IP Library › Granted Patent US 12,357,568
Granted Patent B2
US 12,357,568 · App. 18/153,096 · Granted Jul 15, 2025

Aerosol formulation for COPD

Inventors: Sauro Bonelli (Parma, IT); Francesca Usberti (Parma, IT); Enrico Zambelli (Parma, IT)
Assignee: Chiesi Farmaceutici S.p.A.
A61K9/008A61K31/167A61K31/40A61K31/573A61K45/06A61K47/06A61K47/10B65B31/06B65B31/10
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,357,568
App. No.
18/153,096
Granted
Jul 15, 2025
Kind
B2
Abstract

Stable aerosol solution formulations comprising glycopyrronium bromide are useful for administration to patients with COPD and other respiratory conditions.

Claims (72)

1. A pharmaceutical composition for use with a pressurized metered dose inhaler, comprising glycopyrronium bromide dissolved in HFA-134a and ethanol, wherein:

the composition comprises an amount of hydrochloric acid equivalent to 0.005 to 1.0 μg/μl of 1M hydrochloric acid;

the composition comprises glycopyrronium bromide in an amount of 0.015 to 0.04% w/w of the composition;

the composition comprises ethanol in an amount of 10 to 15% w/w of the composition;

the composition comprises HFA-134a in an amount of 85 to 90% w/w of the composition;

the composition comprises formoterol fumarate; and

the composition comprises beclometasone dipropionate.

2. A composition according to claim 1 , wherein said composition comprises an amount of hydrochloric acid equivalent to 0.099 to 0.74 μg/μl of 1M hydrochloric acid.

3. A composition according to claim 1 , wherein said composition comprises an amount of hydrochloric acid equivalent to 0.18 to 0.32 μg/μl of 1M hydrochloric acid.

4. A composition according to claim 1 , wherein the glycopyrronium bromide is the racemic mixture (3S,2′R), (3R,2'S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.

5. A composition according to claim 1 , comprising water in an amount less than 0.5% w/w of the composition.

6. A composition according to claim 1 , comprising water in an amount 0.005 to 0.5% w/w of the composition.

7. A composition according to claim 1 , wherein the composition is free of excipients other than the ethanol, the HFA-134a, and the hydrochloric acid.

8. A composition according to claim 1 , wherein the concentration of ethanol in the pharmaceutical composition is 12% w/w.

9. A composition according to claim 3 , wherein the concentration of ethanol in the pharmaceutical composition is 12% w/w.

10. A composition according to claim 3 , comprising water in an amount 0.005 to 0.5% w/w of the pharmaceutical composition.

11. A composition according to claim 8 , comprising water in an amount 0.005 to 0.5% w/w of the pharmaceutical composition.

12. A composition according to claim 9 , comprising water in an amount 0.005 to 0.5% w/w of the pharmaceutical composition.

13. A method of filling an aerosol canister with a pharmaceutical composition according to claim 1 , comprising:

a) preparing a solution comprising glycopyrronium bromide, formoterol fumarate, beclometasone dipropionate, ethanol, hydrochloric acid, and optionally a low volatility component;

b) filling an open canister with the solution;

c) placing a valve onto the canister and crimping; and

d) pressure-filling the canister with HFA-134a propellant through the valve.

14. A metered dose inhaler, comprising a pharmaceutical composition according to claim 1 .

15. A metered dose inhaler according to claim 14 , comprising a metering valve capable of delivering a volume of about 63 μl of pharmaceutical composition per actuation.

16. A pressurized metered dose inhaler, comprising a pharmaceutical composition according to claim 3 .

17. A pressurized metered dose inhaler, comprising a pharmaceutical composition according to claim 8 .

18. A pressurized metered dose inhaler, comprising a pharmaceutical composition according to claim 9 .

19. A pressurized metered dose inhaler, comprising a pharmaceutical composition according to claim 10 .

20. A pressurized metered dose inhaler, comprising a pharmaceutical composition according to claim 11 .

21. A pressurized metered dose inhaler, comprising a pharmaceutical composition according to claim 12 .

22. A pressurized metered dose inhaler according to claim 16 , comprising a metering valve capable of delivering a volume of about 63 μl of pharmaceutical composition per actuation.

23. A pressurized metered dose inhaler according to claim 17 , comprising a metering valve capable of delivering a volume of about 63 μl of pharmaceutical composition per actuation.

24. A pressurized metered dose inhaler according to claim 18 , comprising a metering valve capable of delivering a volume of about 63 μl of pharmaceutical composition per actuation.

25. A pressurized metered dose inhaler according to claim 19 , comprising a metering valve capable of delivering a volume of about 63 μl of pharmaceutical composition per actuation.

26. A pressurized metered dose inhaler according to claim 20 , comprising a metering valve capable of delivering a volume of about 63 μl of pharmaceutical composition per actuation.

