Method for operating an aerosol inhalation device and aerosol inhalation device

Abstract

In a first aspect, the invention relates to a method for operating an aerosol inhalation device (10), comprising the steps of transporting a certain amount of an aerosol to a desired location outside said device (10) and vibrating the transported aerosol when it has reached said desired location. In a second aspect, the invention relates to an aerosol inhalation device (10) comprising a pump (1) for flowing a certain amount of an aerosol to a desired location outside the device (10), a vibrator (2) for vibrating the transported aerosol in a vibration mode and a control configured to actuate the vibrator (2) for vibrating the flowed aerosol only when it has reached said desired location.

Claims

1. A method for operating an aerosol inhalation device including a gas pumping component, a vibrator, an aerosol generator and a control, the method comprising the steps of: generating, by the aerosol generator, a certain amount of an aerosol in said aerosol inhalation device, transporting, by the gas pumping component, the certain amount of the aerosol to a desired location outside said aerosol inhalation device, vibrating, by the vibrator, the transported aerosol in a vibrating mode, and controlling, by the control, the vibrator to operate in the vibrating mode when the transported aerosol has reached said desired location and controlling the gas pumping component so that the aerosol transport is stopped when said certain amount of aerosol has reached said desired location and so that the vibration is induced in the transported aerosol only at a time when an aerosol flow rate is substantially zero, wherein the control comprises a computer, and controlling aerosol generation and controlling the vibrator to operate in the vibrating mode are performed by the computer.

2. The method according to claim 1, wherein the duration of the step of vibrating the aerosol lies in the range of 0.1-15.0 s.

3. The method according to claim 1, wherein said desired location is the nasal cavity or the mucosa in the nose.

4. The method according to claim 1, wherein the vibration of the aerosol has a frequency in the range of 1-200 Hz.

5. The method according to claim 1, wherein the vibration of the aerosol has an amplitude in the range of 0 to 50 mbar in the desired location.

6. The method according to claim 1, wherein the aerosol is a pharmaceutical aerosol for the delivery of an active compound.

7. The method according to claim 1 wherein the aerosol generation is stopped before the step of vibrating the aerosol.

8. The method according to claim 7, wherein the aerosol generation is stopped before the step of transporting the aerosol to said desired location.

9. The method according to claim 8, wherein the aerosol generation is stopped when said device is filled with the generated aerosol.

10. The method according to claim 8, wherein the aerosol transport is stopped when said device has been emptied of the generated aerosol.

11. The method according to claim 7, wherein the aerosol is generated at a first flow rate in the aerosol generation step and transported at a second flow rate in the aerosol transporting step.

12. The method according to claim 11, wherein the second flow rate is different from the first flow rate.

13. The method according to claim 11, wherein the second flow rate is lower than 60 l/min.

14. The method according to claim 1, wherein said desired location is the respiratory system.

15. The method according to claim 14, comprising a step of generating said certain amount of aerosol in said device, wherein the volume of the aerosol generated in this aerosol generating step is 0.1-3.0 times the volume of the nasal cavity.

16. The method according to claim 14, wherein the aerosol transport is effected by inhalation through the nasal cavity.

17. The method according to claim 14, wherein both the step of transporting the aerosol and the step of vibrating the aerosol do not require the presence of a counterpressure element in the nasal cavity, such as a nose resistor or a nose plug.

18. The method according to claim 14, wherein the step of vibrating the aerosol is only performed during a period of exhalation through the nasal cavity.

19. An aerosol inhalation device comprising: an aerosol generator configured to generate an aerosol in said aerosol inhalation device in an aerosol generating mode; a gas pumping component configured to transport a certain amount of the aerosol to a desired location outside said aerosol inhalation device; a vibrator configured to vibrate the transported aerosol in a vibrating mode; and a control configured to operate the vibrator in the vibrating mode when the transported aerosol has reached said desired location and to control the gas pumping component so that the aerosol transport is stopped when said certain amount of aerosol has reached said desired location and so that the vibration is induced in the transported aerosol only at a time when an aerosol flow rate is substantially zero, wherein the control comprises a computer, and controlling aerosol generation and controlling the vibrator to operate in the vibrating mode are performed by the computer.

