Source: https://patents.google.com/patent/US9737520B2/en
Timestamp: 2019-03-24 04:11:28
Document Index: 798832914

Matched Legal Cases: ['§371', 'Application No. 61', 'Application No. 11382114', 'Application No. 2006147250', 'Application No. 09', 'Application No. 04763322', 'Application No. 05750538', 'Application No. 09729773', 'Application No. 2009', 'Application No. 1029151', 'art 1', 'art 1', 'art 2', 'art 2', 'art 3', 'art 3', 'art 4', 'art 4', 'art 5', 'art 5', 'art 6', 'art 6', '§ 1', '§ 1', '§ 1', '§ 1', '§1', '§1', '§ 1', '§41', '§ 1', '§1', '§ 1', '§ 1']

US9737520B2 - Aclidinium for use in improving the quality of sleep in respiratory patients - Google Patents
US9737520B2
US9737520B2 US15/161,531 US201615161531A US9737520B2 US 9737520 B2 US9737520 B2 US 9737520B2 US 201615161531 A US201615161531 A US 201615161531A US 9737520 B2 US9737520 B2 US 9737520B2
US15/161,531
US20160263091A1 (en
Maria Esther GARCIA GIL
Maria Jose SALA PEINADO
2011-04-15 Priority to EP11382114 priority Critical
2011-04-15 Priority to EP11382114.4 priority
2011-04-15 Priority to EP11382114A priority patent/EP2510928A1/en
2011-06-16 Priority to US201161497771P priority
2012-04-11 Priority to PCT/EP2012/056575 priority patent/WO2012140081A1/en
2013-12-23 Priority to US201314111211A priority
2016-05-23 Priority to US15/161,531 priority patent/US9737520B2/en
2016-05-23 Application filed by Almirall SA filed Critical Almirall SA
2016-09-15 Publication of US20160263091A1 publication Critical patent/US20160263091A1/en
2017-08-22 Publication of US9737520B2 publication Critical patent/US9737520B2/en
The present disclosure provides aclidinium or any of its stereoisomers or mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, for improving the quality of sleep in respiratory patients.
This application is a continuation of U.S. patent application Ser. No. 14/111,211, having a 35 U.S.C. §371(c) date of Dec. 23, 2013, which is a National Stage Entry of PCT/EP2012/056575, filed Apr. 11, 2012, which claims the benefit of U.S. Provisional Application No. 61/497,771, filed Jun. 16, 2011, and also claims priority to European Patent Application No. 11382114.4, filed Apr. 15, 2011, all of which are incorporated herein by reference.
In COPD patients, sleep-related complaints are the third most commonly reported symptoms, after dyspnoea and fatigue (Kinsman et al, Chest, 1983, 83, 755-761). In the case of asthma, 80% of the patients are woken at least occasionally by nocturnal wheeze and cough, and many patients with severe stable asthma are woken virtually every night (Turner-Warwick, M.; Am. J. Med., 1988, 85 (suppl. 1B), 6-8).
Sleep complaints frequently reported by respiratory patients are for example longer latency to falling asleep, difficulty in staying asleep, frequent arousals and awakenings, superficial sleep, reduction of total sleep time, waking up too early and not being able to get back to sleep, generalised insomnia and, overall, a much poorer quality of sleep. Excessive daytime sleepiness arid restricted physical activity during the day due to breathlessness in the morning are also common consequences of the impaired quality of sleep.
Bronchodilating agents like the beta-adrenergic agonists or the antagonists of cholinergic muscarinic receptors (commonly known as anticholinergics antirnuscarinics) are usually prescribed for inhalation to respiratory patients suffering from obstructive airway diseases, such as asthma or COPD. commercially available antichohnergics are synthetic tropane derivatives, and include ipratropium, oxitropium, and tiotropium. Tiotropium, is the only long-acting anticholinergic currently on the market.
It is well known that the impact of the circadian rhythm on airway responsiveness and airway resistance is much larger in respiratory patients that in normal subjects. As a consequence, respiratory patients are particularly prone to bronchoconstriction at night and in the early morning hours and this is the main factor affecting the quality of their sleep. Therefore, a treatment aimed at overcoming or preventing bronchoconstriction during the night is highly desirable. However, a study by Calverley el al., in Thorax, 2003, 58 (10), 855-860 shows that the administration of the long-acting bronchodilator tiotropium in the evening does not produce more bronchodilation during the night than when it is administered only in the morning.
