Patent Grant
10456538
This application claims priority to European Patent Application No. 12165234.1, filed on Apr. 23, 2012, which is incorporated herein by reference in its entirety.
Field of the Invention
The present invention relates to the field of retropharyngeal instillation of a medicament and particularly to a method and system for the administration of a pulmonary surfactant by atomization.
Discussion of the Background
Administration of a medicament in the lungs is often faced with the problem of finding the right balance between the efficacy and the invasiveness of the treatment. This is particularly difficult with infants (hereinafter the term neonates is used as synonymous of infants). Preterm neonates may be affected by nRDS (neonatal Respiratory Distress Syndrome), a lung disease due to generalized immaturity which causes the lack of pulmonary 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. Although this treatment is very effective, as proven by the reduced mortality, it may present some drawbacks which are intrinsic to the mechanical ventilation (volu/barotrauma) 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 of administration of exogenous pulmonary surfactants. In particular, as a possible 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.
Following this orientation, in the last fifteen years great attention has also been paid to finding an alternative way for pulmonary surfactant administration. Most of the performed studies have been focused on the administration of nebulized surfactant (i.e. particles with a mass diameter<10 μm) by means of commercial nebulizers connected to the ventilator circuit, based on the hypothesis that a gentler and more gradual administration should prevent the high cerebral blood fluctuation that may occur with bolus administration (See e.g. Mazela J, Merrit T A, Finner N N “Aerosolized surfactants” Curr Opin Pediatr. 2007; 19(2): 155; or Mazela J, Polin R A “Aerosol delivery to ventilated newborn infants: Historical challenges and new directions” Eur J Pediatr. 2011:1-12; or Shah S “Exogenus surfactant: Intubated present, nebulized future?” World Journal of Pediatrics. 2011; 7(1): 11-5, both of which are incorporated herein by reference in their entireties). Albeit the surfactant results more homogenously distributed, the improvements in the lung functionalities obtained in the different studies are very contrasting and they do not evidence the effectiveness of the nebulization approach. In other studies surfactant nebulization system was connected to non-invasive ventilator settings (i.e. CPAP through nasal prongs); in these conditions the amount of nebulized surfactant that reached the lung appeared to be negligible (less than 20%). Moreover nebulized surfactant administered during CPAP has no conclusive beneficial impacts on lung functionality as shown in pilot studies on preterm neonates (see e.g. Berggren E, Liljedhal M, Winbladh B, Andreasson B, Curstedt T, Robertson B, et al “Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome” Acta Paediatrica 2000; 89 (4): 460-4; or Firmer N N, Merritt T A, Bernstein G, Job L, Mazela J, Segal R “An open label, pilot study of Aerosurf combined with nCPAP to prevent RDS in preterm neonates” Journal of aerosol medicine and pulmonary drug delivery. 2010; 23(5): 303-9; or Jorch G, Hartl H, Roth B, Kribs A, Gortner L, Schaible T, et al “Surfactant aerosol treatment of respiratory distress syndrome in spontaneously breathing premature infants” Pediatr Pulmonol. 1997; 24(3):222-4, all of which are incorporated herein by reference in their entireties). The studies are very variable and the authors apply different conditions with reference to several parameters, e.g.: 1) placement and type of aerosol generator, 2) mode of ventilation, 3) humidity, 4) air flow, 5) particle size, 6) nRDS models, 7) surfactant dilution, etc. Therefore it is difficult to make a proper comparison among them. However known systems do not generally prove to be very effective.
Moreover, when an aerosolized surfactant is administered with a nebulizer through a mask and not synchronized with the neonate' breath, some part can be exhaled during expiration and either deposits into the upper airways or tubing/connections or it is exhaled by the expiratory limbs. Moreover, the delivery of nebulised surfactant adds dead-space to the breathing circuits and, considering that preterm newborns may have a tidal volume of 1 ml or even less, this can promotes CO2 retention that, eventually, could become dangerous if a final situation of hypercapnia is achieved.
