USE OF ACLIDINIUM

Abstract

The present invention provides aclidinium or any of its stereoisomers or mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, for improving the physical activity in respiratory patients.

Claims

1. A method of improving the physical activity in a patient in need thereof, comprising: administering to the patient a pharmaceutical composition comprising aclidinium, any of its stereoisomers, or mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof.

2. The method according to claim 1, wherein the aclidinium is in the form of aclidinium bromide.

3. The method according to claim 1, wherein the patient suffers from asthma or chronic obstructive pulmonary disease.

4. The method according to claim 1, wherein the aclidinium is in the form of a dry powder formulation suitable for inhalation.

5. The method according to claim 4, wherein the formulation is administered in a metered nominal dose of aclidinium equivalent to an amount of aclidinium bromide ranging from 100 micrograms to 1000 micrograms per inhalation.

6. The method according to claim 4, wherein the formulation is administered in a metered nominal dose of aclidinium equivalent to 400 micrograms of aclidinium bromide per inhalation and/or a metered nominal dose of 343 micrograms of aclidinium per inhalation.

7. The method according to claim 4, wherein the formulation is administered in a delivered dose of aclidinium equivalent to 375 micrograms of aclidinium bromide per inhalation and/or a delivered dose of 322 micrograms of aclidinium per inhalation.

8. The method according to claim 1, wherein the composition comprising aclidinium is administered at least once per day.

9. The method according to claim 1, wherein the composition comprising aclidinium is administered with a therapeutically effective amount of at least one other medication chosen from corticosteroids, beta-adrenergic agonists, and PDE4 inhibitors.

10. The method according to claim 1, wherein the physical activity is improved by increasing at least one of the following: a) average number of steps per day; b) minutes of moderate activity per day; c) average active energy expenditure; or d) physical activity level.

11-13. (canceled)

14. The method according to claim 1, wherein the patient suffers from a respiratory disorder and wherein the patient presents a reduced physical activity.

15. The method according to claim 14, wherein the reduced physical activity involves at least one of the following: a) reduced average number of steps per day; b) reduced minutes of moderate activity per day; c) reduced average active energy expenditure; or d) reduced physical activity level (PAL).

16. (canceled)

17. (canceled)

18. The method according to claim 5, wherein the formulation is administered in a metered nominal dose of aclidinium equivalent to an amount of aclidinium bromide ranging from 200 micrograms to 400 micrograms per inhalation.

19. The method according to claim 5, wherein the metered nominal dose of aclidinium is equivalent to 200 micrograms of aclidinium bromide per inhalation.

20. The method according to claim 5, wherein the metered nominal dose of aclidinium is equivalent to 400 micrograms of aclidinium bromide per inhalation.

21. The method according to claim 8, wherein the composition comprising aclidinium is administered twice daily.

22. The method according to claim 14, wherein the respiratory disorder is asthma or chronic obstructive pulmonary disease.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0030] Typically, aclidinium is administered in the form of a salt with an anion X.sup.−, wherein X.sup.− is a pharmaceutically acceptable anion of a mono or polyvalent acid. More typically, X.sup.− is an anion derived from an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid, or an organic acid such as methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid or maleic acid. Most preferably aclidinium is in the form of aclidinium bromide.

[0031] Aclidinium bromide is a white powder with a molecular formula of C.sub.26H.sub.30NO.sub.4S.sub.2Br and a molecular mass of 564.56. It is very slightly soluble in water and ethanol and sparingly soluble in methanol.

[0032] The compound of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.

[0033] The words “treatment” and “treating” are to be understood as embracing amelioration of symptoms of a disease or condition and/or elimination or reduction of the cause of the disease or condition and/or prevention of the appearance of the disease or its symptoms.

[0034] The term “therapeutically effective amount” refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.

