US 2011 0056089A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0056089 A1 OLSSON et al. (43) Pub. Date: Mar. 10, 2011
54) DRY POWDER INHALER Publicationublication ClassificatiClassification (75) Inventors: MAGNUS OLSSON, Lund (SE): (51) Int. Cl. Eva Trofast, Lund (SE) F26B 3/00 (2006.01) 52) U.S. Cl...... 34/443 (73) Assignee: AstraZeneca AB (52) (21) Appl. No.: 12/876,493 (57) ABSTRACT Ap rOceSS1nging method and apparatusapp are disclosedd1SCIOSed forOrorocess p (22) Filed: Sep. 7, 2010 ing an inhaler component of a dry powder inhaler so as to O O remove any electrostatic charge and improve inhaler perfor Related U.S. Application Data mance in drug delivery to the respiratory tract. The method (63) Continuation of application No. 10/574,873, filed on includes exposing the inhaler component, while it contains an Apr. 6, 2006, filed as application No. PCT/GB2004/ amount of medicament, to a gas in a chamber at a first prede 004202 on Oct. 4, 2004. termined pressure; exposing the inhaler component, in the chamber, to gas at a second pressure greater than the first (30) Foreign Application Priority Data pressure; and repeating the exposure of the inhaler compo nent to gas at a pressure no greater than the first predeter Oct. 7, 2003 (SE) ...... O3O2665-5 mined pressure.
Chamber
Measuring Device
Patent Application Publication Mar. 10, 2011 Sheet 1 of 2 US 2011/0056089 A1
Chamber
Measuring Device
FIG. 1 Patent Application Publication Mar. 10, 2011 Sheet 2 of 2 US 2011/0056089 A1
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FIG. 2 US 2011/0056089 A1 Mar. 10, 2011
DRY POWDER INHALER powder flow properties during the manufacture of the dry powder inhalers and improving powder dispensing properties during application. By Surface modification of the active Sub 0001. The present invention relates to a processing method stance the electrostatic charge acquisition by triboelectrifica and apparatus, more particularly, to processing a body so as to tion during the pharmaceutical processing and during han remove any electrostatic charge and improve inhaler perfor dling/drug administration has been reduced. mance in drug delivery to the respiratory tract. In the manu (0010 WO 03/35028 discloses modulation of charge den facture of many devices, there has been the problem that sity to produce improvements in the characteristics of spray components of the device acquire electrostatic charges, dried proteins. which remain during assembly and/or sale. To overcome the 0011 We have now found that low pressure treatment of problem, it has been proposed to use Corona dischargers, in the part(s) of the dry powder inhaler, the empty dry powder particular by providing ions by using Corona ionisation. The inhaler, the inhaler filled with the powder formulation or the irradiated ions are used to neutralise electrostatic charges on formulation perse will reduce the charges from the plastic components of the devices. details or the powder and give high performance characteris 0002 The use of Corona discharges is itself problematic. tics of the inhaler i.e. dose uniformity. In particular, the discharges are awkward to handle and need 0012. In a first aspect the invention therefore provides a to be brought into close proximity with any device to be process for the preparation of a dry powder inhaler which discharged. Even then, by virtue of the nature of a Corona comprises, during manufacture, exposing a dry powder discharger, the discharging ions are irradiated in a somewhat inhaler optionally filled with a powder formulation, or one or directional manner, such that it is difficult to ensure complete more components thereof, to a gas at low pressure. discharge of the innermost components of the device. It is also 0013 The process of the invention can be used during the difficult to achieve uniform discharge of surfaces of the complete manufacture of an inhaler or during the partial device. Indeed, Surfaces near the Corona discharger may manufacture of an inhaler. actually become charged by it. 0014. The gas is preferably air at a pressure of less than 0003. The charge induced on the plastic inhaler device by 200 mbar, preferably less than 100 mbar, more preferably less the patient has not been extensively studied. It is speculated than 50 mbar and most preferably less than 1 mbar. that a reduced bioavailability might result from a higher pro 0015. According to the present invention, there is also portion of drug being retained in the inhaler from the more provided an apparatus for removing an electrostatic charge highly charged device and adhered to the carrier particles in from a dry powder inhaler optionally filled with a powder the drug formulation. formulation, or one or more components thereof, the appara 0004. It has been suggested that a pressure reduction tus comprising: induced discharge can be