PRESSURISED FLUID

Field of the Invention

The present invention relates to a method and apparatus for manufacturing a container of pressurised fluid. In particular, the invention provides a method and apparatus for providing a rupturable container of pressurised fluid for use in aerosolized drug delivery.

Background to the Invention

Inhalers are commonly used to deliver drugs into the body via the lungs, typically for treating conditions such as asthma and Chronic Obstructive Pulmonary Disease (COPD).

The most common type of inhaler is the so-called metered dose inhaler (MDI) in which the drug to be delivered is stored in solution or suspension in a pressurized container that contains a propellant. In use, the MDI releases the drug in an aerosol. Another type of inhaler is the dry powdered inhaler (DPI) in which a drug in powder form is delivered to a patient. Generally, dry powder drug formulations have the advantage over solutions or suspensions in that they are usually more stable during storage and therefore offer a longer shelf life.

The use of inhalers to deliver drugs in this way has several advantages over other drug delivery methods, such as injections. In particular, inhalers enable very rapid onset of relief, the drugs being delivered are not metabolised before entering the blood of a patient, and delivering drugs in this way is not painful or, indeed, even uncomfortable.

In contrast, injections where drug formulations are delivered in liquid form (either as a solution or a suspension) can be painful when administered and often require cold storage, which is particularly the case for vaccines. This is a particularly costly disadvantage when shipping vaccinations around the world, as they must be kept sufficiently cold throughout the entire journey. Sharing needles used for injections can spread infectious diseases, which is a particularly recognised problem in developing countries. So called needle stick injuries, where a health care worker administering the injection is injured by the needle from the injection are also seen as a threat posed by injections. Because of the numerous advantages of using inhalers, and DPIs in particular, to deliver drugs fast and effectively, there is much research into developing dry powder formulations to treat therapies beyond asthma and COPD. For example, the systemic delivery of drug molecules via the pulmonary route could be used to alleviate chronic pain (such as, breakthrough cancer pain), or DPIs could be used for needleless administration of insulin for the treatment of diabetes.

Many of these drug formulations undergoing development need to be delivered in quantities much higher than the typical doses of several tens or hundreds of micrograms required for treating asthma and COPD. For this reason, there is a drive to create respirable "engineered" drug formulations, which do not use the carrier particles (usually lactose) that are typically usually used for DPIs used for treating asthma and COPD.

The majority of DPI devices currently on the market are 'passive' devices, which are solely reliant on the inspiratory energy of the patient to create a respirable aerosol. Passive DPIs to date have typically been developed to deliver blended dry powder formulations, which use relatively large (50 to 300 pm) lactose carrier particles to bulk up the volume of each dose (typically micrograms) of active pharmaceutical ingredient (API). This improves metering accuracy for small doses (as well as aiding powder handling during manufacture, for example, by improving the flowabiiity of the blend). Even for higher doses, a carrier can still be beneficial, as it is extremely difficult to aerosolise pure API using only the inspiratory power from the patient.

In order for the small API particles to reach the deep lung, the aerosolization engine of the DPI must somehow detach the pure drug from the carrier particle on inhalation. Most aerosolization engines within passive DPIs use combinations of impact and shear forces to break-up, disperse and aerosolize formulations. But even the most effective passive DPIs cannot ensure complete deagglomeration of drug and carrier particles on delivery, and the majority of pure drug delivered from the device (typically 70-80%) remains attached to the larger carrier particles. Rather than being delivered to the deep lung for treatment, these combined particles impact on the mouth and throat, both wasting the drug and potentially leading to unwanted side effects.

To avoid this problem with deagglomeration, it would be desirable to deliver API-only formulations of drug from a DPI. The problem with this is that while aerosolization engines including swirl chambers, cyclones and similar are effective for carrier-based formulations, they do not work well with API-only formulations, as the presence of the large carrier particles has a significant impact on the operation of the DPI. For example, without the presence of larger carrier particles API would accumulate at the walls, where it is not exposed to the aerodynamic drag caused by the airflow (as the size of respirable particles is smaller than the thickness of the boundary layer), and can be held there by a

combination of Van der Waal's, electrostatic and surface energy forces. These close- acting forces can vary depending upon, for example, environmental conditions and consequently the accumulated fraction of deposition can be thought of as 'fragile'. For example, the impact created by knocking or dropping the inhaler could dislodge the deposition (unknown to the user), who could then receive a much higher dose than expected. This would mean that the inhaler product would (rightly) fail the mandatory dose content uniformity requirements, and not be approved for regulated markets. This is a significant reason why current DPIs that use relatively large carrier particles for the API are not suitable for delivering API-only formulations.

