WO2005041922A2

WO2005041922A2 - Composition

Info

Publication number: WO2005041922A2
Application number: PCT/GB2004/004511
Authority: WO
Inventors: Andrew Bruce Brown; Anthony James Taylor; Michiel Mary Van Oort
Original assignee: Glaxo Group Limited
Priority date: 2003-10-24
Filing date: 2004-10-22
Publication date: 2005-05-12
Also published as: WO2005041922A3; GB0324897D0

Abstract

Dry powder pharmaceutical compositions having improved storage stability, dry powder inhalers comprising the same and their use in the treatment of respiratory disorders by inhalation.

Description

COMPOSITION

This invention relates to dry powder pharmaceutical compositions, and their use in the treatment of respiratory disorders by inhalation. The invention also relates to dry powder inhalers comprising the same. More particularly, this invention relates to dry powder p harmaceutical compositions h aving i mproved fine p article d ose p erformance and/or improved stability.

BACKGROUND OF THE INVENTION

Dry powder inhalers (DPI's) are well known devices for administering pharmaceutically active agents to the respiratory tract. Consequently, they are particularly suitable when used for the administration of active agents in the treatment of diseases such as asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, rhinitis etc. Since the drug acts directly on the target o rgan much smaller quantities of the active ingredient may be used, thereby minimising any potential side effects.

Dry powder compositions for use as inhalable medicaments in DPI's typically comprise a pharmaceutically active agent intimately admixed with an excess of pharmaceutically acceptable excipient or excipients (often called carrier(s)). Such excipients serve not only to dilute the quantity of active agent administered in each dose but also to establish acceptable manufacture of the powder mixture and aid in the aerosolisation of the drug. Such a high proportion of excipient will essentially determine the properties of the powder formulation, particularly the manufacturing characteristics.

For effective delivery into the lungs, the active agent particles should be small, typically with a geometric diameter in the range of from 0.1 to 5 μm, or else an equivalent aerodynamic diameter substantially in the range of from 0.1 to 5 μm. However, small particles tend to aggregate with each other and/or with excipient particles, due to their high surface area to volume ratio, which provides excess surface free energy and encourages agglomeration.

It can thus occur that active agent particles, despite having a suitable particle size, do not r each t he I ung b ecause t hey a re a ttached to I arge e xcipient p articles o r t o o ther particles of active agent. T he fine particle dose (FPD), of drug is a m easure of the quantity of drug of effectively deliverable particle size present in a released dosage of drug after actuation of the DPI. In some instances the FPD is referred to as the fine particle mass (FPM), the terms to be taken as identical in meaning. Often it is convenient to refer to the fine particle fraction FPF, the % of the emitted dose that the fine particle dose represents. A high FPF is an indicator that a high portion of the administered drug will reach the lower lungs, where it can be effective. For a constant initial load of drug, the FPF is effectively equivalent to the FPD. In WO96/23485 (Coordinated Drug Development Limited) it is suggested that release of small particulate active from large excipient particles can be promoted (and thus the FPF increased) by the presence of an additive material on the surface of the excipient particles. There remains, however, a demand for further, or alternative, ways to increase the FPF.

It has now surprisingly been found that dry powder pharmaceutical compositions containing a physiologically acceptable metal phosphate salt have surprisingly improved FPD/FPF properties. Such compositions represent an alternative solution to the above- noted problem.

DESCRIPTION OF THE INVENTION

Dry powder pharmaceutical compositions for inhalation therapy comprising a physiologically acceptable metal phosphate salt are believed to be novel. The present invention therefore provides, in a first aspect, a dry powder pharmaceutical composition for inhalation therapy comprising a pharmaceutically active agent, an excipient and a physiologically acceptable phosphate salt. The invention also provides the use of a physiologically acceptable metal phosphate salt in dry powder pharmaceutical compositions for inhalation therapy in order to increase FPD. In some circumstances, the excipient may also be a phosphate salt, such that the invention provides a dry powder pharmaceutical composition for inhalation therapy comprising a pharmaceutically active agent and a physiologically acceptable phosphate salt.

A further problem associated with the use of dry powder pharmaceutical compositions of this type is that they can be susceptible to poor stability performance due to moisture ingress. For example, significant deterioration in the FPD/FPF, is often observed upon protracted exposure of such compositions to conditions of elevated temperature and humidity.