Aclidinium is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane, a long-acting muscarinic receptor antagonist in development by Almirall for administration by inhalation in the treatment of respiratory diseases, especially asthma and COPD. It was first disclosed in WO 01/04118.
SUMMARY AF THE INVENTION
The present invention provides aclidinium, or any of its steroisomers or mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, for use in improving the quality of sleep in respiratory patients.
Preferably, aclidinium is in the form of a salt with anion X−. Most preferably, the anion X− is bromide.
In another embodiment, aclidinium is administered as a pharmaceutical composition suitable for inhalation, preferably in the form of a dry powder. The composition can be administered by means of any inhaler device, more preferably the Genuair®.
In another preferred embodiment, aclidinium is co-administered with an additional medication suitable for the treatment of respiratory diseases, selected for example from one or more of the following: corticosteroids, beta-adrenergic agonists, PDE4 inhibitors, antihistamines, anti-1gE antibodies, leukotriene D4 inhibitors, inhibitors of egfr-kinase, p38 kinase inhibitors and/or NK1-receptor antagonists. The additional medications can be present in the same pharmaceutical composition as aclidinium or in separate pharmaceutical compositions. Preferably, the additional medication is selected from corticosteroids, beta-adrenergic agonists and/or PDE4 inhibitors.
Typically, the aclidinium is administered in the form of a salt with an anion X−, wherein X− is a pharmaceutically acceptable anion of a mono or polyvalent acid. More typically, X− 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 the aclidinium is in the form of aclidinium bromide.
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.
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.
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, dexarnethasone, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, deprodone propionate, fluticasone propionate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betatnethasone 17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate and hydrocortisone probutate. Budesonide and mometasone are especially preferred.
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, salbutatnol, salmeterol, sibenadet, sulfonterol, terbutaline, tulobuterol, vilanterol, olodaterol, KUL-1248, LAS-100977, 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, LAS-100977 and indacaterol in free or pharmaceutically acceptable salt form.
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)cyclohexan1-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 number WO03/097613, and PCT/EP03/14722 and in the Spanish patent application numer P200302613.
Medicaments for administration in a dry powder the 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.
Achieving a 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 he 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 of 90-160 μm, a d50 of 170-270 μm, and d90 of 290-400 μm.
Suitable lactose materials for use in the present invention are commercially available, e.g., from DMW Internacional (Respitose GR-001, Respitose SV-001, Respitose SV-003); Meggie (Capsulac 60, Inhalac 70, Capsulac 60 INH); and Borculo Domo (Lactohale 100-200, Lactohale 200-300, and Lactohale 100-300).
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 μm in diameter, and the lactose particles have have a d10 of 90-160 μm, a d50 of 170-270 μm, and d90 of 290-400 μm.
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 0.001-50 mg, more preferably 0.01-5 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof Alternatively, the active ingredient (s) may be presented without excipients.
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,
Aclidinium is preferably administered with a multi-dose inhaler, more preferably with the Genuair®(formerly known as Novolizer SD2FL), which is described the following patent applications Nos: WO97/000703, WO03/000325 and WO2006/008027.
Dosages will vary depending on, e.g., the individual, the mode and frequency of administration, and the nature and severity of the condition to be treated, Daily dosages for a 70 kg adult human may typically for example be on the order of 100-1000 micrograms of active agent in the form of dry powder for inhalation.
COPD patients with FEV1/FVC<70% were randomised (1:1:1) to aclidinium 200 micrograms, 400 micrograms, or placebo. The quality of sleep was reported daily using electronic diaries and a questionnaire, which assessed symptom frequency and severity and its effect on morning activities. Rescue medication use was also assessed.
At Week 12, aclidinium significantly improved the quality of sleep compared to placebo. Aclidinium 200 mcg and 400 mcg significantly reduced the severity of breathlessness and cough at night, the frequency of awakenings and the difficulty to fall back sleep. Additionally, the production of sputum and the use of rescue medication were also reduced.
In a Phase IIa randomised, double-blind, double-dummy, crossover trial, patients with moderate-to-severe COPD received inhaled aclidinium 400 μg BID, tiotropium 18 μg QD and placebo for 15 days, with a 9-15 day washout between treatment periods.
