P/00/011 Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION INNOVATION PATENT Invention Title: Combination The following statement is a full description of this invention, including the best method of performing It known to us: 2 Combination Field of the invention The invention relates to a delivery system, in particular a delivery system for the 5 treatment of respiratory diseases and conditions. Background of the invention A number of treatments for asthma and like conditions are known in the prior art. Common amongst such known treatments are symptomatic treatments with bronchodilators and prophylactic treatments with corticosteroids. The most common 0 cause of poor compliance with asthma treatments, particularly for chronic asthma, is failure to ensure regular use of prophylactic treatments such as inhaled corticosteroids as these do not give immediate symptomatic relief. Patients will readily take #l 2 -agonist inhalers since these provide rapid relief of symptoms, but often do not take prophylactic therapy, such as inhaled steroids regularly because there is no immediate symptomatic 5 benefit. These difficulties have lead to the development of combination therapies with both a bronchodilator and a glucocorticosteroid in the one delivery unit. As an illustration of such a combination therapy, a product sold under the trade mark Symbicort Turbuhaler* (AstraZeneca) has been efficacious in addressing these problems to some degree. This 20 combination therapy, which includes formoterol and budesonide is described in international patent application WO 93/11773. Formoterol, (N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino] ethyl]phenyl]formamide), is an adrenoceptor agonist which selectively stimulates 82 receptors, thus producing relaxation of bronchial smooth muscle, inhibition of the 25 release of endogenous spasmogens, inhibition of oedema caused by endogenous mediators, and increased mucociliary clearance. Inhaled formoterol fumarate acts rapidly, usually within minutes, which gives the patient immediate confirmation that he has taken an adequate dose; thereby avoiding overdosing of both fl-agonist and steroid. Inhaled formoterol also exerts a prolonged bronchodilation, which in clinical trials has 30 been demonstrated as up to 12 hours.
3 Glucocorticosteroids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger similar effects. Glucocorticosteroids have potent anti-inflammatory and immunosuppressive properties. Budesonide, (16,17-butylidenebis(oxy)-11,21 -dihydroxypregna-1,4-diene-3,20-dione), 5 is a corticosteroid and may be given in a high inhaled dose (up to 2 mg daily) with very low systemic effects, possibly because of its rapid metabolism. The high rapid systemic elimination of budesonide is due to extensive and rapid hepatic metabolism. Long term clinical studies have shown that inhaled budesonide is a pharmacologically safe drug. High doses of inhaled budesonide are highly effective and well tolerated when used in 10 oral steroid replacement therapy. Whilst the Turbuhaler* unit has proved very successful and efficacious, it would be a significant advance in the art if a system could be designed to deliver the formoterol and budesonide combination in different delivery systems. It is, accordingly, an object of the present invention to overcome or at least alleviate one 5 or more of the difficulties or deficiencies related to the prior art. Summary of the invention In one aspect, the present invention provides a powder delivery system for the prophylactic and/or therapeutic treatment of respiratory disorders, the system including: a dry powder inhalation device; and 20 a pharmaceutical powder composition formulated as an ordered mixture, and including an effective amount of the active components: (i) formoterol, a pharmaceutically acceptable salt or solvate thereof or a pharmaceutically acceptable solvate of said salt; (ii) glucocorticosteroid, a pharmaceutically acceptable salt or solvate 25 thereof or a pharmaceutically acceptable solvate of said salt; and carrier particles; 3A the pharmaceutical powder composition being formulated for delivery via the selected inhalation device; the particles of the pharmaceutical powder composition exhibiting a mass median diameter in the range of 30 to 300 pm; at least 90% by mass of the active component 5 4 particles having an aerodynamic diameter of less than 10 pm and being present in an amount that is a function of the number of unit doses contained in the device and the efficiency of the device in delivering the active component particles to the lungs of the patient. 