27. A pressurized metered dose inhaler according to claim 21 , comprising a metering valve capable of delivering a volume of about 63 μl of pharmaceutical composition per actuation.

28. A method for the treatment of a respiratory disorder selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 1 to a subject in need thereof.

29. A method for the treatment of a respiratory disorder selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 3 to a subject in need thereof.

30. A method for the treatment of a respiratory disorder selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 2 to a subject in need thereof.

31. A method for the treatment of a respiratory disorder selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 4 to a subject in need thereof.

32. A method for the treatment of a respiratory disorder selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 5 to a subject in need thereof.

33. A method for the treatment of a respiratory disorder selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 5 to a subject in need thereof.

34. A method for the treatment of a respiratory disorder selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 7 to a subject in need thereof.

35. A method for treatment of asthma, comprising administering an effective amount of a composition according to claim 1 to a subject in need thereof.

36. A method for treatment of asthma, comprising administering an effective amount of a composition according to claim 3 to a subject in need thereof.

37. A method for treatment of asthma, comprising administering an effective amount of a composition according to claim 8 to a subject in need thereof.

38. A method for treatment of asthma, comprising administering an effective amount of a composition according to claim 9 to a subject in need thereof.

39. A method for treatment of asthma, comprising administering an effective amount of a composition according to claim 10 to a subject in need thereof.

40. A method for treatment of asthma, comprising administering an effective amount of a composition according to claim 11 to a subject in need thereof.

41. A method for treatment of asthma, comprising administering an effective amount of a composition according to claim 12 to a subject in need thereof.

42. A method for treatment of chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 1 to a subject in need thereof.

43. A method for treatment of chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 3 to a subject in need thereof.

44. A method for treatment of chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 8 to a subject in need thereof.

45. A method for treatment of chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 9 to a subject in need thereof.

46. A method for treatment of chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 10 to a subject in need thereof.

47. A method for treatment of chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 11 to a subject in need thereof.

48. A method for treatment of chronic obstructive pulmonary disease, comprising administering an effective amount of a composition according to claim 12 to a subject in need thereof.

49. A method for treatment of chronic obstructive pulmonary disease, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 1 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

50. A method for treatment of chronic obstructive pulmonary disease, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 3 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

51. A method for treatment of chronic obstructive pulmonary disease, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 8 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

52. A method for treatment of chronic obstructive pulmonary disease, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 9 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

53. A method for treatment of chronic obstructive pulmonary disease, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 10 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

54. A method for treatment of chronic obstructive pulmonary disease, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 11 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

55. A method for treatment of chronic obstructive pulmonary disease, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 12 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

56. A method for treatment of asthma, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 1 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

57. A method for treatment of asthma, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 3 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

58. A method for treatment of asthma, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 8 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

59. A method for treatment of asthma, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 9 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

60. A method for treatment of asthma, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 10 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

61. A method for treatment of asthma, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 11 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

