Drug-device combinations

Abstract

The present invention relates to a drug-device combination comprising a liquid solution (26) containing a biological agent and a nebulizer (10) for aerosolizing the liquid solution. The nebulizer comprises a reservoir (24) for holding the liquid solution, the reservoir (24) having a vent (48) for maintaining atmospheric pressure within the reservoir (24), a vibratable membrane (60) having an active area (62) with an aperture (110), whereby the liquid solution can be delivered to the active area at the liquid side (64) of the membrane, a piezoelectric actuator for vibrating the membrane, whereby an aerosol of the liquid solution is generated at the active area on the aerosol side (66) of the membrane, and a plenum chamber (23) having an inlet (76) on the inlet side of the aerosol side of the membrane and an outlet (94) on the outlet side for administering the aerosol.

Description

[Technical field]

[0001] The present disclosure relates to drug-device combinations, in particular drug-device combinations that include a liquid solution containing a pharmaceutical ingredient and a nebulizer for aerosolizing the liquid solution. [Background technology]

[0002] Nebulization of liquid solutions containing pharmaceutical ingredients (APIs) has many advantages in delivering drugs to the lungs. However, when the liquid solution (carrier fluid) containing the pharmaceutical ingredients is converted into an aerosol by a nebulizer, each pharmaceutical ingredient behaves differently. The different chemical properties inherent to the pharmaceutical ingredients and / or liquid solutions dictate the device and delivery parameters that allow a therapeutically effective amount of the pharmaceutical ingredient to be delivered as an aerosol. In other words, the selection of a nebulizer device for one pharmaceutical ingredient may not hold for a different pharmaceutical ingredient. Summary of the Invention [Problem to be solved by the invention]

[0003] In view of the above, it is an object of the present invention to provide a nebulizer for aerosolization of a liquid solution containing a biologic, which allows a therapeutically effective amount of the biologic to be delivered as an aerosol.

[0004] In this regard, a biologic drug (biologic) is a preparation produced from or containing components of a living organism. Biologic drugs include a wide variety of preparations derived from humans, animals, or microorganisms by using biotechnology. Types of biologic drugs include vaccines, blood, blood components, cells, allergens, genes, tissues, and recombinant proteins. Biologic products may contain proteins that control the action of other proteins and cellular processes, genes that control the production of vital proteins, modified human hormones, or cells that produce substances that suppress or activate components of the immune system. Biologic drugs are sometimes referred to as biological response modifiers because they change the way natural biological intracellular and cellular processes work. [Means for solving the problem]

[0005] According to an aspect of the present disclosure, a pharmaceutical-device combination is proposed that comprises a liquid solution containing a biologic and a nebulizer for aerosolization of the liquid solution. The nebulizer comprises a reservoir for holding a liquid solution and a vibratable membrane having an active area with an aperture, the liquid solution being supplyable to the active area on the liquid side of the membrane, for example by gravity. The nebulizer further comprises a piezoelectric actuator for vibrating the membrane, whereby an aerosol of the liquid solution is generated in the active area on the aerosol side of the membrane, the aerosol side of the membrane being opposite the liquid side of the membrane. The vibratable membrane may function as a deflection transducer. The piezoelectric actuator may act directly on the vibratable membrane or on a substrate to which the vibratable membrane is attached. The piezoelectric actuator may be attached directly to the vibratable membrane or to the substrate.

[0006] It has been found that the use of nebulizers with a vibratable membrane is advantageous for aerosolizing liquid solutions containing biologics, since the use of such membrane nebulizers reduces the shear forces acting on the biologic as the aerosol is generated, minimizing or even avoiding destruction of the biologic.

[0007] In addition, energy is only provided to the piezoelectric actuator and from the piezoelectric actuator to the vibrable membrane. Therefore, only a gentle energy input is required to aerosolize the liquid solution. The gentle energy input has the advantage that no or little heat is generated and no or little heat is transferred to the liquid solution. As a result, the destruction of the biological agent can be further minimized or even avoided.

[0008] However, it has been found that when using a nebulizer with a vibrable membrane vibrated by a piezoelectric actuator, the liquid solution containing the biological agent tends to foam. This phenomenon has been linked by the inventors to the presence of negative pressure in the reservoir. Such negative pressure may occur during the nebulization process due to a decrease in the amount of liquid solution in the sealed reservoir, or may be purposefully already created before the nebulization process begins, as suggested, for example, in International Patent Application Publication No. WO1997 / 29851A1 or U.S. Patent No. 6,983,747B2, in order to increase efficiency and total output rate. Due to such negative pressure, air may be sucked into the reservoir through the apertures in the membrane, causing the generation of bubbles in the reservoir. The generation of bubbles increases the surface of the liquid solution and thus the biological agent. Furthermore, oxygen is introduced into the liquid solution, which denatures the biological agent. As a result, the quality of the aerosol is reduced. The formation of bubbles may even lead to the cessation of the nebulization process. To avoid, or at least minimise, the tendency of the liquid solution to foam within the reservoir, the reservoir has a vent to maintain atmospheric pressure (atmospheric pressure + / - 10 mbar) within the reservoir during the (entire) spraying process.

[0009] The nebulizer further comprises a plenum chamber having an inlet on the inlet side of the aerosol side of the membrane and an outlet on the outlet side for administering the aerosol, the outlet of the plenum chamber being opposite to the inlet of the plenum chamber. In a particular embodiment, the plenum chamber can be defined between the inlet of the mixing chamber on the aerosol side of the membrane and the outlet of the mouthpiece or mask covering the nose and mouth. In other words, the plenum chamber can be defined by the membrane at one end and the outlet of the mouthpiece / mask at the other end, with the mixing chamber and the mouthpiece / mask being located between them. The mouthpiece or mask can be coupled to a connection at the outlet side of the mixing chamber. The connection can be as simple as a cylindrical socket.

[0010] The use of a plenum chamber for liquid solutions containing biologics has been found to be advantageous for reducing the amount of residue in the nebulizer due to increased aerosol coalescence, and thus a relatively high delivery rate of the liquid solution can be achieved.

[0011] The vent may be a passive vent. A passive vent is a cost-effective solution that does not require additional parts. The size / dimensions of the passive vent may be selected to achieve a venting function to avoid foaming of the liquid solution in the reservoir and at the same time to prevent the liquid solution from leaking out of the reservoir through the vent, for example when the nebulizer is tilted during use. Thus, the area of ​​the passive vent may be less than 0.5 mm 2 ~5mm 2 , or 0.5 mm 2 ~2mm 2 In an embodiment, the area of ​​the passive vent may be 5 mm 2 Less than 4mm 2 Less than 3 mm 2 Less than or equal to 2 mm 2 In one example, the area of ​​the passive vent can be less than 0.8 mm 2 ~1mm 2The width of the passive vent may be 0.5 mm to 3 mm, or 0.5 mm to 2 mm. The height may be 0.5 mm to 3 mm, or 0.5 mm to 2 mm. The depth of the passive vent may be greater than 1 mm, greater than 2 mm, or greater than 2.5 mm. The depth may be 1 mm to 4 mm, or 2 mm to 3 mm. Using these dimensions, leakage of the liquid solution is avoided.

