HK1169050B - Dose unit, pack of dose units and inhaler for inhalation of combination of drugs - Google Patents

Description

Dose unit, package of dose units and combined inhaler for inhaling medicament

Background

The present invention relates to a dosage unit for a dry powder inhaler, comprising:

-a dose carrier comprising a plurality of pockets each adapted to contain a dose of medicament powder suitable for inhalation, the pockets being arranged in series such that the contents of the pockets can be sequentially exposed to an air flow for continuous inhalation, and

-a plurality of medicament powder doses arranged in pockets of said dose carrier.

Typically, all pouches of these dosage units contain a pharmaceutical dose comprising a mixture of at least one pharmaceutically active ingredient and at least one excipient. It has been proposed to use a pair of such dosage units in the same inhaler, and more particularly to provide an inhaler adapted to deliver medicament powder simultaneously from both units. Such embodiments are described, for example, in WO 2005/002654 and WO 2004/011070. In particular embodiments known in these references, a first dosage unit contains a first drug powder and a second dosage unit contains a second drug powder different from the first drug powder, whereby the inhaler can be used to deliver a combination of pharmaceutically active ingredients stored in different carriers. This is of particular interest in certain treatments for administering to a patient pharmaceutically active ingredients that have to be delivered in combination but stored separately for stability reasons.

Then, it may be necessary to administer not only a combination of two drug powders to the patient, but alternatively only one of the two drug powders in case the two drugs have to be administered at different frequencies. For example, it may be desirable to administer the first drug powder four times a day (QID) and the second drug powder twice a day (BID).

With the known dose unit and associated inhaler, which cannot be achieved with one inhaler, the patient must alternately use the first inhaler to inhale the first medicament powder and the second inhaler to inhale the combination of the first and second medicament powders.

This method is not only inconvenient but also confusing to the patient, whereby it may increase the risk of wrong administration.

It is an object of the present invention to address the above problems and allow delivery of multiple inhalable drugs for combination therapy at different frequencies through a single inhalation device.

Brief description of the invention

This is achieved by the dosage unit of the invention, wherein the doses are regularly distributed in the pockets in a series of identical groups, each group comprising at least one blank pocket and one pocket containing a dose of medicament powder.

Each blank bag may be an empty bag or, alternatively, a bag containing excipient powder.

According to a first embodiment of the invention, the dose carrier comprises a disc-shaped support structure and the pockets are held in the support structure in an annular arrangement, the support structure being adapted to be rotatably mounted in a dry powder inhaler to sequentially expose the contents of the pockets.

Preferably, the disc-shaped support structure comprises an annular array of perforations, and the dose carrier further comprises rigid inserts defining pockets, each of the inserts being slidably adjustable in each perforation in a storage position and adapted to move out of the storage position into a dispensing position protruding from the disc-shaped support structure, wherein the contents of the pockets are exposed to the airflow.

According to a second embodiment of the invention, the dose carrier comprises an elongate strip of continuous cavities defining the pockets aligned in a main direction of the strip.

Preferably, the elongate strip is flexible and forms a loop whereby the strip is adapted to be deployed in a dry powder inhaler to sequentially expose the contents of the pouch.

Each of said identical groups may consist of one bag containing a dose of pharmaceutical powder and one blank bag, whereby the bags of said dosage unit are alternating blank bags and bags containing a dose of pharmaceutical powder.

The pharmaceutical powder may comprise a single pharmaceutical active ingredient, preferably selected from the group consisting of muscarinic M3 receptor agonists or anticholinergic agents, β 2-adrenoceptor agonists, compounds with dual muscarinic antagonist and β 2-agonist activity, and glucocorticoid receptor agonists.

More specifically, the single pharmaceutically active ingredient is selected from ipratropium, tiotropium, oxitropium, trospium, aclidiniums, pirenzepine (perenzapine), telenzapine, ephedrine, epinephrine, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, ethylisoproterenol, carmoterol, salbutamol, terbutaline, bambuterol, fenoterol, salbutamol, tulobuterol, formoterol, salmeterol, prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, ciclesonide, mometasone and salts and/or solvates thereof.

Alternatively, the pharmaceutical powder may comprise a combination of pharmaceutically active ingredients, preferably a combination of a β 2-adrenoreceptor agonist and a glucocorticoid receptor agonist.

More specifically, the combination of the pharmaceutically active ingredients may be a combination of salmeterol xinafoate and fluticasone propionate or a combination of budesonide and formoterol fumarate dehydrate.

