USOO595.5058A United States Patent (19) 11 Patent Number: S.9SS,0589 9 Jager et al. (45) Date of Patent: Sep. 21,9 1999 54). STABILIZED MEDICINAL AEROSOL 56) References Cited SOLUTION FORMULATIONS CONTAINING U.S. PATENT DOCUMENTS IPRATROPIUM BROMIDE a 5,118,494 6/1992 Schultz et al. ............................ 424/45 75 Inventors: Paul Donald Jager, Waterbury; Mark 5,190,029 3/1993 Byron et al. ... ... 128/200.14 James Kontny, New Milford, both of 5,225,183 7/1993 Purewal et al. ........................... 424/45 Conn.; Jurgen Hubert Nagel 5.439,670 8/1995 Purewal et al. ... 424/45 Ingelheim/Rhein, Germany s 5,605,674 2/1997 Purewal et al. ........................... 424/45 FOREIGN PATENT DOCUMENTS 73 Assignee: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, 0372 777 6/1990 European Pat. Off.. Conn. Primary Examiner Raj Bawa Attorney, Agent, or Firm Morgan & Finnegan, LLP 21 Appl.pp No.: 08/843,180 57 ABSTRACT 22 Filed: Apr. 14, 1997 Stabilized medicinal aeroSol Solution formulations compris O O ing medicaments that degrade or decompose by interaction Related U.S. Application Data with solvents or water, an HFC propellant, a cosolvent and an acid are described. Further, Specific medicinal aeroSol 63 Staggypt.NE "A iGs Solution formulations comprising ipratropium bromide or No. 08/153.549, Nov. 22, 1993, abandoned E. is a fenoterol, ethyl alcohol, 1,1,1,2-tetrafluoroethane or 1,1,1, continuation-in-part of application No. 07/987,852, Dec. 9, 2,3,3,3-heptafluoropropane, and either an inorganic acid or 1992, abandoned. an organic acid are described. The acids are present in 51 Int. CI. A61K 9/12 amounts Sufficient to reduce the degradation of the medica 52) US C - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 424/45. 424/46 ments to acceptable levels. 58 Field of Search .......................................... 424/45, 46 28 Claims, 1 Drawing Sheet 100 STORAGE CONDITION=50 C/AMBRH 1000 90.0 80.0 700 -o-o-o- O% H2O/NO N2 600 A-AA 4% H2O/N2 500 -H- O% H2O/N2 ---- 4% 0.03M HCI/N2 400 300 200 OO OO O 4 2 3 4. 5 6 STORAGE TIME (MONTHS) U.S. Patent Sep. 21, 1999 5,955,058 100 STORAGE CONDITION=50 C/AMBRH 1000 90.0 8O.O 700 -O-O-O-O% H2O/NO N2 60.O A-AA H2O/N2 500 -H- O% H2O/N2 ---- 4%, O.O3M HCI/N2 40.0 300 2O.O OO OO O 4 2 3 4. 5 6 STORAGE TIME (MONTHS) FIG. 5,955,058 1 2 STABILIZED MEDICINALAEROSOL route. Also, PCT Published Application No. WO91/11496 SOLUTION FORMULATIONS CONTAINING (PCT/EP91/00178) discloses the use of 1,1,1,2,3,3,3- IPRATROPIUM BROMIDE heptafluoropropane (HFC-227), optionally mixed with other propellant components, for use in preparing Suspension This application is a continuation of U.S. Ser. No. 5 aeroSol formulations of medicaments. 08/475,060, Jun. 7, 1995, now U.S. Pat. No. 5,676,930 It has now been found that the use of propellant Systems which is a continuation of U.S. Ser. No. 08/153,549, Nov. containing an HFC and a coSolvent in aeroSol Solution 22, 1993, abandoned, which is a continuation-in-part of U.S. formulations presents a chemical Stability problem that has Ser. No. 07/987,852, Dec. 9, 1992, abandoned. not been previously recognized or resolved in the prior art. This invention relates to Stable pharmaceutical Solution This is because in such HFC propellant/cosolvent systems, formulations Suitable for aerosol administration. More the medicament may interact with the coSolvent and/or particularly, this invention relates to stable pharmaceutical water present in the System to produce decomposition or Solution formulations Suitable for aerosol administration degradation products. It has now further been found that the wherein either an inorganic acid or an organic acid is added addition of an acid, either an inorganic acid or an organic to the aeroSol Solution formulation which contains a medi 15 acid, to the HFC propellant/cosolvent system provides the cament in Solution with an environmentally Safe hydrofluo requisite chemical Stability to the medicament. rocarbon (HFC) as a propellant, together with an organic compound as a coSolvent. The acid provides Stability against BRIEF DESCRIPTION OF THE DRAWING degradation or decomposition of the medicament resulting largely from interaction of the medicament with the cosol FIG. 1 depicts the stability profiles of ipratropium bro vent and/or water present in the Solution formulation. mide aeroSol Solutions. DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION The administration of aerosol formulations of medica The term “aeroSol Suspension formulation” means a phar ments by means of pressurized, metered-dose inhalers 25 maceutical formulation of a medicament Suitable for aeroSol (MDIs) is used widely in therapy, such as in the treatment of administration wherein the medicament is Suspended, in the obstructive