used as a Surface charge elimination 0016 i) a chamber for containing one or more inhaler method (J. Electrostatic 49 (2000), 15-22), but nothing is said components, or a complete inhaler, optionally filled with or implied of any influence of Such treatment on improving a powder formulation, the performance of a drug delivery device for inhalation. The 0017 ii) a device for reducing the pressure of gas in the performance of Such a drug delivery device is depending on chamber the complex interactions between the device and the drug 0.018 iii) a controller/device for a) reducing the pres formulation perse. Sure of gas in the chamber and b) then returning the 0005 Dry powders tend to become electrostatically pressure to atmospheric pressure charged. Triboelectrification in pharmaceutical powders is a (0019. The controller/device for step suitable reduces the very complicated and ill-defined process although it has been pressure to a value Sufficiently low that ions of the gas, which shown to be influenced by many factors, such as particle size accelerate under the influence of the electrostatic field of the and shape, physicochemical properties of the contacting Sur a dry powder inhaler or components thereof, travel suffi face, contact area and frequency, Surface purity and atmo ciently far between collisions and gain Sufficient energy, upon spheric conditions (Powder Technology, 37 (1), 71-85 collision, ionise another molecule and trigger an avalanche. (1984). 0020. In a further aspect the invention provides a process 0006 Electrostatic charging occurs during nearly every for reducing electrostatic charges from a dry powder inhaler powder-handling process such as milling, micronisation, optionally filed with a powder formulation, or one or more flow, fluidisation, tabletting and capsule filling. components thereof, the process comprising: 0007 Electrostatic charge can also arise from collisions 0021 i) placing a dry powder inhaler optionally filled with between particles and the container walls. Triboelectrifica a powder formulation, or one or more components thereof in tion is also one of the major reasons why powders stick to the a chamber, walls of any contacting containers. This creates a problem for 0022 ii) reducing the pressure of gas in the chamber, a plastic inhaler where it is desired to get an accurate and 0023 iii) returning the pressure to atmospheric pressure uniform dose every time. 0024 iv) optionally repeating steps ii) and 0008 Moisture sorption of the particle surface is one of the 0025. An advantage of the invention is that the process can most effective ways to remove Surface charge. This is contra be accomplished at ambient temperature. dictory to what is desired in dry powder inhalers. 0026. According to the present invention, there is provided 0009. The handling of micronised powder for use in dry a method of removing an electrostatic charge from a dry powder inhalers may be due to particle agglomeration, cohe powder inhaler optionally filled with a powder formulation, sion and adhesion to manufacture equipment, inhaler devices or one or more components thereof, the method comprising and container materials. WOO2/80884 relates to a method for the step of exposing one or more inhaler components, or a the surface modification of powders in order to reduce elec complete inhaler, optionally filled with a powder formulation trostatic chargeability of the fine particles thereby improving one or more times to a gas, preferably air, at a pressure of no US 2011/0056089 A1 Mar. 10, 2011
more than 200 mbar, preferably less than 50 mbar and most sulfonamide derivatives like 3-(4-6-({(2R)-2-hydroxy-2- preferably less than 1 mbar. In the case of powder present, the 4-hydroxy-3-(hydroxymethyl)phenylethylamino)-hexyl charges will be removed from the powder as well. Preferably oxybutyl)benzenesulfonamide as disclosed in WO 2002/ the process of discharge is repeated a number of times. 881 67, and the like; glucocorticosteroids such as budesonide, Optionally the powder could be treated alone. fluticasone (e.g. as propionate ester), mometaSone (e.g. as 0027. The present invention will be more clearly under furoate ester), beclomethasone (as 17-propionate or 17,21 stood from the following description, given by way of dipropionate esters), ciclesonide, triamcinolone (e.g. as example only, with reference to the accompanying drawings. acetonide), flunisolide, ZoticaSone, flumoxonide, rofile 0028 FIG. 1 illustrates schematically an apparatus ponide, butiXocort (e.g. as propionate ester), prednisolone, embodying the present invention. One or more assembled, or prednisone, tipredane, steroid esters according to WO 2002/ at least partly assembled inhalation devices are placed into a 12265, WO 2002/12266 and WO 2002/88167 (ed. 6C.9o chamber 2 which, after being closed has its internal pressure difluoro-17C2-furanylcarbonyl)oxy-11 B-hydroxy-16C.