WO2025252974A1

WO2025252974A1 - Dry powder inhaler with a mixing element

Info

Publication number: WO2025252974A1
Application number: PCT/EP2025/065842
Authority: WO
Inventors: Caelan ANDERSON; Wei Ann YONG; Lelio CEREDA
Original assignee: Vectura Delivery Devices Ltd
Current assignee: Vectura Delivery Devices Ltd
Priority date: 2024-06-07
Filing date: 2025-06-06
Publication date: 2025-12-11
Anticipated expiration: 2026-12-07

Abstract

The present invention provides a dry powder inhaler comprising: one or more doses of powdered medication; an outlet through which a user may inhale a dose of medication; an airway, and a mixing element located in the airway When a user inhales on the outlet, medication is entrained in an air flow and flows through the airway and out through the outlet. The mixing element is in the form of three generally orthogonal generally circular discs with a common centre.

Description

Dry powder inhaler with a mixing element

Technical Field of the invention

The present invention relates to a dry powder inhaler for oral or nasal delivery of medication in powdered form, in particular an inhaler having a mixing element for deagglomerating aerosolized powder into fine particles.

Background to the invention

Inhalers that have a dispersion chamber containing one or more balls for deagglomerating powder are known, e.g. from W02009/092434. US 2004/0118399 describes an inhaler with a dispersion chamber that contains one or more spherical beads. When the user inhales, air carrying the powder is drawn into the dispersion chamber via a tangential inlet. The air causes the beads to circulate rapidly around in the chamber, which disperses the powder. The air and powder then move out of the chamber through a mouthpiece for inhalation by the user. The inhaler may have openings for bypass air that moves generally parallel to the cylindrical sidewalls of the mouthpiece. This bypass air is said to form a sheath around the powder-laden air and hence to help to reduce deposition of powder. US2022/401358 describes inhalers in which a capsule or reservoir contains a freely movable mixing element for helping to disperse the particles. The mixing element may alternatively be freely movable in a chamber in the flow channel of an inhaler. Many different shapes for the mixing element are shown. DE102014017065 discloses an inhaler with a deagglomerator located inside the powder container (e.g. a blister). The deagglomerator may have various shapes. However, these mixing elements / deagglomerators are not optimal for deagglomerating powder and / or are quite difficult shapes to manufacture.

Brief Description of the invention

The present inventors have found that some or all of these drawbacks can be addressed by providing a mixing element in the form of three generally orthogonal, generally circular discs with a common centre, i.e. a three-dimensional cruciform shape within a generally spherical envelope. Accordingly, the present invention provides a dry powder inhaler comprising:

• one or more doses of powdered medication;

• an outlet through which a user may inhale a dose of medication;

• an airway;

• a mixing element located in the airway; wherein, when a user inhales on the outlet to create an air flow, medication is entrained in the air flow and carried through the airway and out through the outlet; characterised in that the mixing element is in the form of three generally orthogonal, generally circular discs with a common centre.

The mixing element is suitable for manufacture by injection moulding, and preferably is formed by injection moulding.

The three discs are preferably arranged orthogonally, i.e. at 90° to each other. However, it is not necessary that they are exactly orthogonal to each other, for example they could be arranged such that they are at an angle of from about 75° to about 105° to each other.

The three discs are preferably circular. However, it is not necessary that they are exactly circular. The radius of the discs (i.e. the radius of the generally spherical envelope of the mixing element) is preferably from 1 to 5mm, such as from 2 to 4mm, for example around 3mm. The discs preferably all have the same radius. However, it is not necessary that they have exactly the same radius, for example they could have different radii within these ranges.

The thickness of each disc is preferably from 0.3 to 0.8mm, such as 0.4 to 0.7mm, for example 0.5 to 0.6mm. The three circular discs are not necessarily exactly planar. The discs may taper from the centre to the edge, for example they may taper from a thickness of around 0.6mm near the centre to around 0.5mm at the edge. The taper helps to ensure that the mixing element can be removed from the mould at the end of the injection moulding process.

The airway may comprise a deagglomeration chamber, and the mixing element may be located inside the deagglomeration chamber. The deagglomeration chamber has a powder inlet channel through which powder-containing air from the blister enters the deagglomeration chamber. The deagglomeration chamber may have one or more bypass inlet channels through which external, powder-free air enters the deagglomeration chamber. The powder inlet channel and/or the bypass inlet channel(s) may be tangential to the wall of the deagglomeration chamber, so that the air flow(s) into the chamber create a vortex. Thus, the deagglomeration chamber may be a vortex chamber.

