Lid Sheet For Use In A Blister Pack

Cross-Reference to Related Applications The present application claims priority to EP 05 405 561.1 filed 27 September 2005, the disclosure of which is incorporated herein by reference in its entirety.

Technical field

The present invention relates to a lid sheet for use in a peelable blister pack and suitable for packaging of products (e.g. pharmaceutical and medical products). The present invention in particular, relates to a tear-resistant and tear propagation- resistant peelable lid sheet for use with thermoformed and cold-formed base sheets to form such a blister pack.

Background to the invention

The use of drug dispensers in the delivery of drugs to the lung is well-known. Such dispensers generally comprise a body or housing within which a drug (i.e. medicament) carrier is located. Known inhalation devices include those in which the drug carrier is in blister pack form (e.g. an elongate blister strip) containing a number of discrete doses of powdered drug. In use, the blister pack is typically housed within the dispenser in such a way that the blisters may be transported through the dispenser in indexed fashion to enable accessing of the discrete doses of drug carried thereby. Such devices usually contain a mechanism of individually accessing the doses contained within the blisters. Known access mechanisms typically comprise either blister piercing means or means to peel a lid sheet away from a base sheet of the blister pack. The powdered drug can then be accessed and inhaled.

Blister packs having peelable lid sheets are also suitable for the packaging of other products including other pharmaceutical and medical products, cosmetic products, food and non-food products and for other technical applications.

It is desirable that the lid sheet of a peelably accessible blister pack is sufficiently robust to maintain its integrity during the opening of the pack (e.g. by peelable separation of the lid sheet from a base sheet) within a drug dispenser. It is further desirable that such lid sheet is also sufficiently robust to maintain its integrity during the full lifetime of use of the drug dispenser such as during any coiling or winding up of the lid sheet once separated from the base sheet.

Known elongate peelable blister strip form drug packs for use in containing inhalable drug in dry powder form are described in Applicant's pending PCT Patent Application No. WO2004/041672. The lid sheet thereof typically comprises a laminate including at least the following successive layers: (a) paper; bonded to (b) plastic polymeric film; bonded to (c) aluminium foil. The plastic polymeric film layer suitably comprises a material selected from the group consisting of polyester, polyamide, polypropylene and PVC. Typically, the aluminium foil layer of the lid sheet is further provided with a layer of heat seal lacquer, which bonds with the inner layer of the base sheet. That bond is disrupted during opening of the blister strip by peelable removal of the lid sheet from the base sheet.

Other known peelable blister form packaging pharmaceutical and medical products with a protective function against humidity, gases and light typically have the following structure:

• Lacquered / aluminium foil > 30μm / seal layer

• Paper, 40-50 g/m ² / aluminium foil, 20-30//m / seal layer • OPA or PET film, 12-25//m / aluminium foil, 20-25 μm I seal layer

• Paper, 20-50 g/m ² / OPA or PET film, 12-25 μm / aluminium foil, 20-25 μm / Seal layer

The Applicant has now found that the robustness of the lid sheet may be enhanced by the use of particular, unconventional polymeric materials for use in laminate sheets thereof that are additional to the paper and aluminium foil layers. In particular, the tear resistance and tear propagation resistance of the lid sheet during use may be enhanced. Improved blister form drug packs including such lid sheets may thereby, be achieved.

Summary of the invention

According to one aspect of the present invention there is provided a lid sheet for use in a blister form pack for packaging of (e.g. pharmaceutical and medical) products, wherein said lid sheet is a laminate comprising four layers A, B, C and D with the layer sequence A-B-C-D and the layers comprising as follows:

(Layer A) a layer A material selected from the group consisting of cellulose material (e.g. cellulose film or paper); aluminium foil; plastic film with a temperature resistance of at least 1 second at 22O ⁰ C; lacquer with a temperature resistance of at least 1 second at 22O ⁰ C; and anti-adhesive coating;

(Layer B) a layer B material selected from the group consisting of at least two non-orientated, mono-orientated or biaxially orientated plastic films displaced at an angle and bonded by means of lamination or hot calendaring or plastic coating with a net-like structure; non-woven material made from a plastic polymer; at least one fibre or a plastic film possessing a net-like web; a foil comprising a material selected from the group consisting of Polysulfone, Polyethylenenaphthalate PEN, polyphenylsulfone (PPSU), polyimide (Pl); Polyetherimide (PEI) and Tetrafluoroethylene/ethylene; and a multilayer foil consisting of at least two of the aforementioned materials;

(Layer C) aluminium foil; and

(Layer D) a heat seal layer (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

The lid sheet ('cover foil') herein is suitable for use as a tear-resistant and tear propagation-resistant peelable lid sheet, for example for use with thermoformed and cold-formed base sheets to form a blister pack for packaging of products including pharmaceutical and medical products, cosmetic products, food and non-food products and for other technical applications.

These and other embodiments of the present invention are set forth in the later description, which describes for illustrative purposes only various embodiments thereof.

Detailed description of the invention

Suitably, layers A and B and layers B and C are bonded using a laminating aid to achieve a bond strength of at least 2N/15 mm. Suitable laminating aids are chosen such that during peelable opening of the blister pack no delamination of the laminate occurs.

For example, laminating aids can be:

• Aqueous, solvent-free or solvent-based single or multi component adhesives or • Extrusion resin as a monolayer or coextruded.

Surprisingly it was found that the combination of individual materials with different physical and special mechanical properties running lengthwise and crossways to the machine direction together with the layers made from aluminium and heat seal lacquer provided a lid sheet of suitable robustness.

Layers A to D have the following functions, in particular:

• Layer A: Prevention of adhesion of the laminate on the sealing machine

• Layer B: Prevention of tear and tear propagation of the cover foil during opening 5 • Layer C: Carrier with a barrier effect against humidity, gases and light

• Layer D: Sealing layer for peelable opening

The paper of layer A can be untreated, coated or satined (calendared) and suitably has a weight of from 15 to 100 g/m ² , preferably from 20 to 50 g/m ² . 10

The aluminium foil of layer A suitably has a thickness of from 6 to 60 μm, preferably from 7 to 25 μm.

The temperature-resistant plastic film of layer A suitably has a thickness of from 7 to 15 25 μm, preferably from 12 to 25 μm.

The temperature-resistant plastic film of layer A by way of example consists of Polyethylenterephthalate (PET), orientated Polyamide (OPA), Polysulfone (PSU), Polyphenylsulfone (PPSU), Polyaryletherketone (PEEK), Polyimide (Pl) or 0 Polyetherimide (PEI) with a suitable thickness of from 7 to 25 μm, preferably from 12 to 25 μm.

The plastic films of layer B consist for example of Polyethylene (PE), in particular VLDPE, LLDPE, LMDPE, LDPE or HDPE, Polypropylene (PP), Polyester, Polyamide 5 (PA), Polystyrene (PS), Polycarbonate (PC), halogen-containing plastics; in particular Polyvinylchloride (PVC), Polyvinylidenchloride (PVDC), or Polychlorotrifluoroethylene (PCTFE), Poly-Acrylic-Nitrile (PAN),

Tetrafluoroethylene/ethylene or a combination of the aforementioned plastics and suitably have a thickness of from 8 to 200 μm, preferably from 12 to 100 μm. 0 Suitable plastic films might have a woven structure.

The plastic coating of the net-like structure of layer B consists preferably of Polyetheylene (PE) ₁ in particular VLDPE, LLDPE, LMDPE, LDPE, or HDPE, Polypropylene (PP), Polyester, Polyamide (PA), halogen-containing plastics, in particular Polyvinylchloride (PVC), Polyvinylidenchloride (PVDC) or Polychlorotrifluoroethylene (PCTFE) or albumen (silk) and has a preferred weight of from 30 to 150 g/m2, particularly from 40 to 120 g/m ² . Suitable plastic coatings might have a woven structure.

The non-woven material of layer B consists for instance of HDPE (e.g. Tyvec®), Polyester (e.g. Spunbond® or Evolon®) Polyethylenterephthalate (PET) / Polybutylenterephthalate (PBT) with Polyamide 6 or Polyamide 6.6, Polyester with polyolefines, in particular PET with PP or Polyamide with polyolefines and suitably possesses preferably a surface weight of from 10 to 120 g/m ² .

The foil consisting of at least one fibre or a plastic film having a net-like web (e.g. woven) of layer B consists for instance of Polyethylene (PE), in particular VLDPE, LLDPE, LMDPE, LDPE or HDPE, Polypropylene (PP), Polyester, Polyamide (PA), Polystyrene (PS), Polycarbonate (PC), halogen-containing plastics, in particular Polyvinylchloride (PVC), Polyvinylidene chloride (PVDC) or Polychlorotrifluoroethylene (PCTFE), Poly-Acrylic-Nitrile (PAN),

Tetrafluorothylene/ethylene or a combination of the aforementioned plastics and has a suitable thickness of from 8 to 200 μm, preferably from 12 to 80 μm.

