Aerosol Administration Method

Field of the Invention

The present invention relates to a nebuliser system

comprising a nebuliser for assisted breathing devices, such as continuous positive airway pressure (CPAP) devices, and to a method of administering an aerosol to a patient using such a nebuliser system. Further, the invention relates to a holding system for holding a nebuliser or a nebuliser system and to a combination comprising such a nebuliser system and such a holding system.

Background Art

Nebulisers for assisted breathing devices, such as continuous positive airway pressure (CPAP) devices, are well known in the art. For example, WO 2005/048982 A2 discloses such a nebuliser. This nebuliser comprises a body having a first connection that comprises two connecting pieces for

connecting the nebuliser to an air supply line and an air exhaust line of a continuous positive airway pressure (CPAP) device. Opposite the first connection, the body comprises a second connection that again has two connecting pieces which are to be connected via a Y-piece and two tubes with a line leading to the patient. Two separate flow channels that are connected via a connecting channel are formed in the body, one (first one) of which serves the flow of respiratory air from the air supply line to the patient and the other (second one) of which serves the flow of consumed air from the patient into the air exhaust line. The nebulising device is coupled perpendicular, similar to a T-connection, to the first flow channel, with the aerosol being supplied in a direction perpendicular to the direction of flow in this first flow channel. A problem associated with this design is on the one hand that owing to the non-return valve, an element is integrated in the air supply line, i.e. in the line that leads to the patient, which could have serious consequences should it malfunction .

There is on the other hand the problem that the aerosol is introduced into the flow perpendicular to the direction of flow of the respiratory air through the body, and thus a high deposition of the aerosol on the surfaces of the flow channel occurs, which has a high loss associated therewith. Hence, significant aerosol losses occur, affecting the achievable aerosol dosage precision and, thus, also the aerosol

treatment efficiency. This problem is especially pronounced for the treatment of children, in particular, neonates, since in this case aerosol administration with a high degree of accuracy is of crucial importance.

It is known from other fields of technology to prevent deposition of the aerosol on surfaces in particular of the nebulisation chamber in that the nebulising device nebulises in a direction that is parallel to a flow towards the

patient. For example, US-A-2003/0072717 discloses an

inhalation device in which a nebulising device is arranged in a closed and bypassed housing. The housing is disposed in a flow channel of the inhalator, which comprises a mouthpiece. The nebulising device thereby nebulises in the direction of the mouthpiece. However, dead volumes, flow resistance by the nebulising device as well as the filling thereof only play minor roles therein. In assisted breathing devices, such as continuous positive airway pressure (CPAP) devices, however, the nebulisers must meet predefined criteria in this regard. EP-A-1 818 070 also discloses an inhalation therapy device having such a nebulisation direction, in this case, however, for premature babies. The system requires the patient to be able to breathe on their own and is specifically adapted to the small line cross-sections with an inner diameter of between 2 mm and 3.5 mm for premature babies such that air may easily pass around the nebulisation device without flow resistance occurring. Furthermore, since the patient is able to breathe on their own, the system operates at a low

pressure difference of up to 15 mbar. Moreover, filling of the nebuliser with a fluid to be nebulised is not necessary or intended when the system is in operation since operation can be interrupted for filling and/or a loss in pressure in the system can be accepted without risk. Therefore, the above-described systems from the prior art were not

transferable for use in assisted breathing devices, such as continuous positive airway pressure (CPAP) devices.

Further, in order to ensure a high aerosol dosage efficiency and precision, it is not only important to minimise any aerosol losses in the nebuliser but also to achieve efficient transport of the generated aerosol from the nebuliser to the patient, i.e., to the patient's nose and/or mouth. For this purpose, efficient and reliable communication between

nebuliser and patient has to be established and securely maintained over the respiration period.

Hence, there is a need for a nebuliser system enabling efficient aerosol treatment with enhanced aerosol dosage efficiency and precision in an assisted breathing device, such as a continuous positive airway pressure (CPAP) device, in particular, for the treatment of children, especially neonates. Moreover, a need exists for a method of

administering an aerosol to a patient, in particular, a neonate, using such a nebuliser system.

Further, there is also a need for a holding system for holding a nebuliser or a nebuliser system which allows for efficient aerosol transport from nebuliser to patient to be secured and reliably maintained. Summary of the Invention

Hence, it is an object of the present invention to provide a nebuliser system enabling efficient aerosol treatment with enhanced aerosol dosage precision in an assisted breathing device, such as a continuous positive airway pressure (CPAP) device, in particular, for the treatment of children, especially neonates. Moreover, the invention aims to provide a method of administering an aerosol to a patient, in

particular, a child, especially a neonate, using such a nebuliser system. A further object of the present invention is to provide a holding system for holding a nebuliser or a nebuliser system which allows for efficient aerosol transport from the nebuliser to a patient, in particular, a child, especially a neonate, to be secured and reliably maintained.

These goals are achieved by a nebuliser system with the technical features of claim 1, a holding system with the technical features of claim 26, a combination with the technical features of claim 28 and a method with the

technical features of claim 29. Preferred embodiments of the invention follow from the dependent claims.

The invention provides a nebuliser system comprising a nebuliser for assisted breathing devices, e.g., positive pressure assisted breathing devices, such continuous positive airway pressure (CPAP) devices. The nebuliser comprises a body with a first connection for connecting the nebuliser to an assisted breathing device and a second connection for connecting the nebuliser to a patient, in particular, a child, especially a neonate. The body forms a flow channel from the first connection to the second connection. The nebuliser further comprises a nebulising device for

nebulising a liquid. The nebulising device is arranged in the flow channel between the first connection and the second connection. The nebuliser is configured for being adapted or connected to an oral and/or nasal communication element, such as nasal prongs, a nose mask, a face mask or a mouthpiece.

The oral and/or nasal communication element is configured for establishing fluid communication between the nebuliser and a patient's nose and/or mouth.

The first connection may be configured for connecting the nebuliser to the assisted breathing device directly or indirectly, e.g., via a tube. The second connection may be configured for connecting the nebuliser to the oral and/or nasal communication element, such as the nasal prongs, a nose mask, a face mask or a mouthpiece, directly or indirectly, e.g., via an adapter. The oral and/or nasal communication element is configured for establishing fluid communication between the nebuliser, in particular, the second connection, and the patient's nose and/or mouth.

The body of the nebuliser may form a single flow channel from the first connection to the second connection. Only one flow channel from the first connection to the second connection may be present. In this case, the body forms only one flow channel through which respiratory air flows from the first connection to the second connection during inhalation and consumed air flows from the second connection to the first connection during exhalation.

The connection to the assisted breathing device, such as a continuous positive airway pressure (CPAP) device, may be effected by way of both an air supply line of the assisted breathing device for supplying respiratory air and an air exhaust line of the assisted breathing device for expelling consumed air. In this case, the first connection may comprise or consist of a Y-piece for connection to the assisted breathing device. However, alternatively, the first

connection of the body of the nebuliser may be configured to be connected only to the air supply line. Thus, a possible Y- piece may be arranged only downstream of the second

connection . The nebuliser of the nebuliser system of the present

invention further comprises a nebulising device for

nebulising a liquid. The liquid may be a liquid composition, such as an aqueous solution or an aqueous suspension, which preferably contains at least one active ingredient. The term "nebulising device" refers to any aerosol generator or producer by means of which the liquid can be transformed into an aerosol form.

In the nebuliser system of the invention, the nebulising device is arranged or disposed in the flow channel between the first connection and the second connection.

The nebuliser is configured for being adapted or connected to an oral and/or nasal communication element, such as the nasal prongs, a nose mask, a face mask or a mouthpiece. The oral and/or nasal communication element is configured for

establishing fluid communication between the nebuliser and a patient's nose and/or mouth.

Hence, an aerosol generated by the nebulising device can be efficiently and reliably transported to the oral and/or nasal communication element, such as the nasal prongs, a nose mask, a face mask or a mouthpiece, via the flow channel and the second connection. In this way, aerosol losses in the

nebuliser are reduced, allowing for the generated aerosol to be administered to the patient with a high degree of

precision. Thus, an efficient aerosol treatment can be achieved .

Therefore, the invention provides a nebuliser system enabling efficient aerosol treatment with enhanced aerosol dosage precision in an assisted breathing device, such as a

continuous positive airway pressure (CPAP) device.

In order to regulate the respiratory air, assisted breathing devices, such as continuous positive airway pressure (CPAP) devices, commonly produce a continuous basic flow, i.e., a so-called "bias flow". Outside of an inhalation cycle, wherein respiratory air is transported to the patient via the air supply line, this bias flow, which may be of the order of up to 30 1/min, normally flows directly into the air exhaust line from the air supply line. To achieve this without the bias flow passing the nebulising device and nebulised liquid thus permanently flowing into the air exhaust line, the first connection of the body of the nebuliser preferably may be configured to connect with an air supply line coming from the assisted breathing device and an air exhaust line leading to the assisted breathing device in such a manner that a side- flow channel, i.e., a bypass, from the air supply line to the air exhaust line is formed on the side of the nebulising device that is opposite the second connection. In this way, the aerosol dosage efficiency and precision can be further enhanced .

The air supply line and the air exhaust line of the assisted breathing device can thus be formed by a common element, such as a tube, that is divided into two sections. This division may be formed either by a partition in the element, e.g., the tube, or for example by a coaxial tube, i.e., two tubes arranged one inside the other. The common tube is to be connected to the first connection of the nebuliser. The first connection and the common tube are thereby configured in such a manner that a bypass is formed between the nebulising device and the front face of the partition and/or of the inner tube of the coaxial tube, which is facing the

nebulising device. The bypass allows the bias flow to flow, outside of an inhalation cycle, directly into the air exhaust line from the air supply line without flushing any possibly nebulised liquid into the air exhaust line. Hence, the efficiency of the nebuliser system can be further improved.

Alternatively, the air supply line and the air exhaust line of the assisted breathing device may each be formed by a separate tube. In this configuration, it is preferred for the first connection to have a first connecting piece for

connection to the air supply line and a second connecting piece for connection to the air exhaust line, each of which may be formed by a tube. The bypass is then formed in the body itself between the first connecting piece and the second connecting piece and, outside of an inhalation cycle, allows a flow from the air supply line into the air exhaust line. This arrangement further leads to a tilt-stable unit of the nebuliser being formed by the two connecting pieces and the opposite second connection.

The nebuliser system may be configured so that the mean lung deposition of an inhaled surfactant is at least 10%,

preferably at least 12%, more preferably at least 14%, even more preferably at least 15% and yet even more preferably at least 20% of the total administered dose of the surfactant.

The nebulising device may be configured to generate an aerosol, e.g., a liquid aerosol, with a particle size of less than 10 ym, preferably less than 5 ym, more preferably between 1 ym and 5 ym, and even more preferably between 2 ym and 4 ym.

The nebulising device may comprise a vibratable membrane and a vibrator. The vibrator may be configured to vibrate the vibratable membrane so as to nebulise the liquid.

For example, the nebulising device may comprise or be a vibrating membrane aerosol generator. The nebulising device may comprise or be an electronic aerosol generator, e.g., a piezoelectrically driven aerosol generator, i.e., an aerosol generator driven by a piezoelectric element. In this case, the vibrator of the nebulising device may comprise or consist of a piezoelectric element which is arranged for vibrating or oscillating the vibratable membrane. The vibratable membrane is provided with a plurality of openings, in particular, micro openings, i.e., openings with diameters in the micrometer range, for nebulising the liquid. Preferably, the vibratable membrane is arranged substantially perpendicular to the direction of flow from the first

connection to the second connection so as to achieve

nebulisation in the direction of flow or parallel to the direction of flow. The term "substantially" is to be

understood in this respect such that the membrane may also be arranged in the flow channel at a slight angle deviating by up to 45° from the perpendicular.

As regards the functionality of such a nebulising device, reference is made to DE 101 22 065 A1 and US 9,168,556 B2 for further details.

The openings of the membrane are preferably laser-drilled.

The laser-drilling process may include at least two laser drilling steps and, preferably, three laser drilling steps. The membrane may have more than 1.500 openings to generate the aerosol, and preferably around 3.000 openings.

During the production of such a vibrating membrane, the membrane must be connected to the vibrator, actuator or oscillator that causes the membrane to vibrate (oscillate) , in particular, a piezo-electric vibrator, actuator or

oscillator. This connection may be realised by attaching the membrane to a carrier or substrate, e.g., by gluing the membrane to the carrier or substrate using an adhesive.

The membrane and/or the carrier or substrate may be formed from stainless steel or another metallic material

which is suitable and approved for medical use. The wall thickness of the membrane is thereby preferably less than 200 ym, more preferably between 25 ym and 200 ym and even more preferably between 50 ym and 120 ym. The wall thickness of the carrier is preferably less than 500 ym, more preferably between 50 ym and 500 ym and even more preferably between 100 ym and 400 ym.

Furthermore, as mentioned above, a vibrator, actuator or oscillator may be provided to cause at least the membrane for nebulising the fluid to oscillate, whereby the vibrator, actuator or oscillator may form the carrier or may be

connected, for example adhered, to the carrier. The vibrator, actuator or oscillator may be arranged on the same side as the membrane or on an opposite second side of the carrier. Furthermore, the vibrator, actuator or oscillator is

preferably a piezoceramic vibrator, actuator or oscillator, in particular, a piezo vibrator, a piezo actuator or a piezo oscillator. The wall thickness of the vibrator, actuator or oscillator is thereby of a comparable size and is preferably less than 500 ym, more preferably between 25 ym and 500 ym and even more preferably between 100 ym and 400 ym.

The carrier or substrate may be configured so as to have a substantially circular shape. However, other shapes of the carrier or substrate, such as an oval shape, are also

possible .

The vibrator, actuator or oscillator may be configured so as to have a substantially annular shape, i.e., a ring shape with an opening in the centre. However, other shapes of the vibrator, actuator or oscillator, such as an oval shape with an opening in the centre, are also possible. The membrane may be arranged so as to be disposed at least partly within the opening of the vibrator, actuator or oscillator.

In some embodiments, the nebulising device may comprise the carrier or substrate, the membrane, a housing, and the vibrator, actuator or oscillator. For example, the housing may be made of a plastic material. The carrier or substrate may be at least partly received in and held by the housing. The membrane and the vibrator, actuator or oscillator may be provided on the carrier or substrate.

The housing may have an opening, in particular, a central opening. In particular, the housing may be configured so as to have a substantially annular shape, i.e., a ring shape with an opening in the centre. However, other shapes of the housing, such as an oval shape with an opening in the centre, are also possible. The membrane may be exposed to the outside through the opening of the housing.

