WO2023186758A1

WO2023186758A1 - Dry powder formulation inhaler and capsule

Info

Publication number: WO2023186758A1
Application number: PCT/EP2023/057753
Authority: WO
Inventors: Hakan Glad; Joakim LUDVIGSSON; David SAHLIN; Gunilla PETERSSON
Original assignee: Astrazeneca Ab
Priority date: 2022-03-28
Filing date: 2023-03-27
Publication date: 2023-10-05

Abstract

A dry powder formulation inhaler (DPI) capsule, is disclosed herein. The dry powder formulation inhaler capsule comprises two capsule halves, each capsule half comprising elongate domed portion, at least one of which comprises a dose of powdered medicament for inhalation. Each capsule half is formed from a membrane configured to inhibit moisture ingress. The wings of the two capsule halves are welded together about a bisecting plane and form a wing that extends outward in the bisecting plane around the capsule and circumscribing the base of each elongate domed portion of each capsule half to form a moisture impermeable seal, such that the two elongate domed portions when welded together approximate an ellipsoidal shape and form a cavity that contains a dose of powdered medicament for inhalation.

Description

Dry powder formulation inhaler and capsule

Field of the Invention

The present invention relates to a dry powder formulation inhaler capsule, a method of manufacturing a dry powder formulation inhaler capsule, and an inhaler for a dry powder formulation inhaler capsule.

Background

Dry powder formulations constitute a large part of all inhaled pharmaceutical formulations to the lung. For the administration of these formulations a dry powder inhaler (DPI) is used. DPIs may be of either reservoir type or pre-metered. Depending on the physical and chemical properties of the powder such as, for example, stability, bulk density, particle size distribution, flow, hygroscopicity, adhesiveness, cohesiveness etc., the design and construction of a reservoir device may be challenging since each dose needs to be accurately metered by the device before administration.

In a pre-metered DPI each dose of the dry powder is pre-packaged in its primary packaging. A multiple unit pre-metered device may come loaded with multiple such packaging units either as part of the device itself or with various kinds of inserted blister packages. Among single unit pre-metered devices, the majority are capsule devices where the dry powder formulation is pre-filled into a gelatin or HPMC capsule to be inserted into the DPI device upon use. Capsule inhalers are advantageous with respect to their common use of a standardized primary packaging platform in terms of capsule geometry and sizes. Also, as the capsule is being emptied during use of a capsule inhaler, the capsule moves in the air flow which creates a sound that constitutes feedback, reassuring the user that the medication has been taken successfully.

However, a large portion of dry powder formulations are sensitive to moisture. This may be due to the fact that the active pharmaceutical ingredient (API) is prone to chemical degradation, loss of bioactivity and/or that agglomeration of the powder prevents effective dispersion of the formulation resulting in sub-optimal performance in terms of the dose delivered to the lung. In particular, this is the case for spray dried powders.

Traditional capsules of gelatin or HPMC do not constitute a protective barrier against moisture ingress and therefore need a secondary packaging in terms of an aluminiumaluminium blister pack. Furthermore, these capsules generally need drying before the filling of the moisture sensitive formulation and this renders the capsules brittle and prone to fracture during handling. During filling under very dry conditions with these capsules, static electricity constitutes a further difficulty which makes it challenging to fill the exact dose and static electricity may also affect the emptying of the capsule during inhalation. Also, piercing of the brittle capsule in the inhaler device to empty the formulation may fracture the capsule and may produce small fragments that may follow the inhalation air flow to the user’s mouth or throat.

Attempts to overcome these problems include using a single pocket blister packaging unit instead of a capsule, but some of these do not provide full protection against moisture ingress and therefore still need a moisture tight secondary packaging such as an aluminium pouch to guarantee the required shelf life. Also, the blister unit does not produce a sound during use, therefore not providing the user with the useful feedback as mentioned above in relation to standard capsules. Furthermore, static blisters do not provide as efficient turbulence enhanced powder dispersion as seen with the rotating capsule inhalers. Furthermore, unit blisters typically need to be pierced for emptying with the top foil typically then being bent inwards, to the powder chamber, impairing efficient powder emptying for the blister.

US 9,988,194 describes a double-shell blister packaging for medicinal contents comprising one or more cavities of a similar shape to the medicinal content, said doubleshell packaging being the assembly of a first and second multilayer structures sealed to each other, each multilayer structure comprising a seal layer, one or more aluminium layers with a thickness of at least 20 pm, and two or more support layers. However, in this document the packaging is a blister packaging, and contains the medicinal content in the form of a pill or capsule that is accessed through tearing, peeling or pushing-through the pill or capsule contained inside through the blister packaging. It is therefore clearly not designed for use as a dry powder formulation inhaler capsule.

Therefore, there is a need for a primary packaging which is able to protect moisture sensitive dry powder formulations without the need for a secondary packaging. Summary of the Invention

Aspects of the invention are as set out in the independent claims and optional features are set out in the dependent claims. Aspects of the invention may be provided in conjunction with each other and features of one aspect may be applied to other aspects.

In a first aspect there is provided

In a first aspect there is provided a dry powder formulation inhaler, DPI, capsule. The capsule comprises two capsule halves, optionally of equal shape and geometry, each capsule half comprising a wing that extends outward in a plane around an elongate domed portion, the wing of each capsule portion circumscribing the base of the elongate domed portion. Each capsule half is formed from aluminium foil. The wings of the two capsule halves are welded together to form a moisture-resistant seal about a bisecting plane that bisects the welded capsule, such that the two elongate domed portions when welded together approximate the ellipsoidal shape of a standard pharmaceutical capsule and form a cavity that contains a dose of powdered medicament for inhalation.

Advantageously, the dry powder formulation inhaler capsule may improve the lifespan of the content (e.g., medicament) of the capsules by inhibiting the uptake of moisture and preventing or inhibiting chemical degradation. This in turn may preserve or maintain the bioactivity and/or dispersion of the formulation. The wing of each capsule half provides a surface to which the wing of the other capsule half may be welded. The presence of a wing on each capsule therefore may help to improve the hermetic seal of the two capsule halves to thereby inhibit the uptake of moisture by providing an increased surface area over which the two capsule halves can be joined, for example by welding.

The wing of each capsule may also improve uptake of medicament when used in a dry powder inhaler. For example, the wing may act to help create turbulence and improve spinning of the capsule when entrained in an air flow, thus improving the dispensing of powder/medicament from a capsule when pierced.

The wing may also improve ease of use. The wing may make it easier for a user to pick up and insert a capsule into an inhaler and/or reduce the chance that the user accidentally drops the capsule. Furthermore, the moisture-proof capsule means standard tablet bottles may be used, which then replace the peelable blisters, traditionally used for inhaled capsules, which are difficult to open.

Furthermore, the dry powder formulation inhaler capsules are not brittle and prone to fracture like conventional gelatin or HPMC capsules. Moreover, the dry powder formulation inhaler capsules of the disclosure do not suffer with issues of static electricity even under very dry conditions due to the conductive nature of the aluminium foil. This may improve filling (in that it reduces the demands on filling equipment and the need for strict control of electrostatic fields in the manufacturing zone) and emptying of the capsules, ensuring that a consistent quantity of medicament is supplied in each capsule and delivered to the patient in use. In addition, as the powder is protected directly after capsule filling/sealing, the next unit operation in the supply chain does not require strict control of humidity and electrostatic fields. Moreover, the aluminium foil does not have to be dried prior to filling which is the case for polymer capsules when used for very moisture sensitive powders.

Additionally, the dry powder formulation inhaler capsules may be pierced in a more reliable and effective way, due to the fact that they are not brittle like conventional gelatin or HPMC capsules. This means that the capsules may be pierced more reliably, thereby not only improving user safety in that fragments may no longer follow the inhalation air flow into the user’s mouth or throat, but also that the correct quantity of medicament can be delivered effectively and reliably to the user.

Finally, because the dry powder formulation inhaler capsules inhibit moisture ingress relative to conventional dry powder formulation inhaler capsules, they do not require secondary packaging, which obviously has a clear environmental benefit in terms of the packaging needed for the medicament. Advantageously, there is no need for a user to open and remove capsule from complicated and frustrating blister pack. There may be reduced risk for capsule distortion and capsule dropping. There may be no ’’time restriction” between blister opening & inhalation. There may be no in-use shelf life restrictions after opening of a blister strip or an added outer pouch.