Patent application WO 00/28979 (SkyePharma) describes one approach to overcoming the above noted problems. It is claimed that dry powder formulations comprising a pharmaceutically active agent, an inhaled vehicle of non-inhalable particle size and magnesium stearate have improved storage stability under extreme (temperature and humidity) conditions.

We have now discovered that dry powder pharmaceutical compositions containing a physiologically acceptable metal phosphate salt demonstrate surprisingly enhanced stability performance. Such compositions therefore represent an alternative solution to the above-noted problem.

The present invention therefore provides, in a second aspect, the use of a physiologically acceptable metal phosphate salt in dry powder pharmaceutical compositions for inhalation therapy in order to improve stability performance.

The invention also provides for the use of a physiologically acceptable metal phosphate salt in dry powder pharmaceutical compositions for inhalation therapy in order to eliminate or reduce the detrimental effect on fine particle dose caused by storage of said compositions.

The physiologically acceptable metal phosphate salt is preferably present in particulate form. The physiologically acceptable metal phosphate salt can be in amorphous or crystalline form. Preferably the physiologically acceptable metal phosphate salt is in crystalline form.

It is to be understood that the dry powder pharmaceutical compositions according to this invention include not only those in which the components are incorporated as individual particles but also those including matrix particles of more than one component. For example, matrix particles of pharmaceutically active agent and a physiologically acceptable metal phosphate salt or matrix particles of excipient and a physiologically acceptable metal phosphate salt may be utilised. Such matrix particles can be prepared by solid dispersion technology e.g. co-precipitation and particle coating methods which are familiar to those skilled in the art. Suitably, the components are incorporated as individual particles.

Preferred physiologically acceptable metal phosphate salts include monovalent and divalent metal phosphate salts, preferably divalent metal phosphate salts. Preferred divalent metal phosphate salts include, for example, alkali metal phosphate salts (group 1 metals), alkaline earth metal phosphate salts (group 2 metals) and zinc group metal phosphate salts (group 12 metals). Especially preferred are alkaline earth metal phosphate salts, for example magnesium phosphate and calcium phosphate. Most preferably, the phosphate salt of use in the invention is calcium phosphate.

Preferably, the phosphate salt for use in the invention is only sparingly soluble. For example, the phosphate salt may be soluble to less than 5% w/w in neutral water at 20 degrees C, more preferably to a level of less at 1 % w/w, more preferably to a level of 0.1 % w/w/ under those conditions.

The term "calcium phosphate" as used herein includes calcium phosphate, dibasic anhydrous (CaHPO₄, also known as anhydrous calcium hydrogen phosphate, anhydrous dibasic calcium phosphate, Calcii hydrogenophosphas anhydricus or dibasic calcium phosphate), calcium phosphate, dibasic dihydrate (CaHPO . 2H₂O also known as calcium hydrogen phosphate, dibasic calcium phosphate, Calcii hydrogenophosphas dihydricus or dibasic calcium phosphate) calcium phosphate, monobasic (Ca(H₂PO₄)₂, also known as acid calcium phosphate, calcium bisphosphate, monocalcium orthophosphate, monocalcium phosphate, primary calcium phosphate or calcium superphosphate) and calcium phosphate tribasic (Ca₃(PO )₂, or Ca₅(OH)(PO₄)₃, also known as calcium phosphate, tricalcii phosphate or tribasic calcium phosphate).

Preferably, the calcium phosphate is calcium phosphate dibasic or calcium phosphate tribasic.

The phosphate salt for use in the invention can be in anhydrous or in a hydrated form. For example, calcium phosphate may be calcium phosphate, dibasic anhydrous or calcium phosphate, dibasic dihydrate. Preferably, calcium phosphate, dibasic anhydrous is used.

Typically, the geometric size of the phosphate salt is in the range from 0.1 to 50μm, and more particularly from 1 to 20μm. Alternatively (depending on the density of the particles), the aerodynamic diameter of the particles is in the range from 0.1 to 50μm, and more particularly from 1 to 20μm. The phosphate salt for use in the preparation of compositions in accordance with this invention is typically micronised but controlled precipitation, supercritical fluid methodology and spray drying techniques familiar to those skilled in the art may also be utilised. For some applications, it may be desirable for the phosphate salt to comprise mixtures of phosphate salts materials of more than one particle size (or more than one particle size range). For example, the phosphate salt may comprise a coarse portion and a fine portion. Typically, such a fine portion phosphate salt has an aerodynamic size in the range from 0.1 to 50μm, and more particularly from 1 to 20μm.

