WO2006108557A1

WO2006108557A1 - Dry nebulizer

Info

Publication number: WO2006108557A1
Application number: PCT/EP2006/003154
Authority: WO
Inventors: Tobias Gessler; Andreas Günther; Tim Kuchenbuch; Thomas Schmehl; Werner Seeger
Original assignee: Nycomed Gmbh
Priority date: 2005-04-08
Filing date: 2006-04-07
Publication date: 2006-10-19
Also published as: DE102005016229B3

Abstract

The present invention relates to a dry nebulizer (1) comprising a housing (2) with an area for receiving nebulizable material (8), a gas intake line (3) which is connected to the housing and one end of which extends into the housing and has a gas inlet opening (4) for introducing carrier gas into the nebulizable material, and a gas discharge line (5) connected to the housing, with a gas outlet (6) for discharging the carrier gas with the nebulized material contained therein, the gas outlet (6) being designed as a filter. The dry nebulizer permits, for example, nebulization of powdered pharmaceutical preparations, which include lusupultide, a large proportion of the medicament used reaching the site of action in the pulmonary alveoli. The present invention further relates to respirators into which dry nebulizers of this kind are integrated.

Description

Dry nebulizer

Field of the invention

The present invention relates to a dry nebulizer according to US 5,186,166. The present invention relates in particular to dry nebulizers for nebulization of pharmaceutical preparations, such as lung surfactants, which are suitable for continuous use, and to respirators into which dry nebulizers of this kind are integrated.

Background of the invention

Critically ill patients requiring mechanical ventilation often suffer from pulmonary infections and diseases which have to be treated by medication. Ideally, they are treated by direct administration of the medication into the lungs.

This requires the production of small particles which are able to access the lungs and alveoli. This is achieved using nebulizers. There are two main types of nebulizers, namely liquid nebulizers and dry nebulizers.

In liquid nebulizers, the medicament in liquid form is nebulized into fine aerosol droplets which are able to reach as far as the lungs and alveoli. Systems for continuous nebulization of liquids are, for example, described in WO 94/03225, WO 98/51361 and WO 94/27664. These are systems which can be built into respirators.

Dry nebulizers, which can be used for nebulization of solid, usually powdered medicaments, cannot in most cases be used in continuous operation, i.e. in respirators. Examples of dry nebulizers for non-continuous operation are described in WO 01/62323, DE-A-42 11 475 and DE-A-36 12 473. In the prior art, only a small number of dry nebulizers suitable for continuous operation have hitherto been described. Such dry nebulizers are disclosed, for example, in US 1,599,959, US 2,693,805 and US 5,186,166. A general problem of dry nebulizers is that they are not selective in terms of particle size. Large particles do not get into the lungs and are instead deposited before reaching them. In concrete terms, therefore, deposition of large particles takes place in the tube when dry nebulizers are used in continuous operation in a respirator. Once the large particles have deposited in the tube, they cannot readily be brought back into the airborne state. Consequently, the dose actually reaching the site of action in the lungs is relatively small. Since previous dry nebulizers are not selective in terms of particle size, the described problem with the large particles also occurs when dry nebulizers are used on spontaneously ventilating patients. There, large particles are deposited already in the mouth and throat and cannot therefore reach the lungs.

In US 1,599,959, an attempt is made to tackle the problem of large particles by providing a chamber for deposition of coarse particles in the gas discharge line. However, powder particles deposited there are not available for further nebulization. This is a serious disadvantage, especially in the case of expensive powdered pharmaceutical preparations. Moreover, the provision of a chamber in addition to the nebulizer container represents a not insignificant outlay in operating and maintenance terms.

In the dry nebulizers in US 2,693,805, a baffle plate is used to hold back coarse particles. However, this is achieved only with extremely large particles, which are referred to as "lumps" in US 2,693,805. The selectivity of the system in US 2,693,805 depends on many factors, mainly the aerodynamic diameter and shape of the particles, the gas flow, and the baffle plate geometry, in particular the width of the space between the circular baffle plate and the inner wall of the container of the dry nebulizer.

