Inhalation compositions comprising muscarinic receptor antagonist

Abstract

The invention relates to pharmaceutical powder compositions administered by means of inhalers. More particularly, it relates to pharmaceutical powder compositions having the content uniformity and the desired stability used in inhaler devices.

Claims

1. A dry powder inhalation composition comprising, (a) at least one muscarinic receptor antagonist or a pharmaceutically acceptable salt thereof; (b) fine particle lactose in the amount of 1-20% by weight of said composition and having a (d50) particle size in the range of 4-10 m; and (c) coarse particle mannitol in the amount of 80-99% by weight of said composition and having a (d50) particle size in the range of 50-120 m and a (d90) particle size of 120-300 m.

2. The pharmaceutical composition according to claim 1, wherein the (d50) particle size of said fine particle lactose is 4-7 m, a (d10) particle size of said fine particle lactose is 1-5 m, and/or a (d90) particle size of said fine particle lactose is 7-20 m.

3. The pharmaceutical composition according to claim 1, further comprising coarse particle lactose with a (d50) particle size of 50-80 m, coarse particle lactose with a (d10) particle size of 10-50 m, and/or coarse particle lactose with a (d90) particle size of 120-300 m.

4. The pharmaceutical composition according to claim 1, further comprising fine particle mannitol with a (d50) particle size of 4-7 m; fine particle mannitol with a (d10) particle size of 1-5 m; and/or fine particle mannitol with a (d90) particle size of 10-20 m.

5. The pharmaceutical composition according to claim 1, wherein the amount of said lactose is in the range of 1-15%, by weight of the composition.

6. The pharmaceutical composition according to claim 1, wherein the amount of said course particle mannitol is in the range of 85-99% by weight of the composition.

7. The pharmaceutical composition claim 1, wherein said muscarinic receptor antagonist is selected from the group consisting of at least one or a mixture of tiotropium, glycopyronium, aclidinium, darotropium, oxitropium, and ipratropium.

8. The pharmaceutical composition according to claim 1, wherein said composition further comprises one or more 2-adrenergic agonists.

9. The pharmaceutical composition according to claim 8, wherein said one or more beta-2 adrenergic agonists are selected from at least one or a mixture of salmeterol, formoterol, arformoterol, salbutamol, indacaterol, terbutaline, metaproterenol, vilanterol, carmoterol, olodaterol, bambuterol, and clenbuterol.

10. The pharmaceutical composition according to claim 1, further comprising one or more corticosteroids selected from at least one or a mixture of ciclesonide, budesonide, fluticasone, aldosterone, beclomethasone, betametazone, chloprednol, cortisone, cortivasol, deoxycortone, desonide, desoxymethasone, dexamethasone, difluocortolone, fluchloralin, flumetasone, flunisolide, fluocinolone, fluocinonide, flurocortisone, fluocortolone, flurometolone, flurandrenolone, halcinonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, and/or triamcinolone.

11. The pharmaceutical composition according to claim 10, wherein the one or more corticosteroids are selected from ciclesonide, budesonide, fluticasone, and mometasone.

12. The pharmaceutical composition according to claim 1, further comprising (a) one or more corticosteroids, (b) one or more 2-adrenergic agonists; or (c) one or more corticosteroids and one or more 2-adrenergic agonists.

13. The pharmaceutical composition according to claim 1, further comprising an excipient selected from at least one or a mixture of glucose, glucose anhydrous, trehalose, cellobiose, and sorbitol.

14. The pharmaceutical composition according to claim 1, wherein said composition comprises one of the following therapeutically active combinations: i. Aclidinium and tiotropium ii. Aclidinium and glycopyrronium iii. Aclidinium and darotropyum iv. Aclidinium and oxitropium v. Aclidinium and ipratropium vi. Aclidinium and ciclesonide vii. Aclidinium and budesonid viii. Aclidinium and fluticasone ix. Aclidinium and mometazon x. Tiotropium and glycopyrronium xi. Tiotropium and darotropyum xii. Tiotropium and oxitropium xiii. Tiotropium and ipratropium xiv. Tiotropium and ciclesonide xv. Tiotropium and budesonid xvi. Tiotropium and fluticasone xvii. Tiotropium and mometazon xviii. Glycopyrronium and tiotropium xix. Glycopyrronium and glycopyrronium xx. Glycopyrronium and darotropyum xxi. Glycopyrronium and oxitropium xxii. Glycopyrronium and ipratropium xxiii. Glycopyrronium and ciclesonide xxiv. Glycopyrronium and budesonid xxv. Glycopyrronium and fluticasone xxvi. Glycopyrronium and mometazon xxvii. Oxitropium and tiotropium xxviii. Oxitropium and darotropyum xxix. Oxitropium and aclidinium xxx. Oxitropium and ipratropium xxxi. Oxitropium and ciclesonide xxxii. Oxitropium and budesonid xxxiii. Oxitropium and fluticasone xxxiv. Oxitropium and mometazon xxxv. Darotropyum and tiotropium xxxvi. Darotropyum and aclidinium xxxvii. Darotropyum and oxitropium xxxviii. Darotropyum and ipratropium xxxix. Darotropyum and ciclesonide xl. Darotropyum and budesonid xli. Darotropyum and fluticasone xlii. Darotropyum and mometazon xliii. Aclidinium and salmeterol xliv. Aclidinium and formoterol xlv. Aclidinium and arformoterol xlvi. Aclidinium and salbutamol xlvii. Aclidinium and indacaterol xlviii. Aclidinium and vilanterol xlix. Aclidinium and carmoterol l. Aclidinium and olodaterol li. Aclidinium and bambuterol lii. Tiotropium and salmeterol liii. Tiotropium and formoterol liv. Tiotropium and arformoterol lv. Tiotropium and salbutamol lvi. Tiotropium and indacaterol lvii. Tiotropium and vilanterol lviii. Tiotropium and carmoterol lix. Tiotropium and olodaterol lx. Tiotropium and bambuterol lxi. Glycopyrronium and salmeterol lxii. Glycopyrronium and formoterol lxiii. Glycopyrronium and arformoterol lxiv. Glycopyrronium and salbutamol lxv. Glycopyrronium and indacaterol lxvi. Glycopyrronium and vilanterol lxvii. Glycopyrronium and carmoterol lxviii. Glycopyrronium and olodaterol lxix. Glycopyrronium and bambuterol lxx. Oxitropium and salmeterol lxxi. Oxitropium and formoterol lxxii. Oxitropium and arformoterol lxxiii. Oxitropium and salbutamol lxxiv. Oxitropium and indacaterol lxxv. Oxitropium and vilanterol lxxvi. Oxitropium and carmoterol lxxvii. Oxitropium and olodaterol lxxviii. Oxitropium and bambuterol lxxix. Darotropium and salmeterol lxxx. Darotropium and formoterol lxxxi. Darotropium and arformoterol lxxxii. Darotropium and salbutamol lxxxiii. Darotropium and indacaterol lxxxiv. Darotropium and vilanterol lxxxv. Darotropium and carmoterol lxxxvi. Darotropium and olodaterol lxxxvii. Darotropium and bambuterol lxxxviii. Aclidinium, tiotropium and salmeterol lxxxix. Aclidinium, tiotropium and formoterol xc. Aclidinium, tiotropium and arformoterol xci. Aclidinium, tiotropium and indacaterol xcii. Aclidinium, tiotropium and olodaterol xciii. Aclidinium, tiotropium and vilanterol xciv. Aclidinium, tiotropium and carmoterol xcv. Aclidinium, tiotropium and bambuterol xcvi. Aclidinium, glycopyrronium and salmeterol xcvii. Aclidinium, glycopyrronium and formoterol xcviii. Aclidinium, glycopyrronium and arformoterol xcix. Aclidinium, glycopyrronium and indacaterol c. Aclidinium, glycopyrronium and olodaterol ci. Aclidinium, glycopyrronium and vilanterol cii. Aclidinium, glycopyrronium and carmoterol ciii. Aclidinium, glycopyrronium and bambuterol civ. Aclidinium, oxitropium and salmeterol cv. Aclidinium, oxitropium and formoterol cvi. Aclidinium, oxitropium and arformoterol cvii. Aclidinium, oxitropium and indacaterol cviii. Aclidinium, oxitropium and olodaterol cix. Aclidinium, oxitropium and vilanterol cx. Aclidinium, oxitropium and carmoterol cxi. Aclidinium, oxitropium and bambuterol cxii. Glycopyrronium, tiotropium and salmeterol cxiii. Glycopyrronium, tiotropium and formoterol cxiv. Glycopyrronium, tiotropium and arformoterol cxv. Glycopyrronium, tiotropium and indacaterol cxvi. Glycopyrronium, tiotropium and olodaterol cxvii. Glycopyrronium, tiotropium and vilanterol cxviii. Glycopyrronium, tiotropium and carmoterol cxix. Glycopyrronium, tiotropium and bambuterol cxx. Glycopyrronium, oxitropium and salmeterol cxxi. Glycopyrronium, oxitropium and formoterol cxxii. Glycopyrronium, oxitropium and arformoterol cxxiii. Glycopyrronium, oxitropium and indacaterol cxxiv. Glycopyrronium, oxitropium and olodaterol cxxv. Glycopyrronium, oxitropium and vilanterol cxxvi. Glycopyrronium, oxitropium and carmoterol cxxvii. Glycopyrronium, oxitropium and bambuterol cxxviii. Daratropium, tiotropium and salmeterol cxxix. Daratropium, tiotropium and formoterol cxxx. Daratropium, tiotropium and arformoterol cxxxi. Daratropium, tiotropium and indacaterol cxxxii. Daratropium, tiotropium and olodaterol cxxxiii. Daratropium, tiotropium and vilanterol cxxxiv. Daratropium, tiotropium and carmoterol cxxxv. Daratropium, tiotropium and bambuterol cxxxvi. Daratropium, glycopyrronium and salmeterol cxxxvii. Daratropium, gikopironyum and formoterol cxxxviii. Daratropium, glycopyrronium and arformoterol cxxxix. Daratropium, glycopyrronium and indacaterol cxl. Daratropium, glycopyrronium and olodaterol cxli. Daratropium, glycopyrronium and vilanterol cxlii. Daratropium, glycopyrronium and carmoterol cxliii. Daratropium, glycopyrronium and bambuterol cxliv. Daratropium, aclidinium and salmeterol cxlv. Daratropium, aclidinium and formoterol cxlvi. Daratropium, aclidinium and arformoterol cxlvii. Daratropium, aclidinium and indacaterol cxlviii. Daratropium, aclidinium and olodaterol cxlix. Daratropium, aclidinium and vilanterol cl. Daratropium, aclidinium and carmoterol cli. Daratropium, aclidinium and bambuterol clii. Daratropium, oxitropium and salmeterol cliii. Daratropium, oxitropium and formoterol cliv. Daratropium, oxitropium and arformoterol clv. Daratropium, oxitropium and indacaterol clvi. Daratropium, oxitropium and olodaterol clvii. Daratropium, oxitropium and vilanterol clviii. Daratropium, oxitropium and carmoterol clix. Daratropium, oxitropium and bambuterol clx. ndacaterol, tiotropium and salmeterol clxi. ndacaterol, tiotropium and formoterol clxii. ndacaterol, tiotropium and arformoterol clxiii. ndacaterol, tiotropium and olodaterol clxiv. ndacaterol, tiotropium and vilanterol clxv. ndacaterol, tiotropium and carmoterol clxvi. ndacaterol, tiotropium and bambuterol clxvii. ndacaterol, glycopyrronium and salmeterol clxviii. ndacaterol, glycopyrronium and formoterol clxix. ndacaterol, glycopyrronium and arformoterol clxx. ndacaterol, glycopyrronium and olodaterol clxxi. ndacaterol, glycopyrronium and vilanterol clxxii. ndacaterol, glycopyrronium and carmoterol clxxiii. ndacaterol, glycopyrronium and bambuterol clxxiv. ndacaterol, aclidinium and salmeterol clxxv. ndacaterol, aclidinium and formoterol clxxvi. ndacaterol, aclidinium and arformoterol clxxvii. ndacaterol, aclidinium and olodaterol clxxviii. ndacaterol, aclidinium and vilanterol clxxix. ndacaterol, aclidinium and carmoterol clxxx. ndacaterol, aclidinium and bambuterol clxxxi. ndacaterol, oxitropium and salmeterol clxxxii. ndacaterol, oxitropium and formoterol clxxxiii. ndacaterol, oxitropium and arformoterol clxxxiv. ndacaterol, oxitropium and olodaterol clxxxv. ndacaterol, oxitropium and vilanterol clxxxvi. ndacaterol, oxitropium and carmoterol clxxxvii. ndacaterol, oxitropium and bambuterol clxxxviii. Vilanterol, tiotropium and salmeterol clxxxix. Vilanterol, tiotropium and formoterol cxc. Vilanterol, tiotropium and arformoterol cxci. Vilanterol, tiotropium and indacaterol cxcii. Vilanterol, tiotropium and olodaterol cxciii. Vilanterol, tiotropium and carmoterol cxciv. Vilanterol, tiotropium and bambuterol cxcv. Vilanterol, glycopyrronium and salmeterol cxcvi. Vilanterol, glycopyrronium and formoterol cxcvii. Vilanterol, glycopyrronium and arformoterol cxcviii. Vilanterol, glycopyrronium and indacaterol cxcix. Vilanterol, glycopyrronium and olodaterol cc. Vilanterol, glycopyrronium and carmoterol cci. Vilanterol, glycopyrronium and bambuterol ccii. Vilanterol, aclidinium and salmeterol cciii. Vilanterol, aclidinium and formoterol cciv. Vilanterol, aclidinium and arformoterol ccv. Vilanterol, aclidinium and indacaterol ccvi. Vilanterol, aclidinium and olodaterol ccvii. Vilanterol, aclidinium and carmoterol ccviii. Vilanterol, aclidinium and bambuterol ccix. Vilanterol, oxitropium and salmeterol ccx. Vilanterol, oxitropium and formoterol ccxi. Vilanterol, oxitropium and arformoterol ccxii. Vilanterol, oxitropium and indacaterol ccxiii. Vilanterol, oxitropium and olodaterol ccxiv. Vilanterol, oxitropium and carmoterol ccxv. Vilanterol, oxitropium and bambuterol ccxvi. Carmoterol, tiotropium and salmeterol ccxvii. Carmoterol, tiotropium and formoterol ccxviii. Carmoterol, tiotropium and arformoterol ccxix. Carmoterol, tiotropium and indacaterol ccxx. Carmoterol, tiotropium and olodaterol ccxxi. Carmoterol, tiotropium and vilanterol ccxxii. Carmoterol, tiotropium and bambuterol ccxxiii. Carmoterol, glycopyrronium and salmeterol ccxxiv. Carmoterol, glycopyrronium and formoterol ccxxv. Carmoterol, glycopyrronium and arformoterol ccxxvi. Carmoterol, glycopyrronium and indacaterol ccxxvii. Carmoterol, glycopyrronium and olodaterol ccxxviii. Carmoterol, glycopyrronium and vilanterol ccxxix. Carmoterol, glycopyrronium and bambuterol ccxxx. Carmoterol, aclidinium and salmeterol ccxxxi. Carmoterol, aclidinium and formoterol ccxxxii. Carmoterol, aclidinium and arformoterol ccxxxiii. Carmoterol, aclidinium and indacaterol ccxxxiv. Carmoterol, aclidinium and olodaterol ccxxxv. Carmoterol, aclidinium and vilanterol ccxxxvi. Carmoterol, aclidinium and bambuterol ccxxxvii. Carmoterol, oxitropium and salmeterol ccxxxviii. Carmoterol, oxitropium and formoterol ccxxxix. Carmoterol, oxitropium and arformoterol ccxl. Carmoterol, oxitropium and indacaterol ccxli. Carmoterol, oxitropium and olodaterol ccxlii. Carmoterol, oxitropium and vilanterol ccxliii. Carmoterol, oxitropium and bambuterol ccxliv. Olodaterol, tiotropium and salmeterol ccxlv. Olodaterol, tiotropium and formoterol ccxlvi. Olodaterol, tiotropium and arformoterol ccxlvii. Olodaterol, tiotropium and indacaterol ccxlviii. Olodaterol, tiotropium and vilanterol ccxlix. Olodaterol, tiotropium and bambuterol ccl. Olodaterol, glycopyrronium and salmeterol ccli. Olodaterol, glycopyrronium and formoterol cclii. Olodaterol, glycopyrronium and arformoterol ccliii. Olodaterol, glycopyrronium and indacaterol ccliv. Olodaterol, glycopyrronium and vilanterol cclv. Olodaterol, glycopyrronium and bambuterol cclvi. Olodaterol, aclidinium and salmeterol cclvii. Olodaterol, aclidinium and formoterol cclviii. Olodaterol, aclidinium and arformoterol cclix. Olodaterol, aclidinium and indacaterol cclx. Olodaterol, aclidinium and vilanterol cclxi. Olodaterol, aclidinium and bambuterol cclxii. Olodaterol, oxitropium and salmeterol cclxiii. Olodaterol, oxitropium and formoterol cclxiv. Olodaterol, oxitropium and arformoterol cclxv. Olodaterol, oxitropium and indacaterol cclxvi. Olodaterol, oxitropium and vilanterol cclxvii. Olodaterol, oxitropium and bambuterol wherein each of the above therapeutic agents can be present as a pharmaceutically acceptable salt or ester thereof, or in enantiomerically pure form or as a racemic mixture.

