FIELD

[0001] The present specification is directed to metered dose inhalers, and in particular, a stem block for a metered dose inhaler.

BACKGROUND

[0002] Metered dose inhalers, such as the conventional asthma inhaler, are used to deliver aerosolized medicine to the lungs. Although they have been commercially available for decades, metered dose inhalers have remained largely unchanged since their inception.

[0003] Metered dose inhalers generally include a housing with mouthpiece and actuator, a canister that includes the medicine for delivery and a metering valve for dispensing a precise aliquot of the medicinal product. The conventional metered dose inhaler is actuated by depressing the top to release an aerosol from an angled mouthpiece at the bottom. This upside-down configuration avoids the use of a dip tube, which adds costs and prevents the user from accessing all of the medicinal product, however actuating the inhaler in this way can be difficult, particularly for users with small or weak hands.

[0004] Moreover, drug delivery with metered dose inhalers can be inefficient and inconsistent. Drug delivery with metered dose inhalers may be affected by particle size and distribution. Particles between 1 and 2 pm are likely to be deposited in the lungs, whereas particles larger than 8 or 9 pm are likely to deposit in the oropharyngeal region and be swallowed by the user. Drug delivery is further reduced by droplets which deposit on the user's tongue and soft palate.

[0005] The present disclosure provides a more user-friendly inhaler that is actuated in the upright orientation and demonstrates superior atomization efficiency.

SUMMARY [0006] An aspect of the specification provides a stem block for a pressurized metered dose inhaler. The stem block includes a stem passage sized and dimensioned to receive a hollow dispensing member. The stem block further includes an expansion chamber fluidly connected to the stem passage to receive an aerosol from the hollow dispensing member. The expansion chamber has an inner diameter narrower than the inner diameter of the stem passage. The stem block further includes an exit orifice fluidly connected to the expansion chamber for receiving the aerosol from the expansion chamber. The exit orifice has an inner diameter narrower than the inner diameter of the expansion chamber. The stem block further includes an outlet to receive the aerosol from the exit orifice and convey the aerosol from the stem block. The expansion chamber, the exit orifice, and the outlet are axially aligned.

[0007] The exit orifice may have an inner diameter between 0.25 and 0.6 mm. The inner diameter of the exit orifice may be 0.3 ±0.02 mm.

[0008] The exit orifice may have a length between 0.3 and 2 mm. The length of the exit orifice may be 1.0 ±0.2 mm

[0009] The outlet may be conical. A lower end of the outlet may connect to the exit orifice. An upper end, which conveys the aerosol from the stem block, may be wider than the lower end. The upper end may have an inner diameter between 3 and 7 mm. The outlet may include an outwardly curved edge. The outwardly curved edged may have a length of between 0.2 and 1.0 mm.

[0010] A further aspect of the specification provides a pressurized metered dose inhaler comprising the above-described stem block.

[0011] The pressurized metered dose inhaler may include a canister for storing a therapeutic formulation, and the stem block may be axially aligned with the canister.

[0012] These together with other aspects and advantages which will be subsequently apparent, reside in the details of construction and operation as more fully hereinafter described and claimed, reference being had to the accompanying drawings forming a part hereof, wherein like numerals refer to like parts throughout. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Embodiments are described with reference to the following figures.

[0014] Figure 1 is a perspective view of a metered dose inhaler according to one aspect of the invention.

[0015] Figure 2 is a longitudinal cross-section of the inhaler of Figure 1 including a stem block.

[0016] Figure 3 is an exploded view of the inhaler of Figure 1.

[0017] Figure 4 is a front perspective view of the stem block of Figure 2.

[0018] Figure 5 is a top view of the stem block of Figure 2.

[0019] Figure 6 is a bottom view of the stem block of Figure 2.

[0020] Figure 7 is a rear perspective view of the stem block of Figure 2.

[0021] Figure 8 is a side view of the stem block of Figure 2.

[0022] Figure 9 is a cross-section of a stem block according to the prior art.

[0023] Figure 10 is a cross-section of the stem block of Figure 2.

[0024] Figure 11A is a cross-section of another stem block.

[0025] Figure 11 B is a cross-section of another stem block

[0026] Figure 12A is a cross-section of another stem block

[0027] Figure 12B is a cross-section of another stem block

[0028] Figure 13A is a cross-section of another stem block

[0029] Figure 13B is a cross-section of another stem block

[0030] Figure 14A is a perspective view of a valve assembly including the stem block of Figure 2.

[0031] Figure 14B is a perspective view of a housing for the valve assembly of Figure 11 A including a mouthpiece.

[0032] Figure 14C is a perspective view of the mouthpiece of Figure 11 B. [0033] Figure 14D is another perspective view of the housing of Figure 11 B.

[0034] Figure 14E is another perspective view of the valve assembly of Figure 11 A.

[0035] Figure 15 is a graph showing the relationship between melatonin and ethanol content according to one example.

[0036] Figure 16 is a graph showing the relationship between melatonin and ethanol content according to another example.

[0037] Figure 17 is a graph showing the relationship between melatonin and ethanol content according to another example.

[0038] Figure 18 is a graph showing the relationship between melatonin and ethanol content according to another example.

[0039] Figure 19A is a perspective view of a first metering valve with a dip tube according to the examples.

[0040] Figure 19B is a perspective view of a second metering valve without a dip tube according to the examples.

[0041] Figure 20A is a cross-sectional view of a prior art MDI at rest.

[0042] Figure 20B is a cross-sectional view of the prior art MDI of Figure 20A during use.

[0043] Figure 20C is a cross-sectional view of the prior art MDI of Figure 20A during use.

[0044] Figure 20D is a cross-sectional view of the prior art MDI of Figure 20A during use.

[0045] Figure 21 is a graph showing the relationship between cumulative undersize and upper aerodynamic diameter according to one example.

[0046] Figure 22 is a graph showing the relationship between cumulative undersize and upper aerodynamic diameter according to another example.

[0047] Figure 23 is a graph showing the relationship between cumulative drug mass and upper aerodynamic diameter according to another example. [0048] Figure 24 is a graph showing the relationship between cumulative drug mass and upper aerodynamic diameter according to another example.

[0049] Figure 25 is a graph showing the relationship between cumulative drug mass and upper aerodynamic diameter according to another example.

[0050] Figure 26 is a graph showing the relationship between cumulative drug mass and upper aerodynamic diameter according to another example.

[0051] Figure 27 is a graph showing the relationship between cumulative drug mass and upper aerodynamic diameter according to another example.

[0052] Figure 28 is a graph showing the relationship between cumulative drug mass and upper aerodynamic diameter according to another example.

[0053] Figure 39 is a graph showing the relationship between cumulative drug mass and upper aerodynamic diameter according to another example.

[0054] Figure 30 is a graph showing the relationship between cumulative drug mass and upper aerodynamic diameter according to another example.

[0055] Figure 31 is a graph showing the relationship between cumulative drug mass and upper aerodynamic diameter according to another example.

[0056] Figure 32 is a graph showing the relationship between mean cumulative mass undersize and upper aerodynamic particle diameter according to another example.

[0057] Figure 33 is a graph showing the results of Figure 32 where the mean cumulative mass undersize is represented as a percentage.

[0058] Figure 34 is a graph showing the relationship between mean fine particle fraction and mean estimated orifice diameter according to another example.

DETAILED DESCRIPTION

TABLE OF ABBREVIATIONS

[0059]

DEFINITIONS

[0060] “About” herein refers to a range of +/- 20% of the numerical value that follows. In one embodiment, the term “about” refers to a range of +/- 10% of the numerical value that follows. In one embodiment, the term “abouf refers to a range of +/- 5% of the numerical value that follows.

[0061] “Metered dose inhaler” is used interchangeably with “inhaler” herein to describe a device that delivers a measured amount of a pressurized therapeutic formulation for inhalation by a subject.

INHALERAND STEM BLOCK FOR INHALER

[0062] A metered dose inhaler (MDI) fired in the upright orientation was described in US patent application number PCT/CA/2020/051331 (the contents of which are incorporated in their entity herein) which provided an inhaler with a mouthpiece at the top and buttons at the side. When actuated, the side buttons cause an aerosol to be released from the inhaler. Although user-friendly, this design failed to perform to the standards of the conventional metered dose inhaler.

