SK10942001A3 - Compressed air inhaler for pulmonary application of liposomal powder aerosols and powder aerosols suitable therefor - Google Patents

Abstract

The invention relates to a compressed air inhaler for the pulmonary application of a liposomal powder aerosol that carries active agents or is uncharged. The aim of the invention is to provide an inhaler by means of which the pulmonary application of especially liposomes that carry active agents is possible without forced breathing manoeuvres and by means of which the active agent can be transferred to the desired place of action in a sufficient amount without the active agent escaping. To this end, said compressed air inhaler comprises a receptacle (20) for the aqueous dispersion of liposomes. The liposomes carrying the active agents are dispersed in water in said receptacle. The receptacle is connected to an anatomising nozzle (1) and to a drying unit (17) via a device that doses liquids (19), whereby the drying unit can be an atomising chamber for spray drying the liposomes. An outlet (18) and a mouth piece are joined to said drying unit. The anatomising nozzle (1) is provided with separate supply channels (14, 16) for the compressed air and the dispersion of the liposomes (fig.1). The invention also relates to a novel powder aerosol consisting of liposomes or nanoparticles.

Description

Compressed air inhaler for pulmonary delivery of liposomal powder aerosols as well as other powder aerosols suitable for this purpose

Technical field

The present invention relates to a compressed air inhaler for pulmonary delivery of a pulverized aerosol containing an active ingredient of an optionally uncharged liposomal pulverized aerosol.

The invention is preferably intended for use with powdered liposomal aerosols with active ingredients. The invention may also be applied to uncharged liposomes, for example liposomes from special lipids such as surfactant lipids, which may also represent the active ingredients.

The invention further provides powder aerosols containing the active ingredients as well as uncharged powder aerosols which can be used in a compressed air inhaler.

BACKGROUND OF THE INVENTION

Liposomes are becoming increasingly important as a dosage form for the active ingredients. In order to improve the physical stability as well as the durability of the liposomes and to obtain the coated active ingredient, the liposome composition carrying the active ingredients will be lyophilized. Of course, these liposome lyophilates are hygroscopic and therefore cause difficulties in application if they are to be as dry powders. The storage of liposome lyophilisers is then always problematic if this cannot be done under vacuum in a sealed container. For administration, the lyophilisates are reconstituted with water or saline, and are administered, for example, as intravenous injections. It is also possible to encapsulate and encapsulate liposome lyophilates or compress tablets to provide a form for oral use.

For the treatment of broncho-pulmonary diseases such as e.g. asthma, bronchitis or lung cancer, liposomes with active ingredients may be used.

So far, the results of using liposomes to concentrate drugs in the lungs are promising. Liposomes mediating pulmonary drug applications prolong the residence time of the active ingredient in the lungs, while increasing the effectiveness of the treatment by significantly reducing extra-pulmonary side effects. The prolonged residence time of the liposomes in the airways affects the pharmaceutical kinetics of the coated material. There is an increased local concentration at a reduced level of the active substance outside the lung. Toxic studies have shown no chronic lung histological changes in vivo as well as no toxic effects in healthy subjects during chronic inhalation, demonstrating good tolerability of pulmonary liposome administration.

Thus, U.S. Pat. No. 4,895,719 describes a dry powder of liposomes, which is produced by the spray drying method in fluorinated hydrocarbons, which simultaneously serve as propellant, are suspended and sprayed under pressure and inhaled. The propellant vaporizes in the device and the oral cavity. Through the exhalation process, the air in the device and the oral cavity is saturated with water vapor, and the propellant is immediately replaced by water on the basis of the hygroscopic formulation, so that in any case an aqueous aerosol is inhaled.

EP 0 223 831 B1 discloses a system for administering a water-soluble drug in the respiratory tract that uses liposomes to seal the drug and one device, not described in more detail, to spray a defined amount of liposomes by ultrasound or pneumatic inhalation.

The generation of liposome aerosol formulations is not problem-free. When using e.g. ultrasonic atomizer continues to increase the temperature of the aerosol in the so-called. holding chamber effect. This increase in temperature causes the release of the sealed material depending on the phase transition temperature of the lipid used. In studies in which a liposomal aerosol is generated with the aid of a medical spray for compressed air, the release of the active substance was also observed. This phenomenon is derived from the shear force during spraying. This effect is especially developed in conventional medical compressed air nebulizers, since the released liposome suspension serving as an inhalation aerosol must be run through a larger number of spray cycles, since only a small amount of inhalable fraction is generated and dispensed. The residue is deposited in the apparatus and used for a new atomization.

