WO2008039182A1

WO2008039182A1 - Drug carrier in blister pack form

Info

Publication number: WO2008039182A1
Application number: PCT/US2006/037400
Authority: WO
Inventors: Richard Ian ___War Walker; Wilhelm Karl Zuser; Helmut Resch; Elke Klauser; Ingrid Maria Mazanek
Original assignee: Glaxo Group Limited; Smithkline Beecham Corporation
Priority date: 2006-09-26
Filing date: 2006-09-26
Publication date: 2008-04-03

Abstract

There is provided blister form drug pack comprising (a) a base sheet in which blisters are formed to define pockets therein for the containment of inhalable drug; and (b) a lid sheet which is sealable to the base sheet and mechanically peelable from the base sheet to enable release of said inhalable drug.

Description

Drug Carrier In Blister Pack Form

Technical field

The present invention relates to a drug carrier in peelable blister pack form suitable for containing drug for inhaled delivery to the lung.

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.

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 (i.e. by peelable separation of the lid sheet from a base sheet) within the 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 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.

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 strip form drug packs may thereby, be achieved.

Summary of the invention

According to one 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 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 paper lid sheet layer; bonded to

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

iii) an aluminium foil lid sheet layer; bonded indirectly to (iv) an inner lid sheet layer of heat seal lacquer,

wherein a second intermediate lid sheet layer of polymeric material sandwiches between the aluminium foil lid sheet layer and the inner lid sheet layer of heat seal lacquer.

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

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. 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 and mechanically peelable from the base sheet to enable release of the inhalable drug from an opened pocket. In embodiments, the lid sheet does not seal to the base sheet in the region of the blisters. 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) along the 5 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.

10 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.

15 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.

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 20 100 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.

25 The first base sheet layer of aluminium foil typically has a thickness of from 15 to 60 micron, particularly 20 to 40 micron.

The thickness of the second base sheet layer of polymeric material is from 10 to 100 micron such as from 10 to 60 micron, preferably from 20 to 50 micron. 30

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 inches²) (24 hours) (mil) at 25°C, preferably less than less than 0.3 g /(100 inches²) (24 hours) (mil) at 25°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); polypropylene (e.g. in oriented or cast form; standard or metallocene); polyethylene (e.g. in high, low or intermediate density form); 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 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 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 calandering.

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.

Another particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded to (c) oriented polypropylene (OPP). The thickness of the oriented polypropylene (OPP) 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 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 to (c) high density polyethylene (HDPE). The thickness of the high density polyethylene (HDPE) layer is from 10 to 60 micron, particularly from 35 to 45 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) low density polyethylene (LDPE). The thickness of the low density polyethylene (LDPE) 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 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.

A further particular base sheet comprises the following successive layers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil; adhesively bonded 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 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.

The aluminium foil lid sheet layer bonds indirectly to the inner lid sheet layer of heat seal lacquer. One or more additional intermediate lid sheet layers of polymeric material sandwich between the aluminium foil lid sheet layer and the inner lid sheet layer of heat seal lacquer.

In one aspect herein, the 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 to (iii) an aluminium foil lid sheet layer; bonded to

(iv) a second intermediate lid sheet layer of polymeric material; bonded to

(v) an inner lid sheet layer of heat seal lacquer.

In this aspect, the presence of both the first and second intermediate lid sheet layers of polymeric material, one on either side of the aluminium foil lid sheet layer, further adds strength to the lid sheet to improve tear resistance and tear propagation resistance. The (iv) second intermediate layer is suitably oriented polypropylene (oPP). In this aspect, the (ii) first intermediate lid sheet layer is suitably selected from the group consisting of cross-laminated high density polyethylene (HDPE), oriented polyamide (OPA) and poly (ethylene terephthalate) (PET).

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 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) a second intermediate lid sheet layer of oPP of thickness from 10 to 50 micron, particularly from 20 to 30 micron; bonded to (v) an inner lid sheet layer of heat seal lacquer.

Another particular lid sheet comprises (i) an outer paper lid sheet layer; bonded to (ii) a first intermediate lid sheet layer of OPA of thickness from 10 to 50 micron, particularly from 20 to 30 micron; bonded to (iii) an aluminium foil lid sheet layer; bonded to (iv) a second intermediate lid sheet layer of oPP of thickness from 10 to 50 micron, particularly from 20 to 30 micron; bonded to (v) an inner lid sheet layer of heat seal lacquer.

Optionally to further add strength to the lid sheet, a third intermediate lid sheet layer of polymeric material is inserted between the (ii) first intermediate lid sheet layer of polymeric material and the (iii) lid sheet layer of aluminium foil. Thus, another particular lid sheet comprises (i) an outer paper lid sheet layer; bonded to (N) a first intermediate lid sheet layer of PET from 5 to 30 micron, particularly from 10 to 20 micron; bonded to a third intermediate lid sheet layer of OPA of thickness from 10 to 50 micron, particularly from 20 to 30 micron; bonded to (iii) an aluminium foil lid sheet layer; bonded to (iv) a second intermediate lid sheet layer of oPP of thickness from 10 to 50 micron, particularly from 20 to 30 micron; bonded to (v) an inner lid sheet layer of heat seal lacquer.