The phosphate salt may be present in a concentration of 0.01 - 99.9% by weight of the total composition. For certain applications, it may be desirable for the excipient to be a phosphate salt, for example calcium phosphate. In that situation, phosphate salts (for example calcium phosphate) may make up a high proportion of the total composition, for example from 60 to 99.9%. In other applications, the bulk excipient is a material other than a phosphate salt and the phosphate salt makes up only a minor portion of the total composition. For example, the phosphate salt may be present in a concentration of 0.01 - 50% by weight of the total composition, preferably 1 - 20%, more preferably from 1 to 10%.

The pharmaceutically active agent can be any therapeutic molecule in dry powder form that is suitable to be administered by inhalation. In the field of inhalation therapy, the term "suitable to be administered by inhalation" is generally taken to mean therapeutic molecules having an aerodynamic diameter between 0.1 and 10μm, and more particularly 1 - 5μm. Particles of the desired particle size for inhalation are conventionally prepared by micronisation. Other methods of producing such particles are also known in the art. Therefore, such particles can also be prepared using controlled precipitation methods (e.g. methods described in patent applications WO

00/3881 1 and WO 01/32125 (Glaxo Group Limited)), using supercritical fluid methodology or by spray drying techniques. The present invention provides no limitation on the method by which the therapeutic molecule is made suitable to be administered by inhalation.

Examples of pharmaceutical active agents suitable for inhalation therapy include analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; anti-allergies, e.g., cromoglycate (e.g. as the sodium salt), ketotifen or nedocromil (e.g. as the sodium salt); anti-infectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; anti- histamines, e.g., methapyrilene or loratadine; 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), 6 , 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 (also named as 6α, 9 -Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester) or 6α, 9α- Dif I uoro-11 β-hydroxy-16 -methyl-17α-[(4-methyl-1.3-thiazole-5-carbonyl)oxy]-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester; anti-tussives, e.g., noscapine; bronchodilators, e.g., albuterol (e.g. as free base or sulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline, fenoterol (e.g. as hydrobro ide), 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; PDE4 inhibitors e.g. cilomilast or roflumilast; leukotriene antagonists eg montelukast, pranlukast and zafirlukast; 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); iNOS inhibitors; 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; ganglionic stimulants, e.g., nicotine; 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 medicaments 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 medicament.

Further suitable pharmaceutically acceptable agents include compounds known in the art as long acting β_2- adrenoreceptor agonists, particularly those generically and specifically described in patent applications WO 01/42183, WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/042160, WO 03/072539, WO 03/091204, WO 04/016578, WO 04/022547, WO 04/037807, WO 04/037773, WO 04/037768, WO 04/039762 and WO 04/039766 Particularly preferred long acting β₂. adrenoreceptor agonists include:

3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amino) hexyl]oxy}butyl)benzene-sulfonamide (as disclosed in WO 02/066422); 3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl) benzenesulfonamide (as disclosed in WO 02/066422); 4-{(1 f.)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol (as disclosed in WO 03/024439);

4-{(1 f?)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol (as disclosed in WO 04/037773); N-[2-hydroxy-5-[(1 R)-1 -hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino] phenyl]ethyl]amino]ethyl]phenyl]formamide (as disclosed in WO 01/42193) and N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1 -)- quinolinon-5-yl)ethylamine (as disclosed in WO 03/042160).

Where used herein the term "pharmaceutically active agent" can also be taken to include a combination containing two or more pharmaceutically active agents of the type described above. Preferred formulations containing combinations of active ingredients contain salbutamol (e.g., as the free base or the sulphate salt) salmeterol (e.g., as the xinafoate salt), formoterol (e.g. as the fumarate salt) or a long acting β₂. adrenoreceptor agonists in combination with an anti-inflammatory steroid such as a beclomethasone ester (e.g., the dipropionate), a fluticasone ester (e.g., as the propionate 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), or budesonide.

A particularly preferred combination of active agents is fluticasone propionate and salmeterol, or a pharmaceutically acceptable salt thereof (particularly the xinafoate salt). Such a combination is described in patent EP0416951 B1 (Glaxo Group Limited).

