WO2019115802A1

WO2019115802A1 - Pharmaceutical formulation comprising pulmonary surfactant for administration by nebulization

Info

Publication number: WO2019115802A1
Application number: PCT/EP2018/085049
Authority: WO
Inventors: Fabrizio SALOMONE; Thomas Gallem; Uwe Hetzer
Original assignee: Chiesi Farmaceutici S.P.A.
Priority date: 2017-12-15
Filing date: 2018-12-14
Publication date: 2019-06-20
Also published as: TW201927286A; AR113942A1

Abstract

A pharmaceutical formulation in form of aqueous suspension comprising a pulmonary surfactant for use in the treatment of a patient affected by Respiratory Distress Syndrome (nRDS) and kept under ventilation with an artificial respiration machine, wherein i) the dose of said pulmonary surfactant is comprised between 160 and 600 mg/kg; ii) said surfactant is administered as an aerosol generated from a nebulizer connected to an artificial respiration machine. The nebuliser comprises a body with a first connection for connecting the nebuliser to the artificial respiration machine, and a second connection for connecting the nebulizer to a nasal interface leading to the patient. The body of the nebuliser forms a flow channel from the first connection to the second connection. The nebuliser also comprise a nebulising device, e.g. a vibrating membrane, for nebulising said surfactant which is designed and arranged in the flow channel between the first connection and the second connection.

Description

PHARMACEUTICAL FORMULATION COMPRISING PULMONARY SURFACTANT FOR ADMINISTRATION BY NEBULIZATION

FIELD OF TECHNOLOGY

The present invention relates to the field of aerosol administration of medicaments to the lungs, and particularly to the administration of an exogenous pulmonary surfactant by nebulization for the treatment of diseases due to the lack and/or dysfunction of endogenous surfactant.

BACKGROUND OF THE INVENTION

The present invention relates to methods and compositions for treating diseases that alter the surface active properties of the lung.

An important feature in all mammalian lungs is the presence of surface active lining material in the alveoli. These surface active materials are lung surfactants mainly comprising surface active proteins and phospholipids, which are produced naturally in the lungs and are essential to the lungs' ability to absorb oxygen.

In the absence of sufficient lung surfactant or when lung surfactant functionality is compromised, these air sacs tend to collapse, and, as a result, the lungs do not absorb sufficient oxygen.

Lack or dysfunction of the surfactant in the lungs results in a variety of respiratory illnesses in both neonates and adults. For example, insufficient lung surfactant may manifest itself as respiratory distress syndrome in premature neonates ("nRDS"), i.e. those born prior to 32 weeks of gestation, who have not fully developed a sufficient amount of endogenous lung surfactant.

For many years, nRDS has been treated by administration of exogenous pulmonary surfactants as bolus through endotracheal instillation to the intubated pre- term neonates kept under mechanical ventilation.

For instance, modified natural surfactants used in the clinical practice are poractant alfa derived from porcine lung, and sold under the trademark of Curosurf^®, beractant (Surfacten^® or Survanta^®) bovactant (Alveofact^®), both derived from bovine lung, and calfactant derived from calf lung (Infasurf^®).

Although said treatment is very effective, as proven by the reduced mortality, it presents some drawbacks which are intrinsic to the mechanical ventilation (volu/baro trauma) and to the intubation procedure which is anyway invasive.

In view of the potential complications associated with intubation and mechanical ventilation, attention has been focused on different approaches for the manangement of the pre-term neonates.

In particular, as a possible initial respiratory support, use of non-invasive ventilation procedures such as early nasal Continuous Positive Airway Pressure (nCPAP), that delivers air into the lungs through specifically designed nasal devices such as masks, prongs or tubes, has been introduced in neonatal intensive care.

Although this approach is feasible for some neonates, it entails that, if nCPAP fails, the effective delivery of surfactant via intratracheal instillation is substantially delayed, and the atelectrauma associated with persistent alveolar collapse may cause more severe disease than it would be avoided if surfactant were administered early in the course of the disease.

Therefore, in the last twenty years, great attention has been paid to find out alternative ways for pulmonary surfactant administration without concomitant mechanical ventilation.

Most of the efforts have been focused on the aerosol administration of pulmonary surfactants by means of commercial nebulizers connected to the ventilator circuit.

Preclinical studies in animal models with aerosol delivery systems has shown some promise of increased efficiency. The gas exchange and mechanical benefits that have been seen in animal lung models with the aerosol approach were comparable to those seen with the instillation technique, but those benefits were achieved with only a fraction of the conventional 100 mg/kg of body weight (BW) instilled dose (see MacIntyre, N. R., "Aerosolized Medications for Altering Lung Surface Active Properties". Respir Care 2000; 45(3) 676-683).

In Hutten, M et al Ped Res 2015, 78, 664-669, poractant alfa was administered for to spontaneously breathing pre-term lambs kept under binasal CPAP ventilation with the Pari e-Flow Neos device. However, some improved oxygenation and lung function was achieved after rather long nebulization time.

Simultaneous administration of surfactant aerosol therapy in conjunction with a CPAP system has been found to be clinically feasible and to result in improved respiratory parameters. See, for example, Jorch G et al; "To the Editor: Surfactant Aerosol Treatment of Respiratory Distress Syndrome in Spontaneously Breathing Premature Infants"; Pediatric Pulmonology 24:22-224 (1997); and Smedsaas- Lofvenberg A; "Nebulization of Drugs in a Nasal CPAP System"; Acta Paediatr 88: 89- 92 (1999).

Berggren E et al in Acta Pediatr 1990, 89(4), 460-464 treated 34 newborns with RDS using nCPAP and aerosolized poractant alfa. However, the investgators were unable to demonstrate the superiority of aerosolized surfactant delivery over nCPAP alone.

Finer N et al in J Aerosol Med Pulm Drug Del 2010, 23, 1-7 administered the synthetic surfactant to newbors with early sign of RDS with the nebulizer Aeroneb^® Pro. The procedure turned out to be safe but with lack of efficacy.