The inhaler may comprise a cover that holds and protects the inhaler. The cover may cover the outlet when the inhaler is located in the cover. The outlet may be exposed when the inhaler is removed from the cover. The outlet may be a mouthpiece or a nosepiece.

The dose may be contained in a blister comprising a base and a lid, and the inhaler may comprise a piercer for piercing the lid of the blister. The inhaler may comprise a first housing part comprising the outlet and the piercer, and a second housing part comprising the blister, wherein the first and second housing parts are movable relative to each other. The first and second housing parts may be pushed together as the inhaler is removed from the cover, causing the piercer to pierce the lid of the blister.

Alternatively, the dose may be contained in a capsule and the opening mechanism may comprise a pair of needles for piercing the capsule.

The dose of the powdered medication may be 5-300 mg, preferably 20-200 mg, more preferably 30-150 mg, even more preferably 40-100 mg.

The powdered medication may contain a non-steroidal anti-inflammatory drug (NSAID), preferably, a salicylate, most preferably acetylsalicylic acid or a pharmaceutically acceptable salt thereof. Alternatively, the powdered medication may contain a bronchodilator; adrenaline and/or atropine; glucose and/or glucagon; benzodiazepine, phenytoin or anti-seizure medications; dihydroergotamine; naloxone; insulin; or a vaccine.

Brief Description of the Figures

Figure 1 shows an inhaler according to the invention.

Figure 2 shows the inhaler removed from the cover.

Figure 3 A is an expanded view showing the components of the inhaler.

Figure 3B shows a cross-section through the inhaler.

Figure 4 shows the central part of the inhaler from above. Figures 5A - 5H show some prior art mixing elements.

Figure 6 shows a mixing element of the invention from two different perspectives.

Figures 7A and 7B show the trajectories of a solid sphere and of a mixing element according to the invention respectively within the vortex chamber of the inhaler.

Detailed Description of the invention

Figure 1 shows an inhaler according to the invention. The inhaler 1 has a housing 3 and a mouthpiece 4. A cover 2 holds and protects the inhaler. In particular, the cover has an extension 7 that extends over the mouthpiece 4, thereby preventing foreign material from entering the mouthpiece before use. The inhaler has a pair of grips 5 located on either side of the housing, and the cover has a pair of grips 6, for removing the inhaler from the cover.

To prepare the inhaler for use, the user holds the grips 5 of the inhaler 1 between the finger and thumb of one hand, and the grips 6 on the cover 2 between the finger and thumb of their other hand. The inhaler 1 is pulled out of the cover which exposes the mouthpiece as shown in Figure 2. This action also causes a blister containing the medication to be pierced, thereby avoiding the need for any further user steps (such as pressing a button or lever to cause piercing) before use. The user then inhales on the mouthpiece to receive the medication.

Figure 3 A is an expanded view of the components of the inhaler 1. Figure 3B shows a crosssection through the inhaler. The inhaler has an upper housing part 10 with the mouthpiece 4, a central part 30, a mixing element 35, a blister 40 and a lower housing part 20. The central part 30 has two pairs of piercing elements 31 (for example of the type described in WO 2014/114916) on its lower surface.

The central part 30 is fixed (e.g. clipped or welded) in the upper housing part 10 so that the internal surface of the upper housing part and the upper surface of the central part together define an airway that fluidically connects the blister 40 (once it has been pierced) to the mouthpiece 4 via a passage 32 and a deagglomeration chamber 33. The mixing element 35 is located inside the deagglomeration chamber 33. An opening with a mesh 12 is formed in the upper housing part; this connects the deagglomeration chamber 33 to the mouthpiece 4. The blister 40 has a lid 41 and a base 42 with a rim 43 which fits into slots 21 on either side of the second housing part 20, thereby holding the blister in place in the second housing part.