Each capsule half may bisect the welded capsule along its longitudinal axis, the longitudinal axis being in a direction corresponding to the greatest dimension of the welded capsule in the bisecting plane. The two elongate domed portions when welded together may approximate the ellipsoidal shape of a standard pharmaceutical capsule, for example size 4, size 3, size 2, size 1 , size 0 and size 00.

The wing of each capsule half may extend outward from the base of the elongate domed portion by a distance I, and wherein the value of the distance I is constant around the base of the elongate domed portion. Preferably the value or I is at least 2 mm or thereabouts, and preferably at least 3 mm and in some cases may be as much as 4 mm. In some embodiments the value is 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.5 mm,

2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm,

3.7 mm, 3.8 mm, 3.9 mm. It has been found that if the value of I is less than approximately 2 mm (such as less than 1 .7 mm) the hermetic seal between the two capsule halves may not be sufficient and may not be recommended if a strong moisture barrier is required. However, it will be understood that in other examples the distance I may vary around the base of the elongate domed portion, for example so that the distance I may be greater or smaller at the ends of the elongate domed portion than around its waist. In some examples the distance I may be symmetrical for the two capsule halves.

The wing of each capsule half may form an obround shape around the base of the elongate domed portion. The elongate domed portion of each capsule half may have an obround cross-section in the bisecting plane.

In some examples the thickness of the aluminium foil is at least 100 pm. The weight of the aluminium foil may be at least 100 g/m², for example at least 150 g/m², for example at least 177 g/m².

In some examples the aluminium foil comprises a polyamide layer bound to an aluminium layer via an adhesive layer, with a polyethylene-based extrusion coating overlaid on the aluminium layer. The thickness of the polyamide nylon layer may be at least 25 pm. The thickness of the aluminium layer may be at least 45 pm. In some embodiments, the aluminium foil comprises a polyamide layer bound to an aluminium layer via an adhesive layer, with a polyethylene-based extrusion coating overlaid on the aluminium layer in at least 100 pm. In some examples the dimensions of the capsule are selected to approximate the ellipsoidal shape of a standard pharmaceutical capsule size 2 in terms of volume and to obtain an oblong shape that can spin in the air flow of an inhaler. For example, the length of the capsule along the longitudinal axis in the bisecting plane may be less than or equal to 23.5 mm. The width of the capsule in the bisecting plane may be less than or equal to 13.5 mm. The height of the capsule perpendicular to the bisecting plane may be less than or equal to 5 mm.

One of skill in the art would understand that the overall foil design, including any of the protective layers such as aluminium layers, polyamide layers, adhesive layers and polymer-based layers such as polyethylene- or polypropylene-based extrusion coatings should be optimized to tolerate cold forming and give a strong seal with no air channels for water penetration.

In another aspect there is provided a method of manufacturing a dry powder formulation inhaler, DPI, capsule. The method comprises cold forming two capsule halves, optionally of equal shape and geometry, from aluminium foil, each capsule half comprising a wing that extends outward in a plane around an elongate domed portion, the wing of each capsule portion circumscribing the base of the elongate domed portion. The method then comprises filling each elongate domed portion with a powdered dose of medicament for inhalation, and then welding the wings of the two capsule halves together to form a hermetic seal about a bisecting plane that bisects the welded capsule, such that the two elongate domed portions when welded together approximate the ellipsoidal shape of a standard pharmaceutical capsule.

In some examples cold forming the two capsule halves comprises cold forming the two capsule halves such that each capsule half bisects the welded capsule along its longitudinal axis, the longitudinal axis being in a direction corresponding to the greatest dimension of the welded capsule in the bisecting plane.

In some examples cold forming the two capsule halves comprises cold forming the two capsule halves such that the two elongate domed portions when welded together may approximate the ellipsoidal or oblong shape of a standard pharmaceutical capsule. In some examples cold forming the two capsule halves comprises cold forming the two capsule halves such that the wing of each capsule half extends outward from the base of the elongate domed portion by a distance I, and wherein the value of the distance I is constant around the base of the elongate domed portion.

In some examples cold forming the two capsule halves comprises cold forming the two capsule halves such that the wing of each capsule half forms an obround shape around the base of the elongate domed portion.

In some examples cold forming the two capsule halves comprises cold forming the two capsule halves such that the elongate domed portion of each capsule half has an obround cross-section in the bisecting plane.

The method may further comprise forming the aluminium foil by binding an aluminium layer to a polyamide layer via an adhesive layer and overlaying a polyethylene-based extrusion coating on the aluminium layer.

In another aspect there is provided a dry powder inhaler, DPI, device. The DPI comprises a rotatable mouthpiece, at least one air inlet, at least one piercing means and a capsule compartment for supporting a dry powder formulation inhaler capsule, the capsule comprising at least one wing. The capsule compartment comprises a cavity for receiving the capsule, and the cavity comprises at least one slot for receiving the wing of the capsule for inhibiting rotation of the capsule in the cavity. The DPI is configured such that rotation of the mouthpiece is configured to move the capsule relative to the at least one piercing means to lift the capsule out of the cavity

In some examples the cavity comprises a pair of opposing slots either side of the cavity, each slot configured to receive a respective portion of the wing of the capsule on opposing sides of the capsule.

In another aspect there is provided a dry powder inhaler, DPI, device. The inhaler device comprises a mouthpiece defining a conduit having a first cross-sectional area in fluid communication with an air outlet, at least one air inlet, and a capsule compartment between the air inlet and the air outlet for supporting a dry powder formulation inhaler capsule. The capsule compartment comprises a cavity for receiving the capsule and a grid separating the capsule compartment from the conduit, wherein the grid defines a second cross-sectional area. The first cross-sectional area is smaller than the second cross-sectional area.

In some embodiments, having the second cross-sectional area larger than the first cross- sectional area may improve the flow of air through the inhaler and may improve agitation/spinning of a capsule inside the inhaler, which in turn may improve the dispensing of medicament from the capsule.

In some embodiments, the air outlet, or at least a portion of the air outlet, has an ovalshaped cross-section.

Brief Description of Drawings

Embodiments of the disclosure will now be described, by way of example only, with reference to the accompanying drawings, in which:

Figure 1 shows a perspective view of an example dry power formulation inhaler capsule;

Figure 2 shows a plan view of the example dry powder formulation inhaler capsule of Figure 1 ;

Figure 3 shows an end view of the example dry powder formulation inhaler capsule of Figure 1 and 2;

Figure 4 shows an example flow chart of an example method of manufacturing a dry powder formulation inhaler capsule, such as the dry powder formulation inhaler capsule of any of Figures 1 to 3;

Figure 5A shows a perspective view of an example dry powder inhaler;

Figure 5B shows a perspective view of a portion of the example dry powder inhaler of Figure 5A showing a cavity for receiving a dry powder formulation inhaler capsule such as that shown in Figures 1 to 3;

Figure 5C shows a perspective view of the example dry powder inhaler of Figures 5A and 5B;

Figure 6 shows an exploded perspective view of the example dry powder inhaler of Figures 5A to 5C;

Figure 7A shows a cross-section of the example dry powder inhaler of Figures 5A to 6; Figure 7B shows a cross-section of the example dry powder inhaler of Figures 5A to 6 with a dry powder formulation inhaler capsule inserted;

Figure 8 shows a perspective view of the capsule compartment of an example dry powder formulation inhaler of embodiments of the disclosure;

Figure 9A shows a perspective view of another example dry powder inhaler containing a dry powder formulation inhaler capsule;

Figure 9B shows another perspective view of the example dry powder inhaler of Figure 9A;

Figure 10 shows a plan view of an inhaler grid of an example dry powder inhaler of embodiments of the disclosure;

Figure 11A shows a cross-section of the example dry powder inhaler of Figures 9A and 9B with a dry powder formulation inhaler capsule inserted and being pierced with a pair of needles;

Figure 11 B shows a cross-section of the example dry powder inhaler of Figures 9A and 9B with a dry powder formulation inhaler capsule inserted with the needles being retracted from the capsule;

Figure 11C shows a cross-section of the example dry powder inhaler of Figures 9A and 9B with a dry powder formulation inhaler capsule inserted with the needles completely retracted;

Figure 12A shows a cross-section through an example dry powder inhaler;

Figure 12B shows a cross-section through another example dry powder inhaler;

Fig. 13 shows a cross-section through an example active dry powder inhaler; and

Fig. 14 shows a chart of emptying time of capsules according to embodiments of the disclosure compared to conventional capsules.

