up to 50 × approximately pumped. 0.5 ml each after 10, 20, 30, 40 and 50 homogenization cycles removed and the particle size using 3 × 100 ul aliquots of the samples with a Malvern MasterSizer 2000 and a Malver ZetaSizer 3000HSa. The resulting one Submicron suspension (SMS) is then in a glass vessel for 15 min at 121 ° C and 1 bar Overpressure heat sterilized. After cooling, 2 ml of it with a sterile Pipette filled into previously sterilized blow fill seal ampoules and in a sterile bench welded. The particle size of three 100 µl aliquots each is as described above certainly.

Example 8

1 g of budesonide is dissolved in 100 ml of isotonic saline in 1% polysorbate 80 are suspended by an Ultra-Turrax for 1 min at 10,000 revolutions / min. The Suspension is placed in a microfluidizer M110EH at a pressure of 1500 bar up to 50 × approximately pumped. 0.5 ml each after 10, 20, 30, 40 and 50 homogenization cycles removed and the particle size using 3 × 100 ul aliquots of the samples with a Malvern MasterSizer 2000 and a Malver ZetaSizer 3000HSa. The resulting one Submicron suspension (SMS) is then in a glass vessel for 15 min at 121 ° C and 1 bar Overpressure heat sterilized. After cooling, 2 ml of it with a sterile Pipette filled into previously sterilized blow fill seal ampoules and in a sterile bench welded. The particle size of three 100 µl aliquots each is as described above certainly. Before nebulization, the suspension is cleaned using a sterile saline solution, the 0.025% ipratropium bromide and 0.1% salbutamol sulfate diluted 1: 1.

Claims (18)

1. A method for producing a sterile liquid aqueous preparation for pulmonary application of an active substance which is sparingly soluble in water in the form of an aerosol, characterized by the following steps: a) preparation of an aqueous suspension which contains the poorly soluble active ingredient in the form of particles with an average particle size of more than 1 μm and a dissolved surfactant; b) application of a particle size reduction process until the suspended active substance particles are comminuted to an average particle size of - less than 1 μm; and c) application of a heat sterilization process until the pathogenic germs contained in the suspension are killed while maintaining an average particle diameter of the suspended drug of less than 2 μm. 2. The method according to claim 1, characterized in that the sparingly soluble Active ingredient from the group of corticosteroids, beta sympathomimetics, anticholinergics, Immunomodulators, anti-infectives, cytostatics include budesonide, ciclesonide, Fluticasone, mometasone, beclomethasone, flunisolide; Formoterol, salmeterol, levalbuterol; Thiotropium, oxitropium, ipratropium; Ciclosporin, tacrolimus, azathioprine; ciprofloxacin, Moxifloxacin, azithromycin, clarithromycin, erythromycin, metronidazole, ketoconazole, Itraconazole, clotrimazole, bifonazole, fluconazole, amphotericin B, natamycin, nystatin, Aciclovir, famciclovir, valaciclovir, didanosine, saquinavir, ritonavir, lamivudine, stavudine, zidovudine; Carmustine, Lomustine, Taxol, Etopside, Cis-Platinum as well as the pharmaceutical acceptable derivatives, water-insoluble salts, enantiomers, racemates, epimers, or diastereomers of one of these active ingredients is selected. 3. The method according to claim 1 or 2, characterized in that the surfactant Polysorbate 80 (Tween® 80). 4. The method according to any one of the preceding claims, characterized in that that the surfactant content of the suspension is approximately 0.01 to 2.0% and preferably 0.05 to 0.5% is. 5. The method according to any one of the preceding claims, characterized in that the particle size reduction process is cyclical High pressure homogenization process or a collision jet grinding process. 6. The method according to claim 5, characterized in that more than 20 Homogenization cycles are carried out. 7. The method according to any one of the preceding claims, characterized in that that the particle size reduction process until reaching a medium one Particle size of less than about 850 nm, determined as the z-average, is carried out. 8. The method according to any one of the preceding claims, characterized in that the heat sterilization process at a temperature of about 100 to 130 ° C and below increased pressure is carried out. 9. The method according to claim 8, characterized in that the Heat sterilization process at a temperature of about 110 ° C or about 121 ° C and below increased pressure is carried out. 10. Liquid preparation for pulmonary application in the form of an aerosol, thereby characterized in that the preparation in the form of a poorly water-soluble active ingredient contains suspended particles with an average particle size of 500 nm to 2 microns and is sterile. 11. Liquid preparation according to claim 10, characterized in that the poorly soluble active ingredient from the group of corticosteroids, beta sympathomimetics, Anticholinergics ,, immunomodulators, anti-infectives, cytostatics comes from extensive Budesonide, ciclesonide, fluticasone, mometasone, beclomethasone, flunisolide; formoterol, Salmeterol, levalbuterol; Thiotropium, oxitropium, ipratropium; Ciclosporin, tacrolimus, azathioprine; Ciprofloxacin, moxifloxacin, azithromycin, clarithromycin, erythromycin, Metronidazole, ketoconazole, itraconazole, clotrimazole, bifonazole, fluconazole, amphotericin B, Natamycin, nystatin, acyclovir, famciclovir, valacyclovir, didanosine, saquinavir, ritonavir, Lamivudine, stavudine, zidovudine; Carmustine, Lomustine, Taxol, Etopside, Cis-Platinum as well as the pharmaceutically acceptable derivatives, water-insoluble salts, enantiomers, Racemates, epimers, or diastereomers of one of these active ingredients is selected. 12. Liquid sterile preparation for pulmonary application in the form of an aerosol, characterized in that this is achieved by a method according to one of claims 1 to 9 will be produced. 13. Liquid sterile preparation according to one of claims 10 to 12, characterized characterized that it contains more than one active ingredient and also as sterile Combination product can be nebulized. 14. Liquid sterile preparation according to one of claims 10 to 13, characterized characterized that it is largely isotonic, a physiologically acceptable pH Has value and, if necessary, other auxiliaries that are harmless to inhalation toxicity, such as B. contains flavoring and complexing agents (mannitol, cyclodextrins, etc.). 15. Use of a liquid preparation according to one of claims 10 to 14 for Nebulization in an ultrasonic principle, nozzle principle, electrohydrodynamic, with a vibrating membrane or nebulizer working with pores of a defined size, such as z. B. e-FIow ™, AeroNeb ™, AeroDose ™ or AERx ™. 16. Use according to claim 15 for inhalation by humans or others Mammals for therapeutic, prophylactic or diagnostic purposes. 17. Use according to claim 16 for local therapy of the nasal mucosa or the lungs. 18. Use according to claim 16 for systemic therapy.