The invention also relates to a package comprising a first and a second dose unit as described above for a dry powder inhaler, comprising:

-a dose carrier comprising a plurality of pockets adapted to contain doses of medicament powder suitable for inhalation, the pockets being arranged in series such that the contents of the pockets can be sequentially exposed to an air flow for continuous inhalation, and

-a plurality of medicament powder doses arranged in respective pockets of the dose carrier such that all pockets of the second dose unit contain a medicament powder dose.

Advantageously, the dose carrier of the first dose unit and the dose carrier of the second dose unit have the same pocket distribution.

The pharmaceutical powder of the second dosage unit may comprise a single pharmaceutically active ingredient, preferably a muscarinic M3 receptor agonist or an anticholinergic agent, a β 2-adrenoceptor agonist, a compound with dual muscarinic antagonist and β 2-agonist activity, and a glucocorticoid receptor agonist.

More specifically, the single pharmaceutically active ingredient is selected from ipratropium, tiotropium, oxitropium, trospium, aclidiniums, pirenzepine, telenzepine, ephedrine, epinephrine, isoproterenol, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, ethylisoprenol, carmoterol, salbutamol, terbutaline, bambuterol, fenoterol, salbutamol, tulobuterol, formoterol, salmeterol, prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, ciclesonide, mometasone and salts and/or solvates thereof.

Alternatively, the drug powder of the second dosage unit may comprise a combination of multiple pharmaceutically active ingredients.

The invention also relates to a dry powder inhaler for administering a medicament powder to a patient, comprising a package as described above and means for simultaneously exposing the respective contents of the pockets of the first dosage unit and the corresponding pockets of the second dosage unit in an inhalation airflow.

Brief Description of Drawings

Preferred embodiments of the present invention will now be described in more detail, by way of example only, with reference to the accompanying non-graduated drawings in which:

figure 1 is a perspective view of a dry powder inhaler of the type adapted to comprise a package of dosage units according to a first embodiment of the present invention;

figure 2 is an enlarged partial and diagrammatic cross-sectional view of the inhaler of figure 1, showing one pocket of each dosage unit in the storage position prior to inhalation;

figure 3 is a similar view showing the bag in the dispensing position during inhalation;

figures 4-7 show different views of a package of dose units applicable to the inhaler of figure 1 according to the invention, showing various distribution patterns in the medicament dose; and

figure 8 is a perspective view of a package of dosage units according to a second embodiment of the invention, illustrating the removable cover of the dosage carrier in an open position.

Detailed description of the invention

Figures 1-3 illustrate a dry powder inhaler 1 from which a patient may inhale successive doses of medicament in dry powder form, said inhaler being of a type known from the above-mentioned patent application WO 2005/002654, suitable for the first preferred embodiment of the present invention illustrated in figures 4-7.

In fig. 1, the inhaler 1 is shown in an exploded view along the main axis Z of the inhaler. In the figure, axis Z is an arbitrarily indicated vertical line, but the orientation is not assumed to reflect the orientation of the device in the actual position of use. In this specification, terms describing a position or direction, such as "axis" and "radius", should be interpreted with reference to the axis Z.

The inhaler 1 essentially comprises an outer casing consisting of a pair of complementary shells 3a, 3 b; a pair of dosage units 5a, 5 b; a pair of supports (only one 7b of which is visible in fig. 1) defining an internal structure 7 (fig. 2 and 3) to accommodate the dosage units 5a, 5 b; and a mechanism 9 operable by the patient to activate the inhaler.

Referring more particularly to fig. 1, the housing contains an inlet valve formed by apertures in the shells 3a, 3b which make up the housing. Only the hole 11a formed in the case 3a can be seen in fig. 1. The outer covers 3a, 3b also comprise a mouthpiece formed by two half-shells (malces) 13a, 13b, which are formed separately on each shell.

As shown in fig. 1-3, the dosage units 5a, 5b each comprise a dosage carrier 15 having a plurality of pockets 17 each adapted to contain a dose of medicament powder suitable for inhalation, a plurality of doses 19 of medicament powder being arranged in the pockets 17 of the dosage carrier 15 (fig. 2 and 3).

In the present patent application, the phrase "pharmaceutical powder dose" is to be understood as a dose of powder which is suitable for inhalation by a patient and comprises at least one pharmaceutically active ingredient. Typically, as indicated previously in this specification, the pharmaceutical powder is composed of a mixture of particles of one or more pharmaceutically active ingredients with particles of one or more excipients. Such formulations are commonly designated as dry powder formulations. In contrast, a dose powder comprising one or more excipients but no pharmaceutically active ingredient should not be considered as a "pharmaceutical powder dose" in the context of the present specification.