5 In another aspect, the present invention provides a powder delivery system for the prophylactic and/or therapeutic treatment of respiratory disorders, the system including: a dry powder inhalation device; and a pharmaceutical powder composition formulated as an ordered mixture and providing a unit dose of: 10 (i) a formoterol salt in an amount of 3 to 50 jig; and (ii) budesonide in an amount of 25 to 2400 pg; as the sole active components; and carrier particles; the pharmaceutical powder composition being formulated for delivery via the 15 selected inhalation device; the particles of the pharmaceutical powder composition exhibiting a mass median diameter in the range of 30 to 300 pm and at least 90% of the active component particles having an aerodynamic diameter of less than 10 pm. In a further aspect, the present invention provides a method of treating respiratory 20 disorders, the method including administration of an effective amount of a composition including formoterol and a glucocorticosteroid from a powder delivery system, the delivery system including: a dry powder inhalation device; and a pharmaceutical powder composition formulated as an ordered mixture and 25 providing a unit dose of: (i) a formoterol salt in an amount of 3 to 50 pag; and (ii) budesonide in an amount of 25 to 2400 jig; as the sole active components; and carrier particles; 30 the pharmaceutical powder composition being formulated for delivery via the selected inhalation device; 4A the particles of the pharmaceutical powder composition being present as particles exhibiting a mass median diameter in the range of 30 to 300 pm and at least 90% of the active component particles having an aerodynamic diameter of less than 10 pm. 5 The powder delivery system is preferably not of the reservoir twist type, such as Turbuhaler* or Twisthaler* (Twisthaler* is a registered trade mark of Schering-Plough Ltd). The powder delivery system according to this aspect of the present invention may be utilised to treat a variety of respiratory disorders including asthma, rhinitis and other lung 10 disorders collectively referred to as chronic obstructive pulmonary disease (COPD) and including chronic bronchitis and emphysema. It will be understood that, as a result of the inherent internal resistance in the dry powder inhaler, the drug formulation to be delivered by the inhaler may be specifically designed for optimum delivery from that inhaler. It follows that using a drug formulation 15 in a dry powder inhaler different from the one for which it was designed will result in sub-optimal delivery of the drug from that inhaler. In addition, the patient may not realise that a different dry powder inhaler may require a higher air flow to deliver a therapeutic dose which may magnify the problem. Accordingly, the pharmaceutical powder composition utilised in this aspect of the 20 present invention is formulated to achieve efficient functioning in the particular dry power inhalation device selected. For lung deposition, the active particle size is less than 10 pm, preferably less than 5 pm, as specified above. In an ordered mixture, (sometimes called a carrier-based mixture or adhesive mixture), the active particles tend to adhere to the surface of the larger (approximately 30-300 pm) carrier particles. 25 The resulting relatively large aggregated particles are easier to handle than the small active particles when filling the device. More importantly, the particles deaggregate relatively easily on exit from an inhaler upon inhalation. The active particles separate from the larger carrier particles and at least a proportion of the active particles are carded deep into the lung. The carrier particles, due to their larger size, are in the main 30 deposited in the oral cavity and throat.
5 The pharmaceutical powder composition may be used as a bulk powder as in Turbuhaler*. However, the formulation is particularly suited for packaging into capsules, blister packs, cartridges and the like. Similarly, the particle shape of the pharmaceutical powder composition may be chosen depending on the dry powder inhaler selected. 5 Preferably, the particles of the pharmaceutical powder compostion have a mass median diameter of between 30 pm and 200 pm, more preferably between 40 Im and 150 Pim. Detailed description of the embodiments The term "mass median diameter" as used herein (as would be known by a person skilled in the art) refers to the diameter of an ideal spherical particle having a mass 0 equivalent to the median of the distribution of actual particle masses. The mass median diameter may suitably be measured utilising a laser diffraction method, for example, utilising a Malvern Mastersizer 2000 made by Malvern Instruments Ltd, UK. It will be understood, throughout the specification and claims, the diameter of the active particles referred to is the aerodynamic diameter of the particles. As would be known by 5 the person skilled in the art, "aerodynamic diameter" is an expression of a particle's aerodynamic behavior as if it were a perfect sphere with unit-density and diameter equal to the aerodynamic diameter. In this specification, it will be assumed that aerodynamic diameter is measured by an Anderson Cascade Impactor - a device well known in this art. 20 The formoterol component and glucocorticosteroid component may be present in the pharmaceutical powder composition in any suitable relative amounts. The formoterol component and glucocorticosteroid component may be present in a molar ratio of approximately 1:2500 to 12:1, more preferably approximately 1:555 to 2:1, most preferably approximately 1:150 to 1:1. 