- reduced by a pump 4. A measuring device 6 is provided to methyl-3-oxo-androsta-1,4-diene-17 B-carbothioic acid control the pump 4 So as to reduce the air pressure in the S-fluoromethyl ester, 6C.9C.-difluoro-1 13-hydroxy-16C.-me chamber 2 to a desired pers.Sure. The measuring device 6 is thyl-3-oxo-17C-propionyloxy-androsta-1,4-diene-17B-car preferably configurated automatically to control the system to bothioic acid S-(2-oxo-tetrahydrofuran-3S-yl) ester and repeat the process a plurality of times. It is generally only 6C.9C.-difluoro-1 13-hydroxy-16C.-methyl-17C.-(4-methyl necessary to fully decompress the chamber 2 two or three 1,3-thiazole-5-carbonyl)oxy-3-oxo-androsta-1,4-diene times in order to effectively remove substantially all electro 17 B-carbothioic acid S-fluoromethyl ester; anticholinergic static charges from the device and/or powder. bronchodilators such as tolterodine, ipratropium bromide, 0029. As a result, the internal working parts of the inhala tiotropium bromide and oxitropium bromide; PDE-IV inhibi tion device may be kept free of electrostatic charges for sub tors; antihistamines; expectorants; mucolytics; cyclooxyge sequent sale and use of the device. nase inhibitors; leukotriene synthesis inhibitors; leukotriene 0030 A plurality of devices may be put in the chamber at antagonists; phospholipase-A2 inhibitors; platelet aggregat once. In particular, a container (not shown). Such as a bag, ing factor (PAF) antagonists and prophylactics of asthma and holding the device may be put in the chamber 2 and, after chronic obstructive pulmonary disease (COPD), antiarrhyt decompression, closed for the transportation of the devices. mic medicaments, tranquilisers, statins, cardiac glycosides, 0031 FIG. 2 illustrates component parts of an inhalation hormones, antihypertensive medicaments, antidiabetic-, anti device which is for storing and dispensing predetermined parasitic and anticancer medicaments, sedatives and analge doses of dry powder for inhalation. These parts are typically sic medicaments, antibiotics, antirheumatic medicaments, produced from one or more polymer materials and will immunotherapies, antifungal and antihypotension medica almost certainly acquire electrostatic charges during the steps ments, vaccines, antiviral medicaments, proteins, polypep of injection moulding, handling and assembly. Thus, when tides and peptides for example peptide hormones and growth assembled, the inhalation device will typically have a number factors, polypeptides vaccines, enzymes, endorphines, lipo of internal electrostatic charges, often of conflicting polarity proteins and polypeptides involved in the blood coagulation in adjacent parts. Indeed, dry powder is almost always inevi cascade, vitamines and others, for example cell Surface recep tably charged. As will be appreciated, dry powder of a size tor blockers, antioxidants and free radical scavengers. suitable for inhalation is particularly sensitive to electrostatic 0034 Several of these compounds could be administered forces. Therefore, for an inhalation device such as illustrated in the form of pharmacologically acceptable esters, acetals, in FIG. 2, but not limited hereto, it is particularly desirable to salts, Solvates, such as hydrates, or Solvates of Such esters or reduce any electrostatic charges in the component parts of the salts, if any. Both racemic mixtures as well as one or more device. optical isomers of the above compounds are within the scope 0032. The effect of electrostatic discharge at low pressures of the invention. for the performance of an inhalation device has not previously 0035) Suitable physiologically acceptable salts include been recognised. The method of using low pers.Sure has many acid addition salts derived from inorganic and organic acids, technical and economical advantages compared to other pos for example the chloride, bromide, Sulphate, phosphate, sible methods of reducing charges e.g. ethanol treatment of maleate, fumarate, citrate, tartrate, benzoate, 4-methoxyben plastic details (needs drying processes etc). Zoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-tolu 0033 Medicaments suitable for administration by using enesulphonate, methaneSulphonate, ascorbate, acetate. Suc the present invention are any which may be delivered by cinate, lactate, glutarate, tricarballylate, inhalation. Suitable inhalable medicaments include for hydroxynaphthalene-carboxylate (Xinafoate) or oleate salt or example B2-adrenoceptor agonists for example salbutamol. solvates thereof. terbutaline, rimiterol, fenoterol, reproterol, bitolterol, salme 0036 Many of the above mentioned classes of pharmaco terol, formoterol, clenbuterol, procaterol, broxaterol, picn logically active compounds may be administered in combi meterol, TA-2005 (chemically identified