A wiring for supplying power to the vibrator, actuator or oscillator, in particular, a piezo vibrator, a piezo actuator or a piezo oscillator, may be provided on the carrier or substrate .

In addition to the aforementioned membrane nebuliser, the present invention also provides a nebuliser system having such a membrane nebuliser or vibrating membrane.

The membrane is preferably configured so as to have a

circular shape. However, other shapes of the membrane, such as an oval shape, are also possible.

By using a nebulising device having such a vibratable

membrane, a fluid flow out of the flow channel and out of the system can be reliably prevented, even when a liquid

container of the nebuliser system is opened, for example, a lid of the liquid container is unscrewed for filling. Thus, it can be ensured in a simple and reliable manner that a loss in pressure via the nebulising device is avoided. In this way, a nebuliser system is provided which efficiently allows filling thereof with liquid during breathing assistance, such as a continuous positive airway pressure (CPAP) application, e.g., by filling the liquid into a liquid container, without a loss of pressure in the system. The flow channel may have a dead volume, which may be defined by the volume between, e.g., a Y-piece bifurcation and the second connection or outlet channel to the patient. The dead volume may be 30 ml or less, preferably 15 ml or less, more preferably 10 ml or less. In this way, the aerosol dosage efficiency and precision can be further enhanced, in

particular, for the case of treating children, especially neonates .

The nebulising device may be arranged in the flow channel such that an air flow, generated by the assisted breathing device and flowing through the flow channel from the first connection towards the second connection, i.e., a respiratory air flow, flows around the nebulising device.

By employing such an arrangement of the nebulising device, it can be achieved that liquid droplets generated by the

nebulising device are surrounded by the respiratory air flow, e.g., in a sheath-like manner. In this way, the deposition of liquid droplets in the nebulising device, e.g., on inner walls thereof, is suppressed, while ensuring efficient mixing of the liquid droplets and the respiratory air with each other, thus enhancing aerosol generation. Hence, the

occurrence of aerosol losses in the nebulising device can be prevented in a particularly efficient and reliable manner.

A flow-around portion of the flow channel, through which the respiratory air flow can pass, may be configured in the radial direction between the nebulising device, e.g., a vibratable membrane thereof, and the body in such a manner that a cross-sectional area of the flow-around portion is substantially equal to or larger than the smallest cross- sectional area of a line of the assisted breathing device that leads to the patient. The smallest cross-sectional area of this line for adults is commonly of the order of

approximately 400 mm ² . For small children, such as neonates, the smallest cross-sectional area of this line is commonly in the range of approximately 80 to 180 mm ² .

By choosing a flow-around portion with such a cross-sectional area, an increase in flow resistance due to the integration of the nebuliser in the air supply and patient line can be minimised, thus reliably ensuring efficient operation of the assisted breathing device.

The nebuliser or nebuliser system may further comprise a holding member. The holding member may hold the nebulising device in position in the flow channel. The holding member may comprise a plurality of through holes. The through holes may allow an air flow, generated by the assisted breathing device and flowing through the flow channel from the first connection towards the second connection, i.e., a respiratory air flow, to flow therethrough.

By adopting such a holding member configuration of the nebuliser or nebuliser system, it can be particularly

reliably ensured that the respiratory air flow can flow around the nebulising device.

The through holes may be configured to allow the respiratory air to flow substantially unimpeded around the nebulising device .

The through holes may be configured to cause a respiratory air flow to be guided in a direction parallel to the aerosol plume emerging from the nebulising device by passing through the through holes, like a sheet air, which is favourable for an efficient transport of liquid droplets generated by the nebulising device. In particular, in this way, it can be ensured that the deposition of the aerosol on the inner surface via this transport is minimised. The holding member may comprise a plurality of support elements, e.g., in the form of spokes or the like. Each support element may extend in a radial direction of the flow channel. The support elements may hold the nebulising device in position in the flow channel.

This configuration of the holding member allows for a

particularly simple and efficient arrangement of the

nebulising device in the flow channel. For example, the through holes may be provided between and/or within the support elements.

The flow channel may comprise a tapered portion arranged downstream of the nebulising device, wherein, in the tapered portion, the diameter of the flow channel decreases in the direction from the first connection or the vibrating membrane towards the second connection. In this way, the efficiency of aerosol transport towards the oral and/or nasal communication element, such as the nasal prongs, a nose mask, a face mask or a mouthpiece, can be further improved.

The nebulising device may be configured such that the liquid is nebulised substantially parallel to the flow direction from the first connection to the second connection. Thus, the nebulising device may be configured such that the liquid is nebulised in a direction which is substantially parallel to the flow direction from the first connection to the second connection. Preferably, the nebulising device is configured such that the liquid is nebulised substantially in the flow direction from the first connection to the second connection.

In this case, respiratory air can pass around the nebulising device in the inhalation cycle and the liquid to be nebulised is nebulised by the nebulising device parallel to, and preferably in, the direction of the respiratory air flow. Thus, an aerosol flow is generated parallel to, and

preferably in, the direction of the respiratory air flow. Hence, the impaction and thus deposition of aerosol on surfaces in the flow channel is suppressed, thus minimising the occurrence of aerosol losses, so that the aerosol can be supplied to the patient with a particularly high degree of dosage efficiency and precision.

Such a configuration of the nebulising device may be

achieved, for example, by providing a nebulising device which comprises a vibratable membrane for nebulising the liquid and by arranging the vibratable membrane substantially

perpendicular to the flow direction from the first connection to the second connection.

The nebulising device may be configured such that the liquid is nebulised within an angle of +/-45° to, and preferably in, the flow direction from the first connection to the second connection. In this way, a high degree of freedom for

arranging the nebulising device within the flow channel can be achieved, while reducing the occurrence of aerosol losses in the nebuliser.

The oral and/or nasal communication element may be a nasal communication element, such as the nasal prongs, configured for establishing fluid communication between the nebuliser and a patient's nose.

As has been indicated above, the nebuliser system may further comprise a liquid container for receiving the liquid to be nebulised by the nebulising device. The liquid container may be in fluid communication with the body of the nebuliser. The liquid container may be connected to the body. In particular, the liquid container may be connected to the body in such a manner that it can be coupled and uncoupled. The liquid container may form part of the nebuliser.

The liquid container may be integrally connected to the body of the nebuliser. In this way, in particular in combination with the provision of two connecting pieces and the second connection, which result in a tilt-stable unit, the flow of the liquid out of the liquid container can be further

improved .

The liquid container may be configured for directly

accommodating the liquid to be nebulised.

The liquid container may have a fluid communication interface and be configured for receiving, for example, a liquid- containing ampoule that comes into fluid communication with the liquid container via the fluid communication interface. The fluid communication interface may be formed by or

comprise an opening device, such as a hollow spike or the like, and be configured to receive a liquid-containing ampoule to be opened by the opening device, e.g., similar to that disclosed, for example, in WO 2007/020073 for a known nebuliser/aerosol generator, to which reference is made for further details in this respect.

The nebuliser, in particular, the body of the nebuliser, may comprise a nebulisation chamber into which the liquid is to be nebulised. If the nebulising device comprises a vibratable membrane, the membrane may be arranged between the liquid container and the nebulisation chamber.

Preferably, the nebulisation chamber is arranged between the vibratable membrane and the second connection. In this way, the occurrence of aerosol losses in the nebuliser can be particularly efficiently suppressed.

It is preferable for the liquid container to be configured to supply a constant dosage of liquid to the nebulising device, e.g., to a vibratable membrane thereof, up to a tilting angle of 45° in every direction from the vertical. By adopting such a configuration, a particularly reliable and uniform

nebulisation or aerosol generation can be achieved. For this purpose, the unit consisting of the body of the nebuliser and the liquid container may be configured in a tilt-stable manner, e.g., by the two connecting pieces and the opposite second connection. To further enhance the above-identified beneficial effect, the liquid container may have a tapering in the direction of the membrane, which opens out into a liquid chamber that is closed by the membrane, with the tapering extending at least obliquely from a cylindrical portion of the liquid container to the liquid chamber.

It is particularly preferred for a partial section of the tapering that is facing away from the membrane to extend with an angle range of between 10° and 40° to the vertical and, in the case of a perpendicularly arranged membrane, preferably also to the membrane, i.e., a lower portion of the liquid container that is closed in cross-section is configured, for example, in the shape of a cone and the central axis of the cone has an angle range of between 10° and 30° to the

vertical and, in the case of a perpendicularly arranged membrane, preferably also to the membrane.

The nebuliser system may further comprise a control for controlling the nebuliser, in particular, the nebulising device. The control may be configured for controlling the nebuliser, in particular, the nebulising device, and for controlling the assisted breathing device. In this way, the efficiency of the system can be further enhanced. In

particular, the control may be configured or set so that nebulisation of the liquid and thus aerosol generation is only triggered during an inhalation cycle, i.e., so that nebulisation by the nebulising device only occurs when the patient inhales.

The nebuliser system may further comprise an assisted

breathing device, e.g., a positive pressure assisted

breathing device, such as a continuous positive airway pressure (CPAP) device. The nebuliser system may further comprise an adapter. The adapter may be configured for adapting the nebuliser to the oral and/or nasal communication element, such as the nasal prongs, a nose mask, a face mask or a mouthpiece.

By employing such an adapter, the nebuliser can be adapted or connected to the oral and/or nasal communication element, such as the nasal prongs, in a particularly efficient and reliable manner. In particular, by means of the adapter, the oral and/or nasal communication element can be connected directly to the nebuliser, e.g., to the second connection thereof. Thus, no intermediate elements, such as tubes, pipes or lines, are necessary for this connection. Hence, the occurrence of aerosol losses can be further suppressed.

The adapter may be integrally formed with the nebuliser, in particular, with the body of the nebuliser. In this case, a particularly reliable and steady fluid flow through the adapter to the oral and/or nasal communication element can be ensured .

Alternatively, the adapter may be attached, e.g., detachably or releasably attached, to the nebuliser, in particular, to the body of the nebuliser. In this case, the adapter can be easily replaced.

The adapter may have an interface port arranged at the second connection for connecting the oral and/or nasal communication element, such as the nasal prongs, a nose mask, a face mask or a mouthpiece, to the nebuliser. The interface port may be substantially rectangular, i.e., have a substantially

rectangular shape, in a view along the direction of fluid flow through the adapter. In particular, the interface port may be in the form of a recess or a cavity, e.g., a

substantially rectangular recess or cavity.

Providing such an interface port offers a particularly simple and reliable connection between nebuliser and oral and/or nasal communication element, such as nasal prongs, a nose mask, a face mask or a mouthpiece.

The adapter may have an adapter flow channel for allowing fluid flow from the second connection of the nebuliser to the oral and/or nasal communication element, such as the nasal prongs, a nose mask, a face mask or a mouthpiece.

At least a portion of the adapter flow channel may have an elongate, in particular, substantially oval or elliptic, cross-section in a plane perpendicular to the axial direction of the adapter flow channel, i.e., to the direction of fluid flow through the adapter flow channel.

The adapter flow channel may be arranged adjacent to and/or at least partly within the interface port.

The at least a portion of the adapter flow channel having an elongate cross-section may be arranged adjacent to and/or at least partly within the interface port.

The cross-section of the adapter flow channel may be constant or vary along the axial direction of the adapter flow

channel. The area of the cross-section of the adapter flow channel may be constant or vary along the axial direction of the adapter flow channel. The area of the cross-section of the adapter flow channel may decrease in the direction from the second connection of the nebuliser to the oral and/or nasal communication element. This decrease in cross-sectional area may be an at least partly continuous decrease or an abrupt, e.g., step-like, decrease.

By configuring the adapter flow channel so that the cross- sectional area thereof decreases in the direction from the second connection of the nebuliser to the oral and/or nasal communication element, the efficiency of aerosol transport towards the oral and/or nasal communication element, such as the nasal prongs, can be further improved.

The shape of the cross-section of the adapter flow channel may vary along the axial direction of the adapter flow channel. In particular, the shape of the cross-section of the adapter flow channel may change from a substantially circular shape to an elongate, in particular, substantially oval or elliptic, shape in the direction from the second connection of the nebuliser to the oral and/or nasal communication element .

The adapter may be provided with a temperature sensor. The temperature sensor may be configured to determine, detect, sense or measure the temperature of a fluid flowing through the adapter. The temperature sensor may be configured to determine, detect, sense or measure the temperature of a fluid flowing through the adapter flow channel.

The temperature sensor may be at least partly arranged within the adapter flow channel. The temperature sensor may extend into the adapter flow channel. For example, the temperature sensor may extend into the adapter flow channel through an opening provided in a wall, e.g., an outer wall, of the adapter .

The temperature sensor allows for the temperature of a fluid flowing through the adapter, in particular, through the adapter flow channel, to be reliably monitored. Thus, it can be ensured that the fluid supplied to a patient has the desired temperature.

For example, the temperature of the fluid flowing through the adapter can be monitored by means of the temperature sensor and be controlled so as to be in the range of 35°C to 46°C, preferably 36°C to 45°C, more preferably 36°C to 43°C, even more preferably 36°C to 42°C, yet even more preferably 37°C to 39°C and still even more preferably around 37°C. The assisted breathing device and/or the nebuliser may be

configured so that fluid supply to the patient is stopped if the temperature determined by the temperature sensor exceeds a threshold value. The nebuliser may be configured so that the nebulising device is switched off if the temperature determined by the temperature sensor exceeds a threshold value. In the switched off state of the nebulising device, no liquid is being nebulised. The threshold value may be, for example, 46°C, 45°C, 44°C, 43°C, 42°C, 41°C, 40°C, 39°C or 38 °C .

The temperature sensor allows for the temperature of the fluid flowing through the adapter to be reliably monitored. Hence, the temperature of the fluid exiting the nebuliser system, in particular, through the oral and/or nasal

communication element, can be accurately determined. For example, the difference between the temperature of the fluid at the position of the temperature sensor and the temperature of the fluid at the position where the fluid exits the nebuliser system, in particular, through the oral and/or nasal communication element, can be established or

determined, e.g., by performing temperature measurements at these two positions. When this temperature difference is known, the temperature of the fluid exiting the nebuliser system can be accurately determined on the basis of the temperature detected by the temperature sensor. For example, this temperature difference may be in the range of 1°C to 5°C, 2°C to 4°C or 2°C to 3°C. The threshold value of the temperature determined by the temperature sensor may be chosen so that the temperature of the fluid exiting the nebuliser system does not exceed a desired limit, such as 43 °C, 42 °C, 41 °C, 40°C, 39°C or 38°C.