Pillow J et al J Ped Child Health 2013, 49(Suppl. 2), A 126 reported about the administration of 200 mg/kg poractant alfa administered to neonates of 29-33 gestional age kept under standard or bubble CPAP using the investigational Pari flow Neos device. A facial mask was used as interface. No conclusive data about the reduction of need for intubation at 72 h versus CPAP alone are provided.

The poor clinical results achieved so far, are likely due to the fact that aerosol delivery of surfactant to the lungs may be much less efficient than direct instillation, mainly because of large losses of aerosol in the delivery system. Estimates of lung delivery of aerosolized surfactants with most conventional delivery systems have been generally estimated of less than 1-10% of amount the liquid surfactant placed in the nebulizer.

Linner R et (Neonatology 2015, 107, 277-282) al compared surfactant deposition achieved via mask, nasal prongs, or tracheal tube upon administration of 200 m/kg poractant alfa to piglets kept under standard or bubble CPAP using an investigational Pari flow Neos device. The authors reported that, with said nebulizer, an improved deposition with nasal prongs, i.e 14%. However, even though these findings might be physiologically relevant, they have been achieved in an animal species with anatomic characteristics very different from a human nenonate. The variability of the data was also dramatically high.

Furthermore, no data are reported with different doses of pulmomary surfactant.

Due to the above variability, so far no conclusion has been reached about the most suitable therapeutic dose of pulmonary surfactants upon administration by nebulisation.

It follows that many important respiratory therapies for the treatment of lung surfactant deficiency or dysfunction have not been cost-effective or practical to pursue due to the inefficiencies of existing aerosol delivery technology.

Therefore there is still a need of more efficient surfactant administration approaches, in terms of dose and time of nebulization, to be performed with minimal risks in neonates kept under non-invasive re spiratory support and that might further avoid clinical instabilities associated with bolus fluid instillation.

It is an object of the present invention to overcome some of the problems associated with the prior art.

SUMMARY OF THE INVENTION

According to a first aspect, the invention is directed to a pharmaceutical formulation in form of aqueous suspension comprising a pulmonary surfactant for use in the treatment of a patient affected by Respiratory Distress Syndrome (nRDS) and kept under ventilation with an artificial respiration machine, wherein: i) the dose of said pulmonary surfactant is comprised between 160 and 600 mg/kg; ii) said surfactant is administered as an aerosol generated from a nebulizer connected to an artificial respiration machine, said nebuliser comprising a body with a first connection for connecting the nebuliser to the artificial respiration machine, and a second connection for connecting the nebulizer to a nasal interface leading to the patient, wherein the body forms a flow channel from the first connection to the second connection; and a nebulising device for nebulising said surfactant which is designed and arranged in the flow channel between the first connection and the second connection.

In a preferred embodiment the pulmonary surfactant is a modified natural pulmonary surfactant or a reconstituted surfactant having a viscosity equal to or less than 15 mPas (cP) at room temperature when it is suspended in an aqueous solution at a concentration of 80/mg/ml. Preferably the pulmonary surfactant is selected from poractant alfa or a biosimilar thereof.

In a preferred embodiment, the nebulizer have a rectangular interface port on the second connection to connect the nasal interface to the nebulizer. In a preferred embodiment, the nasal interface includes nasal prongs, more preferably said prongs having a length comprised between 8 and 13 mm and an inner diameter comprisied between 3.50 and 5.0 mm.

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.

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.

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.

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 of 35°C to 42°C, more preferably 37°C to 39°C and 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 threshold value may be, for example, 46°C, 45°C, 44°C, 43°C, 42°C, 4l°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.

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.

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 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 nebulizing device shall include 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 gradient 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 Al 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 pm, more preferably between 25 pm and 200 pm and even more preferably between 50 pm and 120 pm. The wall thickness of the carrier is preferably less than 500 pm, more preferably between 50 pm and 500 pm and even more preferably between 100 pm and 400 pm.

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 pm, more preferably between 25 pm and 500 pm and even more preferably between 100 pm and 400 pm.

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 artificial respiration, 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 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 assistant 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 assistant 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 mm². For small children, such as neonates, the smallest cross- sectional area of this line is commonly in the range of approximately 80 to 180 mm².

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 assistant 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 assistant 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 that is initially turbulent to be converted into a largely laminar flow by passing through the through holes, 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 impact of inertia on 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 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.

In a particular aspect, the nebulizer can be supported by a holding system.

Preferably, the holding system for holding the nebulizer comprises: a base having a curved shape, preferably of a U-shape; a single armed holding structure extending from the base; and a holding element configured to hold the nebuliser, wherein 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, and the holding element is attached to the holding arm substantially at the second end of the holding arm. Preferably, the holding arm is flexible.

According to a second aspect, the present invention is directed to the use a pharmaceutical formulation in form of aqueous suspension comprising a pulmonary surfactant selected from poractant alfa or a biosimilar thereof in the manufacture of a medicament for the treatment of a patient, preferably a neonate affected by Respiratory Distress Syndrome (RDS), more preferably a spontaneously breathing neonate, and kept under ventilation with an artificial respiration machine, wherein i) the dose of said pulmonary surfactant is comprised between 160 and 600 mg/kg; ii) said surfactant is administered as an aerosol generated from nebulizer connected to an artificial respiration machine, said nebuliser comprising a body with a first connection for connecting the nebuliser to the artificial respiration machine, and a second connection for connecting the nebulizer to a nasal interface leading to the patient, wherein the body forms a flow channel from the first connection to the second connection; and a mesh-vibrating nebulising device for nebulising said surfactant which is designed and arranged in the flow channel between the first connection and the second connection.

