Nasal spray device and method for spraying liquid formulations

Abstract

Nasal spray device and method for atomizing liquid formulations The nasal spray device has a non-pressurized reservoir (25) for containing a liquid formulation, a spray nozzle (50), and a manually energizable pump (10) configured to pressurize a quantity of the liquid formulation and move the liquid formulation through the spray nozzle such that the liquid formulation is expelled from the spray nozzle as an aerosol spray. The spray nozzle (50) includes a membrane having a plurality of microscopic holes of substantially identical size, less than 8 microns and greater than 3 microns, through which the liquid formulation passes as it is expelled from the device. The membrane is configured to emit the dose of the liquid formulation as a cone-shaped plume having an apex, for a period of at least 500 milliseconds. Energy of less than 20 Joules / gram is diffused into the liquid to maintain molecular integrity of macromolecules in the liquid.

Description

[Technical field]

[0001] The present invention relates to a nasal spray device comprising a nostril cap having an end for insertion into a nasal cavity, the nostril cap including a spray cavity opening through said end, the nostril cap including a suspended spray nozzle configured to receive a liquid medicament at an inlet and to emit a liquid spray of the liquid medicament at an outlet opening into said spray cavity. [Background technology]

[0002] Current manually operable nasal spray devices nebulize nasal sprays produced by pressurized swirl nozzles, also known as hollow cone nozzles. A stationary core in such nozzles induces a rotational fluid motion that causes the fluid to swirl in the swirl chamber. A liquid sheet film is expelled around the exit orifice, producing a characteristic hollow cone spray pattern. Air or other ambient gas is drawn into the swirl chamber, forming an air core within the swirling liquid. To produce this hollow cone pattern, various fluid inlet shapes are used, depending on the nozzle capacity and material of construction. These swirl nozzles produce relatively large, variable droplets on the order of 20-200 microns, with the average droplet size typically being 50-80 microns. The flow rate or discharge of the spray produced by swirl nozzles is relatively high, typically exceeding 200 microliters per second.

[0003] Another prior art method of atomization involves vibrating a flexible mesh attached to a piezoelectric lead zirconate titanate (PZT) ring actuator (ultrasonic transducer) by stretching and contracting it to eject relatively large droplets of liquid, on the order of 1-10 microns in size. These vibrations are transmitted to the liquid formulation, generating heat that dissipates into the liquid, thus increasing the temperature of the formulation during the atomization process.

[0004] Finally, atomization of liquid formulations is achieved by intersecting jets colliding at high speed. The impinging jet (also called impinging jet) method involves colliding two jets at high speed to form a thin liquid sheet (also called a subaerted sheet) at the impact point, which breaks into randomly sized droplets. Typically, the droplets are in a wide size range of 1-10 microns. To obtain sufficient velocity for the two jets to form droplets smaller than 10 μm after the subaerted sheet is broken, the system pressure required is typically 150-200 bar. Summary of the Invention [Problem to be solved by the invention]

[0005] All these known spraying techniques require the supply of a substantially minimal amount of energy to the liquid, which results in a rather large impact of the liquid spray in the nasal cavity. The latter is not only a drawback from a sensory point of view for the user, but also leads to a drawback of a relatively short administration time. Typically, such conventional nasal spray devices administer a dose of 40 microliters with an administration time of less than 200 milliseconds, so that most of the liquid only reaches the nasal vestibule. In particular, many spray pump swivel nozzle devices deposit a significant amount of the drug in the anterior vestibule, which is considered to be a less active area of ​​the nasal cavity. This deposition in the anterior vestibule is believed to be due to chronic deposition, because most spray pumps are designed to release the majority of aerosol particles larger than 20 microns at a relatively high speed for a short period of time upon actuation.

[0006] Furthermore, the high energy levels and impact on the liquid associated with these known nebulization techniques are likely to disrupt the integrity of delicate macromolecules when present in the liquid formulation, making known nebulization devices and methods less suitable for nebulizing large macromolecules such as lipid particles often found in biotherapeutic formulations.

[0007] In particular, it is an object of the present invention to provide a nasal spray device that overcomes the above-mentioned drawbacks without sacrificing user convenience. In one aspect of the present invention, it is an object of the present invention to provide a nasal spray device that provides greater coverage of the nasal cavity, particularly including the olfactory region of the nasal cavity. More particularly, in a further aspect, the present invention aims to provide a nasal spray device that is capable of aerosolizing nanoparticles, including relatively long molecules, particularly fragile biomolecules, that substantially maintain the nanoparticle structure and molecular integrity. [Means for solving the problem]

[0008] In order to achieve the above object, a nasal spray device of the type described at the outset is, according to a first aspect of the invention, characterized in that the spray nozzle has a membrane between the inlet and the outlet, which has a plurality of micro-holes of substantially identical size, between 1 micron and 10 microns, in particular between 3 microns and 8 microns, which carry the liquid formulation to be ejected from the device, the micro-holes being configured to emit a jet of micro-droplets with a deflection angle relative to the axial centerline of each micro-hole, the micro-holes being distributed so as to form a spray plume expanding in a substantially conical shape having an apex.

[0009] The device according to the invention is based on a relatively gentle Rayleigh breakup of the liquid formulation after passing through relatively short micro-holes of defined size, which generates a soft mist of ultra-fine droplets with substantially identical size, regardless of the propagation speed. In particular, the micro-holes are arranged and configured to generate a slowly propagating, substantially cone-shaped expanding plume, which improves nasal coverage of the nostril area, especially in the direction perpendicular to the propagation direction. The deflection of the individual spray jets emitted by the micro-holes may be influenced and configured, in particular, by techniques disclosed in co-pending European patent application EP..., the contents of which are incorporated herein by reference.

[0010] This invention is based on the realization that Rayleigh breakage of a liquid formulation through micropores smaller than 8 microns produces spray droplets of substantially identical initial size, typically two to three times larger than the micropores. These relatively small micron droplets, due to the relatively low kinetic energy of each individual droplet, instantly slow down significantly when released and exposed to the surrounding air, forming an ultra-fine spray plume. In particular, the resulting spray plume is slowed down to a propagation speed not exceeding 1 m / s. It has been found that the turbulence within this spray plume, and the slow motion at such a speed, results in unprecedented coverage of essentially the entire nasal cavity, particularly the upper olfactory region.

[0011] Surprisingly, it has been found that in a first particular embodiment of a nasal spray device according to the invention, characterized in that the cone-shaped spray plume has an apex of about 5 degrees, the inferior and middle turbinates may be specifically targeted.

[0012] On the other hand, a second particular embodiment of the nasal spray device is characterized in that the spray plume of the cone-shaped spray has an apex in particular of 5° to 30°, in particular of 20° to 25°, more particularly of about 20°. This spray device can be advantageously used to target in particular the nostrils and / or olfactory areas of the nasal cavity and the nasopharynx.

[0013] A further embodiment of the nasal spray device according to the invention is characterized in that a chamber is provided for accommodating a predetermined dose of the liquid formulation, in particular having a volume of 25 to 150 microliters, and a manually actuatable, manually pressurizable positive displacement pump is configured to pressurize the dose of the liquid formulation and force the liquid formulation into the inlet of the spray nozzle under an elevated working pressure of 5 to 15 bar, thereby expelling the predetermined dose of the liquid formulation.

