(19) TZZ Z¥_T (11) EP 2 037 879 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/00 (2006.01) A61K 9/12 (2006.01) 15.05.2013 Bulletin 2013/20 A61K 9/14 (2006.01) A61K 31/40 (2006.01) (21) Application number: 07764925.9 (86) International application number: PCT/EP2007/005744 (22) Date of filing: 28.06.2007 (87) International publication number: WO 2008/000482 (03.01.2008 Gazette 2008/01) (54) COMPOSITIONS OF GLYCOPYRRONIUM SALT FOR INHALATION FORMULIERUNGEN ENTHALTEND GLYCOPYRRONIUMSALZ ZUR INHALATION COMPOSITIONS À INHALER À BASE D’UN SEL DE GLYCOPYRRONIUM (84) Designated Contracting States: • WIRTH, Wolfgang AT BE BG CH CY CZ DE DK EE ES FI FR GB GR CH-4422 Arisdorf (CH) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • BAUMBERGER, Anton SI SK TR CH-4102 Binningen (CH) • ABEL, Stephan (30) Priority: 30.06.2006 GB 0613161 79576 Weil am Rhein (DE) • KAERGER, Sebastian (43) Date of publication of application: D-07407 Rudolstadt (CH) 25.03.2009 Bulletin 2009/13 • KIECKBUSCH, Thomas 79539 Lörrach (DE) (73) Proprietor: Novartis AG 4056 Basel (CH) (74) Representative: McLean, Craig Sutherland Novartis Pharma AG (72) Inventors: Patent Department • HAEBERLIN, Barbara 4002 Basel (CH) CH-4142 Münchenstein (CH) • STOWASSER, Frank (56) References cited: 79730 Murg (DE) WO-A-01/76575 WO-A-2005/105043 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 037 879 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 037 879 B1 Description [0001] This invention relates to organic compounds and their use as pharmaceuticals, or more specifically a process for preparing dry powders of glycopyrronium salts. 5 [0002] Glycopyrronium bromide i.e. 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethyl-pyrrolidinium bromide but also known as glycopyrrolate is an antimuscarinic agent that is currently administered by injection to reduce secretions during anaesthesia and or taken orally to treat gastric ulcers. It has the following chemical structure: 10 15 and can be prepared using the procedure described in United States patent US 2956062. [0003] Schroeckenstein et al J. Allergy Clin. Immunol. 1998; 82(1): 115-119 discloses the use of glycopyrrolate in an 20 aerosol formulation for treating asthma where a single administration of a metered dose achieved bronchodilation for up to 12 hours. [0004] It is known that quaternary ammonium compounds with antimuscarinic activity tend to agglomerate during storage. For example, Ticehurst et al, International Journal of Pharmaceutics 193 (2000) pages 247-259 observes this in micronised revatopate hydrobromide. This problem affects the physical and chemical stability of the drug substance 25 and its performance in formulations. [0005] International patent application WO 2005/105043 discloses dry powder compositions that exhibit improved stability over time, and methods for preparing them. [0006] International patent application WO 2001/76575 discloses glycopyrrolate can be formulated as a dry powder for pulmonary delivery in controlled release formulation. In the example micronised glycopyrrolate is mixed with mag- 30 nesium stearate in the ratio of 75:25 by mass and that mixture is ball milled and dried to give a dry powder. [0007] International patent application WO 2005/25536 discloses a method for making composite active particles for use in a pharmaceutical composition for pulmonary inhalation that involves jet milling active particles with certain additive materials to enhance fine particle fraction and fine particle dose. [0008] It has now been found, surprisingly, that it is advantageous to micronise a glycopyrronium salt together with 35 an anti-adherent agent and then admix carrier particles as this reduces the tendency for the resulting drug substance to agglomerate and therefore improves the stability of the resulting drug substance. [0009] Accordingly in broad terms the present invention provides a process for preparing a dry powder formulation of a glycopyrronium salt for inhalation that comprises the steps of (a) mixing a glycopyrronium salt and an anti-adherent agent to give a homogeneous blend; (b) micronising the blend; and (c) admixing carrier particles to form a dry powder 40 formulation, wherein the process enhances the stability of the glycopyrronium salt. [0010] Processing the glycopyrronium salt in this way reduces the tendency for the resulting drug substance to ag- glomerate, a commonly known behaviour of micronised quaternary ammonium compounds particularly when stored in humid conditions or otherwise exposed to moisture. [0011] Preferably the glycopyrronium salt is glycopyrrolate. 