The upper 10 and lower 20 housing parts are movable relative to each other. When the inhaler is in the cover 2, the upper and lower housing parts are held in an initial position in which the piercing elements 31 are spaced apart from the lid 41 of the blister 40. The cover prevents the upper and lower housing parts from accidentally being pushed together before use. When the inhaler is removed from the cover, the cover interacts with the upper and lower housing parts, so that they are pushed together into an actuated position in which the piercing elements 31 pierce the lid 41 and enter the blister 40. The mechanism for this consists of a pair of cams 8 in the form of pegs on the inside of the cover and two sloping cam surfaces 22, one in each side of the lower housing part 20. As the inhaler 1 is removed from the cover 2, the cams 8 slide along the cam surfaces 22, pushing the lower housing part 20 upwards into the upper housing part 10. One pair of piercing elements 31 creates an air entry opening in the lid 41 of the blister 40, and the other pair creates an exit opening.

Once the inhaler has been removed from the cover, the user inhales on the mouthpiece 4. This creates an air flow into the blister through the entry opening which aerosolizes the powder, and then carries it out through the exit opening into the passage 32 and then into deagglomeration chamber 33.

The central part 30 is shown from above in Figure 4. The powder-containing air flows from the passage 32 through a powder inlet channel 36 into the deagglomeration chamber 33. External (i.e. powder-free) air also enters the deagglomeration chamber through two bypass inlet channels 37, 38. The powder inlet channel 36 and the bypass inlet channels 37, 38 are tangential to the wall of the deagglomeration chamber, so that the air flow into the chamber creates a vortex. This, in combination with the mixing element 35 (not shown in Figure 4) which is freely movable within the deagglomeration chamber, breaks the powder up into fine particles. The diameter of the mixing element is larger than the width of the powder inlet channel 36 and the bypass inlet channels 37, 38 at the points where they enter the deagglomeration chamber, so that the mixing element cannot enter the inlet channels. The aerosolized fine powder then leaves the deagglomeration chamber 33 via the mesh and flows out through the mouthpiece to the user’s lungs. The mesh prevents any large lumps of powder from leaving the deagglomeration chamber.

Mixing elements in the form of spherical balls are well known for helping to deagglomerate powder in dry powder inhalers, as disclosed for example in W02009/092434 and US 2004/0118399. The presence of a ball has been found to reduce the air flow resistance (defined as the ratio of the square root of the pressure differential to the volumetric flow rate) once the ball has been accelerated by the inhaled air flow. However solid spherical balls are quite heavy, so are slow to accelerate due to their inertia.

Non-spherical mixing elements are also known. For example, US2022/401358 discloses mixing elements with various shapes that can be produced by 3D printing. Preferred mixing elements have walls arranged about a cavity with at least one open aperture. The mixing element may be located inside a capsule or reservoir for the powder, or it may be located inside a flow channel of an inhaler. DE102014017065 discloses an inhaler with a freely movable deagglomerator (i.e. a mixing element) located inside a powder container such as a blister). The deagglomerator may have various shapes, shown in Figure 5A - 5H.

The present inventors have found that a mixing element having a very specific shape performs particularly well, especially when it is located in a deagglomeration chamber of the inhaler (as opposed to being located inside a powder container such as blister or capsule, as in DE102014017065).

A mixing element according to the invention is shown in Figure 6, from two different perspectives. It is formed by three orthogonal circular discs, resulting in a cruciform shape with a spherical envelope. The cruciform mixing element has a number of advantages.

Firstly, it is straightforward to produce by conventional, large volume manufacturing processes, in particular by injection moulding.

Secondly, it is lightweight, because the volume, and hence the mass of the mixing element, is only a fraction of the mass of a solid sphere of equal diameter. For example, the mixing element suitably has a radius of 3mm and a disc thickness of 0.6mm. It therefore has a mass of about 40% of that of a solid sphere of equal diameter. The cruciform mixing element has less inertia than a solid sphere of equal diameter, so it accelerates more quickly and consequently is effective over a greater proportion of the inhalation.

Thirdly, an inhaler with the cruciform mixing element has been found to have a lower air flow resistance than an inhaler with a hollow spherical ball of the same diameter. Measurements were performed on an inhaler of the type shown in Figures 1 to 4 using three different mixing elements, a solid sphere, a hollow sphere and the cruciform mixing element shown in Figure 6. The radius of each mixing element was 3mm. The mass of each mixing element was recorded and the pressure differential required to produce a flow rate of 90 litres per minute through the inhaler was measured in each case. The results are shown in Table 1.