An interesting approach that could partially mitigate the above risk has been proposed by Wagner et al (Wagner M H, Amthauer H, Sonntag J, Drenk F, Eichstädt H W, Obladen M “Endotracheal surfactant atomization: an alternative to bolus instillation?” Crit Care Med. 2000; 28(7):2540, which is incorporated herein by reference in its entirety) showing encouraging results. It is based on a modified tracheal tube with an atomizer inserted at the tip of the tube which produces particles, that have a SMD (Souter Mean Diameter)>100 μm, only during inspiration (identified by an operator). The choice of putting the atomizer directly into the tube has been technologically challenging.
The promising results of the Wagner approach are probably due to the bigger dimensions of the particles which allow the distribution and absorption of the pulmonary surfactant similar to the mechanisms involved in the bolus administration. In particular, it can be hypothesized that big particles will deposit on more central airways, being able to reach the non-expanded alveoli by diffusion gradient, Marangoni effect and capillarity, while, on the contrary, the small nebulized particles, which are able to pass through the upper airways, are likely to be either exhaled during expiration or being deposited into the already opened alveoli which produces the airflow during breathing, without reaching the attelectatic region of the lung and contributing to an even more inhomogeneous distribution of lung time constants. Another advantage of Wagner is that the pulmonary surfactant is administered during inspiration phase only and this helps in better controlling the quantity of medicament effectively delivered (with improvements in terms of saving and clinical results).
A drawback of Wagner is that the tube must reach the trachea (where the nebulizer is placed), in order to be able to deliver the big sized particles which would be filtered out by the upper airways, and this procedure is invasive and can cause problems, in particular for neonates. On the other hand, all known prior art systems implementing a non-invasive (i.e. not entering the tracheal tube) delivery method are capable of administering only small sized particles which are able to overcome the outer barrier, but are less efficient in reaching all the lung regions needing treatment.
Furthermore, according to Wagner's experiment, the “synchronization” of the delivery of medicament with the inspiration rhythm is done manually, which is not ideal for obvious reasons including a waste of the product. On the other hand all attempts known in the art for implementing such synchronization, for example those described in EP 692 273, which is incorporated herein by reference in its entirety, depend on the presence of devices such as a mechanical ventilator. However, this solution needs connections to the airway of the newborn, adding dead space and mechanical load to the patient's breathing.
For all these reasons, an improved non-invasive method and system for administering the exogenous surfactant which is capable of combining the advantages of big size particle nebulization with proper automatic synchronization of the delivery would be greatly appreciated.
Accordingly, it is one object of the present invention to overcome at least some of the problems associated with the prior art.
It is another object of the present invention to provide novel methods and systems for the administration of a pulmonary surfactant by atomization.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that a system for delivering a medicament to spontaneously breathing patients, comprising:
is effective for delivering a pulmonary surfactant.
Thus, according to one aspect of the present invention, the present invention provides a system for delivering a medicament to spontaneously breathing patients, comprising:
The use of the liquid-filled lumen of the catheter for estimating the pressure swings at the pharyngeal cavity allows specific advantages compared to other approaches: 1) it provides a very fast response of the catheter-pressure transducer system (liquids are not compressible and adds a minimal compliance of the measuring system, resulting in very fast time constants), allowing a fast detection of the newborns breathing phase (respiratory rate in small preterm neonates can be greater than 60 breaths per minute, one order of magnitude greater than for adults); 2) the use of small and low-cost disposable catheters with no extra lumens for pressure sampling and with the pressure transducer being placed close to the main device; 3) the presence of liquid in the lumen prevents the tip of the catheter to be occluded by the fluids always present in the pharynx, for example saliva or moist due to the water vapor saturated environment, an important advantage against air-filled lumens for pressure sensing; 4) as the pressure swing due to the low-resistance pathway provided by the liquid-filled lumen is small compared to the gas ones, it is much easier to detect the very small pressure swings in the pharyngeal cavity due to breathing of the neonate, which are on the order of 1 cmH2O.