US 5,186,166 describes dry nebulizers in which the inflowing stream of gas is accelerated by nozzles and, in the conical or funnel-shaped container, a swirling movement is generated by means of which the particle-charged gas is expelled. According to the details in the patent, very high doses can be attained. However, as before, there is still the problem of large particles which deposit before reaching the site of action in the lungs. Consequently, the ability to anticipate the dose of the amount of pharmaceutical preparation actually reaching the lungs is not yet satisfactory, and this applies both to use in ventilated patients and also in spontaneously ventilating patients.

Against the background of the prior art discussed here, the inventors have set themselves the object of developing a dry nebulizer in which a greater proportion of the medicament used reaches the site of action in the pulmonary alveoli, and with which, consequently, higher doses of the medicament can be administered.

Summary of the invention

The object formulated above is achieved by a dry nebulizer comprising a housing with an area for receiving nebulizable material. Connected to this housing is a gas intake line, one end of which extends into the housing and has a gas inlet opening. The gas intake line with the gas inlet opening is used for introducing carrier gas into or through the nebulizable material. The housing of the dry nebulizer according to the invention is also connected to a gas discharge line with a gas outlet which is used for discharging the carrier gas with the nebulized material contained therein. The dry nebulizer according to the invention is characterized in that the gas outlet is designed as a filter.

Preferred embodiments of the dry nebulizer according to the invention are the subject of the dependent claims.

The dry nebulizer according to the invention can advantageously be used for nebulization of a pharmaceutical preparation, in particular a lung surfactant. It can be attached to a respirator for continuous operation. Alternatively, it can be used on spontaneously ventilating patients.

The dry nebulizer according to the invention is suitable for administration of suitable pharmaceutical preparations for treating a wide variety of lung diseases, in particular adult respiratory distress syndrome (ARDS).

Description of the drawings

Fig. 1 shows a schematic side view of a preferred embodiment of the dry nebulizer according to the invention;

Fig. 2a shows a schematic side view of the lower part of the dry nebulizer depicted in Fig. 1;

Fig. 2b shows a schematic side view of the upper part of the dry nebulizer depicted in Fig. 1;

Fig. 3 shows a schematic side view of the lower part of the dry nebulizer depicted in Fig. 1, which lower part of the dry nebulizer is enclosed by a device for shaking it and is filled with nebulizable material;

Fig. 4a shows a schematic side view of the end of the gas intake line with gas inlet opening of the dry nebulizer depicted in Fig. 1;

Fig. 4b is a schematic view of the underside of the end of the gas intake line with gas inlet opening of the dry nebulizer from Fig. 1 ;

Fig. 5 is a schematic side view of the end of the gas outlet with admission openings of the dry nebulizer from Fig. 1 ;

Figures 6a and 6b show the results in the lung irrigation model of ARDS when rSP-C surfactant was administered using the dry nebulizer according to the invention; and

Figures 7a and 7b show the results in the bleomycin-induced ARDS model when rSP-C surfactant was administered using the dry nebulizer according to the invention.

Detailed description of the invention

For the purposes of the present invention, nebulization of nebulizable material is understood as the dispersion, swirling and/or deagglomeration of at least some of the nebulizable material and its conversion into a state carried by carrier gas.

By way of the gas intake line of the dry nebulizer, which gas intake line is connected to the housing, a carrier gas can be introduced through the gas inlet opening and into or through the nebulizable material which is located in an area of the housing provided for receiving the material.

The nebulizable material can in this way be nebulized, i.e. at least partially converted to a state in which it is carried by carrier gas. The carrier gas, with the nebulized material contained therein, then passes to the gas outlet which is designed as a filter. This filter has the effect that the particles of the nebulizable material passing together with the carrier gas into the gas discharge line are mainly, preferably exclusively, particles of the nebulizable material which have a mass median aerodynamic diameter (MMAD) lying in a specific desired range. The range of the MMAD is preferably such that the particles can access the lungs, i.e. the site of action in the alveoli of the lungs. The MMAD of lung- accessible particles lies in the range of 1 to 5 μm. The desired MMAD range according to the invention is consequently 1 to 5 μm, preferably 1 to 3 μm.