25 For treatment of asthma and rhinitis, the molar ratio of formoterol component to glucocorticosteroid may be in the range of approximately 1:4 to 1:70, preferably 1:5 to 1:50, more preferably 1:20 to 1:40. The weight ratio of formoterol to glucocorticosteroid may be in the range from 1:800 to 6 1:0.5, preferably, the ratio is in the range of from 1:267 to 1:2.08, more preferably in the range of from 1:400 to 1:5. The powder delivery system according to the present invention may be designed to deliver approximately 4 to 100 pg, preferably approximately 6 to 75 pg, more preferably 5 approximately 6 to 48 pg of formoterol and approximately 50 to 4800 ig, preferably 100 to 2400 jg, more preferably 200 to 1600 jig of a glucocorticosteroid, preferably budesonide. The unit doses may be selected for administration once daily, preferably twice daily, up to four times a day. The size of each unit dose may be commensurately reduced where multiple daily administrations are contemplated. The particular dose 0 used will depend on the patient (age, weight, etc) and the severity of the disease (mild, moderate, severe asthma, etc). Thus for the treatment of COPD, unit doses of approximately 6 jpg of formoterol and 200 pg of budesonide, which may be administered up to four times a day. Alternatively the pharmaceutical powder composition may include unit doses of 12 pg of formoterol 5 and 400 pg of budesonide, of 9 pg of formoterol and 320 pg of budesonide, either of which may be administered once or twice a day. Most preferably the pharmaceutical powder composition includes unit doses of 6 jg of formoterol and 400 jig of budesonide, or 4.5 pg of formoterol and 320 pg of budesonide, either of which may be administered up to four times a day. 20 The formoterol component may be provided in any suitable form. The formoterol component may be in the form of a mixture of enantiomers. Preferably the formoterol is in the form of a single enantiomer, preferably the R,R enantiomer. The formoterol can be in the form of the free base, salt or solvate, or a solvate of a salt. Preferably the formoterol is in the form of its fumarate dihydrate salt. Other suitable physiologically 25 salts include chloride, bromide, sulphate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p toluenesulphonate, benzenesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricaballate, hydroxynaphthalenecarboxylate or oleate. Preferably the glucocorticosteroid component may be selected from one or more of the 7 group consisting of budesonide, fluticasone propionate, mometasone furoate, ciclesonide and epimers, ester, salts and solvates of these compounds. More preferably the glucocorticosteroid component is budesonide or an epimer thereof, most preferably the 22R-epimer of budesonide. 5 Preferably the active components are used in admixture with one or more pharmaceutically acceptable diluents or carriers. The carrier or diluent may be present in an amount of from approximately 50 pg to 50 mg per unit dose, more preferably in an amount of from 1 mg to 50 mg, most preferably in an amount of from 1 mg to 30 mg per unit dose. 0 Preferably the carrier is a carbohydrate having a high storage stability, preferably a carbohydrate such as lactose, glucose, galactose, mannose, xylose, maltose, cellobiose, melibiose, maltotriose (e.g. as monohydrate). More preferably the carrier is lactose monohydrate. The ingredients used in the present invention may be obtained in these preferred forms 5 using methods known to those of skill in the art. Accordingly, in a preferred embodiment, there is provided a powder delivery system as described above, including a dry powder inhalation device; and a pharmaceutical powder composition providing a unit dose of the active 20 components: (i) 3 to 50 [tg of a formoterol salt; (ii) 25 to 2400 ig of budesonide; and 1 mg to 50 mg of a carrier; the pharmaceutical powder composition being formulated as an ordered mixture, 25 the carrier particles of the pharmaceutical powder composition exhibiting a mass median diameter of 30 pim to 200 pm; at least 90% of the active component particles having an aerodynamic diameter of less than 10 pm. Preferably, the carrier is present in an amount in the range of 3 mg to 30 mg. Preferably, the inhalation device is not a Turbuhaler* device.