20. The aerosol inhalation device according to claim 19, wherein the control is further configured to stop the aerosol generating mode before operating the vibrator in the vibrating mode.

21. The aerosol inhalation device according to claim 19, wherein the control is further configured to stop the aerosol generating mode before the gas pumping component is operated for transporting the aerosol to said desired location.

22. The aerosol inhalation device according to claim 19, wherein said desired location is the nasal cavity or the mucosa in the nose and the device further comprises an adaptation element, such as a nosepiece, for communicating with the nasal cavity.

23. The aerosol inhalation device according to claim 19, wherein one and the same element is used as both the gas pumping component and the vibrator.

24. The aerosol inhalation device according to claim 19, wherein said desired location is the respiratory system and the aerosol inhalation device further comprises an adaptation element, such as a nosepiece, mouthpiece, face mask or ventilator tube, for communicating with the respiratory system.

25. The aerosol inhalation device according to claim 19, wherein said aerosol inhalation device comprises an inhaler, atomizer or nebulizer, which is of the ultrasonic, jet or electro-hydrodynamic type, a metered dose inhaler (MDI), dry powder inhaler (DPI) and/or vibrating membrane with pores of defined size.

26. The aerosol inhalation device according to claim 19, wherein the gas pumping component includes a gas compressor.

27. The aerosol inhalation device according to claim 19, wherein said desired location is the nasal cavity or the mucosa in the nose and the aerosol inhalation device further comprises a sensor and control element configured to allow actuation of the vibrator for vibrating the aerosol only during a period of exhalation through the nasal cavity.

28. The aerosol inhalation device according to claim 19, wherein said aerosol inhalation device comprises a vibrating membrane nebulizer and the vibrating membrane is disposed in such a way that its plane is substantially perpendicular to the direction of transport of the aerosol.

29. The aerosol inhalation device according to claim 28, wherein the gas pumping component includes a gas compressor, further comprising a connector located upstream of the vibrating membrane for connection to the gas compressor.

30. The aerosol inhalation device according to claim 24, wherein the vibrator is directly connected to the adaptation element.

31. The aerosol inhalation device according to claim 24, wherein said aerosol inhalation device comprises a vibrating membrane nebulizer and the vibrating membrane is disposed in such a way that its plane is substantially perpendicular to a direction of transport of the aerosol and wherein the adaptation element is located downstream of the vibrating membrane.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Hereinafter, non-limiting examples are explained with reference to the drawings, in which:

(2) FIG. 1 shows a schematic view of an aerosol inhalation device according to a currently preferred embodiment of the present invention;

(3) FIG. 2 shows a schematic view of an aerosol inhalation device according to another currently preferred embodiment of the present invention;

(4) FIG. 3 shows a schematic view of an aerosol inhalation device according to yet another currently preferred embodiment of the present invention;

(5) FIG. 4 shows a longitudinally cut cross-sectional view of the aerosol inhalation device schematically shown in FIG. 1;

(6) FIG. 5 shows a flow diagram illustrating a possible operation of the aerosol inhalation devices shown in FIGS. 1 to 4, with an aerosol generating flow 1 and a transportation flow 2;

(7) FIG. 6 shows a flow diagram illustrating another possible operation of the aerosol inhalation devices shown in FIGS. 1 to 4, with an aerosol generating flow 1 and a transportation flow 2;

(8) FIG. 7 shows a flow diagram illustrating yet another possible operation of the aerosol inhalation devices shown in FIGS. 1 to 4, without an aerosol generating flow 1 and with a transportation flow 2; and

(9) FIG. 8 shows a flow diagram illustrating yet another possible operation of the aerosol inhalation devices shown in FIGS. 1 to 4, without an aerosol generating flow 1 and with a transportation flow 2.

DETAILED DESCRIPTION OF CURRENTLY PREFERRED EMBODIMENTS

(10) FIGS. 1 to 4 show schematic views of aerosol inhalation devices 10 according to currently preferred embodiments of the present invention.