According to the present invention, the pharmaceutically active ingredient may be selected from any kind of medicament suitable for the treatment or prevention of diseases, conditions and disorders by inhalation. Examples of such diseases, conditions and disorders include, for example, allergic, inflammatory and/or respiratory diseases such as rhinitis, sinusitis, asthma, infant wheezing syndrome, bronchiolitis, bronchitis, bronchopulmonary disease, nasal polyps, Chronic Obstructive Pulmonary Disease (COPD), emphysema, Acute Respiratory Distress Syndrome (ARDS), fibrocystic disease, interstitial lung disease, pulmonary fibrosis, bronchospasm, pulmonary hypersensitivity, exacerbation of airway hyperreactivity due to other drug therapy, pulmonary hypertension, pneumonia, pulmonary embolism, tuberculosis, common cold, influenza, pharyngitis, lung cancer, and the like.

Thus, one or more pharmaceutically active ingredients according to the invention may be selected from a wide variety of classes of drugs, such as glucocorticoid receptor agonists, PDE inhibitors, in particular PDE4 inhibitors, cromolyn sodium, muscarinic M3 receptor agonists or anticholinergic agents, β 2-adrenoreceptor agonists, compounds with dual activity of muscarinic antagonists and β 2-agonists, anti-tumour necrosis factor (anti-TNF- α) drugs, adenosine A2a receptor agonists and A2b antagonists, histamine H3 antagonists and H4 antagonists, modulators of prostaglandin D2 including DP1 antagonists, DP2 antagonists and inhibitors of hematopoietic prostaglandin D synthase (hPGDS), modulators of the NF κ β pathway such as IKK inhibitors, modulators of the cytokine signalling pathway such as p38MAP kinase, PI3 kinase, JAK kinase, syk kinase, EGFR, MK-2, fyn kinase or ITK, etc.

According to a preferred embodiment of the present invention, the one or more pharmaceutically active ingredients may be selected from:

muscarinic M3 receptor agonists or anticholinergic agents such as ipratropium, tiotropium, atropine, trospium, aclidinium, pirenzepine, telenzepine and other muscarinic agonists such as those described in WO03/035599, WO 2007/034325, WO 08/035157 or WO2009/034432, as well as salts and/or solvates thereof;

- β 2-adrenoceptor agonists such as ephedrine, epinephrine, isoproterenol, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, ethylisoproterenol, carmoterol, salbutamol, terbutaline, bambuterol, fenoterol, salbutamol, tulobuterol, formoterol, salmeterol and other β 2-agonists such as those described in WO04/032921, WO05/080313, WO 05/080324, WO 05/090287, WO05/092840 and WO2007/010356, as well as salts and/or solvates thereof;

compounds having dual activity as muscarinic antagonist and β 2-agonist, such as those described in WO2007/107828 or WO 2008/041095;

glucocorticoid receptor agonists such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, ciclesonide, mometasone and salts and/or solvates thereof;

and combinations of two or three thereof.

Prior to use of the dry powder formulation, the pharmaceutically active ingredient should be present in a size suitable for delivery by inhalation for administration. This may be done by controlled crystallization and separation of the pharmaceutically active ingredient by e.g. high shear wet milling or sonication (sonocrystallization) followed by any suitable comminution method such as spiral jet dynamic milling, fluidized bed jet dynamic milling, supercritical fluid treatment, high pressure homogenisation or spray drying. The particles thus obtained typically have an average aerodynamic particle size of less than 10 μm, preferably less than 6 μm, more preferably less than 5 μm.

The excipient used in the context of the present invention may be any physiologically acceptable excipient that can be used in the field of inhalable formulations. For example, the excipient may be selected from monosaccharides, disaccharides, oligo-and polysaccharides. Examples of such excipients include glucose, arabinose, lactose, sucrose, maltose, dextran. Preferably, mono-or disaccharides are used. More preferably, the excipient used in the context of the present invention is lactose, most preferably lactose monohydrate.

The excipient powder according to the invention may also consist of a mixture of a component comprising the components described herein before and another component selected from the group consisting of: for example, phospholipids such as lecithin phosphate, modifiers such as/-leucine, mannitol or magnesium stearate. Suitable flavouring agents, such as methanol and levomenthol, or sweetening agents, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhalation/intranasal administration.

The excipient powders which can be used in the context of the present invention are composed of particles having an average particle size of less than 200 μm, preferably less than 100 μm. More preferably, the excipient powder is composed of particles having an average particle diameter of 10 μm to 80 μm, more preferably 15 to 60 μm.

According to a preferred embodiment, the pharmaceutical powder dose of the invention comprises one or more pharmaceutically active ingredients selected from the group of muscarinic M3 receptor agonists, β 2-adrenoceptor agonists and/or glucocorticoid receptor agonists as described herein before, and lactose as an excipient.