8 In a further aspect, the present invention provides a method of treating respiratory disorders, the method including administration of an effective amount of a composition including formoterol and a glucocorticosteroid from a powder delivery system, the delivery system including: 5 a dry powder inhalation device; and a pharmaceutical powder composition including an effective amount of the active components: (i) formoterol, a pharmaceutically acceptable salt or solvate thereof or a pharmaceutically acceptable solvate of said salt; and 10 (ii) glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof or a pharmaceutically acceptable solvate of said salt; and carrier particles; the pharmaceutical powder composition being formulated for delivery via the selected inhalation device; 15 the particles of the pharmaceutical powder composition exhibiting a mass median diameter in the range of 30 to 300 pm; at least 90% of the active component particles having an aerodynamic diameter of less than 10 pm and being present in an amount that is a function of the number of unit doses contained in the device and the efficiency of the device in delivering the active component particles to the lungs of the patient. 20 The powder delivery system is preferably not of the reservoir twist type (such as Turbuhaler* or Twisthaler*). In a preferred embodiment, there is provided a method as described above, wherein the delivery system includes a dry powder inhalation device; and 25 a pharmaceutical powder composition providing a unit dose of the active components: (i) 3 to 50 pg of a formoterol salt; (ii) 25 to 2400 pg of budesonide; and 8A 1 mg to 50 mg of a carrier; the pharmaceutical powder composition being formulated as an ordered mixture; the particles of the pharmaceutical powder composition exhibiting a mass median diameter of 30 pm to 200 pm; at least 90% of the active component particles having an 9 aerodynamic diameter of less than 10 jpm. Preferably, the carrier is present in an amount in the range of 3 mg to 30 mg. In determining the efficiency of delivery of drugs from dry powder inhalers, it has been found that the efficiency may vary significantly between different inhaler devices. In 5 general terms, the efficiency of delivery of the drug may vary between 5 and 25%, preferably 15 to 20% based on the unit dose of the drug composition supplied to the inhaler device. In selecting the unit dose of the pharmaceutical composition, the efficiency of delivery of the composition to the lungs of the patient from the selected device is first determined. 0 The metered dose of the composition to deliver an effective amount of the composition to the patient may then be determined. The dry powder inhalation device may be of any type, but is preferably not a device of the reservoir twist type. Dry powder inhalers contain an inhalable drug in a form that is dispersed into particles 5 when the patient rapidly inhales. Dry powder inhalers vary in the means of storing, metering and dispensing the drug doses. There are generally three types of dry powder inhalers available, single-dose, multi-dose and reservoir. In single dose dry powder inhalers, the drug is supplied in individual single dose capsules which are inserted into the inhaler before use. The drug is usually formulated with an excipient, for example 20 lactose. Multi-unit dose dry powder inhalers include multiple individual blister-packed doses of the drug as a coiled strip. Reservoir dry powder inhalers contain a bulk supply of the drug in the form of a powder in a reservoir, with each dose being dispensed following actuation of the device prior to use. Dry powder inhalers deliver the drug by drawing air through a dose of a drug 25 formulation. The performance of a dry powder inhaler is dependent upon the design of the device, the powder formulation and the airflow generated by the patient. Some dry powder inhalers require the use of a carrier substance in the form of large particles (typically between 20 and 1000 ptm in size), for example lactose, to enable the micronised drug powder to more readily flow out of the device. The micronised drug 10 particles (typically < 10 jim in diameter) are stripped from the carrier by the energy from the inhalation. The carrier particles deposit primarily in the mouth and throat. Dispersion of the powder into particles suitable for inhalation depends upon the generation of turbulent airflow in the dry powder inhaler. The generation of the airflow 5 depends in turn upon the design of the dry powder inhaler and the internal resistance in the device. Each different dry powder inhaler will have its own specific flow rate (typically between 30 and 120 L/min) for optimal performance. Thus, if the patient cannot generate the required flow rate for a particular dry powder inhaler, the delivered dose will be less than optimal, which will impact on the therapeutic efficacy of the drug. 0 In addition, loss of powder invariably occurs in the dry powder inhaler resulting in delivered doses less than the metered dose stated on the label. The