Within the meaning of the invention, filter is understood as any means which is able to separate at least part of the nebulized material from the carrier gas, in particular that part of the nebulized material which has a particle diameter outside the desired range. Such means can, for example, include openings, commercially available filters, meshes, membranes or also lattices and suitable combinations of these means.

The gas inlet opening should be large enough to ensure that, at the selected input pressure of the carrier gas delivered through the gas intake line, it is possible to maintain the flow of gas to the gas outlet and the gas discharge line. The gas flow permitted by the size of the opening should be enough to transport at least some of the nebulizable material to the gas outlet and through the gas discharge line. To achieve this, in the case of a circular gas inlet opening, a diameter of 0.1 to 2 mm is suitable, for example. The diameter is preferably 0.3 to 0.7 mm and particularly preferably 0.5 mm. A circular gas inlet opening is of course just one possibility. Other shapes of the gas inlet opening are likewise included in the scope of the invention, for example round and slit-shaped configurations. In this case, the gas inlet opening preferably has a cross section corresponding to the cross section of a circle with the aforementioned diameters. The gas intake line can also have several gas inlet openings, and their shape and size can be varied independently of one another. The variation in the number and geometry of the gas inlet opening(s) permits adaptation of the dry nebulizer to different sources of pressure.

The gas outlet serves to discharge the carrier gas, with the nebulized material contained therein, through the gas discharge line. As regards the spatial arrangement of the gas outlet relative to the gas inlet opening, there are no particular limitations, as long as the carrier gas permits transport of nebulized material to the gas outlet. According to a preferred embodiment, however, the gas outlet is situated above the gas inlet opening.

The housing outlet preferably has a smaller cross section of flow relative to the gas discharge line. According to a particularly preferred embodiment, the gas outlet has one or more admission openings. The size and number of these is variable and is limited only by the requirement that, for the predefined carrier gas flow, a sufficient proportion of the nebulizable material can pass into the gas discharge line. Here, a smaller size of the admission openings can in principle be compensated by a greater number of such openings. Typical diameters of the admission openings in the case of circular openings are 0.2 to 2 mm. They are preferably 0.5 to 1.5 mm, particularly preferably 1 mm. A circular configuration of the openings of the gas outlet is just one possibility. Quite generally, it is also possible to use round shapes, which also include oval configurations, and also slit-shaped or angled configurations. Accordingly, the invention also includes admission openings with a non-circular cross section. As regards their preferred size, their cross section corresponds to the cross section that was defined above for the preferred diameter ranges of circular openings. In the case of a plurality of admission openings, the shape and size of the individual openings can be varied independently of one another.

Within the meaning according to the invention, the area of the housing for receiving nebulizable material is understood as an area of the housing into which material is introduced, for example filled in, or which is already filled with material. The area can, for example, be configured in such a way that the nebulizable material lies on an element which is permeable to the carrier gas. This can, for example, be a plate which is permeable to the carrier gas. In this case, the carrier gas flows from below through the gas inlet opening and through the nebulizable material and in this way nebulizes the latter. According to a preferred embodiment, the area for receiving nebulizable material is a base of the housing. The base has a shape which is suitable for conveying the carrier gas, with nebulized material contained therein, to the gas outlet. The base of the housing is preferably designed in the shape of a concave hollow body segment. Here, a concave hollow body segment also includes bodies having a polygonal cross section. The base is particularly preferably designed in the shape of a sphere segment. Funnel-shaped bases are also possible.

The part of the housing connected to the gas discharge line is shaped in such a way that it can convey the carrier gas, with nebulized material contained therein, to the gas outlet. Here too, it is possible to use shapes of a concave hollow body segment, particularly preferably sphere segments. The delivery of the carrier gas, with nebulized material contained therein, to the gas outlet is then particularly efficient.