In a conventional nebulizer, the energy yield is not very efficient, so that a larger proportion of larger non-inhalable drops is produced. These drops fall back into the reservoir. On average, the liposome suspension recycles more than ten times and always disperses again before leaving the nebulizer as a exhaled aerosol. In particular, substances which are susceptible to mechanical loading may cause sensible problems, especially in the case of substances which are susceptible to mechanical stress. During the spraying process, a considerable amount of water evaporates from the liposome suspension, since the spraying air is dry and the aerosol droplets with their large surface promote evaporation. The liposome concentration therefore increases during the nebulization period and hence the inhaled dose. A dose of the same shape is therefore difficult for liposomes in conventional nebulisers. The effectiveness of an inhaled therapeutic aerosol depends on many factors, depending on the particle size of the aerosol. Commercially available atomizers generate, on average, a droplet size from 5 microns. Such an aerosol is deposited in the upper airways. However, since numerous bronchopulmonary diseases are found in deeper areas of the lung, it would be desirable for the particle size spectrum to be adaptable.

Also known are dry powder inhalers (dpi) that promote the inhalation of dry liposome powder by deep inhalation. Such a dry powder inhaler is shown in US 4,895,719 (Fig. 6). This dosage form has the disadvantage that patients suffering from respiratory diseases must be capable of breathing maneuvers so that they can inhale the powder. There may also be a risk of aggregation of the liposome powder, which is due to the hygroscopy of the dry liposomes, as well as the possible release of the active ingredient, making accurate dosing impossible. Aggregation of the liposome powder increases the particle size and thereby changes the liposome deposition pattern. The areas of the lungs in which the effect is to be achieved are no longer reached. This results in insufficient dosage and poor effect.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It was therefore an object of the present invention to provide an inhaler such that pulmonary delivery of liposomes is made possible without a violent breathing maneuver and by which the active ingredient can be introduced in a sufficient amount and at a suitable location without excretion.

It is a further object of the invention to provide a suitable aerosol formulation in this inhaler.

The object of the invention has been solved by providing a compressed air inhaler according to the definitions of claim 1. This comprises a compressed air inhaler for pulmonary delivery of a carrier effective or uncharged liposome powder aerosol, a container for an aqueous liposome dispersion in which the liposomes are dispersed in water; this is connected via a pump to a spray nozzle and a drying unit as a spray chamber for spray drying the liposomes to which the mouthpiece is attached, the spray nozzle having separate inlets for compressed air and a liposome dispersion.

The compressed air inhaler according to the invention permits, starting from an aqueous liposome dispersion which generates the formation of an aerosol of powder so that, firstly, no forced breathing maneuver is required and, secondly, there are no problems with handling the dry liposome powder. Aqueous liposome dispersion shows low toxicity and high stability of liposomes compared to organic media, it can be easily produced with the possibility of Scaling Up effect.

The advantage is that according to the invention no propellant is required and that the particle size of the aerosol-powder can be controlled according to individual requirements.

Compared to known inhalers, there is no multiple atomization. Anything that will be sprayed will also be powder dried in situ and inhaled immediately, the liposomes will not circulate in the inhaler. There is no stress on the composition.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the invention are described in the defined claims. The invention will be explained in more detail by way of example of an embodiment of a compressed air inhaler as illustrated. The images show:

Fig. 1 is a schematic representation of a compressed air inhaler according to the invention; and

Fig. 2 is a schematic representation of a section of the nozzle body in the compressed air inhaler of FIG. 1

DETAILED DESCRIPTION OF THE INVENTION

As shown in FIG. 1, the compressed air inhaler consists essentially of a nozzle body 1 with a compressed air inlet 16 and a liquid inlet 14, an equalizing and drying vessel (spray chamber) 17 and an aerosol outlet (mouthpiece) 18. The liquid inlet 14 is connected to a liquid dosing device. 19 and a container 20 for an aqueous liposome dispersion.

To adjust the pressure, the inlet 16 is connected to a pressure valve (not shown).

The nozzle body 1 consists of a two-component nozzle in which the supplied liquid will be atomized by the applied air pressure adjustable at the pressure level. As a rule, the active ingredient is dissolved in the introduced liquid, for example water or ethanol, and in the present case (liposome) is available as a dispersion.

The air and liquid flow can be adjusted independently of each other.