According to a third aspect, the present invention provides a method for treating a patient, preferably a neonate affected by Respiratory Distress Syndrome (RDS), more preferably a spontaneously breathing neonate, and kept under ventilation with an artificial respiration machine, said method comprising the step of administering a pharmaceutical formulation in form of aqueous suspension comprising a pulmonary surfactant selected from poractant alfa or a biosimilar thereof, wherein: i ) the dose of said pulmonary surfactant is comprised between 160 and 600 mg/kg; ii) said surfactant is administered as an aerosol generated from nebulizer connected to an artificial respiration machine, said nebuliser comprising a body with a first connection for connecting the nebuliser to the artificial respiration machine, and a second connection for connecting the nebulizer to a nasal interface leading to the patient, wherein the body forms a flow channel from the first connection to the second connection; and a nebulising device for nebulising said surfactant which is designed and arranged in the flow channel between the first connection and the second connection.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 shows a perspective view of a nebuliser system according to an embodiment of the present invention, which is schematically coupled to an artificial respiration machine;

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 artificial respiration machine;

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 artificial respiration machine;

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 illustrates the results of the in vivo deposition study of Example 1 ;

Fig. 19 shows a perspective bottom view of the adapter of Fig. 9 according to an embodiment;

Fig. 20 shows a perspective bottom view of an adapter according to another embodiment of the present invention; and

Fig. 21 shows a perspective view of an adapter according to another embodiment of the present invention.

DEFINITION

The terms“neonate” and“newborn” are used as synonymous.

In the context of the specification, the term“patient” refers to a human patient.

With the term“pulmonary surfactant” it is meant an exogenous pulmonary surfactant administered to the lungs that could belong to one of the following classes:

“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), poractant alfa (Curosurf™, Chiesi Farmaceutici SpA, Parma, Italy), and beractant (Survanta™, Abbott Laboratories, Inc., Abbott Park, Ill.).

“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).

“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, lucinactant (Surfaxin™, Windtree Therapeutics, Inc., Warrington, Pa.) and the product having the composition disclosed in WO 2010/139442.

As used herein the term“poractant alfa” refers to a modified natural surfactant extracted from porcine lungs substantially consisting of polar lipids, mainly phospholipids and the proteins, SP-B and SP-C. Poractant alfa is available under the trademark Curosurf^®.

The term“non-invasive ventilation (NIV) procedure defines a ventilation modality that supports breathing without the need for intubation.

The term“respiratory support" includes any intervention that treats respiratory illness including, for example, the administration of supplemental oxygen, mechanical ventilation, and nasal CPAP.

The term "treatment" refers to the use for curing, symptom-alleviating, symptom- reducing of a disease or condition.

The term "prevention" refers to the use for progression-slowing and/or onset delaying of a disease or condition. “Surfactant activity” for a surfactant preparation is defined as the ability to lower the surface tension.

The in vitro efficacy of exogenous surfactant preparations is commonly tested by measuring their capability of lowering the surface tension using suitable apparatus such as Wilhelmy Balance, Pulsating Bubble Surfactometer, Captive Bubble Surfactometer and Capillary Surfactometer.

The in vivo efficacy of exogenous surfactant preparations is tested by measuring lung mechanics in pre-term animal models according to methods known to the skilled person in the art.

With the term“nasal prongs” it is meant an interface used to deliver the airflow to the patient. Said interface consists of a lightweight tube which on one end splits into two prongs which are placed in the nostrils of the patient. The terms“nasal prongs” and “nasal cannulae” are used as synonymous.

With the term“vibrating mesh nebulizing device” it is meant a device wherein aerosol droplets are generated by a perforated vibrating membrane.

With the term“biosimilar of poractant alfa” it is meant a modified natural pulmonary surfactant which has the same safety profile, it is therapeutically equivalent, it has a similarity in the quali-quantitative composition of at least 80% (in particular regarding phospholipid and surfactant proteins SP-B and SP-C) and it has a viscosity equal to or less than 15 mPas (cP) at room temperature when it is suspended in an aqueous solution at a concentration of 80/mg/ml.

DETAILED DESCRIPTION OF THE INVENTION

Generally, the present invention comprises the steps of providing a pharmaceutical formulation of a pulmonary surfactant aerosolizing the pulmonary surfactant formulation with a nebulizing device, e.g. a vibrating mesh type aerosol generator, to form an aerosolized pulmonary surfactant; and introducing the surfactant aerosol into the gas flow within a circuit of a non-invasive respiratory support coupled to the nenoate respiratory system through nasal prongs, whereby a therapeutically effective amount of surfactant is delivered to the patient's lungs. In the examples herein reported, we address the problem of delivering the right amount of nebulized pulmonary surfactant to a patient: in particular we administrate the pulmonary surfactant poractant alfa, commercially available as Curosurf™ (from Chiesi Farmaceutici SpA) to e.g. a preterm neonate.

However, any biosimilar of said pulmonary surfactant currently in use, or hereafter developed for use in respiratory distress system and other pulmonary conditions could be suitable for use in the present invention.

The pulmonary surfactant is preferably administered as a suspension in a sterile pharmaceutically acceptable aqueous medium, preferably in a buffered physiological saline (0.9% w/v sodium chloride) aqueous solution. Advantageously, the concentration of the surfactant might be comprised between 25 and 160 mg/ml, preferably between 40 and 100 mg/ml, more preferably between 40 and 80 mg/ml, even more preferably of 80 mg/ml.

Preferably, the pulmonary surfactant is administered undiluted at a concetration of 80 mg/ml.

The applied volume should generally be not more than 8.0 ml, preferably not more than 7.5 ml. In some embodiments, it could be 2.5 ml, while in other it could be 6 ml.

Advantageously, the dose shall be comprised between 160 and 600 mg/kg.

More advantageously, the dose could be comprised between 160 and 320 mg/kg, preferably 200 mg/kg, or between 320 and 480 mg/kg, preferably 400 mg/kg, or between 480 and 600 mg/kg, preferably 600 mg/kg.

In an embodiment, the dose could range from 160 to 320 mg/ kg, preferably 200 mg administered in a volume of 2-4 ml, preferably of 2.5 ml.

In another embodiment, the dose could vary between 320 and 480 mg/kg administered in a volume of 4-6 ml.