The nebuliser may be configured so that the nebulising device is switched off if no more liquid to be nebulised is present in the nebulising device. In this way, an undesired increase of the temperature of the fluid flowing through the adapter can be minimised or even eliminated. Such a configuration of the nebuliser may be used in combination with the temperature sensor, allowing for the temperature of the fluid flowing through the adapter to be kept within a desired range in a particularly reliable and efficient manner.

The temperature sensor may be arranged in a housing. The housing may be, e.g., made of a metal or a polymer material. For example, the housing may be made of stainless steel, a plastic material and/or a flexible material. As a material of the housing, for example, polypropylenes (PP) , also known as polypropenes (a thermoplastic polymer) , polyurethane

thermoplastic elastomers (PTE), silicones and/or the like may be used.

The temperature sensor may comprise or consist of a Negative Temperature Coefficient (NTC) sensor, in particular, a

Negative Temperature Coefficient (NTC) thermistor. Such a sensor exhibits a decrease in electrical resistance when subjected to a temperature increase. The temperature sensor may comprise or consist of a Positive Temperature Coefficient (PTC) sensor, in particular, a Positive Temperature

Coefficient (PTC) thermistor. Such a sensor exhibits an increase in electrical resistance when subjected to a

temperature increase.

Particularly preferably, the temperature sensor comprises or consists of a Negative Temperature Coefficient (NTC) sensor, in particular, a Negative Temperature Coefficient (NTC) thermistor .

The liquid to be nebulised by the nebulising device may be a pharmaceutical formulation, e.g., in form of an aqueous solution or an aqueous suspension. The liquid may be a pharmaceutical formulation comprising an active compound, enabling generation of a pharmaceutical aerosol by the nebulising device for the delivery of the active compound to the patient. An active compound is a natural, biotechnology-derived or synthetic compound or mixture of compounds useful for the diagnosis, prevention, management or treatment of a disease, condition or symptom of a human, in particular, a neonate, or an animal. Other terms which may be used as synonyms of active compounds include, for example, active ingredient, active pharmaceutical

ingredient, drug substance, diagnostic material, drug, medicament and the like. The fluid could be of a liquid, solution, suspension, colloidal mixture or liposomal

formulation form and can be prepared, mixed or opened before or during the application.

The active compound comprised in the fluid to be nebulised or aerosolised by the nebuliser or a so-called aerosol generator may be a drug substance or a medicament which is useful for the prevention, management, diagnosis or treatment of any disease, symptom or condition affecting the body cavities, the abdomen, the eyes, the intestine, the stomach, the nose, the nasal cavities, the sinuses, the osteomeatal complex, the mouth, the trachea, the lungs, the bronchi, the bronchioles, the alveoli and/or the respiratory tract.

In particular, an aerosol comprising an active compound which is useful for the prevention, management, diagnosis or treatment of any disease, symptom or condition affecting pulmonary development such as surfactant compounds, which may be derived from: surface active agent (surfactant) , which may be synthetic surfactant , recombinant surfactant proteins, pulmonary surfactant, exogenous pulmonary surfactant, natural pulmonary surfactants, modified natural pulmonary

surfactants, artificial pulmonary surfactants and

reconstituted pulmonary surfactants. Among the active compounds which may be useful for serving one of the purposes named previously and that may be used together with the present invention are, for example, substances selected from the group consisting of anti

inflammatory compounds, anti-infective agents, antiseptics, prostaglandins, endothelin receptor agonists,

phosphodiesterase inhibitors, beta-2-sympathicomimetics, decongestants, vasoconstrictors, anticholinergics,

immunoglobulins, immunomodulators , mucolytics, anti-allergic drugs, antihistaminics , mast-cell stabilising agents, tumor growth inhibitory agents, wound healing agents, local

anaesthetics, antioxidants, oligonucleotides, peptides, proteins, vaccines, vitamins, plant extracts, cholinesterase inhibitors, vasoactive intestinal peptide, serotonin receptor antagonists, and heparins, glucocorticoids, anti-allergic drugs, antioxidants, vitamins, leucotriene antagonists, anti- infective agents, antibiotics, antifungals, antivirals, mucolytics, decongestants, antiseptics, cytostatics,

immunomodulators, vaccines, wound healing agents, local anaesthetics, oligonucleotides, xanthin derived agents, peptides, proteins and plant extracts. Such compound may be used in the form of a suspension, a solution, a colloidal formulation (i.e., liposomal), etc.

Examples of potentially useful anti-inflammatory compounds are glucocorticoids and non-steroidal anti-inflammatory agents such as betamethasone, beclomethasone, budesonide, ciclesonide, dexamethasone, desoxymethasone, fluoconolone acetonide, fluocinonide, flunisolide, fluticasone,

icomethasone, rofleponide, triamcinolone acetonide,

fluocortin butyl, hydrocortisone, hydroxycortisone-17- butyrate, prednicarbate, 6-methylprednisolone aceponate, mometasone furoate, pirfenidone, dehydroepiandrosterone- sulfate (DHEAS) , elastane, prostaglandin, leukotriene, bradykinin antagonists, non-steroidal anti-inflammatory drugs (NSAIDs) , such as ibuprofen and acetylsalicylic acid (ASA) , including any pharmaceutically acceptable salts, esters, isomers, stereoisomers, diastereomers , epimers, solvates or other hydrates, prodrugs, derivatives, or any other chemical or physical forms of active compounds comprising the

respective active moieties.

Examples of anti-infective agents, whose class or therapeutic category is herein understood as comprising compounds which are effective against bacterial, fungal, and viral

infections, i.e. encompassing the classes of antimicrobials, antibiotics, antifungals, antiseptics, and antivirals, are penicillins, including benzylpenicillins (penicillin-G- sodium, clemizone penicillin, benzathine penicillin G) , phenoxypenicillins (penicillin V, propicillin) ,

aminobenzylpenicillins (ampicillin, amoxycillin,

bacampicillin) , acylaminopenicillins (azlocillin,

mezlocillin, piperacillin, apalcillin) , carboxypenicillins (carbenicillin, ticarcillin, temocillin) , isoxazolyl

penicillins (oxacillin, cloxacillin, dicloxacillin,

flucloxacillin) , and amiidine penicillins (mecillinam) ; cephalosporins, including cefazolins (cefazolin,

cefazedone) ; cefuroximes (cefuroxim, cefamandole, cefotiam) , cefoxitins (cefoxitin, cefotetan, latamoxef, flomoxef) , cefotaximes (cefotaxime, ceftriaxone, ceftizoxime,

cefmenoxime) , ceftazidimes (ceftazidime, cefpirome,

cefepime) , cefalexins (cefalexin, cefaclor, cefadroxil, cefradine, loracarbef, cefprozil) , and cefiximes (cefixime, cefpodoxim proxetile, cefuroxime axetil, cefetamet pivoxil, cefotiam hexetil) , loracarbef, cefepim, clavulanic acid / amoxicillin, Ceftobiprole ; synergists, including beta-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam; carbapenems, including imipenem, cilastin, meropenem, doripenem, tebipenem, ertapenem, ritipenam, and biapenem; monobactams, including aztreonam; aminoglycosides, such as apramycin, gentamicin,

amikacin, isepamicin, arbekacin, tobramycin, netilmicin, spectinomycin, streptomycin, capreomycin, neomycin,

paromoycin, and kanamycin; macrolides, including erythromycin, clarythromycin, roxithromycin, azithromycin, dithromycin, josamycin,

spiramycin and telithromycin; gyrase inhibitors or fluroquinolones , including

ciprofloxacin, gatifloxacin, norfloxacin, ofloxacin,

levofloxacin, perfloxacin, lomefloxacin, fleroxacin,

garenoxacin, clinafloxacin, sitafloxacin, prulifloxacin, olamufloxacin, caderofloxacin, gemifloxacin, balofloxacin, trovafloxacin, and moxifloxacin; tetracyclins , including tetracyclin, oxytetracyclin, rolitetracyclin, minocyclin, doxycycline, tigecycline and aminocycline ; glycopeptides , inlcuding vancomycin, teicoplanin, ristocetin, avoparcin, oritavancin, ramoplanin, and peptide

4; polypeptides, including plectasin, dalbavancin,

daptomycin, oritavancin, ramoplanin, dalbavancin, telavancin, bacitracin, tyrothricin, neomycin, kanamycin, mupirocin, paromomycin, polymyxin B and colistin; sulfonamides, including sulfadiazine, sulfamethoxazole, sulfalene, co-trimoxazole, co-trimetrol , co-trimoxazine, and co-tetraxazine ; azoles, including clotrimazole, oxiconazole, miconazole, ketoconazole, itraconazole, fluconazole, metronidazole, tinidazole, bifonazol, ravuconazol, posaconazol, voriconazole, and ornidazole and other antifungals including flucytosin, griseofulvin, tolnaftal, naftifin, terbinafin, amorolfin, ciclopiroxolamin, echinocandins , such as

micafungin, caspofungin, anidulafungin; nitrofurans, including nitrofurantoin and

nitrofuranzone; polyenes, including amphotericin B, natamycin, nystatin, flucytosine ; other antibiotics, including tithromycin, lincomycin, clindamycin, oxazolindiones ( linzezolids ) , ranbezolid, streptogramine A+B, pristinamycin A+B, Virginiamycin A+B, dalfopristin /quinupristin (Synercid) , chloramphenicol, ethambutol, pyrazinamid, terizidon, dapson, prothionamid, fosfomycin, fucidinic acid, rifampicin, isoniazid,

cycloserine, terizidone, ansamycin, lysostaphin, iclaprim, mirocin B17, clerocidin, filgrastim, formycin, pentamidine, and Fabl-Inhibitors ; antivirals, including aciclovir, ganciclovir, birivudin, valaciclovir, zidovudine, didanosin, thiacytidin, stavudin, lamivudin, zalcitabin, ribavirin, nevirapirin, delaviridin, trifluridin, ritonavir, saquinavir, indinavir, foscarnet, amantadin, podophyllotoxin, vidarabine, tromantadine, and proteinase inhibitors, siRNA based drugs; antiseptics, including acridine derivatives, iodine- povidone, benzoates, rivanol, chlorhexidine, quarternary ammonium compounds, cetrimides, biphenylol, clorofene, and octenidine ; plant extracts or ingredients, such as plant extracts from chamomile, hamamelis, echinacea, calendula, thymian, papain, pelargonium, pine trees, essential oils, myrtol, pinen, limonen, cineole, thymol, mentol, camphor, tannin, alpha-hederin, bisabolol, lycopodin, vitapherole; wound healing compounds including pirfenidone,

dexpantenol, allantoin, vitamins, hyaluronic acid, alpha- antitrypsin, anorganic and organic zinc salts/compounds, salts of bismuth and selen; antifibrotic compounds, for example, pirfenidone; interferones (alpha, beta, gamma) , tumor necrosis factors, cytokines, interleukines ; immunomodulators including methotrexat, azathioprine, cyclosporine, tacrolimus, sirolimus, rapamycin, mofetil; mofetil-mycophenolate . antibody (Ab) , also known as an immunoglobulin (Ig), including immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM); as well as fragments of antibodies, also known as Fab (fragment, antigen-binding) region, complementarity determining regions (CDRs) , Fc (Fragment, crystallizable) region, or Fc receptors; cytostatics and metastasis inhibitors; alkylants, such as nimustine, melphanlane, carmustine, lomustine, cyclophosphosphamide, ifosfamide, trofosfamide, chlorambucil, busulfane, treosulfane, prednimustine, thiotepa; antimetabolites, e.g. cytarabine, fluorouracil ,

methotrexate, mercaptopurine, tioguanine; alkaloids, such as vinblastine, vincristine, vindesine; antibiotics, such as alcarubicine, bleomycine,

dactinomycine, daunorubicine, doxorubicine, epirubicine, idarubicine, mitomycine, plicamycine; complexes of transition group elements (e.g. Ti, Zr, V, Nb, Ta, Mo, W, Pt) such as carboplatinum, cis-platinum and metallocene compounds such as titanocendichloride ; amsacrine, dacarbazine, estramustine, etoposide, beraprost, hydroxycarbamide, mitoxanthrone, procarbazine, temiposide ; paclitaxel, gefitinib, vandetanib, erlotinib, poly-ADP- ribose-polymerase (PRAP) enzyme inhibitors, banoxantrone, gemcitabine, pemetrexed, bevacizumab, ranibizumab.

Examples of potentially useful mucolytics are DNase, P2Y2- agonists (denufosol) , drugs affecting chloride and sodium permeation, such as N- (3, 5-Diamino-6-chloropyrazine-2- carbony) -N' -{4- [4- (2, 3-dihydroxypropoxy) - phenyl ] butyl } guanidine methanesulfonate (PARION 552-02), heparinoids, guaifenesin, acetylcysteine, carbocysteine, ambroxol, bromhexine, tyloxapol, lecithins, myrtol,

surfactant, synthetic surfactant and recombinant surfactant proteins .

Examples of potentially useful vasoconstrictors and

decongestants which may be useful to reduce the swelling of the mucosa are phenylephrine, naphazoline, tramazoline, tetryzoline, oxymetazoline, fenoxazoline, xylometazoline, epinephrine, isoprenaline, hexoprenaline, and ephedrine. Examples of potentially useful local anaesthetic agents include benzocaine, tetracaine, procaine, lidocaine and bupivacaine .

Examples of potentially useful antiallergic agents include the afore-mentioned glucocorticoids, cromolyn sodium, nedocromil, cetrizin, loratidin, montelukast, roflumilast, ziluton, omalizumab, heparinoids and other antihistamins , including azelastine, cetirizin, desloratadin, ebastin, fexofenadin, levocetirizin, loratadin.

Examples of potentially useful anticholinergic agents include ipratropium bromide, tiotropium bromide, oxitropium bromide, glycopyrrolate .

Examples of potentially useful beta-2-sympathicomimetic agents include salbutamol, fenoterol, formoterol,

indacaterol, isoproterenol, metaproterenol , salmeterol, terbutaline, clenbuterol, isoetarine, pirbuterol, procaterol, ritodrine .

Examples of xanthine derived agents include theophylline, theobromine, caffeine.

An Example for a PDE5-Inhibitor is sildenafil.