[0012] The reservoir may be an ampoule or container that is opened in the nebulizer to supply the liquid solution to the liquid side of the active area of ​​the membrane, and the vent is formed, for example, by piercing the ampoule before inserting the ampoule or when inserting the ampoule into the nebulizer. According to a further aspect of the present disclosure, the reservoir is a cup reservoir having a body (housing) that is sealed at its lower part by the liquid side of the vibratable membrane, in particular its active area or the area surrounding the active area. The body has a circumferential rim that defines an opening for receiving the liquid solution and a sealing surface. The liquid solution may be injected into the reservoir through the opening. Furthermore, a closure is provided to engage the circumferential rim to close the reservoir and seal against the sealing surface. The vent is formed to connect the head space of the reservoir to the atmosphere and is spaced from the lower part sealed by the vibratable membrane. The head space is the part of the reservoir above the liquid solution and is filled with air. In particular, the vent may be provided with a vent that may be provided in the circumferential rim. In this case, the depth of the vent is governed by the width of the circumferential rim. As a result, the vent can be realized in a simple and effective manner, providing on the one hand an effective ventilation of the reservoir to avoid the mentioned foaming, and on the other hand preventing the liquid solution from leaking out of the reservoir through the vent.

[0013] The vent can be a notch formed in the circumferential rim from the sealing face and crossing the circumferential rim to connect the interior of the reservoir to the atmosphere. Providing the vent as a notch in the circumferential rim of the reservoir provides an easy solution. In addition, the notch is open at the sealing face, thus simplifying the cleaning process. This configuration is therefore beneficial from a hygiene point of view.

[0014] The plenum chamber may have a volume of at least 60 cubic centimeters and / or no more than 90 cubic centimeters. The plenum chamber may have a length of 104 mm to 154 mm, and / or a width of 40 mm to 60 mm, and / or a height of 30 mm to 50 mm. The plenum chamber mixing chamber itself may have a length of 54 mm to 94 mm, and / or a width of 40 mm to 60 mm, and / or a height of 30 mm to 50 mm. The height of the plenum chamber and / or mixing chamber is a factor in minimizing settling of the aerosol in the plenum chamber / mixing chamber. The length serves to calm the airflow during inhalation with the aim of approaching laminar flow as much as possible.

[0015] The aperture of the vibratable membrane may have a size on the aerosol side of 1.0 μm to 5 μm, or 1.5 μm to 4.5 μm, or 2.0 μm to 4.0 μm. The vibratable membrane may have 500-6000, or 2000-6000, or 2800-6000 apertures. The active area of ​​the vibratable membrane may have a diameter of 3 mm-6 mm and the distance between the apertures in the active area may be 40 μm-90 μm, or 40 μm-80 μm, such as 70 μm. In one example, the active area of ​​the vibratable membrane may have a diameter of 4 mm and the distance between the apertures in the active area may be 70 μm, resulting in about 3,000 apertures in the active area.

[0016] The apertures can be laser drilled and / or laser milled. According to one embodiment, the through-holes can be laser drilled through-holes formed in at least two stages, one stage forming the nozzle portion and at least one remaining stage forming the remainder of the through-hole. In another embodiment, the vibratable membrane comprises a single layer of a single material (one monolayer). A single layer of a single material has no clear boundaries, interfaces, or containment layers in a polished cut image of the monolayer. The vibratable membrane may further comprise a layer attached to the monolayer in one embodiment. In another embodiment, the vibratable membrane may consist of a monolayer. A plurality of recesses can be formed in the monolayer. The recesses each have an opening facing the fluid side or, if the vibratable membrane consists of a monolayer, each have an opening on the fluid side of the vibratable membrane. The recesses each have a bottom facing the opening, i.e., on the side facing the aerosol side or on the aerosol side of the vibratable membrane. The recesses may also be referred to as blind holes introduced from one side of the monolayer (from the fluid side (first side) of the vibratable membrane). In one embodiment, at least two recesses are provided. In another embodiment, at least three recesses are provided. Furthermore, the number of recesses is not limited, but may be less than 3,000, less than 1,000, or less than 500, preferably. Alternatively, less than 50 or less than 20 recesses may be provided. A relatively large number of smaller recesses, such as 500-3,000 or 500-1,000, may be beneficial to obtain high stability of the vibratable membrane. The more recesses are provided in the vibratable membrane, the higher the remaining reinforcement between the recesses that provides the entire thickness of the monolayer, and therefore the higher the stability. Conversely, a smaller number of larger recesses, such as 2-50 or 2-20, may be beneficial to obtain a larger effective area for atomization with less dead area. In this context, "dead areas" are areas of the vibratable membrane that do not have an aperture therethrough and therefore do not participate in the atomization process. In other words, in these areas, no fluid passes through the vibratable membrane to be atomized on the fluid side. In addition, the manufacturing process can be simplified when using a small number of recesses.The area of ​​the recesses relative to the total area of ​​the vibratable membrane is, in one example, 50% or less. Furthermore, a plurality of apertures are formed at the bottom of each of the recesses. The plurality of apertures may each have an inlet opening formed at the bottom of each recess and an outlet opening facing or formed on the aerosol side of the vibratable membrane. According to one embodiment, there are no additional apertures formed in the vibratable membrane other than those formed at the bottom of the recesses. According to another embodiment, there are at least no additional apertures formed in a single layer between the recesses and that are blind holes. Thus, the fluid on the fluid side of the vibratable membrane is nebulized during vibration of the vibratable membrane through the recesses and apertures and exiting the apertures through the outlet openings on the aerosol side of the vibratable membrane. Thus, an aerosol is formed on the aerosol side of the vibratable membrane for inhalation by the patient. In this embodiment, the entrance openings of the apertures can be relatively small, so that the density of the apertures can be increased compared to the density of apertures laser-drilled in three stages, and therefore the TOR can be increased. Furthermore, TOR and MMD are strongly dependent on the geometry of the nozzle part, i.e. the geometry of the aperture (especially the length and diameter). The formation of the recess results in a thin and relatively uniform or constant thickness at the bottom of the recess. The length of the aperture is therefore very well defined. In addition, the formation of a relatively short aperture is much more precise in terms of diameter at the inlet side (corresponding to the fluid side) and outlet side (corresponding to the aerosol side). As a result, a much more consistent aperture geometry can be obtained with respect to each other, which reduces the GSD. Thus, the aerosol (atomized fluid) properties are more consistent when comparing different aperture plates obtained from the same manufacturing process. However, in one embodiment, the recess is laser cut and / or the aperture is laser drilled. With a view to a relatively uniform and constant thickness of the remaining material in the region of the bottom of the recess, it is also beneficial to use a laser milling process to form the recess. Thus, an even more precise formation of the aperture in terms of diameter and length can be achieved with the above-mentioned advantages related to the reproducibility of certain aerosol properties.In a specific example, an ultrashort pulse laser is used for laser milling. An ultrashort pulse laser is defined as a laser with a laser pulse of less than 10 picoseconds. An ultrashort pulse laser has the advantage of being more accurate and further improving the advantages related to the reproducibility of the constant aerosol properties mentioned above. The aperture can still be formed by using a short pulse laser (e.g., a nanosecond laser) or an ultrashort pulse laser. A short pulse laser is defined as a laser with a laser pulse of more than 10 picoseconds and less than 500 nanoseconds.