More preferably, the pharmaceutical powder dose according to the present invention comprises one or more pharmaceutically active ingredients selected from ipratropium, tiotropium, oxitropium, trospium, aclidinium, pirenzepine, telenzepine, ephedrine, epinephrine, isoproterenol, metaproterenol, phenylpropanolamine, pirbuterol, reproterol, rimiterol, ethylisoprenol, carmoterol, salbutamol, terbutaline, bambuterol, fenoterol, salbutamol, tulobuterol, formoterol, salmeterol, prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, ciclesonide, mometasone and salts and/or solvates thereof, and lactose as an excipient.

Still more preferably, the pharmaceutical powder dose according to the present invention comprises one or more pharmaceutically active ingredients selected from ipratropium, tiotropium, oxitropium, trospium, aclidiniums, pirenzepine, telenzepine, ephedrine, epinephrine, isoproterenol, metaproterenol, phenylephrine, pirbuterol, reproterol, rimiterol, ethylisoprenol, carmoterol, salbutamol, terbutaline, bambuterol, fenoterol, salbutamol, toloterol, formoterol, salmeterol, prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, ciclesonide, mometasone and salts and/or solvates thereof, and lactose monohydrate as an excipient.

As can be seen in fig. 2 and 3, each dose carrier 15 comprises a support structure in the form of a rigid disc 21 and a rigid insert 25 defining a pocket 17, the rigid disc 21 having a plurality of perforations 23 extending from one face of the disc to the other, the rigid insert 25 being separately adjustable within each perforation 23. Each insert 25 is cup-shaped with an outer surface that fits over the inner surface of the corresponding perforation 23, whereby the insert 25 can slide axially in the perforation from a storage position (fig. 2) to a dispensing position (fig. 3). The insert 25 has a bottom wall defining a cup-shaped closed side and has an outer flat surface 27, the outer flat surface 27 extending to the plane of the first side of the tray 21 in the storage position. On the open side of the cup-shape, the insert 25 has an outer edge 29, the outer edge 29 in the storage position extending substantially to the plane of the second side of the disc 21. All inserts 25 of the same dose carrier 15 are oriented in the same way, which means that all inserts 25 have their closed side on the same side of the disc 21.

Each dose carrier 15 also comprises a pair of foils (not shown) attached to the first and second faces of the disc 21 respectively to tightly wrap the insert 25 and the powder contained therein and to protect the powder from any moisture ingress and contamination prior to delivery. The foil applied to the second side of the disc is designed to: is broken open by the outer edge 29 of the insert 25 when the insert is pushed axially from the first side to the second side to allow the powder to be exposed to the gas flow.

Returning again to fig. 1, the perforations 23 are formed in the disc 21 according to an annular distribution in which the holes are angular and regularly spaced from each other around the axis Z. The inserts 25 are thus held in the disc 21 in an annular arrangement, defining the distribution of the pockets 17 of the dosage units 5a, 5 b. It should also be noted that the two dosage units 5a, 5b have a corresponding or identical distribution of pockets 17, which means having the same number of pockets with the same angular spacing therebetween.

The supports 7a, 7b may comprise a anvil plate (not shown) and an airway plate (not shown), respectively, designed to be attached to the respective dosage unit 5a, 5b and rotatably mounted with the respective dosage unit in the housing 3a, 3 b. The internal structure 7 defined by the supports 7a, 7b is designed to allow the inserts 25 to be appropriately withdrawn from their storage positions to their dispensing positions and to provide respective passages for the flow of suction air between the air inlet valve 11a and the air outlet of the mouthpiece 13a, 13b through the respective pocket 17.

On fig. 2 and 3, the inner structure 7 is diagrammatically shown as a single sheet for the sake of clarity, although in practice this is not the case. As can be seen in these figures, for each pocket 17 of each dosage unit 5a, 5b, the structure 7 defines a path 33 for the air flow, the path 33 having a portion 35 for causing the air flow to flow upwards through the relative pocket and a portion 37 for causing the air flow to flow downwards through the same pocket. The downstream portions 37 of the respective paths 33 finally converge at a common duct 38 to an outlet.