[0014] The present invention provides in particular a nasal spray device that generates a so-called microjet spray. A microjet spray consists of multiple jets that issue simultaneously, each of which is initially split into a train of monodisperse primary droplets according to a jet splitting mechanism. As a result, successive primary droplets are substantially of the same size and propagate in the same direction downstream of the nozzle. Typically, the diameter of the primary droplets is two to three times the diameter of the microhole that releases them. That is, according to the present invention, the primary droplets are of the same size, between 6 and 30 microns, depending on the size of the microhole from which they are generated. Eventually, the individual droplets may merge with each other, causing a shift and some broadening of the droplet size distribution in the overall spray. Nevertheless, the droplet size distribution remains relatively sharp and well-defined.

[0015] In this application, the size of a microhole is defined as the diameter of a circle having the same surface area as the cross-sectional surface area of ​​the microhole. Similarly, the size of a droplet is defined as the diameter of a sphere having the same volume as the volume contained by the droplet. Furthermore, the expressions nebulizer, atomizer, and spray device are used interchangeably without any essential difference, unless otherwise specified.

[0016] The nasal spray device of the present invention operates on the basis of a pump, particularly a manually actuable pump, and releases an ultra-fine mist of these relatively small droplets. These droplets have a relatively low momentum and tend to decelerate relatively quickly when they come into contact with the surrounding air. In practice, residence times of the order of 500 milliseconds and even longer have been observed. This slow release of the relatively small droplets provides a slow-moving soft mist of the liquid formulation.

[0017] By slowly inhaling through the nostrils, the patient can deliver the soft mist particles to the target areas of the nose further down the nasal passages. The majority of uniformly sized droplets can be targeted specifically to the respiratory and olfactory nasal regions. This enhanced penetration is due to the spray device of the present invention being designed to produce small, slow moving particles that pass through the nasal passages at normal inhalation speeds, thereby minimizing inertial impaction ahead of the nasal valve.

[0018] Due to the relatively sharp droplet size profile of the spray associated with Rayleigh formation, the droplets of the soft mist spray, especially those smaller than 10 microns in size, may further penetrate the respiratory system of the user, especially the lungs. Targeting the olfactory region specifically targets the topical agent for direct uptake into the brain, thereby avoiding the blood-brain barrier. Also, the nasal discharge in the olfactory region is much less than the vestibular region, allowing the formulation to take longer to be absorbed into the nasal mucosa tissue. These factors contribute greatly to the significant improvement of the absorption efficiency and coverage of the nasal cavity. The pump-type nasal spray device according to the present invention is equipped with a nozzle that generates a slow-moving fine mist of the liquid formulation, which can cover more than 80% of the nasal mucosa.

[0019] In a further aspect, the present invention aims to provide a method suitable for nebulizing a liquid formulation, which maintains, at least in large part, the molecular integrity of any macromolecules present in said liquid.To this end, a method for nebulizing a liquid formulation, in particular a liquid formulation comprising macromolecules, more particularly a biomolecule, is provided, which is characterized in that said liquid formulation is subjected to a treatment that converts it into a mist of said liquid formulation, which liquid formulation is subjected to an energy not exceeding 20 Joules / gram, preferably not exceeding 10 Joules / gram, in particular forming a plume of soft mist spray during the conversion of the liquid formulation into a mist of said liquid formulation.

[0020] It has been found that at least most fragile macromolecules, such as complex proteins, peptides, long DNA and RNA, large vesicles, liposomes, and antibodies, can withstand the atomization process if only a limited amount of energy is dissipated during the atomization of the liquid. This can be achieved by generating a fine mist of the liquid formulation by a process called Rayleigh breakage. Thus, a preferred embodiment of the method according to the present invention is characterized in that the liquid formulation is pressurized to at least an operating pressure for pressurized administration, and the pressurized administration of the liquid formulation is forced through at least one microhole, in particular a plurality of microholes, in the membrane of a Rayleigh breakage type spray nozzle.

[0021] The present invention relates in particular to a nasal spray device used to aerosolize pharmaceutical formulations for nasal administration. To that end, a particular embodiment of the nasal spray device according to the invention is characterized in that the reservoir contains a pharma- ceutically active liquid formulation, in particular a formulation comprising nanoparticles, such as formulations comprising complex proteins, peptides, long chain DNA and RNA, large vesicles, liposomes, antibodies, etc.

[0022] For example, the pump nasal spray device of the present invention can protect the user from allergic reactions and diseases caused by microorganisms and viruses, such as the SARS-Cov-2 virus, with the appropriate anti-allergic or prophylactic formulation. Current prophylactic formulations against the SARS-Cov-2 virus use angiotensin receptor blockers, ACE inhibitors, heparin, and enoxaparin derivatives to prevent the virus from binding to epithelial cells in the nasal cavity. Other prophylactic drugs and vaccines include ivermectin, antibodies, glycoproteins, mRNA ribosomes, and other bioactive agents. The pump nasal spray device of the present invention can be equipped with a nozzle that maintains the integrity of polymeric and / or nanoparticle-based formulations, especially in the case of biological agents, which are generally polymeric and / or nanoparticle-based formulations, such as formulations containing complex proteins, peptides, long DNA and RNA, large vesicles, liposomes, and antibodies. Meanwhile, currently used nasal fine mist nebulizers have been found to disrupt the molecular structure of the polymers contained in many mRNA lipid nanoparticle vaccines. For this reason, these conventional nebulizers are not suitable for nasal administration of many protein-based or other biological agents.

[0023] The nasal spray device according to the present invention may be configured to target the deeper respiratory system, in particular the lungs, in addition to the nasal cavity.To this end, a particular embodiment of the nasal device according to the present invention is characterized in that the membrane of the spray nozzle comprises a second set of micro-holes of substantially identical size, less than 3 microns, through which the liquid formulation passes when it is expelled from the device.These relatively small micro-holes can deliver correspondingly smaller droplets, typically less than 10 microns, which can pass through the nasal cavity and ultimately target the deeper tracheal and / or even bronchial regions of the respiratory system.

[0024] In a preferred embodiment, the nasal spray device according to the invention is characterized in that the pump comprises a manually actuated piston which pressurizes the dose of the liquid formulation to the actuation pressure in one stroke of the piston. A piston which pressurizes the entire dose in one stroke provides convenience to the user, especially if the pump mechanism is further configured to automatically fill the dose into a dedicated predefined volume of the device before pressurization. The pump may comprise a multi-shot nasal pump comprising a dosing chamber for at least temporarily holding the dose of the liquid formulation and releasing the dose into the spray nozzle under the actuation pressure. Alternatively, the pump may be formed of a medical syringe.

[0025] A particular embodiment of the nasal spray according to the invention is characterized in that the pump opens into a male luer tip, the nostril cap has an inlet providing a female luer slip connection with the male luer tip and is receivable over the male luer tip with an outlet for releasing the nasal spray, and the nostril cap includes the spray nozzle between the inlet and the outlet. In particular in this embodiment, a standard medical syringe can be used as a pump and a container for containing a liquid formulation. Simply attaching a nostril cap embodying a spray nozzle according to the invention to the tip of the syringe converts the syringe into a nasal spray device that outperforms many conventional nasal spray devices. Both the syringe and the nostril cap may be provided as low-cost disposable items.