The incidence of sleep difficulties was recorded daily on a patient diary card. As in Example 1, the scores ranged from 0 for none to 1-4 for increasing severity of the sleep difficulties. The change in the score produced by each treatment with respect to the baseline was then measured.
The average score (+/−SEM) of the patients treated with tiotropium was −0.011 (0.091), which is practically identical to the baseline and very similar to the score of 0.061 (0.088), observed in the patients treated with placebo. There is no statistically significant difference between these two scores (p>0.05). In contrast, the score of the patients treated with aclidiniurn was −0.123 (0.089). In this case there is a statistically significant difference with placebo (p<0.05).
These phase IIa results demonstrate that the remarkable improvement of sleep quality produced by aclidinium is not observed when the patients are treated with tiotropium, the reference anticholinergic drug currently in the market. This unexpected effect of aclidinium is therefore not obvious and involves an inventive step.
1. A method for improving the quality of sleep in a respiratory patient experiencing sleep disturbances, comprising:
administering to the patient a pharmaceutical composition comprising aclidinium or any of its stereoisomers or mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof.
3. The method according to claim 1, wherein the respiratory patient suffers from asthma or chronic obstructive pulmonary disease (COPD).
5. The method for use in a dry powder formulation according to claim 4, providing a metered nominal dose of aclidinium equivalent to from 100 to 1000 micrograms of aclidinium bromide per inhalation.
6. The method according to claim 5, wherein the metered nominal dose of aclidinium is equivalent to 200 micrograms of aclidinium bromide per inhalation.
7. The method according to claim 5, wherein the metered nominal dose of aclidinium is equivalent to 400 micrograms of aclidinium bromide per inhalation.
8. The method according to claim 1, wherein aclidinium is administered at least once per day.
9. The method according to claim 8, wherein aclidinium is administered twice daily.
10. The method according to claim 1, wherein aclidinium is co-administered with a therapeutically effective amount of at least one other medication chosen from corticosteroids, beta-adrenergic agonists, and PDE4 inhibitors.
11. The method according to claim 1, wherein the quality of sleep is improved by reducing at least one of the following sleep disturbances:
a) latency to falling asleep;
b) total number of awakenings;
c) early awakenings;
d) difficulty in staying asleep;
e) superficial sleep;
f) insomnia;
g) daytime sleepiness or fatigue;
h) restriction of activities during the morning;
12. The method according to claim 1, wherein the pharmaceutical composition comprises aclidinium in an effective amount of aclidinium.
13. The method according to claim 1, wherein the patient suffers from a respiratory disorder and wherein the patient suffers from impaired sleep caused by sleep disturbances.
14. The method according to claim 13, wherein the patient suffers from asthma or chronic obstructive pulmonary disease.
15. The method according to claim 5, wherein the formulation is administered in a dosage comprising an amount of aclidinium ranging from 200 micrograms to 400 micrograms of aclidinium bromide per inhalation.
US15/161,531 2011-04-15 2016-05-23 Aclidinium for use in improving the quality of sleep in respiratory patients Active US9737520B2 (en)
EP11382114 2011-04-15
EP11382114.4 2011-04-15
EP11382114A EP2510928A1 (en) 2011-04-15 2011-04-15 Aclidinium for use in improving the quality of sleep in respiratory patients
US201161497771P true 2011-06-16 2011-06-16
US201314111211A true 2013-12-23 2013-12-23
US15/161,531 US9737520B2 (en) 2011-04-15 2016-05-23 Aclidinium for use in improving the quality of sleep in respiratory patients
US14/111,211 Continuation US20140100246A1 (en) 2011-04-15 2012-04-11 Aclidinium for use in improving the quality of sleep in respiratory patents
PCT/EP2012/056575 Continuation WO2012140081A1 (en) 2011-04-15 2012-04-11 Aclidinium for use in improving the quality of sleep in respiratory patients
US201314111211A Continuation 2013-12-23 2013-12-23
US20160263091A1 US20160263091A1 (en) 2016-09-15
US9737520B2 true US9737520B2 (en) 2017-08-22
US14/111,211 Abandoned US20140100246A1 (en) 2011-04-15 2012-04-11 Aclidinium for use in improving the quality of sleep in respiratory patents
US15/161,531 Active US9737520B2 (en) 2011-04-15 2016-05-23 Aclidinium for use in improving the quality of sleep in respiratory patients
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