Preferably the catheter is made of flexible plastic material and as an alternative it can include partially rigid scaffolding. Preferably the at least second channel includes a plurality of channels arranged around the first channel.
Preferably, the aerosol medicament comprises an exogenous pulmonary surfactant, e.g. selected from the group consisting of modified natural pulmonary surfactants (e.g. poractant alfa), artificial surfactants, and reconstituted surfactants, while the pressurized gas includes air or oxygen.
According to a further embodiment, the catheter includes spacers means arranged on its external surface so that, when the catheter is in place for the aerosol treatment, the second end of the at least first and at least second channel are kept separated from the wall of the pharyngeal cavity.
In a second embodiment, the present invention provides a method for preventing and/or treating a respiratory distress syndrome in spontaneously breathing patients, said method comprising the step of delivering an atomized medicament to the retro-pharyngeal region of the patient by means of a multi-channel flexible catheter a low pressure column of liquid medicament through at least a first channel of the multi-channel catheter and an pressurized flow of gas through at least a second channel of the multi-channel catheter; wherein the liquid column of medicament is broken into a plurality of particles when the liquid column and the pressurized flow of gas meet in the retro-pharyngeal cavity. Preferably the method comprises the step of detecting the inspiration activity of the patient, preferably by means of a pressure sensor being connected to the at least first channel; wherein the step of providing is performed only during the inspiration activity.
More preferably, the method of the invention comprises applying to the patient a non-invasive ventilation procedure such as nasal Continuous Positive Airway Pressure (nCPAP).
In a third embodiment, the present invention provides a kit comprising:
In a fourth embodiment, the present invention provides a method for preventing and/or treating a respiratory distress syndrome in spontaneously breathing pre-term neonates, said method comprising the step of delivering a pulmonary surfactant in the retro-pharyngeal cavity of said neonates.
A still further aspect of the present invention provides a computer program for controlling the above described method.
The method and system according to preferred embodiments of the present invention allow optimizing the dispensing of surfactant with an efficient delivery of the atomized particles to the lungs without requiring an invasive operation for placing the catheter. The method and system of the present invention provides several advantages including: a more gentle atomizing process, thanks to the air-blasting atomizing catheter, whose mechanical impact on the surfactant is minimal; an easier manufacturing and a more compact design of the atomizing catheter thanks to the absence of the ending taper; the possibility to monitor and to synchronize to the breathing pattern of the patient without the introduction of a sensor, connections at the airway opening or a second lumen; the flexibility of the device, which can be used either during spontaneous breathing or when non-invasive respiratory support is provided, such as during nCPAP or other non-invasive ventilation procedures such as nasal intermittent positive-pressure ventilation (NIPPV); the use of components which are already familiar to the hospital personnel, e.g. catheters and disposable pressure sensors (similar to the ones used for invasive monitoring of blood pressures); all the part in contact with the pulmonary surfactant and the patient are low cost and disposable, granting for hygienically and safer treatments than those of the prior art, which is particularly important when the patient is a pre-term neonate.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same become better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:
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:
The term “non-invasive ventilation (NIV) procedure defines a ventilation modality that supports breathing without the need for intubation.
With reference to
However, any 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. These include modified natural, artificial and reconstituted pulmonary surfactants (PS).
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.)
Examples of artificial surfactants include, but are not limited to, pumactant (Alec™, Britannia Pharmaceuticals, UK), and colfosceril palmitate (Exosurf™, GlaxoSmithKline, plc, Middlesex).
Examples of reconstituted surfactants include, but are not limited to, lucinactant (Surfaxin™, Discovery Laboratories, Inc., Warrington, Pa.) and the product having the composition disclosed in Table 2 of Example 2 of WO 2010/139442, whose teaching is incorporated herein by reference in its entirety.