[0017] The aperture may have a nozzle portion on the aerosol side of the active area of ​​the membrane. The nozzle portion has a length of 10 μm to 25 μm, or 10 μm to 20 μm, or 10 μm to 15 μm. Said length may be less than 20 μm, or less than 18 μm, or less than 16 μm. The diameter of the nozzle portion on the aerosol side may be 1.5 μm to 5 μm, or 1.5 μm to 3 μm. One end of the nozzle portion ends flush with the aerosol side of the vibratable membrane. The diameter may be measured at one end and should be within the ranges mentioned above. Such a defined nozzle portion reduces the shear forces acting on the liquid solution and may avoid or minimize the destruction of the biological agent contained in the nozzle portion as explained above.

[0018] The liquid solution may have a viscosity of 0.900 mPa·s to 5.000 mPa·s, or preferably 0.950 mPa·s to 3.500 mPa·s, or more preferably 1.000 mPa·s to 2.000 mPa·s, or even more preferably 1.000 mPa·s to 1.800 mPa·s, or most preferably 1.000 mPa·s to 1.400 μmPa·s.

[0019] The liquid solution may have a surface tension of 32 mN / m to 108 mN / m, or preferably 50 mN / m to 100 mN / m, or more preferably 52 mN / m to 78 mN / m, or even more preferably 57 mN / m to 73 mN / m, or most preferably 58 mN / m to 68 mN / m. In other cases, the liquid solution may have a surface tension of 32 mN / m to 108 mN / m, or preferably 32 mN / m to 78 mN / m, or preferably 37 mN / m to 73 mN / m, or more preferably 58 mN / m to 68 mN / m.

[0020] The liquid solution may have an osmolarity of 200 mOsmo / kg to 700 mOsmo / kg, preferably 200 mOsmo / kg to 500 mOsmo / kg, or even more preferably 300 mOsmo / kg to 350 mOsmo / kg.

[0021] The amount of liquid solution held in the reservoir for one dose is 1 mL to 2 mL. The volume of the reservoir can be from 1 mL to 8 mL, or from 3 mL to 5 mL. Biological products may be from the main types of biopharmaceutical groups, which include blood factors (factor VIII and factor IX), thrombolytics (tissue plasminogen activator), hormones (insulin, glucagon, growth hormone, gonadotropins), hematopoietic growth factors (erythropoietin, colony stimulating factors), interferons (interferon-α, -β, -γ), interleukin-based products (interleukin-2), vaccines (hepatitis B surface antigen), monoclonal antibodies (various), polyclonal antibodies, proteins, peptides, tRNA, siRNA, mRNA, RNA interference, antisense oligonucleotides, surfactants, immunoglobins (IgG, IgM, IgAM), bacteriophages, exosomes, stem cells, cells, recombinant viruses, bacteria, enzyme hormones, insulin, additional products (tumor necrosis factor and therapeutic enzymes), and similar biopharmaceuticals or similar drug products.

[0022] A biologic may comprise one or more proteins. Possible proteins are, for example, immunoglobins (A, G, M, ...), immunoglobin-CTLA-4 fusion proteins, monoclonal antibodies, polyclonal antibodies, immunoglobin-G1 fusion proteins, recombinant proteins, recombinant human TNF-receptor fusion proteins, monoclonal antibodies, humanized monoclonal antibodies, diphtheria toxin engineered proteins combining interleukin 2 and diphtheria toxin, and similar proteins or similar protein fragments.

[0023] In a specific embodiment, the protein may be granulocyte-macrophage colony stimulating factor (GM-CSF), and in a more specific embodiment, recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF).

[0024] A biologic may comprise at least two or more proteins, to which at least a second protein may be added, most usefully a carrier, additive, etc., such as human serum albumin (HA), or especially recombinant human serum albumin (rHA). [Brief description of the drawings]

[0025] [Figure 1] FIG. 2 is a perspective view of a nebulizer of an embodiment of a drug and device combination. [Diagram 2] Exploded view of the nebulizer. [Diagram 3](A) A longitudinal cross-sectional view of an embodiment of a nebulizer without ribs in a state where the lid is simply placed on the body, (B) A longitudinal cross-sectional view of an embodiment of a nebulizer without ribs in a state where the lid is screwed and fixed to the body, and (C) A partially enlarged longitudinal cross-sectional view of an embodiment of a nebulizer with ribs in a state where the lid is simply placed on the body. [Figure 4] FIG. 2 is a longitudinal cross-sectional view of only the body defining the reservoir. [Diagram 5] FIG. 2 is a perspective view of a body of a nebulizer defining a reservoir. [Figure 6] FIG. 6 is an enlarged view of a portion of the body of the nebulizer shown in FIG. [Figure 7] 4A and 4B are partial cross-sectional views of an active area of ​​a vibratable membrane according to an embodiment. [Figure 8] 4A and 4B are partial cross-sectional views of an active area of ​​a vibratable membrane according to another embodiment; DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The nebulizer 10 shown in FIGS. 1 to 3 comprises a body (housing) 12, a closure 14, a sealing 16, an aerosol generator 18, an elastic valve member 19, a mixing chamber 20, and a mouthpiece 22.