Detailed

Figure 1 shows a perspective view of an example dry power formulation inhaler capsule 100. The dry powder formulation capsule 100 is formed from two capsule halves 100A, 100B, which in this example are of equal shape and geometry but it will be understood that in other examples the two capsule halves 100A, 100B may differ in shape or geometry so long as they can be welded together. In the example shown, each capsule half 100A, 100B comprises a wing or rim 102 that is formed when the two capsule halves 100A, 100B are welded together and that extends outward in a bisecting plane 150 around an elongate domed portion 105A, 105B. The elongate domed portion 105A, 105B of each capsule half has an obround or race-track shaped cross-section in the bisecting plane 150, as shown more clearly in Figure 2.

The wing 102A, 102B of each capsule portion circumscribes the base 106A, 106B of the elongate domed portion 105A, 105B and extends outward from the base 106 of the elongate domed portion by a distance I. In the example shown, the value of the distance I is constant around the base 106A, 106B of the elongate domed portion 105A, 105B and has an obround or race-track shape when viewed in in the bisecting plane as shown more clearly in Figure 2. The distance I of the wings 102A, 102B affects the seal the couples the two capsule halves 100A, 100B and thereby the properties of the capsule to inhibit moisture ingress. It has been found that preferably the distance I is between 2 and 3 mm.

In this example each capsule half 100A, 100B is formed from aluminium foil as it is a moisture impermeable membrane. The thickness of the aluminium foil may be the same for both the wing 102A, 102B and the elongate domed portion 105A, 105B of each capsule half 100A, 100B.

The aluminium foil used may be Aluthene® foil produced by Amcor®, although it will be understood that other foils such as Dessiflex® and Dessiflex Plus® foils may be used. For example, suitable foils may include PATZ 498/25-60-40 (oPA/Alu/PE), Constantia; PATZ 49862/25-45-40 (oPA/Alu/PE), Constantia; oPA/60 ALU/25pm PE, Constantia; Dessiflex Plus TDSP0069-E (oPA/Alu/PE), Amcor; Aluthene® 25PA 45II E110/16 (oPA25/Alu45/ PE25), Amcor; Aluthene® 70 IV E116/8 (oPA25/Alu70/PP CoEx 50).

In some examples the weight of the aluminium foil is at least for example 100 g/m², 150 g/m², 177 g/m². The aluminium foil may be a multi-layered structure, for example comprising at least one polymer layer (for example, a polymer layer, such as polyethylene or polypropylene, on the inside facing the medicament when the capsule 100 is formed), and optionally two polymer layers, for example wherein the aluminium layer is sandwiched between two polymer layers (wherein the two polymer layers may be the same or different to each other).

Preferably, the aluminium foil comprises a polyamide (preferably oriented polyamide (oPA)) outer layer bound to an aluminium layer via an adhesive layer, with a polyethylene- based extrusion coating overlaid on the aluminium layer providing an inner layer to the capsule 100. In some examples there may additionally or alternatively be a moisture absorbing layer, for example comprising a CaO desiccant. It will, however, be understood that other polymer layers may be used to support the aluminium layer and improve its formability in cold-forming processes. For example, a polymer having a tensile strength at break in machine transversal direction of at least 200 N/mm² and an elongation at break of at least 50%, preferably at least 70%, measured according to EN ISO 527-3 published in 1995, sample type 2, parts 1-6.

The thickness of the polyamide nylon layer may range from 12 to 30 pm, and preferably may be at least 25 pm. The thickness of the aluminium layer may range from 20 to 120 pm, for example from 40 to 100 pm, for example from 30 to 60 pm, and may preferably be at least 45 pm, and the thickness of the polyethylene-based extrusion coating may be at least 25 pm.

The polyamide layer (which may preferably be an oriented polyamide (oPA) film) supports the cold-forming process, reducing the stiffness. A minimum aluminium layer thickness is needed for ultimate moisture and oxygen barrier properties. A very thin aluminium layer may through stress crack/open up during blister forming. The minimum thickness depends on the medicament/powder moisture sensitivity.

The polymer layer (which will be on the inside of the capsule facing the medicament) can be modified as cold forming is possible in the range 10 pm to 100 pm with current foils and processes. Using a very thick polymer layer may reduce the moisture barrier efficiency as the seal will be wider and that is where the moisture goes. Different sealing methods may be used, for example: heat sealing and ultrasonic sealing. Different foils require different sealing temperatures and because some medicaments may be very heat sensitive some foils may therefore be less applicable. Polyethylene is a good choice if heat reduction is important, due to the relatively low melting point (~126-132°C, dependent on the quality).

It is possible to maximize moisture protection, if needed, by decreasing the thickness of the polyethylene layer and the same time increase the thickness of the aluminium layer.

The polymer layer may be made of one of HDPE, LDPE and PP; both the material selected, and the thickness, are of importance.

Although preferably the two capsule halves 100A, 100B may be made from the same material having the same properties, it will be understood that in some examples the two capsule halves 100A, 100B may have different properties and may be made from different materials, for example having different polymer and/or aluminium foil thicknesses.

As can be seen in Figures 1 to 3, the wings 102A, 102B of the two capsule halves 100A, 100B are welded together to form a hermetic seal about the bisecting plane 150 that bisects the welded capsule 100, such that the two elongate domed portions 105A, 105B when welded together approximate an ellipsoidal shape, which in this example approximates the ellipsoidal shape of a standard pharmaceutical capsule, and form a cavity that contains a dose of powdered medicament for inhalation.

Preferably the two elongate domed portions 105A, 105B when welded together approximate the oblong or ellipsoidal shape of a standard pharmaceutical capsule of a range of sizes, for example ranging from any of size 4, 3, 2, 1 , 0 or 00 in terms of volume. Advantageously this means that the capsule 100 may contain the same quantity of medicament as conventional inhaler capsules. It will be understood that the capsule 100 comprises two long edges and two short edges, the two long edges being parallel to each other and parallel to the longitudinal axis of the capsule 100 and separating the two curved portions at either end of the capsule 100, to therefore form a three-dimensional obround shape. In the example shown in Figures 1 to 3, the short edges of the capsule 100 are curved and connect the two long edges.

Each capsule half 100A, 100B bisects the welded capsule 100 along its longitudinal axis, the longitudinal axis being in a direction corresponding to the greatest dimension of the welded capsule 100 in the bisecting plane 150.

As can be seen in Figure 3, the elongate domed portion 105A, 105B of each capsule half 100A, 100B has an incline portion 107A, 107B and a summit portion 108A, 108B. The incline portion 107A, 107B has an obround or race-track profile when viewed in the bisecting plane 150. The summit portion 108A, 108B has elongate rectangular profile with rounded ends when viewed in the bisecting plane 150 and may also be described as having an obround profile when viewed perpendicular to the bisecting plane 150. As such, the summit portion 108A, 108B is surrounded on all sides by an inclined portion 107A, 107B and is parallel to but offset from the bisecting plane 150 and the plane of the wing portion 102A, 102B by a distance corresponding to approximately half the capsule height. The inclined portion 107A, 107B is in turn surrounded on all sides at its base 106A, 106B (the base corresponding to the bisecting plane) by the wing 102A, 102B. The angle of the incline portion 107A, 107B relative to the bisecting plane 150 is consistent regardless of the point on the elongate domed portion 105A, 105B around the capsule half 100A, 100B.

The dimensions of the capsule 100 may be selected to obtain a capsule volume of 0.37 mL (size 2), although it will be understood that the dimensions of the capsule 100 may be selected to obtain a capsule of a range of sizes, for example sizes 3, 2, 1 , 0 and 00. In the example shown in Figures 1 to 3, the capsule is size 2 and so the length of the capsule 100 along the longitudinal axis in the bisecting plane 150 is less than or equal to 23.5 mm, the width of the capsule 100 in the bisecting plane 150 is less than or equal to 13.5 mm and the height of the capsule 100 perpendicular to the bisecting plane 150 is less than or equal to 5 mm.

Advantageously, the dry powder formulation inhaler capsule 100 of the disclosure may preserve or maintain the lifespan of the medicament contained within the capsules 100 by inhibiting the uptake of moisture and preventing or inhibiting chemical degradation. This in turn may preserve or maintain bioactivity and the dispersion of the formulation. This is illustrated in Table 1 , below.