15. The pharmaceutical composition according to claim 1, wherein said composition comprises a blister having air and moisture barrier property, enabling simultaneous, respective and synchronic application.

16. The pharmaceutical composition according to claim 1, wherein said composition comprises a blister having air and moisture tightness property, enabling simultaneous, respective and synchronic application.

17. The pharmaceutical composition according to claim 1, wherein said composition comprises a dry powder inhaler device suitable for simultaneous, respective and synchronic application in a blister and having at least one locking mechanism ensuring the device to be maintained locked in both of the positions in which it is ready for inhalation and its lid is closed and ensuring the device to be automatically re-set once the lid is closed.

18. The pharmaceutical composition according to claim 1, wherein said composition comprises a dry powder inhaler device suitable for simultaneous, respective and synchronic application in a capsule.

19. The pharmaceutical composition according to claim 1, wherein the amount of said fine particle lactose is in the range of 1-10% by weight of said composition.

20. The pharmaceutical composition according to claim 1, wherein the amount of said course particle mannitol is in the range of 90-99% by weight of the composition.

21. The pharmaceutical composition according to claim 1, wherein said coarse particle mannitol has a (d10) particle size of 10-50 m.

22. The pharmaceutical composition according to claim 21, wherein said fine particle lactose has a (d10) particle size of 1-4 m.

23. The pharmaceutical composition according to claim 21, wherein said fine particle lactose has a (d90) particle size of 7-15 m.

24. The pharmaceutical composition according to claim 21, wherein said fine particle lactose has a (d10) particle size of 1-4 m and a (d90) particle size of 7-15 m.

25. The pharmaceutical composition according to claim 1, further comprising coarse particle lactose with a (d50) particle size of 50-120 m.

26. The pharmaceutical composition according to claim 1, further comprising coarse particle lactose with a (d50) particle size of 50-120 m and a (d10) particle size of 10-50 m.

27. The pharmaceutical composition according to claim 1, further comprising coarse particle lactose with a (d50) particle size of 50-120 m and a (d90) particle size of 120-300 m.

28. The pharmaceutical composition according to claim 1, further comprising fine particle mannitol with a (d50) particle size of 4-10 m.

29. The pharmaceutical composition according to claim 1, further comprising fine particle mannitol with a (d50) particle size of 4-10 m and a (d10) particle size of 1-5 m.

30. The pharmaceutical composition according to claim 1, further comprising fine particle mannitol with a (d50) particle size of 4-10 m and a (d90) particle size of 7-20 m.

31. The pharmaceutical composition according to claim 1, wherein the coarse particle mannitol has a (d50) particle size of 50-75 m.

32. The pharmaceutical composition according to claim 1, wherein the coarse particle mannitol has a (d90) particle size of 75-250 m.

33. The pharmaceutical composition according to claim 1, wherein a ratio of the (d50) particle size to the (d90) particle size equals to 0.40 or greater for the coarse particle mannitol.

34. The pharmaceutical composition according to claim 33, wherein the mannitol is spray-dried mannitol.

35. The pharmaceutical composition according to claim 1, wherein a ratio of the (d50) particle size to the (d90) particle size is between 0.45 and 0.50 for the coarse particle mannitol.

36. The pharmaceutical composition according to claim 1, wherein a ratio of the (d50) particle size to the (d90) particle size is between 0.50 and 0.70 for the coarse particle mannitol.

37. A dry powder inhalation composition comprising, at least one muscarinic receptor antagonist or a pharmaceutically acceptable salt thereof, fine particle lactose in the amount of 1-20% by weight of said composition and having a (d50) particle size in the range of 4-10 m and coarse particle mannitol in the amount of 80-99% by weight of said composition and having a (d50) particle size in the range of 50-120 m, wherein said fine particle lactose has a (d10) particle size of 1-5 m.

38. A dry powder inhalation composition comprising, at least one muscarinic receptor antagonist or a pharmaceutically acceptable salt thereof, fine particle lactose in the amount of 1-20% by weight of said composition and having a (d50) particle size in the range of 4-10 m and coarse particle mannitol in the amount of 80-99% by weight of said composition and having a (d50) particle size in the range of 50-120 m, wherein said fine particle lactose has a (d90) particle size of 7-20 m.

39. A dry powder inhalation composition comprising, (a) at least one muscarinic receptor antagonist or a pharmaceutically acceptable salt thereof; (b) fine particle lactose in the amount of 1-20% by weight of said composition and having a (d50) particle size in the range of 4-10 m; and (c) coarse particle mannitol in the amount of 80-99% by weight of said composition and having a (d50) particle size in the range of 50-120 m and a (d10) particle size of 10-50 m.

40. The pharmaceutical composition according to claim 39, wherein the fine particle lactose has a (d50) particle size of 4-7 m.

41. The pharmaceutical composition according to claim 39, wherein the fine particle lactose has a (d50) particle size of 4-7 m and a d(10) particle size of 1-4 m.

42. The pharmaceutical composition according to claim 39, wherein the fine particle lactose has a (d50) particle size of 4-7 m and a d(90) particle size of 7-15 m.

43. The pharmaceutical composition according to claim 39, wherein the fine particle lactose has a (d50) particle size of 4-7 m, a d(10) particle size of 1-4 m, and a d(90) particle size of 7-15 m.

44. A method of treating chronic obstructive pulmonary disease in a mammalian subject, comprising administering to the subject a pharmaceutical composition according to claim 1.

45. The method according to claim 44, wherein a pharmaceutically acceptable amount of said composition is administered once a day or twice a day.

46. A method of treating asthma in a mammalian subject, comprising administering to the subject a pharmaceutical composition according to claim 1.

47. The method according to claim 46, wherein a pharmaceutically acceptable amount of said composition is administered once a day or twice a day.

Description

DETAILED DESCRIPTION OF INVENTION

ExamplesA

(1) a)

(2) TABLE-US-00001 Content % Weight (w/w) Muscarinic receptor antagonist 0.1-12 Lactose (fine particle) 4.3-5.3 Mannitol (coarse particle) 84-96 b)

(3) TABLE-US-00002 Content % Weight (w/w) Muscarinic receptor antagonist 0.1-12 Mannitol (fine particle) 4.3-5.3 Lactose (coarse particle) 84-96 c)

(4) TABLE-US-00003 Content % Weight (w/w) Muscarinic receptor antagonist 0.1-12 Mannitol + Lactose (fine particle) 4.3-5.3 Lactose + Mannitol (coarse 84-96 particle)

(5) TABLE-US-00004 TABLE 1 Content Lactose + Amount Aklidinyum Glycopyrronium Darotropyum Tiotropium ipratropium Oxitropium Mannitol % (w/w) 5 mg 25 mg 5 mg 25 mg 5 mg 25 mg 5 mg 25 mg 5 mg 25 mg 5 mg 25 mg 5 mg 25 mg Ex. 1.1 (% w/w) 4 0.8 96.0 99.2 Ex. 1.2 (% w/w) 8 1.6 92.0 98.4 Ex. 1.3 (% w/w) 2 0.4 98.0 99.6 Ex. 1.4 (% w/w) 4 0.8 96.0 99.2 Ex. 1.5 (% w/w) 0.4 0.08 99.6 99.92 Ex. 1.6 (% w/w) 0.36 0.072 99.64 99.28 Ex. 1.7 (% w/w) 0.5 0.1 99.5 99.9 Ex. 1.8 (% w/w) 4 0.8 96 99.2

Examples B

(6) a)

(7) TABLE-US-00005 Content Amount % (w/w) Muscarinic receptor antagonist Beta-2 adrenerjik agonist Lactose + mannitol