[0027] The body 12 defines a reservoir 24 for holding a liquid solution 26 containing a biologic. The biologic may include a protein. The protein may be recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF). In certain embodiments, the human GM-CSF may be produced in E. coli, as compared to other recombinant human GM-CSF proteins produced in other expression systems, such as yeast or mammalian cells. Human GM-CSF has a molecular weight of about 28-32 kDa, whereas the recombinant human GM-CSF of the embodiment (produced in E. coli) may have a molecular weight of 14.5 kDa. This difference is due to the lack of glycosylation on the recombinant human GM-CSF molecule. Thus, the SVRA protein may be referred to as "molgramostim, recombinant human GM-CSF produced in bacterial cells (hereinafter referred to as GM-CSF)."

[0028] The liquid solution may have a viscosity of 1.000 to 1.400 mPa·s. The liquid solution may have a surface tension of 37 mN / m to 73 mN / m. The liquid solution may have an osmotic pressure of 300 to 350 mOsm / kg.

[0029] In the specific examples, the compositions were as shown in Table 1 below.

[0030] [Table 1]

[0031] In a specific example, the physicochemical parameters of the 250 μg / mL formulation were as shown in Table 2.

[0032] [Table 2]

[0033] Compared to pure water, its density and viscosity are slightly higher, but its surface tension is lower. The volume of one dose of liquid solution may be 1 mL to 2 mL. In this context, one dose is understood as one dose of the dosing strategy, administered at once, for example without stopping the nebulizer 10, i.e. stopping the vibration of the membrane 61 and the generation of the aerosol, or reopening the lid 14.

[0034] The reservoir 24 may have a volume of 1 mL to 8 mL, preferably 3 mL to 5 mL. In this embodiment, the reservoir 24 is a cup-shaped reservoir. The body 12 has a circumferential rim 28 at its top defining an opening 30 that communicates with the reservoir 24. When the nebulizer is placed on a horizontal surface, the area of ​​the opening 30 may be oriented approximately (±20°) horizontally. The liquid solution 26 may be injected into the reservoir 24 through the opening 30. For example, the liquid solution may be held in an ampoule and may be injected into the reservoir 24 upon opening the ampoule.

[0035] The outer circumferential surface 32 of the rim 28 may be provided with a helical passageway 33 having a number of slots 34 as part of a bayonet closure / mount for attaching the lid 14 to the body 12. The lid 14 has projections 36 (protrusions) that project radially inward from an inner surface of the lid 14 as counterparts to the slots 34. When the lid 14 is attached to the body 12, the projections 36 pass through the helical passageway 33 by entering the slots 34. Rotation of the lid 14 locks the lid 14 to the body 12 as the projections 36 hook onto the underside of the helical passageway 33.

[0036] A top surface (sealing surface) 38 of the rim 28 serves as a first counter surface which cooperates with the sealing 16 to seal the opening 30 upon attachment of the lid 14 to the body 12. For this purpose, the lid 14 has a corresponding second counter surface 40 (see FIG. 3C). When the lid 14 is attached to the body 12 and the lid 14 is rotated, the lid 14 is pushed towards the body by the helical path 33. Thus, the second counter surface 40 of the lid 14 is pushed towards the top surface 38 of the rim 28, so that the sealing 16 is sandwiched / clamped between the top surface 38 and the second counter surface 40, thereby sealing the opening 30.

[0037] The sealing 16 may comprise a sealing ring 162 as a portion that is sandwiched / clamped between the top surface 38 and the second opposing surface 40. The sealing 16 may further comprise a movable sealing hinge 164 extending from the sealing ring 162. The movable sealing hinge 164 may further be connected to a central sealing 166. The central sealing 166 may be retained within the lid 14 such that it is axially movable upon attachment of the lid 14 to the body 12, and in particular upon rotation of the lid 14 relative to the body 12 as described above.

[0038] As can be seen in FIGS. 3 a and 3 b , the sealing hinge 164 additionally seals against the inner periphery 52 of the rim 28 . In addition, the central sealing ring 166 moves from position 1 in FIG. 3A to position 2 in FIG. 3B upon attachment of the lid 14 to the body 12, which may create a negative pressure in the reservoir 24, as described as beneficial in, for example, European Patent Application Publication No. EP1353759A2. As is clear from FIG. 3, the sealing ring 16 and the lid 14 are screwed together. Since the sealing ring 164 is sandwiched between the top surface 38 and the opposing surface 40, the sealing ring 16 cannot rotate with the lid, and therefore the rotation of the lid 14 is converted into a translational movement from position 1 in FIG. 3A to position 2 in FIG. 3B.

[0039] To maintain atmospheric pressure within the reservoir 24 during attachment of the lid 14 to the body 12 and / or during nebulization, the reservoir 24 has a vent 48 (here a passive vent), which in this embodiment is configured as a notch or groove 50 formed from the top surface 38 of the circumferential rim 28. The notch 50 crosses the circumferential rim 28 from the outer circumferential surface 32 to the inner circumferential surface 52, communicating the interior of the reservoir 24 with the outside of the nebulizer 10, i.e., the atmosphere. Thus, the notch 50 is open at the top surface 38 and extends from the inner circumferential surface 32 to the outer circumferential surface 52 of the rim 28. The notch 50 has a base 54 spaced from the top surface 38. The height of the notch 50 from the base 54 to the top surface 38 can be between 0.5 mm and 3 mm, or between 0.5 mm and 2 mm. The width of the notch 50 in the circumferential direction may be 0.5 mm to 3 mm, or 0.5 mm to 2 mm. As a result, the opening area of ​​the notch 50 on the inner peripheral side surface 52 of the rim 28 is 0.5 mm 2 ~5mm 2 , or 0.5 mm 2 ~2mm 2 In an embodiment, the area of ​​the passive vent may be 5 mm 2 Less than 4mm 2 Less than 3 mm 2 Less than or equal to 2 mm 2 In one example, the area of ​​the passive vent can be less than 0.8 mm 2 ~1mm 2 It could be.

[0040] As can be seen, the vent 48 is located at the top of the reservoir 24, and thus in the head space 27 (see Figure 3) of the reservoir 24 above the level of the liquid solution 26, and is spaced apart from the supply opening 42 (see Figures 4 and 5) and thus from the bottom of the body 12.

[0041] The vent 48 may be located on the rear side of the body 12 or the nebulizer 10. In embodiments, the vent 48 may be located in a portion of the body 12 opposite the feed opening 42. Additionally, the vent 48 may be located on the longitudinal centerline of the nebulizer or approximately above (within an angle of ±10°) the longitudinal centerline of the nebulizer.

[0042] At least one longitudinal rib 56 may be provided to prevent the sealing hinge 164 from blocking the vent 48, thus maintaining ventilation of the reservoir 24. In Figures 3(A) and (B) the sealing hinge 164 abuts the inner perimeter wall 52, although it is apparent from the enlarged view of Figure 3(C) that the sealing hinge 164 is pulled away from the inner perimeter wall 52 by the rib 56 to improve ventilation.

