RU2801255C2 - High pressure inhalation device - Google Patents

Abstract

FIELD: medical equipment.

SUBSTANCE: group of inventions relates to an inhalation device for generating an aerosol from a liquid and a method of generating an aerosol from a liquid. The inhalation device comprises a housing (1), inside the said housing (1) there is a reservoir (2) for storing the said medical fluid, further than the said reservoir (2) along the flow of the fluid, there is an injection unit (3) for creating pressure connected to the agent (4) for supplying mechanical energy to the said injection unit (3), and there is nozzle (5) further to the said injection unit (3) along the flow of the fluid. The discharge block (3) contains a hollow cylindrical part (3A) and a plunger (3B), wherein the cylindrical part (3A) has an internal space (3C) with a given first cross section (A1) configured to accommodate an upstream end section (3B') of the said plunger (3B). The cylindrical part (3A) and the plunger (3B) are movable relative to each other linearly so as to form an injection chamber with a variable volume. An agent (4) for supplying mechanical energy is a pressurized gas. The inhalation device contains a pressurized chamber (6) having an internal volume for storing the said pressurized gas. The wall of the injection pressure chamber (6) is formed by a piston (7) configured to perform reciprocating linear movement so as to change the internal volume of the injection pressure chamber (6). The piston (7) is mechanically coupled with the plunger (3B) or with the cylindrical part (3A) of the pressure block (3), and the piston (7) has a cross section (A2) that is larger than the cross section (A1) of the pressure chamber. The method includes a step in the filling phase, providing a negative gauge pressure inside the injection chamber by increasing its volume and thus filling the injection chamber with liquid from the reservoir (2) due to the said negative gauge pressure. The method includes the step in the ejection phase, providing a positive gauge pressure inside the pressurization chamber (6) having the specified second cross section (A2) and, thus, the movement of the piston (7). The method includes the step of mechanically transmitting the said movement to the plunger (3B) in such a way that the volume of the injection chamber is reduced and a positive pressure is created in its interior; and thus ejecting the medical fluid is performed from the injection chamber through the nozzle (5) while increasing the pressure in the injection pressure chamber (6).

EFFECT: ejection of large volumes of liquid for medical purposes in a fairly short time in just one dosing cycle.

20 cl, 4 dwg

Description

Technical field

The invention relates to the field of inhalation devices for liquids for medical purposes. In particular, the invention relates to an inhalation device providing a particularly high pressure for nebulization.

State of the art

Nebulizers or other aerosol generators for liquids have long been known in the art. In particular, such devices are used in medicine for therapeutic and research purposes. In these areas, they serve as inhalation devices for the application of active ingredients in the form of aerosols, i. in the form of small liquid particles distributed in the gas. Such an inhalation device is known in particular from EP 0627230 B1. The essential components of said inhalation device are: a reservoir containing the liquid to be aerosolized; a pressure unit for creating a pressure that is high enough to effect spraying; as well as a device for fine spraying in the form of a nozzle.

An improvement to such an inhalation device is disclosed in patent application PCT/EP 2018/061056 filed by the same applicant as the present invention, the contents of which are incorporated herein in their entirety.

Depending on the particular application, the amount of finely nebulized liquid per dose, using currently available soft aerosol inhalation devices, is typically on the order of 15 μl, while delivery of large volumes of up to 250 μl per dose would be desirable. dose. Even conventional propellant metered dose inhalers are only suitable for delivering single doses up to 50-80 µl per actuation. One possible solution is to simply repeat the dosing cycle one or more times such that one single dose is delivered by two or more successive actuations of the device. However, this results in a longer ejection time, which is further increased by the fact that the time required to refill the device's plenum chamber must also be added. In addition, repeated and reproducible actuation of the device by the user can be problematic; in particular with respect to active ingredients which are to act immediately, such as, for example, drugs used in the treatment of bronchial asthma or the like.

The task of the invention

The object of the present invention is to provide a device that avoids the disadvantages of the prior art. The device should allow large volumes of medical fluid to be ejected in a fairly short time in just one dosing cycle.

Disclosure of the essence of the invention

In a first aspect, the present invention provides an inhalation device for generating an aerosol from a medical fluid, comprising:

housing (1), inside said housing (1) a reservoir (2) for storing said medical fluid, further than said reservoir (2) along the flow of the fluid, an injection unit (3) for creating pressure, connected to a means (4) for supplying a mechanical the energy of the specified injection unit (3), and then the specified injection unit (3) in the direction of the fluid nozzle (5); and

the injection unit (3) contains a hollow cylindrical part (3A) and a plunger (3B), moreover, the cylindrical part (3A) has an internal space (3C) with a given first cross section (A1), made with the possibility of accommodating an end valve located upstream of the fluid section (3B') of the specified plunger (3B), wherein the specified cylindrical part (3A) and the specified plunger (3B) are made with the possibility of linear movement relative to each other so as to form an injection chamber having a variable volume, and

means (4) for supplying mechanical energy is a pressurized gas, wherein the inhalation device comprises an injection pressure chamber (6) having an internal volume for storing said pressurized gas, the wall of said injection pressure chamber (6) being formed by a piston (7), made with the possibility of reciprocating linear movement in such a way as to change the internal volume of the pressure chamber (6), and

the piston (7) is mechanically coupled with the plunger (3B) or with the cylindrical part (3A) of the injection unit (3), and

the piston (7) has a cross section (A2) which is larger than the cross section (A1) of the pressure chamber.

In a second aspect, the invention provides a method for generating an aerosol from a liquid by means of an inhalation device according to the first aspect of the present invention, the method comprising the following steps:

- in the filling phase, providing a negative gauge pressure inside the pressure chamber by increasing its volume and thus

- filling the injection chamber with liquid from the tank (2), due to the indicated negative gauge pressure;

- in the ejection phase, providing a positive gauge pressure inside the pressurization chamber (6) having said second cross section (A2) and thus

- the implementation of the movement of the piston (7);

- transmitting said movement mechanically to the plunger (3B) or cylindrical part (3A) in such a way that the volume of the pressure chamber is reduced and a positive pressure is created in its interior; and thus,

- ejection of medical fluid from the injection chamber through the nozzle (5);

while the pressure in the pressure chamber (6) is increased.