According to a preferred embodiment, the shape of the housing is chosen such that an additional optimization of the filtration result is obtained through the gas outlet if the larger and thus heavier particles can fall back unimpeded into the area for receiving nebulizable material. This can be achieved by using a housing with a substantially constant cross section of flow. The housing preferably has a substantially cylindrical shape. The described additional optimization of the filtration result can be further enhanced by the gas outlet being arranged at a distance from the wall of the housing. For this purpose, the further preferred arrangement of the gas outlet is suitable in which said gas outlet is arranged at a distance from the wall of the housing. In the case where the gas outlet has one or more openings, these are particularly preferably arranged in a surface parallel to the main axis of the housing. Moreover, the gas intake line preferably extends substantially coaxially with respect to the main axis of the housing. According to a preferred embodiment, the same also applies to the gas discharge line. According to a particularly preferred embodiment, the gas intake line and gas discharge line are both arranged substantially coaxially with respect to the main axis. Accordingly, in the case of a substantially cylindrical shape of the housing, the gas intake line and gas discharge line preferably lie along the cylinder axis of the housing. Typical diameters of the housing in the cylinder shape are over 10 mm, preferably 35 mm.

It is possible, via the spatial arrangement of the gas inlet opening in relation to the nebulizable material, to influence the energy input to the nebulizable material and, therefore, the proportion of the material nebulized by the carrier gas.

The gas inlet opening is preferably arranged in or below the nebulizable material. In this way, an especially large amount of material is able to be nebulized. According to a particularly preferred embodiment, the gas intake line is immersed into the nebulizable material during operation of the dry nebulizer. It is further advantageous if the gas inlet opening is located at the end of the gas intake line and the latter immerses into the material when the dry nebulizer is filled with nebulizable material.

The dry nebulizer according to the invention can be designed in one part or in several parts. The multi-part design includes, for example, a two-part form in which the housing is composed of an upper part and of a lower part. The gas intake line in this case is preferably connected to the lower housing part, and the gas discharge line is connected to the upper housing part. A seal can be provided to close off the connection of the gas intake line to the housing.

The nebulization of the nebulizable material and thus its conversion to the state carried by a carrier gas can be further enhanced by a device for agitating the nebulizable material, which device preferably at least partially encloses the lower part of the housing. Alternatively, a vibrator is used for this purpose. Mechanical agitators are preferably used. According to a particularly preferred embodiment, an ultrasonic agitator is used. The agitator thus improves the conversion of the nebulizable material to the state in which it is carried by carrier gas, by means of energy input. The device for agitating the nebulizable material thus permits further improved utilization of the nebulizable material, ensures a continuous rate of nebulization and minimizes the residual amount of nebulizable material in the dry nebulizer.

There is no particular limitation on the materials used for producing the dry nebulizer. For example, glass can be used. Here, in the case of a two-part design of the dry nebulizer, the preferably gas-tight connection between the lower part and upper part of the housing is advantageously formed by a ground-in connection. Such is also shown in Figures 2a and 2b. Other possible materials are commercially available plastics which, for example, have been processed by injection moulding. Such plastics are used in particular in dry nebulizers intended to be disposed of after one use. Aluminium and stainless steel alloys can also be used. Anodized aluminium is particularly advantageous if the nebulizable material is a lung surfactant based on recombinant surfactant protein C (rSP-C surfactant), because the powder of this material has only a slight surface adherence to anodized aluminium.

The dry nebulizer according to the invention can be suitable for repeated use or for disposal after one use.. In the case of repeated use, it is preferably designed in several parts so that the housing can be opened and cleaned and can be filled with new nebulizable material. To make this cleaning easier, such a dry nebulizer is preferably made from a sterilizable material. The sterilizing can be carried out, for example, by ethylene oxide, radiation, steam or dry heat. In the case of a design for disposal after one use, the dry nebulizer is preferably already filled with nebulizable material and is bought in this condition. In this case, it is preferably designed as a discardable article complying with the regulations governing medical products.

