The present invention relates to a blister pack and, in particular, to a strip of blisters that are used to store individual doses of medicament in dry powdered form prior to the sequential inhalation of each dose by a patient using an inhalation device equipped with an indexing and piercing mechanism and in which the strip is pre-loaded or fitted by the patient ready for use. The invention also relates to a method of imparting a line of weakness in a blister pack according to the invention, a device or sealing tool for imparting said line of weakness either during or after manufacture of the blister pack and, an inhalation device containing a strip of blisters according to the invention.
Oral or nasal delivery of a medicament using an inhalation device is a particularly attractive method of drug administration as these devices are relatively easy for a patient to use discreetly and in public. As well as delivering medicament to treat local diseases of the airway and other respiratory problems, they have more recently also been used to deliver drugs to the bloodstream via the lungs thereby avoiding the need for hypodermic injections.
In one type of conventional metered dose inhalation device, the powdered medicament is held in a reservoir within a dispensing device that is operable to measure out and dispense a predetermined amount of powder for each dose. However, these devices suffer from poor dose metering capability especially when the size of the dose is relatively small as it is difficult to accurately measure out small amounts of dry powder in such a device. It is also difficult to protect the drug from the ingress of moisture and to seal it from the atmosphere until it is required for administration to a patient.
In view of the foregoing, it has become common for dry powder formulations to be pre-packaged in individual doses, usually in the form of capsules or blisters that each contain a single dose of the powder which has been accurately and consistently measured. A foil blister is preferred over capsules as each dose is protected from the ingress of water and penetration of gases such as oxygen in addition to being shielded from light and UV radiation all of which can have a detrimental effect on the delivery characteristics of the inhaler if a dose becomes exposed to them.
Inhalation devices that receive a blister pack or strip of blisters are known. Actuation of the device causes a mechanism to index and pierce a blister so that when the patient inhales, air is drawn through the blister entraining the dose, which is then carried out of the blister through the device and via the patient's airway down into the lungs.
A blister pack generally comprises a base having a number of spaced apart cavities defining blisters to receive individual doses of medicament and, a lid in the form of a generally planar sheet that is sealed to the base except in the region of the cavities using a sealing tool which compresses the base and lid material together in a region surrounding each cavity. The tool is heated so that the lid is sealed to the base during the compression step. The base material is typically a laminate comprising a polymer layer in contact with the drug, a soft tempered aluminium layer and an external polymer layer. The aluminium provides the moisture and oxygen barrier, whilst the polymer aids the adherence of the foil to the heat seal lacquer and provides a relatively inert layer in contact with the drug. Soft tempered aluminium is ductile so that it can be “cold formed” into a blister shape. It is typically 45 μm thick. The outer polymer layer provides additional strength and toughness to the laminate.
The lid material is typically a laminate comprising a heat seal lacquer, a hard rolled aluminium layer (typically 20-30 μm thick) and an external lacquer layer. The heat seal lacquer bonds to the polymer layer of the base foil laminate during heat-sealing to provide a seal around the top of the blister cavity. The aluminium layer is hard rolled to facilitate piercing of the blister by the inhalation device when access to the medicament contained therein is required. Materials for the polymer layer in contact with the drug include poly vinyl chloride (PVC), polypropylene (PP) and polyethylene (PE). In the case of PE, the heat seal lacquer on the foil lid is replaced with a further layer of PE. On heat sealing, the two layers of PE melt and weld to each other. The external polymer layer on the base foil is typically oriented polyamide (oPA). The polymer layer in contact with the drug is typically PVC of 60 μm thickness. However, a thinner layer of 30 μm or 15 μm may be used, for example, where a more flexible laminate is required.
It will be appreciated that different types of medicament possess varying degrees of sensitivity to various environmental influences and so a foil blister of the type described above provides good environmental protection for the medicament and protects it against moisture ingress, oxygen and other gases. The foil conveniently also protects the drug from light. Although the foil material itself is impermeable to moisture and gases, providing it is not punctured, the polymer layers are permeable to a greater or lesser extent. The permeability is typically defined by a moisture or gas transmission rate over a given time. The transmission rate depends on the type of material, the thickness of the permeable layer and distance of the transmission path. Thus the level of protection provided is determined in part by the breadth of the seal around the blister as this determines the distance any moisture or oxygen has to travel through the polymer layer from the edge of the foil laminate to the blister cavity.