Implementation of the invention

The object of the present invention is solved by means of an inhalation device for the formation of an aerosol from a liquid for medical purposes, containing:

housing (1), inside said housing (1) reservoir (2) for storing said medical fluid, further (below) said reservoir (2) in the direction of the fluid injection unit (3) to create pressure, connected to means (4) for supplying mechanical energy to the specified injection unit (3), and further (below) the specified injection unit (3) along the fluid nozzle (5); and

the injection unit (3) contains a hollow cylindrical part (3A) and a plunger (3B), moreover, the cylindrical part (3A) has an internal space (3C) with a given first cross section (A1), made with the possibility of accommodating an end valve located upstream of the fluid section (3B') of the specified plunger (3B), wherein the specified cylindrical part (3A) and the specified plunger (3B) are made with the possibility of linear movement relative to each other so as to form an injection chamber having a variable volume, and

means (4) for supplying mechanical energy is a pressurized gas, wherein the inhalation device comprises an injection pressure chamber (6) having an internal volume for storing said pressurized gas, the wall of said injection pressure chamber (6) being formed by a piston (7), made with the possibility of reciprocating linear movement in such a way as to change the internal volume of the pressure chamber (6), and

the piston (7) is mechanically coupled with the plunger (3B) or with the cylindrical part (3A) of the injection unit (3), and

the piston (7) has a cross section (A2) which is larger than the cross section (A1) of the pressure chamber.

Preferred embodiments of the invention are described in the respective dependent claims, the following description, as well as in the attached drawings.

The inhalation device is suitable for aerosolization of medical fluids for inhalation therapy. In particular, the inhalation device is capable of metered generation and ejection of nebulized aerosols suitable for delivering medically active ingredients to the lungs. The term "medical fluids" as used herein also includes medical fluids.

Typically, such an inhalation device comprises a housing, within said housing a reservoir for storing a liquid, such as, for example, a medical fluid. The reservoir may be configured to store, for example, a liquid volume of from about 1 to about 50 ml, or from about 5 ml to about 15 ml. Downstream (below) said reservoir, the device comprises a pumping unit, preferably based on the principle of a piston pump or plunger pump, and downstream (below) said pumping unit, a nozzle. Obviously, the injection unit is in fluid communication with both the nozzle and the reservoir.

The pressure block, which serves to generate pressure, is connected to or driven by a means for supplying mechanical energy to said pressure block. By means of said means, the injection unit is supplied with a predetermined, relatively constant, maximum amount of mechanical energy that is sufficient to generate the necessary pressure to produce an ejection, which is typically in the range of about 30 bar to about 300 bar, as described in more detail below. As a result, the ejection or delivery parameters of the device are exceptionally reproducible compared to devices in which the ejection pressure is provided manually by the user and thus varies considerably during the ejection phase.

More specifically, said pumping unit comprises a hollow cylindrical portion having an internal space that typically ranges in volume from about 1 µl to about 500 µl, or from about 5 µl to about 250 µl. It should be noted that the term "cylindrical part" refers to a part having a cylindrical inner surface; the outer side, as well as the part that does not come into contact with the outlet pipe and / or insulation, should not be cylindrical.

The injection unit also contains a plunger. The inner space of the cylindrical part has a predetermined cross section (hereinafter also referred to as the "first" cross section) and is made with the possibility of accommodating the end section of the specified plunger located upstream of the fluid medium. It should be understood that the cross section of the plunger should substantially correspond to the cross section of the specified internal space. In case the internal space has a substantially wider cross section, the present definition of "first cross section" refers only to that part of the cross section which corresponds to the cross section of the plunger. Thus, alternatively, the cross section of the plunger can also be used to describe the present invention in more detail.

In addition, said cylindrical part and said plunger are movable relative to each other in a linear manner so as to form an injection chamber having a variable volume. Thus, by changing the volume, the pressure in said pressure chamber is changed accordingly.

According to the present invention, the above means for supplying mechanical energy is a pressurized gas.

The known devices, in particular, use resilient springs as means for supplying mechanical energy, which are manually charged before the ejection phase. Although said springs have the advantage that they provide, in principle, an unlimited number of dispensing cycles, the amount of mechanical energy that can be stored by such a spring during one cycle, and thus that is provided during the phase ejection is limited, as well as the achievable pressure inside the injection chamber and, consequently, the dosing volume and dosing time.

In contrast, the present invention uses a means that can provide a much higher injection pressure. Depending on the particular embodiment of the invention, said pressure may also be provided for a longer time within the injection cycle, thus allowing a higher volume to be dispensed per cycle.

In addition, the device contains a "pressure chamber" (not to be confused with the aforementioned pressure chamber). Said pressurization chamber has an internal volume for storing said pressurized gas. One of the walls of said pressurization chamber is formed by a movable piston which is capable of reciprocating linear movement so as to change the internal volume of the pressurization chamber. In other words, the piston is driven by increasing (or decreasing) the pressure in the pressurization chamber, which contains the pressurized gas. The higher the pressure, the greater the force acting on the piston.

In addition, the piston is mechanically coupled to the plunger or to the cylindrical part (depending on which of these components of the injection unit is movable). As a result, movement of the piston results in movement of the plunger or barrel. In other words, the piston "drives" the plunger or barrel and thus can cause a change in volume (and thus pressure) within the pressure chamber.

In order to achieve the pressure increase, the piston has a cross section (second cross section) that is larger than the cross section (first cross section) of the pressure chamber with which it is mechanically coupled. Thus, the principle of "pneumatic lever" is provided, which uses the fact that the force is proportional to the product of pressure and area. Since the areas, namely the first and second (larger) cross sections, are different, the first pressure (inside the pressure chamber) is converted into a second (and higher) pressure inside the pressure chamber. Said pressure can advantageously be used to provide high ejection rates and/or short ejection times.

