Nasal spray device and method of atomizing liquid formulation

Abstract

A nasal spray device and a method of atomizing a liquid formulation. The nasal spray device comprises: a non-pressurized reservoir (25) for containing a liquid formulation; a spray nozzle (50); and a manually energizable pump (10) configured to pressurize an amount 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) comprises a membrane having a plurality of micropores of substantially the same size, the micropores having a size of less than 8 microns and greater than 3 microns through which the liquid formulation passes when the liquid formulation is expelled from the device. The membrane is configured to release the dose of the liquid formulation as a conical plume having a tip over a period of at least 500 milliseconds. Energy less than 20 Joules per gram is dissipated in the liquid to maintain molecular integrity of macromolecules within the liquid.

Description

[0001] The present invention relates to a nasal spray device, comprising a nostril cap having an end portion received inside a user's nostril cavity, wherein the nostril cap includes a spray cavity opening through the end portion, and wherein the nostril cap includes a spray nozzle configured and suspended to receive a liquid formulation at an inlet and release a liquid spray of the liquid formulation at an outlet opening into the spray cavity.

[0002] Currently, manually operable nasal spray devices deliver nasal sprays, which are generated by pressurized vortex nozzles, also known as hollow cone nozzles. The fixed core inside the nozzle induces a rotating fluid motion, which causes a fluid vortex in the vortex chamber. The liquid sheet film is discharged from the periphery of the outlet orifice, producing a unique hollow cone spray pattern. Air or other surrounding gases are sucked into the vortex chamber to form an air core in the vortex liquid. According to the nozzle capacity and construction materials, a variety of geometric fluid inlets are used to produce this hollow cone pattern. The droplets produced by these vortex nozzles have a more or less random size between 20 and 200 microns in a relatively wide droplet size distribution, and the droplet size distribution generally has an average droplet size between 50 and 80 microns. The volume flow rate or discharge rate of the spray generated with the vortex nozzle is relatively high, generally greater than 200 microliters per second.

[0003] Another conventional technology for atomization is based on a flexible grid mounted on a piezoelectric lead zirconate titanate (PZT) annular actuator (ultrasonic transducer) that stretches and vibrates, ejecting droplets of relatively random size, typically ranging between 1 and 10 microns. The vibrations extend into the liquid formulation and generate heat, which is dissipated in the liquid, raising the temperature of the formulation during atomization.

[0004] Finally, atomization of liquid formulations can be achieved by cross jets that allow high-speed collisions. The collision jet (also called impact jet) method is based on such a collision of two jets at high speeds, forming a thin liquid sheet (also called Savart sheet) at the impact location, which disintegrates into droplets of random size, typically with a wide size range between 1 and 10 microns. In order to ensure that the two jets have sufficient speed to form droplets smaller than 10 μm after the Savart sheet breaks, the required system pressure is typically between 150-200 bar.

[0005] All these known atomization techniques need to supply a large amount of minimum energy to the liquid, and therefore cause the liquid spray to produce a considerable impact in the nose. The latter is not only a disadvantage from the user's sensory perspective, but also causes a relatively short administration time. Usually, utilizing this conventional nasal spray device, a dose of 40 microliters is delivered within a dosing time of less than 200 milliseconds, and most of the liquid spray just falls on the nasal vestibule. Especially, many spray pump vortex nozzle devices deposit a large amount of their medicines in the front vestibule that is considered to be a lower active area in the nasal cavity. This front vestibule deposition may be due to inertial impact, because most spray pumps are designed to release most of the aerosol particles greater than 20 microns, and these aerosol particles leave the device at a relatively high speed in a short time when actuated.

[0006] Furthermore, the same high energy levels and impacts on the liquid associated with these known atomization techniques appear to damage the integrity of fine macromolecules if they remain in the liquid formulation. This makes known atomization devices and methods less suitable for atomizing large macromolecules, such as lipid particles often found in biotherapeutic formulations.

[0007] One of the main objects of the present invention is to provide a nasal spray device that overcomes the above-mentioned disadvantages without sacrificing substantial convenience for the user. In one aspect of the present invention, an object is to provide a nasal spray device that provides improved coverage of the nasal cavity, particularly including the olfactory region of the nasal cavity. More particularly, in a further aspect, an object of the present invention is to provide a nasal spray device that enables nanoparticles to form an aerosol, which nanoparticles may include relatively long molecules, particularly fragile biomolecules, while substantially maintaining their nanoparticle structure and molecular integrity.

[0008] In order to achieve the above-mentioned purpose, according to the first aspect of the present invention, a nasal spray device of the type described in the opening paragraph is characterized in that the spray nozzle includes a membrane located between the inlet and the outlet, the membrane having a plurality of micropores of substantially the same size, the size of the micropores being between 1 micron and 10 microns, in particular between 3 microns and 8 microns, the micropores conveying the liquid formulation to be discharged from the device as a spray jet, wherein the micropores are configured to release a micro-droplet jet at a deflection angle relative to an axial centerline of the corresponding micropore, and wherein the micropores are distributed to form together a substantially conical divergent spray plume having a top.

[0009] The device according to the invention is based on a relatively gentle Rayleigh breakup of a liquid formulation after passing through relatively short micro-apertures of defined size. This will produce a soft mist of ultrafine droplets of substantially the same size, regardless of their propagation speed. In particular, the micro-apertures are arranged and configured so that they produce a slowly propagating substantially conical diverging plume, which helps to improve the nasal coverage of the nostril area, especially in the direction opposite to the propagation direction. The deflection of the individual spray jets released by the micro-apertures can be achieved and configured in particular with the aid of the technology disclosed by the applicant in the co-pending European patent application EP ..., the content of which is incorporated herein by reference.

[0010] Thus, the present invention is based on the recognition that Rayleigh breakup of a liquid formulation with the aid of micropores of less than 8 microns will deliver spray droplets of substantially the same initial size, typically between two and three times the size of the micropores. These still relatively small micron-sized droplets together form an ultrafine spray plume that is substantially instantaneously delayed once released and exposed to ambient air due to the relatively small kinetic energy of the individual droplets. In particular, the resulting spray plume will be decelerated to have a propagation velocity of the order of no more than 1 m / s. It has been found that the turbulence within the spray plume, together with this slow rate of motion, delivers unprecedented coverage in substantially the entire nasal cavity, including the higher olfactory region.

[0011] It has surprisingly been found that a first particular embodiment of the nasal spray device according to the invention can specifically target the inferior and middle turbinate, characterized in that the conical spray plume has a tip of around 5 degrees.

[0012] On the other hand, a second particular embodiment of the nasal spray device is characterized in that the conical spray plume has an apex between 5 and 30 degrees, particularly between 20 and 25 degrees, and more particularly around 20 degrees. The spray device can be advantageously used to specifically target the nostrils and / or the olfactory region and the nasopharynx of the nasal cavity.

[0013] Another embodiment of the nasal spray device according to the invention is characterized in that a chamber is provided for containing a predetermined dose of the liquid preparation, in particular having a volume between 25 and 150 microliters, wherein a manually energizable positive displacement pump is configured to pressurize the dose of the liquid preparation and force the liquid preparation at an elevated operating pressure between 5 and 15 bar to the inlet of the spray nozzle releasing the predetermined dose of the liquid preparation.