[0063] In one aspect, the present disclosure provides an improved stem block for the inhaler of PCT/CA/2020/051331. The stem block demonstrates atomization efficiency that is superior to the performance of a conventional metered dose inhaler.

[0064] Figure 1 illustrates an exemplary metered dose inhaler 100 for dispensing a therapeutic formulation from a canister as an aerosol (also referred to herein as an “aerosolized therapeutic formulation”). The metered dose inhaler 100 comprises a housing 104 with a mouthpiece 108. In comparison with the mouthpiece of PCT/CA/2020/051331, the present disclosure provides a shorter and wider mouthpiece that does not interfere with the plumes emitted by the inhaler. The presently described mouthpiece 108 is sized and shaped to conform to the user’s mouth without interfering with the exit path of the aerosol. The housing 104 is hollow, in order to receive a pressurized canister of a therapeutic formulation. In some examples, the mouthpiece 108 is integral to the housing 104. In further examples, at least the mouthpiece 108 ora bottom end cap 110 is removable from the housing 104 for insertion of the therapeutic formulation. The housing 104 further includes one or more actuation buttons 114, which, when activated, cause the metered dose inhaler 100 to dispense a pre-determined amount of the therapeutic formulation. In particular examples, the pre-determined amount is between 25 and 100 pl.

[0065] A longitudinal cross-section of the metered dose inhaler 100 is shown in Figure 2. The housing 104 is configured to receive the canister 200, which stores the therapeutic formulation. The process of filling the canister 200 with a volume of therapeutic formulation, may be conducted at a pressure higher than atmospheric pressure, such that the therapeutic formulation is pressurized. The metered dose inhaler 100 further includes two actuation buttons 114 operably connected to engagement protrusions 206 to depress a stem block 208. The stem block 208 sits on the canister 200 which includes a metering valve assembly. When the actuation buttons 114 are activated or pressed laterally or perpendicular to axis A of the metered dose inhaler 100, the stem block 208 activates the metering valve assembly and releases the therapeutic formulation out of the mouthpiece 108 of the metered dose inhaler 100.

[0066] Canister 200 may include a dip tube 209 for conveying the therapeutic formulation from the canister 200 to a metering valve assembly, which includes a hollow dispensing member or valve stem 204. The end of the dip tube 209 may be weighted so that gravity directs the weighted end into the therapeutic formulation, even when the metered dose inhaler 100 is held at an angle. The weighted end may reduce the likelihood that the dip tube conveys gas phase towards the valve stem 204. The metering valve assembly is mounted so as to allow the valve stem 204 to slide relative to the canister 200 between an extended position, to which the valve stem is guided by a biasing mechanism (not shown) in the valve assembly, and a depressed position. Movement of the valve stem 204 from the extended position to the depressed position results in a dose of the therapeutic formulation being dispensed from the canister 200.

[0067] The stem block 208 is configured to engage both the engagement protrusions 206 of the actuation buttons 114 and the valve stem 204 of the canister.

[0068] In the extended position of the valve stem 204, the pressurized therapeutic formulation in the canister 200 is placed in fluid communication with the metering chamber through the valve stem 204 so that the metering chamber is filled with pressurized therapeutic formulation.

[0069] When the valve stem 204 is depressed, the pressurized therapeutic formulation in the metering chamber is isolated from the canister 200 and placed in fluid communication with the external environment through the mouthpiece 108 via the stem block 208. Thus, the volume of pressurized therapeutic formulation in the metering chamber (which includes a metered amount of the therapeutic formulation) is discharged into the external environment via the valve stem 204, then the stem block 208 and ultimately the mouthpiece 108. The user inhales the contents of the mouthpiece 108, thus delivering the aerosolized therapeutic formulation into the user’s lungs.

[0070] The stem block 208 may be distanced from the mouthpiece 108. The distance between the stem block 208 and the mouthpiece 108 may be selected to control the momentum of the droplets as the droplets enter the user’s oropharyngeal region. At lower speeds, oropharyngeal deposition is less likely.

[0071] Deposition may also be reduced by selecting suitable dimensions for the mouthpiece 108. Mouthpieces with larger inner diameters can reduce the speed of the droplets exiting the mouthpiece 108, while mouthpieces with narrower inner diameters can interfere with the movement of the plume. Similarly, mouthpieces with longer lengths can interfere with the movement of the plume. The distance from the stem block 208 to an upper end 210 of the mouthpiece 108 may be about 21 to 22mm when the stem block 208 is in the extended position. When the stem block 208 is in the depressed position, the distance may be about 22.5 to 23.5 mm.

[0072] The stem block 208 of the present disclosure is suitable for use in inhalers where the canister 200 is axially aligned with the mouthpiece. In contrast, traditional inhalers include a mouthpiece which is angled away from the longitudinal axis of the canister. Weakness or stiffness in the fingers and hands, particularly in individuals with arthritis and hand size impacts the ability to use traditional metered dose inhalers.

[0073] Figure 3 shows an exploded view of the inhaler. The actuation mechanism includes two actuation buttons 114 each having a button face that is contact surface for the user's digit, a stem block engagement element shown as engagement protrusions 206, and an elongated resilience or spring member 304, which can be flexible plastic member, a flexible metal member, a metal coil, a plastic coil, or the like. The actuation button 114 can be of unitary construction or formed from two or more components, for example, the stem block engagement element and resilience or spring member can be a single piece thereby providing for the use of a different material for the button face. In some embodiments, the stem block engagement element is an engagement protrusion 206.

[0074] The resilience or spring member 304 is operatively attached to the actuation button 114 and the engagement protrusion 206 to return the button and the engagement protrusion 206 to their resting positions after release. At a first end, the resilience or spring member 304 is contiguous with or connected to the engagement protrusions 206. The second end of the resilience or spring member 304 is attached either to a band 308 as illustrated in Figure 3 or a holder for the canister 200. [0075] The engagement protrusions 206, are shaped so that when the button is pressed, the engagement protrusion 206 moves along the stem block 208, thereby pushing the stem block down.

[0076] The housing 104 includes openings 312 for the actuation buttons 114. The openings 312 for the actuation buttons 114 are generally in diametrically opposite locations or on opposite sides of the housing 104. The size and configuration of the openings 312 is generally dependent on size and configuration of the actuation buttons 114. Optionally, when inserted into the housing 104, the actuation button 114 surfaces are flush with the surface of the housing 104.

[0077] In other examples, the openings 312 in the housing and the actuation buttons 114 can be replaced with pre-formed actuation buttons that are part of the housing 104. The perimeter or edges of each of the buttons being configured to be resiliently flexible so that after the buttons are pressed and released, they return to their starting position.

[0078] The mouthpiece 108 may be covered with a mouthpiece cover 324. The mouthpiece 108 and bottom end cap 110 may be threadably connected or snapped to the housing 104. The mouthpiece 108 may include a seal 328 for sealing the mouthpiece to a mouthpiece cover.

[0079] The mouthpiece 108 is connected to the housing 104 and the actuation buttons 114 and associated mechanism are placed inside the housing 104. The stem block 208 is connected to the metered canister and together they are inserted into the housing and held in place by a bottom end cap 110, which is removably attached to the housing 104.

[0080] In other examples, the canister 200 is inserted into a holder (not shown) which is then inserted into the housing.

[0081] The canister 200 may be replaceable by the user such that the inhaler can be reused after the therapeutic formulation in the canister 200 is depleted. Once the canister 200 is spent, the user may remove the empty canister from the housing 104 and replace the empty canister with a full canister.

[0082] During use, when pressing the actuation buttons 114 simultaneously, engagement protrusions 206 will move along the top surfaces of the stem block 208 at a predetermined angle to cause the valve stem 204 to travel from the extended position to the depressed position along the longitudinal axis A of the metered dose inhaler 100 which activates the metered-dose canister valve. After one activated spray has been performed, a valve spring (not shown) will return the stem block 208 to the extended position. The actuation buttons 114 retur to their original predetermined position once the pressure is removed from the actuation buttons 114.

[0083] The linear internal design and configuration of the stem block 208 coupled in linear fluid communication with the valve stem 204 permits the pressurized therapeutic formulation from the canister 200 to exit from the mouthpiece 108 of the metered dose inhaler 100 in a linear direction along longitudinal axis C of the stem block 208.