In a further embodiment, the dose could vary between 480-600 mg/kg, preferably 600 mg/kg, administered in a volume of 6-7.5 ml.

In a particular embodiment of the invention, the dose could be 400 mg/kg administered in a volume of 5 ml. According to a preferred embodiment the pharmaceutical formulation is delivered by a nebulizer system enabling efficient aerosol treatment with enhanced aerosol dosage precision in an artificial respiration machine, in particular, for the treatment of any patient, especially neonates.

The nebuliser system may be configured so that a 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 pm, preferably less than 5 pm, more preferably between 1 pm and 5 pm, and even more preferably between 2 pm and 4 pm.

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 neonate, to be secured and reliably maintained.

Advantageously, the holding system for holding the nebulizer comprises: a base having a curved shape, preferably of a U-shape; a single armed holding structure extending from the base; and a holding element configured to hold the nebuliser, wherein 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, and the holding element is attached to the holding arm substantially at the second end of the holding arm. Preferably, the holding arm is flexible.

It has been found that by using the nebulizer as disclosen herein, different doses of pulmonary surfactant ranging from 160 mg/kg to 600 mg/kg could be aministered could be administerde within an acceptable time of delivery, i.e lesse than 60 minutes.

Furthermore, if the pulmonary surfactant is administered by connecting the nebulizer to nasal prongs instead of other tools such as facial mask, lesser leakage is observed and the deposition in the lungs turned out to be significantly higher.

Any nasal prongs commercially available may be used, for example those provided by Inspiration Healthcare Ltd (Leicestershire, UK) or Fisher & Paykel Healthcare (Auckland, New Zealand). Preferably, nasal prongs are used wherein the length of the prongs is comprised between 8.0 and 13.0 mm, preferably from 9.0 to 12.0 mm, and their inner diameter is comprised between 3.5 and 5.0 mm.

For instance, said prongs are available on the market as Inspire extra small (ES), small (S), medium (M) and large (L) from Inspiration Healthcare Group plc (Albourne, UK).

In fact, it was found that prongs having a shorter and slightly wider fluidic path from the nebuliser and the nose that the aerosol has to pass through give rise to a higher deposition of the surfactants in the lungs in comparison to those used in the prior art (about 19% vs about 14%).

Within being limited by the theory, the advantage is supposed to be linked to the fact that the aerosol impact on the walls of the prongs is reduced.

Said improvement is achieved for all the tested doses with a very low variability (CV less than ± 5%).

It has also been found that the slower the nebulization the higher is the lung dose. Therefore the output rate shall be adjusted to have the shorter time of nebulisation, but wothout jeopardizing the percentage of the dose deposited in the lungs.

Advantageosuly, the output rate is adjusted to have a nebulisation time no longer than 60 minutes, preferably no longer than 45 minutes, more preferably no longer than 30 minutes.

Typically, if a dose comprised between 150 and 300 mg/kg is administered, the nebulisation time shall be lesser than 30 minutes. In other embodiments, if a dose comprised between 300 and 500 mg/kg is administered, the nebulisation time shall be lesser than 45 minutes, while if a dose comprised between 450 and 600 mg/kg is administered, the nebulisation time shall be lesser than 60 minutes.

In some cases, the treatment could be repeated after 12 hours or after 24 hours.

Typically, the physician shall suitably evaluate if redosing is necessary as well its frequency.

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 20mbar, preferred between 3 and l5mbar, and more preferred at 5 to 1 1 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 and 42°C, preferred between 37°C and 39°C and more preferred around 37oC. Typically, the humidified air is utilized at body temperature. In another case especially a temperature around 42°C were used to simulate fever effects. Preferably the humidity is between 95% and 100% (not condensing), more preferably between 99% and 100%. As humidified and heated air may be used ambient air and/or air mixture and may including 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 pharmaceutical formulation according to the method of the invention may comprise other active ingredients suitable for the prevention and/or treatment of neonatal RDS such as for example steroids for inhalation, i.e. beclometasone dipropionate and budesonide, and vitamin A.

The method of the invention is suitable for the prevention and/or treatment of any human patient, preferably a neonate, affected by a disease due to the lack and/or dysfunction of endogenous surfactant, preferably the respiratory distress syndrome (RDS).

In a preferred aspect, the method of the invention is suitable for the prevention and/or treatment of pre-term neonates affected by neonatal RDS (nRDS) of any severity, preferably mild-to-moderate nRDS.

However, it could be advantageously utilized for the prevention and/or treatment of the adult/acute RDS (ARDS) related to a surfactant-deficiency or dysfunction as well as of conditions in which respiratory distress may be present as a consequence of, for instance, meconium aspiration syndrome, pulmonary infection (e.g. pneumonia), direct lung injury and bronchopulmonary dysplasia.

Advantageously, the method of the invention is applied to neonates, preferably pre-term neonates who are spontaneously breathing, of 24-37 weeks gestational age, preferably 26 to 35 weeks gestational age, more preferably 28 to 32 weeks. In a preferred embodiment of the invention, nasal Continuous Positive Airway Pressure (nCPAP) could be applied as non- invasive ventilation support. For example, typical apparatus for nCPAP are commercially available from Inspiration Healthcare Ltd (Leicestershire, UK) Fisher & Paykel Healthcare (Auckland, New Zealand), and Philips Respironics (Murrysville, PA, USA).

Adavantageously, nCPAP could be applied to the above patients, through the use of a nasal interface, according to procedures known to the person skilled in the art.

Other non-invasive ventilation procedures such as nasal intermittent positive- pressure ventilation (nIPPV), synchronized nIPPV (SnIPPV), and bilevel positive airway pressure (BiPAP) could alternatively be applied to the patients.

In a more preferred embodiment of the invention, nCPAP is applied at a pressure comprised between 1 and 12 cm water, preferably 2 and 8 cm water. However the pressure could be adjusted by the physician depending on the age of the patient and the severitiy of the pulmonary condition.

In another embodiment of the invention, synchronized nasal intermittent positive- pressure ventilation (SnIPPV) could be applied as similar results are obtained as reported in Example 2 if this ventilation support is used to replace nCPAP.