Antisense oligonucleotides are short synthetic strands of DNA (or analogs) that are complimentary or antisense to a target sequence (DNA, RNA) designed to halt a biological event, such as transcription, translation or splicing. The resulting inhibition of gene expression makes oligonucleotides

dependent on their composition useful for the treatment of many diseases and various compounds are currently clinically evaluated, such as ALN-RSV01 to treat the respiratory

syncytical virus by, AVE-7279 to treat asthma and allergies, TPI-ASM8 to treat allergic asthma, 1018-ISS to treat cancer. Examples of potentially useful peptides and proteins include antibodies against toxins produced by microorganisms,

antimicrobial peptides such as cecropins, defensins,

thionins, and cathelicidins .

The pharmaceutical formulation may comprise a pulmonary surfactant (derived from: surface active agent) . The pulmonary surfactant may be an exogenous pulmonary surfactant .

The pulmonary surfactant may belong to the class of "modified natural" pulmonary surfactants which are lipid extracts of minced mammalian lung or lung lavage. These preparations have variable amounts of SP-B and SP-C proteins and, depending on the method of extraction, may contain non-pulmonary

surfactant lipids, proteins or other components. Some of the modified natural pulmonary surfactants present on the market, like Survanta™, are spiked with synthetic components such as tripalmitin, dipalmitoylphosphatidylcholine and palmitic acid .

Current modified natural pulmonary surfactants include, but are not limited to, bovine lipid pulmonary surfactant

(BLES™, BLES Biochemicals, Inc. London, Ont) , calfactant (Infasurf™, Forest Pharmaceuticals, St. Louis, Mo.),

bovactant (Alveofact™, Thomae, Germany) , bovine pulmonary surfactant (Pulmonary surfactant TA™, Tokyo Tanabe, Japan) , and beractant (Survanta™, Abbott Laboratories, Inc., Abbott Park, Ill . ) .

The pulmonary surfactant may belong to the class of

"artificial" pulmonary surfactants which are simply mixtures of synthetic compounds, primarily phospholipids and other lipids that are formulated to mimic the lipid composition and behaviour of natural pulmonary surfactant. They are devoid of pulmonary surfactant proteins. Examples of artificial

surfactants include, but are not limited to, pumactant

(Alec™, Britannia Pharmaceuticals, UK) , and colfosceril palmitate (Exosurf™, GlaxoSmithKline, pic, Middlesex) .

The pulmonary surfactant may belong to the class of

"reconstituted" pulmonary surfactants which are artificial pulmonary surfactants to which have been added pulmonary surfactant proteins/peptides isolated from animals or proteins/peptides manufactured through recombinant technology such as those described in WO 95/32992, or synthetic

pulmonary surfactant protein analogues such as those

described in WO 89/06657, WO 92/22315 and WO 00/47623.

Examples of reconstituted surfactants include, but are not limited to, poractant alfa (Curosurf™ Chiesi Farmaceutici S.p.A.) and lucinactant (Surfaxin™, Windtree Therapeutics, Inc., Warrington, Pa.) and the product having the composition disclosed in WO 2010/139442.

The dose of the pulmonary surfactant may be comprised between 150 and 600 mg/kg body weight.

The dose of the pulmonary surfactant may be comprised between 200 and 600 mg/kg, preferably between 300 and 500 mg/kg, more preferably between 150 and 300 mg/kg, and even more

preferably between 400 and 600 mg/kg body weight.

The pharmaceutical formulation may be a natural, modified and/or synthetic pharmaceutical formulation.

The nebuliser system of the present invention may further comprise the liquid to be nebulised, e.g., the pharmaceutical formulation .

The patient to be treated by using the nebuliser system of the present invention may be a spontaneously breathing pre term neonate having a gestational age of 26 to 32 weeks suffering of RDS . As has been detailed above, the nebuliser system of the invention can be particularly advantageously used for the treatment of neonates.

The assisted breathing device, such as the continuous

positive airway pressure (CPAP) device, may be a positive pressure assisted breathing device, such as a PAP (Positive Airway Pressure) , a BiPAP (Bilevel Positive Airway Pressure) , a CPAP (Continuous Positive Airway Pressure) , a nCPAP (nasal CPAP) , a NIPPV (Non Invasive Positive Pressure Ventilation) , an artificial respiration machine, a respirator, a lung ventilator, an Invasive Ventilator (IV), a Non-Invasive

Ventilator (NIV) , or a mechanical ventilator.

There are many modes of mechanical ventilation, and their nomenclature has been revised over the decades as the

technology has continually developed. The same or similar modes, such as a positive pressure assisted mode, may be applicable in different assisted breathing devices, such as the devices mentioned above.

The nebuliser system of the present invention may further comprise the oral and/or nasal communication element, such as the nasal prongs, a nose mask, a face mask, a mouthpiece or an endotracheal tube, as well as a tracheostomy tube as a further communication element.

The oral and/or nasal communication element may comprise an interface member for connection to the interface port of the adapter. The interface member may be configured for being at least partly received within the interface port. The

interface member may have a substantially rectangular shape, i.e., a substantially rectangular shape in a view along the direction of fluid flow through the interface member.

The interface member may have one or more, e.g., two,

communication openings for communication with the adapter flow channel.

The oral and/or nasal communication element may comprise one or more, e.g., two, fluid guiding members for guiding a fluid, such as an aerosol, to the patient's nose and/or mouth. If the oral and/or nasal communication element

comprises an interface member, the one or more fluid guiding members are in fluid communication with the interface member. If the oral and/or nasal communication element comprises more than one, e.g., two, fluid guiding members, the fluid guiding members may be in fluid communication with the interface member through a single, i.e., common, channel or through a plurality of, for example, two, separate channels. In

particular, each fluid guiding member may be in fluid

communication with the interface member through a respective one of a plurality of separate channels.

If the oral and/or nasal communication element comprises a plurality of, e.g., two, fluid guiding members and the interface member has a plurality of, e.g., two, communication openings, each fluid guiding member may be in fluid

communication with a respective one of the communication openings .

In particular, the oral and/or nasal communication element may comprise two fluid guiding members and the interface member may have two communication openings, for establishing fluid communication between the nebuliser and respective nasal entrances of the patient.

The oral and/or nasal communication element may have a support member, such as a strap or the like, for holding the oral and/or nasal communication element in position on the patient's head. Alternatively or in addition, the adapter may have a support member, such as a strap or the like, for holding the oral and/or nasal communication element in position on the patient's head.

The oral and/or nasal communication element may be a nasal communication element, such as the nasal prongs, a nose mask, a face mask or a mouthpiece. The nasal communication element may have two openings, each opening being configured for establishing fluid communication between the nebuliser and a respective nasal entrance of the patient. The nasal communication element may have a support member, such as a strap or the like, for holding the nasal

communication element in position on the patient's head.

The adapter may comprise the support member, such as a strap or the like, or the adapter may be configured to be attached to the support member. The adapter may comprise a plurality of support members, such as a plurality of straps, bands, belts, tapes or the like, or the adapter may be configured to be attached to a plurality of support members.

The support member may be in the form of a loop or a lug. The support member may be configured to form a loop or a lug. For example, the support member may be a strap or the like which is in the form of a loop or a lug or which is configured to form a loop or a lug.

The support member, such as a strap or the like, may be configured to be attached, e.g., at one of its ends, to the patient, for example, to a cap or hood worn by the patient.

In particular, the support member may be configured to be attached to the patient at one of its ends and to the adapter at another one of its ends. For example, the support member may be provided with a Velcro fastener, an adhesive, e.g., a pressure sensitive adhesive, or a snap fastener, such as a push button, for attachment to the patient. In some

embodiments, the support member, such as a strap or the like, may be provided, at one end, with a slit through which another end of the support member can be inserted, thereby forming a loop or a lug.

The adapter may have one or more, preferably two, openings through which one or more, preferably two, support members can be respectively inserted. For example, two such openings may be arranged on opposite sides of the interface port. Two such openings may be arranged on opposite sides and/or at opposite ends of the adapter. Each of the one or more, preferably two, openings may be surrounded by a wall or walls of the adapter. For each of the one or more, preferably two, openings, the wall or walls of the adapter may be provided with a through-hole, such as a slit or a slot. The through-hole, such as a slit or a slot, may be provided in an outer wall or outer walls of the adapter. The through-hole, such as a slit or a slot, may be configured to allow insertion of the support member into the respective opening via the through-hole. The provision of such a through-hole allows for the adapter to be attached to an existing support member, e.g., a support member already attached to the patient, in a particularly simple and

efficient manner, while minimising any disturbance to the patient .

The invention further provides a holding system for holding a nebuliser or a nebuliser system. The holding system comprises a base, a holding arm extending from the base, and a holding element configured to hold the nebuliser or the nebuliser system. The holding arm has a first end and a second end opposite to the first end. The first end of the holding arm is attached to the base. The holding element is attached to the holding arm substantially at the second end of the holding arm. The holding element may be attached to the holding arm at the second end of the holding arm.

The holding system of the invention may be configured for holding the nebuliser system of the invention and/or for holding the nebuliser of the nebuliser system of the

invention .

The holding system allows for the nebuliser or nebuliser system to be stably held in its position, so that efficient aerosol transport from the nebuliser to a patient, in

particular, a child, especially a neonate, can be secured and reliably maintained. Hence, aerosol therapy can be performed with a high degree of efficiency and precision. The base enables secure and stable placement of the holding system, e.g., on a placement surface, such as a hospital bed or the like, or on the patient's body. Since the holding element is arranged in separation from the base, i.e., separated or spaced from the base through the holding arm, accessibility of the patient, e.g., for further treatment or tests, is not considerably impaired. This is particularly beneficial for the treatment of children, especially

neonates. For example, components of the nebuliser system, such as tubes, pipes, leads etc., may be held by and/or guided over the holding element, so that the patient remains readily accessible.

The first end of the holding arm may be detachably or

releasably attached to the base. In this case, the holding arm can be replaced in a simple manner. For example, a longer holding arm may be employed for treatment of an adult, while a shorter holding arm may be used for treatment of a child, in particular, a neonate. Hence, the holding system can be easily adapted to the requirements of the patient to be treated .

The holding element may be detachably or releasably attached to the holding arm substantially at the second end of the holding arm. In this case, the holding element can be

replaced in a simple manner. Thus, the holding system can be easily adapted to different types of nebulisers and/or nebuliser systems.

As has been detailed above, the holding system can hold the nebuliser system safely in position. Further the holding system may lift weight off the nose of the patient, such as a baby or a neonate, and may render additional rest-weight compatible with the assisted breathing device's tubing, as it may be acceptable. The holding system and/or a possible adapter for communication elements, such as nasal prongs, a nose mask, a face mask or a mouthpiece, may be configured to allow slight movement of the patient's head. The nebuliser system position may be adjustable in the x-axis, the y-axis, and/or the z- axis while the nebuliser system is rotatable in the aerosol generating axis or spray axis.

The nebuliser system position advantageously guarantees an easy fluid or liquid (re-) filling for example of the optional reservoir. This may include complete reservoir drainage and ergonomic connection of communication elements, such as nasal prongs, a nose mask, a face mask or a mouthpiece.

The holding system may be used in an incubator (e.g., disposed on a mattress) . The holding system may be configured so as not to obscure vision of or access to the patient

(e.g., a baby or a neonate) for the operator's procedures, such as a physician's procedures, a doctor's procedures, and nursing procedures in the health care system.

Due to its simple configuration, the holding system can be easily set up and used, for example, by nurses and

physicians .

The holding system can be used in the successive treatment of a plurality of patients, i.e., is re-usable.

Preferably, the base has a curved shape. In particularly preferred embodiments, the base has substantially a U-shape. Such a curved shape of the base enables particularly secure and stable placement of the holding system, e.g., on a placement surface. The curved shape allows for the base to be arranged at least partly around the head of a patient, such as a child, in particular, a neonate. Thus, a particularly high degree of accessibility of the patient can be achieved. Further, the position of the patient's head relative to the base can be fixed in a simple manner, e.g., by using a towel or the like. For example, the towel or the like can be placed on the base, e.g., between the patient's head and the base, or be at least partially wrapped around the base. Fixing the position of the patient's head in this manner is particularly beneficial in the treatment of children, especially neonates.

The holding arm may be flexible. In particular, the holding arm may be configured so that it can be, e.g., substantially freely, bent, inflected or deformed into a desired shape and subsequently maintains this shape, i.e., remains in this shape .

By configuring the holding arm in a flexible manner, the holding system can be easily and efficiently adapted to the specific requirements of the patient to be treated. Thus, an optimal arrangement of the nebuliser or the nebuliser system relative to the patient can be achieved.

The holding arm may have a length in the range of 10 cm to 60 cm, preferably 20 cm to 50 cm and more preferably 30 cm to 40 cm. In this way, good accessibility of the patient and, at the same time, a robust arrangement of the holding system can be particularly reliably ensured.

The holding element may have a strap or a string, such as a silicone string, for holding the nebuliser or the nebuliser system. In this way, a particularly simple configuration of the holding system can be achieved.

The holding element may have a plurality of holding portions, e.g., two or more holding portions, three or more holding portions, four or more holding portions, or five or more holding portions. Each holding portion may be configured for holding a component of the nebuliser system, such as a part of the body of the nebuliser, the entire body of the

nebuliser, one or more tubes, one or more pipes, one or more leads etc. For example, the holding portions may be in the form of recesses, cut-outs or cavities. The recesses, cut outs or cavities may be configured for at least partly receiving therein the components of the nebuliser system.

The invention further provides a combination comprising the nebuliser system of the invention and the holding system of the invention.

Moreover, the invention provides a method of administering an aerosol to a patient, in particular, a child, especially a neonate, using the nebuliser system of the invention or the combination of the invention. The method comprises generating an aerosol by nebulising the liquid by means of the

nebulising device and supplying the aerosol to the patient through the second connection.

The method of the invention is a method of using the

nebuliser system of the invention or the combination of the invention. The method thus provides the technical effects and advantages already described in detail above for the

nebuliser system of the invention and the combination of the invention .

The features described above for the nebuliser system of the invention and the combination of the invention also apply to the method of the invention.

Brief Description of the Drawings

Hereinafter, non-limiting examples of the present invention are explained with reference to the drawings, in which:

Fig. 1 shows a perspective view of a nebuliser system according to an embodiment of the present

invention, which is schematically coupled to an assisted breathing device; Fig . 2 shows a top view of the nebuliser of Fig. 1; Fig . 3 shows an upside down side view of the nebuliser of Fig. 1;

Fig. 4 shows a longitudinal cross-section through the nebuliser of Fig. 1 along the line A-A in Fig. 2;

Fig . 5 shows a longitudinal cross-section through the nebuliser of Fig. 1 along the line B-B in Fig. 3;

Fig . 6 shows a perspective view of a nebuliser system according to another embodiment of the present invention, which is schematically coupled to an assisted breathing device;

Fig. 7 shows a perspective view of a nebuliser system according to yet another embodiment of the present invention, which is schematically coupled to an assisted breathing device;

Fig. 8 shows a cross-sectional view of a nebuliser

system according to yet another embodiment of the present invention;

Fig. 9 shows a perspective view of the nebuliser system according to the embodiment of the present invention shown in Fig. 1, comprising the

nebuliser, an adapter and a nasal communication element ;

Fig. 10 shows the adapter and the nasal communication

element of Fig. 9, wherein Fig. 10(a) is a partially exploded perspective view, and Fig.