[0043] The longitudinal ribs 56 may extend parallel to the inner peripheral surface 52 of the rim 28 and may protrude radially inward. The longitudinal ribs 56 may be formed so as not to extend to the top surface 38 of the rim 28. In other words, the top surface 58 of the longitudinal ribs 56 is spaced apart from the top surface 38 of the rim 28. In an embodiment, two longitudinal ribs 56 may be provided on either circumferential side of the vent 48. The ribs 56 may be provided parallel to each other. Furthermore, one of the ribs may be longer in a direction parallel to the inner peripheral surface 52 of the rim 28 than the other of the ribs 56. Furthermore, the top surface 58 of one of the ribs 56 may be spaced further from the top surface 38 of the rim 28 than the top surface 58 of the other of the ribs 56. Moreover, one of the ribs 56 may protrude further from the inner peripheral surface 52 of the rim 28 than the other of the ribs 56. In certain embodiments, the longer ribs 56 protrude further from the inner periphery 52 of the rim 28 than the shorter ribs 56. At least one rib 56 prevents the sealing hinge 164 from binding too tightly to the inner periphery 52 (see FIGS. 3A and 3B), making it easier to remove the lid 14.

[0044] The lower portion of the body 12 may define a feed opening 42 in communication with the reservoir 24 (see Figures 4 and 5). A sealing lip 44 may be provided on the body 12 to surround the feed opening 42 on the side of the body 12 opposite the reservoir 24.

[0045] The body 12 further includes contact openings 46 formed diametrically opposite the feed opening 42 and the sealing lip 44 and may be configured to receive contacts 84 (see FIG. 2).

[0046] The aerosol generator 18 comprises an aerosol generator 18. The aerosol generator 18 comprises a vibratable membrane 60. The vibratable membrane 60 has an active area 62. The active area 62 may be dome-shaped, as shown in Fig. 3a and Fig. 3b. Furthermore, the active area 62 comprises a number of apertures 110, as shown in Fig. 6. The vibratable membrane 60 may have 500-6000 apertures, or 2000-6000 apertures, or 2800-6000 apertures. The active area 62 of the vibratable membrane 60 may have a diameter of 3 mm-6 mm, and the distance between the apertures 110 in the active area 62 may be 40 μm-90 μm, or 40 μm-80 μm, such as 70 μm. In one example, the active area 62 of the vibratable membrane 60 may have a diameter of 4 mm and the distance between the apertures 110 in the active area 62 may be 70 μm, resulting in approximately 3000 apertures 110 in the active area 62.

[0047] The aperture 110 may be laser drilled as shown in Figure 7. The aperture 110 penetrates the membrane 61 of the active region 62 from the liquid side 64 to the aerosol side 66. In use, when the membrane 61 is vibrated to generate an aerosol on the aerosol side 66 and release it into the mixing chamber 20, the liquid solution 26 passes through the aperture 110 from the liquid side 64 to the aerosol side 66. The aerosol may then be drawn out of the mixing chamber 20 through the mouthpiece 21 by the patient's inhalation.

[0048] FIG. 7 shows a cross-sectional view (schematic CT image) of three of the apertures 110 of such a vibratable membrane 60. The through holes 110 of this particular embodiment are respectively formed by laser drilling using three stages with different process parameters. In a first stage, the portion 114 is formed. In a second stage, the portion 116 is formed, and in a third stage, the nozzle portion 112 is formed. In this embodiment, the nozzle portion 112 has an average length of 26 μm, while the second portion 116 has an average length of 51 μm. The first portion 114 has an average length of 24.5 μm. As a result, the total length of each aperture 110 is the sum of the lengths of the first portion 114, the second portion 116 and the nozzle portion 112, which in this particular example is 101.5 μm. The ratio of the total length of each aperture 110 to the length of each of the nozzle portions 112 is therefore about 3.9.

[0049] Alternatively, the apertures 110 may be laser cut and laser drilled, as shown in FIG. The vibratable membrane 60 in this example consists of a single layer of stainless steel 126. Additionally, in other embodiments, the vibratable membrane 60 may comprise further layers attached to the liquid side 64 and / or the aerosol side 66. Additionally, other biocompatible metals may be used instead of stainless steel.

[0050] The exemplary vibratable membrane 60 includes a plurality of recesses 118. The recesses 118 may be annular. The recess 118 has an opening 120 on the liquid side 64 of the vibratable membrane 60. The recess 118 is formed as a blind hole having a bottom 122 opposite the opening 120.

[0051] The recess 118 has a peripheral side wall 124. In the case of a circular recess 118, the peripheral side wall 124 corresponds to the covering of a cylinder. Furthermore, in the cross-sectional view of Figure 8, portions of the peripheral side walls 124 oppose (face) each other.

[0052] The recesses 118 may be formed in the monolayer 128 by using an ultrashort pulsed laser. In this regard, the recesses 118 are preferably made by laser milling, in which a laser beam and / or the monolayers 128 of the vibratable membrane 60 are translated relative to one another, thereby gradually removing material of the monolayer 128.

[0053] Minimum dimension D of recess 118 R may be 300 μm. However, other dimensions are contemplated as well. For example, the smallest dimension D of the opening 120 of the recess 118 facing the liquid side 64 may be R can be 40 μm to 500 μm, 70 μm to 400 μm, or 90 μm to 300 μm.

[0054] In this regard, the minimum dimension D of the circular central recess 118 R corresponds to the diameter of the circle. The thickness T of the monolayer 128 may be 100 μm. Depth or length L of recess 118 R can be selected between 80% and 95% of the thickness T of the monolayer 128. R The thickness may be 80 μm to 95 μm.

[0055] However, the thickness T of the single layer 128 may be in the range of 50 μm to 200 μm. R may be selected to be greater than or equal to 50% of the thickness T of the monolayer 128.

[0056] Each recess 118 has a plurality of apertures 110 formed in a base 122 and extending from the base 122 to the aerosol side 66 of the monolayer 128 . Each recess 118 may have at least 2, at least 20, or at least 50 or at least 100 apertures 110 formed in the bottom 122. Up to a maximum, each recess 118 may have 5,000 or 10,000 apertures 110.

[0057] Each aperture 110 has an entrance opening 128 at the base 122 and an exit opening 130 at the aerosol side 66 of the monolayer 128. The apertures 110 may be approximately cylindrical or conical, with a smaller opening located at the aerosol side 9, thus becoming the exit opening 130. Furthermore, the geometric shape is not limited in this respect, and other geometric shapes are contemplated as well.