Typical apparatus for SnIPPV are available from Medical Produktion AG (Hirze, Switzerland) and Fritz Stephan GmbH Gackenbach, Germany).

A nebuliser system according to an embodiment of the present invention will be described with reference to the Figures.

The nebuliser system shown in Fig. 1 comprises the nebuliser, an adapter 104, such as the adapter 300 shown in Figs. 1 1 and 12 or 19, 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 artificial respiration machine 100. The artificial respiration machine 100 is a currently preferred embodiment of an assistant breathing device. The second connecting piece 12 is in turn configured to be connected to an air exhaust line 102 of the artificial respiration machine 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 patients, 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 precision and efficiency.

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 artificial respiration machine 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 l/min. The basic flow is often also referred to as a“bias flow”.

The artificial respiration machine 100 may be a positive pressure assistant breathing device, such as a BiPAP, a CPAP, or a nCPAP.

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 1 1 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 artificial respiration machine 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 1 1 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 artificial respiration machine 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 artificial respiration machine 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 artificial respiration machine 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 artificial respiration machine 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 artificial respiration machine 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 1 1. The connecting piece 1 1 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 1 1. The connector 105 is configured to connect the connecting piece 1 1 to the air supply line 101 and the air exhaust line 102 of the artificial respiration machine 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 or 19), 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 artificial respiration machine 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 1 1. The connecting piece 1 1 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 1 1. 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 Fig. 19. The modified adapter 300 shown in Fig. 19 differs from the adapter 300 shown in Figures 1 1 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 1 1 and 12 are denoted by the same reference signs and a repeated detailed description thereof is omitted.

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

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 of 35°C to 42°C, more preferably 37°C to 39°C and 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 threshold value may be, for example, 46°C, 45°C, 44°C, 43°C, 42°C, 4l°C, 40°C, 39°C or 38°C.

A further modification of the adapter 300 is shown in Figure 20. The modified adapter 300 shown in Figure 20 substantially differs from the adapter 300 shown in Figure 19 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, as will be further detailed below. In the description of the modified adapter 300 shown in Figure 20, the elements which are identical to those of the adapter 300 shown in Figure 19 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 20, 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 1 1).

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 1 1, 12 and 19. The modified adapter 300 shown in Figure 20 differs from the adapters 300 shown in Figures 11 , 12 and 19 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 20). 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 20 further comprises a connection element 320 for connecting a temperature sensor, such as the temperature sensor 316 (see Figure 19), 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 20). 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 20. 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 has four recesses or grooves which are substantially equidistantly spaced along a circumference of the connection element 320.

A further modification of the adapter 300 is shown in Figure 21. The modified adapter 300 shown in Figure 21 substantially differs from the adapter 300 shown in Figure 20 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 21, the elements which are identical to those of the adapter 300 shown in Figure 20 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 21, 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 21, the insertion process of the support member is facilitated by the provision of protruding portions 330. These protruding portions 330 protmde 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 21). The protruding portions 330 are inclined relative to the side or surface of the adapter 300 from which they protmde or project, as is shown in Figure 21. Each of the protmding 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 precision and efficiency.

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 artificial respiration machine 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.

The invention is illustrated in detail by the following Examples.

EXAMPLE 1 - Curosurf delivery by the nebulization of the invention - in vivo deposition study

For comparative purposes, some animals to be treated as “INSURE,” i.e., intubated with direct instillation of surfactant via an endotracheal tube.

We tested the following groups:

1. CPAP via nasal prongs with Curosurf^® (200 mg/kg) continuous nebulization with the animal lying on one side: group name“n-CPAP+continuous neb(CC 200) side”;

2. CPAP via nasal prongs with Curosurf^® (600 mg/kg) continuous nebulization with the animal lying on one side: group name“n-CPAP+continuous neb(CC 600)”.

1.1 Methods

We studied 12-36 hours old full-term piglets weighing 1550 (1 195- 2150) g [median (min- max)]. The piglets were premedicated with i.m. ketamine, midazolam, and atropine. An ear vein was cannulated, and then they were sedated with a continous iv. infusion of dexmedetomedine and ketamine. Sedation was supplemented with small intermittent boluses of iv. propofol, dexmedetomidine and remifentanyl as needed to keep the animals comfortable. An arterial catheter was placed in the femoral artery under local anesthesia and ultrasound guidance. Temperature, ECG, invasive blood pressure, heart rate, pulse oximetry, cerebral oximetry and transcutaneous carbon dioxide partial pressure were continuously monitored in all animals.

Groups receiving n-CPAP and 200 mg/kg undiluted Curosurf® nebulized via nasal prongs in continuous mode (n=12)

After preparation, the animals were randomized to the treatment group. Once in one of the incubators where nebulization would take place, and after all monitors were in place (EKG, pulse oximeter, cerebral oximeter, rectal temperature, invasive pressure monitoring, esophageal pressure catheter when in incubator A), the nostrils were instilled with the nasal decongestant: Nezeril (oximethazoline chloride). Lidocaine (2 mg)/adrenalin (0.5 mg) mixture was administered as an inhalation to prevent swelling and needless painful stimulation by the nasal prongs. With the animal lying on one side, the prongs were then inserted into the nares and connected to the nebulizer T-piece. The other end of the T-piece was previously connected to the equipment delivering CPAP (Servo-I ventilator), which was set to nasal-CPAP mode, 3 cm H₂0, and F1O2 = 0.4. The nebulizer was thus situated in the apparatus dead space which comprises a volume of approximately eight mL. The air-oxygen mixture was conditioned by an active humidifier (Fisher-Paykel 850). Alternating pigs in the group were randomly placed on the right or left side, respectively, noted in the protocol. Curosurf^® (200 mg/kg, 2.5 mL/kg of 80 mg/mL) was then thoroughly mixed with the radioactive tracer (approximately 0.3 ml) in a syringe and the mixture transferred to the nebulizer chamber. Nebulization was immediately initiated. Every 5 min during treatment all relevant parameters were noted in the protocol. Blood gasses were taken as described above. The time for complete nebulization and/or any interruptions during treatment were noted in the protocol.