[0026] A further particular embodiment of the spray device according to the invention is characterized in that said nostril cap comprises at least one inhalation channel which, while the user is inhaling, carries a parallel airflow of ambient air together with said spray towards the outlet. Such an inhalation channel may for example be provided in the wall of the nostril cap and open to the environment. This induces an additional airflow of ambient air through the nostril cap while the user is inhaling. The spray droplets may be entrained in this additional airflow or carried in its slipstream and delivered deep into the nasal cavity. Even remote nasal regions within the nasal cavity can be targeted in this way. A preferred embodiment of the nasal spray device is characterized in that the nostril cap tapers towards the outlet, allowing for a snug fit in the nose.

[0027] In a preferred embodiment, the membrane consists of a ceramic layer, the micropores extending through the thickness of the ceramic layer. The micropores can be formed, for example, by micromachining using etching and / or photolithography, as is customary in today's semiconductor technology. In this respect, in a particular embodiment, the ceramic layer is a silicon nitride layer located on a carrier body of semiconductor material, in particular silicon, the carrier body comprising at least one cavity below the silicon nitride layer, the at least one cavity opening downstream into at least one of the micropores, the at least one cavity being connected upstream to the exhaust of the pump.

[0028] The present invention further relates to a method for spraying a liquid formulation, wherein the liquid formulation is pressurized to a working pressure of 5-15 bar using a pump to generate at least a pressurized dose of the liquid formulation, wherein the pressurized dose of the liquid formulation is forced through a group of micropores in a membrane of a Rayleigh-type spray nozzle, the micropores having a size smaller than 8 microns, causing the liquid formulation to break into a spray plume of at least one droplet having substantially the same initial droplet size, the spray plume propagating at a plume propagation velocity of less than 1 m / s, particularly in the nasal cavity of a user. Such a spray plume is particularly suitable and effective as a nasal spray for nasal administration of the liquid formulation.

[0029] The present invention particularly relates to a nasal spray device and method for spraying a spray from a liquid formulation comprising nanoparticles, capable of maintaining the integrity of said nanoparticles while the liquid formulation is converted into a spray. To that end, a particular embodiment of the method for spraying a liquid formulation comprises a method for spraying a liquid formulation, the method comprising the steps of: (a) spraying a liquid formulation comprising: a liquid formulation comprising nanoparticles of size δ, the droplets comprising at least one of said nanoparticles, the nanoparticles having a maximum size δ before breaking upon elongation; max The liquid formulation is subjected to a shear rate γ [per second] when passing through the micropores, and the liquid formulation is subjected to the shear rate γ within the micropores for the shear time Δt, which is equal to or longer than δ max / (δ γ) seconds.

[0030] In further embodiments, the nasal spray device and method according to the invention are characterized in that the liquid formulation comprises nanoparticles of size δ and the droplets comprise said nanoparticles, wherein said nanoparticles have a maximum size of δ before breaking upon elongation. max The micropores have a diameter D×δ max / δ has a length L smaller than (L <D.δ max / δ). For tapered pores, the size or diameter D of the micropore is taken as the maximum diameter of the micropore. For long chain molecules such as mRNA, the length L of the micropore must be less than the total chain length λ of the long chain molecule (L<λ). In particular, L is less than 1 micron.

[0031] The nasal spray device and method of the present invention are particularly suited for spraying liquid formulations of nanoparticles from a group including complex proteins, large biomolecules, long DNA and RNA chains, large vesicles, liposomes, bacteriophages and antibodies, while maintaining the integrity of such nanoparticles.

[0032] The present invention will now be described in more detail with reference to specific embodiments and the accompanying drawings. [Brief description of the drawings]

[0033] [Figure 1] 1 shows an embodiment of a nasal spray device according to the present invention. [Diagram 2] 2 shows a schematic diagram of a portion of the apparatus of FIG. 1. [Diagram 3] 2 provides a comparison of droplet size distribution between the device of FIG. 1 and a conventional swirl-jet nozzle nasal spray device. [Figure 4] 1 shows high speed images of the spray emitted from a nasal spray device according to the present invention compared to a conventional swivel nozzle nasal sprayer. [Figure 5A] 1 shows high speed camera images of nasal coverage of liquid spray by the conventional swirl spray nasal spray device. [Figure 5B] 1 shows high speed camera images of a liquid spray being sprayed into the nasal cavity by the nasal spray device according to the present invention. [Figure 6] 1 shows a comparison of total nasal coverage with different types of spray devices. [Figure 7] 4 illustrates the effect of the tip of a spray plume generated by a spray device according to the present invention on a target location. [Figure 8] 1 is a graph showing the performance of a nebulizer according to the present invention for nebulizing a liquid formulation containing mRNA molecules in comparison with a conventional nebulizer. [Figure 9] 9a-e show particle size distributions of mRNA-1273 after nebulization obtained by dynamic light scattering (DLS) in mass-weight mode: a. Initial stock formulation; b. After nebulization with vibrating mesh VM1 at 35 J / g; C. After nebulization with vibrating mesh VM2 method (18 J / g); D. After nebulization with impinging jet (CJ) method (22 J / g); E. After nebulization with nanotechnology membrane (NM) method according to the present invention (2 J / g). [Figure 10]Electropherograms of BNT162b (a,b,c) and mRNA-1273 (d,e,f) vaccines before and after nebulization with vibrating mesh type 1 (VM1; blue), impinging jet (CJ; yellow), vibrating mesh type 2 (VM2; red), and nanotechnology membrane (NM; green), all compared to standard vaccines with and without RNase, demonstrating the impact of nebulization on mRNA integrity, are shown. [Figure 11A] The percentage of intact mRNA versus loss of nebulization energy is shown without the addition of RNase. [Figure 11B] The percentage of intact mRNA and nebulizer energy loss due to the addition of RNase after nebulization is shown. [Figure 12] 1 shows a schematic diagram of a particular embodiment of a nasal adapter for use in a nasal spray device according to the present invention.

[0034] It should be noted that the figures are purely schematic and are not necessarily drawn to scale, in particular certain dimensions may be exaggerated to some extent in order to clarify features, and similar parts are generally designated by the same reference numerals throughout the figures. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] As an example of a nasal spray device according to the invention, Figure 1 shows a standard medical syringe 10 with a movable piston 15 manually operable by a stem 20. In practice, it is possible to apply an operating pressure of 2-10 bar to liquid in a reservoir 25 contained in the syringe 10, which can force said liquid into a nostril cap 40 which is attached to the tip of the syringe by a male-female slip connection and which includes a spray nozzle 50 for receiving the pressurized liquid.

[0036] In FIG. 2 the nostril cap is shown in more detail and basically consists of a plastic cone that fits over the tip of the syringe 10. The nostril cap 40 is sealingly received over the male luer slip tip of the syringe 10 by an internal female luer slip connection at the inlet of the nostril cap 40. The nostril cap houses the spray nozzle 50 in an internal cavity adjacent the outlet 47. The nozzle 50 is configured and connected to receive the liquid at the operating pressure and convert it into an ultra-fine soft mist. To this end, the nozzle 50 consists of a silicone spray microtip that is sealingly mounted in an internal cavity of a plastic adapter body 60. The adapter body 60 facilitates handling and assembly of the nozzle arrangement and can further accommodate one or more filters upstream of the spray tip 50.