62. A method for treatment of asthma, comprising inhalation administration of an effective amount of a pharmaceutical composition according to claim 12 to a subject in need thereof via two actuations of a pressurized metered dose inhaler containing said pharmaceutical composition, wherein the pressurized metered dose inhaler has a metering valve that delivers a volume of about 63 μl of pharmaceutical composition per actuation.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 30, 2025
From: BONELLI, SAURO; USBERTI, FRANCESCA; ZAMBELLI, ENRICO
To: CHIESI FARMACEUTICI S.P.A.
Reel/Frame 071261/0510 →
Priority Claims (1)
EP 09015980 · Dec 23, 2009 · regional
Continuity (4)
Continuation 17019740 · Sep 14, 2020
Division 14791553 · Jul 6, 2015
Continuation 12977181 · Dec 23, 2010
Related Publication 20230157951A1 · May 25, 2023
References Cited (80)
US 6475467B1 · Keller et al. · 2002 [cited by applicant]
US 6716414B2 · Lewis et al. · 2004 [cited by applicant]
US 8313732B2 · Davies et al. · 2012 [cited by applicant]
US 9358224B2 · Bonelli · 2016 [cited by applicant]
US 10159645B2 · Bonelli · 2018 [cited by applicant]
US 10617638B2 · Bonelli · 2020 [cited by applicant]
US 10617669B2 · Bonelli · 2020 [cited by applicant]
US 10806701B2 · Bonelli · 2020 [cited by examiner]
US 11389401B2 · Bonelli · 2022 [cited by examiner]
US 20040101483A1 · Muller-Walz et al. · 2004 [cited by applicant]
US 20060257324A1 · Lewis et al. · 2006 [cited by applicant]
US 20090209502A1 · Haeberlin et al. · 2009 [cited by applicant]
US 20110132355A1 · Gerhart et al. · 2011 [cited by applicant]
US 20110146677A1 · Bonelli et al. · 2011 [cited by applicant]
US 20110150782A1 · Bonelli et al. · 2011 [cited by applicant]
US 20110150784A1 · Bonelli et al. · 2011 [cited by applicant]
US 20140363383A1 · Bonelli et al. · 2014 [cited by applicant]
US 20140363384A1 · Bonelli et al. · 2014 [cited by applicant]
US 20150182450A1 · Bonelli et al. · 2015 [cited by applicant]
US 20150182459A1 · Bonelli et al. · 2015 [cited by applicant]
US 20150306026A1 · Bonelli · 2015 [cited by applicant]
US 20150328144A1 · Bonelli · 2015 [cited by applicant]
CA 2338680A1 · 2000 [cited by applicant]
EP 1157689 · 2001 [cited by applicant]
EP 1894568 · 2008 [cited by applicant]
EP 1157689B1 · 2009 [cited by applicant]
EP 2606891B1 · 2014 [cited by applicant]
WO WO9413262 · 1994 [cited by applicant]
WO WO0007567A1 · 2000 [cited by applicant]
WO 02083079 · 2002 [cited by applicant]
WO WO2004054580A1 · 2004 [cited by applicant]
WO 2005074900 · 2005 [cited by applicant]
WO WO2009051818 · 2009 [cited by applicant]
Dec. 19, 2014 Notice of Opposition in EP 2 515 854 (EP counterpart to U.S. Appl. No. 14/791,553). [cited by applicant]
Jul. 31, 2015 Reply in Opposition in EP 2 515 854 (EP counterpart to U.S. Appl. No. 14/791,553). [cited by applicant]
Jan. 28, 2016 Summons to Attend Oral Proceedings and Preliminary Opinion of Opposition Division in Opposition in EP 2 515 854 (EP counterpart to U.S. Appl. No. 14/791,553). [cited by applicant]
“Glycopyrronium Bromide” in Martindale: The Complete Drug Reference, vol. 33, 2002, p. 467. [cited by applicant]
European Search Report in Application No. 09015980.7, issued May 12, 2010 [cited by applicant]
“Glycopyrronium Bromide” Martindale 29 [cited by applicant]
Oct. 21, 2016 Grounds for Decision in Opposition in EP 2 515 854 (EP counterpart to U.S. Appl. No. 14/791,553). [cited by applicant]
Francis A. Carey et.al., Advanced Organic Chemistry, Fourth Edition, Part A: Structure and Mechanisms, Chapter 8 Reactions of Carbonyl Compounds, pp. 474-479 (1937). Francis A. Carey et.al., Advanced Organic Chemistry, … [cited by applicant]
D. Ganderton et al., “The Formulation and Evaluation of a CFC-Free Budesonide Pressurised Metered Dose Inhaler,” [cited by applicant]
Robert O. Williams III, et al., “Moisture Uptake and Its Influence on Pressurized Metered-Dose Inhalers”, [cited by applicant]
Peter Sykes, “A Guidebook to Mechanism in Organic Chemistry,” [cited by applicant]
Jerry March, Advanced Organic Chemistry, Fourth Edition, Reactions, Mechanisms, and Structure, pp. 378-398 (1929). [cited by applicant]
Andrew Streitwieser, Jr., et al., Introduction to Organic Chemistry, Second Edition, Chapter 5, pp. 86-88 and Chapter 19, pp. 539-548 (1973). [cited by applicant]
G.F. Holland et al., “Labilization of Ester Bonds in Aminocyclitol Derivatives. I. Derivatives of myo- and scyllo-Inositols and of Streptamine,”Myo-and Scyllo-Inositol Derivatives, Contribution from the National Institu… [cited by applicant]
Thomas S. Ingallinera, et al., “Compatibility of Glycopyrrolate Injection with Commonly Used Infusion Solutions and Additives” Am. J. Hosp. Pharm. 36:508-510 Apr. 1979, with appended correction, Am. J. Hosp. Pharm. 36:7… [cited by applicant]