Table 1 shows the water content of the capsules as determined by TGA for capsules made according to embodiments of the disclosure from Aluthene® foil (specifically Aluthene® 25PA 45II E110/16 (oPA25/Alu45Z PE25). The foil used comprises a polyamide layer bound to an aluminium layer via an adhesive layer, with a polyethylene-based extrusion coating overlaid on the aluminium layer. The thickness of the polyamide nylon layer is 25 pm, the thickness of the aluminium layer is 45 pm, and the thickness of the polyethylenebased extrusion coating may be at least 25 pm. The capsule was a size 2 capsule (0.37mL) having a 3 mm wing 102.

Table 1

It can be clearly seen that the dry powder formulation inhaler capsule 100 of the disclosure inhibits moisture ingress even after 6 months, thereby preventing or inhibiting chemical degradation of any medicament contained therein. This in turn may preserve or maintain bioactivity and the dispersion of the formulation.

Furthermore, the dry powder formulation inhaler capsules 100 of the disclosure are not brittle and prone to fracture like conventional gelatin or HPMC capsules. Moreover, the dry powder formulation inhaler capsules 100 of the disclosure do not suffer with issues of static electricity even under very dry conditions due to the conductive nature of the aluminium foil. This may improve filling and emptying of the capsules, ensuring that a consistent quantity of medicament is supplied in each capsule and delivered to the patient in use.

Additionally, the dry powder formulation inhaler capsules of the disclosure may be pierced in a more reliable and effective way, due to the fact that they are not brittle like conventional gelatin or HPMC capsules. This means that the capsules may be pierced more reliably, thereby not only improving user safety in that fragments may no longer follow the inhalation air flow into the user’s mouth or throat, but also that the correct quantity of medicament can be delivered effectively and reliably to the user.

Finally, because the dry powder formulation inhaler capsules of the disclosure inhibit moisture ingress relative to conventional dry powder formulation inhaler capsules, they do not require secondary packaging to protect the medicament (e.g., they do not require packaging to inhibit moisture ingress, and so e.g., a carboard packaging or plastic bottle may be used as secondary packaging), which obviously has a clear environmental benefit in terms of the packaging needed for the medicament. Capsules according to the above description have been reproducibly and accurately filled with moisture sensitive spray dried formulation, as shown in Figure 6. Capsules of the present disclosure may therefore not suffer the same problems resulting from static electricity as may be the case with traditional capsules of gelatin or HPMC.

Capsules according to the above description have also been tested with respect to piercing and emptying of the dry powder formulation with various needle configurations in three major device geometries: horizontally (lying) spinning capsule, vertically (standing) spinning capsule and using an active device principle using compressed air and hollow needles for emptying.

Table 2

*Mass Median Aerodynamic Diameter **Geometric Standard Deviation Capsule filled with spray dried powders of AZD5634 (12.1% drug) and excipients Monodose RSO1, reference device, used with polymer (HPMC) capsules

Table 2 shows the results of a study examining the properties for emptying powder from a capsule 100 & DPI device according to embodiments of the disclosure at low (2kPa) and medium (4kPa) inhalation force rates. The capsule used in table 2 has the same properties as the capsule used in table 1 above. Due to the new capsule design, the inhaler used for the “horizontal device”, “vertical device” and “active device” had to be modified. Examples of such inhalers are described below with reference to Figures 5A to 13.

Table 3

Table 3 shows the results of a study examining the properties for emptying powder from a capsule & DPI device according to embodiments of the disclosure at a medium (4kPa) inhalation force rate as a function of storage time at different temperatures. The capsule used in table 3 has the same properties as the capsule used in table 1 above.

Table 4

Table 3 shows the results of a study examining the properties for emptying powder from a capsule & DPI device according to embodiments of the disclosure at a low (2kPa) inhalation force rate as a function of storage time at different temperatures. The capsule used in table 4 has the same properties as the capsule used in table 1 above.

Studies on capsules manufactured according to the above description therefore demonstrate that retention in the capsule and/or DPI device is low, and comparable to HPMC capsules in Monodose®. Studies have shown capsule retention ~5-7% of charged amount and device retention ~10% of charged amount. No significant flow rate dependence for capsule retention was demonstrated at low and medium inhalation effort.

Furthermore, aerosolisation of powder in a DPI device was tested at low (2kPa) and medium (4kPa) flow rates. Fine particles in aerosol delivered to patient (powder dispersion efficiency) were tested, and the Fine Particle Fraction, FPF (mass <5pm) was very high and comparable to HPMC capsules in Monodose (~80% of delivered dose). Mass Median Aerodynamic Diameter (MMAD) was also on target and comparable (~2.5pm). No significant flow rate dependence for aerosolization efficiency was demonstrated at low and medium inhalation effort. Storage (30C/75%RH and 40C/75%RH) has no significant difference for low and medium inhalation effort, neither for FPF nor for MMAD.

Figure 4 shows an example flow chart of an example method of manufacturing a dry powder formulation inhaler capsule, such as the dry powder formulation inhaler capsule of any of Figures 1 to 3.

The method comprises the steps of cold forming 1010 two capsule halves of equal shape and geometry from aluminium foil, each capsule half 100A, 100B comprising a wing 102A, 102B that extends outward in a plane around a respective elongate domed portion 105A, 105B, the wing 102 of each capsule circumscribing the base 106 of the elongate domed portion 105. The method then comprises filling 1020 each elongate domed portion 105 with a powdered dose of medicament for inhalation, and welding 1030 the wings of the two capsule halves together to form a hermetic seal about a bisecting plane 150 that bisects the welded capsule, such that the two elongate domed portions 105A, 105B when welded together approximate the ellipsoidal shape of a standard pharmaceutical capsule.

Cold forming 1010 the two capsule halves 100A, 100B may comprise cold forming the two capsule halves 100A, 100B such that each capsule half 100A, 100B bisects the welded capsule along its longitudinal axis, the longitudinal axis being in a direction corresponding to the greatest dimension of the welded capsule 100 in the bisecting plane 150.

In some examples cold forming 1010 the two capsule halves 100A, 100B additionally or alternatively comprises cold forming the two capsule halves 100A, 100B such that the two elongate domed portions 105A, 105B when welded together approximate the ellipsoidal shape of a standard pharmaceutical capsule size 2 in terms of volume.

In some examples cold forming 1010 the two capsule halves 100A, 100B additionally or alternatively comprises cold forming the two capsule halves such that the wing 102A, 102B of each capsule half extends outward from the base 106A, 106B of the elongate domed portion 105A, 105B by a distance I, and wherein the value of the distance I is constant around the base 106A, 106B of the corresponding elongate domed portion 105A, 105B.

In some examples cold forming 1010 the two capsule halves 100A, 100B additionally or alternatively comprises cold forming the two capsule halves 100A, 100B such that the wing 102A, 102B of each capsule half 100A, 100B forms an obround shape around the base 106A, 106B of the corresponding elongate domed portion 105A, 105B.

In some examples cold forming 1010 the two capsule halves 100A, 100B additionally or alternatively comprises cold forming the two capsule halves 100A, 100B such that the elongate domed portion 105A, 105B of each capsule half 100A, 100B has an obround cross-section in the bisecting plane 150

As noted above, the capsule halves 100A, 100B may be made from aluminium foil. The aluminium foil used may be Aluthene® foil produced by Amcor®, although it will be understood that other foils such as Dessiflex® and Dessiflex Plus® foils may be used.

In some examples the weight of the aluminium foil is at least 100 g/m², for example at least 150 g/m², for example at least 177 g/m². The aluminium foil may be a multi-layered structure, for example comprising at least one polymer layer (for example, a polymer layer, such as polyethylene or polypropylene, on the inside facing the medicament when the capsule 100 is formed), and optionally two polymer layers, for example wherein the aluminium layer is sandwiched between two polymer layers (wherein the two polymer layers may be the same or different to each other).

Preferably, the aluminium foil comprises a polyamide outer layer bound to an aluminium layer via an adhesive layer, with a polyethylene-based extrusion coating overlaid on the aluminium layer providing an inner layer to the capsule 100. In some examples there may additionally or alternatively be a moisture absorbing layer, for example comprising a CaO desiccant.