45 [0012] Preferably the anti-adherent agent is one or more metal stearates, one or more crystalline sugars or a mixture thereof. Especially preferred metal stearates include magnesium stearate and calcium stearate. Especially preferred crystalline sugars include lactose, more especially lactose monohydrate or anhydrous lactose. [0013] When the anti-adherent agent is a metal stearate, the glycopyrronium salt is suitably micronised with from 1 to 20 % by mass of the anti-adherent agent, more preferably from 2 to 10 % by mass of the anti-adherent agent, but most 50 preferably from 3 to 5 % by mass of the anti- adherent agent. [0014] When the anti-adherent agent is a crystalline sugar, the crystalline sugar is suitably micronised with the glyc- opyrronium salt in a ratio of from 0.5:1 to 10:1 by mass, more preferably from 1:1 to 5:1 by mass, but most preferably from 2:1 to 3:1 by mass. Preferably the carrier particles are mixed with the micronised glycopyrronium salt and anti- adherent agent in a ratio of from 2000:1 to 5: 1 by mass, especially from 200: 1 to 20:1 by mass. The carrier particles are 55 preferably crystalline sugars, for example lactose monohydrate or anhydrous lactose. [0015] The glycopyrronium salt and the anti-adherent agent are optionally micronised together with one, two, three or more additional active ingredients. Alternatively, the glycopyrronium salt and the anti-adherent agent and one or more additional active ingredients are micronised and the resulting product is mixed with one or more additional active ingre- 2 EP 2 037 879 B1 dients that have already been micronised. In each case the or each additional active ingredient is suitably selected from the group consisting of anti- inflammatory, bronchodilatory, antihistamine, decongestant and anti- tussive drug substanc- es. [0016] Terms used in the specification have the following meanings: 5 "Glycopyrronium salt" as used herein is intended to encompass any salt form or counterion of glycopyrronium, including but not limited to glycopyrronium bromide (glycopyrrolate), glycopyrronium chloride, or glycopyrronium iodide, as well as any and all isolated stereoisomers and mixtures or stereoisomers thereof. Derivatives of glycop- yrronium salts are also encompassed. Suitable counter ions are pharmaceutically acceptable counter ions including, 10 for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, pro- pionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl- acetate or triphenylacetate, o-hydroxy-benzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxy- naphthalene-2-carboxylate, methanesulfonate and benzene-sulfonate. 15 "Anti-adherent agent" as used herein means a material that reduces the cohesion between particles and prevents fine particles becoming attached to the inner surfaces of an inhaler device, or a mixture of such materials. Anti-ad- herent agents also include anti-friction agents or glidants, which give the powder formulation better flow properties in the inhaler. They usually lead to better dose reproducibility and higher fine particle fractions. Typical anti- adherent agents include amino acids such as leucine, phospholipids such as lecithin or fatty acid derivatives such as mag- 20 nesium stearate or calcium stearate. "Metered dose" or "MD" of a dry powder formulation as used herein is the total mass of active agent present in the metered form presented by the inhaler device in question. For example, the MD might be the mass of glycopyrronium salt present in a capsule for a particular dry powder inhaler, or in a foil blister for use in a particular dry powder 25 inhaler device. "Emitted dose" or "ED" as used herein is the total mass of the active agent emitted from the device following actuation. It does not include the material left inside or on the surfaces of the device. The ED is measured by collecting the total emitted mass from the device in an apparatus frequently referred to as a dose uniformity sampling apparatus 30 (DUSA), and recovering this by a validated quantitative wet chemical assay. "Fine particle dose" or "FPD" as used herein is the total mass of active agent which is emitted from the device following actuation which is present in an aerodynamic particle size smaller than a defined limit. This limit is generally taken to be 5 mm if not expressly stated to be an alternative limit, such as 1 mm or 3 mm, etc. The FPD is measured 35 using an impactor or impinger, such as a twin stage impinger (TSI), multi-stage liquid impinger (MSLI), Andersen Cascade Impactor (ACI) or a Next Generation Impactor (NGI). Each impactor or impinger has a pre-determined aerodynamic particle size collection cut-off point for each stage. The FPD value is obtained by interpretation of the stage-by-stage active agent recovery quantified by a validated quantitative wet chemical assay where either a simple stage cut is used to determine FPD or a more complex mathematical interpolation of the stage- by-stage deposition 40 is used.