The use of carrier particles greatly increases the costs of formulation development of drugs for use in DPIs, due to the need to create a homogeneous blend of API with the carrier excipient. Particles also have to be made smaller than necessary to account for incomplete deagglomeration by the device engine, and the stability of the carrier-API mix must be ensured. Furthermore, poor carrier-API deagglomeration means that the best passive DPIs (using a carrier) currently available are typically no more than 50% effective or, in other words, 50% of the drug (API) is wasted in normal use.

Although passive devices are low cost, their performance is typically limited by the underlying physics, and they typically require high formulation development costs. A further disadvantage of passive devices is that the delivered dose of API is highly dependent on the inhalation strength of the user, which may not be sufficient in patients with impaired lung function, for example those who are unwell, elderly or very young. For these reasons, the delivery of active pharmaceutical (API)-only engineered

formulations, for DPI therapies beyond asthma and COPD, requires different device technology to carrier-based DPIs.

In order to meet this demand, 'active' dry powder inhalers capable of delivering API-only formulations are under development as an alternative to passive DPIs. Rather than relying on the inspiratory effort of the user, active DPIs provide the power to aerosoiise and deliver the API by another means, leading to a uniform and repeatable drug-delivery step that is independent of the inhalation strength of a user. This power may be provided, for example, via electricity from a battery or from compressed air. Active delivery provides huge performance advantages, but existing devices are complicated to use and manufacture, and as a result are costly for both companies and patients. Due to the high complexity and expense of active DPIs, there are currently no active DPIs on the market.

One form of active delivery mechanism involves providing a compressed gas in a rupturable package, referred to as a pressurised blister. A DPI may be configured so that the blister is ruptured in use and the compressed gas escaping from the blister is used to aerosolize a powdered drug formulation. One difficulty with this delivery mechanism is the cost and complexity of the manufacture of the pressurised blister. There are two main methods for producing pressurised containers - cold filling and pressure filling. Both techniques involve expensive equipment. It would therefore be desirable to be able to produce pressurised containers for active delivery device that are effective and inexpensive.

Summary of the Invention

The invention is defined in the appended independent claims, to which reference should be made. Advantageous features are set out in the dependent claims.

In a first aspect of the invention, there is provided a method of forming a package of pressurised fluid, comprising: providing a sealed container holding a first fluid; compressing a first portion of the container, the first portion of the container having a least one deformable wall, to force fluid out of the first portion into a second portion of the container; and

sealing the first portion from the second portion.

This method of forming a pressurised package does not require the use of a hyperbaric chamber, cold filling apparatus or liquefied gases. It can be performed using standard manufacturing equipment.

The method may further comprise providing a substance to be delivered in the first fluid. The substance may be a powder and in particular a therapeutic agent, such as a powdered medicament. The medicament may include an active pharmaceutical ingredient. As used herein, the term "therapeutic agent" includes any synthetic or naturally occurring

biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and

biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. It also includes compounds administered to an organism as a placebo. The therapeutic agent may consist of an active pharmaceutical ingredient without carrier particles. The substance to be delivered may be held in the second portion.

The method may comprise separating the first portion from the second portion following the step of sealing. The first portion does not contain any pressurised fluid and so can be discarded. Following separating the second portion from the first portion, the periphery of the second portion may be provided with a lock-seam by folding the edges and crimping.

The first portion may comprise a first chamber and the second portion may comprise a second chamber. The container may comprise a connecting portion providing a fluid path between the first chamber and the second chamber. The connecting portion may be a relatively narrow conduit between the first chamber and the second chamber that can be easily closed following compression of the first chamber. The step of sealing may comprise closing the connecting portion. The first chamber and second chamber may be dimensioned to result in a final pressure in the second chamber following compression of the first chamber of at least 50kPa above atmospheric pressure, and more preferably at least 200kPa above atmospheric pressure.

The first portion may surround the second portion. For example, the first portion may be an annular chamber that surrounds a central second portion. The connecting portion may be annular or may be one or more separate conduits. The use of an annular first portion may provide material savings when compared to a side-by-side configuration for the first and second portion. Alternatively, or in addition, the sealed container may comprise a plurality of first portions, each first portion in fluid communication with the second portion in an initial state. The step of providing a sealed container may comprise bonding a first sheet of fluid impermeable material to a second sheet of fluid impermeable material to define a sealed container between the first and second sheets.