Preferably, the ratio of the second cross section to the first cross section is more than 2 or more than 5, and preferably even more than 10, for example, in the range from about 10 to about 500. As a result, the pressure can also be increased by a factor of 10 or more, for example , from about 10 to about 100 times. If, for example, the means for supplying mechanical energy provides a gas at a pressure of 10 bar, a pressure of 100 bar can be obtained in the pressure chamber of the pressure unit, which is particularly advantageous since such a high pressure allows for long phases of aerosol ejection, high ejection velocities and thus large volumes of fluid that can be delivered in one injection cycle. Another potential advantage is that liquids with higher viscosities than typical aqueous formulations can be aerosolized, such as liquids whose viscosities range from about 1 to about 100 mPa⋅s (cP ). In addition, the present invention is particularly suitable for inhalation devices which have nozzles requiring high operating pressure, such as, for example, impact type nozzles. By means of the present invention, depending on the viscosity of the fluid and the type of nozzle, a volume can be sprayed over a period of 1.5 to 2.0 seconds, typically ranging from about 1 µl to about 500 µl, or from about 5 µl to about 250 µl, for example, about 50 µl.

According to one embodiment of the invention, the pressurized gas is provided by means of a container filled with pressurized gas and/or liquefied gas. Preferably, the container contains liquefied gas; as is known, a container that contains some liquefied gas (not being completely filled with liquefied gas) will also contain some pressurized gaseous (non-liquid) gas that is in equilibrium with the gas that is in liquid state. Examples of potentially useful liquefied gases include liquefied propane, n-butane, isobutane, nitrous oxide, carbon dioxide, dimethyl ether, methyl ethyl ether, hexafluoroacetone, hydrofluoroalkanes (eg HFA 134a or HFA 227) or any mixtures thereof. Among the preferred liquefied gases to be used in accordance with the present invention are liquefied propane, propane/butane mixtures and/or nitrous oxide.

Preferably, the container is part of a preferably replaceable cartridge so that when the residual pressure inside the container drops below a minimum threshold, the container can be removed from the body of the inhalation device and a new cartridge can be installed. With a single cartridge, many, for example 50 to 200 cycles, can be achieved without any problem.

In accordance with another embodiment of the invention, the pressurized gas is provided by means of a manually pressurized chamber that can temporarily store and release said pressurized gas in a controlled manner. This means that the pressure inside the pressurization chamber can be manually increased, for example, by repeatedly actuating the pressurizer or the like. Such a pumping device can be actuated by linear as well as rotary motion and is preferably part of an inhalation device. The inhalation device may include means for monitoring pressure and/or for notifying that there is sufficient pressure to use the device. After reaching the required pressure, the device is ready for use. Because the manual pressurization of the pressurization chamber occurs before the actual dosing occurs, the dosing is not interrupted, as is the case with devices known in the art that use a series of dosing movements.

Although the embodiment of the invention in which a container or cartridge of liquefied gas is used provides particular convenience in use, the latter embodiment of the invention, i.e., the embodiment of the invention in which a gas is used that can be manually pressurized on demand, is very technically flexible. solution because it is potentially independent of the need for refilling, except with regard to the liquid to be aerosolised, such as a medical grade liquid. In addition, the fact that the device according to the last embodiment of the invention does not contain any pressurized components in the non-activated state may have the advantage that there are fewer regulatory requirements to be met.

In accordance with one embodiment of the invention, the plunger is hollow. The hollow space may serve as a means for fluid communication of the pressure chamber with the nozzle(s) or reservoir. To do this, the downstream end of the plunger may be in direct or indirect fluid communication with said nozzle, or the upstream end of the plunger may be in direct or indirect fluid communication with the reservoir.

In yet another embodiment of the invention, the plunger is solid. In this case, other possibilities must be used in order to ensure the exit from the injection chamber. This can, for example, be achieved by providing one or more openings in the side walls of the injection chamber that are not obstructed at any stage of the injection cycle by the upstream end of the plunger, for example, at a location close to the inlet that is connected to the reservoir. Said hole(s) is connected(s) to the nozzle(s).

In accordance with one embodiment of the invention, the plunger is stationary and rigidly attached to the body or to the nozzle, and the hollow cylindrical part is movable relative to the body or nozzle. This embodiment of the invention may be referred to as the "moving chamber" embodiment, since most of the chamber, including the side wall, is movable. The movement of the hollow cylindrical part is due to the mechanically coupled piston.

In accordance with another embodiment of the invention, the hollow cylindrical part is stationary and rigidly attached to the body or nozzle, and the plunger is movable relative to the body or nozzle. Accordingly, this embodiment of the invention may be referred to as the "moving plunger" embodiment. The movement of said plunger is driven by a mechanically coupled piston.

In accordance with another embodiment of the invention, the cylindrical part, as well as the plunger, are movable. The relative movement of both parts relative to each other in this case also leads to the desired change in the volume of the injection chamber. Both parts can be configured to move in parallel or in opposite directions when the piston is propulsion.

In one embodiment of the invention, a check valve is placed upstream of the pressure chamber in order to "actively" block the flow of fluid back towards the reservoir. Here, the term "actively" indicates that a dedicated component is provided to prevent said backflow. In contrast, a "passive" means is a means that performs its functions simply due to its dimensions, for example, a particularly narrow pipe or a specially shaped outlet in the direction of the nozzle. In any case, steps must be taken to at least reduce said reverse flow.

In one embodiment of the invention, in addition to the aforementioned "direct" pneumatic/hydraulic interface, which uses different sizes of areas that are subjected to pressure, a mechanical linkage mechanism is provided to further enhance the effect of increasing the aforementioned ratio. In other words, by further providing a mechanical lever or the like that converts, for example, a long but weaker movement into a short but stronger movement, said increase can be further enhanced. Such a lever may, for example, be in the form of a two-arm lever, or it may use a cam mechanism using an inclined surface as lever means.

In yet another embodiment of the invention, a means for temporarily storing mechanical energy is provided, which is configured to cock by propulsion of the piston, and which is configured, by releasing the stored energy, to cause the piston to retropulse.