[0084] Figures 4-8 show the external geometry of the stem block 208. As shown in Figure 4, the stem block 208 may include an outlet 404 for directing the aerosol towards the mouthpiece 108. The outlet 404 may be conical, however , the outlet 404 is not particularly limited. As shown in Figure 6, the stem block 208 further includes an inlet 604 for receiving the hollow dispensing member or valve stem 204. The stem block 208 may comprise any suitable material such as aluminum, a polymer, or the like. In specific examples, the stem block 208 comprises acrylonitrile butadiene styrene (Lavergne: Montreal, Canada).

[0085] Figure 9 shows a cross-section of a prior art stem block 900 as disclosed in US patent application entitled “INHALER” having application number PCT/CA/2020/051331, filed 2 October 2020, which is incorporated by reference herein. The stem block 900 includes a valve stem passage 904 sized to receive the hollow dispensing member or valve stem 204 of a metered dose valve. The valve stem passage 904 is fluidly connected to a narrower dispensing passage 908. The lower end of dispensing passage 908 has a width that is narrower than the upper end of valve stem passage 904 to form a ledge 912 at the intersection of the valve stem passage 904 and dispensing passage 908 to prevent upward axial movement of the stem valve into the valve stem passage 904. In this example, the dispensing passage 908 narrows before expanding into the outlet 916.

[0086] A particular embodiment of the stem block 208 is shown at 208a in Figure 10. Figure 10 is a cross-section of the stem block 208a of Figure 8 at plane B. The stem block 208a includes a valve stem passage 1002 sized and dimensioned to receive the hollow dispensing member or valve stem 204 of a metered dose valve through a lower end of the valve stem passage 1002. The valve stem passage 1002 has a diameter that is wider or equally as wide as the outer diameter of the valve stem 204. A close fit between the valve stem passage 1002 and the corresponding valve stem 204 may prevent leakage of the aerosol between the valve stem and the valve stem passage 1002. In one example, the close fit between the valve stem passage 1002 and the corresponding valve stem 204 is about 0.1mm.

[0087] A narrower sump cavity or expansion chamber 1004 is fluidly connected to the valve stem passage 1002 at an upper end, opposite the inlet 604. The lower end of expansion chamber 1004 has a diameter that is narrower than the upper end of valve stem passage 1002 to form a first ledge portion 1006 at the intersection of the valve stem passage 1002 and the expansion chamber 1004. The first ledge portion 1006 is configured to contact an upper end of the valve stem 204 to prevent upward axial movement of the valve stem 204 into the expansion chamber 1004. Therefore, the inner diameter of the expansion chamber 1004 is smaller than the outer diameter of the valve stem 204. In the example shown in Figure 10, the expansion chamber is 1.5 ±0.2 mm in length and the diameter is 1.85 ±0.2 mm, however the dimensions are not particularly limited. The length of the expansion chamber 1004 may be between 0mm and 10mm. In particular non-limiting examples, the length of the expansion chamber 1004 is between 0.1 mm and 7 mm. In further non-limiting example, the length of the expansion chamber 1004 is between 1 mm and 2 mm. The diameter of the expansion chamber 1004 may be between 0.5 mm and 3 mm. In particular non-limiting examples, the diameter of the expansion chamber 1004 is between 1.5 mm and 2.5 mm.

[0088] When the valve stem 204 is inserted into the valve stem passage 1002, the valve stem 204 is fluidly connected with the expansion chamber 1004. In some examples, the inner diameter of the expansion chamber 1004 is approximately the same as the inner diameter of the valve stem 204. When the valve assembly is actuated, the expansion chamber 1004 receives the therapeutic formulation from the valve stem 204. Due to propellant evaporation, the therapeutic formulation atomizes within the expansion chamber 1004 to form discrete droplets.

[0089] In the example shown, the walls of the expansion chamber are straight and parallel with the longitudinal axis C, however, in other non-limiting examples, the walls of the expansion chamber are angled. In yet further non-limiting examples, the walls of the expansion chamber are curved. In further non-limiting examples, the upper end of the expansion chamber 1004 curves inwardly.

[0090] An exit orifice 1008 is fluidly connected to the expansion chamber 1004 at an upper end, opposite the valve stem passage 1002. The lower end of the exit orifice 1008 has a diameter that is narrower than the upper end of the expansion chamber 1004 to form a second ledge portion 1010 at the intersection of the expansion chamber 1004 and the exit orifice 1008. The walls of the expansion chamber 1004 may meet the second ledge portion 1010 at about 90°. The second ledge portion 1006 encourages recirculation of the droplets within the expansion chamber 1004, causing the droplets to deform into aerosol particles. Therefore, the dimensions of the exit orifice 1008 are selected to control the fine particle fraction of the aerosol dispensed from the metered dose inhaler 100. Generally, the length of the exit orifice 1008 is between 0.5 mm and 1.5 mm, however in non-limiting examples, the length of the exit orifice 1008 is between 0.3 ±0.02 mm and 2 ±0.2 mm. In a further non-limiting example, the length of the exit orifice 1008 is 1 ±0.05 mm. In a further non-limiting example, the length of the exit orifice 1008 is 0.65 ±0.05mm. The diameter of the exit orifice 1008 may be selected according to the therapeutic formulation. The diameter of the exit orifice 1008 is between 0.05 mm and 0.75 mm. In specific non-limiting examples, the diameter for the exit orifice 1008 is between 0.25 mm and 0.6 mm. In further specific non-limiting examples, the diameter of the exit orifice 1008 is between 0.3 and 0.45 mm.

[0091] In the embodiment shown in Figure 10, the exit orifice 1008 is 1 ±0.2 mm long and 0.3 ±0.02 mm in diameter, however the exit orifice 1008 is not particularly limited. As shown in Figure 10, the inner diameter of the exit orifice 1008 may be consistent along its length, however in other examples, the inner diameter of the exit orifice 1008 varies along its length.

[0092] The exit orifice 1008 receives the aerosol from the expansion chamber 1004 and conveys the aerosol through the outlet 404. The lower end of the outlet 404 is fluidly connected to an upper end of the exit orifice 1008, opposite the expansion chamber 1004. At the lower end of the outlet 404, the outlet 404 has the same inner diameter as the upper end of the exit orifice 1008. At the upper end of the outlet 404 which connects to the outside of the stem block 208, the inner diameter of the outlet 404 is wider than the inner diameter of the exit orifice 1008. In the example shown in Figure 10, the upper end of the outlet 404 is 5 ±0.2 mm in diameter, however the outlet 404 is not particularly limited. In other examples, the upper end of the outlet 404 is between 3 and 7 mm in diameter. The walls of the outlet 404 may range from about 30 degrees to about 60 degrees from the longitudinal axis C. In the example shown in Figure 10, the walls of the outlet 404 are angled at 50 ± 2 degrees from the longitudinal axis. The upper end of the outlet 404 may include an outwardly curved edge 1014 to improve performance. The length of the outwardly curved edge 1014 may measure between 0.2 mm and 1.0 mm. In the example shown in Figure 10, the length of the outwardly curved edge 1014 is 0.5 ±0.1 mm. The outlet 404 conveys the aerosol from the stem block 208. The outlet 404 may further direct the aerosol towards the mouthpiece 108 and into the user’s lungs.

[0093] Each of the valve stem passage 1002, the expansion chamber 1004, the exit orifice 1008, and the outlet 404, are axially aligned. As shown in Figure 10, the valve stem passage 1002, expansion chamber 1004, exit orifice 1008 and outlet 404 share a common longitudinal axis: axis C. Furthermore, the stem block 208 may be axially aligned with the inhaler 100 when the valve stem 204 is inserted into the valve stem passage 1002 during use. In particular examples, when the stem block 208 is in use, the axis A of inhaler 100 corresponds with axis C of the stem block 208. In these examples, the valve stem passage 1002, the expansion chamber 1004, the exit orifice 1008, and the outlet 404, are axially aligned with the valve stem 204 and the canister 200.

