JPWO2020123336A5

JPWO2020123336A5 -

Info

Publication number: JPWO2020123336A5
Application number: JP2021533261A
Authority: JP
Publication date: 2022-12-19

Claims

(a) a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable derivative or salt thereof;
(b) a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10; and (c) an aqueous liquid carrier selected from water, isotonic saline, buffered saline and aqueous electrolyte solutions. wherein said bedaquiline or a pharmaceutically acceptable derivative or salt thereof is provided in the form of particles in suspension,
and said particles of bedaquiline, or said pharmaceutically acceptable salt of bedaquiline, have a median size of less than 5 μm and a D90 of less than 6.5 μm,
pharmaceutical composition.

2. The pharmaceutical composition of claim 1, wherein said particles of bedaquiline, or said pharmaceutically acceptable salt thereof, have a median size of less than 2 [mu]m and a D90 of less than 3 [mu]m.

Said nonionic surfactant is polysorbate 20, polysorbate 60, polysorbate 80, stearyl alcohol, a polyethylene glycol derivative of hydrogenated castor oil having a hydrophilic-lipophilic balance value of 14-16, a hydrophilic-hydrophilic of 15-17 Polyethylene glycol derivatives of hydrogenated castor oil with lipophilic balance values, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, polyoxyethylene (20) oleyl ether, polyoxyethylene (20) cetyl ether, polyoxy Ethylene (10) cetyl ether, polyoxyethylene (10) oleyl ether, polyoxyethylene (100) stearyl ether, polyoxyethylene (10) stearyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylene (4) lauryl Ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (2) cetyl ether, caprylocaproyl polyoxyl-8 glyceride, polyethylene glycol monostearate (20), polyethylene glycol stearate (40), polyethylene stearate 2. The pharmaceutical composition of claim 1 , selected from glycol (100), polyethylene glycol (8) stearate, and polyoxyl 40 stearate, and mixtures thereof.

wherein the nonionic surfactant is polysorbate 80, and the aqueous liquid carrier is distilled water, hypertonic saline or isotonic saline;
A pharmaceutical composition according to claim 1 .

5. The pharmaceutical composition of claim 4 , wherein said hypertonic saline is 1%-7% (w/v) sodium chloride.

5. The pharmaceutical composition according to claim 4 , wherein the nonionic surfactant is ultrapure polysorbate 80 and the aqueous liquid carrier is isotonic saline.

The pharmaceutical composition according to claim 1 , wherein the osmolality of said composition is in the range of 200-700 mOsm/kg.

2. The pharmaceutical composition of claim 1, further comprising about 500 mg bedaquiline, about 2.5 ml polysorbate 80, about 450 mg sodium chloride, and about 47.5 ml water;
The composition had an osmolality in the range of 300-400 mOsm/kg, a median bedaquiline particle size of 14.13 μm, and a D90 of 103.0 μm, as measured using a Horiba LA950. 48 μm, the composition.

the concentration of nonionic surfactant is in the range of 0.001% to 5% (v/v) of the total composition; and the amount of bedaquiline is in the range of 0.1% to 20% of the total composition. % (w/v)
A pharmaceutical composition according to claim 1 .

(1) homogenizing a suspension of bedaquiline, said non-ionic surfactant and water to obtain a suspension containing bedaquiline of appropriate particle size;
(2) adjusting the pH of said suspension obtained from (1) to a pH between pH 5.5 and pH 7.5;
(3) adjusting the sodium chloride concentration to a suitable concentration;
(4) adjusting the osmolality to an appropriate level;
2. The pharmaceutical composition of claim 1 , prepared by a method comprising:

11. A pharmaceutical composition prepared by the method of claim 10 , wherein said pH is adjusted to 6.5 and said sodium chloride concentration is adjusted to 154 mM sodium chloride.

11. A pharmaceutical composition prepared by the method of claim 10 , wherein the homogenization in step (1) is performed by high pressure homogenization, high shear homogenization, wet milling, ultrasonic homogenization, or a combination of such processes. .