In the storage position (fig. 2), the insert 25 is fully enclosed in the relative tray 21, and in the dispensing position (fig. 3), it protrudes from the tray so that the entire portion of its wall defines the airflow path 33 and exposes the powder contained in the insert to the airflow. In fig. 3, the air flow associated with the dosage unit 5a is referred to as FaThe air flow associated with the dosage unit 5b is called Fb。

Since similar devices are known from the aforementioned patent application WO 2005/002654, the mechanical device 9 will not be described in great detail in this application, to which reference is made for further details of the construction and operation of the inhaler 1. However, it is important to note for the understanding of the invention that the mechanical means 9 comprise a movable part 40 rotatably mounted in the housings 3a, 3b around the axis Z, said movable part having or in general consisting of a lever 41 and a rotary cam 43. Cam 43 forms an annular portion that extends at an angle substantially to the radial plane and has a thickness that varies with the angle of rotation about axis Z. The mechanism also has two cam followers in the form of two prodgers 45, each axially movable according to the angular position of a cam 43, and each associated with a respective dosage unit 5a, 5 b.

The mechanical means 9 also have means, such as gears provided on the supports 7a, 7b which engage with complementary teeth, in order to operate with the lever 41 to rotate said supports together with the dosage units 5a, 5b for angular movement about the axis Z.

It will be appreciated that in the assembled configuration of the inhaler 1, the dosage units 5a, 5b, the supports 7a, 7b and the mechanism 9 are encased in a casing 3a, 3b, with the rod 41 extending beyond the internal region defined by the casing to facilitate handling by the user.

The inhaler 1 further comprises a mouthpiece cover (not shown) rotatably supported by the outer housings 3a, 3b to be movable between a storage position and a use position, wherein the mouthpiece cover covers the mouthpiece 13a, 13b and the lever 41, thereby preventing access and operation of the inhaler therefrom, wherein the use position allows free access to the mouthpiece and the lever.

Starting from the neutral starting position of the gear, when the lever 41 is activated, it follows

(i) Rotating the supports 7a, 7b and the respective dosage units 5a, 5b with the angular interval between two successive pockets 17 to place a new pocket of each dosage unit corresponding to the respective prodger 45, and then

(ii) These two prodgers 45 are axially displaced by the action of the cam 43 on the prodgers 45 to push the inserts 25 from their storage positions into their dispensing positions as shown in fig. 2 and 3.

As the respective prodgers 45 push the inserts 25 out of the perforations 23, they protrude through the protective cover foil to properly expose the powder to the airflow. As shown in fig. 3, when inhalation occurs the powder of the two respective pockets 17 simultaneously dispense the medicament in respective air streams Fa, Fb which mix together down in the tube 38.

At the end of this operation, the lever is returned to its starting position by means of a tool not shown in the figures, without causing any further or counter rotation of the dosage unit.

It will be appreciated that, as the disc 21 is rotatably mounted in the housing of the inhaler, the annular arrangement of the pockets 17 in the dosage units 5a, 5b defines a sequential arrangement such that the contents of the pockets are sequentially exposed to the airflow for continuous inhalation.

In fig. 4-5 different versions of the first embodiment of the invention are shown, wherein the packaging of two dosage units suitable for use in an inhaler 1 is as described above.

In the manner of FIG. 4, the package 105 includes

The description of the dosage unit 5a, for example with reference to fig. 1, the first dosage unit 105a has a series of pockets in a circular arrangement, which are alternating blank pockets B and pockets containing doses of the first medicament powder X; and

the second dosage unit 105b has a series of pockets in a circular arrangement, all pockets containing a dose of the second medicament powder Y, preferably different from the first medicament powder X, as described for the dosage unit 5b, for example with reference to figure 1.

In the present description, a "blank" pouch is understood to be a pouch that does not comprise a pharmaceutically active ingredient. The blank bag may be an empty bag, but it may preferably be a bag containing an excipient powder (e.g. lactose) without a pharmaceutically active ingredient, whereby the inhalation effect and the user's experience are not affected by the presence of the blank bag. In contrast to the "blank", the term "active pouch" may in some cases be referred to as a pouch containing medicament powder, below the specification.

Each of the first and second pharmaceutical powders X and Y may comprise a single pharmaceutically active ingredient or a combination of two or more pharmaceutically active ingredients.

In a first exemplary embodiment corresponding to the preferred embodiment:

the first pharmaceutical powder X comprises a single pharmaceutically active ingredient selected from the group consisting of β 2-adrenoreceptor agonists such as ephedrine, epinephrine, isoproterenol, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, ethylisoproterenol, carmoterol, salbutamol, terbutaline, bambuterol, fenoterol, salbutamol, tulobuterol, formoterol, salmeterol and other β 2-agonists such as those described in WO04/032921, WO05/080313, WO 05/080324, WO 05/090287, WO05/092840 and WO2007/010356 and salts thereof;

the second pharmaceutical powder Y comprises a single pharmaceutically active ingredient selected from glucocorticoid receptor agonists such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, ciclesonide, mometasone and salts thereof.

