Ipratropium formulation for pulmonary inhalation

Details Ipratropium formulation for pulmonary inhalation Ipratropium formulation for pulmonary inhalation

2001-04-23

2002-09-24

Dees, José G. (Department: 1619)

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Organic pressurized fluid

C424S046000, C424S489000, C424S434000, C424S435000

Reexamination Certificate

active

06455028

ABSTRACT:

TECHNICAL FIELD
The invention relates generally to pharmaceutical formulations, and more particularly relates to pharmaceutical formulations comprising a bronchodilator. In addition, the invention relates to methods for treating patients using the formulations and drug delivery devices for delivering the formulations.
BACKGROUND
Administration of pharmacologically active agents to the lungs of a patient offers many advantages over other modes of drug administration, e.g., oral administration of a tablet or capsule, transdermal administration of an active agent, and the like. Administration of a drug to the lungs provides for increased onset of action, decreased first-pass effect, reduced degradation in the gastrointestinal milieu, minimized side effects, and titrated doses. Conventional means to deliver the active agent to the lungs of a patient include administration of an aerosol formulation containing the active agent from, for example, a manual pump spray or pressurized metered-dose inhaler.
Often, the active agent is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve. The canister, in turn, is fitted into a suitable actuator housing adapted to hold the canister. The entire assembly, e.g., canister with valve, actuator housing, formulation, etc., serves as a drug delivery device suitable for pulmonary administration of the pharmaceutical formulation.
When administering the drug, the patient must actuate the drug delivery device. The actuation releases a fraction of the formulation from within the canister to the external environment. A force, created by vaporized propellant, expels the drug into the air and away from the device. The patient then inhales the aerosolized drug. The metering valve controls the amount of the formulation released, which, in turn, effectively controls the amount of drug available for inhalation by the patient.
Traditionally, chlorofluorocarbons (CFCs) have been used as propellants in aerosol formulations. Although CFCs are effective propellants, controversy has surrounded their use due to their suspected ozone-depleting effects. Essentially, degradation of CFCs in the upper atmosphere produces chloride radicals that react with, and deplete, ozone. As a consequence, alternative formulations are desired that include propellants having the effectiveness of CFCs, yet without their ozone-depleting effects.
The introduction of fluorocarbons and hydrogen-containing fluorocarbons as propellants in aerosol formulations addressed many of the environmental concerns associated with conventional CFC propellants. Although fluorocarbon and hydrogen-containing fluorocarbon compounds have sufficient vapor pressures for use as propellants, the transition to the new propellants has been difficult. Largely, the problem rests with the poor solvency associated with fluorocarbon and hydrogen-containing fluorocarbon propellants. Dellamary et al. (2000)
Pharm. Res.
17(2):168-174. As a consequence, many formulations containing fluorocarbon and hydrogen-containing fluorocarbon propellants require the presence of cosolvents and/or surfactants. See WO 93/11745. Among other drawbacks, these components increase the cost of the final formulation and may impart an unpleasant taste, trigger an asthmatic attack or have other undesirable effects on the patient.
Nevertheless, some researchers have described formulations that do not require the use of any surfactant or cosolvent. For example, WO 93/11743 describes formulations containing a fluorocarbon or hydrogen-containing fluorocarbon propellant in combination with salmeterol, salbutamol, fluticasone propionate, or beclomethasone dipropionate. Further, WO 93/11744 describes formulations containing a fluorocarbon or hydrocarbon-containing fluorocarbon propellant that are free of any surfactants and may be used with nearly any drug. However, such formulations are unsatisfactory for some drugs, particularly ipratropium bromide.
Ipratropium bromide has been described in U.S. Pat. No. 3,505,337 to Zeile et al. as a stomach acid secretion inhibitor.
Ipratropium Bromide
(±)-3-(3-Hydroxyl-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane Bromide
Thereafter, it was recognized that the drug's anticholinergic effects would be advantageous in the treatment of patients requiring bronchodilator therapy. Gross et al. (1984)
Am. Rev. Respir. Dis.
129(5):856-870. Ipratropium bromide as an inhalation aerosol is commercially available as ATROVENT® (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn.). The formulations, however, use the CFC propellants trichloromonofluoromethane (CFC-11), dichlorodifluoromethane (CFC-12) and dichlorotetrafluoroethane (CFC-114).
Aerosol formulations of ipratropium bromide using fluorocarbon and hydrogen-containing fluorocarbon propellants have also been proposed. For example, U.S. Pat. No. 5,225,183 to Purewal et al. describes aerosol formulations of ipratropium bromide having a hydrogen-containing fluorocarbon propellant that is substantially free of CFCs. The described formulations, however, require a surface-active agent, i.e., surfactant, to stabilize the formulation or lubricate a valve stem when used in conjunction with an inhaler.
Furthermore, aerosol formulations containing ipratropium bromide without CFC propellants and without surfactants and solvents have been tried, but were demonstrated to be unsatisfactory for use in conventional metered-dose inhalers. Specifically, applicants found that crystalline ipratropium, due to its acicular, i.e., needle-like shape, tended to cause aggregation in these formulations, thereby clogging the delivery valve and possibly other components of the inhaler as well.
There is, accordingly, a need in the art to provide an aerosol formulation comprising a fluorocarbon or hydrogen-containing fluorocarbon propellant or mixture thereof in combination with ipratropium as an active agent that is readily used with conventional metered-dose inhalers. The present invention addresses both this and other needs by providing a fluorocarbon or hydrogen-containing fluorocarbon aerosol formulation that forms little or no aggregates upon repeated actuation. Specifically, it has been found that by using ipratropium particles having a certain size and morphology, an aerosol formulation can be made that is free of CFC propellants and does not clog the valve of a drug delivery device.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the invention to provide a pharmaceutical aerosol formulation comprising substantially nonacicular particles (or particles treated in a such a manner to render usable) of a bronchodilator selected from the group consisting of ipratropium and pharmacologically acceptable salts, solvates, hydrates, esters and isomers thereof and a propellant selected from the group consisting of a perfluorocarbon propellant, a hydrogen-containing fluorocarbon propellant, and mixtures thereof, wherein the formulation is substantially free of both surfactant and solvent.
It is another object of the invention to provide such a formulation wherein the substantially nonacicular particles are substantially spherical.
It is a further another object of the invention to provide such a formulation wherein the bronchodilator is a pharmacologically acceptable salt of ipratropium.
It is a still another object of the invention to provide such a formulation wherein the particles of the active agent have an average particle size in the range of about 0.5 &mgr;m to about 10 &mgr;m.
It is a further object of the invention to provide such a formulation wherein the propellant is selected from the group consisting of CHF
2
CHF
2
, CF
3
CH
2
F, CHF
2
CH
3
, CF
3
CHFCF
3
, CF
3
CF
3
, CF
3
CF
2
CF
3
and mixtures thereof.
Another object of the invention is to provide a method for treating a patient suffering from a condition that is responsive to treatment with an aerosol formulation of a broncho

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