There was only a slight reduction in the pressure differential (and hence the air flow resistance) when using a hollow ball instead of a solid ball. However, the cruciform mixing element resulted in a significant reduction in the pressure differential. The lower air flow resistance of the inhaler means that for a given pressure differential, the flow rate through the inhaler is higher, which increases the deagglomeration and results in a higher fine particle dose, i.e. the mass of particles below a certain size, such as 5pm, that is delivered from the inhaler, known as the FPD.

Fourthly, the flat surfaces of the cruciform mixing element result in a greater drag coefficient than a spherical ball, so that the moving air causes it to accelerate and spin more quicky. The drag coefficient is a dimensionless quantity that is used to quantify the drag force exerted by a moving fluid, such as air. A lower drag coefficient indicates less aerodynamic drag. Computational fluid dynamics simulations were performed to determine the drag coefficient of a number of different mixing elements, namely a sphere, the cruciform mixing element shown in Figure 6, and three prior art mixing elements shown in Figure 5B, Figures 5C and 5D, and Figure 5H respectively. For the mixing element of Figure 5H, the drag coefficient was calculated in two different orientations, where the air flow is parallel to the axis of symmetry (so that the mixing element appears as a star shape, in which the projected area is relatively small) and perpendicular to this axis (so that the mixing element appears approximately circular, in which the projected area is larger). The drag coefficients were calculated at two different values of the Reynolds number (Re), representative of high and low flow rates through the inhaler. The results are given in Table 2.

Table 2: drag coefficients

The drag coefficients of each of the mixing elements were similar at the low and high Reynolds numbers, indicating that they would perform similarly at lower and higher flow rates in the inhaler. The cruciform mixing element was found to have the largest drag coefficient of all of the mixing elements. The mixing element of Figure 5H had a high drag coefficient perpendicular to the axis of symmetry, but a lower drag coefficient parallel to the axis. The higher the drag coefficient, the greater the force on the mixing element during inhalation, so that the moving air causes the mixing element to accelerate and spin more quicky. The cruciform mixing element of the invention has the highest drag coefficient, and hence is expected to be most effective at deagglomerating powder. While the mixing element of Figure 5H has a high drag coefficient perpendicular to the axis, it is expected to be less effective because it would not always be in this orientation.

Fifthly, the relatively sharp edges of the cruciform mixing element may help to scrape off powder that has stuck to the wall of the deagglomeration chamber, whereas a spherical ball simply rolls over adhered powder and hence is less effective at removing it. The radius of the mixing element is therefore preferably the same as, or somewhat less than, the radius of curvature of the corner between the side walls and base / roof of the deagglomeration chamber. This ensures that the mixing element can get into this region and scrape the whole of the inner surface of the deagglomeration chamber.

Finally, the motion of the cruciform mixing element within the vortex has been found to be quite different from that of a spherical mixing element. High speed video recordings were made of the motion of (a) a solid sphere and (b) a cruciform mixing element within the vortex chamber of an inhaler at a flow rate of 30 litres per minute. The trajectories of the centre of the mixing elements were obtained by analysis of the video images. Figures 7A and 7B show the trajectories of the solid sphere and the cruciform mixing element respectively. It is apparent that the solid sphere moves around the perimeter of the vortex chamber only. Thus, while the sphere is moved by the cyclonic air flow, it does not disrupt it. The vortex is relatively steady, so that its eye (centre) stays near the centre of the chamber. In contrast, the cruciform mixing element moves rather chaotically, often bouncing across the vortex chamber. As a result, the cruciform mixing element disrupts the vortex, making the air flow more turbulent, which helps to break up the powder into fine particles. Moreover, the cruciform mixing element impacts the wall of the chamber with a component of velocity / force that is normal to the wall; this is believed to help to remove powder from the wall. The experiments were repeated at 60 and 90 litres per minute, and essentially the same behaviour was observed in each case.

These effects together result in an inhaler that has a low air flow resistance that provides very effective deagglomeration of the powder, as measured by the fine particle dose of the aerosol that is delivered from the inhaler to the user’s lungs.