[0035] Aclidinium can also be used in combination with other drugs known to be effective in the treatment of the diseases or the disorders indicated above. For example aclidinium can be combined with corticosteroids or glucocorticoids, beta-adrenergic agonists, PDE4 inhibitors, antihistamines, anti-IGE antibodies, leukotriene D4 antagonists, inhibitors of egfr kinase, p38 kinase inhibitors and/or NK-1 receptor agonists.

[0036] Corticosteroids that can be combined with aclidinium in the present invention particularly include those suitable for administration by inhalation in the treatment of respiratory diseases or conditions, e.g., prednisolone, methylprednisolone, dexamethasone, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitate, tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, deprodone propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate and hydrocortisone probutate. Budesonide, fluticasone propionate and mometasone furoate are especially preferred.

[0037] Beta-adrenergic agonists that can be combined with aclidinium in the present invention particularly include β2 adrenergic agonists useful for treatment of respiratory diseases or conditions, for example, selected from the group consisting of arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol, isoprenaline, mabuterol, meluadrine, nolomirole, orciprenaline, pirbuterol, procaterol, reproterol, ritodrine, rimoterol, salbutamol, salmeterol, sibenadet, sulfonterol, terbutaline, tulobuterol, vilanterol, olodaterol, KUL-1248, abediterol, carmoterol and indacaterol, in free or pharmaceutically acceptable salt form. Preferably, the β2 adrenergic agonist is a long-acting β2 adrenergic agonist, e.g., selected from the group consisting of formoterol, salmeterol, carmoterol, vilanterol, olodaterol, abediterol and indacaterol in free or pharmaceutically acceptable salt form.

[0038] PDE4 inhibitors that can be combined with aclidinium in the present invention include denbufylline, rolipram, cipamfylline, arofylline, filaminast, piclamilast, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, 6-[2-(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid, (R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine, N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide, 9-(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine, N-(3,5-Dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide, N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide, 3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride, 4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridin-2(1H)-one, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluroromethoxyphenyl)cyclohexan 1-one, cis [4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol. ONO-6126 (Eur Respir J 2003, 22(Suppl. 45): Abst 2557) and the compounds claimed in the PCT patent application numbers WO 03/097613, WO 2004/058729, WO 2005/049581, WO 2005/123692, WO 2005/123693 and WO 2010/069504.

[0039] Aclidinium for use in the present invention may be administered by any suitable route to provide local antimuscarinic action. It is preferably administered by inhalation, e.g., as a powder, spray, or aerosol, preferably as a dry powder. Pharmaceutical compositions comprising aclidinium may be prepared using conventional diluents or excipients and techniques known in the galenic art.

[0040] Medicaments for administration in a dry powder for inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-10 μm, preferably 2-5 μm. Particles having a size above 20 μm are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means, e.g. by micronisation or supercritical fluid techniques. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline.

[0041] Achieving high dose reproducibility with micronised powders is difficult because of their poor flowability and extreme agglomeration tendency. To improve the efficiency of dry powder compositions, the particles should be large while in the inhaler, but small when discharged into the respiratory tract. Thus, an excipient, for example a mono-, di- or polysaccharide or sugar alcohol, such as lactose, mannitol or glucose is generally employed. The particle size of the excipient will usually be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as lactose particles, preferably crystalline alpha lactose monohydrate, e.g., having an average particle size range of 20-1000 μm, preferably in the range of 90-150 μm. In one embodiment, the lactose particles for use in formulations of the invention have a d10 in the range of 90-160 μm, a d50 In the range of 170-270 μm, and d90 in the range of 290-400 μm.

[0042] Suitable lactose materials for use in the present invention are commercially available, e.g., from DMW Intemacional (Respitose GR-001, Respitose SV-001, Respitose SV-003); Meggle (Capsulac 60, Inhalac 70, Capsulac 60 INH); and Borculo Domo (Lactohale 100-200, Lactohale 200-300, and Lactohale 100-300).

[0043] The ratio between the lactose particles and aclidinium by weight will depend on the inhaler device used, but is typically, e.g., 5:1 to 200:1, preferably 25:1 to 150:1, more preferably 30:1 to 70:1.