[0058] The size of the exit opening 130 of the aperture 110 has a large effect on the MMD. Depending on the fluid, the MMD can be determined by the diameter D of the exit opening 130. A Therefore, the aperture 110 has a diameter D A (diameter of the exit opening 130), the diameter D A is 1 μm to 7 μm, preferably 1.5 μm to 5 μm, more preferably 1.5 μm to 4.5 μm, and most preferably 1.5 μm to 3.5 μm.

[0059] Length L of aperture 110 in monolayer 128 A In another example, the length L of the aperture 118 in the single layer 128 (sometimes referred to as the height or depth) can be between 3 μm and 50 μm. A In a further example, the length L of the aperture 110 in the single layer 128 may be between 5 μm and 20 μm. A The thickness may be in the range of 10 to 20 μm. Other ranges may be 5 to 15 μm, 5 to 12 μm, or 10 to 15 μm.

[0060] Furthermore, the TOR and MMD are strongly dependent on the geometry of the nozzle portion 112, and thus the geometry of the aperture 110 (particularly the length and diameter). The aperture 110 may be formed by the same ultrashort pulse laser used to form the recess 118. However, a short pulse laser as used in the prior art may also be used to form the aperture 110.

[0061] In any case, the formation of the aperture 110 is preferably performed in one laser drilling step at a substantially constant laser fluence. To increase the accuracy of the aperture, i.e. the geometric shape of the nozzle portion 112, it is preferred to have only one drilling step for forming the aperture. When using only one laser drilling step, the diameters of the inlet side (corresponding to the liquid side) and the outlet side (corresponding to the aerosol side) will be very clearly defined with the advantages mentioned above.

[0062] In another aspect, the aperture 110 at the bottom of the recess 118 may also be drilled in two laser drilling stages with different fluences similar to the above embodiment with three drilling stages. For example, a first laser drilling stage with a first fluence may be used to form a first portion of the aperture at the bottom of the recess, and a second laser drilling stage with a second fluence lower than the first fluence may be used to complete the aperture, i.e., to completely penetrate the bottom. In this case, the nozzle portion may be defined only by the second laser drilling stage. Thus, when using two or more laser drilling stages to form the aperture, the bottom may remain thicker (shallower recess depth). This may provide greater mechanical rigidity of the aperture plate.

[0063] The manufacturing method may include, as a first step, forming a recess 118 from the liquid side 64 of the monolayer 128 . In a second, subsequent step, an aperture 110 is formed from the liquid side 64 of the monolayer 128 to the bottom 122 of the recess 118 .

[0064] The vibratable membrane 60 may then be domed. The aperture 110 may have a nozzle portion 112 on the aerosol side 66 of the active area 62 of the membrane 61. The nozzle portion 112 may have a length of 10 μm to 25 μm, or 10 μm to 20 μm, or 10 μm to 15 μm. The length may be less than 20 μm, or less than 18 μm, or less than 16 μm. The diameter D of the nozzle portion at the aerosol side 66A can be 1.5 μm to 5 μm, 1.5 μm to 4 μm, or 1.5 μm to 3 μm.

[0065] The aerosol generator 18 may further comprise a support 80, to which the membrane 61 may be attached (see FIG. 3). Alternatively, the membrane 61 and the support 80 may be formed as one piece.

[0066] The aerosol generator 18 further comprises a piezoelectric actuator 82 for vibrating the membrane 61 (see FIG. 2). The piezoelectric actuator 82 may be annular. The piezoelectric actuator 82 may concentrically surround the active area 62 of the membrane 61. The piezoelectric actuator 82 may be attached to the support 80 or to the membrane 60 if the support 80 and the membrane 61 are integrally formed.

[0067] The electrical contacts 84 can be in electrical contact with the piezoelectric actuator 82 to provide an AC voltage to the piezoelectric actuator 82. The electrical contacts 84 can extend vertically from the piezoelectric actuator 82 towards the body 12. When the aerosol generator 18 is attached to the body 12, the electrical contacts 84 protrude through the contact openings 46 in the body 12 to contact a controller 86 (schematically shown in FIG. 1). The controller 86 is configured to control the nebulizer 10. Thus, application of an AC voltage to the piezoelectric actuator 82 causes a change in its length to be transmitted directly to the support 8 and then from the support 80 to the membrane 61, or directly to the membrane 61 if the piezoelectric actuator 82 is attached directly to the membrane 61. Thus, the piezoelectric actuator 82 vibrates the membrane 61 to generate an aerosol at an aerosol generation rate (AGR) in the range of about 0.2 mL / min to about 1.5 mL / min, preferably about 0.4 mL / min to about 1.2 mL / min.

[0068] In an embodiment, the aerosol generator 18 is adapted to generate an aerosol that meets at least one of the following parameters: MMAD ranges from about 1 μm to about 5 μm, preferably less than 4.5 μm or less than 4.0 μm; MMAD ranges from about 3.0 to about 3.6 μm. Fine particle dose (FPD, <5μm) is more than 60% of the emitted dose or more than 70% of the emitted dose; The amount delivered under simulated breathing is greater than 45% or greater than 50%; -TOR (Total Output Rate: spray amount per minute) is more than 0.45g / min or more than 0.5g / min.

[0069] In the specific examples, the compositions defined above were nebulized. All data from laser diffraction measurements of nebulizers combining a plenum chamber 32 (described in more detail below) with a volume of more than 50 mL and a vented reservoir with aerosol generators 18 defined in Tables 3 and 4 as MS-3 type aerosol generators with MMAD of 2.8 μm to 3.6 μm and MS-4 type aerosol generators with MMAD of 3.8 μm to 4.6 μm are summarized below.

[0070] [Table 3]

[0071] [Table 4]

[0072] In this case, the average MMD for the MS-3 aerosol generator is 3.3 μm compared to 4.1 μm for the MS-4 aerosol generator. The aerosol generator 18 may further have a frame 68 for supporting the aerosol generator 18. The frame 68 may be made of resin and may be provided with a flexible engagement member 70 (see FIG. 2) for releasably securing the aerosol generator 80 to the body 12. To this end, the body 12 has an engagement opening 72 for receiving the engagement member 70. The engagement member 70 may be a flexible hook that hooks onto the underside of a wall 74 of the body 12 that defines the engagement opening 72. Thus, the aerosol generator 18 may be removed from the body 12 for cleaning purposes.

[0073] When the aerosol generator 18 is attached to the body 12, the membrane 61 or support 80 is pressed against the sealing lip 44 when the aerosol generator 18 is mounted on the body 12. As a result, the membrane 61 or support 80 seals the reservoir 24 or the body 12 at its lower part, more specifically at the feed opening 42. The membrane 61 has a liquid side 64. In this regard, the liquid side 64 faces the feed opening 42, so that the liquid solution in the reservoir 24 is applied to the active area 62 of the liquid side 64 of the membrane 61. When the membrane 61 is vibrated, the liquid solution passes through the aperture 110 and an aerosol is formed on the side opposite the liquid side 64. This side is referred to as the aerosol side 66 opposite the liquid side 64.