In a strip of blisters, ingress can occur from the edges of the strip or from an adjacent blister that has been punctured. Thus the required breadth of seal should be maintained both from the blister cavity to the edges of the strip and from one blister cavity to an adjacent blister cavity. This distance between the blister cavities or seal breadth should be at least 2 mm although at least 2.5 mm is more preferable when the medicament is not particularly sensitive to environmental factors. However, a greater distance such as 3, 4 or 5 mm or more will afford improved environmental protection and should be used when the medicament is more sensitive to environmental factors.
It is desirable for an inhalation device, such as those used to treat a respiratory disease such as asthma or COPD, to be able to contain sufficient doses for at least one month's treatment. Typically, this requires an inhaler with 30 blisters (for a once daily dose) or 60 blisters (for a twice daily dose). It is known from GB2242134 to provide a device that is capable of receiving an individually sealed foil blister strip of 60 doses in which the lid is peeled away from the base of the strip by the device to enable access to the dose to be obtained. However, the device disclosed in this document is provided with chambers to receive both the used blister base and the lid that has been peeled away from the base and this makes the device unnecessarily large.
An alternative approach is to facilitate the detachment of used blisters from the unused blisters that remain in the strip so that the used blisters may be discarded. This allows the device to be smaller as there is no longer any requirement to store used blisters in the device.
A problem with detaching used blisters is that the external and internal polymer layers on the base foil laminate make it tough and difficult to tear. It is therefore known, for example from EP0469814A, to provide the strip with a series of perforations in the foil between blisters to facilitate their separation by tearing along the perforations. However, when a strip is provided with perforations, the distance between blisters has to be increased and maybe even doubled because the foil is cut by the perforating process thereby creating a break in the moisture seal. Increasing the distance between adjacent blisters increases the sealing distance, i.e. the distance moisture or gas has to travel to reach the drug, and so restores the environmental protection to a similar level found in a blister strip that is not provided with perforations. However, a disadvantage with increasing the distance between adjacent blisters is that the resulting blister strip is considerably longer and so a larger device is required to contain them. Furthermore, in a device that is equipped with an indexing mechanism for incrementally advancing the blisters to a piercing position, an increase in the distance between blisters requires a greater incremental movement to advance the blister strip leading to an increase in the complexity or size of the indexing mechanism.
The present invention seeks to provide a blister pack which is tearable but overcomes or substantially alleviates the problems associated with a perforated strip. In particular the invention seeks to provide a strip which facilitates easy separation of used blisters from those that remain and enables the minimum distance between blisters to be maintained without compromising the integrity of the seal between the blisters and the environmental protection provided by the seal.
According to the present invention, there is provided a blister pack comprising a plurality of spaced blister cavities each configured to receive and store an individual dose of medicament for inhalation by a user, wherein the pack includes a foil layer, an outer polymer layer and a region of weakness formed by substantially removing or displacing a portion of the outer polymer layer from the foil layer between each blister cavity, or a number of blister cavities.
In one embodiment, the package includes an inner polymer layer on the foil and the region of weakness is formed by substantially displacing the inner polymer layer, in addition to substantially removing or displacing the outer polymer layer, from the foil.
The blister pack preferably comprises a base portion in which the blister cavities are formed and a substantially planar lid portion sealing the blister cavities.
Preferably, the blister package is in the form of an elongate strip of blisters and, most preferably, a region of weakness is provided between each blister of the strip. Advantageously, each region of weakness is in the form of a straight narrow strip or line and extends across the strip substantially at right angles with respect to the longitudinal edges of the strip.
The strip is preferably sufficiently flexible to enable it to be wound into a roll for insertion into an inhalation device equipped with an indexing mechanism for advancing the blisters one at a time to a piercing station to enable the dose contained therein to be accessed and inhaled by a patient.
