Dry powder formulation comprising an anticholinergic, a corticosteroid and a beta-adrenergic for administration by inhalation

Patent metadata

Field	Value
Publication number	US-2016263027-A1
Application number	US-201615160593-A
Country	US
Kind code	A1
Filing date	May 20, 2016
Priority date	Jul 11, 2013
Publication date	Sep 15, 2016
Grant date	—

Abstract

Dry powder formulations for inhalation comprising a combination of an anticholinergic, a long-acting beta 2 -adrenoceptor agonist, and a corticosteroid are useful for the prevention and/or treatment of inflammatory and/or obstructive airways diseases.

First claim

1 . A dry powder formulation for use in a dry powder inhaler (DPI), comprising:
(a) a fraction of fine particles, consisting of a mixture, prepared by co-mixing in a high-energy apparatus for a period of less than 20 minutes, of 90 to 99.5 percent by weight of micronized particles of a physiologically acceptable excipient and 0.5 to 10 percent by weight of magnesium stearate, wherein at least 90% of all said particles have a volume diameter lower than 15 microns and the volume median diameter of said particles is from 3 to 7 microns; (b) a fraction of coarse particles consisting of a physiologically acceptable excipient having a mass median diameter equal to or higher than 100 microns, wherein the ratio between said fine particles (a) and said coarse particles (b) is from 1:99 to 30:70 percent by weight; and (c) micronized particles of an anticholinergic, an inhaled corticosteroid (ICS), and a long-acting β 2 -agonist (LABA) as active ingredients.

2 . A dry powder formulation according to claim 1 , wherein at least 90% of all said fine particles have a volume diameter lower than 12 microns, and the volume median diameter of said fine particles is from 4 to 6 microns.

3 . A powder formulation according to claim 1 , wherein no more than 10% of said fine particles (a) have a diameter lower than 1.8 microns.

4 . A powder formulation according to claim 1 , wherein no more than 10% of said fine particles (a) have a diameter lower than 1.5 microns.

5 . A powder formulation according to claim 1 , wherein said LABA is formoterol fumarate dihydrate, said ICS is beclometasone dipropionate, and said anticholinergic is glycopyrronium bromide.

6 . A powder formulation according to claim 1 , wherein said high energy apparatus is a mechano-fusion apparatus.

7 . A powder formulation according to claim 1 , wherein said high energy apparatus is the CYCLOMIX™ apparatus.

8 . A power formulation according claim 1 , wherein said magnesium stearate coats the surface of said particles of excipient particles (a) in such a way that the extent of the surface coating is at least of 50%.

9 . A dry powder formulation for use in a dry powder inhaler (DPI), comprising:
(a) a fraction of fine particles consisting of a mixture of 90 to 99.5 percent by weight of particles of a physiologically acceptable excipient and 0.5 to 10 percent by weight of magnesium stearate, wherein at least 90% of all said particles have a volume diameter lower than 15 microns, and the volume median diameter of said particles is from 3 to 7 microns; (b) a fraction of coarse particles consisting of a physiologically acceptable excipient having a mass median diameter equal to or higher than 100 microns, wherein the ratio between said fine particles (a) and said coarse particles (b) is from 1:99 to 30:70 percent by weight; and (c) micronized particles of an anticholinergic, an inhaled corticosteroid (ICS), and a long-acting β 2 -agonist (LABA) as active ingredients, wherein at least 90% of all said micronized particles of said active ingredients have a volume diameter lower than 6.0 microns, and the volume median diameter of said particles is from 1.2 to 2.5 microns.

10 . A dry powder formulation according to claim 9 , wherein at least 90% of all said fine particles (a) have a volume diameter lower than 12 microns, and the volume median diameter of said particles is from 4 to 6 microns; and
wherein at least 90% of all said micronized particles of said active ingredients (c) have a volume diameter equal to or lower than 5.0 microns, and the volume median diameter of said particles is from 1.3 to 2.2 microns.

11 . A powder formulation according to claim 7 , wherein said LABA is formoterol fumarate dihydrate, said ICS is beclometasone dipropionate and said anticholinergic is glycopyrronium bromide.

12 . A dry powder formulation for use in a dry powder inhaler (DPI), comprising:
(a) a fraction of fine particles consisting of a mixture of 90 to 99.5 percent by weight of particles of alpha-lactose monohydrate and 0.5 to 10 percent by weight of magnesium stearate, wherein at least 90% of said particles have a volume diameter lower than 12 microns and the volume median diameter of said particles is from 4 to 6 microns; (b) a fraction of coarse particles consisting of alpha-lactose monohydrate having a mass median diameter equal to or higher than 175 microns, wherein the ratio between the fine particles and the coarse particles being between 5:95 and 15:85 percent by weight; and (c) micronized particles of formoterol fumarate dihydrate, glycopyrronium bromide, and optionally beclometasone dipropionate as active ingredients, wherein at least 90% of all said micronized particles of the active ingredients have a volume diameter lower than 6.0 microns, and the volume median diameter of said particles is from 1.2 to 2.5 microns.

13 . A dry powder formulation according to claim 12 , wherein at least 90% of all said micronized particles of the active ingredients (c) have a volume diameter equal to or lower than 5.0 microns, and the volume median diameter of said particles is from 1.3 to 2.2 microns.

14 . A process for preparing a dry powder formulation according to claim 1 , comprising mixing said fraction of fine particles (a), said fraction of coarse lactose particles (b) and all the micronized active ingredients.

15 . A process for preparing a dry powder formulation according to claim 9 , comprising mixing said fraction of fine particles (a), said fraction of coarse lactose particles (b) and all the micronized active ingredients.

16 . A dry powder inhaler device, containing a dry powder formulation according to claim 1 .

17 . A dry powder inhaler device, containing a dry powder formulation according to claim 9 .

18 . A dry powder inhaler device, containing a dry powder formulation according to claim 12 .

19 . A method for the prevention and/or treatment of an inflammatory and/or obstructive airways disease, comprising administering an effective amount of a formulation according to claim 1 to a subject in need thereof.

20 . A method according to claim 19 , wherein said inflammatory and/or obstructive airways disease is chronic obstructive pulmonary disease (COPD).

21 . A method for the prevention and/or treatment of an inflammatory and/or obstructive airways disease, comprising administering an effective amount of a formulation according to claim 9 to a subject in need thereof.

22 . A method according to claim 21 , wherein said inflammatory and/or obstructive airways disease is chronic obstructive pulmonary disease (COPD).

23 . A method for the prevention and/or treatment of an inflammatory and/or obstructive airways disease, comprising administering an effective amount of a formulation according to claim 12 to a subject in need thereof.

24 . A method according to claim 23 , wherein said inflammatory and/or obstructive airways disease is chronic obstructive pulmonary disease (COPD).

Assignees

• Chiesi Farm Spa

Inventors

• Pasquali Irene
• Musa Rossella
• Schiaretti Francesca
• Askey-Sarvar Azita

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/08

  Bronchodilators · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• A61J3/02

  into the form of powders (pulverising in general B02C) · CPC title