airway diseases and asthma. Compared with oral form of finely, divided particles, in an excipient. administration, inhalation provides more rapid onset of The term “aerosol solution formulation” means a phar action while minimizing Systemic side effects. AeroSol for maceutical formulation of a medicament Suitable for aeroSol mulations can be administered by inhalation through the administration wherein the medicament and excipients are mouth or topically by application to the nasal mucosa. completely dissolved. Formulations for aerosol administration via MDIS can be The term “stabilized aerosol Solution formulation” means Solutions or Suspensions. Solution formulations offer the an aerosol Solution formulation which exhibits substantial chemical Stability over time. advantage of being homogeneous in nature with the medi 35 cament and excipient completely dissolved in the propellant Ipratropium bromide is an anticholinergic bronchodilator vehicle. Solution formulations also obviate physical stability marketed under the trademark “ATROVENT. This medi problems associated with Suspension formulations and thus cament is administered as an aeroSol Suspension formulation assure more consistent uniform dosage administration while which contains a mixture of CFCs also eliminating the need for Surfactants. 40 (dichlorodifluoromethane, dichlorctetrafluoroethane, and The administration of aeroSol Solution formulations via trichloromonofluoromethane) as the propellant, and Soya MDIs is dependent upon the propulsive force of the propel lecithin. lant System used in its manufacture. Traditionally, the pro Studies have demonstrated that stable aerosol Solution pellant comprised a mixture of chlorofluorocarbons (CFCs) formulations of ipratropium bromide can be obtained by to provide the desired Solubility, vapor pressure, and Stabil 45 dissolving ipratropium bromide in a homogeneous System ity of the formulation. However, since it has been estab comprising HFC-134(a), ethanol, and either an inorganic lished in recent years that CFCs are environmentally harm acid or an organic acid. The particular type and amount of ful because they contribute to the depletion of the Earth's acid added to the system will define the level of acidity oZone layer, it is desirable to Substitute environmentally Safe which is critical in obtaining a Stable Solution formulation. hydrofluorocarbon (HFC) propellants or other non 50 Thus, the present invention provides Stabilized aeroSol chlorinated propellants for environmentally harmful CFC Solution formulations comprising a medicament, an HFC propellants in aerosol inhalation formulations. For example, propellant, a coSolvent, and an inorganic acid or an organic U.S. Pat. No. 4,174,295 discloses the use of propellant acid. A small amount of water (up to about 5% by weight) Systems consisting of combinations of HFCs, which may may also be present in the propellant/coSolvent System. also contain a Saturated hydrocarbon component, Suitable 55 Suitable HFC propellants are those which, when mixed for application in the fields of home products Such as hair with the cosolvent(s), form a homogeneous propellant Sys lacquers, anti-perspiration products, perfumes, deodorants, tem in which a therapeutically effective amount of the paints, insecticides and the like. medicament can be dissolved. The HFC propellant must be It is known in the art that certain HFCs have properties toxicologically Safe and must have a vapor pressure which Suitable for use as propellants for the aerosol administration 60 is Suitable to enable the medicament to be administered via of medicaments. For example, published European patent a pressurized MDI. Additionally, the HFC propellant must Application No. 0372 777 (EPO89312270.5) describes the be compatible with the components of the MDI device (such use of 1,1,1,2-tetrafluoroethane (HFC-134(a)) in combina as containers, valves, and Sealing gaskets, etc.) which is tion with at least one “adjuvant” (a compound having a employed to administer the medicament. Preferred HFC higher polarity than the HFC-134(a)) and a surface active 65 propellants are 1,1,1,2-tetrafluoroethane (HFC-134(a)) and agent to prepare Suspension and Solution formulations of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227). HFC-134(a) is medicaments Suitable for administration by the aeroSol particularly preferred. Other examples of HFC propellants 5,955,058 3 4 are HFC-32 (difluoromethane), HFC-143(a) (1,1,1- for use in the aeroSol Solution formulations of the present trifluoroethane), HFC-134 (1,1,2,2-tetrafluoroethane), and invention. Those skilled in the art will recognize that other HFC-152a (1,1-difluoroethane). classes of medicaments can in general be used. Examples of It will be apparent