In other words, said means, which should not be confused with the aforementioned means for supplying mechanical energy, which causes an increase in pressure in the pressure chamber, serves to create a vacuum, or negative gauge pressure, inside the pressure chamber, whereby it is refilled with liquid from the reservoir. This is achieved by imparting to said means, during the ejection phase, a quantity of mechanical energy which, during the refilling phase, is sufficient to "push" the cylindrical part away from the plunger or vice versa and thus increase the internal space of the pressure chamber. This amount of energy is substantially lower than that provided by the means for supplying mechanical energy; thus, the energy that can be used to carry out dosing is only slightly reduced by cocking the means for temporary storage of mechanical energy.

Thus, the means for temporarily storing the mechanical energy serves as a means for resetting the volume of the blowing chamber.

Preferably, said means for temporarily storing mechanical energy is an elastic spring, a gas spring, or a magnetic spring. The spring is designed in such a way that it abuts against the inner wall of the housing at one end, and against the movable part (plunger or cylindrical part) at the other end. By compressing the spring during the ejection phase, energy is conserved; it is released again when the spring is released, thereby restoring the volume of the pressure chamber.

It should be understood that if a tension or other type of spring is used, the design must be adapted accordingly.

In one of the preferred embodiments of the invention, the nozzle of the inhalation device is selected from those types of nozzles that are characterized by a high operating pressure or require it to provide a fine spray of liquid. For example, the nozzle may require a pressure of 30 bar or higher, such as 30 to 300 bar; or 50 bar or more, for example 50 to 300 bar; or 100 bar or more, for example 100 to 300 bar, respectively.

In one particularly preferred embodiment of the invention, the nozzle is an impact type nozzle. Such nozzles are well known and provide, by means of the collision of two or more colliding liquid streams, a fine and sufficiently uniform fine particulate atomization which can be inhaled by the user. The nozzle may also be provided with more than one level with nozzle outlets, or more than one pair of nozzle outlets in one level, to further increase the amount of liquid that can be finely atomized in one cycle.

According to another embodiment of the invention, the nozzle is a Reilly nozzle or a vortex type nozzle.

In another embodiment of the invention, the volume of the injection chamber is at least 15 µl, or at least 30 µl, or at least 50 µl, or from about 100 µl to 250 µl, respectively.

In yet another embodiment of the invention, the injection unit is configured to provide a maximum pressure of at least 30 bar, and preferably at least 100 bar, and most preferably at least 200 bar, inside the injection chamber. The means for supplying mechanical energy is configured to provide a pressure of at least 10 bar, and preferably at least 20 bar, and most preferably at least 50 bar, inside the pressure chamber. In the context of the present description, these (maximum) pressure values refer to the maximum pressure in the injection chamber during the injection cycle.

Experiments have shown that the values of this indicator are sufficient to provide the user with a sufficiently large amount of nebulized medical fluid with only one dosing cycle.

In another preferred embodiment of the invention, the injection chamber has an internal volume of at least about 50 µl, for example, from about 50 µl to about 500 µl or up to about 250 µl, and is configured to provide a maximum pressure of at least about 100 bar.

In one embodiment of the invention, (i) the piston and (ii) the plunger and/or the cylindrical part are movable in parallel directions. Both groups of components may be arranged next to each other, but they may also be arranged in a straight line with each other such that their respective directions of motion are collinear.

In one embodiment of the invention, the pressurization chamber is provided by means of two parallel plates, such as discs, slidable within the housing. If the distance between said plates increases, then the volume of the injection pressure chamber increases, and vice versa. One of the plates may serve as a mechanical connection or "mate" to the injection unit. Thus, as the pressure chamber increases in volume, said "interface" plate preferably moves separately and in a direction in which the volume of the pressure chamber decreases. In order to remove the gas that accumulates inside the pressurization chamber after the ejection phase, the mating plate remains in place and the other "pressurizing" plate is moved so that the volume of the pressurization chamber decreases again ("returned to its original state"). In the refilling phase, both plates move in parallel so that the volume of the pressure chamber increases while the volume of the pressure chamber remains constant.

The term "medical fluid" as used herein should be understood in a broad sense, and in specific embodiments of the invention, it means a liquid or liquid composition that may be useful for treating, stabilizing or preventing the onset of a pathological condition, disorder or disease, specifically , pulmonary pathological condition, disorder or disease in an animal or human, preferably in humans.

In specific embodiments of the invention, the "medical fluid" may essentially be a compound or mixture of compounds. In other specific embodiments of the invention, the medical fluid may be a solution, suspension or dispersion of any ingredient or active ingredient in a physiologically acceptable carrier or liquid. In other specific embodiments of the invention, the physiologically acceptable carrier fluid may be water or an aqueous mixture containing water and one or more other physiologically acceptable solvents such as, for example, ethanol, propylene glycol, or polyethylene glycol.

In other specific embodiments of the invention, the medical fluid may be an aqueous solution of a physiologically acceptable salt, such as, for example, sodium chloride (saline). In a specific embodiment of the invention, the medical fluid in the context of the present description may be an aqueous solution of sodium chloride (saline), the concentration of sodium chloride in which can usually be in the range from about 0.5 wt. % to about 15 wt. %, or from about 0.9 wt. % to about 10 wt. %, or from about 2 wt. % to about 5 wt. %, or up to about 4 wt. %, for example, about 3.0 wt. %, with the concentration referring to the mass of the final aqueous solution.

In particular embodiments of the invention, the term "medical fluid" as used herein may refer to a medical fluid in the form of a pharmaceutical composition containing at least one active pharmaceutical ingredient (API), more specifically, at least one inhalable active pharmaceutical ingredient. ingredient. More specifically, such at least one inhaled active pharmaceutical ingredient may, for example, be selected from long-acting muscarinic receptor antagonists (LRTA), long-acting beta-adrenergic agonists (LAAAs), and inhaled glucocorticoids (ICS), as well as from analgesics; and antidiabetics, either alone or in combination.