The fluid impermeable material sheets may be formed from a deformable thin sheet. A foil material that provides a gas and moisture barrier may be used. The material may be a laminated foil. The first sheet may be formed with one or more depressions, defining the first and second chambers, for holding the first fluid. The depressions may be formed by cold forming or thermoforming, depending on the materials used.

The step of bonding may comprise bonding the first sheet of fluid impermeable material to the second sheet of fluid impermeable material to define a plurality of sealed containers between the first and second sheets. Bonding of the first sheet to the second sheet may be achieved by the use of adhesives, welding or heat sealing, for example.

Each of the plurality of sealed containers may be formed to have a shape that tessellates in two dimensions. This allows a plurality of sealed containers to be manufactured within minimal material wastage. For example, the sealed containers may be formed in a hexagonal shape, and may comprise a hexagonal annular first portion and a circular second portion within the first portion. Alternatively, the sealed containers may have a triangular, square or rhomboid shape. Alternatively, the sealed containers may be formed in a circular shape.

The step of sealing may comprise heat sealing or welding the first sheet to the second sheet. The first and second sheets may have a laminar structure, which may include an aluminium layer to provide a moisture barrier and one or more thermoplastic layers, or layers of heat-seal lacquer that can form a heat seal.

The substance to be delivered may be held close to the second sheet. In this way the substance is held close to the exit surface and the pressurised fluid can expand through and around the substance to be delivered, creating an aerosol. The method may further comprise treating the sealed container to provide one or more points of weakness in the second portion. The point of weakness is preferably in the second sheet. The step of treating may comprise kiss-cutting, laser etching or scoring the second sheet to provide one or points of weakness without affecting the barrier properties of the second sheet.

The first fluid is preferably a gas, such as air, nitrogen or carbon dioxide. The gas may be unreactive with the substance to be delivered to ensure that the substance can be stored within the container for a long time.

The method may further comprise providing a separating wall within the sealed container to define a first fluid compartment containing the first fluid and a second fluid compartment containing a second fluid, wherein the step of compressing a first portion of the container comprises compressing a first portion of the first fluid compartment to force the first fluid out of the first portion into a second portion of the first fluid compartment and compressing a first portion of the second fluid compartment to force the second fluid out of the first portion into a second portion of the second fluid compartment, and wherein the step of sealing comprises sealing the first portion of the first fluid compartment from the second portion of the first fluid compartment and sealing the first portion of the second fluid compartment from the second portion of the second fluid compartment.

The method may comprise providing a substance to be delivered, such as a powder, in the second portion of the first fluid compartment or the second portion of the first fluid compartment. The substance may be provided adjacent to the separating wall.

The pressure in the second portion of the first fluid compartment may be the same as or different to the pressure in the second portion of the second fluid compartment. By appropriately designing the ratios of the volumes of the portions in each compartment any desired pressures can be achieved. The step of compressing a first portion of the container may comprise compressing a first portion of the first fluid compartment to force the first fluid out of the first portion into a second portion of the first fluid compartment and

simultaneously compressing a first portion of the second fluid compartment to force the second fluid out of the first portion into a second portion of the second fluid compartment, to ensure that a pressure difference across the separating wall does not exceed a threshold pressure difference. The threshold pressure difference may be a pressure difference above which the separating wall would rupture. The separating wall may be formed from a laminated foil. The laminated foil may include one or more heat sealable layers. The separating foil may be formed from a cold-formed foil with depressions in positions corresponding to depressions in the first sheet. The method may further comprise treating the separating wall to provide one or more areas of weakness so that the separating wall ruptures at a predetermined pressure. Alternatively, or in addition, portions of the separating wall may have a different construction to ensure that the separating wall ruptures at a predetermined pressure. The step of treating the separating wall may comprise kiss-cutting, laser etching or scoring the separating wall.

The second fluid may be the same as or different to the first fluid. The second fluid may be a gas, such as air, nitrogen or carbon dioxide.

The method may comprise providing a plurality of separating walls within the sealed container to provide more than two separate fluid compartments. The resulting pressure in each second portion of each compartment can be chosen by appropriate design of the first portions.

In a second aspect of the invention, there is provided an apparatus for forming a package of pressurised fluid, comprising: a first chamber comprising a first fluid, a second chamber, and a connecting portion providing a fluid path between the first chamber and the second chamber, the first chamber, second chamber and connecting portion together forming a sealed container, wherein the first chamber comprises at least one deformable wall allowing the first chamber to be crushed without rupturing, wherein the connecting portion is configured to be sealed to seal the first chamber from the second chamber following the crushing of the first chamber.