Further combinations of particular interest are budesonide and formoterol (e.g. as the fumarate salt) and also salmeterol, or a pharmaceutically acceptable salt thereof (particularly the xinafoate salt) and an anti-cholinergic such as ipratropium (e.g. as the bromide).

The quantity of active agent in the composition produced in accordance with this invention will vary significantly depending, inter alia, upon the particular active agent under consideration, the age and weight of the patient and the severity of the condition. Such considerations are familiar to the person skilled in the art. The active agent can be present in a concentration of 0.01 - 99%. Typically however, the active agent will be present in a concentration of 0.05 to 50%, more typically 0.1 - 15% of the total weight of the composition. The excipient may be composed of particles of any pharmacologically inert material or combination of materials which is / are suitable for inhalation.

Preferred excipients include mono-saccharides, such as mannitol, arabinose, xylitol and dextrose and monohydrates thereof, disaccharides, such as lactose, maltose and sucrose, and polysaccharides such as starches, dextrins or dextrans. More preferred excipients comprise particulate crystalline sugars such as glucose, fructose, mannitol, sucrose and lactose. Especially preferred excipients are anhydrous lactose and lactose monohydrate.

Generally, the particle size of the majority of the excipient particles is much greater than that of the inhaled active agent and as a result, few penetrate into the respiratory tract. Thus, excipient particles for inhalable compositions may typically have particle sizes greater than 20μm, more preferably in the range 20 - 150μm. The mean geometric diameter (D(0.5)) may be in the range 20 to 150 μm, preferably in the range 25 to 90 μm, for example 65μm.

If desired, the inhalable compositions may contain two or more excipient particle size ranges. For example, the composition may comprise two component of the excipient, the two components having different particle size distributions, a fine component and a coarse component. For example, in order to control the proportion of inhaled medicament, while retaining a good accuracy for metering, it is often desirable to use a fine component of the excipient that has a significant weight of particles (for example 10- 50%, preferably 20-40%) of a size of less than 15μm and a coarse component of the excipient which has a particle size of greater than 20μm but lower than 150μm, preferably lower than 100μm. The fine particle component may have an average geometric diameter of from 15 to 50 μm. For example, the fine component may contain around 30%w/w particles of size <15μm and have an average geometric diameter of around 30 μm. The ratio between the fine and coarse components may be adjusted depending on the application to which the formulation is to be put.

The excipient or excipients may be commercially available in the desired particle size range or may be separated by air classification, sieving or any other method of size classification known in the art.

Preferably the weight ratio of the fine and coarser excipients components will range from 1 : 99 to 50 : 50. Fine and coarse excipient components may consist of chemically identical or chemically different substances. The excipient mixtures may, for example, contain one chemical substance as the fine excipient and a different substance as the coarser excipient. However, the fine and coarser excipients in question may themselves constitute mixtures of different substances. Preferably the fine and coarser excipients will both be lactose.

The proportion of excipient material to be used in the inhalable compositions of this invention may vary depending upon the particular active agent, the powder inhaler for administration etc. The proportion may, for example, be about 75% to 99.9% by weight of the composition as a whole.

It will be appreciated that such inhalable compositions may also contain minor amounts of other additives e.g. taste masking agents or sweeteners. It will be further appreciated that the inhalable compositions of this invention may also include yet further additives which improve stability performance, for example, magnesium stearate. Where such additives are present, they will generally not exceed 10% by weight of the total weight of the composition.

The dry powder pharmaceutical compositions in accordance with this invention can be prepared using standard methods. The pharmaceutically active agent, excipient and phosphate salt can be intimately mixed using any suitable blending apparatus, such as high shear blenders. The particular components of the formulation can be admixed in any order. Pre-mixing of particular components may be found to be advantageous in certain circumstances. The progress of the blending process can be monitored by carrying out content uniformity determinations. For example, the blending apparatus may be stopped, materials removed using a sample thief and then analysed for homogeneity by High Performance Liquid Chromatography (HPLC).