[0014] The present invention provides a nasal spray device for generating so-called micro jet spray in particular. Micro jet spray is composed of a plurality of jets emitted simultaneously, wherein each jet initially can be broken into a monodisperse primary droplet string according to the jet breakup mechanism. Therefore, continuous primary droplets have substantially the same size, and propagate in the same direction downstream of the nozzle. Usually, the diameter of the primary droplet is between two to three times the diameter of the micropore that releases it. This means that according to the present invention, the primary droplet has the same size between 6 and 30 microns, and this depends on the size of the micropore that generates them. Eventually, a single droplet may merge due to mutual coalescence, which will result in a deviation and a certain dispersion of droplet size distribution in the whole spray. Nevertheless, the droplet size distribution is relatively sharp and well-defined always.

[0015] In this context, it should be noted that in the present application, the size of a micropore is defined as the diameter of a circle having the same surface area as the cross-sectional surface area of ​​the micropore. Similarly, the size of a droplet is defined as the diameter of a sphere having the same volume as the volume contained in the droplet. Furthermore, unless otherwise expressly stated, the expressions atomizer, sprayer and spray device are used interchangeably without creating any essential difference.

[0016] The nasal spray device according to the present invention is based on a pump, in particular a manually powered pump, to operate to deliver an ultrafine mist of these relatively small droplets. Due to their relatively low momentum, these droplets tend to decelerate relatively quickly when encountering ambient air. In practice, residence times of the order of 500 milliseconds and even longer have been observed. This slow release of relatively small droplets provides a slow-moving soft mist of the liquid formulation.

[0017] The patient can inhale gently through the nostrils, which deliver the soft mist droplets to the nasal target area and further downstream in the nasal cavity. The mostly uniformly sized droplets are particularly capable of targeting the respiratory and olfactory nasal areas. This enhanced penetration is due to the fact that the spray device of the present invention is designed to generate small and also slow moving particles that pass through the nasal cavity at normal inhalation rates, thereby minimizing inertial impact in front of the nasal valve.

[0018] Due to the relatively sharp droplet size distribution of the spray as associated with Rayleigh formation, only a small portion of the soft mist spray (if any) is composed of droplets that are too small, particularly less than 10 microns, so that they can escape further into the user's respiratory system, particularly into the lungs. Targeting the olfactory area is particularly targeted at local drugs that can be directly absorbed by the brain, thereby avoiding the blood-brain barrier. In addition, the nasal fluid clearance rate in the olfactory area is significantly lower than the nasal fluid clearance rate in the vestibular area, so that the preparation has a longer time to be absorbed by the nasal mucus tissue. These factors greatly contribute to the significant improvement of absorption efficiency and nasal coverage. The pump-based nasal spray device according to the present invention includes a nozzle that generates a slowly moving fine mist of a liquid formulation that can reach and cover up to more than 80% of the nasal mucus layer.

[0019] On the other hand, the present invention aims to provide a method suitable for atomizing a liquid formulation, said liquid formulation retaining at least to a large extent the molecular integrity of any macromolecules retained in said liquid. To this end, according to the present invention, a method for atomizing a liquid formulation, in particular a liquid formulation containing macromolecules, more particularly containing biomolecules, wherein said liquid formulation is subjected to a treatment to convert said liquid formulation into a mist of said liquid formulation, characterized in that said liquid formulation is subjected to an energy of no more than 20 joules / gram, preferably no more than 10 joules / gram, while converting said liquid formulation into a mist of said liquid formulation, in particular forming a soft mist spray plume.

[0020] It has been found that if only a limited amount of energy is dissipated during the atomization of the liquid, at least most fragile macromolecules, such as complex proteins, peptides, long-chain DNA and RNA, large vesicles, liposomes and antibodies, will survive the atomization process. This can be achieved by means of a Rayleigh breakup process to produce a fine mist of the liquid preparation. Therefore, according to a preferred embodiment of the method of the present invention, it is characterized in that the liquid preparation is pressurized to an operating pressure to produce at least one pressurized dose of the liquid preparation, and wherein the pressurized dose of the liquid preparation is forced to pass through at least one micropore in the membrane of a Rayleigh breakup (break-up) type spray nozzle, in particular through a plurality of micropores.

[0021] The present invention particularly relates to a nasal spray device, which can be used to form an aerosol of a pharmaceutical preparation for nasal administration. To this end, according to a specific embodiment of the nasal spray device of the present invention, it is characterized in that the reservoir contains a pharmaceutically active liquid preparation, in particular a preparation containing nanoparticles, such as a preparation containing complex proteins, peptides, long chains of DNA and RNA, large vesicles, liposomes and antibodies.

[0022] For example, the pump-based nasal spray device of the present invention will be able to protect users from allergic attacks or diseases caused by microorganisms or viruses, such as SARS-Cov-2 viruses, through appropriate anti-allergic or preventive preparations. The preventive preparations currently used to prevent the virus from binding to nasal epithelial cells are angiotensin receptor blockers, ACE inhibitors, heparin and enoxaparin derivatives. Other preventive agents and vaccines include ivermectin, antibodies, glycoproteins, mRNA lipid nanoparticles and other bioactive agents. The pump-based nasal spray device of the present invention may include a nozzle that maintains the integrity of such preparations, especially in the case of biological preparations, which are generally based on macromolecules and / or nanoparticles, such as preparations containing complex proteins, peptides, long-chain DNA and RNA, large vesicles, liposomes and antibodies. On the other hand, it has been found that the fine mist atomizer currently used for nasal use destroys the molecular integrity of the macromolecules present in many mRNA lipid nanoparticle vaccines. This makes these conventional atomizers unsuitable for nasal administration of many protein-based drugs or other biological drugs.

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

[0024] In a preferred embodiment, the nasal spray device according to the present invention is characterized in that the pump comprises a manually actuated piston, which pressurizes the liquid formulation of the dose to the operating pressure in a single stroke of the piston. The piston that pressurizes the entire dose in a single stroke provides convenience for the user, especially if the pump mechanism is further configured to automatically fill the dose into a dedicated predetermined and defined volume of the device before pressurizing it. The pump may include a multi-shot nasal pump provided with a dosing chamber, the dosing chamber being used to at least temporarily accommodate the liquid formulation of the dose and release the dose to the spray nozzle at the operating pressure. Alternatively, the pump may be formed by a medical syringe.

[0025] A specific embodiment of the nasal spray according to the present invention is characterized in that the pump opens to the end of a male Luer connector, wherein the nostril cap is receivable on the end of the male Luer connector, the nostril cap has an inlet and an outlet, the inlet provides a female Luer connector slidably connected to the end of the male Luer connector, the outlet releases the nasal spray, and wherein the nostril cap includes the spray nozzle between the inlet and the outlet. This embodiment particularly allows a standard medical syringe to be used as a pump and a reservoir for containing the liquid preparation. Simply mounting the nostril cap embodying the spray nozzle according to the present invention on the top of the syringe converts the syringe into a nasal spray device that is superior to many conventional nasal spray devices. Both the syringe and the nostril cap can be provided as low-cost disposable items.