The second chamber may contain a substance for delivery with the first fluid. The substance may be a powder and in particular a powdered medicament. The medicament may include an active pharmaceutical ingredient. The substance to be delivered may be held in the second chamber.

The first fluid may be a gas such as air, nitrogen or carbon dioxide. The apparatus may comprise a plurality of first chambers, each in fluid communication with the second chamber. The apparatus may comprise a first sheet of fluid impermeable material bonded to a second sheet of fluid impermeable material to define the first chamber, second chamber and connection portion between the first and second sheets. Fluid impermeable in this context means that the fluid in the container does not leak through the material

significantly, so that container remains at a stable pressure. The fluid impermeable material may comprise a layer of aluminium.

The first sheet may be formed with one or more depressions defining the first or second chamber. The first sheet may comprise a deformable cold-formed sheet, which may be, for example, a foil or a laminated plastic sheet. The second sheet may comprise a laminated foil.

The first sheet of fluid impermeable material may be bonded to the second sheet of fluid impermeable material to define a plurality of containers between the first and second sheets, each container comprising a first chamber, a second chamber and connection portion between the first and second chambers.

The first chamber may surround the second chamber. The first chamber may be annular. The first chamber may have a shape that tessellates in two dimensions.

The first or second sheet may be treated in the region of the connection portion so as to bond to the other of the first or second sheets on the application of heat or pressure. The apparatus may further comprise a separating wall that divides each of the first and second chambers into two fluid compartments, a first fluid compartment of the first chamber being in fluid communication with a first fluid compartment of the second chamber through a first connecting portion, and a second fluid compartment of the first chamber being in fluid communication with a second fluid compartment of the second chamber through a second connecting portion.

The first fluid compartment of the first portion may contain the first fluid and the second fluid compartment of the second portion contains a second fluid. The second fluid may be the same as or different to the first fluid. The second fluid may be, for example, air, nitrogen or carbon dioxide. The ratio of the volume of the first compartment of the first chamber to the second compartment of the first chamber may be the same or different to the ratio of the volume of the first compartment of the second chamber to the second compartment of the second chamber. The first chamber and second chamber may be dimensioned to result in a final pressure in the second chamber following compression of the first chamber of at least 50kPa above atmospheric pressure, and more preferably at least 200kPa above atmospheric pressure.

At least a portion of the separating wall may be formed from a laminated foil. A substance for delivery, such as a powdered medicament, may be mounted to the separating wall.

The apparatus may comprise a plurality of separating walls to provide more than two separate fluid compartments within each chamber. The resulting pressure in each compartment of the second chamber can be chosen by appropriate design of the first compartments.

Features described in relation to the first aspect may equally be applied to the second aspect of the invention.

Brief Description of the Drawings

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

Figure 1 is a perspective view of a first sheet used to form a container of pressurised fluid in accordance with the invention; Figure 1 b is a side view of the sheet of Figure 1 a;

Figure 1 c is a cross section view of the sheet of Figure 1 a;

Figure 2 is a perspective view of the sheet of Figure 1 a with a second sheet placed on top;

Figure 3a is a plan view of Figure 2, showing the region in which the first sheet and the second sheet are bonded to one another; Figure 3b is a cross section view of Figure 3a; Figure 4a is a side view of the assembly of Figure 3a and 3b, with a first chamber in crushed configuration;

Figure 4b is a cross section view of Figure 4a;

Figure 5a is a plan view of the assembly of Figures 4a and 4b, with the area of a seal around the second chamber shown;

Figure 5b is a cross section view of Figure 5a;

Figure 6 is a plan view of the assembly of Figure 5a, showing the portion of the assembly that is cut out to form the package of pressurised fluid;

Figure 7a is a perspective view of the final package, containing pressurised fluid; Figure 7b is a cross section view of Figure 7a;

Figure 8a is a perspective view of a first sheet material used to form a package of pressurised fluid in accordance with a second embodiment of the invention;

Figure 8b is a side view of Figure 8a;

Figure 8c is a cross section view of Figure 8b; Figure 9 shows the first sheet of Figure 8 with a second sheet placed on top;

Figure 10a is a plan view of Figure 9, showing area of a bond between the first sheet and the second sheet;

Figure 10b is a cross section view of Figure 10a;

Figure 11a is a side view of the assembly of Figure 10b, with the first chamber in a crushed configuration;

Figure 11 b is a cross section view of Figure 11a;

Figure 12a is a plan view of the assembly of Figures 11 a and 11 b, with the position of a seal around the second chamber shown;