The thickness of the polyamide nylon layer may range from 12 to 30 pm, and preferably may be at least 25 pm. The thickness of the aluminium layer may range from 20 to 160 pm, for example, for example from 40 to 120 pm, for example from 40 to 100 pm, for example from 30 to 60 pm, and may preferably be 45 pm, and the thickness of the polyethylene-based extrusion coating may be at least 25 pm.

The polyamide layer supports the cold forming process, reducing the stiffness. A minimum aluminium layer thickness is needed for ultimate moister and oxygen barrier properties. Very thin aluminium layer may through stress crack/open up during blister forming. The minimum thickness depends on the medicament/powder sensitivity.

The polymer layer (which will be on the inside of the capsule facing the medicament) can be modified as cold forming is possible in the range 10 pm to 100 pm with current foils and processes. Using a very thick polymer layer may reduce the moisture barrier efficiency as the seal will be wider and that is where the moisture goes. Different sealing methods may be used; heat sealing and ultrasonic sealing. Different foils require different sealing temperatures and because some medicaments may be very heat sensitive some foils may therefore be less applicable. Polyethylene is a good choice if heat reduction is important, due to the relatively low melting point (~126-132C, dependent on the quality).

Preferably the capsule 100 is configured such that its contents do not encounter a relative humidity of greater than 15 % during storage. It will be understood that control of the seal formed between the wings 102A, 102B is of particular importance for the control of moisture ingress to the capsule 100.

Accordingly, in some examples the method of manufacture may further comprise forming the aluminium foil by binding an aluminium layer to a polyamide layer via an adhesive layer and overlaying a polyethylene-based extrusion coating on the aluminium layer. As noted above, due to the new capsule design, the inhaler used for the “horizontal device”, “vertical device” and “active device” had to be modified. Figure 5A shows a perspective view of an example modified dry powder inhaler (DPI) 400. The DPI 400 comprises a rotatable mouthpiece 402 that is couplable to a capsule compartment 404. The rotatable mouthpiece 402 comprises an elongate portion 402a for a user to insert into their mouth, and a base portion 402b configured to couple to the capsule compartment 404. The base portion 402b in the example shown is spherical and comprises ribbed portions circumscribing a proximal region of the base portion 402b and configured to enable a user to grip the mouthpiece 402 to rotate it relative to the capsule compartment 404. In the example shown the rotatable mouthpiece 402 comprises an air inlet 402c in the base portion 402b between the ribbed portions and the elongate portion 402a for admitting air into the DPI 400, and an air outlet 402d for drawing air from the DPI 400 at a distal end of the elongate portion 402a of the rotatable mouthpiece 402, although it will be understood that the air inlet 402c may be located elsewhere on the DPI 400.

In the example shown, the elongate portion 402a of the rotatable mouthpiece 402 has an oval cross-section, such that the air outlet 402d has an oval cross-section. It has been surprisingly found that having an oval cross-section improves air flow through the inhaler 400, which in turn improves movement (spinning) of the capsule 100 within the capsule compartment 404 and thereby improves dispensing of the medicament contained therein.

Figure 5B shows a perspective view of a portion of the example DPI 400 of Figure 5A showing the capsule compartment 404. As can be seen in Figure 5B, the capsule compartment 404 comprises a cavity 406 for receiving a dry powder formulation inhaler capsule such as the capsule 100 shown in Figures 1 to 3. In the example shown in Figure 5B, the cavity 406 is elongate and extends in the same longitudinal direction as the elongate portion 402a of the rotatable mouthpiece 402. The cavity 406 comprises a pair of slots 408 on opposing sides of the cavity 406 extending the length of the cavity 406 in the same longitudinal direction as the cavity 406 and the elongate portion 402a of the rotatable mouthpiece 402 for receiving the wing 102 of the capsule 100 for inhibiting rotation of the capsule 100 in the cavity 406. Although not shown in Figure 5B, the cavity 406 also comprises at least one piercing means 412 (shown in Figure 6). Figure 5C shows a perspective view of the example DPI 400 of Figures 5A and 5B and shows how the rotatable mouthpiece 402 couples to the capsule compartment 404. It also shows how a capsule 100 can be inserted in a vertical orientation (so that the longitudinal axis of the capsule 100 is parallel to the longitudinal axis of the elongate portion 402a of the rotatable mouthpiece 402) into the cavity 406 of the capsule compartment 404. Figure 5C also shows how a lower portion 405 comprises the cavity 406 of the capsule compartment 404.

The components of the DPI 400 are shown in more detail in Figure 6, which shows an exploded perspective view of the example DPI 400 of Figures 5A, 5B and 5C. As can be seen, the DPI 400 comprises a mouthpiece 402, a mouthpiece insert 416, a capsule compartment 404, a biasing means 414 (which in this example is a spring), a lower portion 405, a piercing means 412 (which in this example is a pair of flat bevel point needles, although it will be understood that needles or other piercing means may be used), and a base portion 410. The capsule compartment 404 is configured to couple to the rotatable mouthpiece 402 which is fixed to the mouthpiece insert 416. The mouthpiece insert 416 comprises two opposing inclined portions 416a, that are generally curved such that they follow the curve of the insides of the rotatable mouthpiece 402 and are configured to raise and/or lower the cavity 406 holding the capsule 100 when the rotatable mouthpiece 402 is rotated. As a result, the DPI 400 is configured to be operated to raise and/or lower the capsule 100 relative to an air flow pathway formed between the air inlet 420 of the base portion 402b, and the air outlet 421 of the elongate portion 402a of the mouthpiece. In particular, the rotatable mouthpiece 402 is configured to raise the capsule 100 proximate to the air inlet 420 of the base portion 402b. The lower portion 405 has two protrusions 405a configured to engage with the inclined portions 416a of the mouthpiece insert 416, and the biasing means 414 is configured to engage each of the protrusions 405a with a corresponding inclined portion 416a such that when the rotatable mouthpiece 402 is rotated, the mouthpiece insert 416 also rotates, thereby raising or lowering the lower portion 405 and thereby the cavity 406 holding the capsule 100. Beneath the lower portion 405 sits the piercing means 412 (which in this example is a flat bevel point needle) that, when assembled, extends into the cavity 406 of the lower portion 405 when the lower portion 405 is lowered. In the example shown the piercing means 412 extends in the same longitudinal direction as the cavity 406 and the elongate portion 402a of the rotatable mouthpiece 402. The base portion 410 supports the piercing means 410 and is configured to couple to the inside of the capsule compartment 404 to hold the biasing means 414 into engagement with the lower portion 405 and the capsule compartment 404/the mouthpiece insert 416. The base portion 410 may couple to the capsule compartment 404 via clips that are configured to be received by corresponding recesses in the capsule compartment 404. The mouthpiece portion 402 may be configured to be coupled to the capsule compartment 404 via a coupling means, such as a screw, or a protrusion or pair of protrusions (for example, on the mouthpiece portion 402) that are configured to be received by a corresponding receiving portion (for example, on the capsule compartment 404).

Figure 7A shows a cross-section of the example DPI 400 of Figures 5A to 6, and Figure 7B shows a cross-section of the example DPI 400 of Figures 5A to 6 with a dry powder formulation inhaler capsule 100 inserted.

In Figures 7A and 7B it can be seen how the pair of flat bevel point needles 412 are arranged to pierce the short end of the capsule 100 (i.e. , an end corresponding to one of the longitudinal ends of the capsule 100). The orientation of the piercing means/needles 412 relative to the capsule 100 in the capsule compartment 404 is important as it affects the way in which the aluminium foil of the capsule 100 folds inside the capsule 100, thereby affecting the flow of medicament out of the capsule 100. In the example shown the taper of the needles 412 is chosen to taper toward the outside of the capsule, thereby causing the aluminium foil of the capsule to fold inwards and towards the sides of the capsule 100, thereby facilitating the free flow of medicament out of the capsule 100.