(8) TABLE-US-00006 TABLE 2.1 Amount % (w/w) Content 5 mg Aklidinyum Glycopyrronium Darotropyum Tiotropium Oxitropium ipratropium Carmeterol Ex. 2.1 (% 4.0 8.0 w/w) Ex. 2.2 (% 4.0 8.0 w/w) Ex. 2.3 (% 4.0 8.0 w/w) Ex. 2.4 (% 4.0 8.0 w/w) Ex. 2.5 (% 4.0 8.0 w/w) Ex. 2.6 (% 4.0 8.0 w/w) Ex. 2.7 (% 4.0 8.0 w/w) Ex. 2.8 (% 2.0 4.0 w/w) Ex. 2.9 (% 2.0 4.0 w/w) Ex. 2.10 (% 2.0 4.0 w/w) Ex. 2.11 (% 2.0 4.0 w/w) Ex. 2.12 (% 2.0 4.0 w/w) Ex. 2.13 (% 2.0 4.0 w/w) Ex. 2.14 (% 2.0 4.0 w/w) Ex. 2.15 (% 0.4 w/w) Ex. 2.16 (% 0.4 w/w) Ex. 2.17 (% 0.4 w/w) Ex. 2.18 (% 0.4 w/w) Ex. 2.19 (% 0.4 w/w) Ex. 2.20 (% 0.4 w/w) Ex. 2.21 (% 0.4 w/w) Ex. 2.22 (% 3.0 6.0 w/w) Ex. 2.23 (% 3.0 6.0 w/w) Ex. 2.24 (% 3.0 6.0 w/w) Ex. 2.25 (% 3.0 6.0 w/w) Ex. 2.26 (% 3.0 6.0 w/w) Ex. 2.27 (% 3.0 6.0 w/w) Ex. 2.28 (% w/w) Ex. 2.29 (% w/w) Ex. 2.30 (% w/w) Ex. 2.31 (% w/w) Ex. 2.32 (% w/w) Ex. 2.33 (% w/w) Ex. 2.34 (% 0.04 0.08 w/w) Ex. 2.35 (% 0.04 0.08 w/w) Ex. 2.36 (% 0.04 0.08 w/w) Ex. 2.37 (% 0.04 0.08 w/w) Ex. 2.38 (% 0.04 0.08 w/w) Ex. 2.39 (% 0.04 0.08 w/w) Ex. 2.40 (% w/w) Ex. 2.41 (% w/w) Ex. 2.42 (% w/w) Ex. 2.43 (% w/w) Ex. 2.44 (% w/w) Ex. 2.45 (% w/w) Ex. 2.46 (% 0.36 w/w) Ex. 2.47 (% 0.36 w/w) Ex. 2.48 (% 0.36 w/w) Ex. 2.49 (% 0.36 w/w) Ex. 2.50 (% 0.36 w/w) Ex. 2.51 (% 0.36 w/w) Ex. 2.52 (% 0.36 w/w) Ex. 2.53 (% 4 w/w) Ex. 2.54 (% 4 w/w) Ex. 2.55 (% 4 w/w) Ex. 2.56 (% 4 w/w) Ex. 2.57 (% 4 w/w) Ex. 2.58 (% 4 w/w) Ex. 2.59 (% 4 w/w) Amount Content % (w/w) Lactose + 5 mg Olodaterol Salmeterol Formoterol Arformoterol indacaterol Olodaterol Vilanterol Mannitol Ex. 2.1 (% 1.0 95.0 91.0 w/w) Ex. 2.2 (% 0.10 0.24 95.9 91.76 w/w) Ex. 2.3 (% 0.3 95.7 91.7 w/w) Ex. 2.4 (% 3.0 93.0 89.0 w/w) Ex. 2.5 (% 0.1 95.9 91.9 w/w) Ex. 2.6 (% 0.5 95.5 91.5 w/w) Ex. 2.7 (% 95.96 91.92 w/w) Ex. 2.8 (% 1.0 97.0 95.0 w/w) Ex. 2.9 (% 0.10 0.24 97.9 95.76 w/w) Ex. 2.10 (% 0.3 97.7 95.7 w/w) Ex. 2.11 (% 3.0 95.0 93.0 w/w) Ex. 2.12 (% 0.1 97.9 95.9 w/w) Ex. 2.13 (% 0.5 97.5 95.5 w/w) Ex. 2.14 (% 95.96 91.92 w/w) Ex. 2.15 (% 1.0 98.6 w/w) Ex. 2.16 (% 0.10 0.24 99.5 99.36 w/w) Ex. 2.17 (% 0.3 99.3 w/w) Ex. 2.18 (% 3.0 96.6 w/w) Ex. 2.19 (% 0.1 99.5 w/w) Ex. 2.20 (% 0.5 99.1 w/w) Ex. 2.21 (% 99.56 99.52 w/w) Ex. 2.22 (% 1.0 96.0 93.0 w/w) Ex. 2.23 (% 0.10 0.24 96.9 96.76 w/w) Ex. 2.24 (% 0.3 96.7 93.7 w/w) Ex. 2.25 (% 0.1 96.9 93.9 w/w) Ex. 2.26 (% 0.5 96.5 93.5 w/w) Ex. 2.27 (% 96.96 96.92 w/w) Ex. 2.28 (% 1.0 98.5 w/w) Ex. 2.29 (% 0.10 0.24 99.4 99.26 w/w) Ex. 2.30 (% 0.3 99.2 w/w) Ex. 2.31 (% 3.0 96.5 w/w) Ex. 2.32 (% 0.1 99.4 w/w) Ex. 2.33 (% 99.46 99.42 w/w) Ex. 2.34 (% 1.0 98.96 98.92 w/w) Ex. 2.35 (% 0.10 0.24 99.86 99.68 w/w) Ex. 2.36 (% 0.3 99.66 99.62 w/w) Ex. 2.37 (% 3.0 96.96 96.92 w/w) Ex. 2.38 (% 0.1 99.86 99.82 w/w) Ex. 2.39 (% 0.5 99.46 99.42 w/w) Ex. 2.40 (% 0.1 0.2 1.0 98.9 98.8 w/w) Ex. 2.41 (% 0.1 0.2 0.10 0.24 99.8 99.56 w/w) Ex. 2.42 (% 0.1 0.2 0.3 99.6 99.5 w/w) Ex. 2.43 (% 0.1 0.2 3.0 96.9 96.8 w/w) Ex. 2.44 (% 0.1 0.2 0.5 99.4 99.3 w/w) Ex. 2.45 (% 0.1 0.2 99.72 w/w) Ex. 2.46 (% 1.0 98.64 w/w) Ex. 2.47 (% 0.10 0.24 99.54 99.4 w/w) Ex. 2.48 (% 0.3 99.34 w/w) Ex. 2.49 (% 3.0 96.64 w/w) Ex. 2.50 (% 0.1 99.54 w/w) Ex. 2.51 (% 0.5 99.14 w/w) Ex. 2.52 (% 99.64 w/w) Ex. 2.53 (% 1.0 95 w/w) Ex. 2.54 (% 0.10 0.24 95.9 95.76 w/w) Ex. 2.55 (% 0.3 95.7 w/w) Ex. 2.56 (% 3.0 95.7 w/w) Ex. 2.57 (% 0.1 95.9 w/w) Ex. 2.58 (% 0.5 95.5 w/w) Ex. 2.59 (% 96 w/w)

(9) TABLE-US-00007 TABLE 2.2 Amount Content % (w/w) Dara- Tio- ipra- Oxi- 25 mg Aklidinyum Glycopyrronium tropium tropium tropium tropium indacaterol Vilanterol Carmeterol Olodaterol Ex. 2.1 0.8 1.6 (% w/w) Ex. 2.2 0.8 1.6 (% w/w) Ex. 2.3 0.8 1.6 (% w/w) Ex. 2.4 0.8 1.6 (% w/w) Ex. 2.5 0.8 1.6 (% w/w) Ex. 2.6 0.8 1.6 (% w/w) Ex. 2.7 0.8 1.6 (% w/w) Ex. 2.8 0.4 0.8 (% w/w) Ex. 2.9 0.4 0.8 (% w/w) Ex. 2.10 0.4 0.8 (% w/w) Ex. 2.11 0.4 0.8 (% w/w) EX. 2.12 0.4 0.8 (% w/w) Ex. 2.13 0.4 0.8 (% w/w) Ex. 2.14 0.4 0.8 (% w/w) Ex. 2.15 0.08 (% w/w) Ex. 2.16 0.08 (% w/w) Ex. 2.17 0.08 (% w/w) Ex. 2.18 0.08 (% w/w) Ex. 2.19 0.08 (% w/w) Ex. 2.20 0.08 (% w/w) Ex. 2.21 0.08 (% w/w) Ex. 2.22 0.6 1.2 (% w/w) Ex. 2.23 0.6 1.2 (% w/w) Ex. 2.24 0.6 1.2 (% w/w) Ex. 2.25 0.6 1.2 (% w/w) Ex. 2.26 0.6 1.2 (% w/w) Ex. 2.27 0.6 1.2 (% w/w) Ex. 2.28 0.1 (% w/w) Ex. 2.29 0.1 (% w/w) Ex. 2.30 0.1 (% w/w) Ex. 2.31 0.1 (% w/w) Ex. 2.32 0.1 (% w/w) Ex. 2.33 0.1 (% w/w) Ex. 2.34 0.01 0.02 (% w/w) Ex. 2.35 0.01 0.02 (% w/w) Ex. 2.36 0.01 0.02 (% w/w) Ex. 2.37 0.01 0.02 (% w/w) Ex. 2.38 0.01 0.02 (% w/w) Ex. 2.39 0.01 0.02 (% w/w) Ex. 2.40 0.02 0.04 (% w/w) Ex. 2.41 0.02 0.04 (% w/w) Ex. 2.42 0.02 0.04 (% w/w) Ex. 2.43 0.02 0.04 (% w/w) Ex. 2.44 0.02 0.04 (% w/w) Ex. 2.45 0.02 0.04 (% w/w) Ex. 2.46 0.072 (% w/w) Ex. 2.47 0.072 (% w/w) Ex. 2.48 0.072 (% w/w) Ex 2.49 0.072 (% w/w) Ex. 2.50 0.072 (% w/w) Ex. 2.51 0.072 (% w/w) Ex. 2.52 0.072 (% w/w) Ex. 2.53 3.0 6.0 (% w/w) Ex. 2.54 3.0 6.0 (% w/w) Ex. 2.55 3.0 6.0 (% w/w) Ex. 2.56 3.0 6.0 (% w/w) Ex. 2.57 3.0 6.0 (% w/w) Ex. 2.58 3.0 6.0 (% w/w) Ex. 2.59 3.0 6.0 (% w/w) Ex. 2.60 0.8 (% w/w) Ex. 2.61 0.8 (% w/w) Ex. 2.62 0.8 (% w/w) Ex. 2.63 0.8 (% w/w) Ex. 2.64 0.8 (% w/w) Ex. 2.65 0.8 (% w/w) Ex. 2.66 0.8 (% w/w) Amount Content % (w/w) Lactose + 25 mg Salmeterol Formoterol Artormoterol indacaterol Olodaterol Vilanterol Carmeterol Mannitol Ex. 2.1 0.2 99.0 98.2 (% w/w) Ex. 2.2 0.02 0.05 99.18 98.35 (% w/w) Ex. 2.3 0.06 99.14 98.34 (% w/w) Ex. 2.4 0.6 98.6 97.8 (% w/w) Ex. 2.5 0.02 99.18 98.38 (% w/w) Ex. 2.6 0.1 99.1 98.3 (% w/w) Ex. 2.7 0.01 0.02 99.19 98.38 (% w/w) Ex. 2.8 0.2 99.4 99.0 (% w/w) Ex. 2.9 0.02 0.05 99.58 99.15 (% w/w) Ex. 2.10 0.06 99.54 99.32 (% w/w) Ex. 2.11 0.6 99.0 98.6 (% w/w) EX. 2.12 0.02 99.58 99.18 (% w/w) Ex. 2.13 0.1 99.5 99.1 (% w/w) Ex. 2.14 0.01 0.02 99.59 99.18 (% w/w) Ex. 2.15 0.2 99.72 (% w/w) Ex. 2.16 0.02 0.05 99.90 99.87 (% w/w) Ex. 2.17 0.06 99.86 (% w/w) Ex. 2.18 0.6 99.32 (% w/w) Ex. 2.19 0.02 99.9 (% w/w) Ex. 2.20 0.1 99.82 (% w/w) Ex. 2.21 0.01 0.02 99.91 99.90 (% w/w) Ex. 2.22 0.2 99.2 98.6 (% w/w) Ex. 2.23 0.02 0.05 99.38 98.75 (% w/w) Ex. 2.24 0.06 99.43 98.74 (% w/w) Ex. 2.25 0.02 99.38 98.78 (% w/w) Ex. 2.26 0.1 99.3 98.7 (% w/w) Ex. 2.27 0.01 0.02 99.39 98.78 (% w/w) Ex. 2.28 0.2 99.7 (% w/w) Ex. 2.29 0.02 0.05 99.88 99.85 (% w/w) Ex. 2.30 0.06 99.84 (% w/w) Ex. 2.31 0.6 99.3 (% w/w) Ex. 2.32 0.02 99.88 (% w/w) Ex. 2.33 0.01 0.02 99.89 99.88 (% w/w) Ex. 2.34 0.2 99.79 99.78 (% w/w) Ex. 2.35 0.02 0.05 99.97 99.93 (% w/w) Ex. 2.36 0.06 99.93 99.92 (% w/w) Ex. 2.37 0.6 99.39 99.38 (% w/w) Ex. 2.38 0.02 99.97 99.96 (% w/w) Ex. 2.39 0.1 99.89 99.88 (% w/w) Ex. 2.40 1.0 98.88 98.86 (% w/w) Ex. 2.41 0.02 0.05 99.96 99.91 (% w/w) Ex. 2.42 0.06 99.92 99.90 (% w/w) Ex. 2.43 0.6 99.38 99.36 (% w/w) Ex. 2.44 0.1 99.88 99.86 (% w/w) Ex. 2.45 0.01 0.02 99.97 99.94 (% w/w) Ex. 2.46 0.2 99.728 (% w/w) Ex. 2.47 0.02 0.05 99.908 99.878 (% w/w) Ex. 2.48 0.06 99.868 (% w/w) Ex 2.49 0.6 99.328 (% w/w) Ex. 2.50 0.02 99.908 (% w/w) Ex. 2.51 0.1 99.828 (% w/w) Ex. 2.52 0.01 0.02 99.918 99.908 (% w/w) Ex. 2.53 0.2 96.8 93.8 (% w/w) Ex. 2.54 0.02 0.05 96.98 93.95 (% w/w) Ex. 2.55 0.06 96.94 93.94 (% w/w) Ex. 2.56 0.6 96.4 93.4 (% w/w) Ex. 2.57 0.02 96.98 93.98 (% w/w) Ex. 2.58 0.1 96.9 93.9 (% w/w) Ex. 2.59 0.01 0.02 96.99 93.98 (% w/w) Ex. 2.60 0.2 99 (% w/w) Ex. 2.61 0.02 0.05 99.18 99.15 (% w/w) Ex. 2.62 0.06 99.14 (% w/w) Ex. 2.63 0.6 98.6 (% w/w) Ex. 2.64 0.02 99.18 (% w/w) Ex. 2.65 0.1 99.1 (% w/w) Ex. 2.66 0.01 0.02 99.9 99.18 (% w/w)

