JPWO2020002351A5

JPWO2020002351A5 -

Info

Publication number: JPWO2020002351A5
Application number: JP2020571770A
Authority: JP
Publication date: 2022-06-28
Anticipated expiration: 2039-06-25

Claims

A pharmaceutical composition comprising an inhalable immunosuppressive macrocyclic active ingredient for use in the prevention or treatment of lung disease or condition in a subject.
The pharmaceutical composition is administered to the subject by inhalation in the form of an aerosol.
The aerosol is produced by spraying the pharmaceutical composition using a nebulizer (100), the nebulizer is:
a) Aerosol generator (101), the following:
-An interface configured to connect a fluid reservoir (103) or fluid reservoir for holding the pharmaceutical composition, and-an oscillating membrane (110) having a plurality of openings, wherein the openings are: Vibrations adapted to produce aerosols containing droplets with aerodynamic median particle size (MMAD) of up to about 4.0 μm when measured in 0.9% (weight / volume) sodium chloride solution. Aerosol generator (101), comprising a possible membrane (110);
b) A chamber (105) for temporarily accommodating the aerosol produced by the aerosol generator (101), having a cavity having a capacity in the range of about 50 to about 150 ml; And c) a mouthpiece (40) for delivering the aerosol supplied by the nebulizer (100) to the subject, comprising a mouthpiece (40) with an exhalation filter (30) ;
A pharmaceutical composition comprising the disaccharide selected from the group consisting of saccharose, lactose and trehalose in the range of about 5 to about 15% by weight based on the total weight of the pharmaceutical composition.

The lung disease or condition is asthma, refractory asthma, chronic obstructive bronchiitis, parenchymal, fibrous and interstitial lung disease and inflammation, obstructive bronchiolitis obliterans (BOS), and acute and post-lung transplantation. The pharmaceutical composition for use according to claim 1, which is selected from the group consisting of a chronic organ transplant rejection reaction and a disease caused therein.

The disease or condition of the lung is optionally obstructive bronchiolitis obliterans (BOS) after acute and chronic organ transplant rejection after lung transplantation or hematopoietic stem cell transplantation (HSCT), claim 1 or 2. Pharmaceutical composition for the described use.

For the use according to any one of claims 1 to 3, wherein the disease or condition of the lung is obstructive bronchiolitis obliterans (BOS) grade I or higher, specifically BOS grade I or II, particularly BOS grade I. Pharmaceutical composition.

The pharmaceutical composition for use according to any one of claims 1 to 4 , wherein the inhalable immunosuppressive active ingredient is cyclosporin A.

The pharmaceutical composition for use according to any one of claims 1 to 5 , wherein the inhalable immunosuppressive active ingredient is present in a liposome solubilized form (L-CsA).

The pharmaceutical composition for use according to any one of claims 1 to 6 , wherein the composition is a liquid composition containing an aqueous liquid vehicle.

The pharmaceutical composition for use according to claim 7, wherein the aqueous liquid vehicle comprises essentially a saline solution, preferably a saline solution having a concentration of 0.25% (weight / volume).

The pharmaceutical composition for use according to any one of claims 1 to 8, comprising said immunosuppressive macrocyclic active ingredient at a concentration in the range of about 1 mg / mL to about 10 mg / mL.

The use according to any one of claims 1 to 9, wherein the liquid aqueous composition comprises cyclosporin A in a liposome solubilized form (L-CsA) at a concentration in the range of about 3 mg / mL to about 5 mg / mL. Pharmaceutical composition.

An aqueous liquid composition comprising the inhalable immunosuppressive macrocyclic active ingredient in a liposome-solubilized form is obtained by reconstitution of a lyophilized product containing the immunosuppressive macrocyclic active ingredient and a liposome-forming structure. The pharmaceutical composition for use according to any one of Items 1 to 10 .

The inhalable immunosuppressive macrocyclic active ingredient, specifically CsA, predominantly (eg, at least about 90%, or even at least about 95% to about 97.5%) the bilayer of the liposome-forming structure. The pharmaceutical composition for use according to claim 11, which is incorporated in a layered membrane.

The pharmaceutical composition for use according to claim 12 , wherein the liposome-forming structure comprises a double membrane formed of a membrane-forming substance selected from the group of phospholipids.

The pharmaceutical composition for use according to claim 13 , wherein the membrane-forming substance selected from the group of phospholipids is a mixture of natural phospholipids.

13 . Pharmaceutical composition for the described use.

The pharmaceutical composition for use according to any one of claims 1 to 15 , wherein the composition further comprises at least one solubility enhancer selected from the group of nonionic surfactants.

The pharmaceutical composition for use according to claim 16 , wherein the at least one nonionic surfactant is selected from the group of polysorbates.

The pharmaceutical composition for use according to claim 16 or 17 , wherein the solubility enhancer selected from the group of nonionic surfactants is polysorbate 80.

17 or 18 , wherein the weight ratio of phospholipid to polysorbate is selected in the range of about 15: 1 to about 9: 1, preferably about 14: 1 to about 12: 1, such as about 13: 1. The pharmaceutical composition for the described use.

