RESPIRABLE AGGLOMERATES OF POROUS CARRIER PARTICLES AND MICRONIZED DRUG

• US 20140302147A1
• Filed: 03/10/2014
• Published: 10/09/2014
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: HARTMAN, Michael, TARARA, Thomas E, TEUNG, Patrick, WEERS, Jeffry G
• Granted Patent: US 9,452,139 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1682 Processes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system

Abstract

Embodiments of the present invention provide a dry powder composition comprising porous carrier particles associated with one, two, three or more micronized drugs or APIs wherein an ordered mixture between the micronized drug or drugs and the carrier particle results, such that the micronized drug or drugs adhere strongly to the carrier particles forming a stable ordered mixture of respirable agglomerates. Embodiments of the present invention further comprise a spray-drying process to create the respirable agglomerates. Embodiments of the present invention further relate to the use of the dry powder formulation comprising respirable agglomerates for the treatment of a patient having a disease or condition which is treatable thereby.

Claims

1. A pharmaceutical composition for pulmonary delivery, the composition comprising a dry powder comprising a plurality of small porous carrier particles and a plurality of active agent particles and wherein the small porous carrier particles and the active agent particles form an ordered mixture of respirable agglomerates.

3. The pharmaceutical composition of claim 1 wherein the plurality of active agent particles comprise two different actives.

4. The pharmaceutical composition of claim 1 wherein the plurality of active agent particles comprise three different actives.

5. The pharmaceutical composition of claim 4 wherein the three different actives comprise beta-adrenoceptor agonist, anticholinergic, and corticosteroid.

7. The pharmaceutical composition of claim 1 wherein the dry powder is characterized by a tap density of 0.03 to 0.5 g/cm³, the small porous carrier particles comprise an MMD of about 1-5 microns, and the active agent particles comprise an MMD of less than about 3 microns.

8. The pharmaceutical composition of claim 1 wherein the dry powder is characterized by a fine particle fraction, expressed as a percentage of the nominal dose <

3.3 μ

m (FPF<sub><

3.3 μ

m</sub>) of greater than about 40%.

9. The pharmaceutical composition of claim 1 wherein the dry powder is characterized by a fine particle fraction, expressed as a percentage of the nominal dose less than 4.7 μ

m (i.e. FPF<sub><

4.7 μ

m</sub>) of greater than about 50%.

10. The pharmaceutical composition of claim 1 wherein the dry powder is characterized by a fine particle fraction, expressed as a percentage of the nominal dose on stage 4 to filter (FPF_S4-F) of at least 40% of a nominal dose.

11. The pharmaceutical composition of claim 1 wherein the dry powder is characterized by a lung deposition of at least 40% of a nominal dose.

12. The pharmaceutical composition of claim 1 wherein the dry powder is characterized by delivery from a passive dry powder inhaler substantially independently of a peak inspiratory flow rate.

13. The pharmaceutical composition of claim 1 wherein:

the plurality of small porous carrier particles have a geometric diameter of 2-3 microns, and consist essentially of distearoylphosphatidylcholine and calcium chloride;

at least 50% of the active agent particles have a geometric diameter of less than 3 microns; and

the dry powder is characterized by one or more of a tapped density of 0.03 to 0.5 g/cm³, a MMAD of about 1 to 5 microns, and a FPF<sub><

4.7 μ

m</sub> of at least 50%.

14. The dry powder pharmaceutical composition of claim 1 characterized by particles comprising:

a porous carrier particle comprising a MMD of 1 to 5 microns;

a first species of active agent particles comprising glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein at least 50% of the first active agent particles have a geometric diameter of 0.01-3 microns;

a second species of active agent particles comprising indacaterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein at least 50% of the first active agent particles have a geometric diameter of 0.01-3 microns;

a third species of active agent particles comprising mometasone including any pharmaceutically acceptable salts, esters, isomers or solvates thereof;

wherein at least 50% of the first active agent particles have a geometric diameter of 0.01-3 microns;

wherein each of the first, second and third active agent particles adhere to the carrier particle to form an ordered mixture of respirable agglomerate particles, and wherein the composition is characterized by a tapped density of 0.03 to 0.5 g/cm³, and a FPF<sub><

4.7 μ

m</sub> of at least about 50%.

15. The dry powder formulation of claim 14 wherein the respirable agglomerates comprise

(i) about 91-99% small porous carrier particles comprising a 2:

1 molar ratio of DSPC;

CaCl₂; and

(ii) the active species comprise about 0.5-3% w/w indacaterol acetate, about 0.5-3% w/w mometasone furoate, and about 0.5-3% w/w glycopyrronium bromide.

24. A method of treating a patient comprising administering, via an inhaler, to a patient in need of treatment a dry powder formulation according to claim 1.

2. (canceled)

6. (canceled)

16. (canceled)

17. An inhalation unit dosage form comprising

a receptacle;

and

a dry powder composition contained within the receptacle, the dry powder composition deliverable from a passive dry powder inhaler, the dry powder composition comprising particles comprising;

a small porous carrier particle comprising a MMD of about 1 to 5 microns and a tapped density of less than about 0.5 g/cm³;

a first species of active agent particles comprising glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein at least 50% of the first active agent particles have a geometric diameter of less than 3 microns;

a second species of active agent particles comprising indacaterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein at least 50% of the first active agent particles have a geometric diameter of less than 3 microns;

a third species of active agent particles comprising mometasone including any pharmaceutically acceptable salts, esters, isomers or solvates thereof;

wherein at least 50% of the first active agent particles have a geometric diameter of less than 3 microns;

wherein each of the first, second and third active agent particles and the small porous carrier particles form an ordered mixture of respirable agglomerates, and wherein the composition is characterized by a tapped density of 0.03 to 0.5 g/cm³ and an FPF<sub><

4.7 μ

m</sub> of at least about 50%.

18. A process for making a dry powder formulation of respirable agglomerate particles, the process comprising the steps of:

(a) preparing a first feedstock comprising a hydrophobic excipient dispersed in an aqueous liquid phase and spray-drying said first feedstock to provide a bulk powder composition comprising a plurality of small porous powder carrier particles;

(b) providing at least a first active drug ingredient to having a size of at least 50% having a geometric diameter of less than 3 microns;

(c) preparing a second feedstock comprising a suspension of the carrier particles of step (a) and the drug particles of step (b) in a non-aqueous anti-solvent; and

(d) subjecting the second feedstock to a solvent removal process to yield a bulk powder formulation comprising an ordered mixture of respirable aggregate particles comprising small porous carrier particles and micronized drug particles, wherein the respirable agglomerate particles are characterized by a tapped density of 0.03 to 0.5 g/cm³, and a FPF<sub><

4.7 μ

m</sub> of at least about 50%.

19. The process of claim 18 wherein the hydrophobic excipient comprises DSPC and calcium chloride.

20. The process of claim 19 wherein the first active comprises a beta adrenoreceptor agonist, and the second active comprises an anti-inflammatory.

21. The process of claim 20 wherein the beta adrenoreceptor agonist comprises indacaterol, and the anti-inflammatory comprises mometasone.

22. The process of claim 21 and further including a third active.

23. The process of claim 22 wherein the third active comprises a glycopyrrolate.

25. (canceled)