10 (b) is a perspective view showing the adapter and the nasal communication element in the connected state; Fig. 11 shows a perspective top view of the adapter of Fig. 9;

Fig. 12 shows a perspective bottom view of the adapter of

Fig. 9;

Fig. 13 shows an enlarged perspective view of the nasal communication element shown in Figs. 9 and 10;

Fig. 14 shows a perspective view of a nasal communication element of another type;

Fig. 15 shows perspective views of further nasal

communication elements;

Fig. 16 shows a partially exploded perspective view of a holding system according to an embodiment of the present invention;

Fig. 17 shows a perspective view of a combination

according to an embodiment of the present

invention, comprising the nebuliser system of Fig. 9 and the holding system of Fig. 16;

Fig. 18 shows a diagram presenting experimental data of a first example of experimental studies performed using the nebuliser system of the present

invention;

Fig. 19 shows a diagram presenting further experimental data of the first example of experimental studies performed using the nebuliser system of the present invention;

Fig. 20 shows a diagram presenting experimental data of a second example of experimental studies performed using the nebuliser system of the present

invention;

Fig. 21 shows a diagram presenting further experimental data of the second example of experimental studies performed using the nebuliser system of the present invention;

Fig. 22 shows a perspective bottom view of an adapter

according to an embodiment of the present invention;

Fig. 23 shows a perspective bottom view of an adapter

according to another embodiment of the present invention; and

Fig. 24 shows a perspective view of an adapter according to another embodiment of the present invention.

In the different views, the same or corresponding elements are provided with identical reference signs.

Detailed Description of Currently Preferred Embodiments

Currently preferred embodiments of the present invention will now be described with reference to the accompanying drawings. The preferred embodiments relate to a nebuliser system, a holding system, a combination comprising the nebuliser system and the holding system, and a method of administering an aerosol to a neonate using the combination.

In the following, a nebuliser of a nebuliser system according to an embodiment of the present invention will be described with reference to Figs. 1 to 5.

The nebuliser system shown in Fig. 1 comprises the nebuliser, an adapter 104, such as the adapter 300 shown in Figs. 11 and 12, and an oral and/or nasal communication element in the form of nasal prongs 200, a nose mask 600 or a face mask 700. The nasal prongs 200, the nose mask 600 or the face mask 700 can be connected to the nebuliser via the adapter 104, as is indicated by the dashed line 103 in Fig. 1.

The nebuliser shown in Figs. 1 to 5 comprises three main components, namely a first body part 1, a second body part 2 and a nebulising device 3 (see Fig. 2) . The first and second body parts 1 and 2, which together form the body, are

preferably made of plastic and are preferably produced in an injection moulding process.

The first body part 1 comprises a first connection 10, which is composed of two connecting pieces 11, 12. As is apparent from Fig. 1, the first connecting piece 11 is configured so as to connect with an air supply line 101 of an assisted breathing device 100. The assisted breathing device 100 is a currently preferred embodiment of an assisted breathing device. The second connecting piece 12 is in turn configured to be connected to an air exhaust line 102 of the assisted breathing device 100. The air supply line 101 and the air exhaust line 102 are thereby each formed by a separate tube (not shown) , which may have, for example, an inner diameter of 22 mm for adults or an inner diameter of 10 mm and 15 mm for children.

The connecting pieces 11, 12 are each configured such that it is possible to couple these conventional tubes to the

connecting pieces 11, 12. Specifically, as is shown in Fig.

1, each of the connecting pieces 11, 12 has a bent portion at which the respective connecting piece 11, 12 is bent upward by approximately 90°. These bent portions allow for the connecting pieces 11, 12 to be coupled to the tubes of the air supply line 101 and the air exhaust line 102 in a

particularly advantageous manner, without significantly impairing accessibility of a patient to be treated or tested. This is particularly beneficial for the treatment of

children, especially neonates.

The above-identified configuration of the connecting pieces 11, 12 works particularly efficiently when the nebuliser system is used in combination with the holding system of the present invention (see Fig. 17), thereby maximising

accessibility of the patient. Hence, aerosol therapy can be performed with a particularly high degree of efficiency and precision .

A bypass 13 is furthermore formed in the first body part 1 (see Figs. 4 and 5), said bypass 13 being arranged before (i.e., upstream in the direction of flow of the respiratory air) the nebulising device 3. This bypass 13 ensures that a basic flow generated by the assisted breathing device 100 to regulate the respiratory air to a patient 800 (see Fig. 17) can flow, outside of an inhalation cycle and/or an exhalation cycle of the patient 800, directly from the air supply line 101 into the air exhaust line 102 via the connecting piece 11, the bypass 13 and the connecting piece 12, without passing the nebulising device 3 (as is indicated by a dashed arrow in Fig. 5) . This basic flow has a flow rate of up to 30 1/min. The basic flow is often also referred to as a "bias flow" .

The assisted breathing device 100 may be a positive pressure assisted breathing device, such as a PAP, a BiPAP, a CPAP, a nCPAP, a NIPPV, a IV, a NIV, a respirator, a ventilator, or a similar device that uses equivalent modes.

To generate the air flow, a compressor or a pressurized gas source could be used: the pressure is modulated by a pressure regulator with a mechanical filter to avoid dust flowing through the system. Advantageously, the pressure is

maintained below 20 mbar, preferably between 3 and 15 mbar, and more preferably at 5 to 11 mbar. The skilled person in the art shall suitably adjust the pressure value.

Non-invasive ventilation supports require the delivery of humidified and heated air in order to avoid drying of the airway mucosa. Preferably, humidified air is utilized at a temperature between 35°C and 42°C, more preferably between 37°C and 39°C and even more preferably around 37°C.

Typically, the humidified air is utilized at body

temperature. In another case especially a temperature around 42°C was used to simulate fever effects. Preferably, the humidity is between 95% and 100% (non-condensing) , more preferably between 99% and 100%. As humidified and heated air may be used ambient air and/or air mixture and may include additional oxygen, up to 100% oxygen and/or air concentrators and/or oxygen supply. The skilled person in the art shall suitably adjust the temperature and the relative humidity as well as the oxygen content of the air.

The patient 800 may be a spontaneously breathing pre-term neonate having a gestational age of 26 to 32 weeks suffering of RDS (see Fig. 17) .

The first body part 1 furthermore also comprises a liquid container 14 for receiving a liquid to be nebulised. Examples of possible liquids to be received in the liquid container 14 are given above. In particular, the liquid may be a

pharmaceutical formulation in form of an aqueous solution or an aqueous suspension. The pharmaceutical formulation may comprise a pulmonary surfactant. The dose of the pulmonary surfactant may be comprised between 150 and 600 mg/kg body weight .

The liquid container 14 is preferably an integral component of the first body part 1. However, it may also be configured such that it can be partially or completely coupled and uncoupled . It is also conceivable that the liquid container 14 does not directly accommodate the liquid to be nebulised but rather that a device, for example a spike, is provided in the liquid container 14 so as to open, for example pierce, an ampoule that can be inserted into the liquid container 14, out of which the liquid to be nebulised can be supplied to the nebulising device 3 and a liquid chamber 24 to be described later. Such a configuration is shown in Fig. 8.

Specifically, as is shown in Fig. 8, the liquid container 14 may be provided with an opening element 128, such as a spike or the like, which is configured to pierce an ampoule 129 that contains the fluid. In particular, when the ampoule 129 is inserted into the liquid container 14, the opening element 128 pierces a bottom 130 of the ampoule 129 and folds it back so that fluid can flow into the fluid chamber 24. The opening element 128 is configured so as to be hollow for allowing fluid to pass therethrough.

According to the shown embodiment, the liquid container 14 has a substantially cylindrical portion 15 that has a

substantially circular cross-section. An external screw thread 16 is formed on the outer circumferential surface of the cylindrical portion 15 at the end of the cylindrical portion 15 which is facing away from the nebulising device 3. An internal screw thread 17 of a lid 18, which is formed on the inner circumferential surface of the lid 18, can be engaged with this external screw thread 16 so that the lid 18 can be screwed onto the cylindrical portion 15 of the liquid container 14. The lid 18 further comprises a circumferential collar 19 on its inner surface which, when the lid 18 is screwed on, sealingly engages, either directly or indirectly via a sealing material, with the inner surface of the

cylindrical portion 15. Moreover, the cylindrical portion 15 comprises a surrounding groove 20, in which one end of a lid securing means 21 (see Fig. 1) can be fixed, the other end of which can be attached to a mushroom-shaped projection 22 of the lid 18.

A tapering portion 23 is located at the end of the

cylindrical portion 15 which is facing away from the lid 18, said tapering portion 23 tapering in the direction of the nebulising device 3 and opening out into the liquid chamber 24. In the shown embodiment, the tapered portion 23 is composed in cross-section of a wall 26 extending

substantially parallel to the progression of the later described vibratable membrane 37 as well as a wall 25

extending at an angle of between 40 and 50° to the vertical and/or to the membrane 37, and has a substantially conical form. The peak of the cone is thereby substantially in the liquid chamber 24.

The first body part 1 further comprises a surrounding collar 27 at its opposite end to the first connection 10, which collar 27 can be coupled to the second body part 2 (see below) . A sealing material 28 is injection moulded radially inside this collar 27 or is produced in a two-component process together with the first body part 1 that is made of a hard resilient plastic. This sealing material 28 comprises a circumferential projection 29. Also provided is a surrounding sealing lip 30 that abuts the liquid chamber 24 and is pressed against the vibratable membrane 37 for sealing such that the liquid chamber 24 is tightly sealed by the membrane 37 and the sealing lip 30.

The second body part 2 comprises the second connection 31, which is formed by a connecting piece 32. This connecting piece 32 is preferably designed in a similar manner to the tube to be respectively connected to the connecting pieces 11 and 12, which forms lines 101 and 102. In this way, it can be ensured that the shown nebuliser can only be integrated into the assisted breathing device 100 in the proper manner. Other designs for achieving this are also conceivable. It is only important that the connections 31 and 10 are not designed in an identical manner in order to rule out the possibility that one of lines 101, 102, each formed by tubes, is connected to the connecting piece 32 or that the adapter 104 is connected to one of the connecting pieces 11 or 12.

The second body part 2 further comprises a plurality of locking means distributed over its circumference, in this case locking catches 33. In the shown embodiment, six such locking catches 33 or snap-in hooks are provided. However, fewer or more such devices are also conceivable. The locking catches 33 are thereby designed in such a manner that in the assembled state, they can be engaged with the surrounding collar 27 of the first body part 1 in that they grip behind the collar 27 so that the first and second body parts 1 and 2 can be connected with one another. Radially inside the locking catches 33, the second body part 2 further comprises two surrounding, concentrically arranged webs 34 and 35 which are adapted in terms of their distance in the radial

direction to the width of the projection 29 of the sealing material 28 in the radial direction such that upon engagement of the first and second body parts 1 and 2, a labyrinth seal is formed between the projection 29 and the two webs 34 and 35.

The second body part 2 further comprises at least two, preferably four and possibly more, supporting projections 36 for holding the nebulising device 3 (see below) . These are uniformly arranged over the circumference of the second locking body 2 in pairs diametrically opposite one another and, in the case of four elements, each at 90° intervals.

The second body part 2 may be designed so as to be

rotationally symmetrical such that it can be connected to the first body part 1 at any orientation about its central axis. The nebulising device 3 comprises the vibratable membrane 37 having a plurality of minute openings or holes (not shown) with diameters in the micrometer range, which completely penetrate the membrane 37. The membrane 37 is vibratable by means of a vibrator 47, such as a piezoelectric element, i.e., the membrane 37 can be caused to oscillate or vibrate by the vibrator 47. The vibrator 47 has an annular shape and is arranged at a peripheral portion of the membrane 37 (see Figs. 4 and 5) . Owing to the oscillation or vibration of the membrane 37, liquid on one side of the membrane 37, i.e., from the liquid chamber 24, will pass through the openings or holes and, on the other side of the membrane 37, is nebulised into a nebulisation chamber 38 formed in the body. This general principle is explained in more detail, for example, in US 5,518,179, and thus a detailed description of this mode of operation will not be provided here.

According to the invention, the membrane 37, which is a flat and even element, is held in a frame (not shown) by means of spokes (not shown) . The membrane 37 and the frame are

designed so as to be substantially circular or annular. The frame is insert-moulded with a soft resilient material 40, which is the same as or similar to the sealing material 38 and which surrounds the frame as well as parts of its connection 41, shown in Fig. 5, for control and power supply of the nebulising device 3. Except for the spokes along the entire circumference of the membrane, a clearance 42 is formed between the membrane 37 and the radially inner

circumferential surface of the frame surrounding the membrane 37, which consists of the frame and the insert mould 40, said clearance forming part of a flow-around portion in the flow channel of the body 1, 2 that is explained later. Further, with the exception of the region of the connection 41, a further clearance 43 is formed in the assembled state between the outer surface of the frame, which consists of the insert mould 40 and the frame, and the inner circumferential surface of the body (here the first body part 1), said clearance 43 forming a further part of the mentioned flow-around portion.

For assembly, the nebulising device 3, which is pre

assembled, is aligned with the connection 41 according to a recess and is inserted into the first body part 1, whereby the surrounding sealing lip 30 surrounds the part of the membrane 37 which is provided with openings or holes. The second body part 2 is then attached, whereby the projections 36 press against the frame insert-moulded with the resilient material 40 and urge it in the direction of the first body part 1. The nebulising device 3 is thereby pushed in the direction of the sealing lip 30 and the membrane 37 is thus pushed against the surrounding sealing lip 30 such that a seal is formed against the membrane 37 or the area

surrounding the membrane 37 and the liquid chamber 24 is tightly sealed. The nebuliser is supplied ready-assembled and cannot be opened or taken apart.

Furthermore, the concentric webs 34 and 35 engage with projection 29 of the sealing material 28 and form the

labyrinth seal, with the pressure of the seals against the corresponding components being maintained owing to the locking of the locking catches 33 by gripping behind the collar 27. In the region of connection 41, where part of the nebulising device 3 exits the body 1, 2, a seal occurs between the soft resilient plastic 40 and the webs of the second locking part 2 and a projection 44 surrounding a recess in the first locking part 1 for receiving the

connection 41, such that a sufficient seal is also provided here .