Figure 12b is a cross section view of Figure 12a; Figure 13 is a plan view of the assembly of Figures 12a and 12b illustrating the portion of the assembly that is cut away to provide the sealed package of pressurised fluid;

Figure 14a is a perspective view of the final package;

Figure 14b is a cross section view of Figure 14a; Figure 15 is a cross section view of an assembly in accordance with the third embodiment of the invention used to form a package of pressurised fluid having first and second portions separated by a separating wall;

Figure 16 shows the assembly of Figure 15 with the first chamber having been crushed;

Figure 17 shows the assembly of Figure 16 with a seal formed around the second chamber;

Figure 18 shows the final container of pressurised fluid in accordance with the third embodiment;

Figure 19a is a perspective view of an assembly in accordance with a fourth embodiment of the invention, used to provide a container of pressurised fluid having first and second portions separated by a separating wall;

Figure 19b is a cross section of Figure 19a;

Figure 20 shows the assembly of Figure 19b with the first chamber having been crushed; Figure 21 shows the assembly of Figure 20 with a seal formed around the second

Figure 22a is a perspective view of the final package of pressurised fluid; Figure 22b is a cross section of Figure 22a;

Figure 23 shows a first layout of recesses formed in a first sheet, in order to produce packages of pressurised fluid in accordance with the first embodiment;

Figure 24 shows a layout of recesses formed in a first sheet in accordance with the second embodiment of the invention; Figure 25 shows a tessellated layout for the containers in accordance with the second, third or fourth aspects of the invention;

Figure 26 shows an alternative tessellated layout; and

Figure 27 shows a further alternative tessellated layout. Detailed Description

Figure 1 is a perspective view of a first, cold-formed sheet that forms the base of a sealed container in accordance with a first embodiment of the invention. The first sheet 10 comprises a first recess 12 and a second recess 14 formed within it, using a cold-forming or thermo-forming process. The first sheet is formed from laminate of an aluminium foil and a polymer.

Figure 1 b is a side view of Figure 1 a, showing that the first recess 12 is smaller than the second recess 14. However, as will be apparent, the relative size of the first recess and the second recess can be chosen in order to provide a particular pressure within the final container, and the first container need not be smaller than the second container. Figure 1 c is a cross section of Figure 1 b.

After the first sheet has been cold-formed with the required recesses, a second sheet 20 is placed over the first sheet, as shown in Figure 2. The second sheet 20 is formed from a tri- laminate foil.

In order to form a sealed container, the first sheet 10 is bonded to the second sheet 20, as illustrated in Figure 3a. Figure 3a is a plan view and shows the area of a seal 22 that is formed around the first and second recesses to form first and second cavities. The first seal can be formed using standard heat sealing or by another means such as ultrasonic welding, using adhesive or using a lock seam.

In this embodiment, the first sheet is bonded to the second sheet under standard conditions, so that the first and second cavities contain air at atmospheric pressure.

However, the first sheet may be bonded to the second sheet under different conditions, such as in a nitrogen atmosphere, so that the first and second cavities are filled with different fluid. Although not shown in Figures 1 to 7, the second cavity may contain a powder, such as a powdered medicament. This powdered medicament may simply be deposited in the second chamber prior to laying the second sheet over the first sheet. Alternatively the powdered medicament may be suspended in some way within the first chamber. A further alternative is for the powdered medicament to be held close to the second sheet within the region of the second cavity. The powdered medicament may comprise an active

pharmaceutical ingredient. The powdered medicament may consist of an active

pharmaceutical ingredient without any carrier particles.

Figure 3b is a cross section view of Figure 3a showing the position of the seal 22. The seal 22 may not be formed (or may be partially formed) at this stage and may be reinforced during the subsequent step of crushing the first cavity so that the seal 22 does not itself have to provide all the mechanical strength required to withstand the increase in pressure within the first and second cavities.

In order to increase the pressure within the first and second cavities, the first cavity is crushed. Figure 4a is a side view of the assembly of the first and second sheets which have been bonded together, with the first cavity crushed by pressing the first sheet and the region of the first cavity towards the second sheet. Figure 4b is a cross section view of Figure 4a, showing how the first sheet is deformed more clearly. Crushing the first cavity in this way reduces the volume of the first cavity forcing the fluid in the first cavity, which may be air or may be some inert gas, such as nitrogen or carbon dioxide, into the second cavity. Fluid is forced through the connecting portion or pathway 16 between the first and second sheets that exist between the first cavity and the second cavity.