Preferably, the pulmonary surfactant is a modified natural surfactant or a reconstituted surfactant. More preferably the pulmonary surfactant is poractant alfa (Curosurf™).
The dose of the pulmonary surfactant to be administered varies with the size and age of the patient, as well as with the severity of the patient's condition. Those of skill in the relevant art will be readily able to determine these factors and to adjust the dosage accordingly.
A catheter 101 conveys atomized medicament (e.g. surfactant) directly to the retro-pharyngeal region in order to increase efficiency of the medicament administration without being invasive: this is particularly important for very young patients, such as pre-term born neonate suffering from neonatal Respiratory Distress Syndrome (nRDS). According to a preferred embodiment of the present invention the catheter is made of biocompatible flexible material (e.g. plastic material). It is possible to couple the catheter with a rigid scaffolding (e.g. metallic) to increase stiffness of the device and to improve easiness of positioning operations. In a preferred embodiment of the present invention the delivery of the atomized medicament is done by means of an air blasting technique. Using air to assist atomization is a well known technique that grants a fully developed atomization also when low pressure and low flow conditions are required (see e.g. Arthur Lefebvre, “Atomization and spray”, Taylor and Francis, 1989, which is incorporated herein by reference in its entirety). Such technique is based on a relatively small amount of gas (e.g. air, but it could be other compressed gas, e.g. oxygen, nitrogen, or helium) which flows in one or more separate channels than the medicament which is delivered in a liquid form; the air flow accelerates and breaks the liquid column, inducing the atomization of the medicament. Therefore the catheter 101 includes a plurality of channels (at least two, one for the medicament and one for the air) for conveying contemporarily the medicament and the air flow. The liquid medicament column is broken up in droplets by the turbulence due to the air flowing next or around when the two flows (air and liquid medicament) exit the catheter channels and meet in the retro-pharyngeal region. The atomized droplets have a mean diameter of at least 80 microns, preferably higher than 100 microns, more preferably of 80 to 150 microns. It is believed that this effect is caused by the air flow which accelerates the fluid sheet instability. The air also helps in dispersing the droplets, preventing collision among them and facilitating the diffusion of the medicament in the lungs by reducing the likelihood of contact between the particles and the wall of the retropharyngeal cavity.
In a preferred embodiment of the present invention the medicament (e.g. the surfactant) is supplied by means of a pump 103 connected to one end of the catheter, which forces the liquid medicament out of the opposite end of the catheter where it meets the air flow (conveyed by a different channel of the catheter) and is atomized, i.e. broken into a plurality of small particles (droplets) by the pressurized air. Pump 103 may be realized by a device able to generate a flow, such as an infusion pump: in a preferred embodiment of the present invention the pump 103 is made of a mechanical frame comprising a structure that holds a syringe containing the liquid medicament and a stepper motor that pushes the syringe piston. In an embodiment of the present invention, pump 103 can be controlled by a control unit 109; such control unit can be embodied in a computer, a microprocessor or, more generally any device capable of data processing activity. A pump device 105 (possibly including a pressurized source and pressure regulator and filter) is connected to the one or more channel conveying the air flow. Those skilled in the art will appreciate that the term pump includes any device capable of providing a pressure to either a liquid flow or a flow of gas. Pump 105 can be controlled by a control unit, as described for the pump 103. The flow of the pump 103 should be in the range of 9 to 18 ml/H while the pressure of the pump 105 should be comprised between 0.4 and 0.8 Atm (1 Atm=1.01325 Bar).