[0037] The spray tip 50 holds a fragile ceramic silicon nitride membrane with a typical thickness of 1 micron. The membrane is composed of a number of micropores extending through said thickness. A thin silicon oxide layer may be provided between the silicon nitride layer and the silicon body. In that case, the micropores also penetrate this oxide layer. As a result, the micropores communicate with one of many adjacent cavities etched through the silicon body from the back surface to the front surface. These cavities convey pressurized liquid to the micropores. The micropores are made with high precision to be substantially the same size, 4 microns in diameter. For that reason, like other structures of the microchip, the micropores are preferably made by photolithographic etching and deposition techniques commonly used in modern semiconductor manufacturing technology. Using these techniques, at least some of the micropores are modified and configured to emit microjets at a predetermined divergence angle relative to a centerline. The micropores are distributed and aligned across the membrane surface and arranged to form a substantially conical spray pattern overall. The cone has a predetermined apex angle of 5 to 30 degrees, typically 10 to 25 degrees.

[0038] During operation, the liquid breaks up into smaller droplets as it passes through the aforementioned micro-holes due to mismatched surface tension and cohesive forces. This physical phenomenon is commonly referred to as Rayleigh breakup, and the droplets that cause the liquid to break up are essentially equal droplets that are two to three times larger than the micro-holes that emit them. Eventually, the individual droplets merge due to coalescence, causing a change in the droplet size distribution throughout the spray, which can be seen to have some spreading. Figure 3 shows curve A, which represents a typical droplet size distribution of a spray emitted from this nozzle. The droplets have grown to 20-40 microns. However, this spray maintains a relatively sharp symmetrical profile compared to one sprayed from, for example, a swirl nozzle. To illustrate this, Figure 3 also shows two comparison curves B and C, which represent a typical profile of the droplet size distribution of a spray produced using a conventional swirl nozzle.

[0039] To enhance penetration and overall coverage of the nasal cavity by the nasal spray produced by the illustrated spray device, the nostril cap 40 includes a central cavity that allows ambient air to flow in parallel with the spray toward an outlet 47 during inhalation by the user, as well as multiple inhalation passages 45. The spray tip of the nozzle 50 is configured to emit a slow moving liquid spray. A dose on the order of 25 to 150 microliters is typically emitted from the nozzle 50 over a relatively long period of time of at least 500 milliseconds.

[0040] Such slow moving nasal sprays have been proven in many studies to be an excellent method of delivering topical medications beyond the nasal valve area. This superior delivery and penetration is due to the fact that small, slow moving liquid particles can pass through the nasal passages at resting breathing rates, minimizing inertial impingement ahead of the nasal valve. In addition to the delivery device, a combination of other factors also contribute to the effectiveness of nasal formulations. This includes the formulation properties of the drug, the site of deposition, and the ease of use for the patient of the delivery device. These superior deposition characteristics are achieved by a relatively simple spray pump attached to a medical syringe 10.

[0041] To illustrate the striking difference in droplet deposition in the soft mist nozzle of the nasal spray device according to the present invention compared to the standard swirl nozzle, high speed images (FIGS. 4A-4D) of the initial droplet velocity and jet formation were captured. These images show the trajectories of the spray droplets in the two spray nozzles. FIG. 4A shows the spray pattern of the spray generated by the soft mist nozzle according to the present invention, and FIG. 4B is an enlarged view of the marked rectangular area in FIG. 4A. Swirling can be observed as indicated by the arrows. FIG. 4C shows the spray pattern of the spray generated by the standard swirl nozzle, and FIG. 4D is an enlarged view of the marked rectangular area in FIG. 4C. Straight droplet trajectories can be observed as indicated by the arrows in FIG. 4D.

[0042] The spray plume of the swirl nozzle has an initial velocity of about 13 m / s and sprays a total volume of 100 μL in about 100 ms. However, the spray plume of the nozzle according to the present invention has an initial velocity much lower than 1 m / s, especially about 0.7 m / s, and sprays 45 μL in more than 500 ms. Furthermore, as the comparative plot of FIG. 3 shows, the soft mist nozzle according to the present invention produces relatively small droplets (Dv50: 20-25 μm) compared to the standard nasal swirl nozzle (Dv50: 60 μm). Essentially, the standard swirl nozzle produces a short spray of relatively heavy droplets, all of which move in a straight upward trajectory, as shown in FIG. 4C and 4D. On the other hand, the soft mist nozzle of the nasal spray device according to the present invention produces droplets that move relatively slowly in all directions in a turbulent droplet cloud, as shown in FIG. 4A and 4B. Due to the ballistic trajectory of droplets in a swirl nozzle, most droplets of the spray will only land at the entrance of the nasal cavity. This is an essential characteristic of a swirl nozzle, and the mean diameter of the droplets is determined by the competition between the surface tension and inertia of the liquid. In this case, the mean diameter of the droplets is proportional to the velocity v -2 / 3 This means that the smaller droplets desired for deeper intranasal administration can only be obtained by increasing the velocity in the swirl nozzle.

[0043] On the other hand, the droplet size of the soft mist nozzle of the nasal spray device of the present invention is determined primarily by the size of the micro-holes, independent of the spray velocity. First, the micro-holes can be generated very precisely and precisely, allowing for more precise control of the droplet size distribution in the spray. But just as importantly, the droplet size can be reduced without increasing the droplet velocity, allowing a handheld, manually pressurized, pump-driven device to create an ultra-fine, slow-moving nasal spray that achieves unprecedented penetration into the nasal cavity.

[0044] 5A and 5B show the results of an experimental setup to demonstrate the unexpected nasal coverage of the nasal spray device of the present invention. The setup used a 38.6 cm2 nasal spray in combination with a fluorescent liquid formulation under black light conditions to mimic the human nasal region. 3 A commercially available transparent nasal cast (Koken Co., Japan) with a nasal volume of 100 μl was used and recorded with a standard camera. In all cases, the insertion angle was approximately 45 degrees and the insertion depth was 1 cm. The liquid formulation used was 1 mg / ml calcein dissolved in 25% glycerol in water to improve the visibility of the generated spray. The dose was 100 microliters.

[0045] Figure 5A shows the distribution of nasal spray in the nasal cavity using a standard conventional pump nasal spray device and swivel nozzle. In this figure, large droplets and concentration can be seen at the entrance to the nasal cavity, but overall coverage of the nasal mucosa is poor. With the standard nasal spray device, only 18% of the nasal cavity is covered, resulting in deposition of mainly large droplets.

[0046] Meanwhile, Figure 5B shows the same liquid formulation being dispersed and distributed throughout the nasal cavity using the nasal spray device of the present invention. High-speed camera images show the slow-moving aerosol cloud spreading evenly throughout the cast model. Ultimately, ultrafine droplets are highly distributed throughout almost the entire nasal cavity, including the olfactory epithelium region. The soft mist nasal spray covers 58% of the nasal mucosa with a fine mist of micron-sized droplets.

[0047] The spray device of the invention is made up of 48 identically sized micro-holes of 4 microns, generating a plume of soft mist with a cone-shaped tip of about 20 degrees. The device was compared for intranasal administration with a standard commercial swirl nozzle from Aeropump and with a state-of-the-art MAD300 swirl nozzle from Teleflex. In particular, the coverage of different areas in the nasal cavity was measured using one of these spray devices. Figure 6 is a graphical representation of the test results showing that the device of the invention, labeled as "Rayleigh film" in the figure, shows overwhelming coverage in all areas. In particular, the spray device of the invention achieved over 80% coverage in the center and also far surpassed the other devices in other areas.