In the assembled state, the body 1, 2 forms a flow channel from the first connection 10 via connecting piece 11 to the second connection 31 which consists of connecting piece 32, whereby air flows around the nebulising device 3 along flow- around channels 42, 43. The direction of fluid flow into the connecting piece 11 and out of the connecting piece 32 is the same and the membrane 37 and/or the plane in which the membrane 37 lies is arranged perpendicular to this direction of flow or to the central axis of the respective connecting piece 11, 12 or 31. This results in the liquid contained in the liquid container 14 being nebulised through the openings or holes of the membrane 37 into the nebulisation chamber 38 in the direction of flow, i.e. parallel thereto. The

deposition of fluid, i.e., generated aerosol, on the surfaces of the flow channel or in the subsequent tubes is

consequently reduced and the efficiency of the system is increased .

The design of the present embodiment further allows a bias flow to flow from the air supply line 101 into the air exhaust line 102 via the bypass 13 without passing the nebulising device 3 and, in particular, the nebulisation chamber 38, and thus this bias flow does not flush any aerosol, i.e., nebulised liquid, generated by the nebulising device 3 into the air exhaust line 102 outside of an

inhalation cycle and/or exhalation cycle, as a result of which the efficiency of the system is further increased.

Moreover, a unit that is stable against tilting is formed by the three connecting pieces 11, 12 and 32 and the integral connection of the liquid container 14 to the body 1, 2, said tilt-stable unit being beneficial to the flow behaviour of the liquid out of the liquid container 14 into the liquid chamber 24 and up to the membrane 37. A uniform and

consistent supply of the liquid is further facilitated by the design of the tapered portion 23 and, in particular, the inclination of the wall 25. Thus, even if the nebuliser shown in Fig. 4 is rotated about the central axis of the connecting piece 32 by 45° in one of the two directions, the presence of the liquid on the membrane 37 can still be reliably ensured. The cross-sectional area of the flow-around channel 42 and 43 is configured such that it is not significantly smaller than and is not significantly larger (the latter so as not to create an unnecessarily large dead volume that must be displaced during exhalation by the patient in the case of assisted respiration) than the smallest cross-sectional area in the lines of the assisted breathing device 100 that lead to the patient 800 (line 101 and the connection line via the adapter 104 and the oral and/or nasal communication element) . This prevents an increased flow resistance as well as an increased dead volume, which can both have a negative effect on the functionality of the assisted breathing device 100.

Furthermore, tightness is achieved owing to the sealing material 28 and the insert mould 40 of the frame 39, which can also withstand a pressure of up to 100 mbar. Due to the use of the vibratable membrane 37 with the minute openings or holes, a pressure loss in the system when the liquid

container 14 is open is also prevented. A fluid flow out of the flow channel and into the liquid container 14 is not possible through the minute openings.

The nebulising device 3 can be coupled to a control of the assisted breathing device 100 via the connection 41 so as to trigger the nebulising device 3 only in the inhalation cycle. That is to say only when the patient 800 inhales, be it assisted or forced by the assisted breathing device 100, is the membrane 37 vibrated so that nebulisation of the liquid in the liquid container 14 occurs. The efficiency of the system can thereby be increased even further.

The flow channel may comprise a tapered portion arranged downstream of the nebulising device 3, wherein, in the tapered portion, the diameter of the flow channel decreases in the direction from the first connection 10 towards the second connection 31. In this way, the efficiency of aerosol transport can be further improved. Fig. 6 shows a perspective view of a nebuliser system

according to another embodiment of the present invention. The nebuliser system of the embodiment shown in Fig. 6 differs from the nebuliser system of the embodiment shown in Figs. 1 to 5 only in the configuration of the connection to the assisted breathing device 100.

Specifically, in the embodiment of Fig. 6, the first

connection 10 of the first body part 1 of the nebuliser is composed of a single connecting piece 11. The connecting piece 11 has a bent portion at which it is bent upward by approximately 90°. A connector 105, such as a Y-piece, is coupled, e.g., releasably coupled, to the connecting piece 11. The connector 105 is configured to connect the connecting piece 11 to the air supply line 101 and the air exhaust line 102 of the assisted breathing device 100. Also this

arrangement allows for the nebuliser to be coupled to the tubes of the air supply line 101 and the air exhaust line 102 in a particularly advantageous manner, without significantly impairing accessibility of a patient to be treated or tested.

Fig. 7 shows a perspective view of a nebuliser system

according to yet another embodiment of the present invention.

The nebuliser system shown in Fig. 7 comprises the nebuliser, the adapter 300 (see Figs. 11 and 12), and the nasal

communication element 200 (see Fig. 13) . The nasal

communication element 200 can be connected to the nebuliser via the adapter 300.

The nebuliser system of the embodiment shown in Fig. 7 differs from the nebuliser system of the embodiment shown in Figs. 1 to 5 only in the configuration of the connection to the assisted breathing device 100.

Specifically, in the embodiment of Fig. 7, the first

connection 10 of the first body part 1 of the nebuliser is composed of a single connecting piece 11. The connecting piece 11 has a substantially straight shape extending along a longitudinal axis of the nebuliser. A connector 105 is coupled, e.g., releasably coupled, to the connecting piece 11. The connector 105 is configured to connect the connecting piece 11 to the air supply line 101 and the air exhaust line 102 of the artificial respiration machine 100. In particular, as is shown in Fig. 7, the connector 105 is substantially in the form of a Y-piece having a bent portion at which it is bent upward by approximately 90°.

Also this arrangement allows for the nebuliser to be coupled to the tubes of the air supply line 101 and the air exhaust line 102 in a particularly advantageous manner, without significantly impairing accessibility of a patient to be treated or tested.

Each of the nebulisers of the embodiments described above is configured for being adapted to an oral and/or nasal

communication element, in particular, the nasal communication element 200. In particular, the nebuliser system of each of the above embodiments comprises an adapter 300, and the adapter 300 is configured for adapting the nebuliser to the nasal communication element 200.

The nebuliser system according to the embodiment shown in Fig. 7, comprising the nebuliser, the adapter 300 and the nasal communication element 200, is shown in Fig. 9. Fig. 10 also shows the adapter 300 and the nasal communication element 200, wherein Fig. 10(a) is a partially exploded perspective view, and Fig. 10(b) is a perspective view showing the adapter 300 and the nasal communication element 200 in the connected state. Figs. 11 and 12 are perspective top and bottom views, respectively, of the adapter 300.

The adapter 300 is attached to the body 1, 2 of the

nebuliser, as is indicated by an arrow in Fig. 9. Specifically, the adapter 300 has an attachment portion 302 which is received within the connecting piece 32 of the second connection 31 of the nebuliser (see, for example,

Figs. 1 and 9), thereby attaching the adapter 300 to the body 1, 2. The attachment portion 302 has a cylindrical shape with a circular cross-section perpendicular to an axial direction thereof. The adapter 300 is detachably attached to the body 1, 2 and, thus, can be easily replaced.

The adapter 300 further has an interface port 304 (see Figs. 10(a) and 11) arranged at the second connection 31 for connecting the nasal communication element 200 to the

nebuliser. The interface port 304 is substantially

rectangular. Specifically, the interface port 304 is in the form of a substantially rectangular recess (see Fig. 11) .

The adapter 300 has an adapter flow channel 306 extending through the adapter 300, as is shown in Figs. 11 and 12. The adapter flow channel 306 allows fluid flow from the second connection 31 of the nebuliser to the nasal communication element 200. A portion 308 of the adapter flow channel 306 has an elongate cross-section in a plane perpendicular to the axial direction of the adapter flow channel 306 (see Fig.

11) . The elongate portion 308 of the adapter flow channel 306 is arranged partly within the interface port 304.

The cross-section of the adapter flow channel 306 varies along the axial direction of the adapter flow channel 306. Specifically, the area of the cross-section of the adapter flow channel 306 decreases in the direction from the second connection 31 to the nasal communication element 200.

Further, the shape of the cross-section of the adapter flow channel 306 changes from a substantially circular shape (see Fig. 12) to an elongate shape (see Figs. 11 and 12) in the direction from the second connection 31 to the nasal

communication element 200. Moreover, the adapter 300 has a pair of engagement members 310 for engaging respective communication openings (not shown) of the nasal communication element 200 which will be described in detail below. The engagement members 310 protrude from a bottom surface of the interface port 304.

Each of the engagement members 310 has a substantially semi circular shape in a view along the direction of fluid flow through the adapter 300. Further, the engagement members 310 are arranged so as to partly surround an outlet opening 312 of the adapter flow channel 306. Specifically, the engagement members 310 are arranged so as to extend substantially along respective end portions of the outlet opening 312.

By means of the adapter 300, the nasal communication element 200 can be connected directly to the nebuliser, i.e., to the second connection 31 thereof. Hence, no intermediate

elements, such as tubes, pipes or lines, are necessary for this connection, so that the occurrence of aerosol losses can be further suppressed.

The nasal communication element 200 is configured for

establishing fluid communication between the nebuliser and the nose of the patient 800. The nasal communication element 200 is in the form of nasal prongs.

Fig. 13 shows an enlarged perspective view of the nasal communication element 200 shown in Figs. 9 and 10. The nasal communication element 200 comprises an interface member 202 (see Figs. 10(a) and 13) for connection to the interface port 304 of the adapter 300. The interface member 202 is

configured for being received within the interface port 304. The interface member 202 has a substantially rectangular shape in a view along the direction of fluid flow through the interface member 202. The nasal communication element 200 is releasably connected to the adapter 300 by inserting the interface member 202 into the interface port 304 of the adapter 300 (see Fig. 10(b)). The interface member 202 has two communication openings (not shown in Figs. 10(a) and 13; see the communication openings 204 in Figs. 14 and 15(a) to (c) ) for communication with the adapter flow channel 306. When the interface member 202 is inserted into the interface port 304 of the adapter 300, the engagement members 310 of the adapter 300 engage these communication openings, so that the nasal communication element 200 is particularly reliably held in its position relative to the adapter 300.

The nasal communication element 200 further comprises two fluid guiding members 206 for guiding the aerosol generated by the nebulising device 3 to the patient's nose. The two fluid guiding members 206 are in fluid communication with the interface member 202 through two separate channels (not shown) . Each fluid guiding member 206 is in fluid

communication with a respective one of the communication openings of the interface member 202. The two fluid guiding members 206 and the two communication openings establish fluid communication between the nebuliser and respective nasal entrances of the patient 800. Further, as is shown in Fig. 13, the nasal communication element 200 has two side flaps 208 arranged at opposing sides thereof. The side flaps 208 allow for the nasal communication element 200 to be held in its position at the patient's nose in a particularly reliable manner, thus further helping to minimise loss of aerosol occurring at the interface between nebuliser and patient .

The adapter 300 has a support member 314 in the form of a strap for holding the nasal communication element 200 in position on the patient's head.

A modification of the adapter 300 is shown in Figure 22. The modified adapter 300 shown in Figure 22 differs from the adapter 300 shown in Figures 11 and 12 only in that a temperature sensor 316 and an electrical connection 318 of the temperature sensor 316 are provided. In the description of the modified adapter 300, the elements which are identical to those of the adapter 300 shown in Figures 11 and 12 are denoted by the same reference signs and a repeated detailed description thereof is omitted.

The temperature sensor 316 extends into the flow channel 306 through an opening provided in the attachment portion 302.

The electrical connection 318 of the temperature sensor 316 is arranged at an outer surface of the attachment portion 302 for enabling control and power supply of the temperature sensor 316. The electrical connection 318 may be arranged at substantially the same circumferential position as the electrical connection 41 of the nebulising device 3 (see, for example, Figures 1 and 2) . In this way, the nebulising device 3 and the temperature sensor 316 can be electrically

connected, e.g., to a control and/or power supply, in a particularly simple and efficient manner, minimising the space required for cables, wiring etc.

The temperature sensor 316 is configured to determine the temperature of a fluid flowing from the second connection 31 of the nebuliser to the nasal communication element 200 (see, for example, Figure 7) . Hence, this temperature can be reliably monitored.

For example, the temperature of the fluid flowing through the flow channel 306 can be monitored by means of the temperature sensor 316 and be controlled so as to be in the range of 35°C to 46°C, preferably 36°C to 45°C, more preferably 36°C to 43°C, even more preferably 36°C to 42°C, yet even more preferably 37°C to 39°C and still even more preferably around 37°C. In this way, it can be ensured that the fluid supplied to the patient has the desired temperature. The assisted breathing device 100 and/or the nebuliser may be configured so that fluid supply to the patient is stopped if the

temperature determined by the temperature sensor 316 exceeds a threshold value. The nebuliser may be configured so that the nebulising device 3 is switched off if the temperature determined by the temperature sensor 316 exceeds a threshold value. The threshold value may be, for example, 46°C, 45°C,

44 °C, 43 °C, 42 °C, 41°C, 40°C, 39°C or 38°C.

A further modification of the adapter 300 is shown in Figure 23. The modified adapter 300 shown in Figure 23 substantially differs from the adapter 300 shown in Figure 22 only in that a wall of the adapter 300 is provided with through-holes for inserting a support member, such as the support member 314 (see Figure 17), as will be further detailed below. In the description of the modified adapter 300 shown in Figure 23, the elements which are identical to those of the adapter 300 shown in Figure 22 are denoted by the same reference signs and a repeated detailed description thereof is omitted.

The further modified adapter 300 has two openings 322 through each of which a support member, such as the support member 314 (see Figure 17), can be inserted. As is shown in Figure

23, the two openings 322 are arranged on opposite sides of the adapter 300, in particular, on opposite sides of the interface port 304 (see Figure 11) .

Each of the two openings 322 is surrounded by a wall 324 of the adapter 300. The wall 324 is an outer wall of the adapter 300. Such a wall and two such openings are also present in the adapters 300 shown in Figures 11, 12 and 22.

The modified adapter 300 shown in Figure 23 differs from the adapters 300 shown in Figures 11, 12 and 22 in that, for each of the two openings 322, the wall 324 of the adapter 300 is provided with a through-hole 326 (see Figure 23) . In the present embodiment, each through-hole 326 is provided in the form of a slit or slot. Each through-hole 326 is configured to allow insertion of a support member, such as the support member 314, into the respective opening 322 via the

respective through-hole 326.