ExamplesC

(10) a)

(11) TABLE-US-00008 Content De{hacek over (g)}er % (w/w) Muscarinic receptor antagonist Beta-2 adrenerjik agonist Lactose + mannitol

(12) TABLE-US-00009 TABLE 3.1 Amount % (w/w) Content 5 mg Aklidinyum Glycopyrronium Daratropium indacaterol Vilanterol Carmeterol Olodaterol Ex. 3.1 (% w/w) 4.0 8.0 Ex. 3.2 (% w/w) 4.0 8.0 Ex. 3.3 (% w/w) 4.0 8.0 Ex. 3.4 (% w/w) 2.0 4.0 Ex. 3.5 (% w/w) 2.0 4.0 Ex. 3.6 (% w/w) 2.0 4.0 Ex. 3.7 (% w/w) 0.4 Ex. 3.8 (% w/w) 0.4 Ex. 3.9 (% w/w) 0.4 Ex. 3.10 (% w/w) 0.4 Ex. 3.11 (% w/w) 3.0 6.0 Ex. 3.12 (% w/w) 3.0 6.0 Ex. 3.13 (% w/w) 3.0 6.0 Ex. 3.14 (% w/w) 3.0 6.0 Ex. 3.15 (% w/w) 0.5 Ex. 3.16 (% w/w) 0.5 Ex. 3.17 (% w/w) 0.5 Ex. 3.18 (% w/w) 0.5 Ex. 3.19 (% w/w) 0.04 0.08 Ex. 3.20 (% w/w) 0.04 0.08 Ex. 3.21 (% w/w) 0.04 0.08 Ex. 3.22 (% w/w) 0.04 0.08 Ex. 3.23 (% w/w) 0.1 0.2 Ex. 3.24 (% w/w) 0.1 0.2 Ex. 3.25 (% w/w) 0.1 0.2 Ex. 3.26 (% w/w) 0.1 0.2 Amount % (w/w) Content 5 mg Tiotropium Glycopyrronium ipratropium Aklidinyum Lactose + Mannitol Ex. 3.1 (% w/w) 0.1 0.36 95.9 91.64 Ex. 3.2 (% w/w) 2.0 4.0 94.0 88.0 Ex. 3.3 (% w/w) 0.8 95.2 91.2 Ex. 3.4 (% w/w) 0.1 0.36 97.9 95.64 Ex. 3.5 (% w/w) 0.8 93.2 95.2 Ex. 3.6 (% w/w) 4.0 8.0 94.0 88.0 Ex. 3.7 (% w/w) 0.1 0.36 99.5 99.24 Ex. 3.8 (% w/w) 2.0 4.0 97.6 95.6 Ex. 3.9 (% w/w) 0.8 98.8 Ex. 3.10 (% w/w) 4.0 8.0 95.6 91.6 Ex. 3.11 (% w/w) 0.1 0.36 96.9 93.64 Ex. 3.12 (% w/w) 2.0 4.0 95.0 90.0 Ex. 3.13 (% w/w) 0.8 96.2 93.2 Ex. 3.14 (% w/w) 4.0 8.0 93.0 86.0 Ex. 3.15 (% w/w) 0.1 0.36 99.4 99.14 Ex. 3.16 (% w/w) 2.0 4.0 97.5 95.5 Ex. 3.17 (% w/w) 0.8 98.7 Ex. 3.18 (% w/w) 4.0 8.0 95.5 91.5 Ex. 3.19 (% w/w) 0.1 0.36 99.86 99.56 Ex. 3.20 (% w/w) 2.0 4.0 97.96 95.92 Ex. 3.21 (% w/w) 0.8 99.16 99.12 Ex. 3.22 (% w/w) 4.0 8.0 95.96 91.96 Ex. 3.23 (% w/w) 0.1 0.36 99.8 99.44 Ex. 3.24 (% w/w) 2.0 97.9 95.8 Ex. 3.25 (% w/w) 0.8 99.1 99.0 Ex. 3.26 (% w/w) 4.0 8.0 95.9 91.8

(13) TABLE-US-00010 TABLE 3.2 Amount % (w/w) Content 25 mg Aklidinyum Glycopyrronium Daratropium indacaterol Vilanterol Carmeterol Olodaterol Ex. 3.1 (% w/w) 0.8 1.6 Ex. 3.2 (% w/w) 0.8 1.6 Ex. 3.3 (% w/w) 0.8 1.6 Ex. 3.4 (% w/w) 0.4 0.8 Ex. 3.5 (% w/w) 0.4 0.8 Ex. 3.6 (% w/w) 0.08 Ex. 3.7 (% w/w) 0.08 Ex. 3.8 (% w/w) 0.08 Ex. 3.9 (% w/w) 0.08 Ex. 3.10 (% w/w) 0.6 1.2 Ex. 3.11 (% w/w) 0.6 1.2 Ex. 3.12 (% w/w) 0.6 1.2 Ex. 3.13 (% w/w) 0.6 1.2 Ex. 3.14 (% w/w) 0.1 Ex. 3.15 (% w/w) 0.1 Ex. 3.16 (% w/w) 0.1 Ex. 3.17 (% w/w) 0.1 Ex. 3.18 (% w/w) 0.01 0.02 Ex. 3.19 (% w/w) 0.01 0.02 Ex. 3.20 (% w/w) 0.01 0.02 Ex. 3.21 (% w/w) 0.01 0.02 Ex. 3.22 (% w/w) 0.02 0.04 Ex. 3.23 (% w/w) 0.02 0.04 Ex. 3.24 (% w/w) 0.02 0.04 Ex. 3.25 (% w/w) 0.02 0.04 Amount % (w/w) Content 25 mg Tiotropium Glycopyrronium ipratropium Aklidinyum Lactose + Mannitol Ex. 3.1 (% w/w) 0.072 0.02 99.13 98.38 Ex. 3.2 (% w/w) 0.4 0.8 98.8 97.6 Ex. 3.3 (% w/w) 0.16 99.04 98.24 Ex. 3.4 (% w/w) 0.072 0.02 99.53 99.18 Ex. 3.5 (% w/w) 0.16 99.44 99.02 Ex. 3.6 (% w/w) 0.072 0.02 99.85 99.90 Ex. 3.7 (% w/w) 0.4 0.8 99.52 99.12 Ex. 3.8 (% w/w) 0.16 99.76 Ex. 3.9 (% w/w) 0.8 1.6 99.12 98.32 Ex. 3.10 (% w/w) 0.072 0.02 99.33 98.78 Ex. 3.11 (% w/w) 0.4 0.8 99.0 98.0 Ex. 3.12 (% w/w) 0.16 99.24 98.64 Ex. 3.13 (% w/w) 0.8 1.6 98.6 97.2 Ex. 3.14 (% w/w) 0.072 0.02 99.83 99.88 Ex. 3.15 (% w/w) 0.4 0.8 99.5 99.1 Ex. 3.16 (% w/w) 0.16 99.74 Ex. 3.17 (% w/w) 0.8 1.6 99.1 98.3 Ex. 3.18 (% w/w) 0.072 0.02 99.92 99.96 Ex. 3.19 (% w/w) 0.4 0.8 99.59 99.18 Ex. 3.20 (% w/w) 0.16 99.83 99.82 Ex. 3.21 (% w/w) 0.8 1.6 99.19 98.38 Ex. 3.22 (% w/w) 0.072 0.02 99.91 99.94 Ex. 3.23 (% w/w) 0.4 0.8 99.58 99.16 Ex. 3.24 (% w/w) 0.16 99.82 99.80 Ex. 3.25 (% w/w) 0.8 1.6 99.18 98.36

ExamplesD

(14) a)

(15) TABLE-US-00011 Content De{hacek over (g)}er % (w/w) Muscarinic receptor antagonist Beta-2 adrenerjik agonist Lactose + mannitol

(16) TABLE-US-00012 TABLE 4.1 Amount % (w/w) Content 5 mg Aklidinyum Glycopyrronium Daratropium indacaterol Vilanterol Carmeterol Olodaterol Salbutamol Ex. 4.1 (% w/w) 4.0 8.0 2.0 Ex. 4.2 (% w/w) 4.0 8.0 Ex. 4.3 (% w/w) 4.0 8.0 Ex. 4.4 (% w/w) 4.0 8.0 Ex. 4.5 (% w/w) 4.0 8.0 Ex. 4.6 (% w/w) 4.0 8.0 Ex. 4.7 (% w/w) 2.0 4.0 2.0 Ex. 4.8 (% w/w) 2.0 4.0 Ex. 4.9 (% w/w) 2.0 4.0 Ex. 4.10 (% w/w) 2.0 4.0 Ex. 4.11 (% w/w) 2.0 4.0 Ex. 4.12 (% w/w) 2.0 4.0 Ex. 4.13 (% w/w) 0.4 2.0 Ex. 4.14 (% w/w) 0.4 Ex. 4.15 (% w/w) 0.4 Ex. 4.16 (% w/w) 0.4 Ex. 4.17 (% w/w) 0.4 Ex. 4.18 (% w/w) 0.4 Ex. 4.19 (% w/w) 3.0 6.0 2.0 Ex. 4.20 (% w/w) 3.0 6.0 Ex. 4.21 (% w/w) 3.0 6.0 Ex. 4.22 (% w/w) 3.0 6.0 Ex. 4.23 (% w/w) 3.0 6.0 Ex. 4.24 (% w/w) 3.0 6.0 Ex. 4.25 (% w/w) 0.5 2.0 Ex. 4.26 (% w/w) 0.5 Ex. 4.27 (% w/w) 0.5 Ex. 4.28 (% w/w) 0.5 Ex. 4.29 (% w/w) 0.5 Ex. 4.30 (% w/w) 0.5 Ex. 4.31 (% w/w) 0.04 0.08 2.0 Ex. 4.32 (% w/w) 0.04 0.08 Ex. 4.33 (% w/w) 0.04 0.08 Ex. 4.34 (% w/w) 0.04 0.08 Ex. 4.35 (% w/w) 0.04 0.08 Ex. 4.36 (% w/w) 0.04 0.08 Ex. 4.37 (% w/w) 0.1 0.2 2.0 Ex. 4.38 (% w/w) 0.1 0.2 Ex. 4.39 (% w/w) 0.1 0.2 Ex. 4.40 (% w/w) 0.1 0.2 Ex. 4.41 (% w/w) 0.1 0.2 Ex. 4.42 (% w/w) 0.1 0.2 Amount Content % (w/w) Terbutalin Pirbuterol Bitolterol Metaproterenol 5 mg Levosalbutamol 200 mcg 200 mcg 370 mcg 650 mcg Lactose + Mannitol Ex. 4.1 (% w/w) 94.0 90.0 Ex. 4.2 (% w/w) 1.0 95.0 91.0 Ex. 4.3 (% w/w) 4.0 92.0 88.0 Ex. 4.4 (% w/w) 4.0 92.0 88.0 Ex. 4.5 (% w/w) 7.4 88.6 84.6 Ex. 4.6 (% w/w) 13.0 83.0 79.0 Ex. 4.7 (% w/w) 96.0 94.0 Ex. 4.8 (% w/w) 1.0 97.0 95.0 Ex. 4.9 (% w/w) 4.0 94.0 92.0 Ex. 4.10 (% w/w) 4.0 94.0 92.0 Ex. 4.11 (% w/w) 7.4 90.6 88.6 Ex. 4.12 (% w/w) 13.0 85.0 83.0 Ex. 4.13 (% w/w) 97.6 Ex. 4.14 (% w/w) 1.0 98.6 Ex. 4.15 (% w/w) 4.0 95.6 Ex. 4.16 (% w/w) 4.0 95.6 Ex. 4.17 (% w/w) 7.4 92.2 Ex. 4.18 (% w/w) 13.0 86.6 Ex. 4.19 (% w/w) 95.0 92.0 Ex. 4.20 (% w/w) 1.0 96.0 93.0 Ex. 4.21 (% w/w) 4.0 93.0 90.0 Ex. 4.22 (% w/w) 4.0 93.0 90.0 Ex. 4.23 (% w/w) 7.4 89.6 86.6 Ex. 4.24 (% w/w) 13.0 84.0 81.0 Ex. 4.25 (% w/w) 97.5 Ex. 4.26 (% w/w) 1.0 98.5 Ex. 4.27 (% w/w) 4.0 95.5 Ex. 4.28 (% w/w) 4.0 95.5 Ex. 4.29 (% w/w) 7.4 92.1 Ex. 4.30 (% w/w) 13.0 86.5 Ex. 4.31 (% w/w) 97.96 97.92 Ex. 4.32 (% w/w) 1.0 98.96 98.92 Ex. 4.33 (% w/w) 4.0 95.96 95.92 Ex. 4.34 (% w/w) 4.0 95.96 95.92 Ex. 4.35 (% w/w) 7.4 92.56 92.52 Ex. 4.36 (% w/w) 13.0 86.96 86.92 Ex. 4.37 (% w/w) 97.9 97.8 Ex. 4.38 (% w/w) 1.0 98.9 98.8 Ex. 4.39 (% w/w) 4.0 95.9 95.8 Ex. 4.40 (% w/w) 4.0 95.9 95.8 Ex. 4.41 (% w/w) 7.4 92.5 92.4 Ex. 4.42 (% w/w) 13.0 86.9 86.8