[0048] The effect of the tip of the cone-shaped spray created by the same device according to the present invention was further investigated. This is shown in the graph of Figure 7. Apparently, a tip of about 5 degrees seems to be suitable for the target, especially the turbines of the lower and middle jaws. On the other hand, when targeting the olfactory region and nasopharynx, a tip of 20 degrees to 25 degrees is generally advantageous, preferably around 20 degrees. Also, the size range of the droplets in the spray affects where the liquid formulation is deposited after inhalation. Droplets between 0.5 and 4 μm are deposited mainly in the alveolar region, droplets between 4 and 10 μm are deposited in the central and peripheral airways, and droplets over 10 μm are deposited mainly in the oral cavity, nose, and throat.

[0049] Due to its ability to generate an ultra-fine mist of relatively small droplets with unprecedented coverage of the nasal cavity, the spray device according to the invention is particularly suitable for the nasal administration of pharma- ceutically active liquid formulations. This is particularly relevant for biological agents such as prophylactics and vaccines, which may contain antibodies, glycoproteins, mRNA containing lipid nanoparticles, and other bioactive agents. However, these typically delicate molecules or molecular nanoparticle structures tend to be damaged or degraded by exposure to extreme shear forces when using conventional swirling nozzles or vibrating meshes to nebulize liquid formulations. This is illustrated in Figure 8, which shows plots of the molecular size of mRNA in liquid formulations before and after aerosolization of Pfizer / BioNTech's COVID-19 vaccine BNT162b with different nebulizers. The vaccine formulation contains lipid nanoparticles with an average size δ of 300 nm, which are composed of an approximately 4,000 base pair mRNA strand that codes for the viral spike protein. The length of the strand λ is approximately 4,000x0.34 nm (=1.36 microns). The reference curve I shows the molecular length of mRNA in the Pfizer / Biontech stock solution, while curves II and III show the molecular length after spraying the same solution with commercial vibrating mesh nebulizers from Aeroneb and Pari eFlow, respectively. Clearly, spraying with these modern spray devices reduces the average molecular length of mRNA. This makes these conventional devices unsuitable for spraying relatively fragile molecular nanostructures and long molecules.

[0050] However, nebulization of large macromolecules, especially biomolecules such as those found in mRNA therapeutics, is favorable for directly targeting the respiratory tract. Mucosal administration of lipid nanoparticle-based mRNA vaccines could lead to more efficient protection against respiratory viruses. However, conventional nebulization processes destroy the lipid nanoparticle carriers and degrade the mRNA molecules inside.

[0051] However, the present invention provides a novel nebulization method that was tested with two SARS-CoV-2 mRNA vaccines and proved to keep the vaccine substantially intact. In particular, the low energy level at which lipid nanoparticle droplets are generated using the new nebulization method helps to protect the integrity of the lipid nanoparticles and vaccine. Table 1 shows a comparison of nebulization techniques and their different energy dissipation levels. [Table 1] JPEG2025509265000002.jpg59170

[0052] Surprisingly, the inventors discovered that for both vaccines, lipid nanoparticles and mRNA can be nearly completely preserved when the energy loss for aerosolization of the liquid formulation is below a threshold of 20 Joules / gram for lipid nanoparticle integrity and 5-10 Joules / gram for mRNA integrity.

[0053] The nasal spray device according to the invention is based on a relatively gentle Rayleigh destruction of the mRNA-containing liquid formulation after passing through relatively short micropores of about 1 micron in length, which results in almost complete preservation of the mRNA molecules, as shown by curve IV in FIG. 8. The structure of lipid nanoparticles with an average size of δ=300 nm is also maintained using the device according to the invention, unlike conventional vibrating mesh nebulizers, which induce a lot of hydrodynamic agitation of the formulation. In the device according to the invention, the micropores have a relatively short pore length L, such that the transit time Δt, during which the nanoparticles experience a (high) shear rate γ, is short enough to prevent the destruction of the lipid nanoparticle structure. Further experiments have shown that the lipid nanoparticles with an average size δ and a maximum size δ max For nanoparticles up to (until fracture occurs), the maximum shear time Δt is δ max If it is less than / (δ.γ) seconds, then δ maxIt was found that the structure could be maintained when / δ was between 3 and 5. This means that it is desirable for the length L of the micropores not to exceed the diameter D of the micropores, because the shear force acting on the nanoparticles is proportional to the length L of the micropores and inversely proportional to the diameter D of the fraction of the micropores in the channel of diameter D.

[0054] A further finding of the present invention is that for long chain molecules such as mRNA with a chain length λ, the length L of the micropore according to the present invention is preferably shorter than the total chain length λ of the long chain molecule. The rupture force resulting from the presence of a long chain molecule, particularly mRNA, in a shear field is proportional to the chain length λ if the molecule is fully stretched in the shear field. However, when an mRNA molecule passes through a hole of length L, if its length is shorter than the chain length λ of the mRNA molecule, the molecule is prevented from being fully stretched. Instead, the molecule partially maintains its initial spherical shape, reducing the stretching force and ultimately the breaking force imposed on the molecule. Thus, the length L of the micropore according to the present invention is preferably shorter than the total chain length λ of the long chain (mRNA) molecule.

[0055] In particular, micropores with a length L of less than 1 micron have been successfully tested for this purpose. This is the example of the Pfizer / Biontech mRNA liquid vaccine formulation after the liquid formulation with a length λ of the mRNA molecule has been sprayed using a nasal sprayer according to the invention, with micropores of length L smaller than the chain length λ of the mRNA molecule, as shown by curve IV in FIG. 8. This opens up entirely new possibilities for the nasal administration of biological products and nanoparticle-based biotechnological medicines, such as formulations with complex proteins, peptides, long DNA and RNA chains, macroplasmic vesicles, liposomes, antibodies and other biological compounds as active ingredients.

[0056] Figure 9a shows that the size of liposomal nanoparticles containing mRNA-1273 vaccine before nebulization ranges from 300 to 500 nm. Nebulization by the vibrating mesh and impinging jet methods results in an overall larger diameter of the liposomal nanoparticles (see Figures 9b-9d), suggesting aggregation of the liposomal nanoparticles. On the other hand, nebulization by the method according to the present invention results in little change in the size distribution of the liposomal nanoparticles (see Figure 9e). To investigate whether larger lipid nanoparticles are formed by aggregation or destruction of smaller lipid nanoparticles during nebulization, experiments with a specific anti-aggregation formulation were performed. Notably, in the vibrating mesh and impinging jet samples, larger lipid nanoparticles were detected from a wide range of smaller lipid nanoparticles, indicating that the aggregates of 1 μm or more observed after nebulization can be reasonably assumed to be due to aggregation or destruction of smaller lipid nanoparticles.

