Formulation for inhalation

• US 6,030,604 A
• Filed: 01/09/1998
• Issued: 02/29/2000
• Est. Priority Date: 01/20/1997
• Status: Expired due to Term

• Current Assignee: Astra AB (Astrazeneca PLC)
• Original Assignee: Astra AB (Astrazeneca PLC)
• Inventors: Trofast, Jan
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/004,902
• Time in Patent Office: 781 Days
• Field of Search: 514/171, 514/174, 514/653, 514/826, 424/46
• US Class Current: 424/46
• 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 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• 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 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: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics

Abstract

A dry powder composition comprising one or more potent pharmaceutically active substances and a carrier substance, all of which are in finely divided form, wherein the formulation has a poured bulk density of from 0.28 to 0.38 g/ml is useful in the treatment of respiratory disorders.

Claims

1. A dry powder composition comprising (a) two or more potent therapeutically active substances selected from the group consisting of glucocorticosteroids, β

2-agonists and prophylactic agents, and (b) a carrier substance, all of which are in finely divided form, wherein the composition has a poured bulk density of from 0.28 to 0.38 g/ml.

2. A composition according to claim 1 wherein the two or more potent therapeutically active substances are (i) budesonide and (ii) formoterol or a pharmaceutically acceptable salt of formoterol.

3. A composition according to claim 1 wherein the bulk density is from 0.30 to 0.36 g/ml.

4. A composition according to claim 1 wherein the active substance and carrier substance are substantially uniformly distributed.

5. A composition according to claim 1 for use in the treatment of a respiratory disorder.

6. A process for preparing a composition according to claim 1 which comprises

(a) micronizing the two or more potent therapeutically active substances and the carrier substance;

(b) either before, during, or after step (a), mixing the two or more potent therapeutically active substances and the carrier substance until a substantially uniformly distributed mixture is obtained; and

(c) spheronizing said substantially uniformly distributed mixture until a desired bulk density is obtained.

7. A process according to claim 6 which comprises a low energy remicronization step after step (c).

9. A method of treating a patient suffering from a respiratory disorder which comprises administering to the patient a therapeutically effective amount of a composition according to claim 1.

10. A process for preparing a composition according to claim 1 which comprises

(a) micronizing the two or more potent therapeutically active substances and the carrier substance;

and

(b) spheronizing the micronized substances until the desired bulk density is obtained.

11. A process for preparing a composition according to claim 6, wherein said mixing step comprises combining said micronized substances in a mixer to form a first mixture, and then remicronizing said first mixture to form said substantially uniformly distributed mixture.

12. The process of claim 11 wherein said remicronizing is conducted at a pressure of about 1 bar.

13. A method of treating a patient comprising administering to the patient the dry powder composition of claim 1.

14. A method according to claim 13, wherein the two or more potent therapeutically active substances include at least one glucocorticosteroid and at least one β

2-agonist.

15. A method according to claim 14, wherein the glucocorticosteroid is selected from the group consisting of beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone acetonide, fluticasone propionate, ciclesonide, momethasone, tipredane, RPR 106541, budesonide, rofleponide and derivatives thereof.

16. A method according to claim 14, wherein the β

2-agonist is selected from the group consisting of terbutaline, salbutamol, formoterol, salmeterol, TA 2005, pircumarol and pharmaceutically acceptable salts thereof.

17. A composition according to claim 2, wherein the pharmaceutically acceptable salt of formoterol is formoterol fumarate.

18. A composition of claim 17 wherein the pharmaceutically acceptable salt of formoterol is the dihydrate of formoterol fumarate.

19. A composition according to claim 1, wherein the two or more potent therapeutically active substances include at least one glucocorticosteroid and at least one β

2-agonist.

20. A composition according to claim 1, wherein the glucocorticosteroid is selected from the group consisting of beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone acetonide, fluticasone propionate, ciclesonide, momethasone, tipredane, RPR 106541, budesonide, rofleponide and derivatives thereof.

21. A composition according to claim 1, wherein the β

2-agonist is selected from the group consisting of terbutaline, salbutamol, formoterol, salmeterol, TA 2005, pircumarol and pharmaceutically acceptable salts thereof.

22. A composition according to claim 19, wherein the glucocorticosteroid is selected from the group consisting of beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone acetonide, fluticasone propionate, ciclesonide, momethasone, tipredane, RPR 106541, budesonide, rofleponide and derivatives thereof.

23. A composition according to claim 19, wherein the β

2-agonist is selected from the group consisting of terbutaline, salbutamol, formoterol, salmeterol, TA 2005, pircumarol and pharmaceutically acceptable salts thereof.

24. A composition according to claim 19, wherein the two or more potent therapeutically active substances include budesonide and formoterol or a pharmaceutically acceptable salt thereof.

25. A composition according to claim 24, wherein the pharmaceutically acceptable salt of formoterol is formoterol fumarate.

26. A composition according to claim 25 wherein the pharmaceutically acceptable salt of formoterol is the dihydrate of formoterol fumarate.

27. A composition according to claim 1, wherein the prophylactic agent is selected from the group consisting of sodium chromoglycate and nedocromil sodium.

28. A composition according to claim 1, wherein the carrier substance is selected from the group consisting of monosaccharides, disaccharides, polysaccharides and polyols.

29. A composition according to claim 28, wherein the disaccharide is lactose.

30. A composition according to claim 29 wherein the disaccharide is lactose monohydrate.

31. A composition according to claim 1, wherein all of the therapeutically active substances and the carrier substance have a mass median diameter of less than 10 μ

m.

32. A composition according to claim 31, wherein said mass median diameter is from 1 to 7 μ

m.

33. A process according to claim 6, further comprising conditioning the micronized substances.

34. A process according to claim 6 wherein wherein conditioning is performed before spheronization.

8. A method of making a dry powder medicament composition for use in therapy comprising providing two or more potent therapeutically active substances and a carrier substance, all of which are in finely divided form;

mixing the therapeutically active substances and the carrier to form a substantially uniform mixture; and

processing the mixture to obtain a poured bulk density of from 0.28 to 0.38 g/ml.