In a second exemplary embodiment corresponding to another preferred embodiment:

the first pharmaceutical powder X comprises a mixed combination of two pharmaceutical active ingredients, the first being selected from the group consisting of beta 2-adrenoceptor agonists such as ephedrine, epinephrine, isoproterenol, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, ethylisoproterenol, carmoterol, salbutamol, terbutaline, bambuterol, fenoterol, salbutamol, tulobuterol, formoterol, salmeterol and other beta 2-agonists such as those described in WO04/032921, WO05/080313, WO 05/080324, WO 05/090287, WO05/092840 and WO2007/010356 and salts thereof, the second being selected from the group consisting of glucocorticoid receptor agonists such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, and salts thereof, Ciclesonide, mometasone and salts thereof;

the second pharmaceutical powder Y comprises a single pharmaceutically active ingredient selected from muscarinic M3 receptor agonists or anticholinergic agents such as ipratropium, tiotropium, atropine, trospium, aclidiniums, pirenzepine, telenzepine and other muscarinic agonists such as those described in WO03/035599, WO 2007/034325, WO 08/035157 or WO2009/034432, and salts thereof.

In a third exemplary embodiment corresponding to another preferred embodiment:

-the first pharmaceutical powder X comprises a combination of active ingredients which is a combination of salmeterol xinafoate and fluticasone propionate or a combination of budesonide and formoterol fumarate dehydrate; and

-the second pharmaceutical powder Y comprises a single pharmaceutical active ingredient selected from tiotropium bromide.

Using the configuration described with reference to fig. 4 makes it possible to dispense two different medicament powders X, Y at different frequencies with the same inhaler, the medicament powder Y being dispensed at twice the frequency of the medicament powder X. Thus making it possible, for example, to dispense the pharmaceutical powder X twice a day (in combination with Y) and four times a day (including twice in combination with X).

In the manner of fig. 5, the package 205 comprises:

the first dosage unit 205a has, in a regularly repeating manner, a series of two blank pouches B and one active pouch comprising a dose of the first pharmaceutical powder X; and

a second dosage unit 205b comprising all active pockets of a dose of the second pharmaceutical powder Y.

It is easily conceivable that such a configuration allows dispensing of the one or more pharmaceutically active ingredients of powder Y with a frequency that is three times the frequency with which the one or more pharmaceutically active ingredients of powder X are dispensed.

In the version of figures 6 and 7 each dosage unit has two annular arrays of pockets, with each pocket of the first annular array having a respective pocket radially spaced at the same angular position in the second annular array. It should be noted that these dosage units are suitable for use in the inhaler shown in fig. 1-3, provided that the prodgers 45 are suitable for ejecting two respective pockets simultaneously.

In the manner of fig. 6, the package 305 comprises:

a first dose unit 305a comprising:

in a first annular arrangement, which is the outermost radial arrangement, a series of alternating blank pockets B and active pockets each containing a first dose of drug powder X1;

in the second annular arrangement, which is the innermost radial arrangement, only the active pockets each containing a dose of the second medicament powder X2;

a second dosage unit 305b comprising:

in the first circular arrangement, which is the outermost radial arrangement, only the active pockets each containing a dose of the third drug powder Y1;

in the second annular arrangement, which is the innermost radial arrangement, there are only active pockets each containing a dose of the fourth drug powder Y2.

It will be appreciated that this configuration allows the pharmaceutically active ingredients of powders X2, Y1, Y2 to be dispensed at the same frequency and the pharmaceutically active ingredient of powder X1 to be dispensed at half that frequency according to the following repeating sequence:

(i) partitioning the combination X1+ X2+ Y1+ Y2;

(ii) the combination X2+ Y1+ Y2 was assigned.

In the manner of fig. 7, package 405 includes:

a first dosage unit 405a comprising:

in a first annular arrangement, which is the outermost radial arrangement, a series of alternating blank pockets B and active pockets each containing a first dose of drug powder X1;

in a second annular arrangement, which is the innermost radial arrangement, a series of alternating blank pockets B and active pockets each containing a dose of the first medicament powder X2, the blank pockets of the second arrangement being angularly offset from the blank pockets of the first arrangement such that the two corresponding pockets from each pair of the two arrangements have one blank pocket alternating with an active pocket of X1 and X2;

a second dosage unit 405b comprising:

in the first circular arrangement, which is the outermost radial arrangement, only the active pockets each containing a dose of the third drug powder Y1;

in the second annular arrangement, which is the innermost radial arrangement, there are only active pockets each containing a dose of the fourth drug powder Y2.