magnitude of the losses varies with inspiratory flow rate and between the various dry powder inhaler designs. For example, the dry powder inhaler may be of the single-unit dose type, such as the 5 Aerolizer®, the Cyclohaler®, the Rotahaler*, the Spinhaler*, the Inhalator®, and the Handihaler* or the like. Alternatively, the dry powder inhaler may be of the multi-unit dose type, such as the Aerohaler®, the Diskhaler*, and the Diskus*/Accuhaler* or the like. Alternatively, the dry powder inhaler may be of the reservoir type, such as the Clickhaler*, the Easyhaler*, Pulvinal*, the Twisthaler* and the Novolizeroor the like. ?0 It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention. The invention is further illustrated by reference to the following examples. 25 Examples Example I Formoterol fumarate dihydrate (0.02 kg) and lactose monohydrate (0.48 kg) are mixed 11 for one or two hours in a tumbling mixer. This mixture is micronised in a spiral jet mill in order to attain a particle size suitable for inhalation (in this example mass median aerodynamic diameter in the range of 1.8 ptm to 3.5 pm) and thereafter conditioned as described in US patent nos 5,874,063 or 5,709,884. This conditioned product is mixed 5 with micronised budesonide (0.3 kg, mass median aerodynamic diameter 2.0 pm for thirty to sixty minutes in a tumbling mixer. As a second mixing step the powder is fed to a modified spiral jet mill, operating at a very low milling pressure and a high flow of nitrogen. The final formulation is produced by combining 0.5 kg of the blend obtained above with lactose carrier (18.25 kg, Pharmatose 325, DMV-Fonterra, mass median 0 particle diameter 60 pm) and mixing in a tumbling mixer for 2 hours followed by sieving through 1.0 mm mesh size. The mass median particle diameter of the overall formulation is close to 55 pm. Example 2 1.5 g of the formoterol fumarate dihydrate (0.7 mg/g)/budesonide (10 mg/g)/lactose 5 monohydrate (989.3 mg/g) formulation according to Example 1 is loaded into the powder reservoir of an Easyhalerodry powder device (Ranbaxy (UK) Ltd). The device is packaged in moisture resistant aluminium/polyethylene laminated packaging and stored for 6 months at 400C and 75% relative humidity. After storage, the dry powder device continues to function efficiently. 20 Example 3 The formoterol fumarate dihydrate (0.7 mg/g)/budesonide (10 mg/g)/lactose monohydrate (989.3 mg/g) formulation according to Example 1 is filled in the dry powder device Gyrohaler* (Vectura (UK) Ltd) as individual doses of 20 mg, using Omnidose filling technology (HarroHoefliger, Germany). In this way, a Symbicort 25 product is obtained where the formulation is predispensed in separate doses within the inhaler premetered dry powder device. The drug product is stored for 6 months at 400C and 75% relative humidity. After storage, the dry powder device continues to function efficiently.
12 Example 4 Formoterol fumarate dihydrate and budesonide are separately milled in spiral jet mills in order to attain a mass median aerodynamic particle diameter for each component of approximately 2.2 pim. Thereafter, the particles are conditioned, without affecting the 5 size. 0.2 kg of formoterol fumarate dihydrate and 3.0 kg of budesonide are mixed for thirty to sixty minutes in a tumbling mixer. As a second mixing step, the powder is fed to a spiral jet mill, modified in order to operate at a very low milling pressure (approximately 1 bar) and a relatively high flow of nitrogen in order to create a mixing effect rather than a 0 milling effect. This provides efficient mixing and break up of agglomerates, without causing a further size reduction of the particles. The final formulation is produced by combining 0.19 kg of the blend obtained above with lactose carrier (18.25 kg, Pharmatose 125 M, DMV-Fonterra, mass median particle diameter 55 pm) in an intensive mixer for 30 minutes. The mass median particle 5 diameter of the formulation is in the range 50 to 55 pm. Example 5 Formoterol fumarate dihydrate (0.02 kg) and lactose monohydrate (0.48 kg) are mixed for one or two hours in a tumbling mixer. This mixture is micronized in a spiral jet mill in order to attain a particle size suitable for inhalation (in this example, a mass median 20 aerodynamic diameter in the range of 1.8 pm to 3.5 jm) and thereafter conditioned as described in US patent no 5,874,063 or 5,709,884. This conditioned product is mixed with micronised budesonide (0.3 kg, mass median aerodynamic diameter 2.0 pm for thirty to sixty minutes in a tumbling mixer. As a second mixing step the powder is fed to a modified spiral jet mill, operating at a very low milling pressure and a high flow of 25 nitrogen. The final formulation is produced by combining 0.5 kg of the blend obtained above with lactose carrier (18.25 kg, Respitose SVO10, DMV-Fonterra, mass median particle diameter 105 pm) and mixing in a tumbling mixer for 2 hours followed by sieving through 1.0 mm mesh size. The mass median particle diameter of the overall formulation is in the range of 90 to 100 pm.