(11) The aerosol inhalation device 10 contains an aerosol generator 3, which may be an inhaler, atomiser or nebuliser, especially a nebuliser of the ultrasonic, jet or electro hydrodynamic type, Metered Dose Inhaler (MDI), Dry Powder Inhaler (DPI), spinning disc, and/or a nebuliser operating with a vibrating membrane or with pores of defined size.

(12) As can be seen from FIGS. 1 to 4, the aerosol inhalation device 10 according to the currently preferred embodiments comprises a connector 12 for connection with a gas compressor 1 as a source of compressed air and an adaptation element 14 that is equipped with a nosepiece 16 or an optional mouthpiece 50 for adaptation to (communication with) a patient's 100 respiratory system, nasal cavity etc. A fluid container 18 for receiving a fluid to be nebulised is disposed between connector 12 and adaptation element 14. The fluid container 18 is preferably integrally formed with the body of the aerosol inhalation device 10 but, in further embodiments, may be configured such that it is partly or fully detachable from the body. The body of the aerosol inhalation device 10 is preferably made of plastic and preferably manufactured by an injection moulding process. The container 18 may be designed so that it does not directly receive the fluid but rather has an element, such as a spike, arranged on its inside that opens a fluid containing vessel, (e.g., a vial, blister, ampoule, container, canister, reservoir, cartridge, pot, tank, pen, storage, syringe) inserted therein.

(13) In the embodiments shown in FIGS. 1 to 4, a gas compressor 1 is used as the pump and a sinus wave generator that is also connected to the connector 12 in the embodiments shown in FIGS. 1, 3 and 4 is used as the vibrator 2, as will be further explained in the following. In the embodiment of FIG. 2, the sinus wave generator is connected to a nebuliser chamber 32 that is in fluid communication with the connector 12 and the adaptation element 14. In the embodiment of FIG. 3, the connector 12 and the nebuliser chamber 32 are integrally formed. The vibrator 2 and the gas compressor 1 of the embodiment shown in FIGS. 1 and 4 together form a gas supply unit (air supply unit) 60.

(14) In general, any aerosolisable fluid that comprises an active compound, such as those listed above, may be received in the fluid container 18 and used for the generation of an aerosol, depending on the condition or disease to be treated. The fluid composition may of course comprise further excipients, such as one or more solvents, co-solvents, acids, bases, buffering agents, osmotic agents, stabilizers, antioxidants, taste-masking agents, clathrate- or complex-forming compounds, polymers, flavours, sweetening agents, ionic and non-ionic surfactants, thickeners, colouring agents, fillers, and bulking agents.

(15) Solvents and co-solvents, other than water, should be avoided if possible if the composition is intended for inhalation. If the incorporation of a solvent cannot be avoided, the excipient should be selected carefully and in consideration of its physiological acceptability. For example, if the composition is designated for the treatment of a life-threatening disease, the use of some limited amount of ethanol, glycerol, propylene glycol or polyethylene glycol as a non-aqueous solvent may be acceptable. According to the currently more preferred embodiments, however, the composition is substantially free of these solvents, and in particular of glycerol, propylene glycol or polyethylene glycol.

(16) In the embodiments shown in the figures, the one end of the fluid container 18 can be securely and tightly closed with a screw cap (not shown). At its other end, opposite the screw cap, the fluid container may have a tapered portion 22 that tapers towards a fluid chamber 24, as can be seen in FIG. 4. The fluid chamber 24 may be sealed by a sealing lip (not shown) that forms a part of the chamber 24 and is tightly pressed against a membrane 30. The membrane 30 is provided with a plurality of minute openings or holes with diameters in the micrometer range that fully penetrate the membrane 30. Furthermore, the membrane 30 can be vibrated (or oscillated), for example with the use of a piezoelectric element (not shown), such that the direction of the vibrations is perpendicular to the plane of the membrane 30. A terminal element for enabling supply of electrical power and control of the membrane 30 may be integrally formed with the body of the inhalation device 10. By inducing such vibrations in the membrane 30, fluid contained in the fluid chamber 24 is passed through the minute openings of the membrane 30 and nebulised into the nebuliser chamber 32 formed at the other side (opposite the fluid chamber 24) of the membrane 30. In this way, the fluid chamber 24 and the membrane 30 together form a vibrating membrane nebuliser device (aerosol generator) 3. A detailed description of this common concept is given, for example, in U.S. Pat. No. 5,518,179. A control (not shown) comprises a computer and a first control element (not shown), such as a transistor, that is connected to the membrane 30 for stopping the membrane vibration and hence the aerosol generation before a step of transporting the generated aerosol to a desired location outside the inhalation device 10 is carried out.