The individual films of the multilayer foil of layer B consist for instance of Polyethylene (PE), in particular VLDE, LLDPE, LMDPE, LDPE or HDPE, Polypropylene (PP), Polyester, Polyamide (PA), Polystyrene (PS), Polycarbonate (PC), halogen-containing plastics, particularly Polyvinylchloride (PVC). Polyvinylidenchloride (PVDC) or Polychlorotriffuoroethylene (PCTFE), Poly-Acrylic- Nitrile (PAN), Tetrafluoroethylene/ethylene or a combination of the aforementioned plastics and have a thickness of 8 to 200 μm, preferably 12 to 75 μm.

The aluminium foil of layer C preferably has a suitable thickness of from 7 to 60 //m, preferably from 9 to 30 μm.

As a heat sealing lacquer medium, lacquers, plastic foils, and coatings can be used which allow an air-tight seal of the lid sheet ('cover foil') to the inside of the base sheet and at the same time allow removal of the lid sheet by peeling.

Overprinting of both the lid sheet and the base sheet is possible.

There is also provided a blister form pack for packaging of pharmaceutical and medical products comprising

(a) a base sheet in which blisters are formed to define pockets therein; and

(b) a lid sheet as defined herein, and which is sealable to the base sheet (e.g. except in the region of the blisters) and mechanically peelable from the base sheet.

There is further provided a blister form drug pack (e.g. a formed pack) comprising

(a) a base sheet in which blisters are formed to define pockets therein for the containment of inhalable drug;

(b) a lid sheet which is sealable to the base sheet (e.g. except in the region of the blisters) and mechanically (e.g. manually) peelable from the base sheet to enable release of said inhalable drug,

wherein said lid sheet has a laminate structure comprising at least the following successive layers:

(i) an outer paper lid sheet layer; bonded to

(ii) a first intermediate lid sheet layer of polymeric material; bonded directly or indirectly to

(iii) an aluminium foil lid sheet layer; bonded directly or indirectly to

(iv) an inner lid sheet heat seal layer (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

There is provided a blister form drug (i.e. medicament) pack comprising a base sheet and a lid sheet, each of the base and lid sheet having a particular form as described in more detail hereinafter.

In embodiments, the drug pack has multiple distinct (i.e. separate) drug doses carried thereby, and may for example, be in the form of an elongate blister strip, disk or other suitable blister pack form. Preferably, the drug pack is in the form of an elongate blister strip.

The base sheet is provided with blisters that define pockets for the containment of inhalable drug. The pockets may define any suitable profile including those with a square, circular or rectangular profile or rounded-corner variations of the square and rectangular profiles. In embodiments, two or more pockets could be linked with a channel that during the process of inhalation the powder will come together. The term 'inhalable drug' is used herein to mean drug suitable for inhaled delivery to the lung.

The lid sheet is sealable to the base sheet except in the region of the blisters and mechanically (e.g. manually) peelable from the base sheet to enable release of the inhalable drug from an opened pocket.

Preferably, the drug pack is in the form of an elongate blister strip. The elongate blister strip comprises an elongate strip form base sheet, in which blisters are formed to define pockets therein for the containment of inhalable drug. Typically, one or

more series of blisters are arranged (e.g. in linear series arrangement or zig-zag or circular arrangement) along the length of the base sheet. The lid sheet is sealed (e.g. hermetically) to the base sheet except in the region of the blisters in such a manner that the lid sheet and the base sheet can be peeled apart to enable release of the inhalable drug from one or more pockets thereof.

The base and lid sheets are typically sealed to one another over their whole width except for the forward end portions where they are typically not sealed to each other at all. Thus, separate base and lid sheet forward end portions are presented at the forward end of the elongate blister strip. The sealing can be done by all known sealing techniques (rotary, intermittent and a combination of flat bed and sealing roller). The bonding of the lid sheet to the base sheet can be done by all known techniques, e.g. contact heating, ultrasonic welding.

In embodiments, both the lid sheet and the base sheet of the drug pack herein are in the form of a laminate, which comprises multiple layers of different materials. In other embodiments, the base sheet comprises a single material.

The base sheet herein typically comprises (i) a first base sheet layer of aluminium foil; and (ii) a second base sheet layer of polymeric material of thickness from 10 to 150 micron.

Typically, the second base sheet layer is arranged to bond to the inner lid sheet layer and this bond allows for peelable separation of these layers.

The first base sheet layer of aluminium foil typically has a thickness of from 15 to 120 micron, particularly 20 to 90 micron.

The thickness of the second base sheet layer of polymeric material is from 10 to 150 micron such as from 10 to 120 micron, preferably from 15 to 100 micron.

In embodiments, the second base sheet layer comprises a polymeric material of low water vapour permeability. In embodiments, the water vapour permeability is less than 0.6 g /(100 inches ² ) (24 hours) (mil) at 25 ⁰ C, preferably less than less than 0.3 g /(100 inches ² ) (24 hours) (mil) at 25 ⁰ C as suitably measured by ASTM E96-635 (E) which defines a standard test method for measuring water vapour permeability.

In embodiments, the polymeric material of the second base sheet layer comprises a material selected from the group consisting of polyvinyl chloride (PVC) (e.g. in oriented or cast form); polypropylene (e.g. in oriented or cast form; standard or metallocene); polyethylene (e.g. in high, low or intermediate density form; standard or metallocene); polyvinylidene chloride (PVDC); polychlorotrifluoroethylene (PCTFE); cyclic olefin copolymer (COC); and cyclic olefin polymer (COP). Optionally, other layers of material are also present.

Material sold under the tradename Aclar by Honeywell Inc, a United States corporation is a suitable polychlorotrifluoroethylene (PCTFE) polymeric material herein. Suitable cyclic olefin copolymer (COC) is sold by Hoechst AG of Germany, under the trade name Topaz. A suitable cyclic olefin polymer is sold by Nippon Zeon Co. Ltd of Tokyo, Japan under the trade name Zenor.

In embodiments, polypropylene polymeric material and polyethylene polymeric material is manufactured by a process in which a one or more metallocene compounds is employed to modify and/or control the nature of any side-chain groups thereof.

Where the polymeric material of the second base sheet layer is selected from the group consisting of polyethylene (in high density form), polypropylene or polyvinylidene chloride (PVDC), reduced oxygen permeation through the polymeric layer, and hence to the interior of the blister, may be achieved. Oxygen permeation through the polymeric layer may be tested using ASTM test method D3985-81 , in which such oxygen transmission is measured at 25°C and 50% Relative Humidity.

In embodiments, the first base sheet layer of aluminium foil is provided with an outer base sheet layer of a polymeric material, particularly oriented polyamide (OPA). Thus, the base sheet comprises an outer layer of oriented polyamide (OPA), which bonds to (i) the first base sheet layer of aluminium foil; which bonds to (ii) the second 5 base sheet layer of polymeric material of thickness from 10 to 100 micron.

The bonding between layers of the base sheet is suitably provided as an adhesive bond (e.g. solvent-based adhesive wherein the solvent is organic or water-based); solvent free adhesive bond; extrusion laminated bond; or heat calendaring.

10

One particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded to (c) polyvinyl chloride (PVC). The thickness of the polyvinyl chloride (PVC) layer is from 10 to 100 micron, particularly from 50 to 100 micron.

15

Another particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded to (c) polyester. The thickness of the polyester layer is from 10 to 100 micron, particularly from 50 to 100 micron.

20

Another particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded to (c) polypropylene. The thickness of the polypropylene layer is from 10 to 100 micron, particularly from 50 to 100 micron.

25

Another particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded or extrusion laminated to (c) oriented polypropylene (OPP). The thickness of the oriented polypropylene (OPP) layer is from 10 to 60 micron, particularly from 20 to 30 30 micron.

A further particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded to (c) cast polypropylene. The thickness of the cast polypropylene layer is from 10 to 60 micron, particularly from 20 to 30 micron.

A further particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded or extrusion laminated to (c) high density polyethylene (HDPE). The thickness of the high density polyethylene (HDPE) layer is from 10 to 100 micron, particularly from 30 to 70 micron.

A further particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded or extrusion laminated to (c) low density polyethylene (LDPE). The thickness of the low density polyethylene (LDPE) layer is from 10 to 80 micron, particularly from 20 to 50 micron.

A further particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded to (c) polyvinylidene chloride (PVDC). The thickness of the polyvinylidene chloride (PVDC) layer is from 10 to 60 micron, particularly from 20 to 30 micron. The grade of the PVDC is generally from 8 to 95 gsm, particularly from 10 to 40 gsm.

A further particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded to (c) polychlorotrifluoroethylene (PCTFE). The thickness of the polychlorotrifluoroethylene (PCTFE) layer is from 10 to 60 micron, particularly from 20 to 45 micron. The polychlorotrifluoroethylene (PCTFE) layer can be oriented.