as 2(1H)-Qui nation in a separate, sequential or simultaneous way. When nolone, 8-hydroxy-5-1-hydroxy-2-2-(4-methoxyphenyl)- administered together the components can be administered as 1-methylethylaminoethyl-monohydrochloride, R R*, a single pharmaceutical composition Such as a fixed combi R* also identified by Chemical Abstract Service Registry nation. Alternatively the components can be administered Number 137888-11-0 and disclosed in U.S. Pat. No. 4,579, separately i.e. one after the other. The time interval for sepa 854), mabuterol, formanilide derivatives like 3-(4-6-({ rate administration can be anything from sequential admin (2R)-2-3-formylamino)-4-hydroxyphenyl-2- istration to administration several hours apart. hydroxyethylamino)hexyloxybutyl)benzensulfonamide 0037. The preferred pharmacologically active active glu as disclosed in WO 2002/76933 or as in U.S. Pat. No. 6,576, cocortico steroid agents for use in accordance with the 793, arylaniline derivatives as in WO 2003/42164, benzen present invention includes mometasone (e.g. as furoate), US 2011/0056089 A1 Mar. 10, 2011
ciclesonide, ZoticaSone, flumoxonide, fluticaSone (e.g. as Experiment 4 17-propionate) and budesonide, and even more preferred is budesonide. The preferred pharmacologically active long 0046 Mean values of metered dose (mg) and standard acting B-agonist is salmeterol (e.g. as Xinafoate) and formot deviations (mg) for 46 analyses of Bricanyl(RTurbuhaler(R) erol (e.g. as fumarate dihydrate) and even more preferred is 0.5 mg formoterol fumarate dihydrate. The preferred anticholinergic agent is tiotropium bromide. 0038. The preferred combinations include fluticasone pro Untreated O467 O.042 pionate/salmeterol Xinafoate, ciclesonide/formoterol fuma Low pressure O.S34 O.O29 rate dihydrate, mometasone furoate/formoterol fumarate dihydrate, budesonide/formoterol fumarate dihydrate, fluti 0047. It can be seen that the dose from treated inhalers casone propionate/formoterol fumarate dihydrate and tiotro under reduced pressure will retain the nominal dose of the pium bromide/formoterol fumarate dihydrate. The most pre inhaler and the relative standard deviation will decrease ferred combination is budesonide/formoterol fumarate improving the inhaler performance. There is also improve dihydrate. ment when e.g. the mouthpiece is treated as well. The results 0039. The pharmacologically active ingredients may be further indicate that the process is valid for all kind of com administered prophylactically as a preventive treatment or pounds/powder formulations and thereby having a more gen during the course of a medical condition as a treatment of eral applicability. The improvement is lasting for a long CUC. period of time. 0040. The composition used in the invention optionally 0048. Any complete inhaler including the formulation or additionally comprises one or more pharmaceutically accept just the formulation or parts of the inhaler may also be treated able additives (e.g. pH or tonicity adjustment), diluents and/ in the same way. or carriers. The composition is preferably in the form of a dry 0049 FIG. 1 shows a schematic drawing of the apparatus powder for inhalation, wherein the particles of the pharma emboying the present invention where 2-chamber, 4-pump cologically active ingredients have a mass median diameter and 6-a device for measuring and controlling the pressure. of less than 10 Lum. 0050 FIG. 2 shows TurbuhalerR) and its components. 1-11. (canceled) EXAMPLES 12. A method of processing an inhaler component of a dry 0041 Bricanyl(R) Turbuhaler R, 0.5 mg/dose, a registered powder inhaler, the method comprising: trademark from AstraZeneca is a reservoir type of inhaler, exposing the inhaler component, while it contains an where the main assembly (including the dosing mechanism, amount of medicament, to a gas in a chamber at a first without mouth piece) was treated in different ways. The predetermined pressure; metered dose was measured at 601/min. exposing the inhaler component, in the chamber, to gas at 0042. The invention will be illustrated but not limited to a second pressure greater than the first pressure; and the following examples: repeating the exposure of the inhaler component to gas at a pressure no greater than the first predetermined pres Experiment 1 Sure; wherein the exposing steps reduce an electrostatic charge 0043 of the inhaler component. 13. The method of claim 12, wherein the second pressure is atmospheric pressure. Treatment Dose (mg) Standard deviation (mg) 14. The method of claim 12, wherein the inhaler compo nent is the entire dry powder inhaler. Untreated O.384 O.107 15. The method of claim 12, comprising twice repeating Drying agentlow pressure (40 torr) O.S45 O.069 the exposure of the inhaler component to the gas at the first pressure. 