TW201302195A - New use of aclidinium - Google Patents

Abstract

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

Description

New use of acridinium

The present invention relates to a novel use of acilidinium which can be advantageously used to improve the quality of sleep in patients with respiratory diseases.

Respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major global health problems and the incidence is increasing worldwide. Its usual feature is the inflammatory dysfunction of the airways, which can lead to bronchial stenosis.

In asthma, inflammation is caused by exposure to a variety of triggers, including allergens and viruses, which initiate components in both innate and acquired immune responses. In COPD, inflammation occurs primarily due to exposure to harmful particles and gases, especially cigarette smoke. The term COPD includes a variety of diseases (such as chronic bronchitis or emphysema) rather than a single condition.

Asthma and COPD are often accompanied by severe physical impairments caused by, for example, dyspnea (shortness of breath), fatigue, cough, wheezing, chest tightness or congestion, and lung symptoms of sputum. Many patients with respiratory diseases complain that these symptoms seriously affect their sleep quality.

In COPD patients, sleep-related symptoms are the most frequently reported symptoms in the third place following dyspnea and fatigue (Kinsman et al, Chest, 1983, 83, 755-761). In asthma, 80% of patients wake up at least occasionally because of nighttime wheezing and coughing, and many patients with severe persistent asthma actually wake up every night (Turner-Warwick, M.; Am. J. Med., 1988, 85 (suppl. 1B), 6-8).

Sleep symptoms often reported by patients with respiratory diseases are, for example, long waiting time to fall asleep, difficulty in staying asleep, frequent wakefulness and wakefulness, shallow sleep, shortened total sleep time, waking up too early and no longer falling asleep, universal Insomnia and (in general) very poor sleep quality. Extreme daytime sleepiness caused by morning dyspnea and limited body vitality during the day are also common results of decreased sleep quality.

These sleep disorders are more severe as the disease progresses and can seriously degrade the quality of life of patients with respiratory diseases.

Bronchodilators (eg, beta -adrenergic agonists or cholinergic muscarinic receptor antagonists (commonly known as anticholinergics or antimuscarinic agents) are usually prescribed by doctors to suffer from, for example, asthma and Patients with obstructive airway disease of COPD are used for inhalation. All commercially available anticholinergic agents are currently synthetic paraffin derivatives, including ipratropium, oxitropium and tiotropium. Tiotropium is the only long-acting anticholinergic agent on the market.

It is well known that circadian rhythms have far more impact on airway responsiveness and airway resistance in patients with respiratory diseases than on normal subjects. Therefore, patients with respiratory diseases are more prone to bronchoconstriction at night and in the morning, which is a major factor affecting their sleep quality. Therefore, there is a great need for treatment aimed at overcoming or preventing the occurrence of bronchoconstriction at night. However, a study by Calverley et al., Thorax 2003, 58 (10), 855-860, showed that administration of the long-acting bronchodilator tiotropium at night did not result in more production at night than in the morning alone. Bronchiectasis effect.

The present inventors have now unexpectedly discovered that adiponium can significantly reduce the occurrence of sleep disorders common in patients with respiratory diseases, thereby improving sleep quality and overall quality of life.

Adipine is (3R)-(2-hydroxy-2,2-dithiophen-2-ylethoxycarbonyl)-1-(3-phenoxypropyl)-1-azaindole bicyclo[2.2.2 Octane, a long-acting muscarinic receptor antagonist developed by Almirall, is administered by inhalation in the treatment of respiratory diseases, especially asthma and COPD. It was first disclosed in WO 01/04118.

Adipine is rapidly hydrolyzed into two inactive metabolites in human plasma, so it is less likely to cause systemic side effects than other inhaled anticholinergic agents currently on the market, and has more Wide security boundary. Its additional effect of improving sleep quality is an unexpected finding of the present invention.

The present invention provides a mixture of adipic ammonium or a stereoisomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, for improving the sleep quality of a patient suffering from respiratory diseases.