To determine the improved stability associated with compositions prepared according to this invention, the blends thus formed can be placed on accelerated stability screen (e.g. 40°C / 75% relative humidity) and the fine particle fraction reduction (i.e. comparison of pre and post stability FPF data) measured as an analytical parameter using a Cascade Impactor (Cl) or Twin Stage Impinger (TSI). Such procedures are familiar to those skilled in the art. According to the invention, the inhalable compositions can be delivered by any suitable inhalation device that is adapted to administer a controlled amount of such a pharmaceutical composition to a patient. Suitable inhalation devices may rely upon the aerosolisation energy of the patient's own breath to expel and disperse the dry powder dose. Alternatively, this energy may be provided by an energy source independent of the patient's inhalation effort, such as by impellers, patient/device created pressurised gas sources or physically (e.g. compressed gas) or chemically stored energy sources. Suitable inhalation devices can also be of the reservoir type i.e. where the dose is withdrawn from a storage vessel using a suitably designed dosing device or alternatively, inhalation devices that release drug from pre-metered units e.g. blisters, cartridges or capsules.

Packaging of the composition may be suitable for unit dose or multi-dose delivery. In the case of multi-dose delivery, the composition can be pre-metered (e.g. Diskhaler® as described in US4811731 and US5035237) or metered in use (e.g. Turbuhaler® as described in US4668218). An example of a unit-dose device is Rotahaler® (as described in US4353365).

A particularly preferred inhalation device for dry powder pharmaceutical compositions of this invention is the Diskus® inhaler (described in US patents 5590645 and 5860149) which may be charged with blister (medicament) packs as described in US 5873360. The drawings of said United States patents are specifically incorporated by reference.

The present invention therefore also provides for a medicament pack for use in an inhalation device which comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable composition according to the present invention.

Preferably, the strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width. The lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet. As a yet further aspect of the present invention we also provide an inhalation device for use with a medicament pack which comprises an inhalable composition according to the present invention, said device comprising: (i) an opening station for receiving a container of a medicament pack being used with said inhalation device; (ii) means positioned to engage peelable sheets of a container which has been received in said opening station for peeling apart the peelable sheets, to open such a container; (iii) an outlet, positioned to be in communication with an opened container, through which a user can inhale medicament in powder form from such an opened container; and (iv) indexing means for indexing in communication with said outlet containers of a medicament pack in use with said inhalation device.

As an alternative aspect of the present invention we also provide a medicament pack comprising a circular carrier disc which has a plurality of pre-filled, hermetically sealed containers formed integrally therewith and arranged in a circle, each container containing an inhalable composition according to the present invention, each container being puncturable to form a hole on each side thereof to allow in use, air to flow through the container to entrain the powder contained therein.

As a further aspect of the present invention there is also provided an inhalation device by which compositions of the present invention may be administered to a patient which comprises a housing, a tray mounted and capable of moving within said housing (via a plunger) adapted to receive a circular carrier disc medicament pack, an air inlet (through which air can enter said device) and an air outlet (through which a patient may inhale and receive said composition.

As an alternative aspect of the present invention we also provide a medicament pack comprising a piercable capsule which contains an inhalable composition according to the present invention.

As a further aspect of the present invention there is also provided an inhalation device by which compositions of the present invention may be administered to a patient which comprises a body shell which has a nozzle at a forward end and which is open at the rear end, a sleeve fitted on the outside of the body shell and rotatable with respect to it, a means for retaining a piercable capsule extending through the rear wall of the sleeve into the body shell, means for piercing said capsule when sleeve is rotated and a guard to ensure that the inhalable composition and not the pierced capsule, passes through the nozzle.

As a further aspect of the present invention there is also provided an inhalation device by which inhalable compositions of the present invention may be administered to a patient which comprises a nozzle, an air conduit connected to said nozzle for allowing a passage of air to be inhaled, a dosing unit comprising a storage chamber for the inhalable composition (which may also comprise a dosage indicating means) and a displaceable element for dispensing said formulation from the storage chamber into the air conduit, a maneuvering unit for displacing said element in relation to the storage chamber and optional deflector devices to provide accelerated airflow.

In a further or alternative aspect the present invention also provides for a method of treatment or prophylaxis of respiratory disorders which comprises administering to a patient in need thereof of a dry powder pharmaceutical composition according to the present invention.

According to another aspect the present invention provides for the use of a dry powder pharmaceutical composition according to the present invention in the manufacture of a medicament for the treatment of respiratory disorders.

Suitable examples of respiratory disorders include, but are not limited to, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema and rhinitis.