(17) TABLE-US-00013 TABLE 4.2 Amount % (w/w) Content 25 mg Aklidinium Glycopyrronium Daratropium indacaterol Vilanterol Carmeterol Olodaterol Salbutamol Ex. 4.1 (% w/w) 0.8 1.6 0.4 Ex. 4.2 (% w/w) 0.8 1.6 Ex. 4.3 (% w/w) 0.8 1.6 Ex. 4.4 (% w/w) 0.8 1.6 Ex. 4.5 (% w/w) 0.8 1.6 Ex. 4.6 (% w/w) 0.8 1.6 Ex. 4.7 (% w/w) 0.4 0.8 0.4 Ex. 4.8 (% w/w) 0.4 0.8 Ex. 4.9 (% w/w) 0.4 0.8 Ex. 4.10 (% w/w) 0.4 0.8 Ex. 4.11 (% w/w) 0.4 0.8 Ex. 4.12 (% w/w) 0.4 0.8 Ex. 4.13 (% w/w) 0.08 0.4 Ex. 4.14 (% w/w) 0.08 Ex. 4.15 (% w/w) 0.08 Ex. 4.16 (% w/w) 0.08 Ex. 4.17 (% w/w) 0.08 Ex. 4.18 (% w/w) 0.08 Ex. 4.19 (% w/w) 0.6 1.2 Ex. 4.20 (% w/w) 0.6 1.2 Ex. 4.21 (% w/w) 0.6 1.2 Ex. 4.22 (% w/w) 0.6 1.2 Ex. 4.23 (% w/w) 0.6 1.2 Ex. 4.24 (% w/w) 0.6 1.2 Ex. 4.25 (% w/w) 0.1 0.4 Ex. 4.26 (% w/w) 0.1 Ex. 4.27 (% w/w) 0.1 Ex. 4.28 (% w/w) 0.1 Ex. 4.29 (% w/w) 0.1 Ex. 4.30 (% w/w) 0.1 Ex. 4.31 (% w/w) 0.01 0.02 0.4 Ex. 4.32 (% w/w) 0.01 0.02 Ex. 4.33 (% w/w) 0.01 0.02 Ex. 4.34 (% w/w) 0.01 0.02 Ex. 4.35 (% w/w) 0.01 0.02 Ex. 4.36 (% w/w) 0.01 0.02 Ex. 4.37 (% w/w) 0.02 0.04 0.4 Ex. 4.38 (% w/w) 0.02 0.04 Ex. 4.39 (% w/w) 0.02 0.04 Ex. 4.40 (% w/w) 0.02 0.04 Ex. 4.41 (% w/w) 0.02 0.04 Ex. 4.42 (% w/w) 0.02 0.04 Amount Content % (w/w) Terbutaline Pirbuterol Bitolterol Metaproterenol 25 mg Levosalbutamol 200 mcg 200 mcg 370 mcg 650 mcg Lactose + Mannitol Ex. 4.1 (% w/w) 98.8 98.0 Ex. 4.2 (% w/w) 0.2 99.0 98.2 Ex. 4.3 (% w/w) 0.8 98.4 97.6 Ex. 4.4 (% w/w) 0.8 98.4 97.6 Ex. 4.5 (% w/w) 1.5 97.7 96.9 Ex. 4.6 (% w/w) 2.6 96.6 95.8 Ex. 4.7 (% w/w) 99.2 98.8 Ex. 4.8 (% w/w) 0.2 99.4 99.0 Ex. 4.9 (% w/w) 0.8 98.8 98.4 Ex. 4.10 (% w/w) 0.8 98.8 98.4 Ex. 4.11 (% w/w) 1.5 98.1 97.7 Ex. 4.12 (% w/w) 2.6 97.0 96.6 Ex. 4.13 (% w/w) 99.52 Ex. 4.14 (% w/w) 0.2 99.72 Ex. 4.15 (% w/w) 0.8 99.12 Ex. 4.16 (% w/w) 0.8 99.12 Ex. 4.17 (% w/w) 1.5 98.42 Ex. 4.18 (% w/w) 2.6 97.32 Ex. 4.19 (% w/w) 99.0 98.4 Ex. 4.20 (% w/w) 0.2 99.2 98.6 Ex. 4.21 (% w/w) 0.8 98.6 98.0 Ex. 4.22 (% w/w) 0.8 98.6 98.0 Ex. 4.23 (% w/w) 1.5 97.9 97.3 Ex. 4.24 (% w/w) 2.6 96.8 96.2 Ex. 4.25 (% w/w) 99.5 Ex. 4.26 (% w/w) 0.2 99.7 Ex. 4.27 (% w/w) 0.8 99.1 Ex. 4.28 (% w/w) 0.8 99.1 Ex. 4.29 (% w/w) 1.5 98.4 Ex. 4.30 (% w/w) 2.6 97.3 Ex. 4.31 (% w/w) 99.59 99.58 Ex. 4.32 (% w/w) 0.2 99.79 99.78 Ex. 4.33 (% w/w) 0.8 99.19 99.18 Ex. 4.34 (% w/w) 0.8 99.19 99.18 Ex. 4.35 (% w/w) 1.5 98.49 98.48 Ex. 4.36 (% w/w) 2.6 97.39 97.38 Ex. 4.37 (% w/w) 99.58 99.56 Ex. 4.38 (% w/w) 0.2 99.78 99.76 Ex. 4.39 (% w/w) 0.8 99.18 99.14 Ex. 4.40 (% w/w) 0.8 99.18 99.14 Ex. 4.41 (% w/w) 1.5 98.48 98.44 Ex. 4.42 (% w/w) 2.6 97.38 97.34

ExamplesE

(18) a)

(19) TABLE-US-00014 Content Amount % (w/w) Muscarinic receptor antagonist Beta-2 adrenerjik agonist Corticosteroid Lactose + mannitol

(20) TABLE-US-00015 TABLE 6.1 Amount % (w/w) Content 5 mg Aklidinyum Glycopyrronium Daratropium indacaterol Vilanterol Carmeterol Olodaterol Ex. 5.1 (% w/w) 4.0 8.0 Ex. 5.2 (% w/w) 4.0 8.0 Ex. 5.3 (% w/w) 4.0 8.0 Ex. 5.4 (% w/w) 4.0 8.0 Ex. 5.5 (% w/w) 4.0 8.0 Ex. 5.9 (% w/w) 2.0 4.0 Ex. 5.10 (% w/w) 2.0 4.0 Ex. 5.11 (% w/w) 2.0 4.0 Ex. 5.12 (% w/w) 2.0 4.0 Ex. 5.13 (% w/w) 2.0 4.0 Ex. 5.17 (% w/w) 0.4 Ex. 5.18 (% w/w) 0.4 Ex. 5.19 (% w/w) 0.4 Ex. 5.20 (% w/w) 0.4 Ex. 5.21 (% w/w) 0.4 Ex. 5.25 (% w/w) 3.0 6.0 Ex. 5.26 (% w/w) 3.0 6.0 Ex. 5.27 (% w/w) 3.0 6.0 Ex. 5.28 (% w/w) 3.0 6.0 Ex. 5.29 (% w/w) 3.0 6.0 Ex. 5.33 (% w/w) 0.5 Ex. 5.34 (% w/w) 0.5 Ex. 5.35 (% w/w) 0.5 Ex. 5.36 (% w/w) 0.5 Ex. 5.37 (% w/w) 0.5 Ex. 5.41 (% w/w) 0.04 0.08 Ex. 5.42 (% w/w) 0.04 0.08 Ex. 5.43 (% w/w) 0.04 0.08 Ex. 5.44 (% w/w) 0.04 0.08 Ex. 5.45 (% w/w) 0.04 0.08 Ex. 5.49 (% w/w) 0.1 0.2 Ex. 5.50 (% w/w) 0.1 0.2 Ex. 5.51 (% w/w) 0.1 0.2 Ex. 5.52 (% w/w) 0.1 0.2 Ex. 5.53 (% w/w) 0.1 0.2 Amount % (w/w) Content 5 mg Flutikason Siklesoinid Budesonid Mometazon Beklometazon Lactose + Mannitol Ex. 5.1 (% w/w) 2.0 10.0 94.0 82.0 Ex. 5.2 (% w/w) 4.0 88.0 Ex. 5.3 (% w/w) 4.0 8.0 92.0 84.0 Ex. 5.4 (% w/w) 2.0 4.0 94.0 88.0 Ex. 5.5 (% w/w) 2.0 8.0 94.0 84.0 Ex. 5.9 (% w/w) 2.0 10.0 96.0 86.0 Ex. 5.10 (% w/w) 4.0 94.0 92.0 Ex. 5.11 (% w/w) 4.0 8.0 94.0 88.0 Ex. 5.12 (% w/w) 2.0 4.0 96.0 92.0 Ex. 5.13 (% w/w) 2.0 8.0 96.0 88.0 Ex. 5.17 (% w/w) 10.0 97.6 89.6 Ex. 5.18 (% w/w) 4.0 95.6 Ex. 5.19 (% w/w) 4.0 8.0 95.6 91.6 Ex. 5.20 (% w/w) 2.0 4.0 97.6 95.6 Ex. 5.21 (% w/w) 2.0 8.0 97.6 91.6 Ex. 5.25 (% w/w) 2.0 10.0 95.0 84.0 Ex. 5.26 (% w/w) 4.0 93.0 90.0 Ex. 5.27 (% w/w) 4.0 8.0 93.0 96.0 Ex. 5.28 (% w/w) 2.0 4.0 95.0 90.0 Ex. 5.29 (% w/w) 2.0 8.0 95.0 86.0 Ex. 5.33 (% w/w) 2.0 10.0 97.5 89.5 Ex. 5.34 (% w/w) 4.0 95.5 Ex. 5.35 (% w/w) 4.0 8.0 95.5 91.5 Ex. 5.36 (% w/w) 2.0 4.0 97.5 95.5 Ex. 5.37 (% w/w) 2.0 8.0 97.5 91.5 Ex. 5.41 (% w/w) 2.0 10.0 97.96 89.92 Ex. 5.42 (% w/w) 4.0 95.96 Ex. 5.43 (% w/w) 4.0 8.0 95.96 91.96 Ex. 5.44 (% w/w) 2.0 4.0 97.96 95.96 Ex. 5.45 (% w/w) 2.0 8.0 97.96 91.97 Ex. 5.49 (% w/w) 2.0 10.0 97.9 89.8 Ex. 5.50 (% w/w) 4.0 95.9 95.8 Ex. 5.51 (% w/w) 4.0 8.0 95.9 91.8 Ex. 5.52 (% w/w) 2.0 4.0 97.9 95.8 Ex. 5.53 (% w/w) 2.0 8.0 97.9 91.8