[0057] To evaluate the impact of different aerosolization methods on the mRNA integrity of two SARS-CoV-2 vaccines, mRNA-1273 and BNT162b. The mRNA size of untreated and aerosolized mRNA vaccines was analyzed by automated gel electrophoresis. Electropherograms of mRNA isolated from non-aerosolized samples (control conditions) showed dominant peaks between 3,500 and 4,000 for both vaccines (Figure 10a, c). This is consistent with the reported lengths of these mRNAs. To demonstrate the effect of nebulization on mRNA integrity, electropherograms are shown in Figure 10 for BNT162b (see Figures 10a, 10b, 10c) and mRNA-1273 (see Figures 10d, 10e, 10f) vaccines before and after nebulization using vibrating mesh type 1 (VM1; blue), impinging jet (CJ; yellow), vibrating mesh type 2 (VM2; red), and the nanotechnology membrane of the present invention (NM; green), compared to standard vaccines with and without RNase.

[0058] Nebulized samples were treated with RNase to nebulize all mRNA that was not encapsulated in lipid nanoparticles prior to electrophoretic analysis. The horizontal axis shows RNA fragment size based on a series of RNA fragments of known length (200, 500, 1,000, 2,000, 4,000, and 6,000 nucleotides). For clarity, electropherograms were manually adjusted on the horizontal axis to align the full-length mRNA vaccine peak to the profile obtained from the untreated stock solution. The amount of RNA is shown as normalized fluorescence units on the vertical axis.

[0059] Naked mRNA molecules are susceptible to both enzymatic (e.g., RNase) and nonenzymatic degradation (e.g., shear). To disentangle these two degradation mechanisms, we investigated the length of RNA fragments before and after the nebulization process, with and without the addition of RNase. RNase treatment before nebulization did not seem to affect the full-length mRNA of BNT162b (Figure 10a), but it did reduce the full-length mRNA from the mRNA-1273 vaccine (dotted line in Figure 10d). Of note, nebulization with the vibrating mesh 1 (VM1) and impinging jet (CJ) methods resulted in 60-90% degradation of the mRNA in the vaccine (P<0,001). This was observed as a reduction in the full-length mRNA peak (Figures 10b, 10e). In contrast, nebulization with the vibrating mesh 2 (VM2) and nanotech membrane (NM) methods of the present invention reduced the full-length mRNA by only 10-25% (P<0.001).

[0060] RNase treatment appears to significantly reduce the full-length mRNA content of all nebulized samples, except for the NM-nebulized samples (Fig. 10c, f). Surprisingly, while full-length mRNA appears to be virtually unaffected in the VM2 method, subsequent addition of RNase significantly degraded the mRNA. This indicates that the lipid nanoparticles were destroyed or dysfunctional after nebulization with the VM2 method. Results after addition of RNase were degraded to almost the same extent as those of the VM1 and CJ methods (Fig. 10c, f). On the other hand, nebulized samples obtained with the NM method showed significantly less mRNA reduction after RNase treatment, almost equivalent to the stock solution, indicating almost no degradation (BNT162b: 10.1 ± 1.4 and 7.7 ± 1.6 ng / μl, mRNA-1273: 33.8 ± 2.6 and 26.4 ± 2.7 ng / μl after stock and NM-nebulization, respectively).

[0061] To determine whether the energy levels involved in the nebulization methods result in reversible deformation or irreversible destruction of lipid nanoparticles, the percentage of mRNA that remains intact after nebulization as a function of energy dissipation for all three nebulization methods for two vaccine formulations with and without added RNase is plotted in Figures 11A and 11B, respectively.

[0062] For the vibrating mesh (VM) technology, two commercially available nebulizers were used: VM1, manufactured by Pari eflow (Pari GmbH), and VM2, manufactured by Aerogen Solo (Aeroneb). The reservoirs of VM1 and VM2 were filled with 2–4 ml of vaccine-containing sample. The generated aerosol was collected in a 30 mm diameter glass tube, and the collection time was measured to obtain approximately 0.5–1 ml of nebulized liquid. A significant increase in throughput over time (e.g., from 0.3 ml / min to 0.8 ml / min) was observed for both vibrating mesh nebulizers. This was probably due to an increase in the temperature of the formulation caused by the dissipation of vibration energy in the reservoir.

[0063] For the impinging jet (CJ) method, a Respimat (Boehringer Ingelheim) was used. The plastic cartridge of the reusable Respimat nebulizer was filled with the vaccine formulation, and 60 doses or injections of 15 μL each were collected in glass tubes. Each injection lasted approximately 2 seconds. Reloading the spring of the device also took approximately 2 seconds.

[0064] In the nanotechnology membrane (NM) method according to the present invention, a nanotechnology membrane chip was fabricated using silicon semiconductor technology. A free-hanging silicon nitride membrane with a thickness of 800 nanometers was fabricated on a silicon body, and 85 holes with a diameter of 1.9 nm were created in this membrane by reactive ion etching. First, 1 ml of the vaccine formulation was filled into a syringe or spray pump, and manually extruded through a nanotechnology membrane nozzle at a pressure of 20 bar at a flow rate of 2-3 ml / min and collected in a glass tube with a diameter of 10 mm. All experiments were performed for both mRNA-1273 and BNT162b vaccines and were repeated three times.

[0065] mRNA isolation To isolate pure vaccine mRNA, 300 μl of Trizol LS reagent was added to the untreated samples. Phenol and guanidine isothiocyanate used in this Trizol LS method dissolve lipid nanoparticles and protect the released vaccine mRNA from endonuclease degradation. The sample and Trizol LS mixture was then processed according to the manufacturer's instructions until the aqueous phase containing the vaccine mRNA was ±230 μl. Vaccine mRNA was purified and concentrated from the aqueous phase using the RNeasy MinElute Cleanup Kit (Qiagen) according to the procedure described in Appendix D of the product manual, resulting in 12 μl. This RNA extraction procedure was also performed for the nebulized and nebulized + RNase-treated samples.

[0066] Quantification of mRNA Automated gel electrophoresis of purified vaccine mRNA from all samples was performed on an Agilent 2200 TapeStation system using Agilent RNA ScreenTapes (Agilent). Electrophoretic profiles were displayed and quantified with the software Agilent Tape Station System Software (Rev. 4.1.1). The concentration of the full-length vaccine mRNA peak was quantified by strictly manually defining an area around the full-length vaccine mRNA peak, which minimized contamination with degraded vaccine mRNA. The RNA concentration within the defined area was calculated by the software and used as a concentration measure of full-length vaccine mRNA in the sample.

[0067] RNase treatment Freshly sprayed vaccine samples and stock vaccine samples (control condition) were divided into two equal aliquots of 100 μl. One subsample was treated with RNase Cocktail Enzyme Mix (Thermo Fisher Scientific) containing RNaseA and RNaseT1 at final concentrations of 5 U / ml and 200 U / ml, respectively, at 37°C for 5 min. This RNase treatment completely degrades vaccine mRNA that is not protected by intact liposomal nanoparticles. After RNase treatment, 300 μl of Trizol LS reagent (Thermo Fisher Scientific) was added to the mixture to inactivate RNase.

[0068] Atomization Energy Input For impingement jet nebulizers, the spring constant of the spring loading the device was measured, from which the energy stored in the spring and subsequently input into the spray formulation (15 μl) was directly calculated using an energy transfer efficiency of 40-60%. For nanotechnology membrane nebulizers, the amount of energy added to the spray was calculated from the pressure exerted on the syringe piston and the volume change.

