Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1997-03-21
2001-02-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000
Reexamination Certificate
active
06193954
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a methods and formulations for administering a dopamine agonist to the airways of a patient.
BACKGROUND OF THE INVENTION
Dopamine is an important neurotransmitter in the central nervous system (CNS), where it is involved with motor function, perception, arousal, motivation and emotion. Dopamine imbalance is believed to play a key role in a number of CNS-related disorders such as schizophrenia, Parkinson's disease, drug abuse, eating disorders and depression. Dopamine also has several important roles in the peripheral nervous system, such as in the control of blood to the kidneys and in autonomic ganglion transmission.
Dopamine agonists such as those described in U.S. Pat. No. 5,597,832 are useful therapeutic agents. However, these agents are poorly absorbed into the systemic circulation when administered orally, probably due to acid degradation and significant liver extraction. They are, however, well absorbed when administered into the airways. This is probably due to the large absorptive area, low enzymatic activity, and near-neutral pH in the lung.
There is a need to deliver dopamine agonists which may have instability problems and/or poor bioavailability when administered orally by alternative non-invasive routes.
Numerous pharmaceutical compounds are preferentially delivered by means of metered dose inhalation (MDI) devices, in which a physiologically inert propellant of high vapor pressure is used to discharge a precise amount of medication with each operation. These MDI devices, also known as aerosols or inhalers, have found widespread use among patients suffering, for example, from episodic or chronic asthma. The propellants of choice have historically been chlorofluoro-carbons, such Propellant 11 (trichlorofluoromethane), Propellant 12 (dichlorodifluoromethane) and Propellant 114 (dichlorotetrafluoroethane).
In recent years, however, there have been growing concerns that chlorofluorocarbon (CFC) propellants have detrimental environmental effects, and in particular that they interfere with the protective upper-atmosphere ozone layer. Under an international accord (the Montreal Protocol), the use of CFC propellants will be prohibited by the start of the year 2000, and possibly sooner. Alternative propellant vehicles are being developed which exhibit little or no ozone depletion potential (ODP). Such alternative propellants include two—HFC-134a (1,1,1,2-tetrafluoroethane) and HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane) which have negligible ODP and are currently undergoing safety and environmental testing.
However, halogenated alkane propellants such as HFC-134a and HFC-227ea are substantially less polar than traditional CFC propellants and many surfactants which are generally used in known MDI formulations have been found to be immiscible with or insoluble in, and therefore incompatible with, these new, non-CFC propellants. Such surfactants are necessary to prevent aggregation (in the form of “caking” or crystallization, for example) of the medicinally active compound in the reservoir of the inhaler, to facilitate uniform dosing upon aerosol administration, and to provide an aerosol spray discharge having a favorable respirable fraction (that is, a particle size distribution such that a large portion of the discharge reaches the alveoli where absorption takes place, and thus produces high lung deposition efficiencies).
U.S. Pat. No. 5,225,183 discloses a formulation comprising HFC-134a, a surface active agent, and an adjuvant or co-solvent having a higher polarity than HFC-134a Representative adjuvants or co-solvents having a higher polarity than HFC-134a include alcohols such as ethanol, isopropanol and propylene glycol; hydrocarbons such as propane, butane, isobutane, pentane, isopentane and neopentane; and other propellants such as Propellants 11, 12, 114, 113 and 142b. The adjuvant is claimed to provide a propellant system having comparable properties to those based on CFC propellants and therefore allow the use of traditional surfactants. Blends of HFC-134a with other solvents or propellants including dimethyl ether; fluorocarbons such as perfluoropropane, perfluorobutane and perfluoropentane; and hydrochlorofluorocarbons such as HCFC-123 are disclosed in U.S. Pat. No. 5,190,029.
Another approach to solving the incompatibility of HFC-134a with many surfactants is to substitute other surface active agents for those traditionally used in CFC aerosols. The use of polar surfactants such as polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene (20) sorbitan monooleate, propoxylated polyethylene glycol, and polyoxyethylene (4) lauryl ether is disclosed in U.S. Pat. No. 5,492,688. U.S. Pat. No. 5,182,097 discloses that HFC-134a can be used as the sole propellant if oleic acid is used as the surfactant. U.S. Pat. No. 5,182,097 discloses that using fluorinated surfactants allows the HFC-134a as the sole propellant. PCT Application No. WO 91/11173 discloses that mixtures of fluorinated surfactants with conventional surfactants or other adjuvants such as polxamers or polyethylene glycols allow the use of hydrofluorocarbon propellants. Non conventional excipients which have been used to prepare aerosol formulations with halogenated alkane propellants include protective colloids, see PCT Application No. WO 95/15151, and tocopherol, see PCT Application No. WO 95/24892.
Such adjuvants, cosolvents and non-traditional surfactants or excipients may of course be physiologically active, and in some instances may not be tolerated by the user of an MDI medication. Solvent mixtures can present the manufacturer with production complexities, and the use of non-traditional ingredients results in regulatory compliance difficulties. There is, therefore, a continuing need for MDI formulations compatible with non-CFC, non-ozone depleting propellants, which prevent aggregation of drug particles without the use of cosolvents or similar carrier additives, and which provide uniformity of dosing and a favorable respirable fraction.
In addition to delivery via metered dose inhalers, other pulmonary delivery systems include powders, microparticles and aqueous and non-aqueous based solutions or dispersions which are administered through and/or into the airways by nasal or trachael routes.
SUMMARY OF THE INVENTION
Dopamine agonists such as those described below are effectively absorbed from the airways. After absorption from the lung, the drug bypasses the liver and is distributed to the body. The efficacy of fomulations administered to the lungs is similar to that obtained by injection.
Accordingly, the present invention provides a method of administering a dopamine agonist to a patient comprising administering a therapeutically effective amount of a dopamine agonist to the airways of the patient. This deliver means can occur through nasal or tracheal administration and can be in the form of a formulation or composition comprising a dopamine agonist delivered in the form of a solid, microparticle or powder and may further comprise a pulmonary delivery excipient selected from solids or liquids which are aqueous based or non-aqueous based. Liquid formulations delivered through the airways according to this invention may be prepared in aqueous or non-aqueous vehicles and delivered to the airways by means of drops or sprays. The present invention therefore relates to a composition for pulmonary delivery comprising a dopamnine agonist dispersed in an aqueous or non-aqueous delivery vehicle. The aqueous vehicle is selected from pure water, substantially pure water or water combined with other excipients such as salts, ions or other excipients which are generally used in aqueous based systems. The liquid formulations are in the form of solution based dispersions or solutions in solvents or cosolvents such as alcohols or glycols with water. Non-aqueous solutions include those alchohol or glycol based systems which may have some water but which are not comprised of a majority percentage of water and which are known to those of skill in th
Adjei Akwete L.
Gupta Pramod K.
Lee Dennis Y.
Marsh Kennan C.
Wu Vivian
Abbott Laboratories
Anderson Regina M.
Page Thurman K.
Tran Susan
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