[0026] Another specific embodiment of the spray device according to the present invention is characterized in that the nostril cap comprises at least one inhalation channel, which conveys a parallel airflow of ambient air together with the spray towards the outlet when the user inhales. For example, such an inhalation channel can be arranged in the wall of the nostril cap, opening to the environment. When the user inhales, this induces an additional airflow consisting of ambient air to pass through the nostril cap. The spray droplets can be carried on this additional airflow, or can be carried into its slipstream to be delivered deeper into the nasal cavity. Even remote nasal areas located inside 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 to fit the nose tightly.

[0027] In a preferred embodiment, the membrane comprises a ceramic layer, wherein the micropores extend over the thickness of the ceramic layer. For example, the micropores can be formed by etching and / or using micromachining using photolithography methods customary in today's semiconductor technology. In this respect, a specific embodiment is that the ceramic layer is a silicon nitride layer on a carrier body of semiconductor material, in particular silicon, wherein the carrier body is provided with at least one cavity below the nitride layer, wherein the at least one cavity opens downstream to at least one of the plurality of micropores, and wherein the at least one cavity is connected upstream to the outlet of the pump.

[0028] The present invention further relates to a method of aerosolizing a liquid formulation, wherein the liquid formulation is pressurized by a pump to an operating pressure between 5 and 15 bar to produce at least a pressurized dose of the liquid formulation, wherein the pressurized dose of the liquid formulation is forced through a set of micropores in a membrane of a Rayleigh-type aerosol nozzle, the micropores having a size less than 8 microns, to cause the liquid formulation to break up into at least one aerosol plume of liquid droplets having substantially the same initial droplet size, and wherein the aerosol plume is caused to propagate at a plume propagation speed of less than 1 m / s, particularly in a user's nasal cavity. Such an aerosol 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 delivering an aerosol from a liquid formulation comprising nanoparticles, capable of maintaining the integrity of the nanoparticles when the liquid formulation is converted into an aerosol. For this purpose, a particular embodiment of the method of aerosolizing a liquid formulation, characterized in that the liquid formulation contains nanoparticles of size δ and the liquid droplets contain at least one nanoparticle of the nanoparticles, wherein the nanoparticles have a maximum size δmax before elongation rupture; wherein the liquid formulation is subjected to a shear rate γ [per second] when passing through the micropores; and wherein the liquid formulation is exposed to the shear rate γ within the micropores for a shear time Δt of less than δmax / (δ·γ) seconds.

[0030] In another embodiment, the nasal spray device and method according to the present invention, characterized in that the liquid formulation comprises nanoparticles of size δ and the liquid droplets contain the nanoparticles, wherein the nanoparticles have a maximum size δmax before elongation rupture; and wherein the micropores have a length L less than the diameter D of the pore multiplied by δmax / δ (L < D·δmax / δ). In the case of a tapered pore, the size or diameter D of the micropore is considered to be the maximum diameter of the micropore. For long-chain molecules, such as mRNA, etc., the length L of the micropore should be less than the total length λ of the long-chain molecule (L < λ), particularly L less than 1 micron.

[0031] The nasal spray device and method according to the present invention are particularly suitable for aerosolizing a liquid formulation comprising nanoparticles selected from the group consisting of composite proteins, biological macromolecules, long-chain DNA and RNA, large vesicles, liposomes, phages, and antibodies, while maintaining the integrity of these nanoparticles.

[0032] Hereinafter, the present invention will be described in further detail with reference to specific embodiments and the accompanying drawings.

[0033] In the drawings:

[0034] Figure 1A specific example of a nasal spray device according to the present invention is shown;

[0035] Figure 2 Shows Figure 1 A partial schematic diagram of a device;

[0036] Figure 3 Provided Figure 1 Comparison of droplet size distribution between the device and a conventional swirl nozzle nasal spray device;

[0037] Figure 4 ad show high speed photography captured images of the spray generated by a nasal spray device according to the present invention compared to a conventional swirl nozzle nasal spray device;

[0038] Figure 5A High-speed camera images showing nasal coverage of liquid spray by means of the conventional swirl nozzle nasal spray device;

[0039] Figure 5B High-speed camera images showing nasal coverage of liquid spray by means of the nasal spray device according to the present invention;

[0040] Figure 6 A comparison of total nasal coverage between different types of spray devices is shown;

[0041] Figure 7 shows the effect of a spray plume generated by a spray device according to the present invention on the tip of the spray plume at a target location;

[0042] Figure 8 Provides a graphical representation of the performance of a spray device according to the present invention for spraying a liquid formulation containing mRNA molecules compared to a conventional spray device;

[0043] Fig. 9 ae show the particle size distribution of mRNA-1273 after nebulization obtained from dynamic light scattering (DLS) in mass-weight mode, comparing:

[0044] a. Initial stock preparation;

[0045] b. After atomization with vibrating mesh VM1 at 35 J / g;

[0046] c. After atomization with vibrating mesh VM2 at 18 J / g;

[0047] d. After atomization with a collision jet (CJ) at 22 J / g; and

[0048] e. After atomization at 2 J / g using the Nanotechnology Membrane (NM) method according to the present invention.

[0049] Fig.10af show electropherograms of BNT162b (a, b, c) and mRNA-1273 (d, e, f) vaccines before and after nebulization with vibrating mesh type 1 (VM1; blue), collision jet (CJ; yellow), vibrating mesh type 2 (VM2; red), and nanotechnology membrane (NM; green), all compared with stock vaccines with and without RNase to demonstrate the effect of nebulization on mRNA integrity;

[0050] Fig.11A The fraction of intact mRNA versus nebulization energy dissipation without added RNase is shown;

[0051] Fig. 11B shows the fraction of intact mRNA relative to nebulization energy dissipation when RNase is added after nebulization; and

[0052] Fig.12 A schematic diagram is shown of a specific embodiment of a nasal adapter for use with a nasal spray device according to the present invention.

[0053] It should be noted that the drawings are purely schematic and are not necessarily drawn to the same scale. In particular, some dimensions may be more or less exaggerated to help clearly show any feature. In all drawings, similar parts are generally represented by the same reference numerals.

[0054] As an embodiment of the nasal spray device according to the present invention, Figure 1 A standard medical syringe 10 is shown, having a movable piston 15 manually operable by means of a rod 20. In practice, a liquid contained in a reservoir 25 contained in the syringe 10 may be subjected to an operating pressure of between 2 and 10 bar and forced under this operating pressure into a nostril cap 40 mounted on the end of the syringe by means of a male-female sliding connection and containing a spray nozzle 50 to receive the pressurized liquid.

[0055] Figure 2 The nostril cap is shown in more detail in , and basically comprises a plastic cone mounted on the end of the syringe 10. The nostril cap 40 is sealingly received on the male Luer connector end of the syringe 10 by means of an internal female Luer connector sliding connection at the entrance of the nostril cap 40. The nostril cap includes the spray nozzle 50 inside the inner cavity near the outlet 47 side. The nozzle 50 is configured and connected to receive the liquid under the operating pressure and convert it into an ultra-fine soft mist. To this end, the nozzle 50 includes a silicon spray microchip that is sealingly mounted inside the inner cavity of a plastic adapter body 60. The adapter body 60 facilitates easy handling and assembly of the nozzle device, and one or more filters can also be accommodated upstream of the spray chip 50.