The nozzle body 6 consists, as shown in FIG. 2 substantially from a central cavity 2 into which the injection body is concentrically inserted

3, which has a central opening 4 for supplying liquid and which is adjustable from the outlet opening 5 of the nozzle body 5 through the fixing screw 15, and which has an annular opening 6 with the outlet opening 7 in the hollow space 2 of the nozzle body 6.

In one of the walls 8 of the nozzle body 8, a compressed air inlet 9 is fastened parallel to the space 10, which faces a perpendicular opening 11 which communicates with an annular opening 6 of the injection body 2. The opening 11 is closed outwards with a blind The compressed air will be introduced, for example, via a hose coupling (olive) 13 into the compressed air supply 16.

The droplet size at the inlet of the drying vessel 17 can be adjusted by varying the supply air pressure and by selecting the diameter of the liquid capillary (outlet port 5 in Fig. 2). At low air pressure, eg. p = 0.8 bar, mean droplet diameters of 8 µm are produced in the drying vessel 17, and at a set pressure of p = 5 bar, mean droplet diameters of 4 µm are produced.

In addition, in a further variant with virtual impactor integration, the generated drops will be separated by atomizing air before entering the drying vessel 17.

By evaporating the supplied liquid in a drying chamber 17, which is generally water or ethanol, and which acts as a solvent for the active ingredient or as a dispersing medium for liposomes, the atomized droplets reduce their diameter until completely dried. The dependence between the dry particle size at the outlet of the drying vessel 17 of FIG. 1, i.e. at the aerosol outlet 18, is given by the following relation:

where d _tr = the diameter of the dry particle at the aerosol outlet 48, dprim - the diameter of the respective primary droplet at the inlet of the drying vessel 17, c - the active substance mass concentration (liposome dispersion concentration in aqueous solution).

Thus, with a 1% solution, a diameter reduction of 4.6 is obtained.

By varying the supply air pressure, medium-sized particles e.g. at the outlet of the drying chamber 17 of the inhaler (aerosol outlet 18, e.g., mouthpiece) may be formed. 1.7 µm or at a higher pressure e.g. 0,9 pm.

The drying vessel 17 (or evaporation vessel) is sized such that complete evaporation is guaranteed without loss of droplets on the walls.

In order to achieve complete evaporation and thus drying, it is necessary to adjust the flow rate between the liquid and the compressed air, which is determined by the ability of the compressed air to be absorbed in the liquid (eg water or ethanol vapors).

In a preferred variant, the drying vessel 17 for the increased flow of the mist-drying liquid is provided with semipermeable membranes. On the outside of the membrane (s), there is optionally a drying agent for receiving water vapor. In another variation, dry air will flow from the outside of the membrane.

The optimal high concentration of the active ingredient of the aerosol will be achieved through independent adjustment of the fluid flow and the compressed air.

The liquid undergoes only one dispersing process. The recirculation of the dispersion and the associated concentration and / or enrichment of the dispersion are avoided. structural change of active agent particles through shear forces. The droplets are dried immediately after formation.

The compressed air inhaler is designed as a handheld device for convenient patient use, anywhere. The spray chamber, in its function as a drying dough, can be made in a very small design, for example, as a tube.

The present invention also provides a process for treating pulmonary diseases in which a compressed air inhaler will be used in accordance with the present invention.

The invention further provides liposomal and nanoparticular powder aerosols according to claims 7-27.

These powder aerosols have the following characteristics: it is a dry powder in the absence of a cryoprotector. The individual powder particles are spherical and have an amorphous or crystalline structure. They are variable in size from 0.5 - 10 µm. This may determine a deposit site for a certain depth of lung according to the disease being treated. They consist of dry, light liposome or nanoparticular aggregates or individual liposomes, respectively. nanoparticles.

The powder aerosol composition can vary widely. In addition to the active ingredient, the liposomal powder aerosol consists, for example, of phospholipids and cholesterol in varying quantitative proportions, of a natural or articulated pulmonary surfactant, or of cationic amphiphiles. The liposomes used can be e.g. large multilamellar vesicles (MLVs), manufactured, inter alia, by high pressure and high pressure homogenization, or as small unilamellar vesicles (SUVs), inter alia, produced by ultrasound. The nanoparticular powder aerosol consists, for example, of crystals of the active substance or of polymer particles charged with the active substances. Examples of polymers which may be used are: polymethacrylate, polycyanoacrylate, polyglycolate, polylactate, polyvinylpyrrolidone, polyvinyl acetate, alginate, gelatin individually or in variable mixing ratios. The liposomes or nanoparticles may be surface modified e.g. polyethylene glycol-associated proteins with plasma or surfactant or antibody fragments.