Preferably the respiratory disorder is asthma.

Where used herein, unless otherwise stated, the terms "dry powder pharmaceutical composition for inhalation therapy" and "inhalable composition" are to be treated as synonymous.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. Throughout the specification and claims which follow, unless the context requires otherwise, the word "comprise", and variations thereof such as "comprises"' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or groups of integers.

The invention will now be described in detail by way of reference only to the following non- limiting examples.

Example 1 Dry Powder Compositions comprising dibasic calcium phosphate, dibasic anhydrous, lactose and a 50μg : 50μg combination of Salmeterol Xinafoate and Fluticasone Propionate Dibasic calcium phosphate (anhydrous, JT Baker, Catalog number 1430) was micronised to a size of 1.6 μm using standard air-jet milling equipment. The lactose was supplied by Borculo Domo Ingredients.

The blends A, B and C, as tabulated below, were prepared by the following procedure. All material utilised in these blends was sieved using a 500μm aperture screen to remove large agglomerates.

Blends A and B, the controls, are formed by mixing of lactose and Salmeterol Xinafoate and Fluticasone Propionate in a 2.5L QMM (high shear) bowl for approximately 10 minutes (blend uniformity less than 4% RSD for either active material (ten samples each approx. 25mg)).

For blend C, approximately half of the dibasic calcium phosphate was pre-mixed with the Salmeterol Xinafoate and Fluticasone Propionate actives and the other half was pre- mixed with the lactose, both in high shear blenders. The two pre-mixes were then combined and mixing continued in a QMM blender for approximately 10 minutes. The blend uniformity data were found to be in the range 1 - 4% RSD for both active materials.

Table 1

Laser diffraction using Malvern Mastersizer, sample dispersed in lecithin / Isooctane (Fines = material <15μm) Laser diffraction using Sympatec, Vibri sample introduction at 3 bar pressure

The total % fines content (i.e. the % material with size <15μm) in blends A and C was arranged to be the same. Blend A thus forms a control for blend C in that both blends have approximately the same fines content. Blend B, on the other hand, contains lactose with the same lactose fines content as blend C and it thus forms a constant lactose fines control.

The blends thus formed were then added to blister packs, of the type described in patent US 5,873,360, using filling methods according to procedures outlined in WO 00/71419 (Glaxo Group Limited). Each blister contained approximately 12mg of the blend.

The blister pack was then loaded into a Diskus® device.

The loaded Diskus® devices containing blends A and C were placed in an accelerated stability environment at 40°C / 75% relative humidity for period of 12 months. Twin stage impinger analysis was performed (at 60 l/min) by the method detailed in the British Pharmacopoeia (Method A) with the exception that a USP throat was substituted for the glass one and was sealed to the stage 1 jet tube using a rubber gasket. The devices were tested pre and post storage by discharging the contents of 14 blisters into the Twin Stage Impinger apparatus. The results obtained are tabulated below in Table 2. Table 2

These data are represented graphically in Figures 1 and 2.

Figure 1 shows the effect of dibasic calcium phosphate on the twin impinger performance of the Fluticasone propionate component of Salmeterol Xinafoate / Fluticasone Propionate 50μg / 50μg blends (+/- standard deviation).

Figure 2 shows the effect of dibasic calcium phosphate on the twin impinger performance of the Salmeterol Xinafoate component of Salmeterol Xinafoate / Fluticasone Propionate 50μg / 50μg blends (+/- standard deviation).

Example 2 Dry Powder Compositions comprising dibasic calcium phosphate, anhydrous and a 50μg : 50μg combination of Salmeterol Xinafoate and Fluticasone Propionate

A formulation containing no lactose was prepared using similar methodology to that described in Example 1.

Calcium phosphate, dibasic anhydrous was obtained from Sigma Aldrich (catalogue no. 23,475-3) . It was micronised using a 4" APTM microniser using nitrogen with a 7 bar feed pressure and 5 bar grind pressure .

To obtain a blend that contains sufficient fine material to provide an acceptable fine particle fraction whilst having acceptable flow properties, micronised calcium phosphate was added to non-micronised calcium phosphate as shown in Table 3. After addition of active agents the blend uniformity was determined as 8%RSD for salmeterol xinafoate and 4% for fluticasone propionate.