[0056] The spray chip 50 holds a brittle ceramic silicon nitride membrane with a thickness of typically 1 micron. The membrane includes a plurality of micropores extending through the thickness. A thin silicon oxide layer can be provided between the nitride layer and the silicon body. In this case, the micropores will also extend through the oxide layer. Therefore, the micropores are openly connected to one of the plurality of lower cavities etched through the silicon body from the back to its front surface. These cavities deliver pressurized liquid to the micropores. Micropores of substantially the same size with a diameter of 4 microns are produced with high precision. For this reason, the micropores are preferably produced by photolithography-assisted etching and deposition techniques commonly used in modern semiconductor manufacturing technology, as are other structures of the microchip. Using these techniques, at least a portion of the micropores is modified and configured to release their microjets at a predefined deflection divergence angle relative to their center lines. These micropores are distributed and aligned on the membrane surface so that they together produce a substantially conical spray pattern, the cone having a predefined top between 5 degrees and 30 degrees, typically between 10 degrees and 25 degrees.

[0057] During operation, the liquid is forced through the micropores and when the cohesive forces can no longer reconcile with the surface tension, the liquid breaks into small droplets. This physical phenomenon is generally referred to as Rayleigh breakup and causes the liquid to break into droplets of substantially equal size, the size of the droplets initially being approximately between two and three times the size of the release micropore. Eventually, individual droplets may merge due to coalescence, which will result in a shift and some spread in the droplet size distribution throughout the spray. Figure 3 The curve A in the provided figure represents the typical droplet size distribution of the spray generated by this nozzle. The droplets have grown to between 20 and 40 microns. Nevertheless, the spray maintains a relatively sharp and symmetrical profile compared to the spray generated by means of, for example, a swirl nozzle. To demonstrate this, Figure 3 Also included are two comparative curves B, C which represent the typical profile of the droplet size distribution of a spray generated using a conventional swirl nozzle.

[0058] To enhance the penetration and total coverage of the nasal cavity by the nasal spray generated by the depicted spray device, the nostril cap 40 includes a plurality of inhalation channels 45 in addition to the central cavity, which convey a parallel airflow of ambient air along with the spray toward the outlet 47 when the user inhales. The spray chip of the nozzle 50 is configured to release a slow-moving liquid spray. Typically, the nozzle 50 releases a dose of between 25 and 150 microliters over a relatively long period of time of at least 500 milliseconds.

[0059] Many studies have demonstrated that this slow moving nasal spray is an excellent method for delivering topical drugs outside the nasal valve area. This enhanced delivery and penetration is attributed to the ability of small, slow moving liquid particles to pass through the nasal cavity at a static breathing rate, thereby minimizing the inertial impact in front of the nasal valve. In addition to the delivery device, a combination of other factors also contribute to the efficacy of intranasal formulations. These factors include drug formulation characteristics, deposition site, and delivery device that is convenient for patients to use. These excellent deposition characteristics are achieved by a relatively simple spray pump provided by the medical injector 10.

[0060] In order to explain the significant difference in droplet deposition of the soft mist nozzle of the nasal spray device according to the present invention compared with the standard swirl nozzle, high-speed photography captured the initial droplet velocity and plume formation ( Figure 4 A-4D). These images show the spray droplet trajectories of two spray nozzles. Figure 4 A shows the spray pattern of a spray generated by means of a soft mist nozzle according to the present invention, and Figure 4 B is Figure 4 Magnified view of the rectangular area of ​​the marked area in A. As indicated by the arrows, vortices can be observed. Figure 4 C shows the spray pattern of a spray generated by means of a standard swirl nozzle, while Figure 4 D is Figure 4 A magnified view of the rectangular area marked in C. Figure 4 As shown by the arrow in D, a straight droplet trajectory can be observed.

[0061] The spray plume of the vortex nozzle has an initial velocity of about 13 m / s, and the total spray volume is 100 μL in about 100 ms. However, the spray plume through the nozzle of the present invention has a relatively low initial velocity of less than 1 m / s, particularly about 0.7 m / s, and sprays 45 μL in not less than 500 ms. In addition, as Figure 3 As shown in the comparison graph in , the soft mist nozzle according to the present invention produces relatively small droplets (Dv50 20-25 μm) compared to the standard nose swirl nozzle (Dv50 60 μm). Figure 4 C and 4D, a standard swirl nozzle generally produces a short burst of relatively heavy droplets that all travel in a straight trajectory in an upward direction. Figure 4 A and 4B, the soft mist nozzle of the nasal spray device according to the present invention produces droplets in a turbulent droplet cloud that travels relatively slowly in all directions. The ballistic trajectory of the droplets of the vortex nozzle is such that most of the droplets of the spray are deposited only at the entrance of the nasal cavity. This is an inherent property of the vortex nozzle, in which the median droplet size is determined by the competition between the surface tension and inertia of the liquid. In this case, the median droplet size is proportional to v -2 / 3= , where v is the velocity. This means that only by increasing the velocity in the vortex nozzle can relatively small droplets, as required for deeper nasal administration, be obtained.

[0062] On the other hand, the droplet size of the soft mist nozzle of the nasal spray device according to the present invention is determined overwhelmingly by the size of the micropores, and is independent of the spray velocity. First, this allows for better control of the droplet size distribution within the spray, since the micropores can be made with great precision and definition. However, at least as importantly, this allows for a reduction in droplet size without increasing droplet velocity, to provide an ultra-fine slow-moving nasal spray that provides unprecedented intranasal coverage in a handheld, manually powered pump-driven device.

[0063] Figure 5A and 5B Results of an experimental setup are shown to demonstrate the unexpected nasal coverage of a nasal spray device according to the present invention. The setup used a commercially available transparent nose mold produced by Koken Co., Ltd., Japan, to simulate the human nasal area, with an intranasal volume of 38.6 cm 3 , combined with a fluorescent liquid formulation, recorded by a standard video camera under black light conditions. In both cases, the insertion angle was about 45 degrees at an insertion depth of 1 cm. The liquid formulation used contained 1 mg / ml calcein dissolved in a 25% glycerol-water mixture to improve the optical visibility of the deployed spray. The administered dose had a volume of 100 microliters.

[0064] Figure 5A The spread of a nasal spray within the nasal cavity using a standard conventional pump driven nasal spray device with a vortex nozzle is shown. The figure shows large droplets and concentration at the entrance to the nasal cavity, while overall coverage of the nasal mucosa is poor. Only 18% of the cavity was covered by the standard nasal spray device, resulting mainly in large droplet deposition.

[0065] on the other hand, Figure 5B The diffusion and spread of the same liquid formulation over the nasal cavity using the nasal spray device according to the present invention is shown. The high-speed camera image shows a slowly moving aerosol cloud that travels and deposits evenly over the cast model. Finally, the ultrafine droplets are highly distributed over substantially the entire nasal cavity, including the higher olfactory regions. This soft mist nasal spray covers 58% of the nasal mucosa with a fine mist of micron-sized droplets.

[0066] A spray device according to the invention has been set up and tested, comprising a set of 48 micro-holes having the same size of 4 microns and producing a soft mist plume with a conical tip of approximately 20 degrees. This device has been compared for nasal delivery with a standard commercial swirl nozzle from Aeropump and a state-of-the-art MAD300 swirl nozzle from Teleflex. In particular, coverage of different areas within the nasal cavity has been studied with any of these spray devices. Figure 6 A graphical representation of the test results is shown, which shows the overwhelming coverage of the device according to the present invention in each area, denoted as "Rayleigh film" in the figure. In particular, the spray device according to the present invention delivered more than 80% coverage in the middle, and performed better than other devices by more than a factor in other areas.