[0044] In a preferred embodiment, the aclidinium is administered in the form of a dry powder formulation of aclidinium bromide in admixture with lactose, in a ratio by weight of aclidinium to lactose of 1:50 to 1:150, suitable for administration via a dry powder inhaler, wherein the aclidinium particles have an average particle size of from 2 to 5 μm in diameter, e.g., less than 3 m in diameter, and the lactose particles have a d10 of 90-160 μm, a d50 of 170-270 μm, and d90 of 290-400 μm.

[0045] Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Each capsule or cartridge may generally contain between 0.001-200 mg, more preferably 0.01-100 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient (s) may be presented without excipients.

[0046] Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi-dose delivery, the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices.

[0047] Aclidinium is preferably administered with a multi-dose inhaler, more preferably with the Genuair® device (formerly known as Novolizer SD2FL), which is described the PCT patent application numbers WO 97/000703, WO 03/000325 and WO 2006/008027 and in Chrystyn H et al, Int J Clin Pract, March 2012, 66, 3, 309-317 (first published online on 16 Feb. 2012).

Example 1

[0048] In a Phase III randomized, double-blind, placebo controlled, 2 period crossover trial, patients with moderate to severe COPD received a dose of aclidinium equivalent to a metered nominal dose of 400 micrograms of aclidinium bromide per inhalation twice-daily (in the morning, 9 am, and in the evening, 9 μm) and placebo for two periods of 3 weeks, with a washout period of 2 weeks between treatment periods.

[0049] Patients were randomised to receive either a dose of aclidinium equivalent to a metered nominal dose of 400 micrograms of aclidinium bromide per inhalation twice-daily in the first period followed by placebo in the second period, or to receive placebo in the first period followed by aclidinium bromide 400 micrograms twice-daily in the second period. Both aclidinium bromide and placebo were administered with a Genuair® multidose dry powder inhaler.

[0050] Physical activity (as minutes of at least moderate activity per day and as average active energy expenditure expressed in Kcal) was measured in the last week of the treatment with aclidinium and placebo using a multisensor armband (SenseWear™ Pro Armband; BodyMedia, Pittsburgh, Pa., USA), was worn on the upper right over the triceps muscle, according to the method described in Watz B et al, Eur Respir J, 2009; 33: 262-272. The multisensory armband incorporates a biaxial accelerometer that records steps per day and physiological sensors of energy expenditure.

[0051] A valid period of measurement was defined as 5 days of measurement with the patients wearing the accelerometer at least 22 hours per day.

[0052] The Intention-to-Treat (ITT) population included 109 patients.

[0053] Results are displayed in Table 1.

TABLE-US-00001 TABLE 1 Change from baseline in physical activity parameters Change from baseline at week 3 Placebo Aclidinium Δ Comparison Parameter (n = 83) (n = 85) versus placebo Duration of at least  −5.9  4.2 10 (p < 0.05) moderate activity (SE = 4.1) (SE = 4.1) (minutes) Daily active energy −32.7 21.9 55 (p < 0.05) expenditure (Kcal) (SE = 21.0) (SE = 20.8) n = number of patients in the analysis SE = standard error

[0054] As it can be observed in Table 1, after 3 weeks of treatment, 400 micrograms of aclidinium bromide per inhalation twice-daily showed statistically significant increases in the adjusted mean change from baseline compared to placebo in the duration of at least moderate activity (10 minutes; p<0.05 versus placebo). Moderate activity defined as any physical activity >3 metabolic equivalents.

[0055] Aclidinium bromide also showed statistically significant increases in the adjusted mean change from baseline compared to placebo in daily active energy expenditure activity (55 Kcal; p<0.05 versus placebo)

[0056] These phase III results demonstrate a remarkable improvement in physical activity produced by aclidinium, which was not observed with tiotroplum, the reference standard in COPD treatment, in previous trials (Sciurba F C et al, Am J Respir Crit Care Med 183, 2011, A1589).