[0094] The stem block 208a may comprise any suitable material including, but not limited to, metal, metal alloy, polymer, resin, and combinations thereof. In particular nonlimiting examples, the stem block 208a comprises a synthetic polymer. Generally, the material is capable of manufacturing at high tolerances in order to achieve the dimensions described herein. It may be advantageous to select a material with a smooth surface finish. [0095] In examples where stem block 208a comprises a polymer, the stem block 208a may be manufactured by injection molding. The stem block 208a overcomes several of the limitations of injection molding of MDIs. Because valve stem passage 1002, expansion chamber 1004, exit orifice 1008, and outlet 404, are axially aligned, exit orifice 1008 may be any length and the stem block 208a may include undercuts. Furthermore, the inner surface of the stem block 208a can be smoother, particularly the transition from the expansion chamber 1004 to the outlet 404.

[0096] In view of the above, it will now be apparent that variant, combinations, and subsets of the foregoing embodiments are contemplated. For example, variations in the shape and dimensions of the stem block 208a are contemplated. Non-limiting examples of the stem block 208b 208c, 208d, 208e, 208f, 208g are shown in Figures 11 A, 11 B, 12A, 12B, 13A, and 13B respectively. The stem blocks 208a, 208b 208c, 208d, 208e, 208f, 208g are generically referred to herein as “stem block 208” or collectively as “stem blocks 208”.

[0097] Figure 11 A and Figure 11 B show the stem blocks 208b and 208c respectively.

The stem block 208a and 208b differ in the diameter of exit orifice 1008.

[0098] Figure 12A and Figure 12B show the stem blocks 208d and 208e, respectively. The stem blocks 208d and 208e do not include the outlet 404, and the aerosol exits the stem blocks 208d, 208e directly from the exit orifice 1008. Additionally, the expansion chamber 1004 of the stem blocks 208d and 208e is conically shaped. The expansion chamber 1004 narrows gradually along its length such that the diameter of the expansion chamber 1004 is equal to the diameter of the exit orifice 1008, where the expansion chamber 1004 connects to the exit orifice. Thus, the stem blocks 208d and 208e do not include the second ledge portion 1010. In the examples shown in Figures 12A and 12B, the expansion chamber 1004 has a convex cone shape, however expansion chamber 1004 is not particularly limited. In other examples, expansion chamber 1004 has a concave cone shape. In yet other examples, expansion chamber 1004 may have a straight cone shape. The stem blocks 208d and 208e differ in the length of expansion chamber 1004 and the length and diameter of the exit orifice 1008.

[0099] Figure 13A and Figure 13B show stem blocks 208f and 208g, respectively. The stem blocks 208f and 208g include expansion chambers 1004 that are conical and outlets 404 that are conical. In these examples, both the expansion chambers 1004 and the outlets 404 are convexly conical, however the stem block 208 is not particularly limited. The expansion chamber 1004 may be cylindrical, conical, convexly conical, or concavely conical. The outlet 404 (if present) may be straight conical, convexly conical, or concavely conical. The stem blocks 208f and 208g differ in the length and diameter of the exit orifice 1008.

[00100] While the stem block 208 has been described as a distinct component of the metered dose inhaler 100, it should be understood that other variations are contemplated. In specific non-limiting examples, the stem block 208 is integral with housing 104. In other non-limiting embodiments, the stem block 208 is integral to mouthpiece 108. In yet other embodiments, the stem block 208 is integral to actuation button 114.

[00101] The stem block 208 provides a number of improvements over prior art metered dose inhalers (MDIs) such as the conventional asthma inhaler.

[00102] The stem block 208 is suitable for use in an upright orientation with actuator buttons at the side, instead of at the bottom end. This configuration is easier for users to handle, particularly users with small or weak hands, although other users will naturally benefit from the convenience.

[00103] Because the inhaler is easier to manipulate, drug delivery is improved. Metered dose inhalers must be held in a particular orientation during use to ensure that the aerosol is directed towards the oropharyngeal region. Even slight deviations in the angle will cause the aerosol to impact and deposit on the soft palate or tongue. Therefore, an upright inhaler, which is easier to manipulate, will improve the likelihood that the aerosol is delivered to the lungs.

[00104] The stem block 208 overcomes the performance limitations of an upright MDL Inhalers fired “valve up” (with a dip tube) are generally considered less reliable than conventional “valve down” inhalers (without a dip tube). The stem block 208 improves the performance of an upright metered dose inhaler so that drug delivery is superior to a conventional inhaler. As described in the examples below, droplet size and distribution for the stem block 208 meets or exceeds that of a conventional inhaler. [00105] The stem block 208a can also lessen the environmental impact of MDIs by redudng plastic waste. Prior art inhaler devices, as shown in Figures 20A to 20D, are entirely disposed after the formulation is depleted. In contrast, the housing 104 of inhaler 100 can be re-used by inserting a new canister, induding a valve and the stem block 208. This reduces the material consumed in manufacturing MDIs, fuel burned in shipping replacement MDIs, and waste disposal.

[00106] Lastly, the axial alignment of the stem block 208 reduces the occurrence of dogs in the MDL As compared with conventional actuators in which the expansion chamber and the exit orifice are substantially perpendicular, the stem block 208 is axially aligned, which reduces opportunities for the formulation to accumulate within the stem block 208.

EXAMPLES

1. Equipment & Materials

[00107] The equipment and materials used to generate the data presented in this report are listed below.

[00108] Equipment: a. Mettler Toledo™ Analytical Balances: XP205, XS204, AT261, XS802S b. Pamasol™ P2016 Laboratory Plant Crimp and Propellant Filler c. Pamasol™ P2002 Aerosol Filler and Crimper System d. Agilent™ 1100 Series HPLC, G1322A Degasser, G1311A QuatPump, G1313AALS, G1316A COI, G1314AVWD e. Copley Sdentific™ Next Generation Impactors f. MSP™ NGI Leak Tester g. MSP™ NGI Gentle Rocker 4515 h. Copley Sdentific™ HPC5 Pumps

I. Copley Sdentific™ TPK2000 Flow Regulator j. Copley Scientific™ DMF 2000 Mass Flow Meter k. ELGA PureLab® Prime, PureLab Ultra Genetic Water system

I. Decon™ FS400b Ultrasonic Bath m. Vindon Scientific™ Temperature and Humidity Controlled Stability Cabinet n. GenLab™ MINI50/TDIG Temperature Controlled Stability Cabinet o. Metrohm™ 684 KF Coulometer

P- Rainin™ EDP3-Plus Analytical pipettes

[00109] Materials: a. Melatonin, batch: SLBZ6359 (Sigma®: Gillingham, England) b. Bedomethasone dipropionate (BDP), Batch OZID004 c. Budesonide, Batch OZID007 d. Chromasolv™ Methanol (99.9%) (Honeywell: Charlotte, North Carolina, USA) e. Ethanol, batch 314763 and batch 21 J204140 (Scientific Laboratory

Supplies Ltd.™: Nottingham, United Kingdom) f. Purified Water, prepared using Elga PureLab® Ultra system g. Zephex® HFA 134a, Batch RB20610-3 (Koura: San Luis Potosi, Mexico) h. Zephex® HFA 152a, UN1030 (Koura : San Luis Potosi, Mexico)

[00110] Metered Dose Inhaler (MDI) Hardware: a. Actuators i. Stem Block 208a: Bespak™ 0.30 mm actuator (ID 277), Batch

BK0486487 (North Lynn Industrial Estate, England), 1.0 mm length ii. Conventional actuator: Presspart™ 0.30 mm actuator (ID 290), Batch PPT0027735 (Blackbum, United Kingdom), 0.65 mm length b. Valves: i. Bespak™ 50 pl valve for upright use with dip tube, batch BK0760388 (ID: 333 & 346), batch BK0880753 (ID: 364) (North Lynn Industrial Estate, United Kingdom) ii. Bespak™ 50 pl valve for inverted use with glass bottle (ID: 320), Batch BK0642138 (North Lynn Industrial Estate, United Kingdom) ii. Aptar™ 50 pl valve for inverted use, Batch BE-ECHPI-ASS-2021- 66-V1 (ID:330) and Batch SE23-383 (Milton Keynes, United Kingdom) c. Canister: i. Presspart™ C0128-FEP 19 ml canister, Batch PPB0008265 (ID: 240 & 248) (Blackbum, United Kingdom) d. Glass bottle: i. St Gobain™ Type III Glass, 15 ml aerosol tube, batch 711175 (ID:

2) (Leicestershire, United Kingdom)

[00111] The examples described herein further include stem block 208a, as described according to the present specification and shown in Figures 14A to 14E. The stem block 208a used in the examples was manufactured by Presspart™ (Blackbum, United Kingdom). The stem block 208a can be attached to a canister 200 and metering valve with a 3.16mm valve stem diameter as shown in Figures 14A and 14E. To facilitate actuation of the MDI, a housing 104 was fabricated to allow the base of the MDI to be pushed inwards when each dose is fired. The housing 104 includes a mouthpiece 108 as shown in Figures 14B and 14C. In the example shown in Figures 14A to 14E, the exit orifice 1008 of the stem block 208a has an orifice diameter of 0.30 mm and a length of 1 mm. The length of the expansion chamber 1004 is 1.5 mm.