The invention can be used in the treatment of all known respiratory diseases enriched with the corresponding active ingredient. All conventional drugs as well as genetic material are considered as active substances. A non-active liposome powder aerosol can be used for lung surfactant replacement therapy, e.g. in therapy of neonatal dyspnea or shock lungs.

Liposomal and nanoparticular powder aerosols are made by spraying liposomes or nanoparticles together with compressed air through a two-component nozzle in a cylinder (as described above).

By varying the dispersion concentration and the primary spectrum of the droplets, for example by means of spray pressure, the average size of the aerosol particles can be adjusted. In particular, the diameter can be adjusted according to the desired needs when applied to experimental animals or humans. Thus, the inhaled drug can be deposited quantitatively, homogeneously and with greater efficiency. In order to achieve a systemic effect in human application, it is preferable to set average particle sizes to about 1 micrometer in order to achieve optimal particle deposition in the alveolar region of the lungs and to utilize a large gas _: epithelial boundary surface to saturate the drug. For use in topical therapy of bronchial diseases, it is desirable to deposit particles in the peripheral lung area. For this purpose, the optimum particles are in the size range between 3 and 5 µm.

Particle sizes of approximately 1 µm are produced using a spray pressure of 3 bar and a dispersion concentration of 0.5%. At lower spray pressures and at an increased dispersion concentration e.g. by increasing the concentration of liposomes or by adding an excipient (lactose), the average particle size may shift towards higher values.

The invention provides one method in which the inhaled drug can be quantitatively reproduced and homogeneously deposited.

It goes without saying, and it is also within the scope of the invention, that the powder aerosols described can also be used independently of the inhaler within the meaning of the invention.

Custom results:

So far, a powder aerosol having the following composition has been successfully produced:

1. hydrogenated soy-phosphatidylcholine and cholesterol at a molar ratio of 1: 0.25

Ultrasonic SUV

Average particle size of liposomes: 121 nm

Mean particle size of the aerosol: 1.02 µm.

2. Hydrogenated soy-phosphatidylcholine and cholesterol at a molar ratio of 1: 0.25

MLV produced by homogenization

Average particle size of liposomes: 1.5 µm.

Mean particle size of the aerosol: 1.03 µm.

3. Hydrogenated soy-phosphatidylcholine, cholesterol and polyethylene glycol in a molar ratio of 1: 1: 0.1

MLV produced by shaking the dispersed lipid film

Average liposome particle size: 15 µm

The average particle size of the aerosol was 0.7 µm

4. Hydrogenated soy-phosphatidylcholine, cholesterol and polyethylene glycol in a molar ratio of 1: 1: 0.1

Ultrasonic SUV

Average particle size of liposomes: 100 nm

Average particle size of the aerosol: 0.8 μπι

5. Phosphatidylcholine and cholesterol in a molar ratio of 1: 0.5, charged with 5,6-carboxyfluorescein

Ultrasonic SUV

Average particle size of liposomes: 80 nm

Average aerosol particle size: 0.8 µm

6. DAC-chol and DOPE in a 2: 3 weight ratio

Average aerosol size: 0.6 µm

7. DAC-chol and DOPE in a 2: 3 weight ratio complexed with protamine sulfate

Mean particle size of the aerosol: 0.7 µm

8. DAC-chol and DOPE in a 2: 3 weight ratio complexed with poly-Llysine

Average particle size of the aerosol: 0.6 µm

Recipe no. 5 was used in an in vivo experiment to spray 3 BDF1 mice.

The test animals were treated at a time interval of 60 minutes. The aerosol was well tolerated. A total of 385 ng / l carboxyfluorescein was sprayed in the experiment. The concentration in the individual organs of the test animals is shown in the following table:

mouse no. authorities Organ weight in mg CF content in ng / mg tissue 1 trachea 4.6 0,027 - Right pulmonary lobe 35.18 0,095 Left pulmonary lobe 33.55 0,074 2 trachea 16.58 0,068 Right pulmonary lobe 45.68 0,068 Left pulmonary lobe 66.59 0,039 3 trachea 2.53 0,072 Right pulmonary lobe 40.14 0,085 Left pulmonary lobe 65.91 0,032

Claims (26)