(17) A circulation portion 36 is formed between the membrane 30 and the body (not shown) of the inhalation device 10 that allows for the passage of a gas, i.e., air in the present embodiments, supplied from the compressor 1 (not shown in FIG. 4) through the connector 12. In the embodiments shown in FIGS. 1 to 4, the gas compressor 1 is used as the pump and a sinus wave generator (not shown) that is also connected to the connector 12 is used as the vibrator 2, as will be further explained in the following. The control (not shown) further comprises a second control element (not shown), that is disposed between the sinus wave generator and the connector 12 for triggering the vibration of a transported aerosol when it has reached a desired location outside the inhalation device 10. As further embodiments the second control element may be magnetical, electrical and/or mechanical, such as a valve, regulator and/or controller. The second control element can be controlled, for example, with the computer of the control.

(18) Next, different examples of the operation of the above described aerosol inhalation device 10 of the embodiments shown in FIGS. 1 to 4 will be explained. FIGS. 5 to 8 show flow diagrams illustrating the sequence and duration of the different steps carried out for depositing a certain amount of an aerosol at a target area, such as the paranasal sinuses. First, the fluid container 18 is filled, for example, with 15 ml of an aerosolisable fluid that comprises an active compound, such as an anti-allergic drug, and tightly sealed with the screw cap (not shown). Then, the nosepiece 16 of the adaptation element 14 is inserted into a nostril of a patient 100 who has a medical condition to be treated. Since no counterpressure element, such as a nose plug, placed in the patient's other nostril is required for the operation of the inhalation device of the present embodiment, the patient can inhale and exhale freely through said other nostril while the treatment is being carried out.

(19) Subsequently, in the operation examples of FIGS. 5 and 6, a constant flow of gas (air) is supplied at a first flow rate (Flow 1 in FIGS. 5 and 6) of 0.5 l/min by the gas compressor 1, while at the same time the membrane 30 is caused to vibrate, so that it nebulises a certain amount of the fluid received in the container 18 into the nebuliser chamber 32. As can be seen in FIG. 4, the plane of the membrane 30 is substantially perpendicular to the direction of aerosol transport (direction of arrow A in FIG. 4) towards the adaptation element 14, so that the risk of any aerosol loss at the walls of the inhalation device 10 due to impaction is minimised. The air supplied from the compressor circulates around the membrane 30 through the circulation portion 36 and mixes with the nebulised fluid in the nebuliser chamber 32, thus generating an aerosol.

(20) However, the supply of a constant flow of gas (air) during nebulisation of the fluid by the vibrating membrane 30 is not mandatory. An aerosol may also be generated in the absence of such a gas supply, as is shown in FIGS. 7 and 8, by mixing of the nebulised fluid with the gas already present inside the aerosol inhalation device 10.

(21) Once a certain desired amount of an aerosol, such as 0.1 to 3.0 times the volume of the desired location (e.g., the nasal cavity), for example 8 ml, has been generated inside the inhalation device 10 in this way, which in the operation example shown in FIG. 5 requires a time of about 0.3 s, the first control element (not shown) is operated, for example by the computer of the control, in order to halt the vibration of the membrane 30 and hence stop the aerosol generation. Specifically, this step may be, for example, carried out by monitoring the amount of fluid remaining in the fluid container 18 with a sensor element (not shown) placed within the container 18 and switching off with a first control element (electrical circuitry) that is connected to the membrane 30 in order to interrupt the supply of electrical power to the membrane 30, when the remaining amount of fluid has reached a predetermined value.