[0074] The nebulizer 10 further comprises a mixing chamber 20. The mixing chamber has an inlet 76. The inlet 76 is arranged on an inlet side of the mixing chamber 20 facing the aerosol generator 18 and the body 12. The inlet 76 is thus provided on the aerosol side 66 of the membrane 60.

[0075] Furthermore, an elastic valve member 19 is provided between the inlet 76 of the mixing chamber 20 and the body 12 to seal the interface between the mixing chamber 20 and the body 12. In addition, the elastic valve member 19 has two one-way valves 168, specifically flap valves (inhalation valves), which control / allow the flow of external air on both diametric sides into the mixing chamber only during inhalation, as described in European Patent Application Publication No. EP1927373A1. In other words, the one-way valve 168 is provided to control the supplied air, allowing ambient air to flow into the mixing chamber during the inhalation phase, but preventing exhaled air from entering the mixing chamber and passing back through the aerosol generator 18 during the exhalation phase. Thus, the one-way valve 168 reduces the amount of exhaled air flowing into the mixing chamber 20 (the exhaled air rather flows out through the one-way valve 98 (exhalation valve) of the mouthpiece 21 described below), and prevents the aerosol from being blown away from the mixing chamber 20 by the exhaled air, allowing the generation of a bolus in the mixing chamber 20. The valve 168 further allows for the transport of the aerosol bolus from the mixing chamber 20 during the exhalation phase together with the exhaled air and ambient air potentially remaining in the mixing chamber 20. Since aerosol is accumulated in the mixing chamber 20 during the exhalation phase, an increased amount of aerosol, the so-called aerosol bolus, becomes available to the patient, especially at the beginning of the inhalation phase.

[0076] The body 12 further has a projection 100 having an opening 102. The mixing chamber 20 has a corresponding protrusion 104 on its upper surface. Furthermore, the mixing chamber 20 has a cylindrical axis 108 on its lower portion which engages with a groove 106 in the body 12. Thus, the mixing chamber 20 can be rotated about the cylindrical axis 108 upon disengagement of the opening 102 of the projection 100 from the protrusion 104 to provide access to the elastic valve member 19 and the aerosol generator for cleaning purposes.

[0077] The plenum chamber 23 (see FIG. 3) is defined between the inlet 76 of the mixing chamber 20, the mixing chamber 20, the mouthpiece 22 (alternatively a mask), and the outlet 94 of the mouthpiece 22 (alternatively a mask). The plenum chamber 23 has a volume of at least 60 cubic centimeters and no more than 90 cubic centimeters. In this embodiment, the plenum chamber 23 has a volume of 65 cubic centimeters. The plenum chamber 23 has a length of 104 mm to 154 mm, and / or a width of 40 mm to 60 mm, and / or a height of 30 mm to 50 mm. The mixing chamber 20 itself has a length L of 54 mm to 94 mm, and / or a width W of 40 mm to 60 mm, and / or a height H of 30 mm to 50 mm.

[0078] The mixing chamber 20 further comprises a connection 78 for attaching the mouthpiece 22. The connection 78 may be a cylindrical socket 88. The mixing chamber 20 further comprises an outlet 90 on the outlet side of the mixing chamber 20. The outlet 90 is provided at an end opposite the end provided with the inlet 76. The outlet 90 may be defined by an opening 89 in the cylindrical socket 88.

[0079] The mouthpiece 22 has an inlet 92 at one end and an outlet 94 at the opposite end. The inlet 92 is configured to be attached to the connection 78, specifically the socket 88, of the mixing chamber 20. The outlet 94 is configured to fit into the mouth of a user. In addition, the mouthpiece 22 comprises an exhalation opening 96 that is closed by a one-way valve 98. The one-way valve 98 is a flap valve that opens the exhalation opening 96 during the user's exhalation so that air can escape through the exhalation opening 96 during exhalation. During inhalation, the one-way valve 98 closes the exhalation opening 96 so that air is not drawn through the exhalation opening 96 during inhalation.

[0080] Table 5 summarizes all the data from the breathing simulation experiments.

[0081] [Table 5]

[0082] With the MS-3 aerosol generator, a delivered dose (DD) of 60% was reached. Calculated with the data measured by laser diffraction, this results in an inhalable dose <5 μm (=amount theoretically reaching the lungs) of 46% of the charged rhGM-CSF. With the MS-4 aerosol generator, the delivered dose was only 39%. As a result, the inhalable dose <5 μm was only 25%. This can be explained by the unusually high formulation volume in the mixing chamber of the aerosol generator. The residuals in the MS-4 aerosol generator were 37%, which was significantly increased compared to the MS-3 aerosol generator (15%). This can be explained by the high volume of aerosol impinged in the mixing chamber. Due to the high aerosol volume per minute (TOR) of 1123 mg / min with the MS-4 aerosol generator and the low surface tension of the formulation, the droplets tend to agglomerate and accumulate in the mixing chamber. This effect can be reduced by using a larger mixing chamber. This was tested in a small experiment, where the residuals in the nebulizer were measured by weighing them after nebulization with an MS-4-XL nebulizer, i.e., an MS-4 aerosol generator combined with a plenum chamber (XL mixing chamber) with a volume of more than 90 mL, as seen in Table 6. The residuals of the MS-4-XL aerosol generator were only slightly higher than those of the MS-3 aerosol generator.

[0083] [Table 6] [Explanation of symbols]