In a preferred embodiment of the present disclosure the catheter 101 includes multiple channels, with a main (e.g. central) channel conveying the surfactant, being surrounded by a plurality of additional channels (e.g. lateral) which convey a pressurized air flow). The air blasting technique here described provides the advantage of a more gentle fragmentation of the surfactant. Current atomizers for drug delivery are normally based on plain orifices, while the method according to the present disclosure employs an atomizing catheter using the air blasting approach. The geometrical configuration of the plain orifice normally presents a narrowing at the tip of the catheter, the nozzle, which accelerates the liquid producing an high instability in presence of an high pressure drop (more than 1 Atm) and, as a consequence, the fragmentation of the liquid in particles. On the contrary, the air blasting catheter according to a preferred embodiment of the present disclosure is a multi-lumen catheter: the surfactant flows into the main lumen while pressurized air flows in the lateral ones. The turbulences generated by the small airflow fragment the surfactant in a very ‘gentle’ way. Moreover, the use of plain orifices would require very high differential pressure across the nozzle to induce atomization, while the air blasting atomizer doesn't need high driving pressure to the surfactant, as the atomizing process is driven by the turbulence of the air around the surfactant.
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.
Its concentration shall be properly adjusted by the skilled person in the art.
Advantageously, the concentration of the surfactant is 2 to 160 mg/ml, preferably 10 to 100 mg/ml, more preferably 40 to 80 mg/ml.
The applied volume should generally be not more than 5.0 ml, preferably not more than 3.0 ml. In some embodiments, it could be 1.5 ml or 3 ml.
A possible additional feature of the method and system according to the present invention is that of synchronizing the pulmonary surfactant administration with the breathing phase of the patient. To implement this feature, a pressure sensor 107 is inserted along the surfactant catheter, but externally to the pharyngeal tube, and provides an indirect but accurate measurement of the pharyngeal pressure swings. This measurement is possible because of the relatively low pressure in the channel conveying the surfactant, allowing the use of the surfactant line for measuring the retro-pharyngeal pressure with the aim of both synchronizing the atomization with the breathing pattern of the patients and to help the attending medical staff to place the catheter in the proper place and monitoring the maintenance of the proper position during the treatment, allowing the identification of wrong positioning of the catheter tip (e.g. into the oesophagus).
Such pressurized gas flow is not able to significantly alter the pressure in the pharynx, since the flow is rather limited and the anatomical structures are open to the atmosphere.
The distribution of the particles size obtained by means of the preferred embodiment of the present invention has been characterized by a commercial laser diffractive size analyzer (Malvern, Insitec RT). The measurements have been carried out using exemplificative conditions of 0.5 bar of pressurized air and a surfactant flow rate of 3 mL/20 minutes.
As a result, the most of the particles size is comprised between 100 to 200 microns. In particular the median value is 137.47 micron, the 10th percentile is 39.50 micron, the 90th percentile is 130.63 micron as reported in
In one embodiment, the catheter contains a single channel or lumen for the surfactant having an inner diameter of about 0.25 mm, surrounded by 12 channels or lumen for air each having an inner diameter of about 0.12 mm, which leads to a ratio of the area of the surfactant channel to the total area of the air channels of about 0.4. Of course, other diameters may be used. For example, in another embodiment, the surfactant channel may have an inner diameter of about 0.2 mm to about 0.6 mm and the air channels may have inner diameters of about 0.05 mm to about 0.15 mm. In particular, the surfactant channel may have an inner diameter of about 0.5 mm and the air channels may have inner diameters of about 0.12 mm, which leads to a ratio of the area of the surfactant channel to the total area of the air channels of about 1.4. Of course, the catheter itself will have an outer diameter large enough to accommodate the surfactant and air channels.
As a possible additional feature, the catheter used in the method and system of the present invention could be provided with some spacers on the external surface which help in positioning it and keeping a minimum distance between the catheter itself and the wall of the retro-pharyngeal cavity. This separation ensures that the atomised surfactant is conveyed to the lung by inspiratory airflow and not projected on the walls of the pharyngeal cavity. An example is shown in
Laryngoscope is another tool known to the skilled person, that could be suitably utilized for positioning the catheter in the retro-pharyngeal cavity.