(22) In the operation examples of FIGS. 5 and 7, an aerosol transporting step is performed after the aerosol generation has been stopped. However, as is shown in FIGS. 6 and 8, the aerosol transporting step may also be started before the aerosol generation step is finished. In the aerosol transporting step, an air flow is supplied by the gas compressor 1 at a second flow rate (Flow 2 in FIGS. 5 to 8) of, for example, 0.5 to 15 l/min, that transports the generated amount of aerosol (8 ml) through the adaptation element 14 into the patient's nostril. Once the transported aerosol has reached its desired location, for example in the vicinity of the paranasal sinuses (the ostia), the aerosol transport is stopped by switching off the gas compressor 1. The point in time when the aerosol has arrived at said desired location may be for example identified by monitoring the aerosol flow rate and the time from the start of the transport process, taking into account the volume of the inhalation device 10. In this way, the distance the generated aerosol has travelled can be determined. In the present operation examples, the volume of the generated and transported aerosol is 8 ml, which is about half the average volume of the nasal cavity (15 ml) of an adult patient, and the transport of the aerosol to the desired location takes about 0.4 s (see FIGS. 5 to 8). Hence, the nasal cavity is only half filled with aerosol, reducing the amount of inhaled aerosol that does not reach the paranasal sinuses and thus does not contribute to the therapeutic treatment.

(23) The volume of the aerosol that is transported to the desired location depends on the first and second flow rates (Flow 1 and Flow 2) and the time periods (t1, t2−t1 in FIG. 5; t2, t3−t1 in FIG. 6; t2−t1 in FIGS. 7 and 8) over which said first and second flow rates are applied. Specifically, said transported aerosol volume is Flow 1×t1+Flow 2×(t2−t1) for the example of FIG. 5, Flow 1×t2+Flow 2×(t3−t1) for the example of FIG. 6 and Flow 2×(t2−t1) for the examples of FIGS. 7 and 8.

(24) After the transported aerosol has reached the desired location and the aerosol transport has been stopped, as described above, the second control element (not shown) is operated, for example by the computer of the control, in order to trigger a vibration of the transported aerosol. As mentioned above, the vibrator of the present embodiment is a sinus wave generator (not shown) that is connected to the connector 12 and capable of generating pressure oscillations with frequencies in the range of 1 to 200 Hz. The second control element may be for example a magnetically switchable valve that is disposed between the sinus wave generator and the connector 12 and that can be switched on in order to establish an open connection between the sinus wave generator and the aerosol in the patient's 100 nostril through the inhalation device 10 so as to trigger the aerosol vibration. The second control element can be controlled, for example, with the computer of the control that may also monitor the aerosol flow rate and the time from the start of the aerosol transport process in order to determine the point in time when the aerosol has reached the desired location, taking into account the volume of the inhalation device 10. In the present example, the transported aerosol is subjected to a vibration with a frequency of 40 Hz and an amplitude of 40 mbar for a period t.sub.Vibration of 0.5 s (see FIGS. 5 to 8). After this vibration step has been carried out, the therapeutic treatment can be repeated until it is completed and the inhalation device can be removed from the patient's 100 nostril.

(25) By vibrating the transported aerosol when it has reached a desired location, the impaction of aerosols on the walls of the inhalation device and/or the nasal cavity can be significantly reduced, as has been explained in detail above. Comparative studies performed by the inventors showed that by using such a “triggered vibration”, the aerosol output could be increased by about 30% as compared to the case when the vibration is applied constantly throughout the aerosol transport process (as described, for example, in WO 2004/020029).

(26) The described embodiments of the invention have shown the following parameters and results using a prototype of the inhalation device in laboratory measurements. An aqueous levofloxacin solution was nebulised by the inventive device generating an aerosol having a low flow rate and superimposing the pressure fluctuations in a second step. The sinonasal deposition of the aerosol was evaluated in a human nasal cast in-vitro model.