A further particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded or extrusion laminated to (c) cyclic olefin copolymer (COC). The thickness of

the cyclic olefin copolymer (COC) layer is from 10 to 60 micron, particularly from 20 to 30 micron.

A further particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded or extrusion laminated to (c) cyclic olefin polymer (COP). The thickness of the cyclic olefin polymer (COP) layer is from 10 to 60 micron, particularly from 20 to 30 micron.

The lid sheet of the drug pack herein has a particular laminate structure.

In one aspect herein, the lid sheet has a laminate structure comprising at least the following successive layers:

(i) an outer lid sheet layer of cellulose material (e.g. paper or cellulose film); bonded to

(ii) a first intermediate lid sheet layer of polymeric material; bonded directly or indirectly to

(iii) an aluminium foil lid sheet layer; bonded directly or indirectly to

(iv) an inner lid sheet heat seal layer (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

The thickness of each of the layers of the lid sheet may be selected according to the desired properties but is typically of the order of from 3 to 200 micron, particularly from 5 to 50 micron.

The outer paper lid sheet layer typically comprises paper of gauge from 10 to 80 g/m ² , particularly from 20 to 50 g/m ² .

The first intermediate lid sheet layer of polymeric material adds strength to the lid sheet to improve tear resistance and tear propagation resistance. The first intermediate lid sheet layer of polymeric material suitably has a thickness of from 5 5 to 100 micron, particularly 10 to 80 micron.

In one aspect, the first lid sheet intermediate layer of polymeric material comprises woven polyamide, which for example defines a net-like web structure. The interply bonding of the woven polyamide layer to its adjacent layers is suitably achieved as 10 an adhesive lamination or as an extrusion lamination.

One particular lid sheet comprises (i) an outer paper lid sheet layer; bonded to (ii) a first intermediate lid sheet layer of woven polyamide material of thickness from 50 to 120 micron, particularly from 50 to 100 micron; bonded to (iii) an aluminium foil lid 15 sheet layer; bonded to (iv) an inner lid sheet layer of heat seal lacquer.

In another aspect, the optional first intermediate layer of polymeric material comprises spun poly (ethylene terephthalate) (spun-PET), which is a non-woven material. The spun-PET is typically of weight from 10 to 250 g/m ² , particularly from 20 20 to 60 g/m ² . The interply bonding of the spun-PET layer is suitably achieved using an extrusion lamination, particularly polyethylene (PE) extrusion. Suitable spun-PET materials include those sold by Johns Manvilie of Waterville, Ohio under the trade names spunbond 488/20, spunbond 488/30 and spunbond 088/30.

25 One particular lid sheet comprises (i) an outer paper lid sheet layer; bonded using PE extrusion to (ii) a first intermediate lid sheet layer of spun-PET material of weight from 10 to 80 g/m ² ; bonded using PE extrusion to (iii) an aluminium foil lid sheet layer; bonded to (iv) an inner lid sheet layer of a heat seal lacquer, a heat seal film or a heat seal extrusion coating.

30

Another particular lid sheet comprises (i) an outer paper lid sheet layer; bonded using extrusion lamination to (ii) a first intermediate lid sheet layer of spun-PET

material of weight from 10 to 80 g/m ² ; bonded using co-extrusion lamination (one or two co-extrusion layers) to (iii) an aluminium foil lid sheet layer; bonded to (iv) an inner lid sheet layer of a heat seal lacquer, a heat seal film or a heat seal extrusion coating.

5

Another particular lid sheet comprises (i) an outer paper lid sheet layer; bonded using lacquer lamination to (ii) a first intermediate lid sheet layer of spun-PET material of weight from 10 to 80 g/m ² ; bonded using lacquer lamination to (iii) an aluminium foil lid sheet layer; bonded to (iv) an inner lid sheet layer of a heat seal 10 lacquer, a heat seal film or a heat seal extrusion coating.

In another aspect, the optional first intermediate layer of polymeric material comprises spun high density polyethylene (spun-HDPE), which is a non-woven material. The spun-HDPE is typically of weight from 10 to 80 g/m ² , particularly from 15 20 to 60 g/m ² . The interply bonding of the spun-HDPE is suitably achieved using an extrusion lamination, particularly polyethylene (PE) extrusion. The material sold by Du Pont under the trade name Tyvek is a suitable spun-HDPE sheet material.

One particular lid sheet comprises (i) an outer paper lid sheet layer; bonded using 0 PE extrusion to (ii) a first intermediate lid sheet layer of spun-HDPE material of weight from 10 to 80 g/m ² ; bonded using PE extrusion to (iii) an aluminium foil lid sheet layer; bonded to (iv) an inner lid sheet layer of a heat seal lacquer, a heat seal film or a heat seal extrusion coating.

5 In another aspect, the optional first intermediate layer of polymeric material comprises cross-laminated high density polyethylene (HDPE). By cross-laminated HDPE it is meant a material comprising at least two HDPE films cross-laminated to each other at a suitable cross-lamination angle, wherein the cross-lamination angle is typically from 30 to 60°, particularly 45°. The cross-laminated HDPE is typically of 0 thickness from 30 to 100 micron, particularly from 50 to 80 micron. The material sold by Illinois Tool Works, Inc. under the trade name Valeron is a suitable cross- laminated HDPE material herein.

One particular lid sheet comprises (i) an outer paper lid sheet layer; bonded to (ii) a first intermediate lid sheet layer of cross-laminated HDPE material of thickness from 30 to 100 micron, particularly from 50 to 80 micron; bonded to (iii) an aluminium foil lid sheet layer; bonded to (iv) an inner lid sheet layer of a heat seal lacquer, a heat seal film or a heat seal extrusion coating.

In another aspect, the optional first intermediate layer of polymeric material comprises cross-laminated polyethylene terephthalate (PET). By cross-laminated PET it is meant a material comprising at least two PET films cross-laminated to each other at a suitable cross-lamination angle, wherein the cross-lamination angle is typically from 30 to 60°, particularly 45°. The cross-laminated PET is typically of thickness from 30 to 100 micron, particularly from 50 to 80 micron.

One particular lid sheet comprises (i) an outer paper lid sheet layer; bonded to (ii) a first intermediate lid sheet layer of cross-laminated PET material of thickness from 30 to 100 micron, particularly from 50 to 80 micron; bonded to (iii) an aluminium foil lid sheet layer; bonded to (iv) an inner lid sheet layer of a heat seal lacquer, a heat seal film or a heat seal extrusion coating.

The thickness of the aluminium foil lid sheet layer is typically from 10 to 60 micron, particularly 15 to 40 micron.

The aluminium foil lid sheet layer bonds directly or indirectly to the inner lid sheet heat seal layer. When bonded indirectly, one or more additional intermediate lid sheet layers sandwich between the aluminium foil lid sheet layer and the inner lid sheet heat seal layer.

The inner lid sheet heat seal layer is arranged for bonding to the base sheet, typically to the second base sheet layer of polymeric material.

The bonding between layers of the lid sheet is suitably provided as an adhesive bond (e.g. solvent-based adhesive wherein the solvent is organic or water-based); solvent free adhesive bond; extrusion laminated bond; or heat calendaring.

According to another aspect of the present invention there is provided a blister form drug pack comprising

(a) a base sheet in which blisters are formed to define pockets therein for the containment of inhalable drug;

(b) a lid sheet which is sealable to the base sheet except in the region of the blisters and mechanically peelable from the base sheet to enable release of said inhalable drug,

wherein said lid sheet has a laminate structure comprising at least the following successive layers:

(i) an outer lid sheet layer of cellulose material (e.g. paper or cellulose film); bonded directly or via an optional first intermediate layer of polymeric material to

(ii) an aluminium foil lid sheet layer; bonded to

(iii) an inner lid sheet layer of polymeric material.

In this aspect, the base sheet may comprise any of the previously described base sheet laminate structures; the outer paper lid sheet layer typically comprises paper of gauge from 10 to 80 g/m ² , particularly from 20 to 50 g/m ² ; and the thickness of the aluminium foil lid sheet layer is typically from 10 to 60 micron, particularly 15 to 40 micron.

The outer lid sheet layer of cellulose material (e.g. paper or cellulose film) bonds directly or via an optional first intermediate layer of polymeric material to the

aluminium foil lid sheet layer. In variations herein, the outer paper lid sheet layer is absent.

In aspects, the (iii) inner lid sheet layer does not comprise a heat seal lacquer component but rather another polymeric material (e.g. a film or extrusion coating). When this is so, the lid sheet is most suitable for use with a base sheet that has heat seal lacquer or another substance capable of providing peel function provided as its inner base sheet layer.

In one aspect, the optional first intermediate layer of polymeric material comprises a polyethylene (PE) extrusion layer and the inner lid sheet layer of polymeric material comprises a peelable co-extrusion coating (e.g. polyethylene/polybutylene). Examples of other suitable peelable co-extrusion coating materials include those produced by Alcan Packaging Singen GmbH: (1) Intermediate extrusion layer (APS- reference No. X2228EX): a copolymerisate of ethylene and ethylene acrylic acid provided by DOW Plastics; and (2) Co-extrusion coating (of APS-reference No. X2253EX and X2311EX) where X2253EX is a random terpolymer of ethylene, butylacrylate and maleic anhydride provided by Arkema and X2311 EX is a mixture of polyethylene provided by Shuman and a copolymer of ethylene and acrylic ester provided by Arkema.

