JPWO2020115032A5

JPWO2020115032A5 -

Info

Publication number: JPWO2020115032A5
Application number: JP2021531031A
Authority: JP
Publication date: 2022-11-21
Anticipated expiration: 2039-12-03

Claims

1. A pharmaceutical composition comprising cyclosporin A in liposomal solubilized form (L-CsA) for use in the prevention or treatment of a pulmonary disease or condition in a subject, comprising:
wherein said pharmaceutical composition is administered to said subject by inhalation in the form of an aerosol, and
wherein said aerosol is produced by nebulizing said pharmaceutical composition using a nebulizer (100), said nebulizer comprising:
(a) an aerosol generator (101),
- a fluid reservoir for holding an interface configured to connect said pharmaceutical composition or fluid reservoir (103);
- A vibratable membrane (110) having a plurality of openings, said openings being aerodynamic up to about 4.0 μm as measured with a 0.9% (w/v) aqueous solution of sodium chloride an aerosol generator comprising a vibratable membrane suitable for producing an aerosol comprising droplets of mass median aerodynamic diameter (MMAD);
(b) a chamber (105) for temporarily containing said aerosol generated by said aerosol generator (101), said chamber having an internal lumen with a volume in the range of about 50 to about 150 ml; a chamber; and
(c) a mouthpiece (40) for delivering said aerosol supplied from said nebulizer (100) to said subject, said mouthpiece having an exhalation filter (30);
The mouthpiece (40) is
a body (46) defining a fluid path (47) from an inlet (41) connectable to the nebulizer (100) to an inlet opening (42) received in the user's mouth;
a filter base (31) in fluid communication with said fluid path (47); a filter top (33) detachably connected to said filter base (31); and said filter base (31) and said filter top (33). An exhalation filter (30) having a filter material (32) disposed between, wherein said filter top (33) is in contact with said fluid path ( an exhalation filter having an exhalation opening (36) cooperating with a one-way valve (39) to allow the evacuation of fluid from 47) through the filter material (32) and out of the mouthpiece (40); including
A pharmaceutical composition wherein said body (46) and said filter base (31) are an integral unit.

wherein said pulmonary disease or condition is asthma, refractory asthma, chronic obstructive bronchitis, parenchymal fibrotic and interstitial lung disease and pulmonary inflammation, bronchiolitis obliterans (BOS), and The pharmaceutical composition for use according to claim 1, selected from the group consisting of acute and chronic organ transplant rejection after lung transplantation and said diseases resulting therefrom.

3. The pulmonary disease or condition according to any one of claims 1-2, wherein the pulmonary disease or condition is bronchiolitis obliterans (BOS) grade I or above, in particular BOS grade I or II, in particular BOS grade I. Pharmaceutical composition for use.

A pharmaceutical composition for use according to any one of claims 1 to 3, comprising cyclosporin A at a concentration ranging from about 1 mg/mL to about 10 mg/mL.

Use according to any one of claims 1 to 4, wherein the aqueous liquid composition comprises cyclosporin A in liposomal solubilized form (L-CsA) at a concentration ranging from about 3 mg/mL to about 5 mg/mL. A pharmaceutical composition for

A pharmaceutical composition for use according to any one of claims 1 to 5, wherein said composition is a liquid composition comprising an aqueous liquid vehicle.

The use according to any one of claims 1 to 6, wherein said aqueous liquid composition comprising cyclosporin A in liposome-solubilized form is obtained by reconstitution of a lyophilisate comprising cyclosporin A and liposome-forming structures. A pharmaceutical composition for

8. The pharmaceutical composition for use according to claim 7, wherein said liposome-forming structure comprises a bilayer formed of a membrane-forming substance selected from the group of phospholipids.

9. A pharmaceutical composition for use according to claim 8, wherein said membrane-forming substance selected from the group of phospholipids is a mixture of natural phospholipids.

9. The membrane-forming substance selected from the group of phospholipids is a lecithin selected from the group consisting of soybean lecithin, Lipoid S75, Lipoid S100, Phospholipon® G90, 100 or equivalent lecithins, or 10. A pharmaceutical composition for use according to 9.

Pharmaceutical composition for use according to any one of claims 1 to 10, wherein said composition further comprises at least one solubility-enhancing substance selected from the group of non-ionic surfactants.

12. The pharmaceutical composition for use according to claim 11, wherein said at least one nonionic surfactant is selected from the group of polysorbates.