(21) TABLE-US-00016 TABLE 6.2 Amount % (w/w) Content 25 mg Aklidinyum Glycopyrronium Daratropium indacaterol Vilanterol Carmeterol Olodaterol Ex. 5.1 (% w/w) 0.8 1.6 Ex. 5.2 (% w/w) 0.8 1.6 Ex. 5.3 (% w/w) 0.8 1.6 Ex. 5.4 (% w/w) 0.8 1.6 Ex. 5.5 (% w/w) 0.8 1.6 Ex. 5.9 (% w/w) 0.4 0.8 Ex. 5.10 (% w/w) 0.4 0.8 Ex. 5.11 (% w/w) 0.4 0.8 Ex. 5.12 (% w/w) 0.4 0.8 Ex. 5.13 (% w/w) 0.4 0.8 Ex. 5.17 (% w/w) 0.08 Ex. 5.18 (% w/w) 0.08 Ex. 5.19 (% w/w) 0.08 Ex. 5.20 (% w/w) 0.08 Ex. 5.21 (% w/w) 0.08 Ex. 5.25 (% w/w) 0.6 1.2 Ex. 5.26 (% w/w) 0.6 1.2 Ex. 5.27 (% w/w) 0.6 1.2 Ex. 5.28 (% w/w) 0.6 1.2 Ex. 5.29 (% w/w) 0.6 1.2 Ex. 5.33 (% w/w) 0.1 Ex. 5.34 (% w/w) 0.1 Ex. 5.35 (% w/w) 0.1 Ex. 5.36 (% w/w) 0.1 Ex. 5.37 (% w/w) 0.1 Ex. 5.41 (% w/w) 0.01 0.02 Ex. 5.42 (% w/w) 0.01 0.02 Ex. 5.43 (% w/w) 0.01 0.02 Ex. 5.44 (% w/w) 0.01 0.02 Ex. 5.45 (% w/w) 0.01 0.02 Ex. 5.49 (% w/w) 0.02 0.04 Ex. 5.50 (% w/w) 0.02 0.04 Ex. 5.51 (% w/w) 0.02 0.04 Ex. 5.52 (% w/w) 0.02 0.04 Ex. 5.53 (% w/w) 0.02 0.04 Amount % (w/w) Content 25 mg Fluticasone Siklesoinid Budesonid Mometazon Beklametazon Lactose + Mannitol Ex. 5.1 (% w/w) 0.4 2.0 98.8 96.4 Ex. 5.2 (% w/w) 0.8 97.6 Ex. 5.3 (% w/w) 0.8 1.6 98.4 96.8 Ex. 5.4 (% w/w) 0.4 0.8 98.8 97.6 Ex. 5.5 (% w/w) 0.4 1.6 99.88 Ex. 5.9 (% w/w) 0.4 99.2 97.2 Ex. 5.10 (% w/w) 0.8 98.8 98.4 Ex. 5.11 (% w/w) 0.8 1.6 98.2 97.6 Ex. 5.12 (% w/w) 0.4 0.8 99.2 97.6 Ex. 5.13 (% w/w) 0.4 1.6 99.2 97.6 Ex. 5.17 (% w/w) 2.0 99.52 97.92 Ex. 5.18 (% w/w) 0.8 99.12 Ex. 5.19 (% w/w) 0.8 1.6 99.12 98.32 Ex. 5.20 (% w/w) 0.4 0.8 99.52 99.12 Ex. 5.21 (% w/w) 0.4 1.6 99.52 98.32 Ex. 5.25 (% w/w) 0.4 2.0 99.0 96.8 Ex. 5.26 (% w/w) 0.8 98.6 98.0 Ex. 5.27 (% w/w) 0.8 1.6 98.6 97.2 Ex. 5.28 (% w/w) 0.4 0.8 99.0 98.0 Ex. 5.29 (% w/w) 0.4 1.6 99.0 97.2 Ex. 5.33 (% w/w) 0.4 2.0 99.5 97.9 Ex. 5.34 (% w/w) 0.8 99.1 Ex. 5.35 (% w/w) 0.8 1.6 99.1 98.3 Ex. 5.36 (% w/w) 0.4 0.8 99.5 99.1 Ex. 5.37 (% w/w) 0.4 1.6 99.5 98.3 Ex. 5.41 (% w/w) 0.4 2.0 99.59 97.98 Ex. 5.42 (% w/w) 0.8 99.19 99.18 Ex. 5.43 (% w/w) 0.8 1.6 99.19 98.38 Ex. 5.44 (% w/w) 0.4 0.8 99.59 99.18 Ex. 5.45 (% w/w) 0.4 1.6 99.59 98.38 Ex. 5.49 (% w/w) 0.4 2.0 99.58 97.96 Ex. 5.50 (% w/w) 0.8 99.18 99.16 Ex. 5.51 (% w/w) 0.8 1.6 99.18 98.36 Ex. 5.52 (% w/w) 0.4 0.8 99.58 99.16 Ex. 5.53 (% w/w) 0.4 1.6 99.58 98.36
rnekF

(22) TABLE-US-00017 Content Amount % (w/w) Muscarinic receptor antagonist Corticosteroid Lactose + mannitol

(23) TABLE-US-00018 TABLE 7.1 Amount % (w/w) Content 5 mg Aklidinyum Glycopyrronium Daratropium Tiotropium ipratropium Oxitropium Fluticasone Ex. 5.1 (% w/w) 4.0 8.0 2.0 10.0 Ex. 5.2 (% w/w) 4.0 8.0 Ex. 5.3 (% w/w) 4.0 8.0 Ex. 5.4 (% w/w) 4.0 8.0 Ex. 5.5 (% w/w) 4.0 8.0 Ex. 5.9 (% w/w) 2.0 4.0 2.0 10.0 Ex. 5.10 (% w/w) 2.0 4.0 Ex. 5.11 (% w/w) 2.0 4.0 Ex. 5.12 (% w/w) 2.0 4.0 Ex. 5.13 (% w/w) 2.0 4.0 Ex. 5.17 (% w/w) 0.4 10.0 Ex. 5.18 (% w/w) 0.4 Ex. 5.19 (% w/w) 0.4 Ex. 5.20 (% w/w) 0.4 Ex. 5.21 (% w/w) 0.4 Ex. 5.25 (% w/w) 0.36 2.0 10.0 Ex. 5.26 (% w/w) 0.36 Ex. 5.27 (% w/w) 0.36 Ex. 5.28 (% w/w) 0.36 Ex. 5.29 (% w/w) 0.36 Ex. 5.33 (% w/w) 3 6 2.0 10.0 Ex. 5.34 (% w/w) 3 6 Ex. 5.35 (% w/w) 3 6 Ex. 5.36 (% w/w) 3 6 Ex. 5.37 (% w/w) 3 6 Ex. 5.41 (% w/w) 4 2.0 10.0 Ex. 5.42 (% w/w) 4 Ex. 5.43 (% w/w) 4 Ex. 5.44 (% w/w) 4 Ex. 5.45 (% w/w) 4 Ex. 5.49 (% w/w) 2.0 10.0 Ex. 5.50 (% w/w) Ex. 5.51 (% w/w) Ex. 5.52 (% w/w) Ex. 5.53 (% w/w) Amount % (w/w) Content 5 mg Ciclesonide Budesonid Mometazon Beklametazon Lactose + Mannitol Ex. 5.1 (% w/w) 94.0 82.0 Ex. 5.2 (% w/w) 4.0 88.0 Ex. 5.3 (% w/w) 4.0 8.0 92.0 84.0 Ex. 5.4 (% w/w) 2.0 4.0 94.0 88.0 Ex. 5.5 (% w/w) 2.0 8.0 94.0 84.0 Ex. 5.9 (% w/w) 96.0 86.0 Ex. 5.10 (% w/w) 4.0 94.0 92.0 Ex. 5.11 (% w/w) 4.0 8.0 94.0 88.0 Ex. 5.12 (% w/w) 2.0 4.0 96.0 92.0 Ex. 5.13 (% w/w) 2.0 8.0 96.0 88.0 Ex. 5.17 (% w/w) 97.6 89.6 Ex. 5.18 (% w/w) 4.0 95.6 Ex. 5.19 (% w/w) 4.0 8.0 95.6 91.6 Ex. 5.20 (% w/w) 2.0 4.0 97.6 95.6 Ex. 5.21 (% w/w) 2.0 8.0 97.6 91.6 Ex. 5.25 (% w/w) 97.64 89.64 Ex. 5.26 (% w/w) 4.0 95.64 Ex. 5.27 (% w/w) 4.0 8.0 95.64 91.64 Ex. 5.28 (% w/w) 2.0 4.0 97.64 95.64 Ex. 5.29 (% w/w) 2.0 8.0 97.64 91.64 Ex. 5.33 (% w/w) 97.5 89.5 Ex. 5.34 (% w/w) 4.0 93 90 Ex. 5.35 (% w/w) 4.0 8.0 93 86 Ex. 5.36 (% w/w) 2.0 4.0 95 90 Ex. 5.37 (% w/w) 2.0 8.0 95 86 Ex. 5.41 (% w/w) 94 86 Ex. 5.42 (% w/w) 4.0 92 Ex. 5.43 (% w/w) 4.0 8.0 92 88 Ex. 5.44 (% w/w) 2.0 4.0 94 92 Ex. 5.45 (% w/w) 2.0 8.0 96 88 Ex. 5.49 (% w/w) 97.9 89.8 Ex. 5.50 (% w/w) 4.0 95.9 95.8 Ex. 5.51 (% w/w) 4.0 8.0 95.9 91.8 Ex. 5.52 (% w/w) 2.0 4.0 97.9 95.8 Ex. 5.53 (% w/w) 2.0 8.0 97.9 91.8

(24) TABLE-US-00019 TABLE 7.2 Amount % (w/w) Content 25 mg Aklidinyum Glycopyrronium Daratropium Tiotropium ipratropium Oxitropium Fluticazon Ex. 5.1 (% w/w) 0.8 1.6 0.4 2.0 Ex. 5.2 (% w/w) 0.8 1.6 Ex. 5.3 (% w/w) 0.8 1.6 Ex. 5.4 (% w/w) 0.8 1.6 Ex. 5.5 (% w/w) 0.8 1.6 Ex. 5.9 (% w/w) 0.4 0.8 0.4 Ex. 5.10 (% w/w) 0.4 0.8 Ex. 5.11 (% w/w) 0.4 0.8 Ex. 5.12 (% w/w) 0.4 0.8 Ex. 5.13 (% w/w) 0.4 0.8 Ex. 5.17 (% w/w) 0.08 2.0 Ex. 5.18 (% w/w) 0.08 Ex. 5.19 (% w/w) 0.08 Ex. 5.20 (% w/w) 0.08 Ex. 5.21 (% w/w) 0.08 Ex. 5.25 (% w/w) 0.072 0.4 2.0 Ex. 5.26 (% w/w) 0.072 Ex. 5.27 (% w/w) 0.072 Ex. 5.28 (% w/w) 0.072 Ex. 5.29 (% w/w) 0.072 Ex. 5.33 (% w/w) 3 6 0.4 2.0 Ex. 5.34 (% w/w) 3 6 Ex. 5.35 (% w/w) 3 6 Ex. 5.36 (% w/w) 3 6 Ex. 5.37 (% w/w) 3 6 Ex. 5.41 (% w/w) 0.8 0.4 2.0 Ex. 5.42 (% w/w) 0.8 Ex. 5.43 (% w/w) 0.8 Ex. 5.44 (% w/w) 0.8 Ex. 5.45 (% w/w) 0.8 Ex. 5.49 (% w/w) 0.4 2.0 Ex. 5.50 (% w/w) Ex. 5.51 (% w/w) Ex. 5.52 (% w/w) Ex. 5.53 (% w/w) Amount % (w/w) Content 25 mg Ciclesonide Budesonid Mometason Beklametazon Lactose + Mannitol Ex. 5.1 (% w/w) 98.8 96.4 Ex. 5.2 (% w/w) 0.8 97.6 Ex. 5.3 (% w/w) 0.8 1.6 98.4 96.8 Ex. 5.4 (% w/w) 0.4 0.8 98.8 97.6 Ex. 5.5 (% w/w) 0.4 1.6 99.88 Ex. 5.9 (% w/w) 99.2 97.2 Ex. 5.10 (% w/w) 0.8 98.8 98.4 Ex. 5.11 (% w/w) 0.8 1.6 98.2 97.6 Ex. 5.12 (% w/w) 0.4 0.8 99.2 97.6 Ex. 5.13 (% w/w) 0.4 1.6 99.2 97.6 Ex. 5.17 (% w/w) 99.52 97.92 Ex. 5.18 (% w/w) 0.8 99.12 Ex. 5.19 (% w/w) 0.8 1.6 99.12 98.32 Ex. 5.20 (% w/w) 0.4 0.8 99.52 99.12 Ex. 5.21 (% w/w) 0.4 1.6 99.52 98.32 Ex. 5.25 (% w/w) 99.0 96.8 Ex. 5.26 (% w/w) 0.8 98.6 98.0 Ex. 5.27 (% w/w) 0.8 1.6 98.6 97.2 Ex. 5.28 (% w/w) 0.4 0.8 99.0 98.0 Ex. 5.29 (% w/w) 0.4 1.6 99.0 97.2 Ex. 5.33 (% w/w) 96.6 92 Ex. 5.34 (% w/w) 0.8 96.2 93.2 Ex. 5.35 (% w/w) 0.8 1.6 96.2 92.4 Ex. 5.36 (% w/w) 0.4 0.8 96.6 93.2 Ex. 5.37 (% w/w) 0.4 1.6 96.6 92.4 Ex. 5.41 (% w/w) 98.8 97.2 Ex. 5.42 (% w/w) 0.8 98.4 Ex. 5.43 (% w/w) 0.8 1.6 98.4 97.6 Ex. 5.44 (% w/w) 0.4 0.8 98.8 98.4 Ex. 5.45 (% w/w) 0.4 1.6 98.2 97.6 Ex. 5.49 (% w/w) 99.58 97.96 Ex. 5.50 (% w/w) 0.8 99.18 99.16 Ex. 5.51 (% w/w) 0.8 1.6 99.18 98.36 Ex. 5.52 (% w/w) 0.4 0.8 99.58 99.16 Ex. 5.53 (% w/w) 0.4 1.6 99.58 98.36
rnekG

(25) TABLE-US-00020 Content % Weight (w/w) Muscarinic receptor antagonist Corticosteroid Lactose Mannitol
1

(26) TABLE-US-00021 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Budesonid 0.2 0.8 0.2 4 Lactose 1.2391 4.9564 0.2391 4.782 Mannitol 23.5429 94.1716 4.5429 90.858 TOTAL 25 5
2

(27) TABLE-US-00022 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Budesonid 0.2 0.8 0.2 4 Mannitol 1.2391 4.9564 0.2391 4.782 Lactose 23.5429 94.1716 4.5429 90.858 TOTAL 25 5
3

(28) TABLE-US-00023 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Budesonid 0.4 1.6 0.4 8 Lactose 1.2291 4.9164 0.2291 4.582 Mannitol 23.3529 93.4116 4.3529 87.058 TOTAL 25 5
4

(29) TABLE-US-00024 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Budesonid 0.4 1.6 0.4 8 Mannitol 1.2291 4.9164 0.2291 4.582 Lactose 23.3529 93.4116 4.3529 87.058 TOTAL 25 5
5