[0069] With the vibrating mesh nebulizer, the formulation was nebulized for 60 seconds and the temperature rise of the reservoir fluid was measured. This was done for three different reservoir fluid volumes (1 g, 3 g, and 6 g). The temperature rise was multiplied by the specific heat of water and the volume of fluid in the reservoir to calculate the amount of energy absorbed by the reservoir fluid during the nebulization process. The energy absorbed by the reservoir fluid was extrapolated to a volume of 0 g of reservoir fluid to give an indication of the amount of energy added to the spray fluid. Dividing this amount by the volume of fluid sprayed gave the energy density (J / g) added to the spray fluid.

[0070] Figure 11A shows the percentage of intact mRNA without the addition of RNase. The absence of RNase means that liposome disruption and subsequent mRNA strand breakage occurs solely due to hydrodynamic shear forces. At an energy dissipation of approximately 10-20 J / g, a sort of transition from intact to intact mRNA is observed. Figure 11B shows the percentage of intact mRNA with the addition of RNase after nebulization. This suggests that the degradation of lipid nanoparticles is due to both hydrodynamic forces and enzymatic RNase activity.

[0071] The change from intact to non-intact can be seen at an energy dissipation of about 5-10 J / g. Combining these figures, it can be seen that the lipid nanoparticles start to break and release the mRNA strands at an energy dissipation of about 5-10 J / g. It can also be seen that the hydromechanical disruption of these (naked) mRNA strands occurs at energy densities of more than 10-20 J / g. Therefore, according to the invention, the process of nebulizing liquid formulations containing long fragile molecules is preferably carried out in such a way that less than 20 J / g, preferably less than 10 J / g, of energy is dissipated in the liquid to be nebulized.

[0072] Figure 12 shows a particular embodiment of a nasal adapter 77 for a nasal spray device according to the invention. The nasal adapter consists of a spray nozzle 70 of a nasal spray device, further comprising means for generating two additional air streams 71, 73. These means generate a high-velocity coaxial air pit stream 71 along the path of the liquid micro-jets 72 emerging from the spray nozzle 70. This coaxial pit stream prevents the coalescence of the liquid droplets in the jet emerging from the spray nozzle tip 70. Preferably, the velocity of the pit stream 71 is initially higher than the initial velocity of these micro-jets 72.

[0073] Moreover, this means generates a sheet-like airflow 73 along the inner wall of the adapter 77 as the user inhales, as indicated by the white dotted arrow. This sheet airflow 73 suppresses turbulence along the inner wall of the airflow containing the microjet droplets, preventing the droplets from impinging on the wall of the interface of the nasal adapter. The housing of the nasal adapter 77 has a conical top intended to be placed in a substantially sealing manner on one of the user's nasal cavities, directing the microjet droplets into the user's nasal cavity. The additional airflows 71, 73 may be generated passively as the user inhales through the nostrils, or may be generated actively by a supply of supplemental pressurized air. In that case, a suitable means such as a ventilator or pressurized gas is used, and the pressurized gas is released after the user inhales.

[0074] Overall, the nasal spray device of the present invention provides a nasal spray device that maintains the convenience and simplicity of a conventional swivel nozzle, for example, while maintaining the convenience and simplicity of a swivel nozzle device, as follows: - The dose required for nebulization is small, as little as 25μL, ensuring a sufficient amount of medicinal solution for the administered treatment. - Achieve a slow-moving, soft mist of ultra-fine droplets with droplet size independent of fluid flow rate or fluid formulation. - Narrow droplet size distribution can be tailored to deposit only in the targeted nasal region, avoiding deposition through deep breathing. - Low jet velocity below 1.0 m / s and narrow droplet size distribution optimize deposition efficiency in the nasal cavity. - Jet cone angle is optimized to 10-25 degrees to allow for wider deposition in the nasal cavity. - Droplet deposition over a large surface area limits droplet shedding and removal. - Impact forces are reduced due to slower jet velocity and smaller droplets. - The luer lock attachment feature allows for easy attachment to existing medical luer lock syringes, etc. - The ambient air flows parallel to the device through the purposefully designed air slits.

[0075] As described above, although various embodiments of the present invention have been described, it should be understood that they are presented by way of example and not limitation. It is apparent to those skilled in the relevant art that various changes in form and details are possible. Therefore, the present invention should not be limited by any of the above-described embodiments, but should be defined only according to the following claims and their equivalents.

[0076] In particular, the nasal spray device can include a silicon chip that functions as a nozzle body carrying a nozzle membrane. For example, the nozzle membrane can be formed from a silicon nitride ceramic layer having a thickness on the order of 1 micron. In such a layer, micro-holes (openings) can be etched on the nanometer to micrometer scale using ultra-precise photolithographic imaging, masking, and etching techniques utilized in modern semiconductor manufacturing.

[0077] The size of the microholes inside the spray tip largely determines the initial size of the droplets emitted in the spray. This size largely determines the target area where the droplets will mainly reach the respiratory system. Microholes between 3 and 8 microns usually emit droplets larger than 10 microns. As a result, the droplets mainly target the nasal cavity, especially the nasal turbinates, and do not penetrate deeper into the respiratory system, because droplets larger than 10 microns generally cannot pass through the nasopharynx and instead remain in the upper respiratory tract. On the other hand, droplets between 1 and 10 microns in size generally pass through the nasopharynx and may eventually deposit mainly in the lower respiratory tract (trachea and alveoli). Droplets smaller than 1 micron do not deposit at all and are almost entirely expelled with exhaled air, reaching deeper parts of the respiratory system, such as the bronchi and lungs.

[0078] As shown in FIG. 5B, the nasal spray device of the present invention allows for intranasal administration with high coverage of nasal tissue. For many preventative and other applications, such intranasal administration provides high coverage. However, other preventative and other conditions may require deeper deposition in the lower airways. Thus, certain embodiments of the nasal spray device of the present invention are configured to deliver the liquid formulation to both the upper and lower airways in a single inhalation step when inhaled through the nose.

[0079] For that purpose, the same or a further microtip may be simultaneously provided in the nasal spray device with the pressurized liquid and comprised of a second group(s) of micropores having a diameter of 3 microns or less, for example 1.5 to 3 microns. The droplets emitted from these micropores will typically be 10 microns or less in size and will tend not to lodge in the nasal cavity but to pass through the nose into the downstream airways.

[0080] The first set of micropores, with diameters between 3 and 8 microns, produce larger droplets that are intended to be captured in the upper airways, especially the nasal vestibule, turbinates, and olfactory regions. The second set of micropores, with openings smaller than 3 microns, produce droplets that are small enough to target the nasopharynx and lower airways (lungs) when inhaled through the nose. Because these droplets are smaller and therefore have a lighter mass, the smaller droplets have lower kinetic energy and lower jet velocity. These smaller droplets ride the air current and move from the upper to the lower airways. By varying the ratio of the number of small and large pores, it is possible to adjust the deposition ratio of the prophylactic formulation in the upper and lower airways.

[0081] Thus, such a nasal device according to the invention is capable of delivering liquid formulations, e.g. containing prophylactic or medicinal drugs, to both the upper and lower respiratory tract in one inhalation step when inhaled through the nose. The size of the micropores in the spray nozzle mainly determines the size of the initial droplets, thereby controlling the target location of deposition in the upper and / or lower respiratory tract. If the micropores are grouped in one group with pore sizes between 3 and 8 microns and in another group with pore sizes smaller than 3 microns, the device produces a nasal spray that, when inhaled, acts on the entire respiratory tract. A unique dual therapy is provided in one nasal spray device for conditions that require coverage of not only the nasal mucosa but also the deeper respiratory regions, especially the mucosa of the bronchi and lungs.