It will be appreciated that this configuration allows the pharmaceutically active ingredients of powders X1, X2 to be dispensed at a first frequency and the pharmaceutically active ingredients of powders Y1, Y2 to be dispensed at a second frequency, wherein the second frequency is twice the first frequency, according to the following repeating sequence:

(iii) partition combination X1+ Y1+ Y2;

(iv) the combination X2+ Y1+ Y2 was assigned.

In all of the above configurations, the medicament powder doses of the first dose unit are regularly distributed in the pockets in the same group of orders, each group comprising at least one blank pocket and one pocket containing a dose of medicament powder.

With reference to fig. 8, a second embodiment of the invention will now be described, which relates to an inhalation device of the type disclosed in, for example, patent application WO 004/011070. Using the device, a combination of medicaments may be dispensed from a pair of dosage units comprising elongate and flexible bands.

As also shown diagrammatically in fig. 8, which shows a pocket 505 of dosage units 505a, 505b of the present invention, a typical dosage unit 505b suitable for use in such an inhaler comprises a dose carrier in the form of an elongate strip 515 formed from a continuous cavity 517. Said cavities 517, which define pockets to contain the inhalation powder, are aligned along the main direction Δ of the strip 515. The dosage unit 505b also contains a cover sheet 524 which is initially sealed to the strip 515 to seal the pouch, and can be peeled from the strip 515.

The elongate strip 515 attached to the cover sheet 524 is adapted to form a loop and in inhalers of the type known from WO 004/011070 is adapted to be unfolded and advanced in a main direction delta step by step as the cover sheet 524 is progressively peeled from the strip 515, whereby the contents of the continuous bag may be exposed to an inspiratory airflow.

Likewise, another dosage unit 505a of the package 505 shown in fig. 8 is suitable for use in the same type of inhaler which dispenses a combination of medicament powders in combination with a dosage unit 505 b.

According to the invention, the first dosage unit 505a comprises an arrangement of consecutive pockets along the main direction Δ comprising alternating blank pockets B and active pockets comprising the first medicament powder X.

The second dosage unit 505b of the package 505 of the present invention comprises an arrangement of consecutive pockets along the main direction Δ, said arrangement containing only active pockets comprising the second active powder Y.

Similar to the configuration shown in fig. 4, the embodiment of fig. 8 allows two different medicament powders X, Y to be dispensed at different frequencies with the same inhaler. In this particular example, drug powder Y is dispensed twice as often as drug powder X, which is dispensed in combination with drug powder Y.

It will be appreciated that the present invention provides means for achieving different medicament powder dispensing at different frequencies with a single inhaler according to a repeating sequence, irrespective of the type of inhaler and the type of associated dose carrier.

Claims (19)

1. A dosage unit for a dry powder inhaler, comprising:

-a dose carrier (15; 515, 524) comprising a plurality of pockets (17; 517) each adapted to contain a dose of medicament powder suitable for inhalation, the pockets being arranged in succession such that the contents of the pockets (17; 517) can be sequentially exposed to an airflow (Fa) for continuous inhalation, and

-a plurality of doses (X; X1, X2) of pharmaceutical powder arranged in pockets (17; 517) of said dose carrier (15),

characterized in that said doses are regularly distributed in said pockets according to a series of identical groups, each group comprising at least one blank pocket (B) and one pocket containing a dose of pharmaceutical powder (X; X1, X2), wherein said blank pocket (B) is a pocket containing excipient powder, not containing a pharmaceutical active ingredient.

2. Dosage unit according to claim 1, characterised in that the dosage carrier (15) comprises a disc-shaped support structure (21) and the pockets (17) are held in the support structure in a ring-like arrangement, the support structure being adapted to be rotatably mounted in the dry powder inhaler (1) to sequentially expose the contents of the pockets (17).

3. Dosage unit according to claim 2, characterised in that the disc-shaped support structure (21) comprises an annular array of perforations (23) and the dose carrier (15) further comprises rigid inserts (25) defining pockets (17), each of which is slidably adjustable in a respective perforation (23) in a storage position and adapted to be moved out of the storage position into a dispensing position protruding from the disc-shaped support structure (21), wherein the contents of the pocket are exposed to the airflow (Fa).

4. Dosage unit according to claim 1, characterised in that the dosage carrier comprises an elongate strip (515) formed by successive cavities (517) to define the arrangement of the pockets along a main direction (Δ) of the strip.

5. A dosage unit according to claim 4, characterised in that the elongate strip (515) is flexible and forms a loop, whereby the strip is adapted to be deployed in a dry powder inhaler to sequentially expose the contents of the pockets (517).