Group receiving n-CPAP and 600 mg/kg undiluted Curosurf® nebulized via nasal prongs in continuous mode (n=12)

As above. Curosurf^® (600 mg/kg, 7.5 mL/kg of 80 mg/mL) was then thoroughly mixed with the radioactive tracer (approximately 0.3 ml) in a syringe and the mixture transferred to the nebulizer chamber.

1.1.1 Animal ventilation system

The non-invasive ventilation interface consisted of customized nasal prongs we assembled ourselves. Two Rusch soft PVC tracheal tubes of ID (internal diameter) 3.0 mm and OD (outer diameter) 4.7 mm (Teleflex Medical GmbH, Kernen, Germany), were cut at the proximal end to a total length of 3.5 cm from the tracheal tip. These two pieces were then attached to the rigid plastic connector/mount from Kendall Argyle’s neonatal nasal cannula size Large as shown in Figure 2. The compiled prongs were connected to the e-Flow nebulizer (PARI Pharma GmbH, Grafelfmg, Germany) and its connector attached to the Y-piece of a dual limb infant Evaqua™ breathing circuit (Fisher&Paykel Healthcare, Auckland, New Zealand) connected to the ventilator used as CPAP generator: a Servo-I (Maquet, Solna, Sweden) in nasal-CPAP mode or noninvasive pressure support mode. A Servo Duo Guard filter (Maquet Critical Care AB, Solna, Sweden) was used at the end of the expiratory limb, at the entrance to the ventilator, to absorb moisture and the radioactive mixture exhaled. The air-oxygen mixture delivered was conditioned through an active humidifier FP850 (Fisher&Paykel Healthcare, Auckland, New Zealand). In the nasal-CPAP mode, the ventilator maintained a continuous positive airway pressure (CPAP) of 3 cm H₂0, with an inspired oxygen fraction (Fi0₂) of 40 %. The mouth was kept closed. In noninvasive pressure support mode, 3 cm H₂0 above a PEEP of 3 cm H₂0 were administered, with an inspired oxygen fraction (Fi0₂) of 40 %. The mouth was kept closed.

1.1.2 Measurement of surfactant distribution

The activity of the ^99mTc-labelled nanocolloid was measured by a radiation counter. For each piglet receiving nebulized Curosurf^®, 200 MBq of technetium 99m- labelled nanocolloid particles were thoroughly mixed with Curosurf^® immediately before administration. The total volume of Curosurf^® to be delivered to each piglet was 2.5 mL/kg (80 mg/mL, 200 mg/kg) or 7.5 mL/kg (80 mg/mL, 600 mg/kg) depending on group assignment.

The distribution of the nebulized or instilled surfactant was evaluated with gamma scintigraphy. Images were taken before and after i.v. injection of ^99mTc-labelled macroaggregated human serum albumin (MAA), a substance that is trapped in the lung capillaries, allowing delineation of the lung fields. Also, the MAA injection was used for calibrating the images. That way, the amount of ^99mTc-labelled nanocolloid, deposited in the lungs, could be determined and, by inference, also the amount of deposited surfactant. The procedure is detailed in the next series of illustrations.

The animals were transported to the Gamma-camera spontaneously breathing and receiving extra oxygen via standard nasal prongs.

1.2 Results

As shown in Figure 18, the mean lung deposition of inhaled surfactant was 15.9 % (range 3.3-38.6) for the 200 mg/kg group and 23.1% (5.3-47.8) for the 600 mg/kg group. Even if the two groups present marked inter-subject variability (probably related to each animal specific breathing pattern and upper airways congestion status), the reported data show a significant deposition improvement compared to what has been reported in the literature for non-invasive delivery deposition study with a mask, i.e. about 5% (Linner R et al.Neonatology 2015, 107, 281).

1.3 Conclusions

The main findings of this study were:

1 - The new neonatal nebulizer by PARI Pharma with eFlow technology showed a stable output throughout the study with very few outliers.

2 - There was a large variability in the observed lung deposition. The deposition range in a group could vary from a few percent of the total administered dose up to 51% of the total dose. We have not been able to identify any single factor that can explain this large in vivo variability. The mean deposition in all groups was above 15% (32.9% in the prone group) of the total administered dose.

3 - We have confirmed the feasibility of administering surfactant using unsynchronized nebulization. Taking into consideration that the upper airway of the piglets should have a higher resistance to flow (which facilitates rain out of the administered aerosol), it seems reasonable to assume that larger amounts of nebulized surfactant would reach the larger airways of human neonates.

EXAMPLE 2 - Curosurf nebulisation delivery dose finding study in a respiratory distress adult rabbit model managed in nCPAP

2.1 MATERIALS AND METHODS

2.1.1 Nebulizer

Curosurf nebulization was performed using the customized vibrating membrane nebulizer of the invention (eFlow Neonatal Nebulizer System, PARI Pharma, Munich, Germany). The nebulizer 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 nebulizer through a PARI custom made adapter (Figures 11, 12, 19, 20 and 21).

2.1.2 Animal and delivey protocol

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 stabilized on positive pressure ventilation (Acutronic Fabian HFO) with the following settings: Fi02 100%, Flow Insp = lO/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 < l5cm 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 theairways with 30 ml of pre -warmed 0.9% NaCl solution, followed by a short recovery period in-between, until a Pa02 value < l50mmHg was reached. Then, if after 15 min of stabilization in mechanical ventilation the respiratory failure was re-confirmed with a new blood gas analysis (stabilization 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 nebulizer was inserted between the nasal prongs and the Y connector. Animals were then randomized to one of the six study groups:

- nCPAP group, n= 6: rabbits with surfactant deficiency induced by BALs were maintained in nCPAP for 180 minutes. In this group, the nebulizer was placed in the circuit for 30 minutes without surfactant treatment. Negative control group.