The increased pressure in the second cavity is dependent on the volume of fluid that has been forced out of the first cavitv and into the second cavitv. TvDicallv the manufacturina process is carried out at atmospheric pressure so that the pressure in the second cavity after the crushing of the first cavity is above atmospheric pressure. In order to retain the gas in the second cavity at this elevated pressure, the next step is to seal the second cavity. The position of the seal 26 is illustrated in Figure 5a, which is a plan view of the assembly. The seal 26 is formed fully around the circumference of the second cavity, bonding the first sheet to the second sheet. The seal may be formed by heating, sealing, welding or by the use of adhesive. Figure 5b is a cross section view of Figure 5a showing the position of the seal 26. Following the sealing of the second cavity, the second cavity can then be cut out from the sheet material to provide a stand-alone package of pressurised fluid. Figure 6 is a plan view of the assembly showing the position of a cut 28 through the sealed portion of the second cavity is made. A kiss-cut 29 is formed in the second sheet 20 at the centre of the second cavity. This kiss-cut is made before the sheets are assembled to each other. This ensures that the second sheet will rupture within a predetermined pressure range.

Following cutting out of the second cavity, the periphery of the package may be provided with a lock-seam by folding the edges and crimping.

The first and second cavity may have any desired volumes and any desired ratio of volumes to provide a final container of a particular volume and pressure. For aerosolising powder it is desirable that the finished package is at least 200kPa above atmospheric pressure.

Figure 7a is a perspective view of the final package. Figure 7b is a cross section of Figure 7a. The final package is a sealed blister containing a gas, such as air, at a pressure above atmospheric pressure. When the sealed blister is ruptured, typically by puncturing or compressing the second sheet, the gas within the blister expands rapidly as it escapes. This rapid expansion of gas escaping from the blister can be used to aerosolise powders and in particular to deliver powdered medicaments into the respiratory tract of a patient.

Figures 8 to 14 illustrate a method of manufacturing a package of pressurised fluid in accordance with a second embodiment of the invention. In the second embodiment, the first cavity is formed as an annular cavity surrounding the second cavity. Figure 10 is a perspective view of a first sheet used in accordance with the second embodiment. The first sheet 30 comprises a first, annular cavity 32 that surrounds a central, second cavity 34. As with the first embodiment, the first sheet is formed from an aluminium foil and is cold- formed to provide the first and second cavities. However, it should be clear that other materials and forming methods may be used. Figure 8b is a side view of the sheet of Figure 8a. Figure 8c is a cross section of the sheet shown in Figure 8a. A second sheet 40 is laid on top of the first sheet, covering the first and second cavities 32, 34, as illustrated in Figure 9. A seal 42 is formed between the first and second sheet, around the first cavity to provide a sealed container. Figure 10a shows the position of the seal 42 around the second cavity. The seal 42 is a heat seal. Figure 10a is a plan view of the assembly shown in Figure 9. Figure 10b is a cross section view of Figure 10a and shows the position of the seal 42 around the annular first cavity 32. As in the first embodiment, in order to increase the pressure of the fluid within the sealed container, the first cavity 32 is crushed. Any suitable crushing tool may be used to crush the first cavity. Figure 11 a is a side view of the assembly, with the first cavity 32 having been crushed. Figure 1 1 b is a cross section view of Figure 1 1 a showing how the first sheet 30 is deformed when the first cavity is crushed by a crushing tool. Fluid in the first cavity 32 is forced through connecting portion 36 into the second cavity 34 as a result of the crushing of the first cavity, resulting in an increase in pressure of the fluid within the second cavity.

The second cavity 34 is subsequently sealed by bonding the first and second sheets together in the connecting portion 36 between the first cavity and the second cavity. Figure 12a illustrates the position of a second seal 46, formed around the second cavity 34. The second seal may be formed by heat sealing or welding or by pre-applying adhesive in the connecting portion and applying pressure, for example. Figure 12b is a cross section view of Figure 12a clearly showing the position of the second seal 46 around the second cavity 34.

Once the second seal 46 around the second cavity has been formed, the second cavity can be cut out of the assembly to provide a finished sealed container. Figure 13 shows the position of a cut line 48 through the second seal 46 that is used to provide the final, package of pressurised fluid as shown in Figures 14a and 14b. As in the first embodiment, the second sheet is kiss-cut prior to assembly to provide a point of weakness 49. Other methods of providing a desired rupture pressure may be used.

Figure 14a is a perspective view of the final package and Figure 14b is a cross section of Figure 14a.