Examples of long-acting muscarinic receptor antagonists (LADD) include, but are not limited to, aclidinium bromide, glycopyrronium salts such as, for example, glycopyrronium bromide, revefenacin, tiotropium, such as tiotropium bromide, umeclidinium bromide, oxitropium bromide, flutropium bromide, ipratropium bromide , trospium chloride, tolterodine.

Examples of long acting beta-adrenergic agonists (BAAp) include but are not limited to albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, indacaterol, indacaterol, isoetharine, isoprenal nom, levosalbutamol, mabuterol, meluadrin, metaproterenol, olodaterol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol, soterenot, sulfonterol, thiaramide, terbutaline, tolubuterol.

Examples of inhaled glucocorticoids (ICS) include, but are not limited to, prednisone, prednisone, butixocort propionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, etiprednol-dichlorocitate, deflazacort, etiprendol, loteprednol, RPR- 106541, NS-126, ST-26.

In addition, active pharmaceutical ingredients may be selected from analgesics such as opioid analgesics (eg morphine, fentanyl) or non-opioid analgesics (eg salicylic acid derivatives eg acetylsalicylic acid) or cannabinoids (eg tetrahydrocannabinol), antidiabetic agents such as insulin.

The medicinal liquid or liquid pharmaceutical composition which can be sprayed or aerosolized by means of the inhalation device of the present invention may contain at least one pharmaceutically active ingredient as described above, but may also contain a mixture of two or more active pharmaceutical ingredients which can be introduced into the body by inhalation.

A medical liquid or pharmaceutical composition that can be aerosolized by means of an inhalation device according to the present invention is preferably presented as a composition suitable or adapted for inhalation use, in other words, as a composition that can be nebulized or aerosolized for inhalation and which is physiologically acceptable for inhalation by the patient.

The medical fluid or pharmaceutical composition which may be administered by means of an inhalation device according to said aspect of the present invention or may be contained within the inhalation device and reservoir may be in the form of a dispersion, for example a suspension with a liquid continuous phase and a solid dispersed phase, or in the form of a solution.

In other embodiments of the invention, the medical fluid or pharmaceutical composition as described above may contain, optionally or in addition to one or more active pharmaceutical ingredients, one or more physiologically acceptable excipients suitable for inhalation use. Excipients that may be present in the composition may include, but are not limited to, one or more buffering agents for adjusting or controlling the pH of the solution, salts, flavoring agents, surfactants, lipids, antioxidants, and co-solvents that can be used to increase or improve solubility, such as ethanol, or glycol.

In specific embodiments of the invention, the medical fluid, as described above, may be substantially free of propellant.

In other specific embodiments of the invention, the medical fluid as described above may be an aqueous solution in which one or more of the active pharmaceutical ingredients described above are dissolved or solubilized in a carrier liquid solution containing water. Such aqueous solutions may optionally also contain one or more excipients as described above.

In a second aspect, the present invention also relates to a method for generating an aerosol from a medical fluid by means of an inhalation device as defined above. In order to avoid repetition, reference is made to the relevant explanations relating to such an inhalation device and its preferred embodiments and to medical fluids and preferred embodiments of the invention.

The method includes the following steps, which form the entire dosing cycle:

- In the filling phase, a negative gauge pressure is provided inside the pressure chamber by increasing its volume. Negative gauge pressure can, for example, be created by partially retracting the plunger and/or the hollow cylindrical part, depending on which of these parts is movable, away from the corresponding other part. The energy for this action is preferably provided by the aforementioned means for temporarily storing mechanical energy.

- Owing to said volume expansion and said negative gauge pressure, the injection chamber is filled with liquid, or more particularly medical liquid, from a reservoir with which it is in fluid communication. Preferably, the deformable bag can accommodate the liquid in such a way that an increase in the degree of emptying of the reservoir does not result in an increase in counter pressure within the reservoir.

- In the subsequent ejection phase, a positive gauge pressure is provided inside the pressurization chamber. It should be recalled that the pressurization chamber has said second cross section which is larger than the first cross section that the pressurization chamber/plunger has. As a result, said wall/piston is subjected to said positive pressure.

Positive gauge pressure causes the piston to propulsion. The higher the pressure, and the larger the second cross-sectional area, the higher the force that acts on the piston.

- Due to the mechanical interface between the piston and the injection unit, said movement is mechanically transmitted or transferred to the plunger or to the cylindrical part, depending on which of them is movable, so that the volume of the injection chamber is reduced. It should be recalled that the injection chamber has an internal space having said first cross section. As a result, a positive pressure is created in the interior of the injection chamber.

- Due to the increase in pressure in the discharge chamber, the medical fluid is ejected from the discharge chamber through a nozzle in which said liquid is finely atomized.

Due to the fact that the ratio of the second cross section, which has a pressurization chamber, to the first cross section, which has an interior space of the injection chamber, is greater than 1, the pressure in the injection chamber is increased relative to the pressure in the injection chamber in accordance with the specified ratio . As a result, a high rate of delivery of the finely atomized liquid and/or an increased duration of the aerosol ejection per actuation of the device (or per injection cycle) can be provided. In particular, a large amount of liquid can still be finely atomized within a fairly short period of time, for example, an amount of about 50 μl over a period of 1 s to 3 s.

In one embodiment of the invention, the pressure inside the pressure chamber is provided by opening the valve of the pressurized gas container.

Thus, in accordance with one embodiment of the invention, the pressure inside the pressurization chamber is maintained at a relatively constant level during the ejection phase. As a result, the pressure that is increased and transferred to the pressure chamber is also constant, resulting in a more constant volume flow of the fine atomized liquid from the nozzle.

In accordance with another embodiment of the invention, only at the beginning of the ejection phase is a brief ejection of pressurized gas into the pressurization chamber such that the pressure decreases as its volume increases.

In yet another embodiment of the invention, the pressure within the pressurization chamber is provided by manually pressurizing said pressurization chamber. As a result, pressure is built up before the ejection phase begins. Then, during the ejection phase, the pressure also decreases as its volume increases.