Preferably, the aclidinium is the anion X ^- in the form of the salts formed. Most preferably, the anion X ^- is bromine.

In a preferred embodiment, the respiratory disease patient has a disease selected from the group consisting of acute or chronic bronchitis, emphysema, asthma, and chronic obstructive pulmonary disease; preferably asthma and chronic obstructive pulmonary disease, most Good chronic obstructive pulmonary disease.

In another embodiment, the adipine is administered as a pharmaceutical composition suitable for inhalation, preferably in the form of a dry powder. This composition can be administered by any inhalation device, preferably by Genuair®.

Dry powder formulations generally comprise a pharmaceutically acceptable carrier selected from the group consisting of monosaccharides, disaccharides, polysaccharides and sugar alcohols, preferably in the form of lactose.

At least one dose of adiponium is administered daily, preferably in the morning or at night. More preferably, the adiponium is administered twice a day. In a preferred embodiment, the dose of adipine is administered twice a day, once in the morning and another in the evening.

The effective dose of adiponium used per inhalation is equivalent to a metered nominal dose of 100 to 1000 micrograms, more preferably 200 or 400 micrograms, of dry powder of adiponium bromide in the dry powder for inhalation.

In another preferred embodiment, adiponium is co-administered with another drug suitable for treating respiratory diseases selected from the group consisting of corticosteroids, beta-adrenergic agonists, PDE4 inhibitors, anti-groups Amine, an anti-IgE antibody, a leukotriene D4 inhibitor, an egfr kinase inhibitor, a p38 kinase inhibitor, and/or an NK1-receptor antagonist. The additional drug and adiponium may be present in the same pharmaceutical composition or in different pharmaceutical compositions. Preferably, the additional drug is selected from the group consisting of a corticosteroid, a beta-adrenergic agonist and/or a PDE4 inhibitor.

The improvement in sleep quality of patients with respiratory disease by adiponectin can be measured by observing a decrease in one or more of the following factors and/or by an increase in overall sleep time: a) waiting time before going to sleep; b) total number of awakenings; c) early awakening; d) difficulty in maintaining sleep; e) light sleep; f) insomnia; g) daytime sleepiness or fatigue; h) limited vitality at morning.

Among the clinical factors that may promote adenosine to improve the sleep quality of patients with respiratory diseases, mainly the reduction of one or several respiratory symptoms in the following sleep processes: a) the severity and/or frequency of cough; b) oysters; c) wheezing; d) chest tightness; e) chest congestion; f) bronchoconstriction; g) shortness of breath; h) need for rescue medication; the present invention also provides a method for improving sleep quality in patients with respiratory diseases A pharmaceutical composition comprising adiponium.

The invention also provides the use of adiponium for the preparation of a medicament for improving the sleep quality of a patient suffering from respiratory diseases.

The present invention also provides a method for improving sleep quality in a respiratory disease patient, the method comprising administering the patient an effective amount as described above Adipine.

detailed description

Aclidinium generally with an anion X ^- in the form of a salt formed is hurl, wherein X ^- represents a monovalent or multivalent pharmaceutically acceptable acid anion. More commonly, X ^- anions are anions derived from inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, such as methanesulfonic acid, acetic acid, fumaric acid , succinic acid, lactic acid, citric acid or maleic acid. Most preferably, adiponium is in the form of adiponium bromide.

The compounds of the invention may exist in unsolvated or solvated forms. The term "solvate" as used herein is used to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. When the solvent is water, the term "hydrate" is used. Examples of solvate forms include, but are not limited to, associated with water, acetone, dichloromethane, isopropanol, ethanol, methanol, dimethylarsine (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. A compound of the invention. It is especially contemplated in the present invention that a solvent molecule can be associated with a molecule of a compound of the invention, such as a hydrate.

The term "treating" or "treating" is understood to include alleviating the symptoms of a disease or condition, and/or eliminating the cause of the disease or condition, and/or preventing the occurrence of the disease or its symptoms.

The term "therapeutically effective amount" refers to a dose sufficient to achieve a therapeutic effect when administered to a patient in need of treatment.

Adiponium can also be used in combination with other drugs known to be effective in the treatment of the above mentioned diseases and conditions. For example, adipine can be combined with corticosteroids or glucocorticoids, beta-adrenergic agonists, PDE4 inhibitors, antihistamines, anti-IgE antibodies, leukotriene D4 antagonists, egfr kinase inhibitors, p38 kinase inhibition The agent and/or NK-1 receptor agonist binds.

Corticosteroids which may be combined with adipine in the present invention specifically include those suitable for administration by inhalation in the treatment of respiratory diseases or conditions, for example, prednisolone, methylprednisolone, Dexamethasone, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrogenation Hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, soft fat Dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halogen Halometasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, method Prednisolone farnesylate, ciclesonide (ciclesonide), deprodone propionate, fluticasone propionate, halobetasol propionate, loteprednol etabonate, culture He betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-pentanoic acid Betamethasone 17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, hydrogen Prednisolone sodium phosphate and hydrocortisone probutate. Particularly preferred are budesonide and mometasone.

May be combined with aclidinium in the present invention, in particular β- adrenergic agonists useful for treating respiratory diseases comprising disorder or β 2- adrenergic agonists, for example selected in free or pharmaceutically acceptable salt forms of A Arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol , dopexamine, phenofol, fenoterol, formoterol, hexoprenaline, ibuterol, isopropyl Isoprenaline, mabuterol, meludrine, nolomirole, orciprenaline, pirbuterol, procaterol (procaterol), reproterol, ritodrine, rimoterol, salbutamol, salmeterol, sibenadet, nail Sulfontergine, sulfonterol, terbutal Ine), tulobuterol, vilanterol, olodaterol, KUL-1248, LAS-100977, carmoterol, and indacaterol . The β2 -adrenergic agonist is preferably a long-acting β2 -adrenergic agonist, for example, formoterol, salmeterol, carmoterol, vitamins selected from the group consisting of free or pharmaceutically acceptable salts Lantro, Odattro, LAS-100977 and Trentaro.

PDE4 inhibitors that can be used in combination with the adipine of the present invention include: denbufylline, rolipram, cipamfylline, arofylline, non-Ministine Filaminast, piclamilast, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilostatin (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-pyridyl Pyridyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoethylamine, 9-(2-fluorobenzyl)-N6 -Methyl-2-(trifluoromethyl)adenine, N-(3,5-dichloro-4-pyridyl)-8-methoxyquinolin-5-carboxamide, N-[9- Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrole[3,2,1-jk][1,4]benzodiazepine-3(R)- Pyridine-4-carboxamide, 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-indole hydrochloride Salt, 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridine-2(1H)-one , 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)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), PCT Patent Application Compounds of the patents of WO 03/097613 and PCT/EP03/14722 and the Spanish patent application P200302613.

The adiponium used in the present invention can be administered by any suitable route to provide a local antimuscarinic effect. It is preferably administered by inhalation, for example, as a powder, spray or aerosol, preferably as a dry powder. Pharmaceutical compositions containing adiponium can be prepared using conventional diluents or excipients known in the art of galenic art.

A drug for administration by inhalation in the form of a dry powder needs to have a controlled particle size. The particle size which is inhaled into the bronchial system is usually 1-10 μm, preferably 2-5 μm. Particles with a particle size of more than 20 μm are usually too large to be inhaled to reach a small airway. In order to achieve these particle sizes, the particle size of the active ingredient particles produced can be reduced by conventional methods, such as by micronization or supercritical fluid techniques. The required fraction can be selected by wind or The wind screen is used to separate. The particles are preferably crystalline.

It is difficult to obtain high dose reproducibility with micronized powders because of their poor fluidity and their tendency to coalesce. In order to improve the efficacy of the dry powder composition, these particles should be relatively large in the inhaler and relatively small when entering the respiratory tract. Thus, excipients such as monosaccharides, disaccharides, polysaccharides or sugar alcohols such as lactose, mannitol or glucose are generally employed. The particle size of the excipients is generally much greater than the inhaled medicament of the present invention. When the excipient is lactose, it is generally present in the form of lactose granules, preferably crystalline alpha-lactose monohydrate, such as crystalline alpha-lactose having an average particle size of from 20 to 1000 μm, preferably from 90 to 150 μm. Monohydrate. In one embodiment, the lactose particles used in the formulations of the invention have a d10 of from 90 to 160 μm, a d50 of from 170 to 270 μm and a d90 of from 290 to 400 μm.

Lactose materials suitable for use in the present invention are commercially available, for example, from MW Internacional (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).

The weight ratio of lactose particles to adiponium depends on the inhalation device used, but is generally, for example, from 5:1 to 200:1, such as from 50:1 to 150:1, such as from 60 to 70:1.

In a preferred embodiment, the adenosine is administered in the form of a dry powder formulation of adiponium bromide suitable for administration by a dry powder inhaler, wherein the weight ratio of adiponium to lactose is one. : 50 to 1:150, wherein the average particle size of the adipine particles is 2-5 μm in diameter, for example, the diameter is less than 3 Mm, while the lactose particles have a d10 of 90-160 μm, a d50 of 170-270 μm and a d90 of 290-400 μm.

Dry powder compositions for local delivery to the lung by inhalation may be present in capsules and cartridges such as gelatin or blister (e.g., aluminum foil sheets) for use in an inhaler or insufflator. Each capsule or cartridge may generally contain from 0.001 to 50 mg, more preferably from 0.01 to 5 mg, of the active ingredient or an equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient may also be in the form of no excipients.

The package of the formulation may be suitable for unit or multi-dose delivery. In the case of multiple dose delivery, the formulation can be metered in by the expected amount or at the time of use. Dry powder inhalers are therefore divided into three types of equipment: (a) single dose; (b) multiple unit doses; (c) multiple doses.

Adipic is preferably administered by a multi-dose inhaler, more preferably with Genuair® (formerly Novolizer SD2FL), which is described in the following patent applications: WO 97/000703, WO 03/000325 and WO 2006/008027.

The dosage will vary with the individual, the mode of administration and frequency, and the nature and severity of the condition being treated. The daily dose for a 70 kg adult can generally be, for example, the order of 100-1000 micrograms of active agent in dry powder form for inhalation.

Example 1

In a randomized, double-blind, crossover trial of stage IIa, patients with moderate to severe COPD received 400 micrograms of adiponectin twice a day (9 am) A total of 15 days with 9:00 pm or placebo and a 9 to 15 day washout between treatment sessions.

Sleep quality is assessed according to the daily record of the patient's diary card using 0 to 4 points according to the following criteria:

The quality of sleep in patients treated with adiponium was significantly improved compared to untreated patients.

Example 2

In a double-blind, randomized, and placebo-controlled phase III trial, sleep quality and use of first aid medications were assessed during twice-daily treatment with adiponium bromide in patients with COPD.

Patients with FEV1/FVC <70% of COPD were randomized (1:1:1) to receive 200 micrograms of adipine, 400 micrograms of adipine or placebo. Sleep quality was reported daily using an electronic journal and questionnaire, which assessed the frequency and severity of symptoms and their impact on morning vitality. The use of emergency medicines was also evaluated.

At week 12, adipic significantly improved sleep quality compared to placebo. 200 micrograms and 400 micrograms of adiponium significantly reduce the severity of nighttime shortness of breath and cough, as well as the frequency of wake up at night and difficulty falling asleep degree. In addition, the production of sputum and the use of emergency medicines are also reduced.

The two doses of adipine dose also significantly reduced the severity of morning shortness of breath, as well as the effects of shortness of breath and cough on morning vitality.

Example 3

In a randomized, double-blind, double-dummy, crossover trial of stage IIa, patients with moderate to severe COPD received inhaled adiponectin 400 μg BID, tiotropium 18 μg QD, and placebo for 15 days. There is a 9 to 15 day wash period between the periods.

The incidence of sleep difficulties was recorded daily on the patient log card. As described in Example 1, the score ranged from 0 points representing no sleep difficulties to 1-4 points representing a progressive increase in sleep difficulty. The change in score relative to the background value produced by each treatment was then measured.

The mean score (+/- SEM) of patients treated with tiotropium was -0.011 (0.091), which was actually the same as the background value, and the score observed in patients treated with placebo was 0.061 (0.088). )very close. There was no statistically significant difference between the two component values (p>0.05). In contrast, patients treated with adipine had a score of -0.123 (0.089). In this case, there was a statistically significant difference (p < 0.05) compared to placebo.

These Phase IIa results demonstrated that no significant improvement in sleep quality similar to that of adiponium was observed when patients were treated with the current reference anticholinergic drug, tiotropium. Therefore, this unexpected effect of adipine is not obvious and progressive.

Claims (14)

A mixture of adipic ammonium or any of its stereoisomers or stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, can be used to improve the quality of sleep in patients with respiratory diseases. Adipine, as in claim 1, wherein the adiponium is in the form of adiponium bromide. The adipine of claim 1 or 2, wherein the respiratory disease patient has asthma or chronic obstructive pulmonary disease (COPD). Adipine, as claimed in claim 1 or 2, wherein the adiponium is in the form of a dry powder formulation suitable for inhalation. Adipine, as claimed in claim 4, which can be used in a dry powder formulation which provides an equivalent of from 100 to 1000 micrograms of adiponium bromide, preferably from 200 to 400 micrograms of adiponium bromide per inhalation. The nominal dose of adipic ammonium. Adipine, as claimed in claim 1 or 2, wherein the adiponium can be administered once or more times a day, preferably twice a day. Adipine, as claimed in claim 1 or 2, wherein adipine is co-administered with a therapeutically effective amount of a corticosteroid, a beta -adrenergic agonist and/or a PDE4 inhibitor. Adipine, as claimed in claim 1 or 2, wherein sleep quality is improved by reducing one or more of the following factors and/or by increasing overall sleep time: a) waiting time before going to sleep, b) total arousal times, c) wake up early, d) difficulty maintaining sleep, e) light sleep, f) insomnia, g) sleepiness or fatigue during the day, and h) limited vitality in the morning. A pharmaceutical composition comprising adipine, as defined in any one of claims 1 to 7, which can be used for improving sleep of a respiratory disease patient as defined in any one of claims 1 to 7. quality. A use of adiponium as defined in claim 1 or 2 for the preparation of a medicament for improving the sleep quality of a respiratory disease patient as defined in any one of claims 1 to 9. Adipine, as defined in claim 1 or 2, can be used to treat respiratory diseases in patients with poor sleep, preferably asthma or chronic obstructive pulmonary disease. For example, the adipine solution of claim 11 wherein the poor sleep comprises one or more of the following: a) delay in falling asleep, b) awakening one or more times at night, preferably 2 or more times, more preferably 3 times. Or more often, c) wake up early, d) difficulty maintaining sleep, e) light sleep, f) insomnia, g) sleepiness or fatigue during the day, and h) limited vitality in the morning. A use of adiponium as defined in claim 1 or 2 in the preparation of a medicament for the treatment of a respiratory disease in a patient with poor sleep, preferably a respiratory or chronic obstructive pulmonary disease. The use of the scope of claim 13 wherein the poor sleep comprises one or more of the following: a) delay in falling asleep, b) awakening one or more times at night, preferably 2 or more times, more preferably 3 times or more. Many times, c) wake up early, d) difficulty maintaining sleep, e) light sleep, f) insomnia, g) sleepiness or fatigue during the day, and h) limited vitality in the morning.