One suitable drug pack thus, comprises (i) an outer paper lid sheet layer; bonded via an optional first intermediate layer of polyethylene (PE) extrusion to (ii) an aluminium foil lid sheet layer; bonded to (iii) an inner lid sheet layer of peelable co-extrusion coating having a weight of from 5 to 50 g/m ² , particularly from 10 to 30 g/m ² .

In embodiments, the inner lid sheet layer of polymeric material comprises a peel film. The peel film is for example, a polyethylene (PE) peel film, a polyvinyl chloride (PVC) peel film or a polypropylene (PP) peel film. This peel film is particularly suitable for peelable sealing to an inner base sheet layer comprising polyvinyl chloride (PVC) or polyethylene (PE).

A suitable peel film for sealing onto polyethylene (PE) is produced by Nordenia Gronau GmbH of Germany (Alcan trade reference FSN097). A suitable peel film for sealing onto polyvinyl chloride (PVC) is produced by Nordenia Gronau GmbH of Germany (Alcan trade reference X3496FSN). 5

In one aspect, no optional first intermediate layer of polymeric material is present and the inner lid sheet layer of polymeric material comprises a peel film (e.g. a polyethylene (PE) peel film, a polyvinyl chloride (PVC) peel film or a polypropylene (PP) peel film).

10

One suitable lid sheet thus, comprises (i) an outer paper lid sheet layer; bonded to (ii) an aluminium foil lid sheet layer; bonded to (iii) an inner lid sheet layer of polyethylene (PE) peel film of thickness from 10 to 80 micron, particularly from 15 to 50 micron. This lid sheet is particularly suitable for use with a base sheet having PE

15 peel film as its inner base sheet layer.

A further suitable lid sheet thus, comprises (i) an outer paper lid sheet layer; bonded to (ii) an aluminium foil lid sheet layer; bonded to (iii) an inner lid sheet layer of poly vinyl chloride (PVC) peel film of thickness from 10 to 80 micron, particularly from 15 20 to 50 micron.

In a further aspect, the optional firsjt intermediate layer of polymeric material comprises polyethylene terephthalate (PET) and the inner lid sheet layer of polymeric material comprises polyvinyl chloride (PVC).

25

One suitable drug pack thus, comprises (i) an outer paper lid sheet layer; bonded via an optional first intermediate layer of PET of thickness from 5 to 30 micron, particularly 10 to 25 micron bonded to (ii) an aluminium foil lid sheet layer; bonded to (iii) an inner lid sheet layer of PVC of thickness from 5 to 50 micron, particularly from 30 10 to 40 micron. This lid sheet is particularly suitable for use with a base sheet having heat seal lacquer as its inner base sheet layer.

In a further aspect, the optional first intermediate layer of polymeric material comprises spun poly (ethylene terephthalate) (spun-PET) and the inner lid sheet layer of polymeric material comprises a peel film (e.g. a polyethylene (PE) peel film, a polyvinyl chloride (PVC) peel film or a polypropylene (PP) peel film). This lid sheet

5 is particularly suitable for use with a base sheet having PVC as its inner base sheet layer. The spun-PET is typically of weight from 10 to 250 g/m ² , particularly from 20 to 60 g/m ² . The interply bonding of the spun-PET layer is suitably achieved using an extrusion lamination, particularly polyethylene (PE) extrusion. Suitable spun-PET materials include those sold by Johns Manville under the trade names spunbond

10 488/20, spunbond 488/30 and spunbond 088/30.

One suitable drug pack thus, comprises (i) an outer paper lid sheet layer; bonded via an optional first intermediate layer of spun-PET of thickness from 10 to 60 micron, particularly 20 to 30 micron bonded to (ii) an aluminium foil lid sheet layer; bonded to 15 (iii) an inner lid sheet layer of a peel film of thickness from 5 to 50 micron, particularly from 10 to 40 micron. Where the inner lid sheet layer is of PE peel film, this lid sheet is particularly suitable for use with a base sheet having PVC as its inner base sheet layer.

0 In a further aspect, the optional first intermediate layer of polymeric material comprises the optional first intermediate layer of polymeric material comprises cross- laminated high density polyethylene (HDPE) and the inner lid sheet layer of polymeric material comprises a peel film (e.g. a polyethylene (PE) peel film, a polyvinyl chloride (PVC) peel film or a polypropylene (PP) peel film). By cross- 5 laminated HDPE it is meant a material comprising at least two HDPE films cross- laminated to each other at a suitable cross-lamination angle, wherein the cross- lamination angle is typically from 30 to 60°, particularly 45°. The cross-laminated HDPE is typically of thickness from 30 to 100 micron, particularly from 50 to 80 micron. The material sold by Illinois Tool Works, Inc. under the trade name Valeron 0 is a suitable cross-laminated HDPE material herein. This lid sheet is particularly suitable for use with a base sheet having PVC as its inner base sheet layer.

One suitable drug pack thus, comprises (i) an outer paper lid sheet layer; bonded via an optional first intermediate layer of cross-laminated HDPE of thickness from 30 to 100 micron, particularly 50 to 80 micron bonded to (ii) an aluminium foil lid sheet layer; bonded to (iii) an inner lid sheet layer of a peel film of thickness from 5 to 50 micron, particularly from 10 to 40 micron. Where the inner lid sheet layer is of PE peel film, this lid sheet is particularly suitable for use with a base sheet having PVC as its inner base sheet layer.

Various known techniques can be employed to join the lid sheet and base sheet herein and hence to seal the blister pockets. Such methods include adhesive bonding, radio frequency welding, ultrasonic welding, inductive sealing and hot bar sealing.

The base sheet herein is particularly suitable for forming by 'cold form' methods (e.g. one or two step cold forming - advanced forming technology (AFT); high pressure cold forming (HPCF) ), which are conducted without heating up the material of the base sheet. Such 'cold form' methods are of particular utility where the drug or drug formulation for containment within the blister is very sensitive to moisture, oxygen, other gases and/or flavours. To reduce the influence of the heat of the sealing process to avoid damages of the filling good, material for the sealing is used with low melting point, e.g. polyethylene, polyethylene/metallocene; Surlyn® as sold by Du Pont. If the packed product does not request a very high barrier to moisture and gases, thermoforming of plastic materials like PVC; polypropylene; PVC/PVDC; PVC/Aclar® or COC-laminates are used to form the blister.

One method for forming a drug pack herein comprises the steps of (a) providing a base sheet having a first mating surface and a lid sheet a having a second mating surface, the base sheet including at least one blister pocket having a periphery region, the blister pocket being adapted to receive a drug composition; (b) filling the blister pocket with the pharmaceutical composition (e.g. in an amount from 10 to 3000 μg, such as from 25 to 500 μg); (c) bonding the base sheet to the lid sheet to create a primary seal therebetween. The blister pocket can be of any shape for

good airflow (e.g. to assist aerosolization of the powder contained therein), preferably, substantially elongated or substantially circular.

In embodiments, the base sheet includes at least a first bonding material disposed on the first mating surface and the lid sheet includes at least a second bonding material disposed on the second mating surface. In one embodiment, one or both of the first or second bonding materials comprises at least one polymeric material. In an additional embodiment, one or both of the first or second bonding material comprises a substance that enables peelable separation e.g. a heat seal lacquer, plastic film or coating.

A suitable manufacturing system herein comprises (a) a base transporter for transporting a base sheet to a filling station, the base sheet including at least one blister pocket adapted to receive an inhalable drug composition, the base sheet further including a first bonding material; (b) a filling apparatus for filling the blister pocket with the inhalable drug composition; (c) a lid transporter for transporting a lid sheet proximate to the filled base sheet, the lid sheet including a second bonding material; (d) a bonding mechanism for bonding the first and second bonding materials to create a primary seal therebetween.

In use, the drug pack herein is suitably receivable by a drug dispenser that comprises a housing for receipt of the drug pack. In one aspect, the drug dispenser has unitary form and the housing is integral therewith. In another aspect, the drug dispenser is configured to receive a refill cassette and the housing forms part of that refill cassette.

In embodiments, the interior of the housing is shaped, or alternatively provided with specific guiding features, to guide the drug pack appropriately into the housing. In particular, the guiding should ensure that the drug pack is suitably located to interact with internal mechanisms (e.g. indexing and opening mechanisms) of the housing.

In embodiments, the dispenser has an internal mechanism for dispensing the distinct inhalable drug doses carried by the drug pack for administration to the patient (e.g. by inhalation). In embodiments, the mechanism comprises,

a) receiving means for receiving the drug pack;

b) release means for releasing a distinct drug dose from the drug pack on receipt thereof by said receiving means;

c) an outlet, positioned to be in communication with the drug dose releasable by said release means;

d) indexing means for individually indexing the distinct drug doses of the drug pack; and

The mechanism comprises receiving means (e.g. a receiving station) for receiving the drug pack.