The dry nebulizer according to the invention can be used for acute treatment in spontaneously ventilating patients. For this purpose, the gas discharge line can be provided with a breathing mask, a spacer (inhalation auxiliary), a mouthpiece or an attachment piece for nasal administration. In the treatment of spontaneously ventilating patients, the gas inlet opening is preferably connected to a carrier gas source which is under pressure.

In use on ventilated patients, the dry nebulizer is built into the respirator. It is joined to the respiratory air intake line of the respirator, preferably to the side port of the respirator. In the dry nebulizer, the carrier gas source of the respirator normally suffices to nebulize the material and deliver it via the gas discharge line to the ventilated patient. This is a further advantage compared to the system in US 5,186,166, where an additional external compressed gas source is required. During operation of a respirator with built-in dry nebulizer according to the invention, the stream of the ventilation gas, i.e. carrier gas, is set such that the desired transport of nebulized material into the gas discharge line is achieved. The carrier gases used in the dry nebulizer in respirators are ventilation gases, such as air, oxygen and other commercially available ventilation gases.

The dry nebulizer can similarly be used to apply nebulizable material, for example pharmaceutical preparations for topical application or cosmetics, onto surfaces of the body or tissue surfaces. In this case, the gas discharge line is preferably connected to a spray gun. In this area of use of the dry nebulizer, it is possible to use not just ventilation gases, but also any other desired carrier gases, as long as these are not toxic.

The preliminary pressure of the carrier gas at the gas intake line, i.e. the overpressure relative to the environment or to the pressure level of the dry nebulizer, is typically between 100 mbar and 5 bar, preferably between 0.5 bar and 2.5 bar. The streams of carrier gas can be controlled and regulated in a manner well known to the skilled person, for example by valves.

Within the meaning of the application, nebulizable material is understood as a material which can be nebulized by the stream of carrier gas passing into the dry nebulizer via the gas inlet opening. The nebulizable material must therefore have such properties that at least parts of it are converted to a carrier-gas-borne state during the operation of the dry nebulizer according to the invention.

The nebulizable material is preferably a pharmaceutical preparation. This pharmaceutical preparation is advantageously powdered, for example a micronized powder. According to a preferred embodiment, the pharmaceutical preparation comprises a surfactant, in particular a lung surfactant. A lung surfactant is a substance mixture which is contained in the lungs of all vertebrates. It has surface-active properties and reduces the surface tension in the alveolar region of the lungs to such an extent that collapse of the pulmonary alveoli is avoided during exhalation. Essential components in the lung surfactant are proteins, designated by SP-A, SP-B and SP-C. The lung surfactant contained in the nebulizable material is particularly advantageously a recombinant lung surfactant, such as is described in WO 95/32992. This is a mutant of human SP-C (also designated as rSP- C). The most preferred lung surfactant is Venticute® (INN: lusupultide, also designated as rSP-C (FF/I)). rSP-C (FF/i) is described in WO 95/32992. In addition to the described surfactant based on the recombinant surfactant protein C (rSP-C), the pharmaceutical preparation can contain a further lung surfactant based on proteins SP-A and SP-B. Moreover, it may also contain phospholipids and other additives familiar to the skilled person.

Particularly preferably, the pharmaceutical preparation is or comprises a powdered lung surfactant preparation which is produced as described in EP-B-877 602. In the process in EP-B-877 602, an organic solution or suspension containing lung surfactant and possibly other constituents is subjected to spray drying. Venticute® is the most preferred lung surfactant in this context.

Accordingly, the nebulization in particular of powdered pharmaceutical preparations containing lung surfactants, in particular Venticute®, is a particularly preferred use of the device.