- Curosurf nebulized 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.

- Curosurf nebulized 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.

- Curosurf nebulized 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.

- Curosurf nebulized 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.

- 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. Positive control group.

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 = lO/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 euthanized 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.

2.1.3 Physicologic Lung Function Analysis

Arterial pH and blood gases were measured at baseline (basal value), after BAL- induced lung injury, at the end of the stabilization period (15 minutes after BALs in mechanical ventilation, 15 ST), and after extubation, right after placing the animals on nCPAP. With the animals on nCPAP, arterial blood gases were measured at 15 min and 30 min and then every 30 min until the end of the experiment. Alveolar- arterial (A-a) oxygen tension difference (A-aD02) and arterial/alveolar (a/A) ratio were calculated. Pa02 (mmHg) / (7l3*Fi02) - (PaC02 (mmHg)/0.8). RR was calculated by counting peaks of the respiratory flow on the ventilator display for 1 min. RR was determined at baseline (basal), after BALs collection, at the end of the stabilization period on mechanical ventilation and, after extubation, while on nCPAP, at 15 min and 30 min, and then every 30 min until the end of the experiment. Values of dynamic compliance (Cdyn), tidal volume (VT), ventilation efficiency index (VEI) and oxygenation index (01) were measured at baseline (basal value), after BAL-induced lung injury, at the end of the stabilization period (15 minutes after termination of BALs), and at the end of experiment. The VEI was calculated to evaluate the overall ventilation efficiency of mechanically ventilated animals independently from the different ventilator pressure, respiratory rate and PaC02 values. The oxygenation index (01) was calculated to describe the severity of pulmonary dysfunction in ventilated animals. A P/V curve was performed post mortem by progressively applying through a syringe 5, 10, 15, 20, 25 and 30 ml of air-volume. The pressure of the system was recorded at each volume point. Semi-quantitative measurements of surfactant proteins and phospholipids will be performed on BAL samples collected at the beginning (during surfactant depletion) and at the end of the experiments (after treatment with exogenous surfactant).

2.1.4 Data Analysis

All data are presented as mean ± SEM. Raw data were analyzed and compared by repeated measures two- way analysis of variance (ANOVA) as a function of group and time, followed by Tukey’s t post-hoc test. Statistical analysis was performed using GraphPad software, version 6.0.

2.2 RESULTS

2.2.1 Body weights

Irrespective of the group, the body weight of the animals did not significantly differ (nCPAP: 1.72 ± 0.09 kg; InSurE + nCPAP group: 1.7 ± 0.07 kg; nCPAP + Curosurf 600 mg/kg: 1.74 ± 0.07 kg; nCPAP + Curosurf 400 mg/kg: 1.76 ±0.06 kg; nCPAP ± Curosurf 200 mg/kg: 1.71 ± 0.07 kg; nCPAP ± Curosurf 100 mg/kg: 1.8 ± 0.06 kg).

2.2.2 Surfactant depletion in adult rabbits Surfactant depletion was produced by repeated BALs using 30ml/kg of pre- warmed saline (37°C). Multiple lavages were performed for all groups: nCPAP group: 7.33 ± 1.02; InSurE+nCPAP group: 5.1 ± 0.7; nCPAP+Curosurf 600 mg/kg: 6.3 ± 0.66; nCPAP+Curosurf 400 mg/kg: 6.22±0.59; nCPAP+Curosurf 200: 5.78 ± 1.05; nCPAP+NeblOO: 7.44 ± 0.67). The average number of lavages necessary required to reach surfactant depletion did not differ among groups.

2.2.3 Gas exchange, ventilation parameters and lung mechanics at basal

All animals had similar gas exchange and ventilation parameters at baseline as well as 15 min after induction of surfactant deficiency (15ST) (Table. 1). BALs produced an abrupt decrease of Pa02, VEI and a/AD0 , with a significant increase of OI, A-aD0₂ and PaC0₂ levels in all groups. Moreover, after BALs, all groups showed a significant decrease of VT and Cdyn. The impairment of the above- described parameters indicated that repetitive BALs in adult rabbits induce a stable and severe respiratory failure, making surfactant depleted animals a useful preclinical model to evaluate the effectiveness of different modes of surfactant administration.

2.2.4 Depleted animal treatment. Follow-up of 120 min after the end of treatment

In this section, results were compared along the two hours following the end of the treatment.

Gas exchange and ventilation parameters

Immediately after the end of surfactant administration (bolus or nebulization), 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. After the end of surfactant administration (bolus or nebulization), all surfactant- treated groups showed a trend towards reduction of PaC0 in comparison to the negative control group. Two hours after the end of the surfactant treatment, PaC0 and pH values of the 400 mg/kg group were significantly improved compared with those of the negative control group. However, on average PaC0₂ and pH values did not recover to baseline.

Immediately after the end of surfactant treatment, the respiratory rate decreased in all treatment groups compared to the negative control group, and significant differences were appreciated two hours after the end of treatment for all surfactant groups, compared to the negative control group.

Lung mechanics

All animals after BALs showed a significant increase of OI and a significant decrease of VEI. At the end of experiment, the OI values decreased significantly in all groups treated with nebulized surfactant, in comparison to the negative control group. The OI values at the 100 mg/kg dose was significantly different in comparison with the Insure group. Moreover, the VEI values increased significantly only in InSurE and 400 mg/kg groups in comparison to the negative control group.

After BALs all groups showed a decrease of dynamic compliance. At the end of experimental period, dynamic compliance improved in all groups treated with nebulized surfactant, in comparison to the negative control group. However, only compliance values of groups treated with 200 and 400 mg/kg doses reached statistical significance compared to the negative control group.