The mechanism further comprises release means for releasing a distinct drug dose from the drug pack on its receipt by the receiving station. The release means typically comprises means for mechanically peeling apart the blister strip.

An outlet is positioned to be in communication with the distinct drug doses releasable by said release means. The outlet may have any suitable form. In one aspect, it has the form of a mouthpiece and in another it has the form of a nozzle for insertion into the nasal cavity of a patient.

The outlet is preferably a single outlet, which communicates with the distinct drug dose releasable by said release means via a common air channelling means (e.g. formed as an air-pipe or common manifold). The patient may therefore breathe in through a single outlet, and that breath be transferred through the common channelling means to the released drug dose, thereby enabling its inhalation.

The mechanism also comprises indexing means for individually indexing the distinct drug doses of the drug pack. Said indexing typically happens in sequential fashion, for example accessing dose portions sequentially arranged along the length of the elongate carrier.

Optionally, the drug dispenser also includes counting means for counting each time a distinct drug dose of the drug pack is indexed by said indexing means.

In one aspect, counting means is arranged to count each time a distinct drug dose of the drug pack is indexed by said indexing means. In embodiments, the indexing means and counting means engage directly or indirectly (e.g. via a coupling) with each other to enable counting of each indexation.

In embodiments, the counting means is provided with (or communicates with) a display for displaying to the patient the number of distinct doses left to be taken or the number of doses taken.

In one preferred aspect, the drug dispenser takes the form of a dispenser for use with a drug pack having multiple distinct pockets for containing inhalable drug doses, wherein said pockets are spaced along the length of and defined between two peelable sheets secured to each other, said dispenser having an internal mechanism for dispensing the drug doses contained within said drug pack, said mechanism comprising,

a) an opening station for receiving a pocket of the drug pack;

b) peeling means positioned to engage a base sheet and a lid sheet of a pocket which has been received in said opening station for peeling apart such a base sheet and lid sheet, to open such a pocket, said peeling means including lid driving means for pulling apart a lid sheet and a base sheet of a pocket that has been received at said opening station;

c) an outlet, positioned to be in communication with an opened pocket through which a user can access a drug dose from such an opened pocket;

d) indexing means for individually indexing the distinct pockets of the drug pack.

In embodiments, the indexing means comprises a rotatable index wheel having recesses therein, said index wheel being engageable with a drug pack herein, in use with said drug dispenser such that said recesses each receive a respective pocket of the base sheet of a blister strip form drug pack in use with said drug dispenser.

Preferably, the drug dispenser has the general form as described in US Patents Nos. 5,860,419, 5,873,360 and 5,590,645 in the name of Glaxo Group Ltd, each of which is incorporated herein by reference. An example of a drug dispenser of this type is the well-known Diskus (trade mark) inhaler device as sold by GlaxoSmithKline PIc. The drug dispenser also may be employed as described in WO 03/061743 and WO 03/061744, the disclosures of which are incorporated by reference in their entirety.

According to another aspect of the present invention there is provided a drug dispenser comprising (e.g. loaded with) at least one drug pack herein.

Brief Description of the Drawings

The invention will now be described with reference to the accompanying drawings in which:

Figure 1 shows a perspective view of the form of a drug pack of a form suitable for use in accord with the present invention;

Figure 2 shows a top view of the form of a drug pack of a form suitable for use in accord with the present invention;

Figure 3 shows a top view of the form of another drug pack of a form suitable for use in accord with the present invention; and

Figure 4 shows a cross-sectional side view of the form of a laminate form drug pack in accord with the present invention; and

Figure 5 shows a cross-sectional side view of the form of a further laminate form drug pack in accord with the present invention; and

Figure 6 shows a cross-sectional side view of the form of a further laminate form drug pack in accord with the present invention; and

Figure 7 shows a cross-sectional side view of the form of a further laminate form drug pack in accord with the present invention; and

Figure 8 shows a cross-sectional side view of the form of a laminate form lid sheet in accord with the present invention.

Detailed Description of the Drawings

Figure 1 shows a drug pack 100 that may be constructed to have a detailed form in accord with the present invention. The drug pack comprises a flexible strip 101 defining a plurality of pockets 103, 105, 107 each of which would contain a portion of a dose of drug which can be inhaled, in the form of powder.

The strip comprises a base sheet 109 in which blisters are formed to define the pockets 103, 105, 107 and a lid sheet 111 which is hermetically sealed to the base sheet except in the region of the blisters in such a manner that the lid sheet 111 and the base sheet 109 can be peeled apart. The sheets 109, 111 are sealed to one another over their whole width except for the leading end portions 113, 115 where

they are preferably not sealed to one another at all. The lid 111 and base 109 sheets are formed of a laminate and are suitably adhered to one another by heat sealing.

The strip 101 is shown as having elongate pockets 103, 105, and 107 that run transversely with respect to the length of the strip 101. This is convenient in that it enables a large number of pockets 103, 105, 107 to be provided in a given strip 101 length. The strip 101 may, for example, be provided with sixty or one hundred pockets but it will be understood that the strip 101 may have any suitable number of pockets.

Referring now to Fig. 2, there is shown a drug pack in the form of a laminate assembly or blister strip 200 viewed from underneath. The blister strip has a substantially elongated shape and includes a plurality of blisters 203, 205, 207 formed in the base 209 thereof adapted to receive a pharmaceutical composition, preferably in the form of a dry powder. Each blister 203, 205, 207 has a length U that is preferably from 1.5 to 15.0 mm, more preferably, from 1.5 to 8.0 mm, and in an actual embodiment is equal to 7.5 mm, measured along its longer axis, and a width b that is preferably from 1.5 to 10.0 mm, more preferably, from 1.5 to 8.0 mm, and in an actual embodiment is equal to 4.0 mm, measured along its shorter axis.

In the illustrated example of Fig 2, the blister strip 200 has a width of 12.5 mm. The thickness of the base 209 is in the range of 75 to 200 micron. The thickness of the lid is in the range 40 to 100 micron. The combined thickness of the base 209 and lid (not visible) is approximately 115 to 300 micron. The blisters 203, 205, 207 are typically at 7.5 mm spacings along the blister strip 200. Each blister 203, 205, 207 contains an effective dosage of powder, preferably less than 30 mg of powder, more preferably, between 5 - 25 mg of powder, and most preferably, approximately 12.5 mg of powder. The powder is an inhalable drug composition comprising at least one drug active.

Suitable materials are employed to construct the base 209 and lid (not visible). In accord with the invention, the base 209 and / or lid comprise laminate structures having at least one bonding material on at least one mating surface of either the base 209 or lid. The bonding material(s) preferably comprise at least one polymeric material and a heat seal layer (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer such as a vinyllic heat seal lacquer).

Referring now to Fig. 4, there is shown a blister pack 400 herein having a lid sheet which has a four layer structure and comprises the following successive layers:

(i) an outer paper lid sheet layer 425; bonded to

(ii) a first intermediate lid sheet layer of polymeric material 427; bonded to

(iii) an aluminium foil lid sheet layer 429; bonded directly or indirectly to

(iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

One particular lid sheet variation comprises (i) an outer paper lid sheet layer 425 of weight 25 g/m ² ; bonded to (ii) a first intermediate lid sheet layer 427 of woven polyamide material of thickness from 50 to 120 micron; bonded to (iii) an aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

Another particular lid sheet variation comprises (i) an outer paper lid sheet layer 425 of weight 20 g/m ² ; bonded to (ii) a first intermediate lid sheet layer 427 of woven polyamide material of thickness from 50 to 100 micron; bonded to (iii) an aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

Another particular lid sheet comprises (i) an outer paper lid sheet layer 425 of weight 25 g/m ² ; bonded using PE extrusion to (ii) a first intermediate lid sheet layer 427 of spun-PET material of weight 30 g/m ² ; bonded using PE extrusion to (iii) an 5 aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

Another particular lid sheet comprises (i) an outer paper lid sheet layer 425 of weight 10 25 g/m ² ; bonded using PE extrusion to (ii) a first intermediate lid sheet layer 427 of spun-PET material of weight 50 g/m ² ; bonded using PE extrusion to (iii) an aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

15

Another particular lid sheet comprises (i) an outer paper lid sheet layer 425 of weight 25 g/m ² ; bonded using extrusion lamination to (ii) a first intermediate lid sheet layer 427 of spun-PET 488/20 material of weight 20 g/m ² ; bonded using two layers of co- extrusion lamination to (iii) an aluminium foil lid sheet layer 429 of thickness 20 20 micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

Another particular lid sheet comprises (i) an outer paper lid sheet layer 425 of weight 25 g/m ² ; bonded using lacquer lamination to (ii) a first intermediate lid sheet layer 25 427 of spun-PET 088/30 material of weight 30 g/m ² ; bonded using two layers of lacquer lamination to (iii) an aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

30 Another particular lid sheet comprises (i) an outer paper lid sheet layer 425 of weight 50 g/m ² ; bonded using lacquer lamination to (ii) a first intermediate lid sheet layer 427 of spun-PET 088/30 material of weight 30 g/m ² ; bonded using two layers of

lacquer lamination to (iii) an aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

Another particular lid sheet comprises (i) an outer paper lid sheet layer 425 of weight 25 g/m ² ; bonded using PE extrusion to (ii) a first intermediate lid sheet layer 427 of spun-HDPE material of weight 50 g/m ² ; bonded using PE extrusion to (iii) an aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer).