[0067] The effect of the tip of the cone spray produced by the same device according to the invention was further investigated. Figure 7 . Clearly, an apex of around 5 degrees appears to be advantageous for targeting the lower and middle turbinates in particular, while an apex between 20 and 25 degrees is generally advantageous, and preferably around 20 degrees if the olfactory region and nasopharynx are to be targeted. The droplet size range within the spray also affects where the liquid formulation is deposited after inhalation. Droplets in the 0.5-4 μm range are primarily deposited in the alveolar region, droplets of 4-10 μm are primarily deposited in the central and peripheral airways, and droplets larger than 10 μm are primarily deposited in the mouth, nose, or throat.

[0068] The ability to produce an ultrafine mist of relatively small droplets with unprecedented nasal coverage makes the spray device according to the present invention particularly suitable for nasal administration of pharmaceutically active liquid preparations. This particularly relates to biopharmaceuticals, such as prophylactic agents and vaccines, which may include antibodies, glycoproteins, lipid nanoparticles containing mRNA, and other bioactive agents. However, when conventional vortex nozzles or vibrating screens are used to atomize liquid preparations, these usual fine molecular or molecular nanoparticle structures tend to break or otherwise deteriorate when exposed to extreme shear forces applied thereto.

[0069] This is Figure 8It is demonstrated in, which shows a diagram of the molecular size of mRNA in a liquid formulation before and after the COVID-19 vaccine BNT162b from Pfizer / Biontech is formed into an aerosol with different nebulizers. The vaccine formulation contains lipid nanoparticles with an average size δ of 300nm, and the nanoparticles further include an mRNA chain of about 4.000 base pairs, and the mRNA chain encodes a viral spike protein of about 4.000x0.34 nm (=1.36 microns) of chain length λ. Reference curve I gives the molecular length of mRNA in Pfizer / Biontech reserve liquid, while curves II and III respectively depict the molecular length after spraying the same liquid formulation using commercially available vibrating mesh nebulizers of Aeroneb and Pari eFlow. Obviously, the average mRNA molecular length is reduced due to spraying with these current spray devices. This makes these conventional devices unsuitable for spraying relatively fragile molecular nanostructures and long molecules.

[0070] However, the aerosolization of large macromolecules, especially those found in mRNA therapeutics, can be advantageously used to directly target the respiratory tract. A promising prospect is that mucosal administration of mRNA vaccines based on lipid nanoparticles (lipid nanoparticles) may lead to more effective protection against respiratory viruses. However, conventional aerosolization processes can rupture the lipid nanoparticle carrier and degrade the mRNA molecules inside.

[0071] However, the present invention provides a new nebulization method, which was shown to substantially maintain the integrity of the vaccine, as tested with two SARS-CoV-2 mRNA vaccines. In particular, the lower energy levels used to generate lipid nanoparticle droplets using the new nebulization method helped to maintain the integrity of the lipid nanoparticles and the vaccine. Table 1 shows a comparison of nebulization techniques and their different energy dissipation levels

[0072] technology Energy input [J / g] Vibrating screen, VM 35 Colliding Jets, CJ 22 Rayleigh Nanotechnology Membranes, NM 2

[0073] Table 1

[0074] The inventors surprisingly found that if the energy dissipation of the nebulized liquid formulation remains below a threshold of 20 J / g, the lipid nanoparticle integrity of the two vaccines is 5-10 J / g, and the mRNA integrity is 10-20 J / g, then the lipid nanoparticles and mRNA can be kept mostly intact.

[0075] like Figure 8As shown in curve IV in , the nasal spray device according to the present invention retains the mRNA molecules to a large extent based on the relatively gentle Rayleigh decomposition of the liquid preparation containing mRNA after passing through a relatively short micropore of about 1 micron in length. In addition, the lipid nanoparticle structure with an average size of δ=300nm is maintained using the device according to the present invention, which is in contrast to conventional vibrating mesh nebulizers. These vibrating mesh nebulizers cause a large amount of fluid mechanical agitation in the preparation. In the device according to the present invention, the micropores have a relatively short pore length L, so that the passage time Δt of the nanoparticles experiencing a (high) shear rate γ is short enough to prevent the lipid nanoparticle structure from rupturing. Further experiments have shown that when the maximum shear time Δt is less than δ 最大 / (δ.γ) seconds, δ 最大 When / δ is between 3 and 5, the maximum elongation of nanoparticles with an average spherical diameter of δ can be maintained up to δ 最大 (Before rupture occurs.) This means that the length L of the micropore preferably does not exceed the diameter D of the micropore, because in a channel of diameter D, the amount of shear on the nanoparticle is proportional to the length L of the micropore and inversely proportional to the diameter D of the microporosity.

[0076] Another discovery of the present invention is that for long-chain molecules, such as mRNA with a chain length of λ, according to the present invention, the length L of the micropore is preferably shorter than the total chain length λ of the long-chain molecule. When the molecule is fully stretched in the shear field, due to the presence of the shear field, the breaking force on the long-chain molecule, especially the mRNA, is shown to be proportional to the chain length λ. However, when the mRNA molecule passes through a hole whose length L is less than the chain length λ of the mRNA molecule, the molecule is prevented from being fully stretched. On the contrary, it will partially maintain its initial spherical shape, reducing the tensile force and the final breaking force applied to the molecule. Therefore, 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.

[0077] In particular, micro-holes with a length L of less than 1 micron have been successfully tested in this regard. Figure 8 Curve IV in Figure 1 shows that the length λ of the mRNA molecule of the liquid formulation of the same Pfizer / Biontech mRNA liquid vaccine is less than the chain length λ of the mRNA molecule after the formulation is sprayed using a nasal spray device according to the present invention having a micropore with a length L of 1 micron. This opens up completely new opportunities for nasal administration of biotech drugs, which are often based on biologics and nanoparticles, such as formulations containing as their active ingredients: complex proteins, peptides, long chains of DNA and RNA, large vesicles, liposomes, antibodies and other biological compounds.

[0078] Fig. 9a shows that lipid nanoparticles containing mRNA-1273 vaccine have a size range of 300-500 nm before nebulization. Nebulization by vibrating mesh and collision jet methods resulted in an overall shift to larger lipid nanoparticle diameters (see Fig. 9 b-9d), indicating that lipid nanoparticles aggregate, while the size distribution of lipid nanoparticles remains largely unchanged by nebulization according to the method of the present invention (see Fig. 9 e) To investigate whether larger LNPs are formed by aggregation of smaller or ruptured LNPs during nebulization, experiments were performed with specific anti-aggregation agents. Notably, a wide range of small to large LNPs were detected in both the vibrating mesh and impinging jet samples, suggesting that aggregates larger than 1 μm observed after nebulization can reasonably be considered to be due to aggregation of smaller and ruptured LNPs.