Lung surfactants are suitable for the prevention and early treatment of acute lung diseases. This use is described in WO 01/76619. Diseases to be treated by lung surfactant are, for example, asthma, pulmonary fibrosis, pneumonias, bronchitis, chronic obstructive pulmonary disease (COPD) and various respiratory distress syndromes (RDS), adult respiratory distress syndrome (ARDS), and infant respiratory distress syndrome (IRDS). The use of the dry nebulizer for nebulization of Venticute® for treatment of ARDS is a particularly preferred area of use.

The function and, in particular, preferred embodiments of the dry nebulizer are described below with reference to the attached drawings. The drawings serve only as an illustrative presentation of preferred embodiments of the invention and are not intended to limit the general underlying concept of the invention.

In the figures:

Fig. 1 shows a sectioned side view of a dry nebulizer according to the invention in the assembled state;

Fig. 2 shows a sectioned side view of a dry nebulizer according to the invention in the dismantled state;

Fig. 3 shows a sectioned partial view of the dry nebulizer arranged in an agitator device;

Fig.4a shows a side view of the housing end of the gas intake line;

Fig. 4b shows a bottom view of the housing end of the gas intake line;

Fig. 5 shows an enlarged partial view of the gas outlet according to the invention;

Fig. 6a is a graph illustrating the dependence of the pa0₂/Fi0₂ quotient on time in a lung irrigation model of ARDS in rabbits;

Fig. 6b is a graph illustrating the dependence of the compliance on time in a lung irrigation model as shown in Fig. 6a;

Fig. 7a is a graph illustrating the dependence of the paO₂/FiO₂ quotient on time in a model of bleomycin-induced ARDS in rabbits; and

Fig. 7b is a graph illustrating the dependence of the compliance on time in a lung irrigation model as shown in Fig. 7a.

Fig. 1 shows a dry nebulizer 1 whose housing 2 is composed of two parts, namely an upper part 2a and a lower part 2b. Fig. 2a and Fig. 2b show the corresponding dry nebulizer in the dismantled state. Through the gas intake line 3, the carrier gas passes in the arrow direction through the gas inlet opening 4 and into the housing, which can be filled, in an area 11 , with nebulizable material 8, and it flows upwards in the direction of the gas outlet 6 connected to the gas discharge line 5. The connection of the gas intake line 3 to the housing is sealed off by means of a seal 12. The housing 2 has a substantially cylindrical shape, and the gas intake line 3 and gas discharge line 5 have substantially a common axis, namely the main axis 10 of the housing. Therefore, with the dry nebulizer 1 shown in Fig. 1 , a carrier gas stream can be obtained which in addition to the filtration effect of the filter (here of the admission openings 7) of the gas outlet 6 permits further optimization of the filtration result by virtue of the fact that larger particles, which cannot pass through the admission openings 7, can fall unimpeded to the base of the vessel. Moreover, the housing shape and the arrangement of gas intake line 3, gas inlet opening 4, gas discharge line 5 and gas outlet 6 of the dry nebulizer shown in Fig. 1 permit a particularly advantageous routing of the carrier gas, and of the nebulized material contained therein, to the gas outlet 6. Fig. 4a shows a schematic view of the side, and Fig. 4b of the underside, of the housing end of the gas intake line 3 of the dry nebulizer shown in Fig. 1. Fig. 5 shows the gas outlet 6 with several admission openings 7 which, in the dry nebulizer in Fig. 1, are arranged in a surface parallel to the main axis 10 of the housing 2. Fig. 3 shows a view in which a device 9 for agitating the nebulizable material 8 is provided and at least partially encloses the lower part 2b of the housing. In this embodiment, the end of the gas intake line 3 is immersed in the nebulizable material 8.

The invention is described below on the basis of examples, although these are not intended to limit the present invention.