In use, the mouthpiece 402 is rotated 150 degrees counterclockwise to detach it from the capsule compartment 404. This exposes the cavity 406. A capsule 400 is inserted into the cavity 406 and is pierced by the piercing means 412 extending into the cavity 406 as it is being inserted into the cavity 406. The mouthpiece 402 is then reattached and rotated 150 degrees clockwise to lift up the capsule 100 and the capsule cavity 406, such that the capsule 100 is proximate to the to the air inlet 402c of the base portion 402b and in an air flow pathway formed between the air inlet 402c of the base portion 402b, and the air outlet 402d of the elongate portion 402a of the mouthpiece. As a result, when the pierced capsule 100 is raised into the air flow pathway, if the user sucks on the air outlet 402d of the elongate portion 402a of the mouthpiece 402 (i.e., draws air through the air outlet 402d) air is drawn into the DPI 400 via the air inlet 420 in the base portion 402b of the mouthpiece portion 402, and past the pierced capsule 100. Turbulence may be created (for example due to the relative arrangement and positioning of apertures forming the air inlet 402c), and the capsule 100 may optionally be configured to spin around inside the DPI 400 in the presence of such turbulence, releasing powder/medicament which is drawn into the air flow and up through the air outlet 402d into the user’s mouth and lungs. The presence of wings 106 on the capsule 100 may help to improve the interaction of the capsule 100 with the air flow, thus helping to improve spinning and thereby dispensing of powder/medicament.

By providing slots 408 either side of the cavity 406 to inhibit rotation of the capsule 100 this may help to prevent potential damage that may occur to the piercing means 412 if the capsule were otherwise permitted to rotate in the cavity 406. For example, if the capsule 100 were to rotate inside the cavity, if the piercing means 412 were a pair of flat bevel point needles, the needles may become damaged and/or fragment.

Furthermore, the provision of slots 408 may make it easier for a user to accurately insert a capsule 100 into the DPI 400 in a correct manner.

In some examples the capsule compartment 404, 704 comprises means to aid in the dispensing of medicament when spinning in a capsule compartment 104, 704. An example of this is shown in Figure 8. Figure 8 shows a perspective view of the capsule compartment of an example dry powder formulation inhaler of embodiments of the disclosure, the capsule compartment 104 of Figures 5A to 7B comprising an agitating means 490 to aid in the dispensing of medicament. In this example the capsule compartment 104 also comprises a grid 425 as described above. In the example shown, the agitating means 490 comprises a pair of opposing bumps or protrusions. While the bumps or protrusions are shown with respect to the vertical orientation inhaler 400 of Figures 5A to 7B, it will be understood that the agitating means 490 may be provided on the horizontal orientation inhaler 700 of Figures 9A to 11C (described below) also. The agitating means 490 are configured to knock the capsule 100 as it spins inside the capsule compartment 104 to aid in the dispensing of medicament.

Figure 9A shows a perspective view of another example dry powder inhaler 700 containing a dry powder formulation inhaler capsule 100 such as the capsule 100 described above with reference to Figures 1 to 3, and Figure 9B shows another perspective view of the example dry powder inhaler of Figure 9A. The dry powder inhaler 700 of Figures 9A and 9B is configured to hold the capsule 100 in a horizontal orientation as opposed to the vertical orientation of the inhaler 400 of Figures 5A to 7B. The dry powder inhaler 700 of Figures 8A and 8B nevertheless shares many features in common with the dry powder inhaler 400 of Figures 5A to 7B, and like reference numerals represent features with the same or similar functionality.

As shown in Figure 9A, the dry powder inhaler 700 comprises a mouthpiece portion 702 comprising an elongate portion 703 for a user to insert into their mouth, and a capsule compartment 704. The mouthpiece portion 702 is connected via a hinge to the capsule compartment 704 via a coupling means such as a clip, such that operation of the coupling means permits the mouthpiece portion 702 to hinge relative to the capsule compartment 704 to provide access to the capsule compartment 704, for example to insert a capsule.

In the example shown the capsule compartment 704 is circular in cross-section and comprises a pair of air inlets 720 for admitting air into the DPI 700, and an air outlet 721 for drawing air from the DPI 700 at a distal end of the elongate portion 703 of the mouthpiece 702. In the example shown, the pair of air inlets 720 are configured to permit air to enter into the capsule compartment 704 at a tangent to the circular cross-section of the capsule compartment 704. Advantageously this arrangement may permit air, when drawn via the air outlet 721 , into the capsule compartment 704 to entrain and spin a capsule 100 located therein.

In the example shown, the elongate portion 703 of the mouthpiece portion 702 has an oval cross-section, such that the air outlet 721 has an oval cross-section. It has been surprisingly found that having an oval cross-section improves air flow through the inhaler 700, which in turn improves movement (spinning) of the capsule 100 within the capsule compartment 704 and thereby improves dispensing of the medicament contained therein.

As can be seen in Figure 9B, the capsule compartment 704 comprises a cavity 706 for receiving a dry powder formulation inhaler capsule such as the capsule 100 shown in Figures 1 to 3. In the example shown in Figure 9B, the cavity 706 is elongate and extends in a longitudinal direction transverse to the longitudinal direction of the elongate portion 703 of the mouthpiece portion 702. The cavity 706 is generally oval shaped and is configured to receive an elongate domed portion 105A, 105B of a capsule half 100A, 100B, with the wing 102 of the capsule 100 sitting on the rim of the cavity 706. Although not shown in Figure 9B, the cavity 706 also comprises at least one piercing means 712 (shown in Figures 9A to 9C) that may be operated by a user. The at least one piercing means 712 may be coupled to the mouthpiece portion 702 such that the piercing means 702 may be operated by actuation (e.g., depression) of the mouthpiece portion 702. For example, the mouthpiece portion 702 may move relative to the capsule compartment 704 to move the piercing means 712 relative to a capsule in the capsule compartment 704, as described below with reference to Figures 11A to 11C below).

The capsule compartment 704 also comprises a grid portion 725. The grid portion 725 is configured to guide and entrain air through the elongate mouthpiece 703 and out via the air outlet 721. The grid portion 725 is enlarged relative to the grid portion of conventional dry powder inhalers, such that in this example the cross-sectional area of the grid portion 725 is larger than the cross-sectional area of the elongate mouthpiece 703 and air outlet 721. The grid portion 725 is also configured to prevent the capsule 100 lifting too high inside the cavity 706. The arrangement of the apertures in the grid portion 725 are also selected to help guide and entrain the air in a manner that helps to spin a capsule 100 located in the capsule compartment 704. The grid portion 725 is shown in more detail in Figure 10.

Figure 10 shows a plan view of an inhaler grid 725 of an example dry powder inhaler of embodiments of the disclosure. In Figure 9 the grid is shown as being for use with the horizontal orientation dry powder inhaler 700 of Figures 9A and 9B, however it will be understood that it could also be used with the vertical orientation dry powder inhaler 400 of Figures 5A to 7B, as shown in Figures 11A to 12B and described in more detail below. Through the grid portion 725 the smaller oval-shaped cross-section of the elongate mouthpiece 703 can be seen. In the example shown the grid portion 725 has a circular cross-section comprising a plurality of apertures. In the example shown the apertures form sectors of the circular cross-section. In the example shown the circular cross-section comprises a plurality of sectors divided by a plurality of smaller supporting circular grids intersecting each sector. Advantageously this arrangement has been found to improve air flow.

As described above, the capsule compartment 704 comprises piercing means 712 that may be operated by a user to pierce a capsule 100 in the cavity 706 of the capsule compartment 704. An example of the piercing means 712 is shown in Figures 10A to 10C. Figure 11A shows a cross-section of the example dry powder inhaler 700 of Figures 9A and 9B with a dry powder formulation inhaler capsule inserted and being pierced with a piercing means 712. Figure 11 B shows a cross-section of the example dry powder inhaler 700 of Figures 9A and 9B with a dry powder formulation inhaler capsule 100 inserted with the piercing means 712 being retracted from the capsule. Figure 11C shows a crosssection of the example dry powder inhaler of Figures 8A to 9B with a dry powder formulation inhaler capsule inserted with the piercing means 712 completely retracted. The mouthpiece portion 702 of the inhaler 700 is actuatable by a user to operate the piercing means 712. In the example shown, the piercing means 712 are a pair of flat bevel point needles, similar to those described above with reference to Figures 7A and 7B. In the example shown, the mouthpiece portion 702 is coupled to the piercing means 712. The mouthpiece portion 702 may be depressed and thereby move relative to the capsule compartment 704 to cause the piercing means 712 to move relative to a capsule 100 contained therein and thereby pierce a capsule 100 contained in the capsule compartment 704. The piercing means 712 may then be retracted (for example by releasing the mouthpiece portion 702, for example if the mouthpiece portion 702 comprises a biasing means configured to hold the mouthpiece portion 702 in a separated configuration from the capsule compartment 704) to remove the piercing means 712 from the capsule 100.