[0079] The effects of different nebulization methods on the mRNA integrity of two SARS-CoV-2 vaccines (mRNA-1273 and BNT162b) were evaluated. The mRNA size of untreated and nebulized mRNA vaccines was analyzed by automated gel electrophoresis. The electropherograms of mRNA isolated from non-nebulized samples (control conditions) showed a major peak between 3,500-4,000 ( Fig.10 a, c), which is consistent with the reported lengths of these mRNAs. To demonstrate the effect of nebulization on mRNA integrity, Fig.10 BNT162b is shown (see Fig.10 a, 10b and 10c) and mRNA-1273 (see Fig.10 d, 10e and 10f) Electropherograms of the vaccine before and after nebulization with vibrating mesh type 1 (VM1; blue), collision jet (CJ; yellow), vibrating mesh type 2 (VM2; red) and nanotechnology membrane according to the present invention (NM; green), all compared with stock vaccine with and without RNase.

[0080] Before electrophoresis analysis, the atomized sample was treated with RNase to degrade all mRNA not encapsulated by lipid nanoparticles. The horizontal axis shows the RNA fragment size based on a series of known lengths of RNA fragments (200, 500, 1,000, 2,000, 4,000 and 6,000 nucleotides). For clarity, the electropherogram was manually adjusted on the horizontal axis to align the full-length mRNA-vaccine peak with the profile obtained from the untreated stock solution. The amount of RNA is shown as normalized fluorescence units on the vertical axis.

[0081] Naked mRNA molecules are sensitive to both enzymatic degradation (e.g., RNases) and non-enzymatic degradation (e.g., shearing). To decouple these two degradation mechanisms, the RNA fragment length was studied with and without the addition of RNases before and after the nebulization process. RNase treatment before nebulization did not seem to affect the full-length mRNA of BNT162b ( Fig.10 a), but reduced the full-length mRNA from the mRNA-1273 vaccine ( Fig.10 d). Notably, nebulization by vibrating mesh 1 (VM1) and colliding jet (CJ) methods caused 60-90% degradation of mRNA in the vaccine (p<0.001), as observed by the decrease in the full-length mRNA peak ( Fig.10 b, 10e). In contrast, only a minor decrease (10-25%, p<0.001) of full-length mRNA was observed after nebulization by vibrating mesh 2 (VM2) and the nanotechnology membrane (NM) method according to the invention.

[0082] RNase treatment appeared to significantly reduce the full-length mRNA content in all nebulized samples except the NM nebulized sample ( Fig.10 c, f). Strikingly, although full-length mRNA appeared largely unaffected by the VM2 method, the subsequent addition of RNase degraded the mRNA to a large extent, suggesting that the lipid nanoparticles were ruptured or dysfunctional after nebulization by the VM2 method. After the addition of RNase, the degradation of the resulting preparations was comparable to the results of the VM1 and CJ methods ( Fig.10 c, f). In contrast, after RNase treatment, the nebulized samples obtained with the NM method showed considerably less mRNA reduction and remained comparable to the stock solution, indicating hardly any 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 for stock and after NM nebulization).

[0083] Fig.11A and Fig. 11B The fraction of mRNA remaining intact after nebulization was plotted against the energy dissipated for all three nebulization methods for both vaccine formulations with and without the addition of RNase to determine which energy levels involved in the nebulization method would cause reversible deformation versus irreversible rupture of lipid nanoparticles.

[0084] For the vibrating mesh (VM) technology, two commercially available nebulizers were used: VM1, Pari eflow (Pari GmbH) and VM2, Aerogen Solo (Aeroneb) nebulizer. The reservoirs of VM1 and VM2 were pre-filled with 2-4 ml of sample containing the vaccine. The generated aerosol was collected in a glass tube of 30 mm diameter, and the collection time was measured to obtain about 0.5-1 ml of atomized fluid. It was found that the throughput of the two vibrating mesh nebulizers increased significantly over time (e.g., from 0.3 ml / min to 0.8 ml / min), which may be due to the increase in formulation temperature caused by the dissipation of vibration energy in the reservoir.

[0085] For the collision jet (CJ) method, Respimat (Boehringer Ingelheim) was used. The plastic cartridge of the reusable Respimat nebulizer was prefilled with the vaccine formulation and 60 doses or 15 μL of vaccine per puff were collected in a glass tube. The duration of each puff was about 2 seconds. It also took about 2 seconds to reload the spring of the device.

[0086] For nanotechnology membrane (NM) method according to the present invention, nanotechnology membrane chip is manufactured with silicon semiconductor technology. In silicon body, manufacturing thickness is the free hanging silicon nitride membrane of 800 nanometers, and in this membrane, 85 holes with a diameter of 1.9nm are manufactured by reactive ion etching. First, pre-filled syringe or spray pump with 1ml vaccine preparation is manually pressed through nanotechnology membrane nozzle with the flow velocity of 2-3ml / min under the pressure of 20 bars, and is collected in the glass tube of 10mm diameter. All experiments are carried out to mRNA-1273 and BNT162b vaccine, and repeated three times.

[0087] mRNA isolation

[0088] To isolate pure vaccine mRNA, 300 μl of Trizol LS reagent was added to the untreated sample. The phenol and guanidine isothiocyanate used in the Trizol LS method decompose the lipid nanoparticles and protect the released vaccine mRNA from endonuclease degradation. Next, the sample / Trizol LS mixture was processed according to the manufacturer's instructions until ±230 μl of aqueous phase containing vaccine mRNA was obtained. Vaccine mRNA was purified from the aqueous phase and concentrated to 12 μl using the RNeasy MinEluteCleanup kit (Qigen) according to the procedure described in Appendix D of the product manual. The RNA isolation procedure was also performed on nebulized samples and nebulized + RNase-treated samples.

[0089] mRNA quantification

[0090] Agilent RNA ScreenTapes (Agilent) were used to perform automatic gel electrophoresis on the Agilent 2200 TapeStation system to the purified vaccine mRNA from all samples. The electrophoresis pattern was rendered and quantified by software Agilent Tape Station System Software (Rev.4.1.1). The concentration of the full-length vaccine-mRNA partial peak was quantified by manually defining the region tightly surrounding the full-length vaccine-mRNA peak, preventing the inclusion of the degraded vaccine mRNA as much as possible. The RNA concentration in the defined region was calculated by software and used as a measure of the full-length vaccine mRNA concentration in the sample.

[0091] RNase treatment

[0092] Fresh aerosolized vaccine samples and stock vaccine samples (control conditions) were divided into two equal volumes of 100 μl. One subsample was treated with an RNase Cocktail Enzyme Mix (Thermo Fisher Scientific) at 37°C for 5 minutes, containing a combination of RNase A and RNase T1 at final concentrations of 5 and 200 U / ml, respectively. This RNase treatment will completely degrade any vaccine mRNA that is not protected by intact lipid nanoparticles. After RNase treatment, 300 μl of Trizol LS reagent (Thermo Fisher Scientific) was added to the mixture to inactivate RNase.

[0093] Atomization energy input

[0094] For the impinging jet nebulizer, the spring constant of the spring loading device was measured and from this the energy stored in the spring and subsequently put into the sprayed formulation (15 μl) was directly calculated using an energy transfer efficiency of 40-60%. For the nanotechnology membrane nebulizer, the amount of energy added to the spray was calculated from the pressure exerted on the syringe piston and the volume change.