According to a preferred embodiment of the invention, after the liquid has been ejected from the pressure chamber, due to its volume reduction, the aforementioned temporary mechanical energy storage means, which was cocked during the ejection phase, releases the stored energy. By releasing said temporarily stored energy, the interior of the pressure chamber is enlarged again. This, in turn, leads to the creation of a negative gauge pressure in it, thus ensuring that the injection chamber is refilled with liquid from the reservoir.

In yet another embodiment of the invention, the energy required to "reset" the volume of the injection chamber is provided manually, i. by manually pushing the respective parts to their original position.

During said "return to the initial state" of the volume of the injection chamber, the volume of the injection chamber also returns to its original state (minimum) value. At the same time, the pressurized gas must be released from said chamber in such a way that said volume reduction is achieved with minimum effort; those. so that there is no need to resist high pressure to further compress the already pressurized gas. Therefore, in one embodiment of the invention, at the beginning of the refill phase, or between the ejection phase and the refill phase, the contents of the pressurization chamber are released from the device to the outside.

A valve may preferably be used for this purpose. It can be configured to open and close automatically as well as manually.

In a third aspect, the present invention relates to the use of an inhalation device according to the first aspect of the present invention for the inhalation administration of an aerosol medical fluid to an animal or human, preferably a human.

In a fourth aspect, the present invention relates to a method for treating, stabilizing, or preventing the onset of a pulmonary disease or condition (e.g., bronchial asthma or chronic obstructive pulmonary disease (COPD)) by inhalation administration of a medical fluid, wherein the medical fluid is generated and administered to the body via an inhalation device according to the first aspect of the present invention.

It should be noted that with respect to these aspects, all embodiments of the invention, preferred embodiments of the invention and combinations thereof, as described above with respect to the first and/or second aspect of the invention, are also applicable accordingly.

Brief description of the drawings

Further, the present invention is described using the attached drawings. In the present specification,

On FIG. 1 shows a schematic representation of some components of one embodiment of an inhalation device;

On FIG. 2 shows the device of FIG. 1 at the end of the filling phase;

On FIG. 3 shows the device of FIG. 1 during the ejection phase;

On FIG. 4 shows the device of FIG. 1 during the refill phase.

All drawings are not to scale and contain only selected components and are presented only at a level of detail sufficient to explain the present invention. It should be understood that additional components are necessary for a real working sample, which, however, are known to a person skilled in the art and are omitted in the present description for brevity.

On FIG. 1 shows a schematic representation of some of the components of one embodiment of an inhalation device.

Shown are the components of an inhalation device that serves to generate an aerosol. Inside the housing 1 is placed a reservoir 2 for storing liquid F. The reservoir 2 shown contains a deformable bag, which in turn contains a liquid F (liquid not shown). Further (below) the reservoir 2 in the direction of the fluid medium, an injection unit 3 is placed. The injection unit 3 is connected to a means 4 for supplying mechanical energy, which supplies said energy to the injection unit 3.

Farther (below) said injection unit 3 in the direction of the fluid is a nozzle 5. In the example shown, the nozzle 5 is an impact type nozzle.

As can be seen, the injection unit 3 comprises a hollow cylindrical part 3A and (in this case) a hollow plunger 3B. The hollow cylindrical part 3A is fixed and rigidly attached to the housing 1, and the plunger 3B is movable relative to the housing 1. In the embodiment shown, the piston 7 and the plunger 3B are movable in parallel directions, and in fact along collinear directions.

The cylindrical part 3A has an inner space 3C with a predetermined first cross section A1. The cross section A1 can be of any shape, but is preferably circular. The inner space 3C is configured to accommodate the upstream end section 3B' of said plunger 3B. In case the inner space 3C is large in width, only that part of the space 3C is taken into account which actually serves to accommodate the plunger 3B. The cylindrical portion 3A and the plunger 3B are linearly movable relative to each other so as to form an injection chamber. Due to the possibility of said linear movement, the injection chamber has a variable volume.

According to the present invention, the mechanical power supply means 4 is a pressurized gas as described above. The inhalation device comprises a pressurization chamber 6 having an internal volume for storing said pressurized gas. The wall of said pressurization chamber 6 is formed by a piston 7. Said piston 7 is capable of reciprocating linear movement (up and down in FIG.). The internal volume of the pressurization chamber 6 is related to the position of the piston, which in turn depends on the pressure inside the pressurization chamber. An increase in pressure results in a propulsive movement (in this case, upwards), and a decrease in pressure leads to a retropulsive movement (in this case, down).

Piston 7 is mechanically coupled with plunger 3B; in an embodiment of the invention not shown, it can instead or additionally be paired with the cylindrical part 3A. As can be seen, the piston 7 has a cross section A2 which is larger than the cross section A1 of the injection chamber. As a result, an increase in pressure is provided, that is, the pressure in the pressure chamber is higher than in the pressure chamber 6 by a factor determined by the increase factor or the ratio of the cross section A2 to the cross section A1.

In the embodiment shown, the pressurized gas is provided by a container 8 containing liquefied gas. Part of the gas is present in the gaseous state (above the level of the liquid part, depicted in black). The valve 9 separates the container 8 from the pressure chamber 6.

Another valve 10 is placed in the outlet channel of the pressurization chamber 6 . A non-return valve 11 is located upstream of the pressure chamber in the direction of the fluid medium in order to block a possible reverse flow of liquid towards the reservoir 2.

Means 12 are provided for temporarily storing mechanical energy, in this embodiment of the invention implemented by means of an elastic spring, which is configured to cock by means of a propulsive (in this case, upward) movement of the piston 7. The means 12 is located and configured to call, by releasing the stored energy, retropulsive (in this case, down) movement of the piston 7, which will be shown below.

In this and the following Figures, the same reference numbers are used to refer to the same parts. In the following Figs. some reference numbers have been omitted for a clearer understanding. And also in the future, the body 1 is not shown.