One particular lid sheet comprises (i) an outer paper lid sheet layer 425 of weight 25 g/m ² ; bonded to (ii) a first intermediate lid sheet layer 427 of cross-laminated HDPE material of thickness 70 micron; bonded to (iii) an aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seal lacquer). The material sold by Illinois Tool Works, Inc. under the trade name Valeron is a suitable cross- laminated HDPE material for the layer 427.

The base sheet of the blister pack of Fig. 4 also has a multi-layer structure and comprises the following successive layers: oriented polyamide (OPA) 420 adhesively bonded to aluminium foil 422 adhesively bonded to a base sheet layer 424 of polymeric material of thickness from 10 to 100 micron. The blister pack 400 is filled with inhalable drug 414 in dry powdered form. In embodiments, the base sheet layer 424 of polymeric material meets the requirement that the polymeric material has a water vapour permeability of less than 0.6 g /(100 inches ² ) (24 hours) (mil) at 25°C measured by ASTM E96-635 (E).

In one particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminium foil 422; adhesively bonded to 100 micron thickness polyvinyl chloride (PVC) 424.

In one particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminium foil 422; adhesively bonded to 5 60 micron thickness polyvinyl chloride (PVC) 424.

In one particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 20 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminium foil 422; adhesively bonded to 10 60 micron thickness polyvinyl chloride (PVC) 424.

In one particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminium foil 422; adhesively bonded to 15 30 micron thickness polyvinyl chloride (PVC) 424.

In one particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminium foil 422; adhesively bonded to 20 15 micron thickness polyvinyl chloride (PVC) 424.

In one particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 100 μm layer thickness PVC adhesively bonded to 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 45 micron 25 thickness aluminium foil 422; adhesively bonded to 15 micron thickness polyvinyl chloride (PVC) 424.

In one particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; 30 adhesively bonded to 45 micron thickness aluminium foil 422; adhesively bonded to 30 micron thickness polyvinylidene chloride (PVDC) 424.

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to

20 micron thickness oriented polypropylene 424. 5

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to

25 micron thickness cast polypropylene 424. 10

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to

20 micron thickness oriented polypropylene 424. 15

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to

25 micron thickness cast polypropylene 424.

20

In one particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 60 μm layer thickness polypropylene; adhesively bonded to 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to 25 micron thickness cast 25 polypropylene 424.

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to 30 25 micron thickness polypropylene 424, wherein the polypropylene is manufactured by a process in which one or more metallocene compounds are employed to control side-chain characteristics thereof.

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to 5 40 micron thickness low density polyethylene (LDPE) 424.

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to 10 40 micron thickness high density polyethylene (HDPE) 424.

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to 15 20 micron thickness polychlorotrifluoroethylene (PCTFE) 424.

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to 20 25 micron thickness cyclic olefin copolymer (COC) 424.

In another particular variation, the base sheet of the blister pack of Fig. 4 has the following structure: 25 micron layer thickness oriented polyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminium foil 422; adhesively bonded to 25 25 micron thickness cyclic olefin polymer (COP) 424.

Any of the particular lid sheet variants described in respect of Fig. 4 may be used in combination with any of the particular base sheet variants described in respect of that same Fig. 4. 30

As will be appreciated by one having ordinary skill in the art, various conventional adhesives can be employed to bond the laminate layers within the scope of the

invention. Such adhesives include, but are not limited to, cyanoacrylates, acrylics and polyurethanes and resins for extrusion laminating, like EAA, ionomer structures like Surlyn® and Bynel® (trade names from Du Pont) and malein-acid-anhydride (MAH resins).

During a typical process for manufacturing a drug pack as shown for example in Fig. 4, each blister 412 is filled with a pharmaceutical composition 414 and subsequently sealed. The sealing temperature and other parameters of the sealing method may be varied including tooling, dwell time, sealing pressure and speed of sealing. The heat-sealing step bonds the mating layers (e.g., PVC 424 and heat seal lacquer 430) of the base and lid to seal each blister 412 and, hence forms a secure container for the pharmaceutical composition 414 contained therein. Ideally, the bonding creates a hermetic seal that is formed. As will be appreciated, hermetically sealing each blister 412 to eliminate the possibility of contamination from the external environment can be an important aspect of the manufacturing process.

Figs. 5 and 6 show an alternative drug pack structures herein, in which the lid sheet is provided with an inner peelable layer.

Referring now to Fig. 5, there is shown a blister pack 700 herein having a lid sheet which has a three layer structure and comprises the following successive layers:

(i) an outer paper lid sheet layer 725; bonded to

(ii) an aluminium foil lid sheet layer 729; bonded to

(iii) an inner lid sheet layer of polymeric material 730.

One particular lid sheet of Fig. 5 comprises (i) an outer paper lid sheet layer 725 of weight 25 g/m ² ; bonded by polyethylene (PE) extrusion to (ii) an aluminium foil lid sheet layer 729 of thickness 20 micron; bonded to (iii) an inner lid sheet layer 730 of peelable co-extrusion coating having a weight of 15 g/m ² .

Another particular lid sheet of Fig. 5 comprises (i) an outer paper lid sheet layer 725 of weight 25 g/m ² ; bonded to (ii) an aluminium foil lid sheet layer 729 of thickness 38 micron; bonded to (iii) an inner lid sheet layer of polyethylene (PE) peel film of thickness 30 or 40 micron.

The base sheet of the blister pack of Fig. 5 also has a multi-layer structure and comprises the following successive layers: oriented polyamide (OPA) 720 of thickness 25 micron adhesively bonded to aluminium foil 722 of thickness 45 micron adhesively bonded to a base sheet layer 724 of PE peel film of thickness 30 micron. The blister pack 700 is filled with inhalable drug 714 in dry powdered form.

Referring now to Fig. 6, there is shown a blister pack 800 herein having a lid sheet which has a three layer structure and comprises the following successive layers:

(i) an outer paper lid sheet layer 825; bonded to

(ii) an intermediate layer of polymeric material 827; bonded to

(iii) an aluminium foil lid sheet layer 829; bonded to

(iv) an inner lid sheet layer of polymeric material 830.

One particular drug pack of Fig. 6 thus, comprises (i) an outer paper lid sheet layer 825 of weight 25 g/m ² ; bonded to (ii) intermediate layer 827 of PET of thickness 12 micron bonded to (iii) an aluminium foil lid sheet layer 829 of thickness 20 micron; bonded to (iv) an inner lid sheet layer 830 of PVC film of thickness 15 or 30 micron. This lid sheet is particularly suitable for use with a base sheet having heat seal lacquer as its inner base sheet layer.

Thus, the base sheet of the blister pack of Fig. 6 also has a multi-layer structure and comprises the following successive layers: oriented polyamide (OPA) 820 of

thickness 25 micron adhesively bonded to aluminium foil 822 of thickness 60 micron adhesively bonded to a base sheet layer 824 of heat seal lacquer. The blister pack 800 is filled with inhalable drug 814 in dry powdered form.

Referring now to Fig. 7, there is shown a blister pack 900 herein having a lid sheet which has a three layer structure and comprises the following successive layers:

(i) an outer paper lid sheet layer 925; bonded to

(ii) an intermediate layer of polymeric material 927; bonded to

(iii) an aluminium foil lid sheet layer 929; bonded to

(iv) an inner lid sheet layer of polymeric material 930.

One particular drug pack of Fig. 7 thus, comprises (i) an outer paper lid sheet layer 925 of weight 25 g/m ² ; bonded by extrusion lamination to (ii) intermediate layer 927 of spun-PET 488/20 of thickness 20 micron bonded by two co-extrusion lamination layers to (iii) an aluminium foil lid sheet layer 929 of thickness 20 micron; bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PE peel film of thickness 30 micron.

Another particular drug pack of Fig. 7 thus, comprises (i) an outer paper lid sheet layer 925 of weight 25 g/m ² ; bonded by extrusion lamination to (ii) intermediate layer 927 of spun-PET 488/30 of thickness 30 micron bonded by two co-extrusion lamination layers to (iii) an aluminium foil lid sheet layer 929 of thickness 20 micron; bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PE peel film of thickness 30 micron.