The provision of the through-holes 326 allows for the adapter 300 to be attached to an existing support member, e.g., a support member already attached to the patient, in a

particularly simple and efficient manner, while minimising any disturbance to the patient. In particular, the through- holes 326 enable simple and efficient attachment of the adapter 300 to a support member in the form of a loop or a lug, e.g., a strap or the like which is in the form of a loop or a lug or which is configured to form a loop or a lug. One end of the support member may be attached to the patient, for example, to a cap or hood worn by the patient, and the other end of the support member may be attached to the adapter 300, e.g., by inserting the other end of the support member into the respective opening 322 through the respective through- hole 326.

The adapter 300 shown in Figure 23 further comprises a connection element 320 for connecting a temperature sensor, such as the temperature sensor 316 (see Figure 22), to the adapter 300. In particular, the connection element 320 enables attachment of the temperature sensor to the adapter 300 so that the temperature sensor extends into the flow channel 306 through an opening provided in the attachment portion 302 (see Figure 23) . The temperature sensor may be provided with a sealing component which is configured to seal this opening upon attachment of the temperature sensor to the adapter 300.

The connection element 320 has two opposing recesses or grooves, one of which is shown in Figure 23. These recesses or grooves may be configured for receiving corresponding protrusions of the temperature sensor. In this way, it can be reliably ensured that the temperature sensor is attached to the adapter 300 with a defined angular alignment between temperature sensor and adapter 300. This is particularly beneficial if the temperature sensor has a measuring

directionality. The connection element 320 and the

temperature sensor may be configured so that the temperature sensor can be attached to the adapter 300, for example, by snap fit or friction fit.

The connection element 320 may have more than two recesses or grooves. For example, the connection element 320 of the adapter 300 shown in Figure 24 has four recesses or grooves which are substantially equidistantly spaced along a

circumference of the connection element 320. Also the

connection element 320 of the adapter 300 shown in Figure 23 may have four recesses or grooves which are substantially equidistantly spaced along a circumference of the connection element 320. This at least one recess (or groove) may ensure an especially accurate alignment and/or fixed orientation of the temperature sensor 316 in an attached position on the connection element 320.

A further modification of the adapter 300 is shown in Figure 24. The modified adapter 300 shown in Figure 24 substantially differs from the adapter 300 shown in Figure 23 only in that, instead of the through-holes 326, a pair of protrusions 328 is provided, as will be further detailed below. In the description of the modified adapter 300 shown in Figure 24, the elements which are identical to those of the adapter 300 shown in Figure 23 are denoted by the same reference signs and a repeated detailed description thereof is omitted.

The two protrusions 328 are arranged on opposite sides of the adapter 300. Each of the two protrusions 328 is disposed next to a respective one of the two openings 322. In the

perspective view of Figure 24, only one of the two

protrusions 328 is shown. The protrusions 328 are in the form of engagement members, in particular, hook members. Each of the protrusions 328 is configured for engagement with a support member, such as the support member 314 (see Figure 17) .

The provision of the protrusions 328 allows for the adapter 300 to be attached to an existing support member, e.g., a support member already attached to the patient, in a

particularly simple and efficient manner, while minimising any disturbance to the patient. In particular, the

protrusions 328 enable simple and efficient attachment of the adapter 300 to a support member having, e.g., at one of its ends, an engagement portion, such as an eye, a loop or a bail, for engagement with the protrusion 328. The one end of the support member may be attached to the adapter 300 by engaging the engagement portion with the protrusion 328 and the other end of the support member may be attached to the patient, for example, to a cap or hood worn by the patient.

In addition or as an alternative to attaching the support member to the adapter 300 by means of the protrusion 328, the support member may be attached to the adapter 300 by

inserting the support member, in particular, an end thereof, into a respective one of the openings 322. In the embodiment shown in Figure 24, the insertion process of the support member is facilitated by the provision of protruding portions 330. These protruding portions 330 protrude or project from a side or surface of the adapter 300 which is opposite to the side or surface of the adapter 300 at which the attachment portion 302 is provided (see Figure 24) . The protruding portions 330 are inclined relative to the side or surface of the adapter 300 from which they protrude or project, as is shown in Figure 24. Each of the protruding portions 330 offers an abutment, e.g., an abutment surface, for a

respective support member, in particular, an end of the support member, when inserting the support member into the opening 322, thus considerably facilitating the insertion process of the support member. Further types of nasal communication elements 200 are shown in Figs. 14 and 15(a) to (c) . The general configuration of these nasal communication elements 200 is substantially the same as that of the nasal communication element 200 shown in Figs. 9, 10(a), 10(b) and 13. Hence, the same reference signs are used to denote identical or similar components.

Each of the of nasal communication elements 200 shown in Figs. 14 and 15(a) to (c) has a substantially rectangular interface member 202, two communication openings 204 and two fluid guiding members 206. The nasal communication elements 200 shown in Figs. 14 and 15(a) to (c) mainly differ from the nasal communication element 200 shown in Figs. 9, 10(a) and 10 (b) in the shape and the arrangement of the two fluid guiding members 206. Specifically, the two fluid guiding members 206 of the nasal communication elements 200 shown in Figs. 14 and 15(a) to (c) have a bent, i.e., slightly bent, shape and extend from the interface member 202 at an angle relative to the direction perpendicular to the front surface of the interface member 202 where the communication openings 204 are provided.

The nasal communication elements 200 shown in Figs. 14 and 15 (a) to (c) differ from each other in the size and the arrangement of the two communication openings 204 and the two fluid guiding members 206. The nasal communication element 200 to be used for aerosol treatment can be suitably chosen depending on the anatomy of the patient 800 to be treated.

For example, the nasal communication element 200 of Fig.

15 (a) may be used for treating an adult, while the nasal communication element 200 of Fig. 15(c) may be used for treating a neonate. Hence, the nebuliser system can be readily adapted to the requirements of the patient 800.

The adapter 300 and/or the nasal communication element 200 may be made of plastic. The adapter 300 and/or the nasal communication element 200 may be produced in an injection moulding process.

Fig. 16 shows a partially exploded perspective view of a holding system 400 according to an embodiment of the present invention. The holding system 400 is configured for holding the nebuliser system shown in Fig. 9.

The holding system 400 comprises a base 402, a holding arm 404 extending from the base 402, and a holding element 406 configured to hold the nebuliser system. The holding arm 404 has a first end 408 and a second end 410 opposite to the first end 408. The first end 408 of the holding arm 404 is attached to the base 402. The holding element 406 is attached to the holding arm 404 at the second end 410 of the holding arm 404.

The base 402 and/or the holding arm 404 and/or the holding element 406 may be made of a metal.

The holding system 400 allows for the nebuliser system to be stably held in its position (see Fig. 17), so that efficient aerosol transport from the nebuliser to the patient 800 can be secured and reliably maintained. Hence, aerosol therapy can be performed with a high degree of efficiency and

precision .

The first end 408 of the holding arm 404 is detachably attached to the base 402, as is indicated by an arrow in Fig. 16, allowing for the holding arm 404 to be replaced in a simple manner. The holding element 406 is detachably attached to the holding arm 404 at the second end 410 of the holding arm 404. In both cases, the detachable attachment is effected by a clamping screw, i.e., the clamping screw 412 and the clamping screw 414, respectively. The base 402 has a curved shape, namely a U-shape, allowing for a particularly secure and stable placement of the holding system 400 on a placement surface (see Fig. 17) .

The holding arm 404 is flexible. Specifically, the holding arm 404 is configured so that it can be substantially freely bent into a desired shape and subsequently maintains this shape. Thus, the holding system 400 can be easily and

efficiently adapted to the specific requirements of the patient 800 to be treated.

The holding arm 404 has a length in the range of 20 cm to 50 cm, ensuring good accessibility of the patient 800 and, at the same time, a robust arrangement of the holding system 400.

The holding element 406 has a plurality of holding portions 416, i.e., three holding portions 416. Each holding portion 416 is configured for holding a component of the nebuliser system, in particular, a tube, a pipe or a line of the nebuliser system (see Fig. 17) . Each of the holding portions 416 is in the form of a recess or cut-out configured for partly receiving therein tubes, pipes or lines of the

nebuliser system.

Fig. 17 shows a perspective view of a combination according to an embodiment of the present invention, comprising the nebuliser system of Fig. 9 and the holding system of Fig. 16. In particular, Fig. 17 shows the combination in a state in which it is being used for treating a neonate as the patient 800.

In this state, the nasal communication element 200 is

securely held in its position on the patient's head by means of the support member 314 of the adapter 300. The base 402 of the holding system 400 is placed on a placement surface, such as a hospital bed or the like. Tubes 500 of the nebuliser system, connecting the connecting pieces 11, 12 of the nebuliser to the air supply line 101 and the air exhaust line 102 of the assisted breathing device 100, respectively, are held by respective holding portions 416 and guided over the holding element 406, so that the patient 800 remains readily accessible, as is shown in Fig. 17. In particular, this accessibility of the patient 800 is achieved by the holding arm 404, allowing for the holding element 406 to be arranged in separation from the base 402. Further, by holding the tubes 500 of the nebuliser system, the holding system 400 also securely holds the nebuliser.

By using the combination shown in Fig. 17, an embodiment of the method of the invention of administering an aerosol to a patient can be performed. In particular, in the state shown in Fig. 17, an aerosol may be generated by nebulising the liquid received in the liquid container 14 by means of the nebulising device 3. Subsequently, the aerosol thus generated may be supplied to the patient 800 through the second

connection 31 of the nebuliser, the adapter 300 and the nasal communication element 200. In this manner, a particularly efficient aerosol treatment can be carried out.

In the following, two examples of experimental studies using the nebuliser system of the present invention are provided.

Example 1

The study of Example 1 was carried out in newborn piglets between days 2-4 of life with lung injury and surfactant deficiency induced by repeated saline lavage (BAL) (Lachmann B et al . Acta Anaesthesiol Scand 1980; 24:231-236).

Piglets 2 to 4-d old were sedated with i.m. ketamine (15 mg/kg) -diazepam (2 mg/kg)- atropine (0.05 mg7kg) injection and were anesthetised with sevofluorane (2-3%) . A tracheal tube (4.0 mmID) was inserted and connected to positive pressure ventilator (VIP Bird, Bird Products Corp., Palm Springs, CA) with the following initial settings:

fraction of inspired oxygen (Fi02) =0.25-0.28, respiratory frequency (fR)=20 breaths/min, positive end- expiratory pressure (PEEP) =3 cmH20 and positive inspiratory pressure (PIP) =9-11 cmH20. Deviations from acceptable blood gases values (Pa02 90-110 mmHg, PaC02 35-45 mmHg and pH 7.35-7.45) were corrected by changing ventilator parameters and/or by adding sodium bicarbonate or THAM as needed.

Surfactant-deficient lung injury was achieved by repetitive saline lavage (30 ml/kg; 37°C with FI02 : 1) via endotracheal tube. Lavage procedures were repeated at 5 minutes interval until Pa02 < 100 mmHg for a period of 30 minute (BAL point,

15 min ST and 30 min ST) was obtained.

After 30 min of stabilisation, all newborn piglets received a bolus dose of 20 mg/kg of caffeine citrate (Peyona® 20mg/ml; Chiesi Farmaceutici , S.P.A, Parma, Italy) before extubation. Nasal continuous positive airway pressure (nCPAP) was established in all animals at 5 cmH20 with a flow of 6.5 1/min .

After the period of stabilisation the piglets were assigned to the following groups: nCPAP group (n=6 ) : newborn piglets with surfactant-deficient lung injury maintained in nasal continuous positive pressure (nCPAP) during 180, without surfactant treatment.

Insure + nCPAP group (n=6 ) : newborn piglets with surfactant- deficient lung injury received a 200 mg/kg of Curosurf® using Insure technique. With the animal in supine position, the Curosurf® bolus was administered in about one min without ventilator disconnection. After surfactant administration newborn piglets were maintained in nCPAP during 180 min. nCPAP + Neb 100 group (n=6) : newborn piglets with surfactant- deficient lung injury received 100 mg/kg of nebulised

Curosurf® using a vibrating membrane nebuliser system

(investigational eFlow Neonatal System, Pari Pharma, Munich, Germany) , which was placed between the prongs and the

connection to the ventilator circuit. The animals were positioned in supine position during the experimental period and maintained in nCPAP during 180 min. nCPAP + Neb 200 group (n=6) : newborn piglets with surfactant- deficient lung injury received 200 mg/kg of nebulised

Curosurf® using a vibrating membrane nebuliser system

(investigational eFlow Neonatal System, Pari Pharma, Munich, Germany) , which was placed between the prongs and the

connection to the ventilator circuit. The animals were positioned in supine position during the experimental period and maintained in nCPAP during 180 min. nCPAP + Neb 400 group (n=6) : newborn piglets with surfactant- deficient lung injury received 400 mg/kg of nebulised

Curosurf® using a vibrating membrane nebuliser system

(investigational eFlow Neonatal System, Pari Pharma, Munich, Germany) , which was placed between the prongs and the

connection to the ventilator circuit. The animals were positioned in supine position during the experimental period and maintained in nCPAP during 180 min.

11 physiological measurements were measured, monitored or calculated at baseline (basal) , after bronchoalveolar lavages (BAL) , during the first 30 min after BAL

(stabilisation period) in conventional mechanical ventilation (15 and 30 min ST) and, after extubation, during nCPAP every 30 min until the end of experiment, at 180 min. Oxygenation measurements

Arterial pH, Pa02, PaC02 and Base Excess, lactic acid, glucose (GemPremier 4000, Intrumentation Laboratory,

Lexington, MA) .

Alveolar-arterial (A-a) oxygen tension difference (A-aD02), arterial/alveolar (a/AD02) oxygen ratio were used to

quantitate the degree of respiratory failure.

A-aD02 = PA02-Pa02; where PA02 is alveolar concentration of oxygen. It is used in diagnosing the source of hypoxemia. a/AD02 = Pa02/Pi02- (PaC02/R) ; where R, the respiratory exchange quotient, was assumed to be 0.8. This parameter is frequently used to evaluate impairment of oxygenation.

To assess the effectiveness of mechanical ventilation in each animal, during conventional mechanical ventilation procedure (Basal, BAL, 15 ST, 30 ST), oxygenation index (01) and ventilator efficiency index (VEI) were calculated.

VEI= [3800/ (PIP/PEEP) *respiratory frequency *PaC02]. VEI scores decrease as pulmonary function impairs; it is used as an index of C02 elimination efficiency.

01 = [mean airway pressure (MAP) *FI02/Pa02 ] . This is felt to be a more sensitive indicator for severity of pulmonary illness as MAP is taken into its calculation.