Experiments were conducted to compare the performance of an inhaler according to the invention having a cruciform mixing element as shown in Figure 6 and an identical inhaler having a solid spherical mixing element. The mixing elements both had a radius of 3mm and were made from the same material (acrylonitrile butadiene styrene). The inhalers were as shown in Figures 1 - 4, except that they had one bypass channel, located at 180° to the powder inlet channel, instead of two bypass inlet channels as shown in Figure 4. The blisters in each inhaler contained 150mg of a powder comprising 99.5wt% micronized acetylsalicyclic acid and 0.5wt% magnesium stearate. A Fast Screening Impactor (FSI, Copley Scientific) was used to measure the fine particle dose (< 5pm) delivered from each inhaler. The FSI has a filter which captures emitted aerosol particles of less than 5pm in size. A simulated inhalation manouevre with a pressure differential of 2.5kPa and a volume of 2 litres was performed on each device. The FPD was determined gravimetrically by weighing the filter before and after each inhalation. The flow rate was also recorded in each case. The results are shown in Table 3.

Table 3: FSI results

Table 3 demonstrates that the cruciform mixing element resulted in a higher FPD and a higher flow rate, i.e. a lower air flow resistance, than the spherical ball.

The inhaler described above has a blister that contains the dry powder medication, which is pierced by the piercing elements. However, the invention also encompasses other containers, such as a capsule, and other opening mechanisms, such as peeling a lid off, pulling two halves of a capsule apart or piercing a capsule by means of needles. Regardless of which type of opening mechanism is used, the inhaler may be automatically actuated by the action of removing it from the cover.

The inhaler may have a single dose of medication, and may be pre-loaded with a blister or capsule. The inhaler may be re-usable, so that a new blister or capsule in inserted each time it is to be used. Alternatively, the inhaler may be a multi-dose device and contain a number of doses, for example 30 or 60 does in a blister strip, dose disk or a reservoir, along with a suitable mechanism for preparing each dose.

The blister, capsule or other container contains a dry powder medication for inhalation. The medication comprises a pharmaceutically active ingredient and may also comprise one or more pharmaceutically acceptable excipients. The amount of the powdered medication in the blister or capsule may be 5-300 mg, preferably 20-200 mg, more preferably 30-150 mg, even more preferably 40-100 mg. For example, there may be about 50, 60, 70, 80 or 90 mg of powder in the blister or capsule. The contents of each inhaler may be delivered from the inhaler in a single inhalation or in two or more inhalations. The medication may be capable of treating or preventing a thromboembolic event. The pharmaceutically active ingredient in the medication may be an antiplatelet drug. For example, the pharmaceutically active ingredient may be a non-steroidal anti-inflammatory drug (NSAID). Preferably, the pharmaceutically active ingredient is a salicylate (a salt or ester of salicylic acid), most preferably acetylsalicylic acid or a pharmaceutically acceptable salt thereof. The pharmaceutically active ingredient may be another type of NSAID. For example, the pharmaceutically active ingredient may be Celecoxib (Celebrex), Dexdetoprofen (Keral), Diclofenac (Voltaren, Cataflam, Voltaren-XR), Diflunisal (Dolobid), Etodolac (Lodine, Lodine XL), Etoricoxib (Algix), Fenoprofen (Fenopron, Nalfron), Firocoxib (Equioxx, Previcox), Flurbiprofen (Urbifen, Ansaid, Flurwood, Proben), Ibuprofen (Advil, Brufen, Motrin, Nurofen, Medipren, Nuprin), Indomethacin (Indocin, Indocin SR, Indocin IV), Ketoprofen (Actron, Orudis, Oruvail, Ketoflam), Ketorolac (Toradol, Sprix, Toradol IV /IM, Toradol IM), Licofelone (under development), Lorn oxicam (Xefo), Loxoprofen (Loxonin, Loxomac, O%er|o), Lumiracoxib (Prexige), Meclofenamic acid (Meclomen), Mefenamic acid (Ponstel), Meloxicam (Movalis, Mel ox, Recoxa, Mobic), Nabumetone (Relafen), Naproxen (Aleve, Anaprox, Midol Extended Relief, Naprosyn, Naprelan), Nimesulide (Sulide, Nimalox, Mesulid), Oxaporozin (Daypro, Dayrun, Duraprox), Parecoxib (Dynastat), Piroxicam (Feldene), Rofecoxib (Vioxx, Ceoxx, Ceeoxx), Salsalate (Mono-Gesic, Salflex, Disalcid, Salsitab), Sulindac (Clinoril), Tenoxicam (Mobi flex), Tolfenamic acid (Clotam Rapid, Tufnil), or Valdecoxib (Bextra). The pharmaceutically active ingredient may be an alternative to an NSAID. Such alternatives include P2Y12 inhibitors. Examples of P2Y12 inhibitors include Plavix (clopidogrel), ticlopidine, ticagrelor, prasugrel, and cangrelor. Other pharmaceutically active ingredients may include COX-2 inhibitors, and Nattokinase (an enzyme EC 3.4.21.62, extracted and purified from a Japanese food called natto). The medication may comprise both acetylsalicylic acid, or a pharmaceutically acceptable salt thereof, and a P2Y12 inhibitor.