It can be appreciated that the method in accordance with the second embodiment is very similar to that of the first embodiment. The arrangement of the first cavity in an annular shape, surrounding the second cavity may provide material savings when a plurality of the containers are being manufactured, as will be explained with reference to Figures 23 and 24.

Figures 15 to 18 illustrate a manufacturing process in accordance with a third embodiment of the invention. In a third embodiment of the invention the final fluid package has two separate compartments of pressurised fluid that may be at the same or different pressures. Figure 15 is a cross section view of a sealed container comprising a first sheet of cold- formed material 50 defining a first, annular cavity 52 surrounding a second, central cavity 54, as described with reference to the second embodiment. A second sheet 60 is placed over the first sheet, as in the second embodiment. However, a separating wall formed from a separating sheet 70 comprising first and second depressions 72, 74 corresponding to the first and second cavities 52, 54 formed in the first sheet is positioned between the first and second sheets. The separating wall divides the first and second cavities so that the first cavity 52 has a first compartment 53 and a second compartment 72 and the central, second cavity 54 has a first compartment 55 and a second compartment 74. The first sheet 50 is a cold-formed laminated sheet of aluminium foil. The separating sheet 70 is also a cold-formed laminated sheet of aluminium foil and is heat sealed to the first sheet at seal 62. The second sheet 60 is a laminate lidding foil and is heat sealed to the separating sheet at seal 64. Seals 62 and 64 may be formed simultaneously or separately. A first connecting portion 66 is formed between the first sheet and the separating sheet between the first compartment of the first cavity 53 and the first compartment 55 of the second cavity 54. A second connecting portion 76 is formed between the second compartment 72 of the first cavity 52 and the second compartment of the second cavity 74.

In order to create a pressurised package, as in the first and second embodiments, the first cavity 52 is compressed. Figure 16 shows the first cavity in a compressed state. Fluid from the first compartment 53 of the first cavity 52 has been forced through connecting portion 66 into the first compartment 55 of the second cavity 54, raising the fluid pressure in the first compartment 55 of the second cavity 54. Simultaneously, fluid from the second compartment 72 of the first cavity 52 has been forced through connecting portion76 into the second compartment 74 of the second cavity 54, raising the fluid pressure in the second compartment 74 of the second cavity 54. The fluid pressure in the compartments of the second cavity as a result of the crushing of the first cavity may be equal or unequal depending on the relative sizes of the compartments in the two cavities. By crushing the two compartments of the first cavity simultaneously the maximum pressure difference across the separating sheet 70 can be minimised. The first and second connecting portions 66, 76 are then sealed, as shown in Figure 17. Heat seals 68, 78 are formed to seal the first and second compartments of the second cavity. The crushed first cavity can then be cut away from the second cavity to leave the finished sealed package, as shown in Figure 18. The volumes of the compartments within the first and second cavities can be chosen to provide a finished package with compartments with a desired fluid pressure. For aerosolising powder it is desirable that at least one compartment of the finished package is at least 200kPa above atmospheric pressure. The second sheet and the separating sheet may both be kiss-cut or otherwise treated to ensure that they rupture when the pressure difference across them is within a predetermined pressure range. The pressure range at which each sheet ruptures may be the same or different.

A powder, such as a powdered medicament may be provided with the first 55 or second 74 compartment of the second cavity 54. In use, rupture of one of the separating wall or the second sheet may result in sudden rupture of the other of the separating wall or second sheet, resulting in aerosolization of the powder. The powder may advantageously be held close to the sheet that ruptures last.

As in the first and second embodiments, the sealing of the first sheet, separating sheet and second sheet can take place in air or in a particular gaseous atmosphere so that the cavities are filled with a desired gas. It is also possible to seal the first sheet to the separating sheet in one atmosphere and the separating sheet to the second sheet in another atmosphere so that the first and second compartments contain different fluids.

The method and apparatus of the third embodiment may be modified to include a plurality of separating sheets defining more than two separate compartments within the first and second cavities. The use of a plurality of separating walls may allow for greater pressures to be contained in the final container using a given strength of separating sheet between the sheets. The pressure difference between each adjacent compartment may be small, but the use of a plurality of compartments my allow one of the compartments to hold a very high pressure. Each of the separating walls may be kiss-cut or otherwise treated to ensure that they break within a predetermined pressure range. The pressure at which each sheet ruptures may be the same or different to one another. As an alternative, or in addition, portions of the separating walls may be thinned or have a different material structure in the region of the second cavity to ensure that they break within a predetermined pressure range. Figures 19 to 22 illustrate a manufacturing process in accordance with a fourth

embodiment of the invention. In the fourth embodiment of the invention the final fluid package having two separate compartments of pressurised fluid that may be at the same or different pressures. The process of the fourth embodiment is very similar to the process of the third embodiment but in the fourth embodiment it is the shape of the second sheet that determines the volume of the second compartments rather than the shape of the separating sheet.