11. A pharmaceutical composition prepared by the method of claim 10 , wherein homogenization of bedaquiline is performed in multiple homogenization steps.

11. A pharmaceutical composition prepared by the method of claim 10 , wherein the bedaquiline of suitable particle size is particles having an average size of less than 5 [mu]m and a D90 of less than 6.5 [mu]m.

11. The pharmaceutical composition prepared by the method of claim 10 , wherein the bedaquiline of suitable particle size is particles having an average size of less than 2 [mu]m and a D90 of less than 3 [mu]m.

An aerosol for inhalation, prepared by aerosolization of the composition of claim 1 , by a nebulizing device selected from ultrasonic nebulizers, electrospray nebulizers, vibrating membrane nebulizers, jet nebulizers and mechanical soft mist inhalers. A pharmaceutical combination in the form of
A pharmaceutical combination wherein said aerosol particles produced by said nebulization device have a mass median aerodynamic diameter of 1-5 μm.

A system intended for use in displaying antibiotic activity when treating or providing prophylaxis against pulmonary infections caused by mycobacteria or other Gram-positive bacteria, comprising:
1) (a) a therapeutically effective amount of bedaquiline;
(b) a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10; and (c) an aqueous liquid carrier selected from water, isotonic saline, buffered saline and aqueous electrolyte solutions. nebulized pharmaceutical formulations,
and 2) including a nebulizer,
wherein said bedaquiline is present in the form of a suspension,
and the aerosol particles produced by the system have a mass median aerodynamic diameter of 1-5 μm,
system.

A pharmaceutical composition for dry powder inhalation comprising bedaquiline, or a pharmaceutically acceptable salt or derivative thereof, of suitable particle size and a physiologically acceptable pharmacologically inert excipient, or suitable A pharmaceutical composition comprising a mixture of one or more physiologically acceptable and pharmacologically inert excipients of different particle sizes.

A system intended for use in displaying antibiotic activity when treating or providing prophylaxis against pulmonary infections caused by mycobacteria or other Gram-positive bacteria, comprising:
1) (a) a therapeutically effective amount of bedaquiline,
(b) one or more excipients selected from sugars, amino acids, and phospholipids, and combinations thereof;
A dry powder pharmaceutical formulation comprising
2) a container for said formulation selected from a capsule or blister package; and 3) a dry powder inhaler, wherein said bedaquiline is present in the form of a dry powder and said bedaquiline-containing particles are between 1 μm and 5 μm. A system having a mass median diameter of

19. A method of treating or preventing pulmonary infections caused by mycobacteria or other Gram-positive bacteria in a patient in need thereof, the composition of claim 18 comprising less than 100 mg of bedaquiline A method comprising administering the composition by inhalation.

21. The treatment of claim 20 , wherein the infection is caused by a Mycobacterium spp. selected from nontuberculosis mycobacteria and Mycobacterium tuberculosis complexes, and combinations thereof. Or a method of prevention.

The nontuberculosis mycobacterium includes Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscesses, and Mycobacterium abs. leprae ), and combinations thereof.

21. The treatment of claim 20 , wherein said infection is an opportunistic infection selected from MAC lung disease and non-tuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease or acquired immunodeficiency syndrome, or How to prevent.

24. A method of treatment or prevention according to claim 23 , wherein the infection is a non-tuberculous opportunistic mycobacterial infection in a patient with cystic fibrosis.

A method of treating or preventing pulmonary infections caused by mycobacteria or other Gram-positive bacteria in a patient in need thereof comprising clofazimine or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, claris 19. Inhalation of the composition of claim 18 prior to, concurrently with, or after administration of an agent selected from romycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylate, and mixtures thereof. A method comprising the step of administering by

26. A method of treatment or prevention according to claim 25 , wherein the drug is clofazimine or amikacin.

27. A method of treatment or prevention according to claim 26 , wherein the drug is clofazimine.