6. Dosage unit according to any one of claims 1-5, characterized in that each of said identical groups consists of one bag containing a dose of pharmaceutical powder (X; X1, X2) and one blank bag (B), whereby the bags of the dosage unit are alternating blank bags (B) and bags containing a dose of pharmaceutical powder (X; X1, X2).

7. Dosage unit according to any one of claims 1 to 5, characterised in that the pharmaceutical powder (X; X1, X2) comprises a single pharmaceutically active ingredient.

8. A dosage unit according to claim 7, characterised in that the single pharmaceutically active ingredient is selected from the group consisting of a muscarinic M3 receptor agonist or an anticholinergic agent, a β 2-adrenoreceptor agonist, a compound with dual muscarinic antagonist and β 2-agonist activity, and a glucocorticoid receptor agonist.

9. Dosage unit according to claim 8, characterized in that the single pharmaceutically active ingredient is selected from ipratropium, tiotropium, oxitropium, trospium, aclidiniums, pirenzepine, telenzepine, ephedrine, epinephrine, isoprenaline, metaproterenol, phenylephrine, pirbuterol, reproterol, rimiterol, ethylisoproterenol, carmoterol, salbutamol, terbutaline, bambuterol, fenoterol, salbutamol, tulobuterol, formoterol, salmeterol, prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, ciclesonide, mometasone and salts and/or solvates thereof.

10. Dosage unit according to any one of claims 1 to 5, characterised in that the pharmaceutical powder (X; X1, X2) comprises a combination of several pharmaceutically active ingredients.

11. Dosage unit according to claim 10, characterized in that the combination of pharmaceutical active ingredients is a combination of a β 2-adrenoreceptor agonist and a glucocorticoid receptor agonist.

12. Dosage unit according to claim 11, characterized in that the combination of the plurality of pharmaceutically active ingredients is a combination of salmeterol xinafoate and fluticasone propionate or a combination of budesonide and formoterol fumarate dehydrate.

13. A package comprising a first dose unit (105 a; 205 a; 305 a; 405 a; 505a) and a second dose unit (105 b; 205 b; 305 b; 405 b; 505b) according to any one of claims 1-12 for use in a dry powder inhaler, comprising:

-a dose carrier (15; 515) comprising a plurality of pockets (17; 517) adapted to contain a dose of medicament powder suitable for inhalation, the pockets being arranged in series such that the contents of the pockets can be sequentially exposed to an air flow (Fb) for continuous inhalation, and

-a plurality of drug powder doses (Y; Y1, Y2) arranged in respective pockets (17; 517) of said dose carrier (15; 515) such that all pockets of the second dose unit (105 b; 205 b; 305 b; 405 b; 505b) contain a drug powder dose (Y; Y1, Y2).

14. A package according to claim 13, characterised in that the dose carrier (15; 515) of the first dose unit (105 a; 205 a; 305 a; 405 a; 505a) and the dose carrier (15; 515) of the second dose unit (105 b; 205 b; 305 b; 405 b; 505b) have the same distribution of pockets (17; 517).

15. The package according to claim 13 or 14, characterized in that the pharmaceutical powder (Y) of the second dosage unit (105 a; 205 a; 505a) comprises a single pharmaceutical active ingredient.

16. The package according to claim 15, characterized in that said single pharmaceutical active ingredient is selected from the group consisting of a muscarinic M3 receptor agonist or an anticholinergic drug, a β 2-adrenoceptor agonist, a compound with dual muscarinic antagonist and β 2-agonist activity, and a glucocorticoid receptor agonist.

17. The package according to claim 16, wherein the single pharmaceutically active ingredient is selected from ipratropium, tiotropium, oxitropium, trospium, aclidiniums, pirenzepine, telenzepine, ephedrine, epinephrine, isoprenaline, metaproterenol, phenylephrine, pirbuterol, reproterol, rimiterol, ethylisoprenol, carmoterol, salbutamol, terbutaline, bambuterol, fenoterol, salbutamol, tulobuterol, formoterol, salmeterol, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, ciclesonide, mometasone and salts and/or solvates thereof.

18. The package according to claim 13 or 14, characterized in that the pharmaceutical powder (Y) of the second dosage unit (105 a; 205 a; 505a) comprises a combination of a plurality of pharmaceutical active ingredients.

19. A dry powder inhaler for administering a medicament powder to a patient, comprising a package (105; 205; 305; 405; 505) according to any of claims 13-18 and a means (9) for simultaneously exposing the respective contents of the pockets of the first dosage unit (105 a; 205 a; 305 a; 405 a; 505a) and the corresponding pockets of the second dosage unit (105 b; 205 b; 305 b; 405 b; 505b) in an inhalation airflow (Fa, Fb).