PATENT CLAIMS Compressed air inhaler for pulmonary delivery of a liposomal powder aerosol with a container (20) for an aqueous liposome dispersion in which the liposomes are dispersed in water, which is connected via a liquid dosing device (19) to a spray nozzle (1) and a drying unit (17) as a spray chamber for spray drying the liposomes to which the outlet (18) is connected as a mouthpiece, the spray nozzle (1) having separate inlets (14,16) for compressed air and a liposome dispersion, characterized in that the spray nozzle consists of a nozzle body (1) having a central hollow space (2) in which a syringe body (3) is concentrically connected, having a central opening (4) for delivering a liposome dispersion with an adjustable distance from the nozzle body outlet opening (5) (1) and has an annular opening (6) with an outlet opening (7) in the hollow space (2) of the nozzle body (1) and that it is in one of the sides (8) of the body d A compressed air inlet (9) connected to the wall (1) is connected parallel to a wall which impinges on a perpendicular opening (11) which is connected to an annular opening (6) of the injection body (2). Compressed air inhaler according to claim 1, characterized in that the drying unit (17) has a semipermeable membrane, which is optionally provided with a drying agent on the outside. Compressed air inhaler according to claim 1, characterized in that a virtual impactor is integrated, whereby the generated drops will be separated from the atomizing air before entering the drying unit (17). Compressed air inhaler according to claim 1, characterized in that the compressed air supply and the liquid supply are adjustable independently of one another. Method for the treatment of pulmonary diseases, characterized in that a compressed air inhaler according to claims 1 to 4 is used. An aerosol powder consisting of liposomes and / or nanoparticles characterized by the absence of moisture by the absence of a cryoprotector with a spherical particle form of amorphous or crystalline structure and a particle size of from 0.5 to 10 µm. An aerosol powder according to claim 6 for the treatment of trachea and large bronchi, characterized in that the particle size is 5-10 µm. The aerosol powder of claim 6 for the treatment of small bronchi, wherein the particle size is 3-5 µm. The aerosol powder according to claim 6 for the treatment of bronchioles and alveoli, characterized in that the particle size is from 0.5 -3 µm. Powder aerosol, characterized in that it consists of liposomes and / or nanoparticles produced by compressed air spraying of liposomes and / or dispersion of nanoparticles through a two-component nozzle at a spray pressure of 1-5 bar and a dispersion concentration of 0.2-1%. Powder aerosol according to claims 6 - 10, characterized in that it contains an active substance. Powder aerosol according to claim 11, characterized in that it contains an active ingredient for the treatment of respiratory diseases. Liposomal powder aerosol, characterized in that it contains as active ingredient phospholipids, cholesterol, a natural or articular pulmonary surfactant or cationic amphiphiles. 14. A liposomal powder aerosol comprising as liposomes large multilamellar vesicles (MLV) or small unilamellar vesicles (SUV). 15. A liposomal powder aerosol comprising hydrogenated soy-phosphatidylcholine and cholesterol in a molar ratio of 1: 0.25 as well as ultrasonic-produced SUVs. 16. A liposomal powder aerosol comprising soyaphosphatidylcholine and cholesterol in a molar ratio of 1: 0.25 as well as MLV produced by homogenization. 17. A liposomal powder aerosol comprising hydrogenated soy-phosphatidylcholine, cholesterol and polyethylene glycol in a molar ratio of 1: 1: 0.1 as well as MLV produced by shaking the dispersed lipid film. 18. A liposomal powder aerosol comprising hydrogenated soy-phosphatidylcholine, cholesterol and polyethylene glycol in a molar ratio of 1: 1: 0.1 as well as ultrasonic SUVs. 19. A liposomal powder aerosol comprising phosphatidylcholine and cholesterol in a molar ratio of 1: 0.5 charged with 5,6-carboxyfluorescein as well as ultrasonic SUVs. 20. A liposomal powder aerosol comprising DACchol and DOPE in a weight ratio of 2: 3. 21. A liposomal powder aerosol comprising DACchol and DOPE in a 2: 3 weight ratio complexed with protamine sulfate. 22. A liposomal powder aerosol comprising DACchol and DOPE in a 2: 3 weight ratio complexed with poly-Llysine. 23. Nanoparticular powder aerosol, characterized in that it consists exclusively of active substance crystals. 24. A nanoparticulate powder aerosol consisting of polymeric particles charged with an active ingredient. Nanoparticular powder aerosol according to claim 24, characterized in that polymethacrylate, polycyanoacrylate, polyglycolate, polylactate, polyvinylpyrrolidone, polyvinyl acetate, alginate, gelatin alone or in varying composition ratios may be used as the polymer. 26. The aerosol powder of claim 6, wherein the lipids resp. nanoparticles are surface modified, for example, with polyethylene glycol, plasma-associated or surfactant-associated proteins, or antibody fragments.