Although the region of weakness may be unbroken, it is also envisaged that, in one embodiment, one or more regions of weakness may be discontinuous. In this arrangement, the outer polymer layer, and possibly the inner polymer layer, are substantially removed or displaced from discrete, spaced apart regions extending along each region of weakness so that the region of weakness is formed from a series of weakened and non-weakened sections.
In a preferred embodiment, a region of weakness may be provided at an edge of a pack to facilitate the initiation of a tear As the force required to initiate a tear is greater than the force required to continue tearing once a tear has been initiated, a region of weakness at the edge of the pack is alone sufficient to enable separation.
In one embodiment, an edge of the pack may include a notch or a nick or a perforation or a region which has been highly compressed, scored or impacted or a region that has been heated and compressed or otherwise weakened to facilitate the initiation of a tear.
The blister package may comprise a lid and a base wherein the blisters are formed in the base, the region of weakness also being formed in the base.
In an alternative embodiment, regions of weakness are formed by locally melting or ablating or otherwise weakening the outer polymer layer. In a preferred embodiment a laser locally melts, ablates or softens or otherwise weakens the outer polymer layer.
In alternative embodiments regions of weakness may be formed by scoring with a rotary or straight blade (often called “kiss cutting”) or mechanically forming by nipping between two edges or local impact or by local pressure.
If the blister package is provided with means for initiating a tear where the regions of weakness meet the edge of the package to facilitate the start of a tear along the regions of weakness, these can be formed by any suitable means including kiss cutting, perforation, die cutting, application of a hot tool, application of pressure or laser ablation.
In a preferred embodiment, at least a portion of the region of weakness is a narrow strip or line. The region of weakness may also include an enlarged region where the line meets an edge of the pack. In one particular embodiment, the narrow strip or line extends across the pack between two enlarged regions where the ends of the line meet the edges of the pack.
According to the present invention, there is also provided a method of imparting a region of weakness in a blister pack between adjacent blister cavities of the pack which receive and store individual doses of medicament for inhalation by a user, the pack including a foil layer and an outer polymer layer, wherein the method includes the step of substantially removing or displacing a portion of the outer polymer layer from the foil layer to form said region of weakness.
The step of substantially removing or displacing a portion of the outer polymer layer from the foil layer to form said region of weakness preferably includes the step of applying heat and pressure to the pack to soften or melt a portion of the outer polymer layer and compress and/or push said portion away from the foil in said region.
In one embodiment, the method includes the step of cutting a portion of the pack in a region where a region of weakness meets an edge of the pack to form means for initiating a tear in the region of weakness.
According to the present invention, there is also provided a device for imparting a region of weakness to a blister pack between adjacent blister cavities of the pack which receive and store individual doses of medicament for inhalation by a user, the pack including a foil layer and an outer polymer layer, the device including means for heating and/or compressing a portion of the blister pack in a region where a region of weakness is to be formed so as to substantially remove or displace a portion of the outer polymer layer from the foil layer.
The device preferably comprises a heated blade member. The device may also include a base member on which the blister pack is located and stop members depending from the heated blade member that engage the base member during formation of a region of weakness to maintain a predetermined distance between the heated blade member and the base member.
The device may advantageously include cutting members depending from the heated blade member to cut a portion of the pack in a region where a region of weakness meets the edge of the pack to form means for initiating a tear in a line of weakness.
In another embodiment, the means for heating a portion of the blister pack in a region where a region of weakness is to be formed so as to substantially remove or displace a portion of the outer polymer layer from the foil layer is a laser which may be configured so as to remove or displace a portion of the outer polymer layer from discrete separate regions along each region of weakness.
The present invention also provides an inhalation device containing a blister pack according to the invention.
Although the blister package of the present invention is intended for use in many different devices, it is primarily intended for use in the inhalation device disclosed in the Applicant's co-pending international PCT application No. PCT/GB2004/004416 published as WO2005/037353 A1, which includes an actuator for indexing and piercing each of the blisters and in which used blisters protrude from the housing to facilitate their removal from those unused blisters that remain in the housing.