As with the piercing means 412 of Figures 7A and 7B, the orientation of the piercing means/needles relative to the capsule 100 in the capsule compartment 704 is important as it affects the way in which the aluminium foil of the capsule 100 folds inside the capsule 100, thereby affecting the flow of medicament out of the capsule 100. Preferably, the piercing means 712 are configured to pierce a portion of the capsule 100 proximate to its short end (i.e., a region of the capsule proximate to the wings 102 proximate to one of the longitudinal ends of the elongate domed portion 105). In the example shown, the taper of the needles 712 is chosen to taper toward the centre of the capsule, thereby causing the aluminium foil of the capsule to fold inwards and towards the centre of the capsule 100, thereby facilitating the free flow of medicament out of the capsule 100. In use, a user opens the inhaler 700 to expose the capsule compartment 704. A capsule 100 is inserted into the cavity 706 of the capsule compartment 704, and the inhaler closed again by hinging the mouthpiece portion 702 back and operating the coupling means 780 to couple the mouthpiece portion 702 to the capsule compartment. A user then pierces the capsule 100 contained therein by depressing on the mouthpiece portion. As shown in Figures 11A to 11C, the piercing means 712 pierce the capsule 100 contained therein and then may be retracted from the capsule. A user may then suck on the air outlet 721 of the elongate mouthpiece portion 703, thereby drawing air in through the air inlets 720. This causes the pierced capsule 100 to lift out of the cavity 706 inside the capsule compartment 704 and spin. The grid 725 prevents the pierced capsule 100 from lifting too high and helps to encourage the capsule 100 to spin. As the pierced capsule spins, it releases medicament which is entrained in the air flow and drawn into the user’s lungs.

Figs. 12A and 12B show two alternative examples of a DPI that includes needles or piercing means 712 for piercing a capsule 100 contained therewithin. The orientation of the piercing means/needles relative to the capsule 100 in the capsule compartment is important as it affects the way in which the aluminium foil of the capsule 100 folds inside the capsule 100, thereby affecting the flow of medicament out of the capsule 100. Preferably, the piercing means 712 are configured to pierce a portion of the capsule 100 proximate to its short end (i.e., a region of the capsule proximate to the wings 102 proximate to one of the longitudinal ends of the elongate domed portion 105).

In the example shown in Fig. 12A there are a pair of symmetrical piercing means 712 both configured to pierce the short end of the capsule 100 in a direction parallel to the longitudinal axis of the capsule 100. In the example shown in Fig. 12A, the taper of the needles 712 is chosen to taper toward the centre of the capsule 100, thereby causing the aluminium foil of the capsule to fold inwards and away from the centre of the capsule 100, thereby facilitating the free flow of medicament out of the capsule 100.

In the example shown in Fig. 12B there are a pair of symmetrical piercing means 712 both configured to pierce the short end of the capsule 100 in a direction perpendicular to the longitudinal axis of the capsule 100. In the example shown in Fig. 12B, the taper of the needles 712 is chosen to taper away from the longitudinal axis of the capsule 100, thereby causing the aluminium foil of the capsule to fold inwards and away from the centre of the capsule 100, thereby facilitating the free flow of medicament out of the capsule 100.

Fig. 13 shows a cross-section through an example active dry powder inhaler 1300 for use with the example capsule 100 described above. The active dry powder inhaler 1300 is configured to enable a pressurised air source to be passed into and through a capsule 100 contained therewithin to aid in the dispersion of a medicament to a user who may have difficulty breathing deeply (such as a child or a person with lung disease). The active dry power inhaler 1300 comprises an air inlet 1375 coupled to a first needle, and an air outlet 1370 coupled to a second needle. Both needles are configured, in use, to penetrate a capsule 100 contained within the active dry powder inhaler 1300. To insert or replace a capsule 100 contained within the active dry powder inhaler 1300 there is a removable cap portion 1350 that is removable via a threaded portion 1352 and comprising at least one O- ring 1354 for providing an air-tight seal. The removable cap portion 1350 can be removed to provide access to a cavity within the active dry powder inhaler 1300 configured to receive the capsule 100.

As indicated in Table 2, capsules 100 according to the above description have been tested with respect to piercing and emptying of the dry powder formulation with various needle configurations in three major device geometries; horizontally (lying) spinning capsule (Figures 9A to 12B, vertically (standing) spinning capsule (Figures 5A to 8) and using an active device principle using compressed air and hollow needles for emptying. It has been shown that it is possible to customize these inhaler types to interface the novel aluminum capsule and to optimize performance.

Fig. 14 shows a chart of emptying time of capsules according to embodiments of the disclosure compared to conventional capsules. Powder was filled into both aluminium capsules and conventional HPMC capsules and doses were withdrawn using the horizontal device (described above for example with respect to Figs. 9A to 11C) and Monodose® RS01 , respectively. The inspiratory force was 4kPa and the inhalations continued for 2 sec, corresponding to approx. 2L of inhaled air, standard volume used for delivered dose assessments. For the horizontal device different pierced hole sizes were applied through the use of different needle thicknesses (1 .0 mm, 1 .2 mm, 1 .5 mm and 1 .6 mm). The capsule sizes used for Monodose® (shown in dashed lines on the graph) were size 2 and 3, for the horizontal device the capsule design matched the size 2 capsule. Similar powder fill weights were used; 20mg and 25mg for the two devices. The aerosol delivery is followed by laser diffraction monitoring. It is clear from the graphs that a patient will receive 90% of the dose already in the beginning of a breath for both devices (300-500 msec corresponding to 0.3-0.5L of inhaled air). The needle size and hence the hole diameter, as well as the capsule size, had a minor impact on the emptying time.

In the context of the present disclosure other examples and variations of the apparatus and methods described herein will be apparent to a person of skill in the art.

Aspects of the disclosure are also set out in the following numbered clauses:

1. A dry powder formulation inhaler, DPI, capsule, comprising: two capsule halves, each capsule half comprising an elongate domed portion, at least one of which comprises a dose of powdered medicament for inhalation; wherein each capsule half is formed from a membrane configured to inhibit moisture ingress; and wherein the two capsule halves are welded together about a bisecting plane and form a wing that extends outward in the bisecting plane around the capsule and circumscribing the base of each elongate domed portion of each capsule half to form a moisture impermeable seal, such that the two elongate domed portions when welded together form a cavity that contains a dose of powdered medicament for inhalation.

2. The dry powder formulation inhaler capsule of clause 1 wherein each capsule half bisects the welded capsule along its longitudinal axis, the longitudinal axis being in a direction corresponding to the greatest dimension of the welded capsule in the bisecting plane.

3. The dry powder formulation inhaler capsule of clause 1 or 2 wherein the two capsule halves are identical.

4. The dry powder formulation inhaler capsule of any of the previous clauses wherein the two elongate domed portions when welded together approximate the ellipsoidal shape of a standard pharmaceutical capsule size 2 in terms of volume. 5. The dry powder formulation inhaler capsule of any of the previous clauses wherein the wing extends outward from the base of each elongate domed portion by a distance I, and wherein the value of the distance I is constant around the base of each elongate domed portion.

6. The dry powder formulation inhaler capsule of any of the previous clauses wherein the wing forms an obround shape around the capsule.

7. The dry powder formulation inhaler capsule of any of the previous clauses wherein the elongate domed portion of each capsule half has an obround cross-section in the bisecting plane.

8. The dry powder formulation inhaler capsule of any of the previous clauses wherein each capsule half is formed from aluminium foil.

9. A method of manufacturing a dry powder formulation inhaler, DPI, capsule, the method comprising: forming two capsule halves of equal shape and geometry from aluminium foil, each capsule half comprising an elongate domed portion; filling at least one of the elongate domed portions with a powdered dose of medicament for inhalation; and welding the two capsule halves together to form a moisture-impermeable seal about a bisecting plane that bisects the welded capsule, such that the two elongate domed portions when welded together approximate an ellipsoidal shape and form a wing that extends outward from the ellipsoidal shape in the bisecting plane.

10. The method of clause 9 wherein forming the two capsule halves comprises cold forming the two capsule halves.

11. The method of clause 9 or 10 wherein forming the two capsule halves comprises forming the two capsule halves such that each capsule half bisects the welded capsule along its longitudinal axis, the longitudinal axis being in a direction corresponding to the greatest dimension of the welded capsule in the bisecting plane. 12. The method of any of clauses 9 to 11 further comprising cutting the wing formed by welding the two capsule halves together to form an obround shape around the approximate ellipsoidal shape of the two elongate domed portions.