Moreover, Magill forceps, oro-pharyngeal cannulas such as cannula of Mayo, of Guedel, of Safar and of Bierman can facilitate the introduction of the catheter. In a preferred embodiment the cannula of Mayo is utilized for both facilitating the introduction and keeping the catheter tip in the proper position, i.e. not close to the pharyngeal wall and pointing toward the inlet of the trachea during the whole period of surfactant delivery.
The sensor can be for example a disposable pressure sensor, similar to those used for the invasive measurement of blood pressure.
The administration of surfactant only during the inspiration phase is a big advantage provided by the present invention: this results in a better control on the effective quantity which reaches alveoli and to avoid the waste of the supplied surfactant. This requires the measurement of a signal related to the breathing pattern in the ventilatory condition of the preterm neonate (spontaneously breathing and kept under nCPAP or other non-invasive ventilation procedure such as NIPPV) to detect the end-inspiration and end-expiration and to predict the ‘future’ breathing pattern of the baby. According to an embodiment of the present invention, the administration of surfactant is started before the beginning of the inspiration and stopped before the beginning of the expiration in order to:
In
By using this approach we have obtained in an exemplificative simulation, the administration of the 97±0.8% of surfactant in 60±21 minutes in 7 preterm neonates with a gestational age of 29.5±3 weeks and a body weight of 1614 g (±424 g).
All operations of the system here described are controlled by a microprocessor (e.g. microcontroller of PIC18F family by Microchip Technology Inc.) running a software adapted to implement the method according to a preferred embodiment of the present invention.
It will be appreciated that alterations and modifications may be made to the above without departing from the scope of the invention. Naturally, in order to satisfy local and specific requirements, a person skilled in the art may apply to the solution described above many modifications and alterations. Particularly, although the present invention has been described with a deep degree of particularity with reference to preferred embodiment(s) thereof, it should be understood that eventual omissions, substitutions and changes in the form and details as well as other embodiments are possible; moreover, it is expressly intended that specific elements and/or method steps described in connection with any disclosed embodiment of the disclosure may be incorporated in any other embodiment as a general matter of design choice.
For example, similar considerations apply if the components (e.g. microprocessor or computers) have different structure or include equivalent units; in any case, it is possible to replace the computers with any code execution entity (such as a PDA, a mobile phone, and the like).
Similar considerations apply if the program (which may be used to implement some embodiments of the disclosure) is structured in a different way, or if additional modules or functions are provided; likewise, the memory structures may be of other types, or may be replaced with equivalent entities (not necessarily consisting of physical storage media). Moreover, the proposed solution lends itself to be implemented with an equivalent method (having similar or additional steps, even in a different order). In any case, the program may take any form suitable to be used by or in connection with any data processing system, such as external or resident software, firmware, or microcode (either in object code or in source code). Moreover, the program may be provided on any computer-usable medium; the medium can be any element suitable to contain, store, communicate, propagate, or transfer the program. Examples of such medium are fixed disks (where the program can be pre-loaded), removable disks, tapes, cards, wires, fibres, wireless connections, networks, broadcast waves, and the like; for example, the medium may be of the electronic, magnetic, optical, electromagnetic, infrared, or semiconductor type.
In any case, the solution according to the present invention lends itself to be carried out with a hardware structure (for example, integrated in a chip of semiconductor material), or with a combination of software and hardware. The system of the invention is particularly suitable for the prevention and/or treatment of the respiratory distress syndrome (RDS) of the neonate (nRDS). However, it could be advantageously utilized for the prevention and/or treatment of 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 system of the invention is applied to pre-term neonates who are spontaneously breathing, and preferably to extremely low birth weight (ELBW), very-low-birth-weight (VLBW), and low-birth weight (LBW) neonates of 24 to 35 weeks gestational age, showing early signs of respiratory distress syndrome as indicated either by clinical signs and/or supplemental oxygen demand (fraction of inspired oxygen (FiO2)>30%).