(30) TABLE-US-00025 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Fluticasone 0.1 0.4 0.1 2 Lactose 1.2441 4.9764 0.2441 4.882 Mannitol 23.6379 94.5516 4.6379 92.758 TOTAL 25 5
6

(31) TABLE-US-00026 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Fluticasone 0.1 0.4 0.1 2 Mannitol 1.2441 4.9764 0.2441 4.882 Lactose 23.6379 64.5516 4.6379 92.758 TOTAL 25 5
7

(32) TABLE-US-00027 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Fluticasone 0.25 1 0.25 5 Lactose 1.2366 4.9464 0.2366 4.732 Mannitol 23.4954 93.9816 4.4954 89.908 TOTAL 25 5
8

(33) TABLE-US-00028 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Fluticasone 0.25 1 0.25 5 Mannitol 1.2366 4.9464 0.2366 4.732 Lactose 23.4954 93.9816 4.4954 89.908 TOTAL 25 5
9

(34) TABLE-US-00029 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Fluticasone 0.05 0.2 0.05 1 Lactose 1.2466 4.9864 0.2466 4.932 Mannitol 23.6854 94.7416 4.6854 93.708 TOTAL 25 5
10

(35) TABLE-US-00030 Weight and percentage amount Content 25 mg % 5 mg % Tiotropium 0.018 0.072 0.018 0.36 Fluticasone 0.05 0.2 0.05 1 Mannitol 1.2466 4.9864 0.2466 4.932 Lactose 23.6854 94.7416 4.6854 93.708 TOTAL 25 5

ExamplesF

(36) TABLE-US-00031 Content % Weight (w/w) Corticosteroid 2-adrenerjik agonist Muscarinic receptor antagonist Lactose Mannitol eksipiyan
1

(37) TABLE-US-00032 Weight and percentage amount Content mg % mg % Budesonid 0.2 0.8 0.2 4 Formoterol 0.012 0.048 0.012 0.24 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2385 4.954 0.2385 4.77 Mannitol 23.5315 94.126 4.5315 90.63 TOTAL 25 100 5 100
2

(38) TABLE-US-00033 Weight and percentage amount Content mg % mg % Budesonid 0.2 0.8 0.2 4 Formoterol 0.012 0.048 0.012 0.24 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2385 4.954 0.2385 4.77 Lactose 23.5315 94.126 4.5315 90.63 TOTAL 25 5
3

(39) TABLE-US-00034 Weight and percentage amount Content mg % mg % Budesonid 0.4 1.6 0.4 8 Formoterol 0.012 0.048 0.012 0.24 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2285 4.914 0.2285 4.57 Mannitol 23.3415 93.366 4.3415 86.83 TOTAL 25 100 5 100
4

(40) TABLE-US-00035 Weight and percentage amount Content mg % mg % Budesonid 0.4 1.6 0.4 8 Formoterol 0.012 0.048 0.012 0.24 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2285 4.914 0.2285 4.57 Lactose 23.3415 93.366 4.3415 86.83 TOTAL 25 5
5

(41) TABLE-US-00036 Weight and percentage amount Content mg % mg % Ciclesonide 0.2 0.8 0.2 4 Formoterol 0.006 0.024 0.006 0.12 Tiotropium 0.009 0.036 0.009 0.18 Lactose 1.23925 4.957 0.23925 4.785 Mannitol 23.54575 94.183 4.54575 90.915 TOTAL 25 5
6

(42) TABLE-US-00037 Weight and percentage amount Content mg % mg % Ciclesonide 0.2 0.8 0.2 4 Formoterol 0.006 0.024 0.006 0.12 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2388 4.9552 0.2388 4.776 Lactose 23.5372 94.1488 4.5372 90.744 TOTAL 25 5
7

(43) TABLE-US-00038 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 salmeterol 0.05 0.2 0.05 1 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2416 4.9664 0.2416 4.832 Mannitol 23.5904 94.3616 4.5904 91.808 TOTAL 25 5
8

(44) TABLE-US-00039 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 salmeterol 0.05 0.2 0.05 1 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2416 4.9664 0.2416 4.832 Lactose 23.5904 94.3616 4.5904 91.808 TOTAL 25 5
9

(45) TABLE-US-00040 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 salmeterol 0.05 0.2 0.05 1 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2341 4.9364 0.2341 4.682 Mannitol 23.4479 93.7916 4.4479 8.958 TOTAL 25 5
10

(46) TABLE-US-00041 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 salmeterol 0.05 0.2 0.05 1 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2341 4.9364 0.2341 4.682 Lactose 23.4479 93.7916 4.4479 88.958 TOTAL 25 5
11

(47) TABLE-US-00042 Weight and percentage amount Content mg % mg % Fluticasone 0.05 0.2 0.05 1 salmeterol 0.05 0.2 0.05 1 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2441 4.9764 0.2441 4.882 Mannitol 23.6379 94.5516 4.6379 92.758 TOTAL 25 5
12

(48) TABLE-US-00043 Weight and percentage amount Content mg % mg % Fluticasone 0.05 0.2 0.05 1 salmeterol 0.05 0.2 0.05 1 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2441 4.9764 0.2441 4.882 Lactose 23.6379 94.5516 4.6379 92.758 TOTAL 25 5
13

(49) TABLE-US-00044 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 Arformeterol 0.015 0.06 0.015 0.3 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.24335 4.9734 0.24335 4.867 Mannitol 23.62365 94.4946 4.62365 92.473 TOTAL 25 5
14

(50) TABLE-US-00045 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 Arformeterol 0.015 0.06 0.015 0.3 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.24335 4.9734 0.24335 4.867 Lactose 23.62365 94.4946 4.62365 92.473 TOTAL 25 5
15

(51) TABLE-US-00046 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 Arformeterol 0.015 0.06 0.015 0.3 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.23585 4.9434 0.23585 4.717 Mannitol 23.48115 93.9246 4.48115 89.623 TOTAL 25 5
16

(52) TABLE-US-00047 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 Arformeterol 0.015 0.06 0.015 0.3 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.23585 4.9434 0.23585 4.717 Lactose 23.48115 93.9246 4.48115 89.623 TOTAL 25 5
17

(53) TABLE-US-00048 Weight and percentage amount Content mg % mg % Fluticasone 0.05 0.2 0.05 1 Arformeterol 0.015 0.06 0.015 0.3 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.24585 4.9834 0.24585 4.917 Mannitol 23.67115 94.6846 4.67115 93.423 TOTAL 25 5
18

(54) TABLE-US-00049 Weight and percentage amount Content mg % mg % Fluticasone 0.05 0.2 0.05 1 Arformeterol 0.015 0.06 0.015 0.3 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.24585 4.9834 0.24585 4.917 Lactose 23.67115 94.6846 4.67115 93.423 TOTAL 25 5
19

(55) TABLE-US-00050 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2366 4.9464 0.2366 4.732 Mannitol 23.4954 93.9816 4.4954 89.908 TOTAL 25 5
20

(56) TABLE-US-00051 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2366 4.9464 0.2366 4.732 Lactose 23.4954 93.9816 4.4954 89.908 TOTAL 25 5
21

(57) TABLE-US-00052 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2291 4.9164 0.2291 4.582 Mannitol 23.3529 93.4116 4.3529 87.058 TOTAL 25 5
22

(58) TABLE-US-00053 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2291 4.9164 0.2291 4.582 Lactose 23.3529 93.4116 4.3529 87.058 TOTAL 25 5
23

(59) TABLE-US-00054 Weight and percentage amount Content mg % mg % Fluticasone 0.05 0.2 0.05 1 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2391 4.9564 0.2391 4.782 Mannitol 23.5429 94.1716 4.5429 90.858 TOTAL 25 5
24

(60) TABLE-US-00055 Weight and percentage amount Content mg % mg % Fluticasone 0.05 0.2 0.05 1 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2391 4.9564 0.2391 4.782 Lactose 23.5429 94.1716 4.5429 90.858 TOTAL 25 5
25

(61) TABLE-US-00056 Weight and percentage amount Content mg % mg % Budesonid 0.2 0.8 0.2 4 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2316 4.9264 0.2316 4.632 Mannitol 23.4004 93.6016 4.4004 88.008 TOTAL 25 5
26

(62) TABLE-US-00057 Weight and percentage amount Content mg % mg % Budesonid 0.2 0.8 0.2 4 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2316 4.9264 0.2316 4.632 Lactose 23.4004 93.6016 4.4004 88.008 TOTAL 25 5
27

(63) TABLE-US-00058 Weight and percentage amount Content mg % mg % Budesonid 0.4 1.6 0.4 8 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.2216 4.8864 0.2216 4.432 Mannitol 23.2104 92.8416 4.2104 84.208 TOTAL 25 5
28

(64) TABLE-US-00059 Weight and percentage amount Content mg % mg % Budesonid 0.4 1.6 0.4 8 Indacaterol 0.15 0.6 0.15 3 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.2216 4.8864 0.2216 4.432 Lactose 23.2104 92.8416 4.2104 84.208 TOTAL 25 5
29

(65) TABLE-US-00060 Weight and percentage amount Content mg % mg % Budesonid 0.2 0.8 0.2 4 Olodeterol 0.005 0.02 0.005 0.1 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.23885 4.9554 0.23885 4.777 Mannitol 23.53815 94.1526 4.53815 90.763 TOTAL 25 5
30

(66) TABLE-US-00061 Weight and percentage amount Content mg % mg % Budesonid 0.2 0.8 0.2 4 Olodeterol 0.005 0.02 0.005 0.1 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.23885 4.9554 0.23885 4.777 Lactose 23.53815 94.1526 4.53815 90.763 TOTAL 25 5
31

(67) TABLE-US-00062 Weight and percentage amount Content mg % mg % Budesonid 0.4 1.6 0.4 8 Olodeterol 0.005 0.02 0.005 0.1 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.22885 4.9154 0.22885 4.577 Mannitol 23.34815 93.3926 4.34815 86.963 TOTAL 25 5
32

(68) TABLE-US-00063 Weight and percentage amount Content mg % mg % Budesonid 0.4 1.6 0.4 8 Olodeterol 0.005 0.02 0.005 0.1 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.22885 4.9154 0.22885 4.577 Lactose 23.34815 93.3926 4.34815 86.963 TOTAL 25 5
33

(69) TABLE-US-00064 Weight and percentage amount Content mg % mg % Budesonid 0.2 0.8 0.2 4 Vilanterol 0.025 0.1 0.025 0.5 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.23785 4.9514 0.23785 4.757 Mannitol 23.51915 94.0766 4.51915 90.383 TOTAL 25 5
34

(70) TABLE-US-00065 Weight and percentage amount Content mg % mg % Budesonid 0.2 0.8 0.2 4 Vilanterol 0.025 0.1 0.025 0.5 Tiotropium 0.018 0.072 0.018 0.36 Mannitol 1.23785 4.9514 0.23785 4.757 Lactose 23.51915 94.0766 4.51915 90.383 TOTAL 25 5
35

(71) TABLE-US-00066 Weight and percentage amount Content mg % mg % Budesonid 0.4 1.6 0.4 8 Vilanterol 0.025 0.1 0.025 0.5 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.22785 4.9114 0.22785 4.557 Mannitol 23.32915 93.3166 4.32915 86.583 TOTAL 25 5
36

(72) TABLE-US-00067 Weight and percentage amount Content mg % mg % Budesonid 0.4 1.6 0.4 8 Vilanterol 0.025 0.1 0.025 0.5 Tiotropium 0.018 0.072 0.018 0.36 Lactose 1.22785 4.9114 0.22785 4.557 Mannitol 23.32915 93.3166 4.32915 86.583 TOTAL 25 5
37

(73) TABLE-US-00068 Weight and percentage amount Content mg % mg % Mometazon 0.1 0.4 0.1 2 Indacaterol 0.15 0.6 0.15 3 Glikoporonyum 0.1 0.4 0.1 2 Lactose 1.2325 4.93 0.2325 4.65 Mannitol 23.4175 93.67 4.4175 88.35 TOTAL 25 5
38

(74) TABLE-US-00069 Weight and percentage amount Content mg % mg % Mometazon 0.1 0.4 0.1 2 Indacaterol 0.15 0.6 0.15 3 Glikoporonyum 0.1 0.4 0.1 2 Mannitol 1.2325 4.93 0.2325 4.65 Lactose 23.4175 93.67 4.4175 88.35 TOTAL 25 5
39

(75) TABLE-US-00070 Weight and percentage amount Content mg % mg % Mometazon 0.2 0.8 0.2 4 Indacaterol 0.15 0.6 0.15 3 Glikoporonyum 0.1 0.4 0.1 2 Lactose 1.2275 4.91 0.2275 4.55 Mannitol 23.3225 93.29 4.3225 86.45 TOTAL 25 5
40

(76) TABLE-US-00071 Weight and percentage amount Content mg % mg % Mometazon 0.2 0.8 0.2 4 Indacaterol 0.15 0.6 0.15 3 Glikoporonyum 0.1 0.4 0.1 2 Mannitol 1.2275 4.91 0.2275 4.55 Lactose 23.3225 93.29 4.3225 86.45 TOTAL 25 5
41

(77) TABLE-US-00072 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 Salmeterol 0.05 0.2 0.05 1 Salbutamol 0.1 0.4 0.1 2 Lactose 1.2375 4.95 0.2375 4.75 Mannitol 23.5125 94.05 4.5125 90.25 TOTAL 25 5
42