13. A pharmaceutical composition for use according to claim 11 or 12, wherein said solubility-enhancing substance selected from the group of nonionic surfactants is polysorbate 80.

14. Claim 12 or 13, wherein the weight ratio of phospholipid to polysorbate is selected in the range of about 15:1 to about 9:1, preferably in the range of about 14:1 to about 12:1, such as about 13:1. A pharmaceutical composition for use as described in .

A pharmaceutical composition for use according to any one of the preceding claims, wherein said composition comprises at least one disaccharide selected from the group consisting of saccharose, lactose and trehalose, preferably saccharose.

The composition contains at least one disaccharide selected from the group consisting of saccharose, lactose and trehalose, preferably saccharose, in a range of about 5 to about 15 wt%, preferably about A pharmaceutical composition for use according to any one of claims 1 to 15, comprising in the range of 7.5 to about 12.5 wt%.

The pharmaceutical composition for use according to any one of the preceding claims, wherein said vibratable membrane (110) has from about 100 to about 400 openings/mm ² .

Use according to any one of the preceding claims, wherein the plurality of openings of the vibratable membrane (110) has a tapered shape that narrows towards the aerosol emitting side of the vibratable membrane. A pharmaceutical composition for

19. The vibratable membrane of claims 1-18, wherein the opening of the vibratable membrane has an exit diameter in the range of about 1.5 μm to about 3.0 μm as measured by scanning electron microscopy (SEM). A pharmaceutical composition for use according to any one of the claims.

Cyclosporine A in both of said subjects in an amount (delivered dose: DD) of at least 70% of the amount administered to said subject, more specifically in an amount ranging from about 70% to about 80% A pharmaceutical composition for use according to any one of claims 1 to 19, delivered to the lung (or to one of said lungs).

3. Claims wherein cyclosporin A is administered to said subject at a total output rate (TOR) of at least 200 mg/min, more particularly at a total output rate ranging from about 200 to about 250 mg/min. A pharmaceutical composition for use according to any one of claims 1-20.

22. Any one of claims 1-21, wherein the amount of cyclosporin A exhaled by said subject is up to 10%, more particularly about 4% to about 8%, of the total amount of active ingredient administered to said subject. A pharmaceutical composition for use as described in paragraph 1.

A pharmaceutical composition for use according to any one of claims 1 to 22, wherein 1 mL of said pharmaceutical composition comprising cyclosporin A is aerosolized (nebulized) within a period of up to about 5 minutes. .

is a kit,
- a pharmaceutical composition comprising cyclosporin A in liposome-solubilized form for use in said prevention or treatment of a pulmonary disease or condition in a subject;
- a nebulizer (100), said nebulizer comprising:
(a) an aerosol generator (101),
- a fluid reservoir for holding an interface configured to connect said pharmaceutical composition or fluid reservoir (103); and - a vibratable membrane (110) having a plurality of openings, said openings. is suitable for generating an aerosol containing droplets with a mass median aerodynamic diameter (MMAD) of up to about 4.0 μm as measured in a 0.9% (w/v) aqueous solution of sodium chloride , an aerosol generator comprising a vibratable membrane;
(b) a chamber (105) for temporarily containing said aerosol generated by said aerosol generator (101), said chamber having an internal lumen with a volume in the range of about 50 to about 150 ml; a chamber; and
(c) a mouthpiece (40) for delivering said aerosol supplied from said nebulizer (100) to said subject, said mouthpiece comprising an exhalation filter (30); , and
The mouthpiece (40) is
a body (46) defining a fluid path (47) from an inlet (41) connectable to the nebulizer (100) to an inlet opening (42) received in the user's mouth;
a filter base (31) in fluid communication with said fluid path (47); a filter top (33) detachably connected to said filter base (31); and said filter base (31) and said filter top (33). An exhalation filter (30) having a filter material (32) disposed between the filter top (33) and the fluid path (32) during patient exhalation through the inhalation opening. an exhalation filter having an exhalation opening (36) cooperating with a one-way valve (39) to allow the evacuation of fluid from 47) through the filter material (32) and out of the mouthpiece (40); including
A kit wherein said body (46) and said filter base (31) are an integral unit.

said pharmaceutical composition comprising liposome-solubilized form of cyclosporin A for use in said prevention or treatment of a pulmonary disease or condition in a subject, said lyophilisate comprising liposome-solubilized form of cyclosporin A, and a liquid pharmaceutical composition 25. A kit according to claim 24, provided in the form of a sterile liquid aqueous carrier solution for said reconstitution of said lyophilsate to form