Values were expressed as meaniSEM. Results were assessed using the Levene test to confirm the homogeneity of variance between the different treatments and the Kolmogorov-Smirnoff test for normality (JMP8, Statistical Discovery, SAS, NO,

USA) . One-way analysis of variance (ANOVA) was performed to assess differences in gas exchange, ventilatory

parameters, lung injury score and lung biochemical analysis as a function of group. Comparisons of results (gas exchange, ventilatory parameters) were performed by repeated measures two-way ANOVA as a function of group and time. A p-value of 0.05 was accepted as significant.

Results of the experimental studies are shown in Figs. 18 and 19.

Specifically, Fig. 18 shows mean A-aD02 ratio values in nCPAP, Insure+nCPAP, nCPAP+Neb600 , nCPAP+Neb400 and

nCPAP+Neb200 groups. Mean and SEM are shown: * Vs. nCPAP and # Vs. Insure groups; single-factor ANOVA. $ Vs. nCPAP and & Vs. Insure group; two-factor ANOVA (along the time) .

Fig. 19 shows mean FI02 values in nCPAP, Insure+nCPAP, nCPAP+Neb600 , nCPAP+Neb400 and nCPAP+Neb200 groups. Mean and SD are shown: * Vs. nCPAP and # Vs. Insure groups; single factor ANOVA. $ Vs. nCPAP and & Vs. Insure group; two- factor ANOVA (along the time) .

Immediately after the end of surfactant administration (bolus or nebulisation) Pa02/Fi02 and a/AD02 ratio (see Fig. 18) showed a significant improvement in Insure group,

nCPAP+Neb200 and nCPAP+Neb400 groups in comparison with nCPAP group, while A-aD02 values rapidly decreased. The

improvements of above mentioned parameters were lower in nCPAP+Neb600 than in the other nebulised surfactant groups, showing nCPAP+NeblOO similar behaviour than nCPAP group.

Fi02 was rapidly reduced in Insure and nCPAP+Neb400 groups compared to nCPAP group (see Fig. 19) . Although Fi02 was also reduced in nCPAP+Neb200 and nCPAP+Neb600 groups, it was not as quick as in Insure group. Moreover, Fi02 in nCPAP+NeblOO group could not be reduced in comparison with nCPAP group.

In summary, the study was carried out in newborn piglets between days 2-4 of life with lung injury and surfactant deficiency induced by repeated saline lavage. In this animal model, bronchoalveolar lavages produced a significant

deterioration of gas exchange, ventilatory parameters and lung mechanics. At the end of stabilisation period, all newborn animals treated with repetitive BAL showed a stable and reproducible mild respiratory distress syndrome. In order to stimulate spontaneous breathing, all animals received a bolus dose of 20 mg/kg of Peyona® before extubation, and thereafter a nasal continuous positive airway pressure

(nCPAP) was established at 5 cmH20.

A new way of surfactant administration using a vibrating membrane nebuliser system (investigational eFlow Neonatal System, Pari Pharma, Munich, Germany) , was administered to newborn piglets with surfactant-deficient lung injury using four different administration doses (100 mg/kg, 200 mg/kg,

400 mg/kg or 600 mg/kg of Curosurf®) . The results from these studies were compared with two well-established clinical treatments; surfactant administration using Insure technique and nCPAP treatment.

During nCPAP treatment, a slight improvement of gas exchange, ventilatory parameters, lung mechanics (Cdyn) were observed during the first 90 min of treatment. After that, those parameters were maintained stable without any significant changes along the time.

As expected, bolus administration of Curosurf® using Insure technique, contributed to a rapid improvement of gas exchange (pH and PaC02 showed normal values 30 min after treatment) , ventilatory parameters (a-AD02 and Fi02 were similar to basal values 90 min after treatment) , lung mechanics (Cdyn recovered the basal values) in comparison to nCPAP treatment. Moreover, a significant reduction of total lung injury score was observed after Curosurf bolus administration in

comparison with nCPAP treatment, without significant differences in the evaluation of biochemical analysis of the lung (inflammatory and oxidative stress) .

Curosurf® delivered as a nebulised surfactant using a

vibrating membrane nebuliser improved lung function. However, depending on the surfactant administered doses, significant differences in gas exchange and ventilatory parameters could be observed. Of the four studied doses, the administration of 200 or 400 mg/kg of nebulised Curosurf® demonstrated the same or at least very similar behavior as the administration of surfactant using an Insure technique, in terms of gas

exchange, ventilatory parameters and so on. Moreover, in nebulised groups the results of above described parameters showed a similar time evolution, independently of when the results were evaluated, during 180 min of recovery period or 120 min after the end of surfactant treatment.

The biochemical analysis of the lung reported a significant reduction of catalase activity and TNF-alpha factor in nebulised groups compared with nCPAP and Insure treatment. Moreover, although all nebulised treated groups demonstrated a significant reduction of lung injury score in comparison with nCPAP treatment, showing Neb 400 and Neb 600 groups lower lung injury score than nCPAP+Insure group.

In conclusion, taking into account all the parameters studied in this study, the administration of nebulised Curosurf® in the range 200-400 mg/kg grants a great potential for future clinical applications.

Example 2

In the study of Example 2, Curosurf® nebulisation was

performed using a customised vibrating membrane nebuliser (investigational eFlow Neonatal Nebuliser System, PARI

Pharma, Munich, Germany) . The nebuliser was positioned between the nasal prongs (Fisher & Paykel Healthcare, nasal prongs 3520) and the Y-piece of the CPAP circuit. The prongs were connected directly to the nebuliser through a PARI custom made adapter.

The experiments were carried out in 6- to 7-week-old adult rabbits. The experimental procedure was approved by the local animal ethics committee and met the standard European

regulations on animal research. Management and use of the animals complied with the EEC and national regulations for animal care. Rabbits (body weight of 1.5-2.5 kg) were sedated with medetomidine (Domitor®) 2 mg/kg intramuscolarly (i.m.) and local anaesthesia was performed with lidocaine gel (Luan 1%®) in the anterior neck, after having shaved the throat. Thirty minutes after sedation, the animals received 50 mg/kg of ketamine (Imalgene®) and 5 mg/kg of xylazine i.m. Rabbits, in supine position, were intubated and stabilised on positive pressure ventilation (Acutronic Fabian HFO) with the

following settings: Fi02 100%, Flow Insp = 10/min,

respiratory rate (RR) = 40 breaths/min, positive end- expiratory pressure (PEEP) = 3 cmH20, tidal volume targeted to 7 ml/kg (considering PIP not higher than 23 cmH20) and inspiratory time of 0.5 sec. Airway flow, pressure and tidal volume were monitored continuously with a flow sensor

connected to the endotracheal tube. Body temperature was monitored continuously with a rectal probe and maintained by placing a heating pad underneath the animal. The pulse- oxymeter was attached to the rabbit's leg in order to monitor oxygen saturation and heart rate. After intubation, a

catheter was inserted into the right jugular vein for

continuous infusion of 1 mg/ml ketamine and 0.1 mg/ml

xylazine, while a second catheter was inserted into the right carotid artery for blood sampling. After instrumentation, blood gases were serially measured. If the inclusion criteria of Pa02 value > 450mmHg at PIP < 15cm H20 were met, the animal was featured in the study and it underwent repeated bronchoalveolar lavages (BALs) to achieve surfactant

depletion. BALs were performed by flushing the airways with 30 ml of pre-warmed 0.9% NaCl solution, followed by a short recovery period in-between, until a Pa02 value < 150mmHg was reached. Then, if after 15 min of stabilisation in mechanical ventilation the respiratory failure was re-confirmed with a new blood gas analysis (stabilisation period; 15ST) , the animal was extubated and managed by nCPAP, using Fisher & Paykel nasal prongs. Once spontaneous breathing was

established at a level of 5 cmH20, the nebuliser was inserted between the nasal prongs and the Y connector. Animals were then randomised to one of the six study groups:

Experiment group 1 named "nCPAP" group, n= 6: rabbits with surfactant deficiency induced by BALs were maintained in nCPAP for 180 minutes. In this group, the nebuliser was placed in the circuit for 30 minutes without surfactant treatment. This group works as "negative control group" in this experiment.

Experiment group 2 named "Neb. 100" group and Curosurf® nebulised 100 mg/kg, n=9: rabbits with surfactant deficiency induced by BALs received lOOmg/kg of nebulised Curosurf® and were maintained in nCPAP for 180 minutes.

Experiment group 3 named "Neb 200" group and Curosurf® nebulised 200 mg/kg, n=9: rabbits with surfactant deficiency induced by BALs received 200 mg/kg of nebulised Curosurf® and were maintained in nCPAP for 180 minutes.

Experiment group 4 named "Neb 400" group and Curosurf® nebulised 400mg/kg, n=9: rabbit with surfactant deficiency induced by BALs received 400 mg/kg of nebulised Curosurf® and were maintained in nCPAP for 180 minutes.

Experiment group 5 named "Neb 600" and Curosurf® nebulised 600 mg/kg, n=9: rabbits with surfactant deficiency induced by BALs received 600 mg/kg of nebulised Curosurf® and were maintained in nCPAP for 180 minutes. Experiment group 6 named "Insure" and InSurE 200 mg/kg n=9: rabbits with surfactant deficiency induced by BALs received 200 mg/kg of Curosurf® using the InSurE technique (H. Verder, B. Robertson, G. Greisen et al . , "Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome," New England Journal of

Medicine, vol. 331, no. 16, pp . 1051-1055, 1994). The

Curosurf® bolus was administered in about one minute. After surfactant administration animals were maintained in nCPAP for 180 minutes. This group works as "positive control group" in this experiment.

At the end of the observational period (120 minutes after the end of surfactant administration) , animals were intubated and managed in mechanical ventilation with the same setting used at baseline: Fi02 100%, Flow Insp = 10/min; respiratory rate (RR) = 40 breaths/minutes, positive end-expiratory pressure (PEEP) = 3 cmH20, tidal volume targeted to 7 ml/kg, and inspiratory time of 0.5 sec. After 15 minutes on mechanical ventilation, the respiratory parameters were measured for comparison with baseline and post- BAL values. At the end of the experiment, animals were euthanised with an overdose of Penthotal® 60mg/kg i.v. Ultimately, a pressure/volume (P/V) curve was performed (7) and BALs were collected to recover proteins and phospholipids alveolar contents (repetitive lavages were performed until no visual signs of surfactant was appreciated in the fluid) . Please see reports PRECLI-RP- 1254 and PRECLI-WI- 0186 for more details on the experimental procedure instructions and model validation.

Results of the experimental studies are shown in Figs. 20 and 21.

Specifically, Fig. 20 shows blood oxygenation values in the lavage (0; -15 minutes pre-treatment), stabilisation

(-15; -30 minutes pre-treatment) and post-treatment periods (0-120 minutes post-treatment). During lavage and stabilisation periods, the animals were under mechanical ventilation, while in post-treatment period under nCPAP. Data is reported as Pa02 values (mmHg, meaniSEM) : dashed line with solid circles for negative control group (n=6) , dashed line with solid diamonds for InSurE Curosurf® 200 mg/kg group (n=9) , solid line with empty circles for nebulised Curosurf® 100 mg/kg, dashed line with solid squares for nebulised

Curosurf® 200 mg/kg (n=9) , dotted line with empty triangles for nebulised Curosurf® 400 mg/kg (n=9) , dash-dotted line with solid triangles for nebulised Curosurf® 600 mg/kg (n=9) . Two hours after the end of surfactant treatment, Pa02 values in all treatment groups were significantly different in comparison with negative control group (*p<0.01); Pa02 values in the 100 mg/kg group were significantly different compared to Insure 200mg/kg group († p<0.05).

Immediately after the end of surfactant administration (bolus or nebulisation) , Pa02 values showed a rapid improvement in InSurE, 200, 400 and 600 mg/kg treated groups. After 120 minutes, all these groups showed Pa02 values that were significantly higher in comparison with the nCPAP-treated negative control group. The improvement was mild and slow in the 100 mg/kg group, which at two hours post treatment had significantly lower values than the InSurE group and not significantly different from the nCPAP group. Untreated animals (negative control) did not recover and their

oxygenation values were unchanged (-100 mmHg) despite nCPAP support (see Fig. 20) .

The pressure measured at maximal volume was significantly lower in the InSurE and 200 and 400 mg/kg groups in

comparison with the negative control group. Fig. 21 shows that the pressure P (cmH20) measured at maximal volume, i.e., a volume of 30 ml, was significantly lower in the InSurE, 200 and 400 mg/kg groups as compared to the negative control group (*p<0.05) . In summary, the study was carried out in adult rabbits (6-7 week old) with surfactant deficiency induced by repeated BALs with saline. In this animal model, BALs induced a significant worsening of the overall lung function including gas

exchange, ventilation parameters and lung mechanics. At the end of the stabilisation period (after induction of lung injury) , all animals showed a stable and reproducible strong respiratory distress. At this stage nCPAP was established at 5 cmH20.

Curosurf® was administered by nebulisation using a new vibrating membrane nebuliser (investigational eFlow Neonatal System, Pari Pharma, Munich, Germany) . Four different doses of Curosurf® (100 mg/kg, 200 mg/kg, 400 mg/kg or 600 mg/kg) administered by nebulisation were tested. The results from these groups were compared with two well-established clinical treatments: surfactant administration using the InSurE technique and nCPAP (no surfactant) treatment.

During nCPAP treatment, no improvement of gas exchange, ventilation parameters or lung mechanics was observed. In this group, all values did not change along the course of the study. As expected, bolus administration of Curosurf® using InSurE technique contributed to a rapid improvement of gas exchange (Pa02 values 30 minutes after treatment were

comparable to baseline values) and showed, at the end of the study, ventilation parameters and lung mechanics

significantly improved compared to nCPAP treatment. Among the four doses of nebulised surfactant, 200 and 400 mg/kg

demonstrated an efficacy equivalent to the InSurE technique in terms of gas exchange, ventilation parameters and lung mechanics. Although the 600 mg/kg group showed a significant improvement compared to the nCPAP group, its performance was not always comparable to the InSurE treatment. It is also worth to mention that the amount of surfactant that reaches the lungs after administering the 100 mg/kg dose did probably not suffice to elicit a significant therapeutic effect. In fact, the 100 mg/kg group showed only a slight improvement compared to the nCPAP negative control group. In conclusion, taking into account all the parameters monitored in this study, the administration of nebulised Curosurf® in the range between 200 and 600 mg/kg was found to be effective in the treatment of the surfactant-depleted adult rabbit model of RDS .