13. The method of clause 12 wherein the wing of each capsule half extends outward from the base of the elongate domed portion by a distance I, and wherein the value of the distance I is constant around the base of the two elongate domed portions.

14. The method of any of clauses 9 to 13 wherein forming the two capsule halves comprises forming the two capsule halves such that the elongate domed portion of each capsule half has an obround cross-section in the bisecting plane.

15. A dry powder inhaler, DPI, device, the inhaler device comprising: a mouthpiece; at least one air inlet; at least one piercing means; and a capsule compartment comprising an oval-shaped cavity for receiving a capsule therein, wherein the oval-shaped cavity is coupled to the air inlet and the mouth piece to define an air flow path between the air inlet, the cavity and the mouthpiece, and wherein the relative arrangement of the air inlet, the cavity and the mouthpiece are configured to create an air flow path to spin a capsule contained therein when a user inhales though the mouthpiece; wherein operation of the piercing means is configured to pierce the capsule with the piercing means and then retract the piercing means from the capsule to leave at least one aperture in the capsule for dispensing a medicament contained in the capsule; and wherein the oval-shaped cavity comprises bumper features within the cavity configured to bump or knock the capsule when spinning in the cavity to provoke and enhance emptying of the medicament into the air flow path.

16. The dry powder inhaler device of clause 15 wherein the capsule is elongate and approximately ellipsoidal having two long edges and two short edges, and wherein the piercing means are configured to pierce the capsule proximate to both short edges of the capsule. 17. The dry powder inhaler of clause 16 wherein the capsule comprises a wing that extends outward in a bisecting plane around the capsule, and wherein the cavity comprises at least one slot for receiving the wing of the capsule to position the capsule relative to the piercing means for piercing the capsule proximate to both short edges of the capsule by the piercing means.

18. The dry powder inhaler device of any of clauses 15 to 17 wherein the inhaler device further comprises a grid between the cavity and mouthpiece to prevent the capsule or capsule fragments from travelling from the cavity and through the mouthpiece via the air flow path.

19. The dry powder inhaler device of any of clauses 15 to 18 wherein the capsule compartment is openable and closable to provide access to the cavity to insert or remove a capsule therein.

20. The dry powder inhaler device of any of clauses 15 to 19 wherein the relative arrangement of the air inlet, the cavity and the mouthpiece are configured to create an air flow path to spin a capsule contained therein and cause an audible noise when a user inhales though the mouthpiece.

21. The dry powder inhaler device of any of clauses 15 to 20 wherein the piercing means are configured to be activated by at least one of: i) opening and closing of the device, ii) rotating the mouthpiece, and/or iii) pressing a button on the side of the inhaler device.

22. The dry powder inhaler device of any of clauses 15 to 21 wherein the mouthpiece is rotatable and is configured to lift a capsule off the piecing means upon rotation of the mouthpiece.

23. The dry powder inhaler of any of clauses 15 to 22 comprising the dry powder formulation inhaler capsule of any of clauses 1 to 8.

24. A dry powder inhaler, DPI, device, the inhaler device comprising: a mouthpiece defining a conduit and having an air outlet, the air outlet being elliptical in shape ; at least one air inlet; a capsule compartment between the air inlet and the conduit; wherein the capsule compartment comprises a cavity for receiving a dry powder formulation inhaler capsule, and a grid separating the capsule compartment from the conduit; wherein the conduit comprises a first cross-sectional area proximate to the air outlet and a larger second cross-sectional area proximate to the grid, and wherein the conduit of the mouthpiece comprises a lumen that tapers conically from the air outlet to the grid.

25. The dry powder inhaler device of clause 24 wherein the grid defines a third cross- sectional area, the third cross-sectional area being approximately circular in shape and being larger than the second cross-sectional area.

26. The dry powder inhaler device of clause 24 or 25 wherein the relative arrangement of the air inlet, the cavity and the mouthpiece are configured to create an air flow path to spin a capsule contained therein when a user inhales though the mouthpiece

27. The dry powder inhaler device of any of clauses 24 to 26 wherein the dry powder inhaler device further comprises at least one retractable piercing means, and wherein operation of the piercing means is configured to pierce the capsule with the piercing means and then retract the piercing means to leave at least one aperture in the capsule for dispensing a medicament contained in the capsule

28. The dry powder inhaler device of any of clauses 24 to 27 wherein the dry powder inhaler device comprises a pair of piercing means configured to create four holes in the capsule.

29. The dry powder inhaler device of any of clauses 24 to 28 wherein the capsule is elongate and approximately ellipsoidal having two long edges and two short edges, and wherein the piercing means are configured to pierce the capsule proximate to both short edges of the capsule. 30. The dry powder inhaler of any of clauses 24 to 29 comprising the dry powder formulation inhaler capsule of any of clauses 1 to 8.

Claims

CLAIMS:

2. The dry powder formulation inhaler capsule of claim 1 wherein each capsule half bisects the welded capsule along its longitudinal axis, the longitudinal axis being in a direction corresponding to the greatest dimension of the welded capsule in the bisecting plane.

3. The dry powder formulation inhaler capsule of claim 1 wherein the two capsule halves are identical.

4. The dry powder formulation inhaler capsule of claim 1 wherein the two elongate domed portions when welded together approximate the ellipsoidal shape of a standard pharmaceutical capsule.

5. The dry powder formulation inhaler capsule of claim 1 wherein the wing extends outward from the base of each elongate domed portion by a distance I, and wherein the value of the distance I is constant around the base of each elongate domed portion.

6. The dry powder formulation inhaler capsule of claim 1 wherein the wing forms an obround shape around the capsule.

7. The dry powder formulation inhaler capsule of claim 1 wherein the elongate domed portion of each capsule half has an obround cross-section in the bisecting plane.

8. The dry powder formulation inhaler capsule of claim 1 wherein each capsule half is formed from aluminium foil.

10. The method of claim 9 wherein forming the two capsule halves comprises cold forming the two capsule halves.

11 . The method of claim 9 wherein forming the two capsule halves comprises forming the two capsule halves such that each capsule half bisects the welded capsule along its longitudinal axis, the longitudinal axis being in a direction corresponding to the greatest dimension of the welded capsule in the bisecting plane.

12. The method of claim 9 further comprising cutting the wing formed by welding the two capsule halves together to form an obround shape around the approximate ellipsoidal shape of the two elongate domed portions.

13. The method of claim 12 wherein the wing of each capsule half extends outward from the base of the elongate domed portion by a distance I, and wherein the value of the distance I is constant around the base of the two elongate domed portions.

14. The method of claim 9 wherein forming the two capsule halves comprises forming the two capsule halves such that the elongate domed portion of each capsule half has an obround cross-section in the bisecting plane.

16. The dry powder inhaler device of claim 15 wherein the capsule is elongate and approximately ellipsoidal having two long edges and two short edges, and wherein the piercing means are configured to pierce the capsule proximate to both short edges of the capsule.

17. The dry powder inhaler of claim 16 wherein the capsule comprises a wing that extends outward in a bisecting plane around the capsule, and wherein the cavity comprises at least one slot for receiving the wing of the capsule to position the capsule relative to the piercing means for piercing the capsule proximate to both short edges of the capsule by the piercing means.

18. The dry powder inhaler device of claim 15 wherein the inhaler device further comprises a grid between the cavity and mouthpiece to prevent the capsule or capsule fragments from travelling from the cavity and through the mouthpiece via the air flow path.

19. A dry powder inhaler, DPI, device, the inhaler device comprising: a mouthpiece defining a conduit and having an air outlet, the air outlet being elliptical in shape ; at least one air inlet; a capsule compartment between the air inlet and the conduit; wherein the capsule compartment comprises a cavity for receiving a dry powder formulation inhaler capsule, and a grid separating the capsule compartment from the conduit; wherein the conduit comprises a first cross-sectional area proximate to the air outlet and a larger second cross-sectional area proximate to the grid, and wherein the conduit of the mouthpiece comprises a lumen that tapers conically from the air outlet to the grid.

20. The dry powder inhaler device of claim 19 wherein the dry powder inhaler device further comprises at least one retractable piercing means, and wherein operation of the piercing means is configured to pierce the capsule with the piercing means and then retract the piercing means to leave at least one aperture in the capsule for dispensing a medicament contained in the capsule