2 Methodology

[00112] All manufacturing tolerances were within 2 percent by mass of target.

[00113] Drug residual measurements (total can content) was determined following storage at 40°C and 75% relative humidity.

[00114] Drug delivery was determined in accordance with the United States Pharmacopeia (USP). Drug delivery metrics (metered dose, delivered dose, fine particle dose/fraction, mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD)) were determined using a Next Generation Impactor (NGI) and dose uniformity sampling apparatus (DUSA). Sampling flow rate was 30 L/min for both NGI and DUSA measurements and data processing was performed using CITDAS V3.10 Software (Copley Scientific™: Colwick, United Kingdom).

[00115] Melatonin, Bedomethasone dipropionate (BDP), and Budesonide content within test samples was determined by reverse phase high pressure liquid chromatography (HPLC) with single wavelength ultraviolet detection on an Agilent™ 1100 system running Empower 3 Chromatography Software (Waters, UK).

[00116] HPLC assays were established, and system suitability confirmed. A summary of the routine assays used for analyzing test samples is given in Table 1 (Melatonin), Table 2 (BDP), and Table 3 (Budesonide).

Table 3: Budesonide Routine Assay Summary

3 Determination of Solubllity/Mlsclbllity (Ethanol Selection)

[00117] Solubility of each drug was evaluated in mixtures were investigated in HFA152a and HFA134a propellant.

3.1 Quantitative Solubility of Melatonin and Excipients in Ethanol/HFA152a134a propellent

[00118] Supersaturated melatonin formulations were prepared in HFA 152a containing either 0%, 5%, 8%, 10% or 15% w/w ethanol. The upper solubility limit of melatonin was determined by filtering the supersaturated solutions through 0.2pm PTFE filters (see Table 4) and quantifying test samples by HPLC.

[00119] Data was obtained at 5°C (see Figure 15 and Figure 16) and T = 20°C (see Figure 17 and Figure 18) and presented as % w/w, μg/50pl and μg/63pl (see also Table 4).

Table 4: Concentration of Melatonin in filtered supersaturated HFA152a solutions

[00120] The data presented in Table 4 and Figure 17 show that 5% w/w ethanol in HFA 152a is suitable for delivering 100 μg of melatonin using either a 50 pl or 63 pl valve. However, a 63 pl dose volume or 6% w/w ethanol is preferrable to ensure solubility is maintained at low temperatures (121 μg melatonin per 63 pl of dose volume was observed for 5% w/w ethanol at 5 °C, see Table 4).

[00121] Likewise, 8% w/w ethanol in HFA 152a is shown to deliver 200 μg of melatonin in either a 50-pl or 63-pl dose volume (see Table 4). Increasing ethanol further increases the ability to solubilize melatonin, however, increasing ethanol content decreases drug delivery performance, as described later in Example 1.

[00122] Figure 15 is a graph showing melatonin solubility in ethanol-based HFA 152a formulations at 5 °C.

[00123] Figure 16 is a graph showing melatonin solubility in ethanol-based HFA 152a formulations at 5 °C.

[00124] Figure 17 is a graph showing melatonin solubility in ethanol-based HFA 152a formulations 20 °C.

[00125] Figure 18 is a graph showing melatonin solubility n ethanol-based HFA 152a formulations at 20 °C.

[00126] When packaged in glass bottles, 100μg/50pl (6% w/w ethanol in HFA 152a) and 200μg/50pl (8% w/w ethanol in HFA 152a) were observed to be dear solutions at 5°C.

3.2 Visual Solubility of BDP and Budesonide HFA 152 Formulations [00127] With regards to the propellant HFA 152a, this report compares the performance of the stem block 208a using 100μg/50pl BDP in 6%w/w ethanol and 100μg/50pl budesonide in 8%w/w ethanol.

[00128] Solubility was confirmed visually (at 5°C and 20°C) by packaging each formulation within glass bottles.

3.3 Visual Solubility of Melatonin, BDP& Budesonide HFA 134a Formulations

[00129] This report also presents the drug delivery performance of the stem block 208a when used with the propellant HFA 134a.

[00130] Formulations were prepared containing 100μg/50pl of either Melatonin, BDP or Budesonide in 12% w/w ethanol and HFA 134a. Solubility was confirmed visually (at T = 5°C and T = 20°C) by packaging each formulation within glass bottles.

[00131] Solubility was confirmed visually (at T = 5°C and T = 20°C) for 50μg/50pl melatonin in 5% ethanol and HFA 134a.

3.4 Drug Delivery: Melatonin, BDPand Budesonide Formulations

[00132] Four studies are presented herein. Section 4.1 demonstrates the drug delivery performance of 100μg & 500μg melatonin using HFA 152a as the propellant in a conventional actuator for an MDL Section 4.2 compares “valve up” and “valve down" actuation. Section 4.3 demonstrates the performance of melatonin, BDP, and Budesonide at a concentration of 100μg/50pl using HFA 152a as the propellant.

Sections 4.4-4.6 demonstrate the performance of melatonin, BDP, and budesonide at a concentration of 100μg/50pl using HFA 134a as the propellant. Section 4.7 demonstrates the performance of melatonin at a concentration of 50μg/50pl in 5%w/w ethanol with HFA 134a as the propellant.

[00133] Figure 19A is a perspective view showing a first metering valve 1904 with a dip tube 1906 and Figure 19B is a perspective view showing a second metering valve 1908 without a dip tube. At 1904, a Bespak™ 50pl metering valve is shown with the dip tube 1906 for “valve up” use. At 1908, an Aptar™ 50pl metering valve without a dip tube is shown for “valve down” use. Metered dose inhalers (MDIs) are conventionally actuated in an upright (or “valve down”) orientation using a metering valve that lacks a dip tube, such as the metering valve 1908 shown in Figure 19B. The stem block 208a can be used for inverted (or “valve up") actuation using metering valve 1904 fitted with dip tube 1906.

[00134] The metering chamber filling sequence for a conventional actuator 2000 with no dip tube is presented in Figures 20A to 20D. Figure 20A shows the conventional actuator 2000 at rest. Figure 20B shows the canister 200 being pushed into the housing 2004 causing a dose of therapeutic formulation 2008 to be dispensed from the conventional actuator 2000. In Figure 20C, the metering chamber is empty. Figure 20D shows the canister 200 being released and the chamber refilling in response. It is possible to fire the conventional actuator 2000 in any orientation, however, the conventional actuator 2000 must be in the correct (“valve down”) orientation when the chamber refills for the next dose. In other words, the metering chamber must refill from the liquid phase of the canister.

[00135] In Sections 4.1 , 4.2 and 4.3, each inhaler was fired in the intended orientation: “valve down when fitted with metering valve 1908 (Aptar™, without dip tubes); “valve up” when fitted with metering valve 1904 (Bespak™ valves with dip tube 1906).

[00136] In Sections 4.4-4.S, where necessary, the tested MDI was rotated to the “filling” orientation after actuation but prior to releasing the valve to its rest position (see Figure 17). Thus, in Sections 4.4-4.S it was possible to determine the drug delivery performance of the conventional actuator 2000 fired “valve down”, and “valve up”.

4 RESULTS

4.1 Performance of 100pg & 500pg Melatonin with Conventional Actuator

[00137] Melatonin loading of 100μg/50pl and 500μg/50pl was achieved. Both formulations were confirmed visually to be soluble formulations at 4'C and 20°C.