On FIG. 2 shows the state at the end of the filling phase in which the volumes of the pressure chamber and the pressure chamber are returned to their original state. The interior space 3C of the injection chamber is maximized because the plunger 3B is in its most retracted position with respect to the cylindrical portion 3A. The piston 7 is in its lowest position so that the volume of the pressurization chamber 6 is very small, or almost zero. Means 12 for temporary storage of mechanical energy is in the unclenched state and is ready to impart mechanical energy to it.

On FIG. 3 shows the ejection phase. The valve 9 is currently open, whereby the pressurized gas can flow from the container 8 into the pressure chamber 6. Piston 7 moves in the direction indicated by arrow 13 (in this case, upwards), transferring the force acting on it to plunger 3B. The liquid contained in the injection chamber is therefore ejected through the nozzle 5 under high pressure. Arrows 14 indicate two colliding liquid streams that result in the desired atomization. The means 12 is in a compressed state, thus temporarily storing mechanical energy.

On FIG. 4 shows the state during the refill phase. At this time, the valve 10 is open, whereby the pressurized gas can be released from the pressure chamber 6 . No new gas can flow into said chamber 6 because valve 9 is currently closed. A negative gauge pressure is created inside the pressure chamber, which leads to its refilling from reservoir 2. The flow direction is indicated by arrow 15.

The retropulsive movement of the piston, indicated by arrow 13, is carried out by the action of the means 12 for temporary storage of mechanical energy, which at the moment imparts its energy to the pressure unit 3, and more precisely, the piston 7, which is connected to the plunger 3B. Thanks to the check valve 11, the backflow of fluid from the outside into the hollow plunger 3B is prevented.

The movement of the piston 7 will end when it returns to its original position, which is shown in Fig. 2. The cycle ends and another cycle can start over.

List of reference positions

1 - body

2 - tank

3 - pressure block

3A - hollow cylindrical part

3V - plunger

3C - interior space

4 - means for supplying mechanical energy

5 - nozzle

6 - pressure chamber

7 piston

8 - container

9, 10 - valve

11 - check valve

12 - means for temporary storage of mechanical energy

13, 14, 15 - arrow

A1 - first cross section

A2 - second cross section

F is liquid.

The following list of numbered items are embodiments that the present invention includes:

1. An inhalation device for the formation of an aerosol from a liquid for medical purposes, containing:

housing (1), inside said housing (1) a reservoir (2) for storing said medical fluid, further than said reservoir (2) along the flow of the fluid, an injection unit (3) for creating pressure, connected to a means (4) for supplying a mechanical the energy of the specified injection unit (3), and then the specified injection unit (3) in the direction of the fluid nozzle (5);

moreover, the injection unit (3) contains a hollow cylindrical part (3A) and a plunger (3B), moreover, the cylindrical part (3A) has an internal space (3C) with a given first cross section (A1) made with the possibility of accommodating an end fluid located upstream section (3B') of the specified plunger (3B), wherein the specified cylindrical part (3A) and the specified plunger (3B) are made with the possibility of linear movement relative to each other so as to form an injection chamber having a variable volume,

different in that

means (4) for supplying mechanical energy is a pressurized gas, wherein the inhalation device comprises an injection pressure chamber (6) having an internal volume for storing said pressurized gas, wherein the wall of said injection pressure chamber (6) is formed piston (7) made with the possibility of reciprocating linear movement in such a way as to change the internal volume of the chamber (6) of the injected pressure, and the piston (7) is mechanically coupled with the plunger (3B) or with the cylindrical part (3A), and the piston ( 7) has a cross section (A2) that is larger than the cross section (A1) of the pressure chamber.

2. The inhalation device of claim 1, wherein the ratio is greater than 10.

3. The inhalation device according to claim 1 or 2, wherein the pressurized gas is provided by

- a container (8) filled with pressurized gas and/or liquefied gas, or

- a chamber configured to manually pressurize it and which is configured to temporarily store and release in a controlled manner said pressurized gas.

4. An inhalation device according to any one of 1 to 3, wherein the plunger (3B) is hollow.

5. An inhalation device according to any one of the preceding claims, wherein either

- the plunger (3B) is fixed and rigidly attached to the body (1) or to the nozzle (5), and the hollow cylindrical part (3A) is movable relative to the body (1) or nozzle (5), or

- the hollow cylindrical part (3A) is fixed and rigidly attached to the body (1) or to the nozzle (5), and the plunger (3B) is movable relative to the body (1) or nozzle (5).

6. An inhalation device according to any one of the preceding claims, wherein a check valve (11) is placed upstream of the pressure chamber in order to block the backflow of liquid towards the reservoir (2).

7. An inhalation device according to any one of the preceding claims, wherein a mechanical linkage mechanism is further provided to further increase the aforementioned ratio.

8. An inhalation device according to any one of the preceding claims, wherein means (12) for temporarily storing mechanical energy is provided, which is configured to be cocked by propulsion of the piston (7), and which is configured, by releasing the stored energy, to cause a retropulsive piston movement (7).

9. The inhalation device according to claim 8, wherein said means (12) for temporarily storing mechanical energy is an elastic spring, a gas spring, or a magnetic spring.

10. An inhalation device according to any of the preceding claims, wherein the nozzle (5) is an impact type nozzle and/or in which the volume of the injection chamber is at least 30 µl, or at least 50 µl, or from about 100 to 250 μl, respectively, and in which the injection unit (3) is configured to provide a pressure inside the injection chamber of at least 100 bar.

11. An inhalation device according to any one of the preceding claims, wherein (i) the piston (7) and (ii) the plunger (3B) and/or the cylindrical part (3A) are movable in parallel directions.

12. A method for generating an aerosol from a liquid by means of an inhalation device according to claim 1, the method comprising the following steps:

- in the filling phase, providing a negative gauge pressure inside the pressure chamber by increasing its volume and thus

- filling the injection chamber with liquid from the tank (2), due to the indicated negative gauge pressure;

- in the ejection phase, providing a positive gauge pressure inside the pressurization chamber (6) having said second cross section (A2) and thus

- the implementation of the movement of the piston (7);

- transmitting said movement mechanically to the plunger (3B) or cylindrical part (3A) in such a way that the volume of the pressure chamber is reduced and a positive pressure is created in its interior; and thus,

- ejection of medical fluid from the injection chamber through the nozzle (5);

while the pressure in the pressure chamber (6) is increased.