The blend was transferred into blister packs, of the type described in patent US 5,873,360, using filling methods according to procedures outlined in WO 00/71419 (Glaxo Group Limited). The fill weight per blister was approximately 18mg verses 13mg for lactose based formulations.

Table 3

Laser diffraction using Sympatec, Vibri sample introduction at 3 bar pressure

The loaded Diskus Devices containing blend D was placed on accelerated storage at 40C/75%RH for 3 months. By way of control, the devices containing blend B (see Example 1 ) were placed on accelerated storage at 40°C/75%RH for 7 weeks.

The results of the twin impinger testing are tabulated below in Table 4

Table 4

The data of Table 4 are shown graphically in Figure 3. The salmeterol data are given in Figure 3a and the Fluticasone Propionate data are shown in Figure 3b. The data show that the devices containing drug and calcium phosphate (D) performed better (i.e. had a higher initial emitted fine particle fraction and a smaller deterioration) than the devices containing drug and lactose under the experimental conditions.

The data shown in Example 1 (blends B and C) demonstrate that the incorporation of calcium phosphate in a dry powder pharmaceutical composition significantly increases the fine particle dose (or fine particle fraction) emitted from a DPI device. Furthermore, the data shown in Examples 1 and 2 also show that the incorporation of calcium phosphate in a dry powder pharmaceutical composition significantly reduces the deterioration in fine particle fraction following exposure to high temperature and humidity. It is believed therefore, that such compositions, when incorporated in dry powder inhaler products, would demonstrate improved performance and/or considerably enhanced stability and hence an increased shelf-life.

Without wishing to be bound by this theory, we believe that conventional dry powder blends (e.g. those containing an active agent and excipient such as lactose), when subject to high environmental humidity, result in a liquid film forming on the fine lactose particles (<15μm) which allows dissolution of the lactose. When the humidity decreases, the lactose solution evaporates allowing the formation of permanent crystal bridges between the lactose particles and between active agent and fine lactose particles. The resultant active agent/lactose agglomerates are not readily aerosolised and cause a reduction in the fine particle fraction. The addition of a phosphate salt, for example calcium phosphate, dispersed in the blend with active agent and the lactose particles may therefore prevent the formation of the crystal bridges between the fine lactose particles and active agent particles, hence reducing agglomeration and the consequent decline in fine particle fraction.

Claims

1. The use of a physiologically acceptable metal phosphate salt in dry powder pharmaceutical compositions for inhalation therapy in order to increase fine particle dose.

2. The use of a physiologically acceptable metal phosphate salt in dry powder pharmaceutical compositions for inhalation therapy in order to improve stability performance.

3. The use of a physiologically acceptable metal phosphate salt in dry powder pharmaceutical compositions for inhalation therapy in order to eliminate or reduce the detrimental effect on fine particle dose caused on storage of said compositions.

4. A dry powder pharmaceutical composition for inhalation therapy comprising a pharmaceutically active agent, an excipient and a physiologically acceptable metal phosphate salt.

5. A dry powder composition according to claim 4 in which the physiologically acceptable metal phosphate salt is in particulate form.

6. A dry powder composition according to any one of claims 1 to 5 in which the physiologically acceptable metal phosphate salt is an alkaline earth metal phosphate salt.

7. A dry powder composition according to claim 6 in which the alkaline earth metal phosphate is calcium phosphate.

8. A dry powder pharmaceutical composition according to any one of claims 4 to 7 in which the physiologically acceptable metal phosphate salt is present at a concentration of from 1 to 10% of the total composition.

9. A dry powder pharmaceutical composition according to any one of claims 4 to 8 in which the physiologically acceptable metal phosphate salt has an aerodynamic size in the range 1 - 20μm.

10. A dry powder pharmaceutical composition according to any one of claims 4 to 9 in which one component of the excipient that has a particle size of less than 15μm (the fine excipient component) and another component of the excipient that has a particle size of greater than 20μm but lower than 150μm (the coarse excipient component).

11. A dry powder pharmaceutical composition according to claim 10 in which the fine and coarse excipient components are both lactose.

12. A dry powder pharmaceutical composition according to claim 4 in which the excipient is a physiologically acceptable metal phosphate salt.

13. A dry powder composition according to any one of claims 4 - 12 in which the pharmaceutically active agent is a combination of fluticasone propionate and salmeterol or a pharmaceutically acceptable salt thereof.