The pharmaceutically active ingredient may alternatively be a bronchodilator, such as a beta-2 agonist or anticholinergic for the treatment of an asthma exacerbation; adrenaline and/or atropine for the treatment of cardiac failure, cardiac dysfunction, cardiac arrest, anaphylaxis, drug overdose or the like; glucose and/or glucagon for the treatment of hypoglycaemia, diabetes induced coma or the like; benzodiazepine, phenytoin or anti-seizure medications for the treatment of seizure; dihydroergotamine for the treatment of migraine; naloxone for treating an opioid overdose; insulin for managing blood sugar level or the like. The medication may include one or more agents for inducing an immune response, e.g. a vaccine, such as a measles vaccine, a Hepatitis B vaccine, or an influenza vaccine. The term “pharmaceutically active ingredient” does not include nicotine or nicotine salts. Thus the medication does not contain nicotine or nicotine salts.

Claims

1. A dry powder inhaler comprising:

• one or more doses of powdered medication;

• an outlet through which a user may inhale the medication;

• an airway; and

• a mixing element located in the airway; wherein, when a user inhales on the outlet, medication is entrained in an air flow and flows through the airway and out through the outlet; characterised in that the mixing element is in the form of three generally orthogonal generally circular discs with a common centre.

2. A dry powder inhaler according to claim 1, wherein the mixing element is formed by injection moulding.

3. A dry powder inhaler according to claim 1 or claim 2, wherein the three discs are orthogonal to each other.

4. A dry powder inhaler according to any of claims 1 to 3, wherein the three discs are circular.

5. A dry powder inhaler according to claim 4, wherein three discs each have a radius of from 1 to 5mm, such as from 2 to 4mm, for example around 3mm.

6. A dry powder inhaler according to claim 4 or claim 5, wherein three discs all have the same radius.

7. A dry powder inhaler according to any of claims 1 to 6, wherein the thickness of each disc is from 0.3 to 0.8mm, such as 0.4 to 0.7mm, for example 0.5 to 0.6mm.

8. A dry powder inhaler according to any of claims 1 to 7, wherein the discs taper from the centre to the periphery.

9. A dry powder inhaler according to any of claims 1 to 8, wherein the airway comprises a deagglomeration chamber in which the mixing element is located.

10. A dry powder inhaler according to claim 9, wherein the deagglomeration chamber has a powder inlet channel through which entrained medication enters the deagglomeration chamber and one or more bypass inlet channels through which external, powder-free air enters the deagglomeration chamber.

11. A dry powder inhaler according to claim 10, wherein the powder inlet channel and/or the bypass inlet channel(s) are tangential to the wall of the deagglomeration chamber.

12. A dry powder inhaler according to any of claims 1 to 11 wherein the dose of powdered medication is contained in a blister comprising a base and a lid, and the inhaler comprises a piercer for piercing the lid of the blister.

13. A dry powder inhaler according to claim 12 further comprising:

• a cover;

• a first housing part comprising the outlet and the piercer;

• a second housing part comprising the blister; wherein removing the cover causes the first and second housing parts to be pushed together so that the piercer pierces the blister.

14. A dry powder inhaler according to any of claims 1 to 13, wherein the medication comprises a non-steroidal anti-inflammatory drug; a bronchodilator; adrenaline and/or atropine; glucose and/or glucagon; benzodiazepine, phenytoin or anti-seizure medications; dihydroergotamine; naloxone; insulin; or a vaccine.

15. A dry powder inhaler according to any of claims 1 to 14, wherein each dose is from 5 to 300mg of powdered medication.