The thickness of the aluminium foil lid sheet layer is typically from 6 to 60 micron, particularly 15 to 40 micron.

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

The heat seal lacquer lid sheet 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 calandering.

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 and hot bar sealing.

The base sheet herein is particularly suitable for forming by 'cold form' methods, which are conducted at lower temperatures than conventional methods (e.g. at close to room temperature). Such 'cold form' methods are of particular utility where the drug or drug formulation for containment within the blister is heat sensitive (e.g. degrades or denatures on heating). 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; (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 another 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.

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 li 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 I₂ 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 seat lacquer (e.g. a vinyllic heat seal lacquer). Figs. 4 and 5 show alternative drug packs herein, which utilise the identical multilayer base sheet structure of Fig. 4 (as described below) but which, make use of alternative multi-layer lid sheet structures.

Referring now to Fig. 4 there is shown a drug pack 500, in which the lid sheet has a laminate structure comprising the following successive layers:

(i) an outer paper lid sheet layer 525; bonded to

(ii) a first intermediate lid sheet layer 527 of polymeric material; bonded to

(iii) an aluminium foil lid sheet 529 layer; bonded to

(iv) a second intermediate lid sheet layer 532 of oriented polypropylene (oPP); bonded to

(v) an inner lid sheet layer 530 of heat seal lacquer.

One particular lid sheet comprises (i) an outer paper lid sheet layer 525 of weight 22 g/m²; bonded to (ii) a first intermediate lid sheet layer 527 of cross-laminated HDPE (as sold under the trade name Valeron) of thickness 75 micron; bonded to (iii) an aluminium foil lid sheet layer 529 of thickness 30 micron; bonded to (iv) a second intermediate lid sheet layer 532 of oPP of thickness 25 micron; bonded to (v) an inner lid sheet layer 530 of heat seal lacquer.

Another particular lid sheet comprises (i) an outer paper lid sheet layer 525 of weight 22 g/m²; bonded to (ii) a first intermediate lid sheet layer 527 of OPA of thickness 25 micron; bonded to (iii) an aluminium foil lid sheet layer 529 of thickness 30 micron; bonded to (iv) a second intermediate lid sheet layer 532 of oPP of thickness 25 micron; bonded to (v) an inner lid sheet layer 530 of heat seal lacquer.

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 inches²) (24 hours) (mil) at 25⁰C 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 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 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.

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.

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. 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.

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 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 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 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 20 micron thickness polychlorotrifluoroethyiene (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 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 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.

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.

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.

Referring now to Fig. 5 there is shown a drug pack 600 that is a variant of that shown in Fig. 4 and in which a third intermediate lid sheet layer 634 of polymeric material is inserted between the (ii) first intermediate lid sheet layer 627 of polymeric material and the (iii) lid sheet layer 629 of aluminium foil.

Thus, another particular lid sheet comprises (i) an outer paper lid sheet layer 625 of weight 22 g/m²; bonded to (ii) a first intermediate lid sheet layer 627 of PET of thickness 12 micron; bonded to a third intermediate lid sheet layer 634 of OPA of thickness 25 micron; bonded to (iii) an aluminium foil lid sheet layer 629 of thickness 30 micron; bonded to (iv) a second intermediate lid sheet layer 632 of oPP of thickness 25 micron; bonded to (v) an inner lid sheet layer 630 of heat seal lacquer.

Various bonding schemes and patterns may be employed to bond and seal blister strip packs such as shown in Figs. 4 and 5. 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.

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 inhalable drug products particularly for the inhaled treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), bronchitis and chest infections.

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 furoate 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,16α,17α)-6,9-difluoro-17-{[(fluoromethyl)thio]carbonyl}-11-hydroxy-16- methyl-3-oxoandrosta-1 ,4-dien-17-yl 2-furoate, (6α,11β,16α,17α)-6,9-difluoro-17- {[(fluoromethyl)thio]carbonyl}-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-dien-17-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)phenyl]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]phenyl]ethyl]amino]ethyl]phenyl]formamide, N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophθnyl]ethyl}-2-hydroxy-2-(8-hydroxy- 2(1H)-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), rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2- phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone; 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); α₄ 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 Mi, M₂, M₁/M₂ or Mβ receptor antagonist), other β₂-adrenoreceptor agonists, antiinfective agents (e.g. an antibiotic or an antiviral), and antihistamines. All suitable combinations are envisaged.