16. The method of claim 12, wherein the gas is air. Experiment 2 17. The method of claim 12, wherein the first pressure is less than 100 mbar. 0044 18. The method of claim 12, wherein the first pressure is less than 50 mbar. 19. The method of claim 12, wherein the first pressure is Untreated O439 O.O88 less than 1 mbar. Drying agent O42O O.083 20. The method of claim 12, further comprising: placing the dry powder inhaler or inhaler component in the chamber; Experiment 3 closing the chamber; reducing the internal pressure of the chamber using a 0045 pump; and using a measuring device to control the pump so as to Untreated O451 O.O99 reduce the pressure in the chamber to the first pressure, Low pressure (40 torr) O.S11 O.O79 wherein the measuring device automatically controls the pump to repeat the exposure of the inhaler component to the gas at the first pressure. US 2011/0056089 A1 Mar. 10, 2011
21. The method of claim 12, wherein the medicament is a 33. The method of claim 28, wherein the first pressure is dry powder formulation, the formulation comprising one or less than 50 mbar. more drugs selected from the group consisting of mometa 34. The method of claim 28, wherein the first pressure is Sone, ciclesonide, ZoticaSone, flumoxonide, fluticaSone, less than 1 mbar. budesonide, salmeterol, formoterol, and tiotropium bromide. 35. The method of claim 28, further comprising: 22. The method of claim 12, wherein the medicament is a placing the dry powder inhaler or inhaler component in the dry powder formulation, the formulation comprising one or chamber; more drug combinations selected from the group consisting closing the chamber; of fluticaSone propionate/salmeterol Xinafoate, ciclesonide/ reducing the internal pressure of the chamber using a formoterol fumarate dihydrate, mometasone furoate/formot pump; and erol fumarate dihydrate, budesonide/formoterol fumarate using a measuring device to control the pump so as to dihydrate, fluticasone propionate/formoterol fumarate dehy reduce the pressure in the chamber to the first pressure, drate, and tiotropium bromide/formoterol fumarate dihy wherein the measuring device automatically controls the drate. pump to repeat the exposure of the inhaler component to 23. The method of claim 12, wherein the medicament is a the gas at the first pressure. dry powder formulation, the formulation comprising one or 36. The method of claim 28, wherein the dry powder more drug combinations selected from the group consisting inhaler or inhaler component contains a dry powder formu of budesonide and formoterol fumarate dihydrate. lation, the formulation comprising one or more drugs selected 24. The method of claim 21, wherein the mometasone is from the group consisting of mometaSone, ciclesonide, Zoti furoate. casone, flumoxonide, fluticasone, budesonide, Salmeterol, 25. The method of claim 22, wherein the fluticasone is formoterol, and tiotropium bromide. 17-propionate. 37. The method of claim 28, wherein the inhaler compo 26. The method of claim 21, wherein the salmeterol is nent contains a dry powderformulation, the formulation com Xinafoate. prising one or more drug combinations selected from the 27. The method of claim 21, wherein the formoterol is group consisting of fluticaSone propionate/salmeterol Xin fumarate dehydrate. afoate, ciclesonide/formoterol fumarate dihydrate, mometa sone furoate/formoterol fumarate dihydrate, budesonide/for 28. A method of processing an inhaler component of a dry moterol fumarate dihydrate, fluticasone propionate/ powder inhaler, the method comprising: formoterol fumarate dehydrate, and tiotropium bromide/ exposing the inhaler component, in a chamber, to a gas at a formoterol fumarate dihydrate. first pressure of no more than 100 mbar; 38. The method of claim 28, wherein the inhaler compo exposing the inhaler component, in the chamber, to gas at nent contains a dry powderformulation, the formulation com a second pressure greater than the first pressure; and prising one or more drug combinations selected from the repeating the exposure of the inhaler component to gas at a group consisting of budesonide and formoterol fumarate pressure no greater than 100 mbar; dihydrate. wherein the exposing steps reduce an electrostatic charge 39. The method of claim 36, wherein the mometasone is of the inhaler component. furoate. 29. The method of claim 28, wherein the second pressure is 40. The method of claim 37, wherein the fluticasone is atmospheric pressure. 17-propionate. 30. The method of claim 28, wherein the inhaler compo 41. The method of claim 36, wherein the salmeterol is nent is the entire dry powder inhaler. Xinafoate. 31. The method of claim 28, comprising twice repeating 42. The method of claim 36, wherein the formoterol is the exposure of the inhaler component to the gas at the first fumarate dehydrate. pressure. 32. The method of claim 28, wherein the gas is air.