(78) TABLE-US-00073 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 Salmeterol 0.05 0.2 0.05 1 Salbutamol 0.1 0.4 0.1 2 Mannitol 1.2375 4.95 0.2375 4.75 Lactose 23.5125 94.05 4.5125 90.25 TOTAL 25 5
43

(79) TABLE-US-00074 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 Salmeterol 0.05 0.2 0.05 1 Salbutamol 0.1 0.4 0.1 2 Lactose 1.23 4.92 0.23 4.6 Mannitol 23.37 93.48 4.37 87.4 TOTAL 25 5
44

(80) TABLE-US-00075 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 Salmeterol 0.05 0.2 0.05 1 Salbutamol 0.1 0.4 0.1 2 Mannitol 1.23 4.92 0.23 4.6 Lactose 23.37 93.48 4.37 87.4 TOTAL 25 5
45

(81) TABLE-US-00076 Weight and percentage amount Content mg % mg % Fluticasone 0.5 2 0.5 10 Salmeterol 0.05 0.2 0.05 1 Salbutamol 0.1 0.4 0.1 2 Lactose 1.2175 4.87 0.2175 4.35 Mannitol 23.1325 92.53 4.1325 82.65 TOTAL 25 5
46

(82) TABLE-US-00077 Weight and percentage amount Content mg % mg % Fluticasone 0.5 2 0.5 10 Salmeterol 0.05 0.2 0.05 1 Salbutamol 0.1 0.4 0.1 2 Mannitol 1.2175 4.87 0.2175 4.35 Lactose 23.1325 92.53 4.1325 82.65 TOTAL 25 5
47

(83) TABLE-US-00078 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 Arformeterol 0.015 0.06 0.015 0.3 Salbutamol 0.1 0.4 0.1 2 Lactose 1.23925 4.957 0.23925 4.785 Mannitol 23.54575 94.183 4.54575 90.915 TOTAL 25 5
48

(84) TABLE-US-00079 Weight and percentage amount Content mg % mg % Fluticasone 0.1 0.4 0.1 2 Arformeterol 0.015 0.06 0.015 0.3 Salbutamol 0.1 0.4 0.1 2 Mannitol 1.23925 4.957 0.23925 4.785 Lactose 23.54575 94.183 4.54575 90.915 TOTAL 25 5
49

(85) TABLE-US-00080 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 Arformeterol 0.015 0.06 0.015 0.3 Salbutamol 0.1 0.4 0.1 2 Lactose 1.23175 4.927 0.23175 4.635 Mannitol 23.40325 93.613 4.40325 88.065 TOTAL 25 5
50

(86) TABLE-US-00081 Weight and percentage amount Content mg % mg % Fluticasone 0.25 1 0.25 5 Arformeterol 0.015 0.06 0.015 0.3 Salbutamol 0.1 0.4 0.1 2 Mannitol 1.23175 4.927 0.23175 4.635 Lactose 23.40325 93.613 4.40325 88.065 TOTAL 25 5
51

(87) TABLE-US-00082 Weight and percentage amount Content mg % mg % Fluticasone 0.5 2 0.5 10 Arformeterol 0.015 0.06 0.015 0.3 Salbutamol 0.1 0.4 0.1 2 Lactose 1.21925 4.877 0.21925 4.385 Mannitol 23.16575 92.663 4.16575 83.315 TOTAL 25 5
52

(88) TABLE-US-00083 Weight and percentage amount Content mg % mg % Fluticasone 0.5 2 0.5 10 Arformeterol 0.015 0.06 0.015 0.3 Salbutamol 0.1 0.4 0.1 2 Mannitol 1.21925 4.877 0.21925 4.385 Lactose 23.16575 92.663 4.16575 83.315 TOTAL 25 5

(89) Compositions according to the invention are manufactured by the processes of the state of art in such a way that they include mixtures of fine particle lactose-coarse particle mannitol, fine particle mannitol-coarse particle lactose and the active ingredients.

(90) For Fine Particle Carriers (Lactose or Mannitol) Might be in the Range of:

(91) d10; 1.0-5.0 m or d10; 1.0-4.0 m,

(92) d50; 4.0-10.0 m or d50; 4.0-7.0 m,

(93) d90; 7.0-20.0 m or d90; 7.0-15.0 m

(94) For Coarse Particle Carriers (Lactose or Mannitol) Might be in the Range of:

(95) d10; 10.0-50.0 m

(96) d50; 50.0-120.0 m or d50; 50.0-75.0 m,

(97) d90; 120.0-300.0 m or d90; 75.0-250.0 m.

(98) Said compositions may be formed as: i. Active ingredient+fine particle lactose+coarse particle mannitol, ii. Active ingredient+fine particle lactose+coarse particle lactose, iii. Active ingredient+fine particle lactose+fine particle mannitol+coarse particle mannitol, iv. Active ingredient+fine particle lactose+fine particle mannitol+coarse particle lactose, v. Active ingredient+fine particle lactose+coarse particle mannitol+coarse particle lactose, vi. Active ingredient+fine particle lactose+fine particle mannitol+coarse particle mannitol+coarse particle lactose.

(99) Surprisingly, said mannitol in the invention increases stability by absorbing moisture to it contained in the active ingredients inside the blister having air and moisture barriers or the airtight and moisture-tight capsule. Dehumidification of the active ingredient or ingredients bring the stability values to desired level. Furthermore, by means of ideal lactose and mannitol ratio and their determined particle sizes, compositions with content uniformity are developed. In addition to this, dosage accuracy present in each cavity or capsule is ensured as well. These preferred values facilitate the flowing and filling of the components as well, during the process. It is ensured that a homogeneous mixture is obtained and this filling is economical and fast.

(100) Coarse carrier particles are used in or order to prevent agglomeration (anew) of the fine particles of the active ingredient. In order to obtain this effect, a carrier, the particle size of which is 10 times that of the active ingredient is used. In general, a single layer composed of the active ingredient particles is formed over the large carrier particles. During inhalation, as the active ingredient and the carrier substance need to be separated from each other, shape and surface roughness of the carrier particles are especially important. Particles of smooth surface will be separated much easier from the active ingredient compared to the particles in the same size but of high porosity.

(101) Fine carrier particles are used so as to assist the active ingredient to reach to the lungs safer and in high doses. Active ingredient will tend to concentrate on the regions having higher energy as the surface energy normally does not dissipate on the carrier particle evenly. This might obstruct the active ingredient to separate from the carrier after pulmonary administration, especially in low dose formulations. As the high-energy regions will be covered by fine carrier particles and thus the active ingredient will tend to bind to low energy regions, usage of small fine carrier particles, size of which are less than 10.0 microns or 5.0 microns will help to prevent this situation. It has been discovered that by increasing the fraction of the fine carrier particles, taking into lungs will also increase. According to this, a decrease in the particle size (having finer particles) increases the fluidizing energy and this, in return, increases the amount of drug reached to the lungs.

(102) Drug particles will adhere then to weak adhesion regions and will be released easier during inhalation. Surface area will significantly increase upon addition of fine particles and carrying capacity will decrease. The fact that the fine carrier particles are slightly coarser than the drug particles is sufficient to eliminate the frictional forces between the drug and the carrier during mixing process.

(103) Another object of the invention is to adjust the fluidity of the formulations accurately in order to ensure that correct amounts of active ingredient are given to the DPIs by suitable devices. In other words, present invention provides freely-flowable formulations by choosing right carriers in order to ensure continuous production of formulations, mechanical filling of the powder inhaler, right dosage and release with powder inhaler.

(104) Another object of the invention is to prevent agglomeration by using a suitable carrier except lactose. Active particles have fine or sometimes micro-fine particles in order to be able to penetrate deep into lungs. For this reason, these small drug particles tend to agglomerate.

(105) In an ideal drug carrier system, binding of the active ingredient to the carrier should be as strong as to prevent decaying of the mixture yet it should be so strong as the active ingredient and the carrier need to separate during inhalation. Accordingly, shape of the carrier particles and surface roughness are of particular importance. Spray-dried mannitol particles are observed to detach from the active ingredient easier in comparison with the particles of high porosity in same size. Since, spray-dried mannitol forms more particles of spherical shape and a smooth surface. The characteristic of such particles is that they have a smaller contact area and a smaller and more homogeneous particle size distribution, which leads the inhalable particles to be more, compared to the carriers the diameters of which are diminished mechanically. An advantage of using spray-dried mannitol is to obtain particles in which the particle size distribution is narrow and the diameters are of a few micrometers. And this ensures the drug embedded in the trachea-bronchial and deep alveoli regions to be stored at maximum ratios by normal inhalation rate, once the suitable particle size is obtained. Furthermore, spray-dried mannitol exhibits narrow particle size, i.e., the ratio between the particle size (d50) and (d90) is equal to 0.40 or greater. The ratio between the d50 particle size and d90 is preferably between 0.45 and 0.50, more preferably between 0.50 and 0.70.

(106) In addition to this, this narrow particle size distribution that is equal to 0.40 or greater applies also to mannitol contained in the compositions of present invention. Preferably, narrow particle size distribution is between 0.45 and 0.50, more preferably between 0.50 and 0.70.

(107) Particle size analysis is performed by Malvern Mastersizer 2000 device with laser difraction technique. According to selected active ingredient may prefer particle characterization techniques that it can be wet dispersion (particles dispersed in a liquid) or dry dispersion (particles dispersed in a gas (usually air)). Particle size distribution measured volume-base.

(108) According to a preferred embodiment of the invention, therapeutically active amount of said pharmaceutical compositions is administered once a day and/or twice a day.

(109) According to a preferred embodiment, pharmaceutical compositions are used in the treatment of the respiratory diseases selected from asthma and chronic obstructive pulmonary disease and other obstructive respiratory diseases. Combinations of present invention are particularly useful in the treatment of the respiratory diseases or disorders including asthma, acute respiratory failure, chronic pulmonary inflammatory disease, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease and silicosis or immune diseases and disorders including allergic rhinitis or chronic sinusitis.

(110) According to another application, pharmaceutical compositions are suitable for separate, respective or simultaneous administration with a blister resistant to moisture and encapsulated with a secure barrier or with a capsule.

(111) Blister especially contains aluminum in order to prevent moisture intake and thereby fine particle fraction (FPF) of the dose of the pharmaceutical composition is maintained. Blister is further encapsulated with a secure barrier resistant to moisture. By this means, blister prevents water penetration into the drug dose and moisture intake from outside into the container has been prevented.

(112) In another preferred embodiment of the invention, dry powder is inside a capsule and this capsule may be a gelatin or a natural or synthetic pharmaceutically acceptable polymer such as hydroxypropyl methylcellulose.

(113) Dosage amounts of 25 mg are stored inside air-tight and moisture-tight capsules, whereas dosage amounts of 5 mf are stored inside blisters.

(114) Moreover, as said formulas may contain active ingredient in amounts of 3 or 5 mg alone or else in the amounts that are the multiples of 3 or 5 mg, it is also possible to manufacture combinations of said active ingredient comprising the amounts of 3 or 5 mg or else that are the multiples of 3 or 5 mg.

(115) A pharmaceutically acceptable salt, solvate, polymorph or racemic mixture of said active ingredient may also be used.

(116) Said ciclesonide may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof.

(117) Said budesonide may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof.

(118) As said fluticasone may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof, it is preferably propionate or fluticasone furoate.

(119) As said mometasone may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof, it is preferably mometasone furoate or mometasone furoate anhydrate.

(120) As said tiotropium may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof, it is preferably tiotropium bromide.

(121) As said glycopyrronium may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof, it is preferably glycopyrronium bromide.

(122) Said aclinidium may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof.

(123) As said darotropium may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof, it is preferably darotropium bromide.

(124) As said salmaterol may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof, it is preferably salmeterol xinafoate.

(125) As said formoterol may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof, it is preferably formoterol fumarate.

(126) As said arfomoterol may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof, it is preferably arfomoterol tartarrate.

(127) As said indacaterol may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof, it is preferably indaceterol maleate.

(128) Said salbutamol may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof.

(129) Said vilanterol may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof.

(130) Said carmoterol may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof.

(131) Said olodaterol may contain pharmaceutically acceptable salt, solvate, polymorph or racemic mixture thereof.

(132) Said compositions are inserted in a dry powder inhaler device containing a blister and a cap.

(133) Said device has at least one locking mechanism ensuring the device to be maintained locked in both of the positions in which it is ready for inhalation and its cap is closed and ensuring the device to be automatically re-set once the cap is closed.

(134) Subsequent to opening of the device cap, a force is exerted to the device cock by the user. Afterwards, the cock is bolted by being guided by the tracks within the body of the device and the tracks on itself. Mechanism is assured to function via this action. In the end of bolting, cock is locked upon clamping and single dose drug come out of the blister is enabled to be administered. Pushing of the cock by the user completely until the locking position ensures the blister to be completely peeled off and the dosage amount to be accurately administered. As a result of this locking cock is immobilized and is disabled for a short time. This pushing action further causes the spring inside the mechanism to be compressed between the cock and the inner body of the device. Said device becomes ready to re-use following the closing of the cap by the user after the administration of the powder composition, without needing to be set again, thanks to the mechanism involved.

(135) When said compositions are used in a dry powder inhaler comprising capsule, said capsule is put one by one in the device and used by means of exploding the capsule.