More advantageously, nasal Continuous Positive Airway Pressure (nCPAP) is applied to said neonates, according to procedures known to the person skilled in the art.
Preferably a nasal mask or nasal prongs are utilized. Any nasal mask commercially available may be used, for example those provided by The CPAP Store LLC, and the CPAP Company.
Nasal CPAP is typically applied at a pressure between 1 and 12 cm water, preferably 2 to 8 cm water, although the pressure can vary depending on the neonate age and the pulmonary condition.
Other non-invasive ventilation procedures such as nasal intermittent positive-pressure ventilation (NIPPV), High Flow Nasal Cannula (HFNC), and bi-level positive airway pressure (BiPAP) can alternatively be applied to the neonates.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
In vivo efficacy of atomized surfactant (in this example poractant alfa, as defined above) was evaluated in preterm newborn rabbits at the 27th day of gestation (term=31±1 days). The model chosen closely resembles the conditions of premature babies affected by RDS in that the lungs of these animals are not yet able to produce their own surfactant, but can warrant gas exchange so that they can expand in response to exogenous surfactant administration.
Treatments were intratracheally given at 2 ml/kg volume, corresponding to 160 mg/kg dose. Foetuses, paralyzed with pancuronium bromide (0.02 mg i.p.), were then placed in the plethysmograph system at 37° C. and ventilated with pure oxygen at constant pressure (frequency 40/minute, inspiration/expiration ratio 60/40). No positive end-expiratory pressure (PEEP) was applied. An “opening” pressure of 35 cmH2O was first applied for 1 minute to overcome initial resistance due to capillarity in finer conducting airways. It was then followed by 15 minutes at 25 cmH2O, 5 minutes at 20 cmH2O, 5 minutes at 15 cmH2O and again at 25 cmH2O for the final 5 minutes.
Respiratory flow was measured every 5 minutes by a Fleish tube connected to each chamber of the plethysmograph system. Tidal volume (Vt) was automatically obtained by integration of the flow curve.
Two sets of experiments were performed.
In the first set, five samples (1 ml each) have been received. The pulmonary surfactant administered at each samples is respectively: not atomized poractant alfa, poractant alfa atomized at an air pressure of 0.0, 0.2, 0.5, and 0.8 bar. The pulmonary surfactant has been atomized using the preferred embodiment of the present invention.
In this set of experiments a control group without any treatment was included.
All the atomized samples, including that passed through without any pressure applied, resulted as effective as not atomized poractant alfa (P<0.05, one-way ANOVA followed by Tukey's test; Graphpad Prism). No statistically significant difference was found between the different conditions of atomization.
In the second set, three samples (1 ml each) have been received. The pulmonary surfactant administered at each samples is respectively: non-atomized poractant alfa, poractant alfa atomized at an air pressure of 0.2, 0.5, and 0.8 bar.
In this set of experiments two further groups were included, a control group without any treatment and a group treated with a batch of poractant alfa already released to the market.
The same results were observed in the second set of experiments.
As the results were consistent in the two sets, the data have been pooled (
In conclusion the passage through the atomizer, using the preferred embodiment of this invention, does not affect poractant alfa efficacy in premature rabbit foetuses. In particular, atomization at pressures between 0.2 and 0.8 bar does not significantly affect poractant alfa efficacy and the application of 0.5 bar seems the most suitable although no statistically significant difference has been observed between different atomization conditions.
Where a numerical limit or range is stated herein, the endpoints are included. Also, all values and subranges within a numerical limit or range are specifically included as if explicitly written out.
As used herein the words “a” and “an” and the like carry the meaning of “one or more.”
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
All patents and other references mentioned above are incorporated in full herein by this reference, the same as if set forth at length.
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| 12165234 | Apr 2012 | EP | regional |
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| Number | Date | Country |
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| 10 2010 025 045 | Dec 2011 | DE |
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| Number | Date | Country | |
|---|---|---|---|
| 20130333695 A1 | Dec 2013 | US |