Figure 19a is a perspective view of an apparatus in accordance with the fourth

embodiment. The apparatus is a sealed container comprising a first sheet of cold-formed material 80 defining a first, annular depression 82 surrounding a second, central depression 84, as described with reference to the second and third embodiments. A second sheet 90 is placed over the first sheet, as in the second embodiment. However, a second sheet 90 comprising first and second ribs 92, 94 corresponding to the first and second cavities 52, 54 formed in the first sheet. A separating wall 100 is placed between the first and second sheets.

Figure 19b is a cross section of Figure 19a. It can be seen that the container comprises a first cavity having a first compartment 82 and a second compartment 92 and a central, second cavity having a first compartment 84 and a second compartment 94. The first sheet 80 is a cold-formed laminated sheet of aluminium foil. The second sheet 90 is also a cold-formed laminated sheet of aluminium foil. The separating sheet 100 is a laminate lidding foil. As in the third embodiment, the first sheet, separating sheet and second sheet are heat sealed to one another around a periphery of the apparatus. A first connecting portion 86 is formed between the first sheet and the separating sheet between the first compartment of the first cavity 82 and the first compartment of the second cavity 84. A second connecting portion 96 is formed between the second compartment 92 of the first cavity and the second compartment of the second cavity 94.

In order to create a pressurised container, as in the first, second and third embodiments, the first cavity 82, 92 is compressed. Figure 20 shows the first cavity in a compressed state. Fluid from the compartments of the first cavity has been forced through connecting portions into the compartments of the second cavity, raising the fluid pressure in the compartments of the second cavity. The fluid pressure in the compartments of the second cavity as a result of the crushing of the first cavity may be equal or unequal depending on the relative sizes of the compartments in the two cavities. The first and second connecting portions are then sealed, as shown in Figure 21. Heat seals 88, 98 are formed to seal the first and second compartments 84, 94 of the second cavity. The crushed first cavity can then be cut away from the second cavity to leave the finished sealed package, as shown in Figure 22a. Figure 22b is a cross-section view of Figure 22a.

The volumes of the compartments within the first and second cavities can be chosen to provide a finished package with compartments with a desired fluid pressure. The second sheet and the separating sheet may both be kiss-cut or otherwise treated to ensure that they rupture when the pressure difference across them is within a predetermined pressure range.

As in the third embodiment, a powder, such as a powdered medicament may be provided with the first 84 or second 94 compartment of the second cavity. As with the third embodiment, the method and apparatus of the fourth embodiment may be modified to include a plurality of separating sheets defining more than two separate compartments within the first and second compartments.

Figure 23 illustrates a layout of seals for forming a plurality of packages in accordance with the first embodiment described. Figure 23 is a plan view of the apparatus showing the second sheet 20. The region of the first seal 22 overlaps adjacent containers. A single heat sealing tool may be used to provide all of the first seals 22. The region of the second seal 26 for each package is also shown.

Figure 24 illustrates a layout of seals for forming a plurality of packages in accordance with the second embodiment, which also be applied to the third or fourth embodiments described. Figure 24 is a plan view of the second sheet 40. Again the region of the outer seals 42 is shared between adjacent sealed containers. It can be seen that with this arrangement there is less material wasted between the packages than in the arrangement of Figure 23. The second seals 48 are also shown.

Figures 25 to 27 illustrate other possible shapes for sealed containers in accordance with the invention that minimise material waste. Figure 25 illustrates a hexagonal array of packages of the type described in the second embodiment. The outer, first seal 142 is shared between adjacent containers. The second inner seal 148 is circular. The first cavity 132 is defined between the outer and inner seals, and the second cavity 134, which forms the finished package, is within the second seal. Figure 26 shows a similar layout but with triangular first seals 242 shared between adjacent containers. The second inner seal 248 is circular. The first cavity 232 is defined between the outer and inner seals, and the second cavity 234, which forms the finished package, is within the second seal.

Figure 27 shows another similar layout but with rhombus shaped first seals 342 shared between adjacent containers. The second inner seal 348 is circular. The first cavity 332 is defined between the outer and inner seals, and the second cavity 334, which forms the finished package, is within the second seal.

Features described in relation to one embodiment may be applied to other embodiments.