A further particular drug pack of Fig. 7 thus, comprises (i) an outer paper lid sheet layer 925 of weight 25 g/m ² ; bonded by extrusion lamination to (ii) intermediate layer 927 of spun-PET 088/30 of thickness 30 micron bonded by two co-extrusion

lamination layers to (iii) an aluminium foil lid sheet layer 929 of thickness 20 micron; bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PE peel film of thickness 30 micron.

A further particular drug pack of Fig. 7 thus, comprises (i) an outer paper lid sheet layer 925 of weight 25 g/m ² ; bonded by lacquer lamination to (ii) intermediate layer 927 of spun-PET 088/30 of thickness 30 micron bonded by lacquer lamination to (iii) an aluminium foil lid sheet layer 929 of thickness 20 micron; bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PE peel film of thickness 30 micron.

A further particular drug pack of Fig. 7 thus, comprises (i) an outer paper lid sheet layer 925 of weight 50 g/m ² ; bonded by lacquer lamination to (ii) intermediate layer 927 of spun-PET 088/30 of thickness 30 micron bonded by lacquer lamination to (iii) an aluminium foil lid sheet layer 929 of thickness 20 micron; bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PE peel film of thickness 30 micron.

A further drug pack of Fig. 7 thus, comprises (i) an outer paper lid sheet layer 925 of weight 25 g/m ² ; bonded by lacquer lamination to (ii) intermediate layer 927 of cross- laminated HDPE of thickness 60 micron bonded by lacquer lamination to (iii) an aluminium foil lid sheet layer 929 of thickness 20 micron; bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PE peel film of thickness 30 micron. The material sold by Illinois Tool Works, Inc. under the trade name Valeron is a suitable cross-laminated HDPE material.

A further drug pack of Fig. 7 thus, comprises (i) an outer paper lid sheet layer 925 of weight 50 g/m ² ; bonded by lacquer lamination to (ii) intermediate layer 927 of cross- laminated HDPE of thickness 60 micron bonded by lacquer lamination to (iii) an aluminium foil lid sheet layer 929 of thickness 20 micron; bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PE peel film of thickness 30 micron. The material sold by Illinois Tool Works, Inc. under the trade name Valeron is a suitable cross-laminated HDPE material.

A further drug pack of Fig. 7 thus, comprises (i) an outer paper lid sheet layer 925 of weight 25 g/m ² ; bonded by lacquer lamination to (ii) intermediate layer 927 of cross- laminated HDPE of thickness 60 micron bonded by lacquer lamination to (iii) an aluminium foil lid sheet layer 929 of thickness 20 micron; bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PVC peel film of thickness 30 micron. The material sold by Illinois Tool Works, Inc. under the trade name Valeron is a suitable cross-laminated HDPE material.

A further drug pack of Fig. 7 thus, comprises (i) an outer paper lid sheet layer 925 of weight 50 g/m ² ; bonded by lacquer lamination to (ii) intermediate layer 927 of cross- laminated HDPE of thickness 60 micron bonded by lacquer lamination to (iii) an aluminium foil lid sheet layer 929 of thickness 20 micron; bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PVC peel film of thickness 30 micron. The material sold by Illinois Tool Works, Inc. under the trade name Valeron is a suitable cross-laminated HDPE material.

Thus, the base sheet of the blister pack of Fig. 7 also has a multi-layer structure and comprises the following successive layers: oriented polyamide (OPA) 920 of thickness 25 micron adhesively bonded to aluminium foil 922 of thickness 60 micron adhesively bonded to a base sheet layer 924 of thickness of from 15 to 100 micron PVC. The blister pack 900 is filled with inhalable drug 914 in dry powdered form.

In further embodiments, the respective lid sheets of Figs. 5 to 7 herein may also be employed with any of the base sheets of Fig. 4 herein.

Various bonding schemes and patterns may be employed to bond and seal blister strip packs such as shown in Figs. 4 to 7. Illustrative are the bonding schemes and patterns shown in Figs 2 and 3.

Referring now to Fig. 2, there is shown a bonding scheme that employs substantially uniformly distributed heat across at least one surface of the blister strip 200 to create discrete bond areas of the mating base 209 and lid surfaces. Although various bond

patterns can be formed by this bonding scheme (e.g., zig-zag, dot, checkered, etc.), a checkered grid 216 pattern is employed in this example.

As illustrated in Fig. 2, the grid 216 provides a restricted, tortuous path (designated generally by Arrow M) for the ingress of contaminants and/or moisture into the blisters 203, 205, 207.

Referring now to Fig. 3, there is shown a further bonding scheme that employs substantially uniformly distributed heat across at least one surface of the blister strip 300 to create discrete bond areas of the mating base 309 and lid surfaces. A knurled form bond pattern 316 is employed in this example. The knurling 316 provides a restricted, tortuous path (designated generally by Arrow M) for the ingress of contaminants and/or moisture into the blisters 303, 305, 307.

Fig. 8 shows a lid sheet ('cover foil') 1011 suitable for use in a blister pack herein (not represented) and having the following layer structure from outside inwards:

Layer A 1025 for example, comprised of overprinted satined paper of weight 30 g/m ² ;

Laminating aid 1026;

Layer B 1027 for example, comprised of a non-woven material made from HDPE with a weight of 60 g/m ² ;

Laminating aid 1028;

Layer C 1029 for example, comprised of 25 μm thick aluminium foil; and

Layer D 1030 for example, comprised of heat seal lacquer

The lid sheet of the drug packs herein is designed to provide enhanced tear resistance and tear propagation resistance. Tear resistance is a measure of

resistance of the lid sheet to initial tearing thereof and is generally related to tensile strength and puncture resistance properties of at least one layer of the lid sheet, generally a polymeric material layer. Tear propagation resistance is a measure of the resistance of the lid sheet to tear further once an initial tear (or nick or cut or similar) has been experienced by the lid sheet and in existing lid sheets is generally related to the properties of the paper and aluminium foil lid sheet layers. Tear resistance can be measured in the laboratory by the ASTM method having the reference number ASTM D1004. Tear propagation resistance can be measured in the laboratory by a method called the Elmendorf test (DIN 53128 or EN21974).

The lid sheet of the drug packs herein suitably has a tear resistance of greater than 2ON and a tear propagation resistance of greater than 2.5N.

The drug pack and related drug dispenser device of the invention is suitable for dispensing drug products particularly for the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), bronchitis and chest infections. Other applications are also envisaged.

Appropriate drugs may thus be selected from, for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate (e.g. as the sodium salt), ketotifen or nedocromil (e.g. as the sodium salt); antiinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti- inflammatories, e.g., beclomethasone (e.g. as the dipropionate ester), fluticasone (e.g. as the propionate ester), flunisolide, budesonide, rofleponide, mometasone e.g. as the furcate ester), ciclesonide, triamcinolone (e.g. as the acetonide) or 6α, 9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester, (6α,11β,16 α,17 α)-6,9-difluoro-17-{[(fluoromethyl)thio]carbonyl}-11-hydrox y-16- methyl-3-oxoandrosta-1 ,4-dien-17-yl 2-furoate, and (6 α,11 β,16 α,17 α)-6,9-difluoro- 17-{[(fluoromethyl)thio]carbonyl}-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-dien-i 7-yl 4-methyl-1 ,3-thiazole-5-carboxylate; antitussives, e.g., noscapine; bronchodilators, e.g., 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phen yl]ethyl}amino) hexyl] oxy} butyl) benzenesulfonamide, 3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3- hydroxymethyl) phenyl] ethyl}-amino) heptyl] oxy} propyl) benzenesulfonamide, 4-{(1 R)-2-[(6-{2-[(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]-1-hydroxyethyl}-2- (hydroxymethyl) phenol, 4-{(1 R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl] butoxy}hexyl)amino]-1 -hydroxyethyl}-2-(hydroxymethyl)phenol, N-[2-hydroxyl-5- [(1 R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino]ph enyl] ethyl]amino]ethyl]phenyl]formamide,

N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-h ydroxy-2-(8-hydroxy- 2(1/-/)-quinolinon-5-yl)ethylamine, 5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)- phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy- 1 H-quinolin-2-one, 5- [(1 R)-2-[(5, 6-diethyl-2, 3-dihydro-1 H-inden-2-yl) amino]-1-hydroxyethyl]-8-hydroxy- 2(1 H)-quinolinone, albuterol (e.g. as free base or sulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline, fenoterol (e.g. as hydrobromide), formoterol (e.g. as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride), rimiteroi, terbutaline (e.g. as sulphate), isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2- phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzoth iazolone; adenosine 2a

agonists, e.g. 2R,3R,4S,5R)-2-[6-Amino-2-(1 S-hydroxymethyl-2-phenyl-ethylamino)- purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3 _> 4-diol (e.g. as maleate); α ₄ integrin inhibitors e.g. (2S)-3-[4-({[4-(aminocarbonyl)-1- piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2- methylphenoxy) acetyl]amino}pentanoyl)amino] propanoic acid (e.g. as free acid or potassium salt), diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium (e.g. as bromide), tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin or glucagon; vaccines, diagnostics, and gene therapies. It will be clear to a person skilled in the art that, where appropriate, the drugs may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimise the activity and/or stability of the drug.