[00138] Melatonin drug delivery data is presented in Table 5, Figure 21, and Figure 22 for 100μg/50pl melatonin (5%w/w Ethanol) and 500μg/50pl melatonin (15%w/w Ethanol) using HFA 152a as the propellant. The formulations were delivered using the conventional actuator 2000 (Bespak™, 0.3 mm). [00139] Metered dose values are close to target; 103 ± 4μg and 499 ± 5μg respectively. Fine particle dose <5 pm Aerodynamic diameter (FPD) for the 100μg formulation was 51 ± 1 μg; and Fine Particle Fraction <5pm Aerodynamic diameter (FPF) = 55 ± 2%.

[00140] Ethanol was increased to 15% w/w to maintain the melatonin in solution when the dosage was increased to 500μg/50pl. The increase of ethanol to 15% w/w had the consequence of reducing atomization efficiency; the fine particle dose for the 500μg formulation was 125 ± 5μg; FPF = 28 ± 1%.

[00141] The MMAD was dependent upon the concentration of non-volatile within the formulation. The MMAD was 1.4 ± 0.1 pm for the 100μg/50pl formulation and 2.3 ± 0.1 pm for the 500μg/50pl formulation.

Table 5: Melatonin Delivery from 100μg/50pl (5%w/w Ethanol) and 500pg/50pl (15%w/w Ethanol) HFA 152a using the conventional actuator (0.30 mm)

[00142] Figure 21 is a graph showing the cumulative undersize (μg) for melatonin delivery. 2104 indicates 100μg/50pl melatonin (5%w/w ethanol) and 2108 indicates 500μg/50pl melatonin (15%w/w ethanol). HFA 152a was the propellant. Both formulations were delivered with the conventional actuator 2000 (n = 3, Mean ± standard Deviation).

[00143] Figure 22 is a graph showing the cumulative undersize (%) for melatonin delivery. 2204 indicates 100μg/50pl melatonin (5%w/w Ethanol) and 2208 indicates 500μg/50pl melatonin (15%w/w ethanol). In both formulations, HFA 152a was the propellant (n = 3, Mean ± standard deviation).

4.2 “Valve Up” Orientation vs. “Valve Down" Orientation

[00144] A comparison was conducted between the conventional actuator 2000 (100μg) fired “valve down" (no dip tube), the conventional actuator 2000 (100μg) with dip tube 1906 fired “valve up”, the stem block 208a and housing 104 (100μg) fired “valve up" (with dip tube 1906), and the stem block 208a and housing 104 (200μg) fired “valve up” (with dip tube 1906).

[00145] Results obtained are summarized in Table 6, Figure 23 and Figure 24.

[00146] Table 6 shows that the dip tube 1906 added to the conventional actuator 2000 (as indicated at B) decreases performance of the inhaler as compared to the conventional actuator 2000 without a dip tube. Although MMAD was not affected by the dip tube 1906, metered dose, delivered dose, fine particle dose, and fine particle fraction were significantly reduced by adding the dip tube 1906 to the conventional actuator 2000. Despite including the dip tube 1906 , the stem block 208a performed better than the conventional actuator 2000.

Table 6: Melatonin 152a MDIs: effect of actuation orientation

[00147] Figure 23 is a graph showing the cumulative undersize (%) for melatonin delivery. The formulation comprised 100μg/50pl melatonin with 5%w/w ethanol with HFA 152a as the propellant. Line 2304 indicates the performance of the conventional actuator 2000 with metering valve 1908 (“valve down”), line 2308 indicates the performance of the conventional actuator 2000 with metering valve 1904 (“valve up"), and line 2312 indicates the performance of the stem block 208a (Valve up) (n = 3, Mean ± standard Deviation).

[00148] Figure 24 is a graph showing the cumulative undersize (μg) for melatonin delivery. The formulation comprised 100μg/50pl melatonin with 5%w/w ethanol with HFA 152a as the propellant. Line 2404 indicates the performance of the conventional actuator 2000 with metering valve 1908 (“valve down”), line 2408 indicates the performance of the conventional actuator 2000 with metering valve 1904 (“valve up”), and line 2412 indicates the performance of the stem block 208a (“valve up”) (n = 3, mean ± standard deviation).

[00149] The metered dose determined for 100μg/50pl melatonin (6%w/w ethanol) when actuated with the conventional actuator 2000 was close to target or 98 ± 2 μg. Fine particle dose <5pm aerodynamic diameter (FPD) was 40 ± 2 μg; and fine particle fraction <5pm aerodynamic diameter (FPF) was observed to be 50 ± 3%.

[00150] When the metering valve 1908 was replaced with metering valve 1904 (Bespak™ with dip tube 1906) to allow for “valve up” actuation through the conventional actuator 2000 (0.30mm), metered dose, FPD and FPF reduced to 88 ± 7 μg, 31 ± 4 μg and 43 ± 1% respectively. However, when fired through the stem block 208a, the metered dose returned to 103 ± 7 μg, and surprisingly, FPD and FPD was superior; 50 ± 6 μg and 55 ± 2%.

[00151] Increasing the melatonin dose to 200μg/50pl (8%w/w ethanol) in HFA 152a resulted in drug delivery performance being maintained if the stem block 208a was utilized; metered dose = 208 ± 12μg, FPD = 99 ± 6μg; FPF = 53 ± 2%.

[00152] Particle size distributions were consistent for all MDIs, as shown in Figure 24. MMAD was 1.4 - 1 ,6pm.

4.3 Melatonin, BDP & Budesonide 152a Using Stem Block 208a

[00153] Extended data is provided to include beclomethasone dipropionate (BDP) and budesonide formulated using propellant HFA 152a.

[00154] All inhalers were formulated to deliver 10Oμg of the active ingredient (melatonin, BDP, or budesonide). Solubility of these formulations was previously presented in Section 3.2. Budesonide required additional ethanol (compared with melatonin and BDP) in order to obtain a formulation with a 100μg/50pl dose level.

[00155] Each inhaler was fitted with the fmetering valve 1904 (Bespak™ , with dip tube [906] and fired “valve up” through the stem block 208a and housing 104.

[00156] The results obtained in Section 4.3 are summarized in Table 7.

Table 7: HFA 152a MDIs: Drug Delivery from Melatonin, BDP and Budesonide MDIs

[00157] The higher content of ethanol within the budesonide formulation resulted in a lower fine particle dose (48 ±1 μg) compared to the melatonin (55 ± 2 μg) and BDP (56 t 2μg), however partide size distribution was consistent for all three active ingredients. The mean MMAD was 1.3-1 ,5pm, as shown in Table 7 and Figure 26.

[00158] Figure 25 is a graph showing the cumulative undersize (%) for 100μg/50pl melatonin in 5% w/w ethanol (indicated at 2504), 100μg/50pl BDP in 5% w/w ethanol (indicated at 2508), and 100μg/50pl budesonide in 8% w/w ethanol (indicated at 2512). The propellant was H FA 152a. The actuator was the stem block 208a (n = 3, Mean ± standard deviation).

[00159] Figure 26 is graph showing the cumulative undersize (μg) for 100μg/50pl melatonin in 5% w/w ethanol (indicated at 2304), 100μg/50pl BDP in 5% w/w ethanol (indicated at 2608), and 100μg/50pl budesonide in 8% w/w ethanol (indicated at 2612). The propellant was HFA 152a. The actuator was the stem block 208a (n = 3, Mean ± standard Deviation). 4.4 Melatonin, BDP and Budesonide 134a Using the Stem Block 208a

[00160] These examples extend the data set to include formulations with the propellant HFA 134a.

[00161] All formulations were formulated to deliver 100μg of active material (melatonin, BDP or budesonide) in 12%w/w ethanol with HFA 134a as the propellant. Solubility of these formulations was presented in Section 3.3.

[00162] The results were evaluated for various combinations of actuator, valve, and actuation orientation.

[00163] Study 4a: Metering valve 1908 (Aptar™, without dip tube) fired “valve up” and “valve down" with the conventional actuator 2000, compared to metering valve 1904 (Bespak™ with dip tube 1906) fired “valve up” with either a conventional actuator 2000 or the stem block 208a.

[00164] Study 4b: Metering valve 1908 (Aptar™, without dip tube) fired “valve up” through the conventional actuator 2000.

[00165] Study 4c: metering valve 1904 (Bespak™ with dip tube 1906) and fired “valve up” through the stem block 208a and housing 104.

[00166] In Studies 4a and 4b, where necessary, the respective inhaler is rotated into the “filling” orientation after actuation/dosing, as shown in Figure 20C, but prior to releasing the valve to its rest position. This process allows the evaluation of drug delivery performance from the conventional actuator 2000 without a dip tube that is fired “valve up” (i.e., non-conventionally).