(27) Sinunasal Deposition Model

(28) A human nasal cast model based on the anatomical shapes and dimensions of the nasal cavity and the nasal passage was built from plastic (polyoxymethylen). In this model, the paranasal sinuses are simulated by 6 exchangeable glass bottles, 3 on either side, representing the frontal, maxillary, and sphenoid sinuses, respectively. Exchangeable, artificial ostiae of 10 mm length were used to connect the artificial sinus cavities to the nose model. Moreover, the model has two openings representing artificial nostrils and one opening for the simulation of the pharynx which connects the nasal cavity with the trachea. The deposition model is also equipped with a pressure sensor inside the nasal cavity in order to determine the amplitude of the aerosol pressure pulsation. This model contains also silicone made inlays in the nasal cavities in order to mimic the narrow cross sectional areas of the nasal turbinates. These inlays have, like the human nose, a high filter efficiency and allow the comparison of various devices under more realistic conditions.

(29) The configuration used for this experiment included an internal volume of 12.5 ml for all sinuses. The diameters of the ostiae were 1 mm for all sinuses. The interior space of each of the glass bottles representing the sinuses was empty.

(30) Test Formulation

(31) An aqueous liquid solution of levofloxacin comprising 10 wt.-% of the active ingredient was prepared. The inactive ingredients were xylitol (2 wt.-%), magnesium gluconate (10.5 wt.-%), dexpanthenol (3.0 wt.-%) and water.

(32) Aerosol Generator and Pulsation Means

(33) A prototype electronic vibrating mesh nebuliser was modified to receive an external air flow which transports the aerosol via a flexible tube and with a vibration generator providing pressure pulsations at a frequency of 40 Hz, but without any net air flow. This device was connected via a tightly sealing nosepiece into one of the artificial nostrils of the cast model. An adapter nosepiece was fitted to the other nostril, comprising a filter and a flow resistor. This device was operated in two different modes, first, the continuous mode, where pulsation and net flow of 1.5 l/min were added at the same time continuously to the aerosol.

(34) In the second, the alternating mode, an aerosol was transported by a constant air flow into the model, then aerosol production and constant flow were stopped and the pulsation was added. In this example, aerosol production was for 1000 ms without air flow, then the generated aerosol bolus was transported by a 250 ms lasting constant air flow of 4 l/min into the model and then a 600 ms pulsation at 40 Hz was added.

(35) Test Procedure

(36) For each test, the nebuliser reservoir was charged with 2.5 ml of the levofloxacin solution. The nebulisers were then operated for one minute into each nostril, resulting in a total administration time of two minutes. To evaluate the deposition of the aerosol, the model was then disassembled. The respective components were rinsed with a suitable solvent to extract the active ingredient, which was quantified by HPLC. Similarly, the drug content of the contacting areas of the nebuliser, the drug content of the sinuses including the ostia, of the remaining parts of the cast model, and of the filter restrictor were analysed. Two complete test cycles were conducted for each device setting.

(37) Results

(38) Detailed results are shown in Table 1. The obtained nebuliser deposition in the alternating operating mode is significantly higher (p<0.01) than for the continuous mode. The probability (p) is calculated by analyses of variance (ANOVA).

(39) TABLE-US-00001 TABLE 1 Vibrating Membrane Vibrating Membrane Nebuliser Prototype, Nebuliser Prototype, continuous mode alternating mode 1st 2nd 1st 2nd Drug in right 147.04 152.34 244.26 208.63 frontal sinus [μg] Drug in left frontal 158.62 150.44 208.77 165.23 sinus [μg] Drug in right 136.55 127.51 224.43 239.14 maxillary sinus [μg] Drug in left 141.49 156.97 265.02 256.49 maxillary sinus [μg] Drug in right 94.33 91.78 267.41 274.79 sphenoid sinus [μg] Drug in left 72.67 59.56 205.42 233.64 sphenoid sinus [μg] Mean Drug amount in 745 1397 all sinus cavities [μg] Mean Drug amount in 2.8 3.8 all sinus cavities [% dose used] Mean Drug amount on 693 2531 filter [μg] Mean Drug amount on 2.6 6.9 filter[% dose used] Mean Drug amount in 24801 32835 Nasal Cavity [μg] Drug in Nasal Cavity 94.5 89.3 [% dose used]