The drug product may in aspects, be a mono-therapy (i.e. single active drug containing) product or it may be a combination therapy (i.e. plural active drugs containing) product.

Suitable drugs or drug components of a combination therapy product are typically selected from the group consisting of anti-inflammatory agents (for example a corticosteroid or an NSAID), anticholinergic agents (for example, an M- _t , M ₂ , M-|/M ₂ or M ₃ receptor antagonist), other β ₂ -adrenoreceptor agonists, antiinfective agents (e.g. an antibiotic or an antiviral), and antihistamines. All suitable combinations are envisaged.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs. Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α,9α-difluoro-17α-[(2-furanylcarbonyI)oxy]- 11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-

fluoromethyl ester, 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propion yloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g. the 17-propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (e.g. the furoate ester), triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR- 106541 , and ST-126. Preferred corticosteroids include fluticasone propionate, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]- 3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester and 6α,9α- difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4- diene-17β-carbothioic acid S-fluoromethyl ester, more preferably 6α,9α-difluoro-17α- [(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β- carbothioic acid S-fluoromethyl ester.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed

PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis. Suitable other β ₂ -adrenoreceptor agonists include salmeterol (e.g. as the xinafoate), salbutamol (e.g. as the sulphate or the free base), formoterol (e.g. as the fumarate), fenoterol or terbutaline and salts thereof.

Suitable phosphodiesterase 4 (PDE4) inhibitors include compounds that are known to inhibit the PDE4 enzyme or which are discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 inhibitor which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity. For the purposes of this disclosure, the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low

affinity" binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity" binding site (HPDE 4). This term "HPDE4" should not be confused with the term "hPDE4" which is used to denote human PDE4.

A method for determining IC50S ratios is set out in US patent 5,998,428 which is incorporated herein in full by reference as though set out herein. See also PCT application WO 00/51599 for another description of said assay.

Suitable PDE4 inhibitors include those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC ₅₀ ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC50 value for competing with the binding of 1nM of [ ³ H]R-rolipram to a form of PDE4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 μM[ ³ H]-cAMP as the substrate.

Most suitable are those PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0. Preferred compounds are cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-one and c/s-[4-cyano-4-(3-cyclopropylmethoxy- 4-difluoromethoxyphenyl)cyclohexan-1-ol]; these are examples of compounds which

bind preferentially to the low affinity binding site and which have an IC50 ratio of 0.1 or greater.

Other suitable drug compounds include: c/s-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-1-carboxylic acid (also known as cilomalast) disclosed in U.S. patent 5,552,438and its salts, esters, pro-drugs or physical forms; AWD-12- 281 from elbion (Hofgen, N. et al. 15th EFMC lnt Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering- Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, LJ. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO99/47505, the disclosure of which is hereby incorporated by reference) from Byk-Gulden; Pumafentrine, (-)-p-[(4aR*,10£»S*)-9-ethoxy-1 ,2,3,4 ,4a, 10b-hexahydro- 8-methoxy-2-methylbenzo[c][1 ,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk- Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vemalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), and T2585.

Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds, which are antagonists of the Mi and M ₂ receptors. Exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines.

Particularly suitable anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interest are: methantheline (CAS-53-46-3),

propantheline bromide (CAS- 50-34-9), anisotropine methyl bromide or Valpin 50 (CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71-81-8), mepenzolate bromide (U.S. patent 2,918,408), tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-115-63-9). See also cyclopentolate hydrochloride (CAS-5870-29-1 ), tropicamide (CAS-1508-75-4), trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine (CAS-29868-97-1 ), telenzepine (CAS-80880-90-9), AF-DX 116, or methoctramine, and the compounds disclosed in WO01/04118.

Suitable antihistamines (also referred to as H-i-receptor antagonists) include any one or more of the numerous antagonists known which inhibit Hi-receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with Hi-receptors. Examples include ethanolamines, ethylenediamines, and alkylamines. In addition, other first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines. Second generation antagonists, which are non-sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or piperidine. Exemplary antagonists are as follows: Ethanolamines: carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.

Ethylenediamines: pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate. Alkylamines: chlropheniramine and its salts such as the maleate salt, and acrivastine.

Piperazines: hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI.

Piperidines: Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another Hi receptor antagonist which may be used in combination with a PDE4 inhibitor.

Particularly suitable anti-histamines include methapyrilene and loratadine.

In respect of combination products, co-formulation compatibility is generally determined on an experimental basis by known methods and may depend on chosen type of drug dispenser action.

The drug components of a combination product are suitably selected from the group consisting of anti-inflammatory agents (for example a corticosteroid or an NSAID), anticholinergic agents (for example, an Mi, M ₂ , M-|/M ₂ or M ₃ receptor antagonist), other β ₂ -adrenoreceptor agonists, antiinfective agents (e.g. an antibiotic or an antiviral), and antihistamines. All suitable combinations are envisaged.

In embodiments, the co-formulation compatible components comprise a β ₂ - adrenoreceptor agonist and a corticosteroid; and the co-formulation incompatible component comprises a PDE-4 inhibitor, an anti-cholinergic or a mixture thereof. The β ₂ -adrenoreceptor agonists may for example be salbutamol (e.g., as the free base or the sulphate salt) or salmeterol (e.g., as the xinafoate salt) or formoterol (eg as the fumarate salt). The corticosteroid may for example, be a beclomethasone ester (e.g., the dipropionate) or a fluticasone ester (e.g., the propionate) or budesonide.

In one example, the co-formulation compatible components comprise fluticasone propionate and salmeterol, or a salt thereof (particularly the xinafoate salt) and the co-formulation incompatible component comprises a PDE-4 inhibitor, an anticholinergic (e.g. ipratropium bromide or tiotropium bromide) or a mixture thereof.

In another example, the co-formulation compatible components comprise budesonide and formoterol (e.g. as the fumarate salt) and the co-formulation incompatible component comprises a PDE-4 inhibitor, an anti-cholinergic (e.g. ipratropium bromide or tiotropium bromide) or a mixture thereof.

Generally, powdered drug particles suitable for delivery to the bronchial or alveolar region of the lung have an aerodynamic diameter of less than 10 micrometers, preferably less than 6 micrometers. Other sized particles may be used if delivery to other portions of the respiratory tract is desired, such as the nasal cavity, mouth or throat. The drug may be delivered as pure drug, but more appropriately, it is preferred that drugs are delivered together with excipients (carriers) which are suitable for inhalation. Suitable excipients include organic excipients such as polysaccharides (i.e. starch, cellulose and the like), lactose, glucose, mannitol, amino acids, and maltodextrins, and inorganic excipients such as calcium carbonate or sodium chloride. Lactose is a preferred excipient.

Particles of powdered drug and/or excipient may be produced by conventional techniques, for example by micronisation, milling or sieving. Additionally, drug and/or excipient powders may be engineered with particular densities, size ranges, or characteristics. Particles may comprise active agents, surfactants, wall forming materials, or other components considered desirable by those of ordinary skill.

The excipient may be included with the drug via well-known methods, such as by admixing, co-precipitating and the like. Blends of excipients and drugs are typically formulated to allow the precise metering and dispersion of the blend into doses. A standard blend, for example, contains 13000 micrograms lactose mixed with 50 micrograms drug, yielding an excipient to drug ratio of 260:1. Dosage blends with excipient to drug ratios of from 100:1 to 1 :1 may be used. At very low ratios of excipient to drug, however, the drug dose reproducibility may become more variable.

The drug pack and dispenser device of the invention is in one aspect suitable for dispensing drug for the treatment of respiratory disorders such as disorders of the lungs and bronchial tracts including asthma and chronic obstructive pulmonary disorder (COPD). In another aspect, the invention is suitable for dispensing drug for the treatment of a condition requiring treatment by the systemic circulation of drug, for example migraine, diabetes, pain relief e.g. inhaled morphine.

Accordingly, there is provided the use of a drug pack and dispenser device according to the invention for the treatment of a respiratory disorder, such as asthma and COPD. Alternatively, the present invention provides a method of treating a respiratory disorder such as, for example, asthma and COPD, which comprises administration by inhalation of an effective amount of drug product as herein described from a drug pack or dispenser device of the present invention.

The amount of any particular drug compound or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated. The drugs for treatment of respiratory disorders herein may for example, be administered by inhalation at a dose of from O.OOOδmg to 10 mg, preferably 0.005mg to 0.5mg. The dose range for adult humans is generally from

0.0005 mg to 10Omg per day and preferably 0.01 mg to 1 mg per day.

It will be understood that the present disclosure is for the purpose of illustration only and the invention extends to modifications, variations and improvements thereto.

The application of which this description and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described therein. They may take the form of product, method or use claims and may include, by way of example and without limitation, one or more of the following claims: