Encephaline (RPL-554) for increasing valley value lung function

Abstract

The present invention relates to a compound for use in a method of increasing valley value lung function in a patient suffering from chronic obstructive pulmonary disease (COPD), wherein the compound is empestine or a pharmaceutically acceptable salt thereof. The present invention also relates to a compound for use in the treatment of chronic obstructive pulmonary disease (COPD) in a patient, wherein the compound is ensefen or a pharmaceutically acceptable salt thereof; and the patient is susceptible to disturbed sleep.

Description

Field of the Invention

[0001] The present invention relates to increasing trough lung function in patients suffering from chronic obstructive pulmonary disease (COPD). The present invention also relates to treating COPD in patients susceptible to disturbed sleep. Background of the Invention

[0003] Ensefentin (N-(2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl}ethyl)urea; also known as RPL554) is a dual PDE3 / PDE4 inhibitor and is described in WO00 / 58308A1.

[0004] As a combined PDE3 / PDE4 inhibitor, Enseifentin has bronchodilatory and anti-inflammatory activities and is useful for treating respiratory diseases including chronic obstructive pulmonary disease (COPD). The chemical structure of Enseifentin is shown below.

[0005]

[0006] COPD is a progressive, long-term condition that affects a large number of people worldwide. Persistent symptoms include dyspnea and cough. Treatment of COPD typically includes maintenance therapy, in which medication is given to the patient regularly (e.g., once or twice daily) to improve lung function and improve the symptoms of COPD.

[0007] Lung function in COPD patients is often followed for a period during maintenance therapy. Lung function in COPD can be measured by determining the patient's forced expiratory volume in one second (FEV 1 ) is measured. Over the time after dosing, lung function improves, reaching a peak improvement some time after dosing. The patient's lung function then decreases toward trough lung function: the lowest point in the lung function cycle during maintenance therapy. Trough lung function usually occurs shortly before the next dose of maintenance therapy medication. For example, for twice-daily (morning and evening) maintenance therapy, trough lung function usually occurs immediately before the morning dose (morning trough lung function) and the evening dose (evening trough lung function).

[0008] The trough lung function achieved during maintenance therapy can have a significant impact on the symptoms and / or quality of life of COPD patients. In a stage during maintenance therapy, trough lung function effectively represents the worst lung function. For twice daily administration, morning trough lung function is usually consistent with a period of time when the patient is asleep. This means that the patient can have poor lung function at part of the night, disrupting his or her sleep (e.g., due to limited oxygen being absorbed) and causing fatigue, thereby reducing the quality of life. This is especially true in COPD patients with disturbed sleep, such as caused by sleep disorders and comorbidities that disrupt sleep.

[0009] If lung function can be improved, COPD symptoms and quality of life may be improved more consistently. Improvements in morning trough lung function would be particularly beneficial for those patients who are already susceptible to sleep disruption.

[0010] Many drugs for treating COPD are disclosed. However, they are not all equally effective in improving trough lung function, particularly morning trough lung function. It is clinically advantageous to administer a specific drug that is particularly effective in improving trough lung function to a patient with a specific treatment need in order to optimize the therapeutic effect of the pharmacological intervention. SUMMARY OF THE INVENTION

[0012] The present invention has found that when used as a maintenance therapy, Ensephanin is particularly effective in increasing trough lung function in COPD patients. In particular, Ensephanin can improve morning trough lung function in COPD patients, which is particularly beneficial for COPD patients who are prone to sleep disorders, such as due to comorbidities that affect sleep.

[0013] Accordingly, the present invention provides a compound for use in a method of increasing trough lung function in a patient suffering from chronic obstructive pulmonary disease (COPD), wherein the compound is encefantine or a pharmaceutically acceptable salt thereof.

[0014] The present invention also provides a compound for use in treating chronic obstructive pulmonary disease (COPD) in a patient, wherein the compound is ensephantine or a pharmaceutically acceptable salt thereof; the patient is susceptible to disturbed sleep.

[0015] The present invention also provides a method for increasing trough lung function in a patient suffering from COPD, the method comprising administering to the patient a therapeutically effective amount of a compound which is encefantine or a pharmaceutically acceptable salt thereof.

[0016] The present invention also provides a method for treating COPD in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound, which is encefantine or a pharmaceutically acceptable salt thereof, wherein the patient is susceptible to disturbed sleep.

[0017] The present invention also provides the use of a compound in the preparation of a medicament for use in a method for increasing trough lung function in a patient suffering from COPD, wherein the compound is encefantine or a pharmaceutically acceptable salt thereof.

[0018] The present invention also provides the use of a compound in the preparation of a medicament for treating COPD, wherein the compound is encefantine or a pharmaceutically acceptable salt thereof, wherein the patient is susceptible to disturbed sleep.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The 12-hour FEV at week 12 is shown. 1 curve. DETAILED DESCRIPTION OF THE INVENTION

[0022] Patients typically receive the compound as a maintenance therapy. The compound may be administered to patients once, twice, or three times daily. Preferably, the compound is administered as a twice daily maintenance therapy.

[0023] In patients with COPD, increases in trough lung function are usually measured by trough FEV1. 1 The increase in FEV in the patient shortly before the compound was given as part of maintenance therapy was determined. 1 For example, an improvement in trough lung function may result from a change in maintenance therapy medication.

[0024] The method may include increasing morning trough lung function (i.e., trough lung function after sleep). Morning trough lung function can be measured by measuring the patient's FEV shortly before administration of the compound in the morning as part of maintenance therapy. 1 For example, FEV 1 The measurement can be made less than 1 hour before morning administration of the compound. Morning trough FEV 1 May be FEV1 measured 11.5 to 12 hours after the previous evening dose 1 .

[0025] Generally, the FEV1 used in this article is 1 Spirometry and FVC were measured as described in Standardisation of Spirometry Eur J 2005; 26; 319-338.

[0026] Improving trough lung function in COPD patients can improve sleep. This is particularly important in patients who are prone to disturbed sleep. Patients who are prone to disturbed sleep often suffer from conditions that directly affect their ability to sleep (such as insomnia or sleep apnea), or from conditions that indirectly make it more difficult to sleep (such as skin conditions such as psoriasis that irritate the skin and make it more difficult for patients to fall asleep or stay asleep).

[0027] A "patient susceptible to disturbed sleep" is typically a patient suffering from one or more diseases or conditions selected from obesity, insomnia, sleep apnea, narcolepsy, restless legs syndrome, REM sleep behavior disorder, circadian rhythm dyssomnia, parasomnia, depression, anxiety, psoriasis, dermatitis, eczema, or urticaria. For example, the compound can be used to treat COPD in a patient suffering from COPD and sleep apnea. The compound can be used to treat COPD in a patient suffering from COPD and a skin disease such as psoriasis, dermatitis, eczema, or urticaria.

[0028] Improved trough lung function can significantly help COPD patients exercise.Thus, in a preferred embodiment, the patient suffers from obesity.

[0029] The patient may be male. The patient may be female. The patient may be greater than or equal to 65 years of age. The patient may be less than 65 years of age. The patient may be taking background medication selected from one or more of a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), and an inhaled corticosteroid (ICS).

[0030] The compound is Ensefentin or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are well known to those skilled in the art. Typically, the compound is Ensefentin (i.e., Ensefentin free base).

[0031] The method generally comprises administering the compound to the patient by inhalation. Pharmaceutical compositions comprising the compound and one or more pharmaceutically acceptable excipients or diluents are generally administered to the patient by inhalation, such as by a nebulizer, a pressurized metered dose inhaler (pMDI) or a dry powder inhaler (DPI).

[0032] Preferably, the method comprises administering the compound to the patient by inhalation from a nebulizer. A nebulizer aerosolizes a liquid pharmaceutical composition into an aerosol which is inhaled into the respiratory tract of the patient. Examples of nebulizers include soft mist nebulizers, vibrating mesh nebulizers, jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include the Philips I-neb TM (Philips)、Philips SideStream(Philips)、 (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERxR TM Pulmonary delivery system (Aradigm Corp) and Pari LCPlus reusable nebulizer (Pari GmbH). The nebulizer can be, for example, a PARI PRO Aerosol Delivery System PARI PARI LC Sprint Jet Nebulizer with Compressor. The compound can be inhaled via the nebulizer for 1 to 15 minutes.

[0033] Typically, the method includes administering the compound to the patient once, twice or three times a day, for example twice or three times a day. The compound can be administered to the patient once, twice or three times a day by inhalation. Preferably, the method includes administering the compound to the patient by inhalation twice a day. The method may include administering a first dose of the compound in the morning (e.g., within 3 hours after waking up) and administering a second dose of the compound in the evening (e.g., within 3 hours before going to bed). Typically, the morning and evening doses are administered 10 to 14 hours apart, for example, about 12 hours apart.

[0034] The compound can be used in any suitable therapeutically effective amount. Typically, the daily dose of the compound is 0.1 to 20 mg. Typically, the method comprises administering a total daily dose of 0.5 to 10 mg of the compound. Preferably, the total daily dose of the compound (e.g., Ensefentin free base) is 5 to 7 mg, such as about 6 mg / day. As used herein, the term "about" may represent a variation of ±10% of the value. The total daily dose of the compound may be 6.0 mg.

[0035] Typically, the compound is administered twice a day in two separate doses that are identical or similar. For example, the method may include administering the compound to a patient twice a day in a first dose of 1 to 5 mg and a second dose of 1 to 5 mg. Typically, the method may include administering the compound to a patient twice a day in a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

[0036] Preferably, the method comprises administering two doses of about 3 mg of Ensefentin free base to the patient daily by inhalation. The method preferably comprises administering to the patient about 3 mg doses of the compound twice daily (3 mg BID) by inhalation. More preferably, the method comprises administering to the patient about 3 mg doses of the compound twice a day by nebulizer. Each dose may be 3.0 mg of free base Ensefentin administered by nebulizer.

[0037] The compound is generally used as a maintenance therapy. Typically, the method comprises administering the compound to the patient at least once a day for at least 8 weeks. The compound may be administered to the patient at least once a day for at least 16 weeks, preferably at least 24 weeks. The compound may be administered to the patient daily for at least 1 year. The method may comprise administering the compound to the patient at least once every 24 hours, preferably at least twice every 24 hours for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

[0038] The compound is preferably administered as a suspension formulation, ie, a suspension of particles containing the compound in a diluent. Alternatively, the compound may be delivered in the form of a dry powder, for example a dry powder comprising particles containing the compound and carrier particles such as lactose.

[0039] The method generally comprises administering an inhalable pharmaceutical composition comprising a suspension of particles of the compound in a diluent. The particles comprising the compound generally have a particle size distribution of Dv50 of 0.5 μm to 5.0 μm. The particles preferably have a Dv50 of 1.0 μm to 2.0 μm.

[0040] Particle size is described herein by reference to the Dv50 value, which is the median particle size of the volume distribution. Thus, half the volume of particles has a diameter less than the Dv50 value, and half the volume of particles has a diameter greater than the Dv50 value. This is a well-known way of describing particle size distribution.

[0041] The technique used to measure the Dv50 value as described herein is generally laser diffraction. The particle size distribution of particles comprising the compound can be measured by laser diffraction using a wet powder dispersion system. For example, the particle size distribution can be measured using the laser diffraction of a Malvern Spraytec in combination with a wet dispersion cell. Typically, the instrument parameters of the Malvern Spraytec are as follows:

[0042] · Grains – standard opaque granules;

[0043] Refractive index particles -1.50;

[0044] Refractive index (imaginary part) -0.50;

[0045] Particle density - 1.00;

[0046] ●The refractive index of the dispersant is -1.33;

[0047] Controller unit - 1000RPM;

[0048] Measurement type – timing;

[0049] Initial sampling time - 30s;

[0050] · Shading - 20% to 30%;

[0051] Dispersant - 1% polysorbate 20 in deionized water.

[0052] The particles comprising the compound generally comprise ensephentin (i.e., ensephentin free base). The particles comprising the compound may comprise at least 90% by weight of ensephentin free base relative to the total weight of the particles. The particles may comprise at least 99% by weight of ensephentin. The particles may consist of ensephentin.

[0053] The concentration of particles comprising the compound in the inhalable pharmaceutical composition is generally 0.1 to 5.0 mg / mL, preferably 0.1 to 2.5 mg / mL, more preferably 1.0 to 2.0 mg / mL.

[0054] Inhalable pharmaceutical compositions also typically include one or more tonicity adjusters, one or more buffers, and one or more surfactants. The tonicity adjuster is typically sodium chloride.

[0055] Examples of buffers include citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer. Preferably, the buffer is a phosphate buffer, such as sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0056] Examples of surfactants include lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76, and Brij 97), polypropylene glycol (e.g., PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sorbitan alkyl esters (e.g., sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), and sorbitan trioleate (Span 100). 85)), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (poloxamers), block copolymers of polyethylene glycol and polypropylene oxide (e.g. Pluronic surfactants), polyvinyl pyrrolidone K25, polyvinyl alcohol, oligomeric lactic acid, sodium dioctyl sulfosuccinate and polyethoxylated tallow amine (POEA).

[0057] Preferably, the one or more surfactants include polysorbates and / or sorbitan alkyl esters. The one or more surfactants may, for example, include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). The one or more surfactants may, for example, include sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80) or sorbitan trioleate (Span 85). Preferably, the sterile liquid medium includes polysorbate 20 and / or sorbitan monolaurate (Span 20).

[0058] For example, the method may comprise administering to a patient an inhalable liquid pharmaceutical composition comprising:

[0059] ·water;

[0060] particles consisting of encephalin free base at a concentration of 0.1 to 20 mg / mL;

[0061] One or more tonicity adjusting agents at a total concentration of 1.0 to 15 mg / mL;

[0062] One or more buffering agents at a total concentration of 0.1 to 4 mg / mL; and

[0063] • One or more surfactants at a total concentration of 0.05 to 3 mg / mL.

[0064] The inhalable liquid pharmaceutical composition may comprise:

[0065] ·water;

[0066] particles consisting of encephalin free base at a concentration of 0.5 to 6 mg / mL;

[0067] Sodium chloride, at a concentration of 5 to 12 mg / mL;

[0068] Sodium dihydrogen phosphate dihydrate at a concentration of 0.3 to 2 mg / mL;

[0069] Sodium hydrogen phosphate dihydrate at a concentration of 0.3 to 2 mg / mL;

[0070] Polysorbate 20 at a concentration of 0.1 to 1.5 mg / mL; and

[0071] Sorbitan monolaurate at a concentration of 0.01 to 0.5 mg / mL.

[0072] The compound can be used in combination with a second active agent. The compound can be administered separately or simultaneously with the second active agent. The patient may already be taking the second active agent as a background therapy for COPD. Alternatively, treatment with the second active agent can be started at about the same time as treatment with the compound. The compound and the second active agent can be administered in a fixed combination.

[0073] The second active agent is typically a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid. Thus, the compound can be used in combination with a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid. The second active agent can be a long-acting muscarinic receptor antagonist (LAMA) or a long-acting beta-adrenergic receptor agonist (LABA).

[0074] Examples of LAMAs include aclidinium, darolium, tiotropium, glycopyrronium, and umeclidinium. Examples of LABAs include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abetrol, and carmoterol. Examples of inhaled corticosteroids include beclomethasone, budesonide, fluticasone propionate, ciclesonide, mometasone, and fluticasone furoate.

[0075] Patients can take beta-agonists (such as albuterol) as rescue medication.

[0076] The present invention is described in more detail by the following examples. Example

[0077] Study Design

[0078] A clinical study was conducted to determine the efficacy of Ensefentin in the treatment of COPD compared to placebo. Ensefentin was administered twice a day (BID) at a dose of 3 mg via nebulizer for 24 weeks. The study was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial with approximately 800 patients and 5:3 randomization.

[0079] The study population included patients aged 40 to 80 years with moderate to severe COPD (FEV 1 30% to 70% pn, FEV 1 =2.0% of patients (range, 50% to 100% CI, 2.0 to 3.0, and 1.5% to 2.0) were randomized to follow-up. Patients with a 1:1 ratio of 1:1 to 2:1 (f / FVC ratio <0.7, mMRC ≥2). Randomization was stratified by (a) use of stable background maintenance LAMA or LABA therapy (approximately 50%, yes or no) and (b) smoking (current or former). Inhaled corticosteroid (ICS) maintenance therapy was allowed in up to 20% of patients under certain provisions.

[0080] The primary endpoint of the study was mean FEV compared with baseline at week 12. 1 Area under the curve (AUC)0-12h Secondary endpoints of the study included: 4-hour peak FEV1 at week 12 after dosing 1 ; At week 12, morning trough FEV 1 ; and other endpoints, including frequency of moderate / severe COPD exacerbations over 24 weeks.

[0081] method

[0082] COPD severity is determined as follows: Mild: 80% <= FEV 1 Moderate: 50% <= FEV 1 <80% predicted, severe: 30% <= FEV 1 <50% predicted, and very severe: FEV 1 <30% predicted after bronchodilator administration at screening.

[0083] Baseline FEV 1 It is the average of two measurements taken before the first dose of study drug on the day of administration, i.e., ≤40 minutes, and just before dosing on the first day.

[0084] Mean FEV 1 AUC 0-12h Defined as FEV 1 The area under the curve over 12 hours was divided by 12 hours.

[0085] Morning trough FEV at week 12 1 Defined as FEV1 assessed 11.5 to 12 hours after the previous evening dose 1 .

[0086] preparation

[0087] The study product and placebo were provided in 2.5 mL unit dose form in ampoules and administered by nebulizer. The formulations of the study product (Ensefentin suspension formulation) and placebo are shown in Table 1 below.

[0088] composition Concentration (mg / mL) Ensefentin Granules (RPL554) 1.2 (for active substance) or 0 (for placebo) Polysorbate 20 (Tween 20) 0.50 Sorbitan monolaurate (span20) 0.05 Sodium dihydrogen phosphate dihydrate 0.744 Disodium hydrogen phosphate dihydrate 0.853 Sodium chloride solution 8.60 water Appropriate amount to 1mL

[0089] Table 1

[0090] result

[0091] Achieve mean FEV at week 12 1 (AUC) 0-12h All subgroups showed an improvement in lung function with ensefentin, which was statistically significant. The results are shown in Table 2.

[0092]

[0093] Table 2

[0094] At week 12, encefantine had no effect on morning trough FEV1. 1 The effects of are shown in Table 3.

[0095]

[0096] Table 3

[0097] Morning trough FEV 1 A statistically significant effect was demonstrated at week 12, confirming the twice-daily dosing interval.

[0098] in conclusion

[0099] It has been found that ensephantine provides statistically significant improvements in lung function in all subgroups of COPD patients in the study. In addition, ensephantine has been found to be particularly effective in improving trough lung function, particularly by increasing morning trough FEV 1 .

Claims

1. A compound for use in a method of increasing trough lung function in a patient suffering from chronic obstructive pulmonary disease (COPD), wherein the compound is ensefentin or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is administered as maintenance therapy.

3. The compound of claim 1 or 2, wherein the compound is administered twice daily as maintenance therapy.

4. A compound as claimed in any preceding claim, wherein the method comprises increasing morning trough lung function.

5. A compound for use in treating chronic obstructive pulmonary disease (COPD) in a patient, wherein: The compound is Ensefentin or a pharmaceutically acceptable salt thereof; as well as The patient is susceptible to disturbed sleep.

6. A compound as claimed in any preceding claim, wherein the patient is a patient susceptible to disturbed sleep, and the patient suffering from disturbed sleep suffers from one or more diseases or conditions selected from insomnia, sleep apnea, narcolepsy, restless legs syndrome, REM sleep behaviour disorder, circadian rhythm dyssomnia, parasomnia, depression, anxiety, psoriasis, dermatitis, eczema or urticaria.

7. A compound as claimed in any preceding claim, wherein the method comprises administering the compound to the patient by inhalation.

8. A compound as claimed in any preceding claim, wherein the method comprises administering the compound to the patient by inhalation via a nebuliser.

9. A compound as claimed in any preceding claim, wherein the compound is encefantine.

10. The compound of any preceding claim, wherein the method comprises administering the compound to the patient once, twice or three times per day.

11. The compound of any preceding claim, wherein the method comprises administering the compound to the patient twice a day.

12. A compound as claimed in any preceding claim, wherein the method comprises administering a total daily dose of 0.5 to 10 mg, preferably 5 to 7 mg, of the compound.

13. The compound of any preceding claim, wherein the method comprises administering the compound to the patient twice a day at a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

14. The compound according to any of the preceding claims, wherein the method comprises administering to the patient a dose of about 3 mg of the compound twice a day (3 mg BID), preferably wherein the method comprises administering to the patient a dose of about 3 mg of the compound twice a day via a nebulizer.

15. The compound according to any preceding claim, wherein the method comprises administering the compound at least once per 24 hours, preferably at least twice per 24 hours for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

16. A compound as claimed in any preceding claim, wherein the method comprises administering an inhalable pharmaceutical composition comprising a suspension of particles of the compound in a diluent.

17. A compound according to any preceding claim, wherein the compound is used in combination with a muscarinic receptor antagonist, a beta-adrenergic receptor agonist or an inhaled corticosteroid.

18. A method of increasing trough lung function in a patient suffering from COPD, said method comprising administering to said patient a therapeutically effective amount of a compound which is encefantine or a pharmaceutically acceptable salt thereof.

19. A method of treating COPD in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound which is encefantine or a pharmaceutically acceptable salt thereof, wherein the patient is susceptible to disturbed sleep.

20. Use of a compound in the manufacture of a medicament for use in a method of increasing trough lung function in a patient suffering from COPD, wherein the compound is encefantine or a pharmaceutically acceptable salt thereof.

21. Use of a compound, which is ensefentin or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating COPD, wherein the patient is susceptible to disturbed sleep.

22. A suspension preparation having the following composition: 。

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