Acetylcholine Chloride, http://www.sigmaaldrich.com/catalog/product/sigma/a6625?lang=en&region=GB (retrieved Feb. 23, 2017). [cited by applicant]
Ranga Narayanan, “Interfacial Processes and Molecular Aggregation of Surfactants”, Advances in Polymer Science, ISSN 0065-3195, p. 60 and 68-70 (2008). [cited by applicant]
Oct. 21, 2016 Decision of Opposition Division (with attached Annex) in Opposition in EP 2 515 854 (EP counterpart to U.S. Appl. No. 14/791,553). [cited by applicant]
Feb. 28, 2017 Opponent's Statement of Grounds of Appeal (with attached Annex) in Opposition in EP 2 515 854 (EP counterpart to U.S. Appl. No. 14/791,553). [cited by applicant]
“Glycoppyrolate,” O'Neil, Maryadele J. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, N.J: Merck, 2006. [cited by applicant]
Tzou et al. (1997), Journal of Pharmaceutical Sciences 86(12):1352-1357. [cited by applicant]
Sep. 2, 2016 Submission of Opponent in EP 2 515 854 (EP counterpart to U.S. Appl. No. 14/791,553). [cited by applicant]
Bean et al., “Advances in Pharmaceutical Sciences,” Academic Press, London and New York, vol. 2, 1967, pp. 38-41. [cited by applicant]
A Study to Assess the Safety, Tolerability and Efficacy of NVA237 Versus Placebo, ClinicalTrials.gov archive view of NCT01005901, Dec. 2, 2009. [cited by applicant]
Sep. 30, 2016 Submission of Patent Owner in EP 2 515 854 (EP counterpart to U.S. Appl. No. 14/791,553). [cited by applicant]
Physical Property Data Sheet for Zephex 134a, retrieved from http://www.mexichemfluor.com/products/medical/zephex134a/ on Sep. 23, 2016. [cited by applicant]
Kazempour, Abdol Rassoul, “The Alkaline Hydrolysis of Esters in Aqueous-Organic Solvent Mixtures” Postgraduate School of Studies in Chemistry, Oct. 1978. [cited by applicant]
Yates K, Keith et al., “Mechanisms of Ester Hydrolysis in Aqueous Sulfuric Acids” Journal of the American Chemical Society, vol. 89, No. 11, May 24, 1967. [cited by applicant]
Carey, Francis et al., “Part A: Structure and Mechanisms” Advanced Organic Chemistry, 2000, 474-75. [cited by applicant]
Hopkinson, A.C. et al., “Acid-catalysed Hydrolysis of Alkyl Benzoates” Phys. Org, 1969. [cited by applicant]
Ferreira, Eric, “Hammett Correlations and Their Applications in Elucidating Reaction Mechanism” Stoltz Group Literature Seminar, Jul. 17, 2003. [cited by applicant]
Bender, Myron, “Mechanisms of Catalysis of Nucleophilic Reactions of Carboxylic Derivatives” Department of Chemistry, Illinois Institute of Technology, Sep. 28, 1959. [cited by applicant]
Letter of third party of Mar. 24, 2016 in relation to EP 2 606 891 B1. [cited by applicant]
Preliminary opinion of the Opposition Division in EP 1 787 639. [cited by applicant]
Tol S. Purewal, et al., “Metered Dose Inhaler Technology”, Interpharm Press Inc. US, (1998), pp. 10-17. [cited by applicant]
Robert O. Williams III, et al., “Advanced Drug Formulation Design to Optimize Therapeutic Outcomes”, Informa Healthcare, NY, (2008), pp. 23-36. [cited by applicant]
“Guidance for Industry, Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products—Chemistry, Manufacturing, and Controls Documentation”, U.S. Department of Health and Human Services Food and Drug Administ… [cited by applicant]
“Datasheet for the Decision of Mar. 5, 2015”, T2474/11-3.3.07, (2015), 21 pages. [cited by applicant]
Jul. 2017, Submission in Opposition Procedings in EP 2 515 855 (EP counterpart to U.S. Appl. No. 14/812,190). [cited by applicant]
Jul. 2017, Observations of the Proprietor/Respondent in Response to the Opponent's Appeal, in Opposition in EP 2 515 855 (EP counterpart to U.S. Appl. No. 14/812,190), with Experimental Report (D33). [cited by applicant]
Christian Reichardt, “Solvents and Solvent Effects in Organic Chemistry,” Third, Updated and Enlarged Edition, Wiley-VCH, pp. 93-145, 147-154, 218-237, 273-292, and 526-555 (2003). [cited by applicant]
V. Rangaiah, et al., “Effect of Polarity of the Solvent on the Acid Hydrolysis of Nitrophenyl Esters,” [cited by applicant]
B. Capon, et al., “A Comparison of Neighbouring Group Participation by Phenolic and Alcoholic Hydroxy-Groups in Ester Hydrolysis,” [cited by applicant]
Enrico Emer, et al., “Direct Nucleophilic SN1-Type Reactions of Alcohol,” [cited by applicant]
K. Peter C. Vollhardt, et al., [cited by applicant]
Huaping Mo, et al., “Closed-Shell Ion Paris: Cation and Aggregate Dynamics of Tetraalkylammonium Salts in an lon-Pairing Solvent,” [cited by applicant]
Alex Avdeef, “PH-Metric log p. Part 1. Difference Plots for Determining lon-Pair Ocanol-Water Partition Coefficients of Multiprotic Substances,” [cited by applicant]