In the aforementioned device, a strip of blisters is coiled inside the device. However, it has been established that coiling the strip can cause the lidding foil to come under excessive stress in the vicinity of the regions of weakness. This is caused by the thickness of the laminate and the concentration of stress due to the thinning of the laminate at the region of weakness. These problems are mitigated by using a cold formed foil with a thinner polymer layer in contact with the drug. The polymer layer in contact with the drug is preferably less than 60 μm and, most preferably, between 15 μm and 40 μm thick. In a particularly preferred embodiment, the thickness of the polymer layer is 30 μm. Not only does a thinner polymer layer reduce the stress applied to the lidding foil when the strip is coiled, but a thinner polymer layer also makes the laminate much easier to tear, especially once a tear has been initiated.
According to another aspect of the invention, there is provided a sealing tool for manufacturing a blister pack, the pack comprising a base portion having a plurality of blister cavities therein and a lid portion for attachment to the base portion over the cavities to seal them once a dose has been located in each blister cavity, the pack including a foil layer and one or more polymer layers, wherein the sealing tool comprises a heated surface to compress and heat a blister base and lid positioned on the base to heat seal the lid to the base, wherein the sealing surface includes raised sections to substantially compress the laminate and remove or displace a portion of any outer polymer layer from the foil layer to form a region of weakness as the lid is heat sealed to the base.
In a preferred embodiment, the heated surface is knurled and the raised regions are substantially level with the topmost surfaces of the knurling pattern. Alternatively, the raised region is proud of the knurled pattern by up to 0.2 mm.
In one embodiment, the raised region has a first section to form a region of weakness at the edge of a pack and a second section to form another region of weakness extending from the first section remote from the edges of the pack. The height of the first section from the surface may be greater than the height of the second section from the surface.
Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:
Referring now to the drawings, there is shown in
The blister strip 1 shown in
In a modified blister strip 1, the base portion 2 may include an additional polymer layer (not shown) on the side away from the blister cavity 4 to create a more symmetric laminate that is less susceptible to warping or distortion during the cold forming of the blister cavities 4.
As the force required to initiate a tear in a blister strip 1 at a line of weakness 6 is greater than the force required to continue tearing once a tear has been initiated, initiating features 13 may be provided at one or both of the edges of each line of weakness 6 to facilitate the initiation of a tear. The initiator 13 may be a notch, a nick or a perforation or a region which has been highly compressed, scored or impacted or a region that has been heated and compressed or otherwise weakened. A strip 1 of blisters in which each line of weakness 6 is provided with a tear initiator 13 is illustrated in
Tools for, and methods of, forming the line of weakness 6 shown in the blister strip 1 of
Suitable materials for the blade member 9 include aluminium and aluminium alloys, preferably hard anodised, and stainless steels. Advantageously the blade member 9 may be coated with a low friction or “non-stick” coating such as PTFE (polytetraflourethylene) to help ensure that the outer polymer layer 2c on the base portion 2 does not adhere to the blade member 9 during compression and heating, as material adhering to the blade member 9 would reduce the effectiveness of the line of weakness formation.
If the blister strip 1 is modified by the presence of an additional polymer layer (not shown), this additional layer can help reduce the propensity of the foil layer 2b to adhere to the blade member 9, especially if the additional polymer layer is formed from a material that is less susceptible to “stringiness” when it softens, for example PVC.
The tool tip 10 of the blade member may have a radius of 0.2 to 1.0 mm and more preferably 0.4 to 0.6 mm. In a particularly preferred embodiment, the radius of the tool tip 10 is 0.5 mm. A cross-section through the tool tip 10 is shown in
The table 8 may be formed from aluminium and/or aluminium alloys, preferably hard anodised, stainless steels and high temperature polymers such as PEEK (poly ether ether ketone), polyamide or PTFE. Where required, for example in the case where the medicament 5 is sensitive to temperature, the table 8 may be cooled.