13. The method according to claim 11, in which the pressure inside the pressurization chamber (6) is provided by opening the valve (9) of the pressurized gas container (8) or by manually pressurizing said pressurization chamber (6).

14. The method according to claim 12 or 13, wherein, after ejection of the fluid from the injection chamber due to its volume reduction, the means (12) for temporarily storing mechanical energy, which was cocked during the ejection phase, releases the stored energy, thus again increasing the internal space the injection chamber, which results in the creation of a negative pressure in it, thus ensuring that the injection chamber is refilled with medical fluid from the reservoir (2).

15. The method according to any one of claims 12 to 14, wherein at the beginning of the refilling phase, the contents of the pressurization chamber (6) are released into the atmosphere.

Claims (36)

1. An inhalation device for the formation of an aerosol from a liquid for medical purposes, containing: housing (1), inside said housing (1) a reservoir (2) for storing said medical fluid, further than said reservoir (2) along the flow of the fluid, an injection unit (3) for creating pressure, connected to a means (4) for supplying a mechanical the energy of the specified injection unit (3), and then the specified injection unit (3) in the direction of the fluid nozzle (5); and the injection unit (3) contains a hollow cylindrical part (3A) and a plunger (3B), moreover, the cylindrical part (3A) has an internal space (3C) with a given first cross section (A1), made with the possibility of accommodating an end valve located upstream of the fluid section (3B') of the specified plunger (3B), wherein the specified cylindrical part (3A) and the specified plunger (3B) are made with the possibility of linear movement relative to each other so as to form an injection chamber having a variable volume, and means (4) for supplying mechanical energy is a pressurized gas, wherein the inhalation device comprises an injection pressure chamber (6) having an internal volume for storing said pressurized gas, the wall of said injection pressure chamber (6) being formed by a piston (7), made with the possibility of reciprocating linear movement in such a way as to change the internal volume of the pressure chamber (6), and the piston (7) is mechanically coupled with the plunger (3B) or with the cylindrical part (3A) of the injection unit (3), and the piston (7) has a cross section (A2) which is larger than the cross section (A1) of the pressure chamber. 2. The inhalation device according to claim 1, wherein the ratio of the cross section (A2) of the piston (7) to the cross section (A1) of the pressure chamber is more than 2. 3. An inhalation device according to claim 1 or 2, in which the ratio of the cross section (A2) of the piston to the cross section (A1) of the pressure chamber is more than 10. 4. The inhalation device according to claim 1 or 2, wherein the pressurized gas is provided by - a container (8) filled with pressurized gas and/or liquefied gas. 5. Inhalation device according to any one of paragraphs. 1-3, in which the plunger (3B) is hollow. 6. An inhalation device according to any one of the preceding claims, wherein - the hollow cylindrical part (3A) is fixed and rigidly attached to the body (1) or to the nozzle (5), and the plunger (3B) is movable relative to the body (1) or nozzle (5). 7. An inhalation device according to any one of the preceding claims, in which the check valve (11) is placed upstream of the pressure chamber in the direction of the fluid medium with the ability to block the return flow of liquid towards the reservoir (2). 8. An inhalation device according to any one of the preceding claims, further provided with a mechanical linkage mechanism. 9. An inhalation device according to any one of the preceding claims, wherein a means (12) for temporarily storing mechanical energy is provided, which is configured to be cocked by propulsion of the piston (7) and which is configured, by releasing the energy stored therein, to cause a retropulsive movement piston (7). 10. An inhalation device according to claim 9, wherein said means (12) for temporarily storing mechanical energy is a spring. 11. An inhalation device according to any one of the preceding claims, wherein the nozzle (5) is an impact type nozzle. 12. An inhalation device according to any one of the preceding claims, wherein the volume of the injection chamber is at least 30 µl, or at least 50 µl, or from 100 to 250 µl. 13. An inhalation device according to any one of the preceding claims, wherein the pressure unit (3) is configured to provide a pressure inside the pressure chamber of at least 100 bar. 14. An inhalation device according to any one of the preceding claims, wherein (i) piston (7) and (ii) the plunger (3B) is movable in parallel directions. 15. The method of formation of an aerosol from a liquid by means of an inhalation device according to any one of paragraphs. 1-14, and the method includes the following steps: - in the filling phase, providing a negative gauge pressure inside the pressure chamber by increasing its volume and thus - filling the injection chamber with liquid from the tank (2), due to the indicated negative gauge pressure; - in the ejection phase, providing a positive gauge pressure inside the pressurization chamber (6) having said second cross section (A2) and thus - the implementation of the movement of the piston (7); - transmitting said movement mechanically to the plunger (3B) in such a way that the volume of the discharge chamber is reduced and a positive pressure is created in its interior; and thus, - ejection of medical fluid from the injection chamber through the nozzle (5); while the pressure in the pressure chamber (6) is increased. 16. The method according to claim 15, wherein the pressure inside the pressure chamber (6) is provided by opening the valve (9) of the pressurized gas container (8). 17. The method according to claim 15 or 16, wherein, after ejection of liquid from the injection chamber due to its volume reduction, the means (12) for temporarily storing mechanical energy, which was cocked during the ejection phase, releases the stored energy, thus again increasing the internal space of the injection chamber. 18. The method according to any one of paragraphs. 15-17, in which, at the beginning of the refilling phase, the contents of the pressurization chamber (6) are released into the atmosphere. 19. The use of an inhalation device according to any one of paragraphs. 1-14 for inhalation administration of an aerosol medical fluid to an animal or human. 20. A method for treating, stabilizing or preventing the onset of a pulmonary disease or pathological condition by inhaling a medical fluid, wherein the medical fluid is formed and administered via an inhalation device according to any one of paragraphs. 1-14.