Claims

1. A nasal spray device comprising a nasal cap having an end for receipt within a user's nasal cavity, said nasal cap including a spray cavity opening through said end, said nasal cap including a suspended spray nozzle configured to receive a liquid formulation at an inlet and to emit a liquid spray of said liquid formulation at an outlet opening into said spray cavity; The spray nozzle has a membrane between the inlet and the outlet through which the liquid formulation passes, the membrane having a plurality of micro-holes of substantially identical size, between 1 micron and 10 microns, in particular between 3 microns and 8 microns, the micro-holes being configured to emit a jet of micro-droplets under a deflection angle relative to the axis of each micro-hole, the micro-holes being distributed so as to form a substantially conical shaped, diverging spray plume having an apex.

2. 2. The nasal spray device of claim 1, wherein said cone-shaped spray plume has an apex of about 5 degrees.

3. 2. The nasal spray device of claim 1, wherein the cone-shaped spray plume has an apex of 5 to 30 degrees, particularly 20 to 25 degrees, and more particularly about 20 degrees.

4. A nasal spray device according to any one of claims 1 to 3, characterized in that it comprises a chamber containing a predetermined dose of the liquid formulation, in particular comprising a volume of 25 to 150 microliters, and a manually pressurizable positive displacement pump configured to pressurize the dose of the liquid formulation and force it, under an elevated working pressure of 5 to 15 bar, into the inlet of the spray nozzle which releases the predetermined dose of the liquid formulation.

5. 5. The nasal spray device of claim 4, wherein the pump comprises a manually actuated piston for pressurizing the dose of the liquid formulation to the actuation pressure with a single stroke of the piston.

6. 6. The nasal spray device of claim 4 or 5, characterized in that the pump comprises a multi-shot nasal pump comprising a dosing chamber for at least temporarily holding the dose of the liquid formulation and expelling the dose under the actuation pressure to the spray nozzle.

7. A nasal spray device according to claim 4, 5 or 6, characterized in that the pump is formed by a medical syringe.

8. A nasal spray device as described in any one of claims 4 to 7, characterized in that the pump opens into a male luer tip, the nasal cap has an inlet providing a female luer slip connection to the male luer tip and is receivable onto the male luer tip and has an outlet for releasing the nasal spray, and the nasal cap contains the spray nozzle between the inlet and the outlet.

9. A nasal spray device according to any one of claims 1 to 8, characterized in that the nasal cap includes at least one inhalation channel which conveys a parallel flow of ambient air together with the spray towards the outlet during inhalation by a user.

10. A nasal spray device according to any one of claims 1 to 9, characterized in that the nasal cap tapers towards the outlet so as to fit closely against the nose.

11. A nasal spray device according to any one of claims 1 to 10, characterized in that the membrane comprises a ceramic layer, the micropores extending through the thickness of the ceramic layer.

12. 12. The nasal spray device according to claim 11, characterized in that the ceramic layer is a silicon nitride layer on a carrier body of semiconductor material, in particular silicon, the carrier body comprising at least one cavity below the nitride layer, at least one of the cavities opening downstream into at least one of the micropores, and at least one of the cavities being connected upstream to the outlet of the pump.

13. A nasal spray device as claimed in any one of claims 1 to 12, characterized in that the aerosol spray is emitted from the tiny holes in the membrane within the spray nozzle in a Rayleigh jet which is then broken down into particles of the aerosol spray.

14. A nasal spray device according to any one of claims 1 to 13, characterized in that the reservoir contains a pharma- ceutically active liquid formulation, in particular a formulation containing nanoparticles such as formulations containing complex proteins, peptides, long chain DNA and RNA, large vesicles, liposomes, lipid nanoparticles, mRNA vaccines, mRNA lipid nanoparticles and antibodies.

15. A nasal spray device according to any one of claims 1 to 14, characterized in that the membrane of the spray nozzle comprises a second group of micro-holes of substantially identical size less than 3 microns, and the liquid formulation passes through the membrane of the spray nozzle as it is expelled from the device.

16. 16. A nasal spray device according to any one of claims 1 to 15, wherein the liquid formulation comprises nanoparticles of size δ, the nanoparticles having a maximum size δmax before they break on stretching, and the micropores have a length L which is smaller than the pore diameter D x δmax / δ (L < D.δmax / δ), particularly when L < 4D.

17. 15. A nasal spray device according to claim 14, wherein the liquid formulation comprises macromolecules having a chain length λ, and the micropores have a length L which is smaller than the chain length λ of the macromolecules, in particular L being smaller than 1 micron.

18. 1. A method of aerosolizing a liquid formulation, comprising: A method comprising subjecting a liquid formulation, in particular containing macromolecules, more particularly containing biological molecules, to a treatment to convert said liquid formulation into a mist, said liquid formulation being subjected to an energy not exceeding 20 Joules / gram, preferably not exceeding 10 Joules / gram, while converting said liquid formulation into a mist of said liquid formulation, in particular forming a soft mist spray plume.

19. 19. The method of claim 18, wherein the liquid formulation is pressurized to an actuation pressure to produce at least a pressurized dose of the liquid formulation, and the pressurized dose of the liquid formulation is forced through at least one micro-hole, in particular a plurality of micro-holes, in a membrane of a Rayleigh disruption type spray nozzle.

20. 20. The method of claim 19, characterized in that the liquid formulation is pressurized by means of a pump, in particular a manually actuatable pump, to a working pressure of 5 to 15 bar to generate a pressurized dose of the liquid formulation, and forcing the pressurized dose of the liquid formulation through a group of micro-holes in the membrane of a Rayleigh-type spray nozzle, the micro-holes having a size smaller than 8 microns, the liquid formulation being broken into at least one spray jet of droplets having substantially identical initial droplet sizes, and propagating the mist with a spray plume propagation velocity of less than 1 m / s.

21. The liquid formulation contains nanoparticles of size λ, the droplets contain at least one of the nanoparticles, the nanoparticles having a maximum size λmax before breaking upon elongation, the liquid formulation is subjected to a shear rate γ [seconds] while passing through micropores, and the liquid formulation is exposed to the shear rate γ within the micropores for a shear time Δt less than λmax / (λ.γ) seconds.

21. The method of claim 19 or 20.

22. The liquid formulation comprises nanoparticles, the nanoparticles having a size δ and a maximum size δmax before breaking upon elongation, and the micropores have a length L less than D.δ / δ, particularly when L<4.D, where D is the diameter of the micropore.

22. The method of claim 19, 20, or 21.

23. 23. The method according to any one of claims 19 to 22, wherein the liquid formulation comprises macromolecules having a chain length λ and the micropores have a length L smaller than the chain length λ of the macromolecules, in particular L smaller than 1 micron.

24. 24. The method according to any one of claims 18 to 23, wherein the liquid formulation comprises nanoparticles taken from the group containing complex proteins, large biological molecules, long chain DNA and RNA, large vesicles, liposomes, bacteriophages, lipid nanoparticles, mRNA vaccines, mRNA lipid nanoparticles and antibodies.

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