5 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-furanylcarbonyl)oxy]-

10 11β-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-propionyloxy- 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),

15 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- 0 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, 5 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. 0 Suitable other β₂-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 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.

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 1 nM of [3|-ϊ]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[³H]-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*,106S*)-9-ethoxy-1 ,2,3,4 ,4a,1 Ob-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 Vernalis; 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 M₂ 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 Hi-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 HCl, 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 M-i, M₂, M-ι/M₂ or M₃ receptor antagonist), other β₂-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 β₂- adrenoreceptor agonist and a corticosteroid; and the co-formulation incompatible component comprises a PDE-4 inhibitor, an anti-cholinergic or a mixture thereof. The β₂-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 O.OOδmg to O.δmg. The dose range for adult humans is generally from 0.0005 mg to 100mg per day and preferably 0.01 mg to 1mg 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:

Claims

1. A blister form drug pack comprising

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

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

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

(iv) an inner lid sheet layer of heat seal lacquer,

2. A drug pack according to claim 1 in the form of an elongate blister strip.

3. A drug pack according to either of claims 1 or 2, wherein the second intermediate lid sheet layer comprises oriented polypropylene (oPP).

4. A drug pack according to any of claims 1 to 3, wherein the first intermediate lid sheet layer is selected from the group consisting of cross-laminated HDPE, oriented polyamide (OPA) and PET.

5. A drug pack according to claim 4, wherein said cross-laminated HDPE layer is of thickness from 30 to 100 micron, particularly from 50 to 80 micron.

5 6. A drug pack according to claim 4, wherein said OPA layer is of thickness from 10 to 50 micron, particularly from 20 to 30 micron.

7. A drug pack according to any of claims 1 to 3, wherein a third intermediate lid sheet layer of polymeric material is inserted between the first intermediate lid sheet

10 layer of polymeric material and the lid sheet layer of aluminium foil.

8. A drug pack according to claim 7, wherein the first intermediate lid sheet layer comprises PET of thickness from 5 to 30 micron, particularly from 10 to 20 micron; and said third intermediate lid sheet layer comprises OPA of thickness from 10 to 50

15 micron, particularly from 20 to 30 micron.

9. A drug pack according to any of claims 1 to 8, wherein the base sheet herein 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 100 micron.

20

10. A drug pack according to claim 9, wherein the first base sheet layer of aluminium foil typically has a thickness of from 15 to 60 micron, particularly from 20 to 40 micron.

25 11. A drug pack according to either of claims 9 or 10, wherein the second base sheet layer of polymeric material has a thickness of from 10 to 100 micron, particularly from 20 to 50 micron.

12. A drug pack according to any of claims 9 to 11 , wherein the second base 30 sheet layer comprises a polymeric material of water vapour permeability of less than 0.6 g /(100 inches²) (24 hours) (mil) at 25°C.

13. A drug pack according to claim 12, wherein the second base sheet layer comprises a material selected from the group consisting of polyvinyl chloride (PVC); polypropylene; polyethylene; polyvinylidene chloride (PVDC); polychlorotrifluoroethylene (PCTFE); cyclic olefin copolymer (COC); and cyclic olefin polymer (COP).

14. A drug pack according to any of claims 9 to 13, wherein the first base sheet layer of aluminium foil is provided with an outer base sheet layer of a polymeric material.

15. A drug pack according to claim 14, wherein, said outer layer base sheet layer comprises oriented polyamide (OPA).

16. A blister form drug pack according to any of claims 1 to 15, wherein one or more of said blisters of the pack contain inhalable drug in dry powder form.

17. A blister form drug pack according to claim 16, wherein said inhalable drug comprises one or more drug actives selected from the group consisting of antiinflammatory agents, anticholinergic agents, other p₂-adrenoreceptor agonists, antiinfective agents, antihistamines and any mixtures thereof.

18. A blister form drug pack according to claim 17, wherein said anti-inflammatory agents are selected from the group consisting of corticosteroids, NSAIDs and any mixtures thereof.

19. A blister form drug pack according to claim 17, wherein said corticosteroids are selected from the group consisting of methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)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-propionyloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters, flunisolide, mometasone esters, triamcinolone acetonide, rofleponidθ, ciclesonide, butixocort propionate, RPR-106541 , and ST-126 and any mixtures thereof.

20. A blister form drug pack according to claim 17, wherein said NSAIDs are selected from the group consisting of sodium cromogiycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors, leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists, adenosine receptor agonists or antagonists, cytokine antagonists, inhibitors of cytokine synthesis and any mixtures thereof.

21. A drug dispenser device comprising a housing; and within said housing an elongate form blister form drug pack according to any of claims 16 to 20, wherein the dispenser device includes an internal mechanism for dispensing the inhalable drug from the pockets of the drug pack, said mechanism comprising,

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

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

22. Use of a drug dispenser device according to claim 21 for dispensing inhalable drug.