Examples

A dry nebulizer, as shown schematically in Fig. 1 , was filled with 5 to 7 g of a fresh charge of rSP-C lung surfactant Venticute®. The diameter of the housing was 35 mm, the diameter of the gas inlet opening 0.5 mm, and the diameter of the openings of the gas outlet in each case 1.0 mm. A constant pressure of 0.8 bar was established at the gas intake line. This corresponds to the pressure which is established at the side port of the inspirator branch of most current respirators. Analysis of the particle size distribution and of the mass of the nebulized Venticute® obtained under these conditions and leaving the dry nebulizer through the gas discharge line, revealed a MMAD of 1.40 μm (geometric standard deviation 2.42), determined by the particle size meter Sympatec HELOS. Here, 90% of all the particles were smaller than 5.7 μm. The average mass of the nebulized lung surfactant under these conditions was approximately 0.4 ± 0.07 g/min. Using a pressure of 3 bar, as is used in the side ports of some respirators, even higher output rates were obtainable.

Biochemical and biophysical ("Pulsating Bubble Surfactometer") studies showed that the activity of Venticute® was not impaired by the nebulization with the dry nebulizer according to the invention.

Two animal models of ARDS were used to assess the efficacy of Venticute® which was nebulized using the dry nebulizer according to the invention. These models are discussed below.

1. Lung irrigation model of ARDS in rabbits

Healthy male and female rabbits were anaesthetized, tracheotomized and mechanically ventilated using a Babylog respirator (Drager, Lϋbeck, Germany; FiO₂ 1.0) under pressure monitoring. A catheter was fitted in the carotid artery to analyse the blood gases. Repeated lung irrigations with 50 ml of sterile saline solution were performed until the pa0₂/Fi0₂ quotient (ratio of the arterial O₂ partial pressure to the O₂ component of the inhaled gas) fell below 200 mmHg. Thereafter, 130 mg/kg of Venticute® were administered by inhalation in the course of less than one minute. The effects of the Venticute® administration on the pa0₂/Fi0₂ quotient and compliance as a function of time are set out in Figures 6a and 6b. In these figures, the arrow indicates the time of administration of Venticute®. The pa0₂/Fi0₂ ratio increased considerably within just 20 minutes and reached the base line after 180 minutes. The same applies to the compliance, which was drastically reduced by the lung irrigation, but which completely recovered within a short time after the administration of Venticute® (Fig. 6b). Figures 6a and 6b show the mean value +/- mean standard deviation of eight independent experiments.

2. Model of bleomycin-induced ARDS in rabbits

In the second model, ARDS was provoked by inhaled administration of 1.8 U/kg (ultrasonic administration) of bleomycin in intubated and mechanically ventilated rabbits at day 0. The pressure-controlled mechanical ventilation took place using a Babylog respirator (Drager, Lϋbeck, Germany). After exposure to bleomycin, the animals were extubated. An ARDS-like clinical picture could be observed four days later. The paO₂/FiO₂ values were approximately 100 mmHg and the compliance was greatly reduced. As a consequence of the severe ARDS, the paO₂/FiO₂ quotient was very low, as is shown in Fig. 7a (time = -30 min and time = 0 min). However, the value improved greatly upon inhaled administration of 130 mg/kg of Venticute® using the dry nebulizer according to the invention. Figures 7a and 7b show the effects of Venticute® administration on the paO₂/FiO₂ quotient and the compliance as a function of time. In these figures, the time of administration of Venticute® (time = 0) is shown by an arrow. As can be seen from the drawings, the paO₂/FiO₂ quotient and the compliance both recovered within a short time. Thus, the pa0₂/Fi0₂ quotient reached 350 mmHg at 240 minutes after the administration of the lung surfactant. The compliance was improved within the same time period to approximately 1.5 ml/mbar (control approximately 2.2 ml/mbar).

As the above-described experiments show, the lung surfactant nebulized with the dry nebulizer according to the invention is fully active biophysically. Thus, the dry nebulizers described have considerable advantages in the treatment of a large number of lung diseases, particularly in view of the short time in which a large amount of lung surfactant can reach the site of action in the lungs.