2.3 CONCLUSIONS

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 stabilization 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 nebulization using the customized new vibrating membrane nebulizer of the invention (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 nebulization 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 nebulized surfactant, 200 and 400 mg/kg demonstrated an efficacy equivalent 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 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 nebulized 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. In particular, the 200 and 400 mg/kg doses induced a sustained recovery comparable to the one achieved after administration of Curosurf^® with the InSurE technique. EXAMPLE 3 - In vitro performance of the nebulizer of the invention with different types of interfaces

Background and aims: Aerosol lung deposition is dramatically reduced in preterm infants due to their breathing pattern and to the narrow cross-section of the airways and ventilation interfaces. Our aim was to determine the in vitro performance of the customized vibrating-membrane nebulizer of the invention on poractant alfa (Curosurf) lung deposition when using different types of interface.

Methods: The surfactant aerosol particle size distribution and respirable fraction (RF) were investigated by laser-diffraction and Next Generation Impactor (NGI). Breath simulation studies were conducted in an experimental set-up consisting of a humidified CPAP circuit (5 cmFbO), the nebulizer, placed between the Y-piece and the ventilation interface (nasal mask or prongs, see Table 1), a pre-term upper-airway 3D model (PrINT model of a 1.75 kg preterm baby), and a breath simulator (flow 5 L/min, tidal volume 9 ml/kg, and breath rate 70/min). Collection filters were placed beyond the PrINT cast to estimate the surfactant lung-dose. The phospholipid content of the collected surfactant fraction was determined by liquid chromatography-mass spectrometry. A total mass of 350 mg (200 mg/kg dose) of surfactant (80 mg/ml) was nebulized.

Results: The findings are reported in Table 2. The mass median diameter was 3.0 pm and the RF 93.7%. Irrespective of the ventilation interface, surfactant lung doses were relatively high for neonatal standards ranging between 10 and 19%, with low associated delivery times.

Conclusion: the eFlow Neos nebulization of poractant alfa produces appropriate surfactant aerosol characteristics and provides high lung deposition under realistic neonatal conditions in vitro.

Table 1

Table 2

EXAMPLE 4 - PROTOCOL OF THE CLINICAL STUDY

PROTOCOL OUTLINE

LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

Claims

1. A pharmaceutical formulation in form of aqueous suspension comprising a pulmonary surfactant for use in the treatment of a patient affected by a disease due to the lack and/or dysfunction of endogenous surfactant and kept under ventilation with an artificial respiration machine, wherein

i) the dose of said pulmonary surfactant is comprised between 160 and 600 mg/kg;

ii) said surfactant is administered as an aerosol generated from a nebulizer connected to an artificial respiration machine, said nebuliser comprising a body with a first connection for connecting the nebuliser to the artificial respiration machine, and a second connection for connecting the nebulizer to a nasal interface leading to the patient, wherein the body forms a flow channel from the first connection to the second connection; and a nebulising device for nebulising said surfactant which is designed and arranged in the flow channel between the first connection and the second connection.

2. A pharmaceutical formulation for use in the treatment of a patient according to claim 1 , wherein the pulmonary surfactant is a modified natural pulmonary surfactant or a reconstituted surfactant having a viscosity equal to or less than 15 mPas (cP) at room temperature when it is suspended in an aqueous solution at a concentration of 80/mg/ml.

3. A pharmaceutical formulation for use in the treatment of a neonate according to claim 1 or 2, wherein the pulmonary surfactant is selected from poractant alfa or a biosimilar thereof.

4. A pharmaceutical formulation for use in the treatment of a patient according to any preceding claim, wherein the nasal interface includes nasal prongs.

5. A pharmaceutical formulation for use in the treatment of a patient according to any preceding claim, whereby the nebulizing device comprises a vibratable membrane and a vibrator, and the vibrator is configured to vibrate the vibratable membrane so as to nebulise the liquid.

6. A pharmaceutical formulation for use in the treatment of a patient according to any preceding claim, whereby the nebulizer have a rectangular interface port on the second connection to connect the nasal prongs to the nebulizer.

7. A pharmaceutical formulation for use in the treatment of a patient according to any preceding claim, wherein the nebulizer is supported by a holding system.

8. A pharmaceutical formulation for use in the treatment of a patient according to any preceding claim, whereby the nebulising device for nebulising the pulmonary surfactant is designed and arranged in the flow channel between the first connection and the second connection such that the surfactant can be nebulised essentially parallel to the flow direction from the first connection to the second connection.

9. A pharmaceutical formulation for use in the treatment of a patient according to any preceding claim, wherein the nebulizing device is arranged in the flow channel such that an air flow, generated by the artificial respiration machine and flowing through the flow channel from the first connection towards the second connection, flows around the nebulising device.

10. A pharmaceutical formulation for use in the treatment of a patient according to any preceding claim, wherein the artificial respiration machines is a positive pressure assistant breathing device selected from the group consisting of nasal CPAP and nasal IPPV.

1 1. A pharmaceutical formulation for use in the treatment of a patient according to claim 8 or 9, whereby the nebulising device is configured such that the surfactant can be nebulized within an angle of +/-45° to and preferably in the direction of the flow from the first connection to the second connection.

12. A pharmaceutical formulation for use in the treatment of a patient according to any preceding claim, wherein the dose of poractant alfa is comprised between 160 and 600 mg/kg which is administered in a volume of 2-7.5 ml.

13. A pharmaceutical formulation for use in the treatment of a patient according to claim 12, wherein the dose of poractant alfa is comprised between 160 and 320 mg/kg which is administered in a volume of 2-4 ml.

14. A pharmaceutical formulation for use in the treatment of a patient according to claim 12, wherein the dose of poractant alfa is comprised between 320 and 480 mg/kg, which is administered in a volume of 4-6 ml.

15. A pharmaceutical formulation for use in the treatment of a patient according to claim 12, wherein the dose of poractant alfa is comprised between 480 and 600 mg/kg, which is administered in a volume of 6-7.5 ml.

16. A pharmaceutical formulation for use in the treatment of a patient according to any preceding claim, wherein the patient is a spontaneously breathing pre-term neonate affected by neonatal RDS.

17. A pharmaceutical formulation for use in the treatment of a patient according to claim 16, wherein the neonate has a gestational age of 26 to 32 weeks.