The upper surface 9 of the table 8 may optionally be provided with a thin resilient layer 11. Layer 11 assists in the formation of the line of weakness 6 by reducing the sensitivity of the process to the level of force applied and allows the foil layers 2b,3b of the blister strip 1 to bend slightly during forming so that the stresses, particularly shear and tearing stresses, induced in the foil layers 2b,3b are reduced thereby ensuring that they are not broken or cut by high levels of force. Suitable materials for the resilient layer 11 include polyamides, polyimides, PTFE, ETFE and silicone rubbers. The layer 11 is preferably less than 1 mm thick and more preferably less than 0.5 mm. In a preferred embodiment the resilient layer 11 is formed from a 0.3 mm layer of polyamide.
To ensure that the outer and inner polymer layers 2a,2c are softened sufficiently and so that the material of the outer polymer layer 2c is squeezed to the sides of the blade member 9 without cutting the foil layers 2b,3b, it is important to carefully select the temperature of the blade member 9 and the duration of contact with the blister pack 1. Suitable and preferred ranges for the key operating parameters are shown in the table below. It will be clear to those skilled in the art that the parameters interact with each other, for example increasing the duration will allow a lower force to be applied and increasing temperature may allow a shorter duration to be employed.
The application of heat and pressure needs to be controlled to achieve a repeatable line of weakness 6. One option is to control the force or pressure applied by, for example, using a spring at a predefined level of compression or a pneumatic cylinder at a predetermined pressure to provide the force. Alternatively, the blade member 9 may be provided with one or more stop members 12 which holds the tool tip 10 a predetermined distance from the upper surface 9 of the table 8 so that the blister strip 1 is compressed only by a predetermined amount by the blade member 9. In the embodiment illustrated in
If a tear initiator 13 is to be provided, this can be formed in the same operation as the formation of the line of weakness 6.
An effective line of weakness 6 need not be continuous. For example, one or more unweakened regions may be left in a line of weakness 6 in order to maintain the tensile strength of the strip 1 to, for example, facilitate handling during manufacture and indexing of the strip 1 in an inhalation device and to prevent accidental tearing of the strip 1. A line of weakness 6 may therefore comprise regions that have been weakened and regions that have not bees weakened or regions with differing levels of weakening.
It will be appreciated that more than one line of weakness 6 can be formed at one time by applying the weakening at a plurality of points simultaneously using for example, a tool with multiple blade members 9. Preferably, lines of weakness 6 are formed along a substantial portion or the whole of the strip 1 in a single operation. Alternatively they may be formed in a continuous process. Means for creating intermittent or continuous processes for high volume manufacture are well known in the field of blister processing machinery. Similarly, more than one strip can be processed at a time by processing strips side by side simultaneously.
The laser 16 may be a CO2 laser or a YAG laser but is preferably a CO2 laser. The type and power of the laser 16 is chosen to give effective ablation of the polymer layer 2c without damaging the aluminium foil layer 2b below. Forming a line of weakness with a laser can be combined with any of the aforementioned methods for initiating a tear including a nick, notch or kiss cut.
Advantageously for high volume production the process of making the blister strips 1 is continuous or comprises a combination of continuous and intermittent stations depending on the type of operation. For example, cold forming of a blister shape is often carried out by an intermittent process. In a continuous process, the laser 16 is programmed to scan across the foil layer 2b to form a line of weakness 6 and then index to the next position in synchronisation with the indexing of the strip 1 through the process. This may be achieved by scanning the laser beam 17 or by moving the strip 1. In an intermittent process the laser 16 may form a number of lines of weakness by scanning the beam 17 before the strip 1 is indexed along by a number of blisters 4.
It will be appreciated that all of the aforementioned embodiments address a method and apparatus for forming a region of weakness in a preformed blister strip. However, it is also envisaged that the formation of a region of weakness between blisters can be formed simultaneously with the manufacture of the blister i.e. at the same time as when the lid is sealed to the base.
It will be appreciated that the sealing tool may be applied to either side of the blister strip to seal the lidding material to the base. Furthermore, the lid and base material may be squeezed between two similar sealing tools.
Many modifications and variations of the invention falling within the terms of the following claims will be apparent to those skilled in the art and the foregoing description should be regarded as a description of the preferred embodiments of the invention only.
Number | Date | Country | Kind |
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0507710.2 | Apr 2005 | GB | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/EP2006/061606 | 4/13/2006 | WO | 00 | 12/26/2007 |