Claims

Patent Claims

1. Dry nebulizer (1) comprising a housing (2) with an area (11) for receiving nebulizable material (8), a gas intake line (3) which is connected to the housing and one end of which extends into the housing and has a gas inlet opening (4) for introducing carrier gas into or through the nebulizable material, and a gas discharge line (5) connected to the housing, with a gas outlet (6) for discharging the carrier gas with the nebulized material contained therein, characterized in that the gas outlet (6) is designed as a filter.

2. Dry nebulizer (1) according to Claim 1, in which the gas outlet (6) is located above the gas inlet opening (4).

3. Dry nebulizer (1) according to Claim 1 or 2, in which the housing (2) has a substantially constant cross section of flow.

4. Dry nebulizer (1 ) according to at least one of the preceding claims, in which the gas inlet opening (4) is located in the area (11).

5. Dry nebulizer (1) according to at least one of the preceding claims, in which the gas outlet (6) has a smaller cross section of flow redlative to the gas discharge line (5).

6. Dry nebulizer (1) according to at least one of the preceding claims, in which the gas outlet (6) has several admission openings (7).

7. Dry nebulizer (1) according to Claim 6, in which the admission openings (7) are circular and have a diameter of 0.1 to 2 mm, preferably 0.5 to 1.5 mm.

8. Dry nebulizer (1) according to Claim 6 or 7, in which the admission openings (7) are arranged in a surface parallel to the main axis (10) of the housing (2).

9. Dry nebulizer (1) according to at least one of the preceding claims, in which the housing (2) has a substantially cylindrical shape.

10. Dry nebulizer (1) according to at least one of the preceding claims, in which the part of the housing (2) connected to the gas discharge line (5) has the shape of a concave hollow body segment, preferably a sphere segment.

11. Dry nebulizer (1) according to at least one of the preceding claims, in which the gas outlet (6) is arranged at a distance from the wall of the housing (2).

12. Dry nebulizer (1) according to at least one of the preceding claims, in which the area (11) is a base of the housing (2).

13. Dry nebulizer (1) according to Claim 12, in which the base is designed in the form of a concave hollow body segment, preferably a sphere segment.

14. Dry nebulizer (1) according to at least one of the preceding claims, in which the gas intake line (3) is arranged substantially coaxially with respect to the main axis (10) of the housing (2).

15. Dry nebulizer (1) according to at least one of the preceding claims, in which the gas discharge line (5) is arranged substantially coaxially with respect to the main axis (10) of the housing (2).

16. Dry nebulizer (1) according to Claim 14 or 15, in which the gas intake line (3) and gas discharge line (5) have substantially a common axis.

17. Dry nebulizer (1) according to at least one of the preceding claims, in which the gas inlet opening (4) is arranged in or below the nebulizable material.

18. Dry nebulizer (1) according to at least one of the preceding claims, in which the gas inlet opening (4) is located at the end of the gas intake line (3).

19. Dry nebulizer (1) according to at least one of the preceding claims, in which the housing (2) is designed in several parts.

20. Dry nebulizer (1) according to at least one of Claims 1 to 18, in which the housing (2) is designed in one part.

21. Dry nebulizer (1) according to at least one of the preceding claims, further comprising a device (9) for shaking the nebulizable material, which device (9) preferably at least partially encloses the lower part (2b) of the housing (2).

22. Dry nebulizer (1) according to at least one of the preceding claims, which is filled with nebulizable material and is suitable for disposal after one use.

23. Use of a dry nebulizer (1) according to at least one of the preceding claims, for nebulizing a pharmaceutical preparation.

24. Use according to Claim 23, in which the pharmaceutical preparation is powdered.

25. Use according to Claim 23 or 24, in which the pharmaceutical preparation comprises a lung surfactant.

26. Use according to Claim 25, in which the lung surfactant is a surfactant based on recombinant surfactant protein C.

27. Use according to Claim 26, in which the surfactant based on recombinant surfactant protein C is lusupultide.

28. Respirator with a built-in dry nebulizer according to at least one of Claims 1 to 22.

29. Respirator according to Claim 28, in which the dry nebulizer is attached to the respiratory air intake line of the respirator.