The pharmaceutical composition for use according to any one of claims 1 to 19 , wherein the composition comprises saccharose.

The composition comprises at least one disaccharide selected from the group consisting of saccharose, lactose and trehalose, preferably saccharose, from about 7.5% by weight to about 12.5 based on the total weight of the pharmaceutical composition. The pharmaceutical composition for use according to any one of claims 1 to 20 , which comprises a range of weights.

The use according to any of claims 1-21, wherein the composition is in the form of a dispersion having a polydispersity index (PI) of up to about 0.50, as measured by photon correlation spectroscopy. Pharmaceutical composition.

22. The pharmaceutical composition for use according to claim 22, wherein the dispersion comprises liposomes having a z-average diameter in the range of about 40 to about 100 nm, as measured by photon correlation spectroscopy.

The pharmaceutical composition for use according to any one of claims 1 to 23 , wherein the vibrable membrane (110) has about 100 to about 400 openings per mm ² .

Any of claims 1-24 , wherein the vibrable membrane opening has an outlet with a diameter in the range of about 1.5 μm to about 3.0 μm when measured by scanning electron microscopy (SEM). The pharmaceutical composition for the described use.

The amount of the inhalable immunosuppressive macrocyclic active ingredient to be administered to the subject is at least 70% (delivery dose, DD), more specifically in an amount ranging from about 70% to about 80%. The pharmaceutical composition for use according to any one of claims 1 to 25 , which is delivered to the lungs (or lungs) of the subject.

The inhalable immunosuppressive macrocyclic active ingredient is the test at a total excretion rate (TOR) of at least 200 mg / min, more specifically in the range of about 200 mg / min to about 250 mg / min. The pharmaceutical composition for use according to any one of claims 1 to 26 , which is administered to the body.

The amount of the inhalable immunosuppressive macrocyclic active ingredient exhaled by the subject is up to 10%, more specifically about 4% to about 8% of the total amount of the active ingredient administered to the subject. A pharmaceutical composition for use according to any one of claims 1-27 .

The pharmaceutical for use according to any one of claims 1 to 28 , wherein 1 mL of the pharmaceutical composition containing the inhalable immunosuppressive macrocyclic active ingredient is aerosolized (sprayed) within a maximum of about 5 minutes. Composition.

The mouthpiece (40) is as follows:
A main body (46) defining a fluid path (47) from an inlet port (41) connectable to the nebulizer (100) to an intake opening (42) accepted by the user's mouth.
A filter base (31) that communicates with the fluid path (47), a filter top (33) that is detachably connected to the filter base (31), and the filter base (31) and the filter top (33). ), The exhalation filter (30) having a filter material (32) provided between the filter top (33) and the exhalation opening (36) in cooperation with the one-way valve (39). Allows fluid to be expelled from the fluid path (47) through the filter material (32) to the outside of the mouthpiece (40) as the patient exhales through the inspiratory opening. west,
The pharmaceutical composition for use according to any one of claims 1 to 29 , wherein the main body (46) and the filter base (31) are integrated units.

The pharmaceutical composition for use according to any one of claims 1-30, wherein the chamber (105) has a lumen in a volume ranging from about 75 to about 125 ml.

It ’s a kit,
-A pharmaceutical composition comprising an inhalable immunosuppressive macrocyclic active ingredient for use in the prevention or treatment of lung disease or condition in a subject .
The composition is selected from the group consisting of saccharose, lactose and trehalose in the range of about 5 to about 15% by weight, preferably about 7.5 to about 12.5% by weight, based on the total weight of the pharmaceutical composition. A pharmaceutical composition comprising at least one disaccharide to be made; and
-The nebulizer (100) is provided, and the nebulizer is as follows:
a) Aerosol generator (101), the following:
-An interface configured to connect a fluid reservoir (103) or fluid reservoir for holding the pharmaceutical composition, and-an oscillating membrane (110) having a plurality of openings, wherein the openings are: Vibrations adapted to produce aerosols containing droplets with aerodynamic median particle size (MMAD) of up to about 4.0 μm when measured in 0.9% (weight / volume) sodium chloride solution. Aerosol generator (101), comprising a possible membrane (110);
b) A chamber (105) for temporarily accommodating the aerosol produced by the aerosol generator (101), having a cavity having a capacity in the range of about 50 to about 150 ml; And c) a kit comprising a mouthpiece (40) for delivering the aerosol supplied by the nebulizer (100) to the subject, the mouthpiece (40) having an exhalation filter (30).

The pharmaceutical composition comprising an inhalable immunosuppressive macrocyclic active ingredient for use in the prevention or treatment of a lung disease or condition in a subject is a lyophilized product comprising an inhalable immunosuppressive macrocyclic active ingredient. The kit according to claim 32 , which is provided in the form of a sterile liquid aqueous carrier solution for reconstitution of the lyophilized product to form a liquid pharmaceutical composition.