4.5 Melatonin Delivery for Conventional Actuators and Stem Block

[00167] Table 8 and Figure 27 presents melatonin delivery data with HFA 134a for (A) the conventional actuator 2000 fired “valve down”; (B) the conventional actuator 2000 fired “valve up"; (C) the conventional actuator 2000 with dip tube 1906 fired “valve up”; and (D) the stem block 208a with dip tube 1906 fired “valve up”.

[00168] Melatonin delivered in the “valve up" orientation using the stem block 208a is observed to be at least as efficient as delivery from the conventional actuator 2000, as shown in Table 8. Table 8 shows that the FPD from A, B, C and D was 37 ± 1 , 36 ± 3, 33 ± 2, and 37 ± 1 respectively.

[00169] Partide size distributions for all MDIs were similar and the MMAD for all MDIs was 1.2-1 ,3pm.

[00170] Table 8 shows that the dip tube 1906 added to the conventional actuator 2000 (C) decreases performance of the inhaler as compared to a conventional actuator 2000 without the dip tube 1906 either fired valve up (B) or valve down (A). Although MMAD was not affected by the dip tube 1906, metered dose, delivered dose, fine partide dose, and fine partide fraction were significantly reduced by adding the dip tube 1906 to the conventional actuator. Despite having the dip tube 1906, the stem block 208a performed just as well or better than the conventional actuator.

Table 8: HFA 134a: Melatonin delivery from valves fired upright & inverted (each orientation ± dip tube)

[00171] Figure 27 is a graph showing the cumulative mass undersize (μg) for A (indicated at 2704), B at (indicated at 2708), C (indicated at 2712), and D (indicated at 2716).

4.6 Conventional Actuator versus Stem Block (Melatonin, BDP & Budesonide)

[00172] The data presented in Table 9 and Table 10 further extends the data set to include alternative molecules; Bedomethasone Dipropionate (BDP) and Budesonide formulated using the propellant HFA 134a. Solubility for these formulations was confirmed in Section 3.3.

[00173] All formulations contained 12% w/w ethanol with HFA 134a as the propellant. The MDIs were fired “valve up”. Table 9 shows the results for the Presspart™ 0.30mm conventional actuator 2000 and Table 10 shows the results for the stem block 208a.

[00174] Consistent drug delivery data was observed for the three molecules evaluated (melatonin, BDP and budesonide). Mean metered dose values were consistent between both actuator types (94-97μg). However, the mean delivered dose was lower for the conventional actuator 2000 (79-84μg) than for the stem block 208a and housing 104 (86 - 87 μg). The mean fine particle dose observed was 36-37μg for the conventional actuator 2000 and 37-39μg when delivered using the stem block 208a .

[00175] Particle size distributions were consistent (MMAD = 1.1 - 1.3μm) for all measurements (see Figure 28 and Figure 29).

Table 9: Presspart™ Conventional Actuator (Melatonin, BDP and Budesonide)

[00176] Figure 28 is a graph showing the cumulative undersize (μg) for melatonin (indicated at 2804), BDP at (indicated at 2808) and budesonide at (indicated at 2812). The concentration of the active ingredient in each formulation was 100μg/50pL The concentration of ethanol was 12% w/w. The propellant was HFA 134a. The actuator was the Conventional Actuator 2000 (Presspart™, 0.30mm) (n = 3, Mean ± standard Deviation).

Table 10: Stem Block (Melatonin, BDP and Budesonide)

[00177] Figure 29 is a graph showing drug delivery using the stem block 208a. The cumulative undersize (μg) for melatonin is indicated at line 2904, BDP is indicated at line 2908, and budesonide is indicated at line 2912. The concentration of the active ingredient in each formulation was 100μg/50μl. The concentration of ethanol was 12% w/w. The propellant was HFA 134a (n = 3, Mean ± standard Deviation).

4.7 Performance of Melatonin 50pg/50μl (5%w/w ethanol)

[00178] Section 4.7 extends the data set to include MDIs 50μg/50pl Melatonin formulated with “low” 5%w/w ethanol content using the propellant HFA 134a. The solubility for this formulation is confirmed in Section 3.3.

[00179] Section 4.3 compares the drug delivery for the conventional actuator 2000 to the metering valve 1904 fitted with the dip tube 1906 valve fired “valve up” through the stem block 208a.

[00180] Results obtained in Section 4.7 are summarized in Table 11, Figure 30 and Figure 31.

[00181] As shown in Figure 30, the particle size distributions (%) are similar for the conventional actuator 2000 and the stem block 208a (MMAD = 1.0 - 1.1 pm).

[00182] A fine particle fraction of 62 ± 4% was obtained from the conventional actuator 2000 compared with 67 ± 1% from the stem block 208a.

[00183] The FPD observed for the stem block 208a (FPD = 28 ± 1 μg) was at least as good as when using the conventional actuator 2000 (FPD = 26 ± 1 μg).

Table 11: HFA 134a MDIs: Drug Delivery from Melatonin with 5%w/w Ethanol

[00184] Figure 30 is a graph showing the cumulative undersize (%) for 50μg/pl melatonin in 5% w/w ethanol delivered using HFA 134a as the propellant. Delivery with the conventional actuator 2000 (“valve down”) is indicated at line 3004 and delivery with the stem block 208a (“valve up”) is indicated at line 3008 (n = 3, Mean ± standard Deviation).

[00185] Figure 31 is a graph showing the cumulative undersize (μg) for 50μg/pl melatonin in 5% w/w ethanol delivered using HFA 134a as the propellant. Delivery with the conventional actuator 2000 (“valve down”) is indicated at line 3104 and delivery with the stem block 208a (“valve up”) is indicated at line 3108 (n = 3, Mean ± standard Deviation).

4.8 Stability

[00186] MDI solution formulations containing 100μg/50pl melatonin in 6% w/w ethanol using HFA 152a as the propellant were evaluated for stability in Presspart™ 14ml canisters: plain aluminum or plasma surface treated. Each canister type was packaged with metering valve 1908 (Aptar™, 50pl) (MDI batches OZ211003/RJ/A and OZ211003/RJ/C) and metering valves 1904 (Bespak™ 50pl, with dip tube 1906) (MDI batches OZ211003/RJ/B and OZ211003/RJ/D).

[00187] Table 12 presents melatonin residual following 0-month, 1 -month and 3- month storage at 40°C and 75% relative humidity for MDIs stored either “valve up” or “valve down”.

[00188] The initial time point residual data was 97.5 ± 1.7% of the target formulation.

[00189] Residual melatonin at 1 -month was 96-98% for all packaging and storage conditions.

[00190] For inhalers stored “valve up”, residual melatonin at 3-month for both canister types were 100% when packaged with metering valve 1908 (Aptar™) and 98% when packaged with metering valve 1904 (Bespak™ with dip tube 1906). For MDIs stored “valve down”, residual melatonin at 3-month ranged from 93% to 96%.

5 Drug Delivery From Stem Blocks and Conventional Actuator: BDP Metered Dose Inhalers

5.1 Equipment and Materials

[00191] In Section 5, stem block 208a having exit orifice 1008 with a 0.30 mm diameter and a 1mm length was compared with stem blocks 208b, 208c, 208d, 208e, 208f, 208g. Two of each stem blocks 208b, 208c, 208d, 208e, 208f, 208g were tested. Each of the stem blocks 208 was outfitted with a housing 104 and canister 200 as shown in Figures 14A to Figure 14E and fired in a “valve up" orientation.

[00192] The diameter of the exit orifice 1008 for each stem block 208 was estimated by visual evaluation. Artifacts such as depth of focus may lead to deviation of the estimated diameters with respect to the true value, however the estimated values provide a useful general guide when comparing against the nominal target diameters of each design. The estimated diameter of stem block 208a (0.28mm) compares well with the nominal target value (0.30 mm). The estimated diameters of the exit orifices 1008 are shown below in Table 13:

Table 13: Estimated external orifice diameters for stem blocks 208

5.2 Methodology

[00193] BDP concentrates were prepared in ethanol and added by mass to cut edge aluminum canisters (Presspart™). Valves were crimped to the canisters using a Pamasol™ P2002 Crimper.