[0095] For vibrating mesh atomizer, the preparation is sprayed for 60 seconds, and the temperature increase of the reservoir fluid is measured. This is done to three different amounts of reservoir fluids (1g, 3g and 6g). The temperature increase is multiplied by the specific heat of water and the amount of liquid in the reservoir, to obtain the amount of energy absorbed by the reservoir fluid during atomization. The energy absorbed by the reservoir fluid is extrapolated to the 0g reservoir fluid amount, to obtain the indication of the amount of energy added to the spray fluid. The amount is divided by the amount of liquid sprayed, to obtain the energy density (J / g) added to the fluid sprayed.

[0096] Fig.11AThe fraction of intact mRNA without added RNase is depicted. The absence of RNase means that lipid nanoparticle rupture and subsequent mRNA strand breakage occurs solely due to fluid mechanical shear forces. At energy dissipation of approximately 10-20 J / g, a certain transition from intact to non-intact mRNA can be seen. Fig. 11B The fraction of intact mRNA to which RNase was added after nebulization is depicted. This implies that lipid nanoparticle degradation is due to both fluid mechanical forces and enzymatic RNase activity.

[0097] At an energy dissipation of about 5-10 J / g, a transition from complete to incomplete can be seen. In conjunction with these figures, it can be concluded that at an energy dissipation of about 5-10 J / g, lipid nanoparticles begin to break, releasing mRNA chains, and at an energy density exceeding 10-20 J / g, these (exposed) mRNA chains undergo fluid-mechanical fracture. Therefore, according to the present invention, the process of atomizing a liquid formulation containing fragile long molecules is preferably carried out when the energy dissipated in the liquid to be atomized is less than 20 joules / gram, and preferably less than 10 J / gram.

[0098] Fig.12 A particular embodiment of a nasal adapter 77 for use with a nasal spray device according to the present invention is shown. The nasal adapter includes the spray nozzle 70 of the nasal spray device and also has means for generating two additional air streams 71, 73. These means are capable of forming a high-speed coaxial air dimple stream 71 along the path of the liquid micro-jet 72 released by the spray nozzle 70. The coaxial dimple stream prevents droplets from coalescing in the jet released by the spray nozzle chip 70. Preferably, the velocity of the dimple air stream 71 is initially higher than the initial velocity of these micro-jets 72.

[0099] In addition, when the user inhales, the device allows a sheet flow 73 of air to be generated along the inner wall of the adapter 77, as shown by the white dashed arrow. The sheet flow 73 counteracts the turbulence along the inner wall of the airstream containing micro-jet droplets, which would otherwise hit the wall of the nose adapter interface. The shell of the nose adapter 77 has a conical top that is intended to be located in one of the user's nostrils in a substantially sealed manner while guiding the micro-jet droplets into the user's nasal cavity. When the user inhales through the nostrils, additional air flows 71, 73 can be passively generated, or the additional air flows can be actively generated by using appropriate devices such as pressurized air supplied by a ventilator or pressurized gas released once the user inhales.

[0100] In summary, the nasal spray device described in accordance with the present invention provides an intranasal spray vaporizer that maintains the simplicity and convenience of a vortex nozzle device while having several advantages over conventional vortex nozzles, such as:

[0101] - Low-dose volumes required for nebulization can be as low as 25 μL while still providing ample therapeutic volume for administration;

[0102] - Droplet size is independent of liquid flow rate and liquid formulation; allows for slow-moving soft mist of ultrafine droplets;

[0103] - A narrow droplet size distribution that depends only on the micropore diameter, which allows tailoring the deposition to the nasal area to be targeted and avoiding deep breath deposition;

[0104] - Optimal deposition in the nasal cavity due to low plume velocity below 1.0 m / s and narrow droplet size distribution;

[0105] - Optimized plume cone angle between 10 and 25 degrees to allow wider deposition in the nasal cavity;

[0106] -Liquid dripping and removal is limited due to large deposition surface coverage

[0107] -Low impact forces due to reduced plume velocity and smaller droplet size

[0108] -Luer lock adapter for easy attachment to, e.g., existing medical Luer lock syringes

[0109] - A parallel suction flow of ambient air is created along the device through specially designed air slits.

[0110] Although various embodiments of the present invention have been described above, it should be understood that they are given by way of example and not limitation. It will be apparent to those skilled in the relevant art that various changes in form and detail may be made therein. Therefore, the present invention should not be limited to any of the above embodiments, but should only be limited according to the appended claims and their equivalents.

[0111] In particular, the nasal spray device may include a silicon chip serving as a nozzle body carrying a nozzle membrane, such as a nozzle membrane formed of a silicon nitride ceramic layer having a thickness on the order of one micrometer. Using ultra-high precision photolithographic imaging, masking and etching techniques available in modern semiconductor manufacturing techniques, micropores (orifices) may be etched through such a layer on a nanometer to micrometer scale.

[0112] The size of the micropores inside the spray chip overwhelmingly determines the initial size of the droplets released in the spray. This in turn determines to a great extent that the droplets will mainly fall on the target area in the respiratory system. The micropores of size between 3 microns and 8 microns will deliver droplets that are usually greater than 10 microns, and therefore, mainly target the nasal cavity, particularly the nasal turbinate, and will not penetrate deeper into the respiratory system, because these droplets greater than 10 microns cannot pass through the nasopharynx usually, but stay in the upper airway. On the other hand, the droplets of size between 1 micron and 10 microns can be transported through the nasopharynx usually, and the final overwhelming majority are deposited in the lower airway (trachea and alveoli). Droplets less than 1 micron will not be deposited at all, but are substantially exhaled completely, and are received by the deeper parts of the respiratory system, particularly bronchus and lungs.

[0113] like Figure 5B As shown, the nasal spray device according to the present invention is capable of delivering internasally with high coverage on the internasal tissue. For many preventive and other applications, this internasal delivery with high coverage is sufficient. However, some other preventive and other situations (also) require deeper deposition in the lower airway. Therefore, when inhaled through the nose, a specific embodiment of the nasal spray device according to the present invention is configured to deliver the liquid formulation to the upper airway and the lower airway in a single inhalation step.

[0114] To this end, the same or another microchip within the nasal spray device can simultaneously feed a pressurized liquid that includes a second set of micropores with a diameter less than 3 microns, such as between 1.5 and 3 microns. Droplets emitted from these micropores tend to have a size less than 10 microns, and when inhaled, these droplets are generally not captured by the nasal cavity, but instead pass through the nose into the downstream respiratory tract.

[0115] The larger droplets with a diameter between 3 microns and 8 microns from the first group of micropores are intended to be captured in the upper airway, particularly in the nasal vestibule, nasal turbinate and olfactory region. The second group of micropores with an orifice less than 3 microns will produce sufficiently small droplets so that the nasopharynx and lower airway (lungs) can be targeted when inhaled through the nose. Due to the smaller size of these droplets, their quality is lower, and the smaller droplets have lower kinetic energy and lower plume velocity. These smaller droplets follow the air flow through the upper airway into the lower airway. By changing the ratio between the number of small holes and macropores, the ratio of the deposition of the prevention agent between the upper airway and the lower airway can be adjusted.

[0116] Therefore, when inhaled through the nose, this nasal device according to the present invention can deliver a liquid formulation containing, for example, a prophylactic drug to both the upper and lower airways in a single inhalation step. The size of the micropores inside the spray nozzle determines the size of the initial droplets in the vast majority, thereby controlling the target position of deposition in the upper and / or lower airways. When the micropores have an aperture between 3 microns and 8 microns in one group and an aperture less than 3 microns in another group, the device generates a nasal spray that will target the entire respiratory tract when inhaled. Thus, a single nasal spray device supplies a unique dual treatment for situations where the nasal mucosa needs to be covered as well as deeper respiratory areas (particularly bronchi and lungs).