14. A method of increasing fine particle fraction performance for an active ingredient substance in a dry powder pharmaceutical composition for inhalation therapy comprising a pharmaceutically active agent and an excipient, which comprises mixing a physiologically acceptable metal phosphate salt with said active ingredient substance and said carrier.

15. A method of improving stability performance of an active ingredient substance in a formulation comprising a carrier and an active ingredient substance, which method comprises mixing a physiologically acceptable metal phosphate salt with said active ingredient substance and said carrier.

16. A method of eliminating or reducing the detrimental effect on fine particle fraction of an active ingredient substance caused on storage in a formulation comprising a carrier and the active ingredient substance, which method comprises mixing a physiologically acceptable metal phosphate salt with said active ingredient substance and said carrier.

17. A method as claimed in any one of claims 14 to 16 further comprising one or more of the features described in any one or more of claims 4 to 13.

18. A method of treatment or prophylaxis of respiratory disorders which comprise administering to a patient in need thereof a dry powder pharmaceutical composition according to any one of claims 4 to 13.

19. Use of a dry powder pharmaceutical composition according to any one of claims 4 to 13 in the manufacture of a medicament for the treatment of respiratory disorders.

20. An inhalation device containing therein a dry powder pharmaceutical composition according to any one of claims 4 to 13.

21. An inhalation device according to claim 20 in which the dry powder pharmaceutical composition is released from a pre-metered unit medicament pack.

22. A medicament pack for use in an inhalation device which comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable composition according to any one of claims 4 to 13.

23. A medicament pack according to claim 22 wherein the strip is sufficiently flexible to be wound into a roll.

24. A medicament pack according to claim 22 wherein the lid sheet and base sheet have leading end portions which are not sealed to one another.

25. A medicament pack according to claim 24 wherein at least one of the said leading end portions is constructed to be attached to a winding means.

26. A medicament pack according to claim 22 wherein the hermetic seal between the base and lid sheets extends over their whole width.

27. A medicament pack according to claim 22 wherein the lid sheet may be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.

28. An inhalation device for use with a medicament pack according to any one of claims 22 to 23 which comprises an inhalable composition according to any one of claims 4 to 13, said device comprising: (i) an opening station for receiving a container of a medicament pack being used with said inhalation device; (ii) means positioned to engage peelable sheets of a container which has been received in said opening station for peeling apart the peelable sheets, to open such a container; (iii) an outlet, positioned to be in communication with an opened container, through which a user can inhale medicament in powder form from such an opened container; and (iv) indexing means for indexing in communication with said outlet containers of a medicament pack in use with said inhalation device.

29. A medicament pack comprising a circular carrier disc which has a plurality of pre- filled, hermetically sealed containers formed integrally therewith and arranged in a circle, each container containing an inhalable composition according to any one of claims 4 to 13, each container being puncturable to form a hole on each side thereof to allow in use, air to flow through the container to entrain the powder contained therein.

30. An inhalation device by which inhalable compositions according to any one of claims 4 to 13 may be administered to a patient which comprises a housing, a tray mounted and capable of moving within said housing (via a plunger) adapted to receive a circular carrier disc medicament pack according to claim 28, an air inlet (through which air can enter said device) and an air outlet (through which a patient may inhale and receive said composition.

31. A medicament pack comprising a piercable capsule which contains an inhalable composition according to any one of claims 4 to 13.

32. An inhalation device by which inhalable compositions according to any one of claims 4 to 13 may be administered to a patient which comprises a body shell which has a nozzle at a forward end and which is open at the rear end, a sleeve fitted on the outside of the body shell and rotatable with respect to it, a means for retaining a piercable capsule according to claim 31 extending through the rear wall of the sleeve into the body shell, means for piercing said capsule when sleeve is rotated and a guard to ensure that the composition and not the pierced capsule, passes through the nozzle.

33. An inhalation device by which inhalable compositions according to any one of claims 4 to 13 may be administered to a patient which comprises a nozzle, an air conduit connected to said nozzle for allowing a passage of air to be inhaled, a dosing unit comprising a storage chamber for the composition (which may also comprise a dosage indicating means) and a displaceable element for dispensing said composition from the storage chamber into the air conduit, a maneuvering unit for displacing said element in relation to the storage chamber and optional deflector devices to provide accelerated airflow.