[00194] Propellant HFA 152a was filled to weight through the valve using a Pamasol™ P2016 laboratory Plant. Final compositions were calculated as %(w/w). All manufacturing tolerances were within 2% by mass of target.

[00195] The final composition of MDI batch OZ230808/DIL/A is presented in Table 14.

Table 14: BDP 100pg/50pl, Ethanol (10%w/w), HFA 152a Formulation (MDI Batch OZ230808/DIL/A)

[00196] Drug delivery was determined in accordance with the United States Pharmacopeia (USP). Drug delivery metrics (metered dose, delivered dose, fine particle dose/fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD)), were determined using a Next Generation Impactor (NGI).

[00197] Sampling flow rate was 30l/min for all NGI measurements and data processing was performed using CITDAS V3.10 Software (Copley Scientific, UK). Inhalers were primed before use by firing five shots to waste before performing drug delivery measurements.

[00198] Bedomethasone Dipropionate (BDP) content within test samples was determined by reverse phase high pressure liquid chromatography (HPLC) with single wavelength ultraviolet detection on an Agilent™ 1100 system running Empower 3 Chromatography Software (Waters, UK).

[00199] HPLC assays were established, and system suitability confirmed. A summary of the routine assays used for analysing test samples is given in Table 15.

Table 15: Beclomethasone Dipropionate (BDP) Routine Assay Summary

5.3 Visual Solubility

[00200] Formulations were confirmed visually to be homogenous solutions, by packaging the formulation within glass bottles, and storing at 5°C for 7 days.

5.4 Drug Delivery

[00201] Drug delivery data and summary drug delivery characterization metrics of data presented in this report are provided herein.

[00202] Conventional actuators 2000 are actuated in a valve down orientation using valves without dip tubes, as shown in Figure 19B at 1908. Stem block 208 is intended to be used for inhalers in the “valve up” orientation using an inhaler including the dip tube 1906 as shown in Figure 19A at 1904.

[00203] All drug delivery data presented in this section utilized the first metering valve 1904 with the dip tube 1906; all inhalers were fired in the valve up orientation.

[00204] The metrics evaluated in this section are defined as follow:

[00205] Metered Dose = Mass of BDP per dose ex-valve

[00206] Delivered Dose = Mass of BDP per dose ex-device

[00207] Fine Particle Dose (FPD) = Mass of BDP per dose associated with particles with an Aerodynamic diameter less than 5pm.

[00208] Fine Particle Fraction (FPF) = FPD / Delivered Dose x 100%

[00209] Mass Median Aerodynamic Diameter (MMAD) = The aerodynamic diameter that divides the cumulative undersize by half.

[00210] Geometric Standard Deviation (GSD) = exp(o), where o is the standard deviation of the natural logarithms of data that have a lognormal distribution

[00211] Drug delivery metrics obtained for each stem block investigated are summarized in Table 16, Figure 32 (cumulative undersize, μg) and Figure 33 (cumulative undersize, %). Stem blocks 208b, 208c, 208d, 208e, 208f, 208g were evaluated with Canister 1 from MDI batch OZ230808/DIL/A. Replicates of the stem blocks 208b, 208c, 208d, 208e, 208f, 208g were evaluated with Canister 2 from MDI batch OZ230808/DIL/A. Likewise, data was collected on two separate conventional actuators 2000 (Presspart™) using Canisters 1 & 2 from MDI batch OZ230808/DIL/A.

[00212] For stem block 208a (only one stem block piece), repeat data was collected using canisters 1 & 2 from MDI batch OZ230808/DIL/A.

[00213] Figure 32 shows the mean cumulative mass undersize (μg) vs. upper aerodynamic particle diameter (pm). The results for stem block 208a are indicated at line 3401; results for conventional actuator 2000 are indicated at line 3402; results for stem block 208b are indicated at line 3403; results for stem block 208f are indicated at line 3404; results for stem block 208d are indicated at line 3405; results for stem block 208c are indicated at line 3406; results for stem block 208g are indicated at line 3407; and results for stem block 208e are indicated at line 3408.

[00214] Figure 33 shows the mean cumulative mass undersize (%) versus upper aerodynamic particle diameter (pm).

[00215] The results for stem block 208a are indicated at line 3501; results for conventional actuator 2000 are indicated at line 3502; results for stem block 208b are indicated at line 3503; results for stem block 208f are indicated at line 3504; results for stem block 208d are indicated at line 3505; results for stem block 208c are indicated at line 3406; results for stem block 208g are indicated at line 3507; and results for stem block 208e are indicated at line 3508.

5.5 Comparison With Section 4.3 Results

[00216] Comparison of BDP 100μg/50pl HFA 152a MDI delivery with previously reported data is given in Table 17. All MDIs were formulated to deliver 100μg/50pl of BDP. Each MDI was fitted with a Bespak™ valve (with the dip tube 1906) and fired valve up through stem block 208a and housing 104.

[00217] Increasing the ethanol content from 6%w/w to 10%w/w results in a decrease in fine particle dose from 49 ± 2 μg to 39μg. Demonstrating excellent delivery efficiency for the stem block 208a over the ethanol content range investigated. No change in particle size distribution was observed; MMAD = 1.3pm.

Table 17: HFA 152a MDIs: Drug Delivery BDP 100pg/50pl, Actuated Valve up (Original Feather Stem block )

[00218] Figure 34 shows the mean fine particle fraction (FPF) each of the stem blocks 208. In the graph shown in Figure circle 3602 represents stem block 208a, circle 3603 represents stem block 208b, circle 3604 represents stem block 208c, circle 3605 represents stem block 208d, circle 3606 represents stem block 208e, circle 3607 represents stem block 208e, circle 3608 represents stem block 208f, and circle 3609 represents stem block 208g. The line of best fit 3601 has the formula y = 90.671 e ^{-2 748x} , with R ² = 0.8619. [00219] The trend for drug delivery efficiency for stem blocks 208 with smaller orifice diameters is evident.

6 CONCLUSIONS

[00220] Metered dose inhalers (MDIs) are conventionally atomized “valve down” using valves that do not have dip tubes. This report demonstrates that stem block 208 allows for the actuation of an inhaler with a dip tube in the “valve up” orientation without loss of drug delivery performance. Furthermore, drug delivery has been demonstrated for three different molecules (melatonin, BDP and budesonide) to be at least equivalent to that of MDIs using conventional MDI hardware and conventional actuators in the conventional “valve down” orientation. Having regards to metered dose, delivered dose, fine particle dose/fraction less than 5pm aerodynamic diameter and particle size distribution of the therapeutic dose; drug delivery using the stem block is at least equivalent (and superior in some examples) to the conventional actuators.

[00221] Section 4.2 demonstrates the delivery of a formulation containing 100μg/50pl melatonin, 6% w/w ethanol and HFA 152a. When actuated conventionally in the “valve down” orientation using the conventional actuator 2000 having a 0.30mm exit orifice, the fine particle dose (FPD) observed was 40 ± 2μg. When the same formulation was fired “valve up” with the metering valve 1904, dip tube 1906, and the conventional actuator 2000, the FPD dropped to 31 ± 4μg. Replacing the conventional actuator 2000 with the stem block 208a increased the FPD to 50 ± 6μg.

[00222] In the above-described examples, the performance of the stem block 208a is demonstrated using formulations including the propellant HFA 134a in addition to formulations including the environmentally sensitive propellant HFA 152a. In particular, the disclosed formulation comprising a low global warming potential HFA 152a is of considerable interest due to the recent changes in quotas that regulate the supply of F- Gases such as HFA 134a. This report demonstrates that formulations comprising HFA 152a are suitable for delivering a therapeutically effective dose of melatonin. Such formulations may be suitable for treating conditions such as insomnia, narcolepsy and other sleep disorders. Administering therapeutic agents by inhalation may induce a more rapid physiological response than administration by ingestion. It is anticipated that, active agents such as melatonin, cannabidiol, caffeine, or nicotine will enter the systemic blood stream within about 15 seconds of inhalation, thus avoiding first pass metabolism by the kidneys and liver as would be encountered by an orally administered drug.

[00223] The many features and advantages of the invention are apparent from the detailed specification and, thus, it is intended by the appended claims to cover all such features and advantages of the invention that fall within the true spirit and scope of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation illustrated and described, and accordingly all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.