Claims

1. A nasal spray device comprising a nostril cap having an end portion received inside a nostril cavity of a user, in, The nostril cap includes a spray chamber opening through the end portion, and wherein the nostril cap includes a spray nozzle, which is configured and suspended to receive a liquid agent at an inlet and release a liquid spray of the liquid agent at an outlet opening into the spray chamber, characterized in that the spray nozzle includes a membrane between the inlet and the outlet, the membrane having a plurality of micropores of substantially the same size, the size of the micropores being between 1 micron and 10 microns, particularly between 3 microns and 8 microns, the micropores conveying the liquid agent to be discharged from the device as a spray jet, wherein the micropores are configured to release a micro-droplet jet at a deflection angle relative to an axial centerline of the corresponding micropore, and wherein the micropores are distributed to form together a substantially conical divergent spray plume with a top.

2. The nasal spray device according to claim 1, It is characterized in that The conical spray plume has a tip of about 5 degrees.

3. The nasal spray device according to claim 1, It is characterized in that The conical spray plume has a tip between 5 and 30 degrees, particularly between 20 and 25 degrees, and more particularly around 20 degrees.

4. A nasal spray device according to any one of the preceding claims, It is characterized in that A chamber is provided for containing a predetermined dose of the liquid formulation, in particular having a volume between 25 and 150 microliters, wherein a manually energizable positive displacement pump is configured to pressurize the dose of the liquid formulation and force the liquid formulation at an elevated operating pressure between 5 and 15 bar to the inlet of the spray nozzle that releases the predetermined dose of the liquid formulation.

5. The nasal spray device according to claim 4, It is characterized in that The pump comprises a manually actuated piston which pressurizes the dose of the liquid formulation to the operating pressure in a single stroke of the piston.

6. The nasal spray device according to claim 4 or 5, It is characterized in that The pump comprises a multi-spray nasal pump provided with a dosing chamber for at least temporarily containing said dose of said liquid formulation and releasing said dose to said spray nozzle under said operating pressure.

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

8. A nasal spray device according to any one of claims 4 to 7, It is characterized in that The pump opens to a male luer end, wherein the nostril cap is receivable on the male luer end, the nostril cap having an inlet and an outlet, the inlet providing a female luer for sliding connection with the male luer end, the outlet releasing the nasal spray, and wherein the nostril cap includes the spray nozzle between the inlet and the outlet.

9. A nasal spray device according to any one of the preceding claims, It is characterized in that The nostril cap includes at least one inhalation channel that delivers a parallel airflow of ambient air along with the spray toward the outlet when the user inhales.

10. A nasal spray device according to any one of the preceding claims, It is characterized in that The nostril cap tapers toward the outlet to fit closely to the nose.

11. A nasal spray device according to any one of the preceding claims, It is characterized in that The membrane comprises a ceramic layer, wherein the micropores extend through the thickness of the ceramic layer.

12. The nasal spray device according to claim 11, It is characterized in that The ceramic layer is a silicon nitride layer on a carrier body of semiconductor material, in particular silicon, wherein the carrier body is provided with at least one cavity below the nitride layer, wherein the at least one cavity opens downstream to at least one micropore of the plurality of micropores, and wherein the at least one cavity is connected upstream to an outlet of the pump.

13. A nasal spray device according to any one of the preceding claims, It is characterized in that An aerosol spray is emitted from the micropores of the membrane in the spray nozzle as a Rayleigh jet, which then breaks up into particles of the aerosol spray.

14. A nasal spray device according to any one of the preceding claims, It is characterized in that The reservoir contains a pharmaceutically active liquid formulation, particularly a formulation containing nanoparticles, such as formulations containing complex proteins, peptides, long chains of 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 the preceding claims, It is characterized in that The membrane of the spray nozzle includes a second set of micropores of substantially the same size, less than 3 microns, through which the liquid formulation passes as it is discharged from the device.

16. A nasal spray device according to any one of the preceding claims, in, The liquid formulation comprises nanoparticles of size δ, wherein the nanoparticles have a maximum size δ before elongation rupture. 最大 , and wherein the micropore has a length L that is less than the diameter D of the pore multiplied by δ 最大 / δ(L <D.δ 最大 / δ), in particular, L<4D.

17. The nasal spray device of claim 14, in, The liquid preparation comprises a polymer with a chain length of λ, and the micropore has a length L that is smaller than the chain length λ of the polymer, in particular, L is smaller than 1 micrometer.

18. A method of atomizing a liquid preparation, in particular a liquid preparation containing a polymer, more particularly containing a biomolecule, in, The liquid formulation is subjected to a treatment to convert the liquid formulation into a mist of the liquid formulation, characterized in that the liquid formulation is subjected to an energy of no more than 20 joules / gram, preferably no more than 10 joules / gram, while converting the liquid formulation into a mist of the liquid formulation, in particular forming a soft mist spray plume.

19. The method according to claim 18, It is characterized in that The liquid formulation is pressurized to an operating pressure to produce at least one pressurized dose of the liquid formulation, and wherein the pressurized dose of the liquid formulation is forced through at least one micropore, particularly a plurality of micropores, in a membrane of a Rayleigh breakup type spray nozzle.

20. The method according to claim 19, It is characterized in that The liquid formulation is pressurized to an operating pressure between 5 and 15 bar using a pump, in particular the pump is a manually energizable pump, to produce a pressurized dose of the liquid formulation, wherein the pressurized dose of the liquid formulation is forced through a set of micropores in the membrane of a Rayleigh-type spray nozzle, the micropores having a size of less than 8 microns, to cause the liquid formulation to break into at least one spray jet of liquid droplets having substantially the same initial droplet size, causing the mist to propagate at a spray plume propagation speed of less than 1 m / s.

21. The method according to claim 19 or 20, in, The liquid formulation contains nanoparticles of size λ, and the liquid droplet contains at least one of the nanoparticles, wherein the nanoparticle has a maximum size λ before elongational fragmentation. 最大 wherein the liquid formulation is subjected to a shear rate γ [per second] when passing through the micropores; and wherein the liquid formulation is less than λ 最大 The micropores are exposed to the shear rate γ during a shear time Δt of 1 / (λ.γ) seconds.

22. The method according to claim 19, 20 or 21, in, The liquid formulation comprises nanoparticles, wherein the nanoparticles have a size δ and have a maximum size δ before elongation rupture 最大 , and wherein the micropore has a length L less than D.δ 最大 / δ, in particular, L<4.D, wherein D is the diameter of the micropore.

23. The method according to any one of claims 19 to 22, in, The liquid preparation comprises a polymer with a chain length of λ, and the micropore has a length L that is smaller than the chain length λ of the polymer, in particular, L is smaller than 1 micrometer.

24. The method according to any one of claims 18 to 23, in, The liquid formulation comprises nanoparticles selected from the group consisting of complex proteins, biomacromolecules, long-chain DNA and RNA, large vesicles, liposomes, bacteriophages, lipid nanoparticles, mRNA vaccines, mRNA lipid nanoparticles and antibodies.

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