[0084] 10 Nebulizer 12 Main unit 14 Lid 16. Sealing 18 Aerosol Generator 19 Elastic valve member 20 Mixing Chamber 22 Mouthpiece 23 Plenum Chamber 24 Reservoir 26 Liquid Solutions 27 Upper space 28 Circumferential Rim 30 Opening 32 Outer surface 33 Spiral Passage 34 Slots 36 Lid protrusion 38 Circumferential rim top surface 40 Opposite Surface 42 Supply opening 44 Seal lip 46 Contact opening 48 Vent 50 Cutout 52 Inner surface 54 Bottom 56 Ribs 58 Rib top surface 60 Vibrable membrane 62 Active area 64 Liquid side 66 Aerosol side 68 frames 70 Engagement member 72 Engagement opening 74 Wall 76 Mixing chamber inlet 78 Connection 80 Support 82 Piezoelectric Actuator 84 Contacts 86 Controller 88 Sockets 90 Mixing chamber outlet 92 Mouthpiece inlet 94 Mouthpiece outlet 96 Exhalation opening 98 One-way valve 100 protrusions 102 Opening 104 Mixing chamber protrusion 106 Groove 108 Axis 110 Aperture 112 Nozzle part 114 First Part 116 Second Part 118 Recess 120 Recess opening 122 Bottom of recess 124 Peripheral side wall of recess 126 Single Layer 128 Inlet opening 130 Exit opening 162 Sealing Ring 164 Ceiling Hinge 166 Central Ceiling 168 One-way valve with elastic valve member API Active Pharmaceutical Ingredients CU Control unit (device for electronic control of atomization) DD delivered dose, the amount of drug delivered onto the inhalation filter [mg or % of drug load] GM-CSF Granulocyte-macrophage colony-stimulating factor GSD Geometric standard deviation = width of droplet size deviation curve MMD Mass Median Diameter is the droplet size that divides the frequency distribution in half, such that 50 percent of the aerosol population has larger droplets and 50 percent of the aerosol population has smaller droplets. Neb time Nebulization time [min] Residuals Residual amount in the nebulizer [mg] RF <xμm <xμmでの吸入可能画分は、直径xμm未満の溶滴サイズの割合である。SD standard deviation SDS Sodium dodecyl sulfate rhGM-CSF Recombinant human granulocyte-macrophage colony-stimulating factor RSD Relative standard deviation TOR Minute Aerosol Volume [mg / min] = Mass of aerosol delivered per minute TV tidal volume

Claims

1. A drug-device combination comprising: a liquid solution (26) containing a biological agent; a nebulizer (10) for aerosolizing a liquid solution (26); The nebulizer (10) a reservoir (24) for holding a liquid solution (26), the reservoir (24) having a vent (48) for maintaining atmospheric pressure within the reservoir (24); a vibratable membrane (60) having an active area (62) with an aperture (110), wherein a liquid solution (26) can be supplied to the active area (62) at a liquid side (64) of the membrane (60); a piezoelectric actuator for vibrating the membrane (60), whereby an aerosol of the liquid solution (26) is generated in an active area (62) on an aerosol side (66) of the membrane (60), the aerosol side (66) of the membrane (60) being opposite a liquid side (64) of the membrane (60); a plenum chamber (23) having an inlet (76) on the inlet side of the aerosol side (66) of the membrane (60) and an outlet (94) on the outlet side for administering the aerosol, the outlet (94) of the plenum chamber being opposite the inlet (76) of the plenum chamber (23); A drug-device combination comprising:

2. 2. The pharmaceutical and device combination of claim 1, The vent (48) is a passive vent, a drug and device combination.

3. In the combination of the pharmaceutical and device described in claim 2, the passive vent has an area of ​​0.5 mm 2 to 5 mm 2 ; The width of the passive vent is 0.5 mm to 3 mm; The height of the passive vent is 0.5 mm to 3 mm; The pharmaceutical and device combination, wherein the passive vent has a depth of 1 mm to 4 mm.

4. In the combination of a pharmaceutical product and a device according to claim 1 or 2, The reservoir (24) a body (12) sealed at the bottom by a vibratable membrane (60); a body (12) having a circumferential rim (28) defining an opening (30) for receiving a liquid solution (26) and a sealing surface (38); a lid (14) for engaging the circumferential rim (28) to close the reservoir (24) and seal against the sealing surface (38); a vent (48) connecting the head space (27) of the reservoir (24) to the atmosphere and spaced apart from the sealed lower part; A drug-device combination, wherein the cup reservoir is defined by:

5. The pharmaceutical and device combination of claim 3, The vent (48) is a notch (50) formed in the circumferential rim (28) from the sealing surface (38) and across the circumferential rim (28) connecting the interior of the reservoir (24) with the atmosphere.

6. In a combination of the pharmaceutical agent and device according to claim 1 or 2, The medicament and device combination wherein the plenum chamber (23) has a volume of at least 60 cubic centimeters.

7. In a combination of the pharmaceutical agent and device according to claim 1 or 2, The plenum chamber (23) has a volume of 90 cubic centimeters or less in the drug-device combination.

8. In a combination of the pharmaceutical agent and device according to claim 1 or 2, The plenum chamber (23) has a length of 109 mm to 154 mm, and / or a width of 40 mm to 60 mm, and / or a height of 30 mm to 50 mm.

9. In a combination of the pharmaceutical agent and device according to claim 1 or 2, The aperture (110) has a size of 1.5 μm to 5 μm on the aerosol side (66).

10. In a combination of the pharmaceutical and device according to claim 1 or 2, The vibratable membrane (60) has 500 to 6000 apertures (110), said drug-device combination.

11. In a combination of the pharmaceutical product and device according to claim 1 or 2, A drug-device combination, wherein the aperture (100) is laser drilled and / or laser cut.

12. In a combination of the pharmaceutical agent and device according to claim 1 or 2, The aperture (110) has a nozzle portion (112) on the aerosol side of the active area of ​​the membrane (60), the nozzle portion (112) having a length of less than 20 μm.

13. In a combination of the pharmaceutical agent and device according to claim 1 or 2, The pharmaceutical and device combination, wherein the liquid solution (26) has a viscosity of 0.900 mPa·s to 5.000 mPa·s, preferably 0.950 mPa·s to 3.500 mPa·s, more preferably 1.000 mPa·s to 2.000 mPa·s.

14. In a combination of the pharmaceutical agent and device according to claim 1 or 2, A pharmaceutical and device combination, wherein the liquid solution (26) has a surface tension of 32 mN / m to 108 mN / m, preferably 37 mN / m to 73 mN / m.

15. In a combination of the pharmaceutical agent and device according to claim 1 or 2, The pharmaceutical and device combination, wherein the liquid solution (26) has an osmolality of 200 mOsm / kg to 700 mOsm / kg, preferably 200 mOsm / kg to 500 mOsm / kg.

16. In a combination of the pharmaceutical agent and device according to claim 1 or 2, The pharmaceutical and device combination wherein the volume of a single dose of the liquid solution (26) is 1 mL to 2 mL.

17. In a combination of the pharmaceutical agent and device according to claim 1 or 2, The volume of the reservoir (24) is between 1 mL and 5 mL, preferably between 3 mL and 5 mL.

18. In a combination of the pharmaceutical agent and device according to claim 1 or 2, A biologic is a drug-device combination that includes one or more proteins, preferably two or more proteins.

19. 20. The pharmaceutical and device combination of claim 18, A pharmaceutical and device combination, wherein one of the proteins is granulocyte-macrophage colony-stimulating factor (GM-CSF), preferably recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF).

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