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Pulse drug nebulization systems, formulations therefore, and methods of use

Pulse drug nebulization systems, formulations therefore, and methods of use description/claims

The present application claims priority to U.S. Provisional Patent Application Ser. No. 60/845,087, filed Sep. 15, 2006, and U.S. Provisional Patent Application Ser. No. 60/891,128, filed Feb. 22, 2007, the contents of all of which are incorporated herein by reference in their entirety.

The government may own rights in the present invention pursuant to grant number 1 P01 GM066312-01A2 from the National Institute of Health.

Not applicable.

1. Field of the Invention

The present invention relates to compositions, formulations and methods for the treatment and prevention of cytoxicity, cell damage and inflammation in the pulmonary system of patients, as well as systems for use in delivering such compositions and formulations to the patient. More particularly, the present invention relates to tocopherol compositions and formulations for use in the treatment of pulmonary disorders in patients, methods for their use, and systems for the delivery of such tocopherol-containing compositions and formulations to the pulmonary region of a patient.

2. Description of the Related Art

Burn inhalation injury of the lungs increases morbidity and mortality, with 70% of victims of smoke inhalation dying within the first 12 hours of [Shirani, K. Z., et al., Ann. Surg., Vol. 205(1): pp. 82-87 (1987)]. Lung injury is traumatic, and is typically caused by heat and chemical irritation, with chemical injury being the leading lethal cause of smoke inhalation injury. Similarly, thermally injured patients who sustain inhalation injury have a 20 fold increase in mortality [see, Saffle, J. R., et al., J. Burn Care Rehabil., Vol. 16(3, pt. 1); pp. 219-232 (1995)].

Injury from burn and smoke inhalation has been demonstrated to produce a systemic inflammatory response and increase levels of reactive oxygen species (ROS) [Traber, D. L., et al., Burns Inc. Therm. Inj., Vol. 14(5): pp. 357-364 (1988)]. ROS produces an increase in pulmonary microvasculature and pulmonary edema accompanied by increased lipid peroxidation in lung tissue. Inhibition of lipid peroxidation has been demonstrated to reduce these symptoms in animals subjected to hot sawdust smoke by Z. Min, et al., [J. Med. Cell. PLA, Vol. 5(2): pp. 176-180 (1990)].

Antioxidants are compounds that reduce oxidation products and have been demonstrated to reduce cytotoxicity in smoke inhalation-lung injury, adult respiratory distress syndrome, emphysema and asthma. More recently it has been reported that the use of antioxidants such as vitamin E may be beneficial in the treatment of victims of fire accidents who sustain both thermal injury to the skin and smoke inhalation and exhibit evidence of oxidant injury [Morita, N., et al., Shock, Vol. 25(3): pp. 277-282 (2006)]. For example, vitamin C and vitamin E (alpha-tocopherol and gamma tocopherol) are antioxidants in vivo which may act together to scavenge ROS to produce non-reactive compounds within the human body. One of the important chemical features of the tocopherols is that they are redox agents which act under certain circumstances as antioxidants. In acting as an antioxidant, tocopherols presumably prevent the formation of toxic oxidation products, such as perioxidation products formed from unsaturated fatty acids. Further, it has recently been discovered that individual members in the class of tocopherols may exhibit different biological properties from one another despite their structural similarity. Some investigators, for example, believe that γ-tocopherol, unlike α-tocopherol, acts in vivo as a trap for membrane-soluble electrophilic nitrogen oxides and other electrophilic mutagens [Christen, S., et al. Proc. Natl. Acad. Sci. 94: 3217-3222 (1997]. Vitamin E is remarkably safe, and falls within a class of compounds that are “generally regarded as safe” or “GRAS”. Vitamin E is available in several forms that present varied activities between them. Whereas alpha-tocopherol has been widely investigated for therapeutic uses, until recently gamma-tocopherol (a form of “des-methyl tocopherol”) has received much less attention in science. However, gamma-tocopherol presents a variety of beneficial advantages over alpha-tocopherol in various considerations. In one particular regard, gamma-tocopherol has been characterized to exhibit much more potent anti-oxidant qualities, resulting in a unique anti-inflammatory activity not shared with the alpha-tocopherol. In addition, gamma-tocopherol is believed to enhance outcomes of therapy when combined with certain other bioactive agents or drugs. Antioxidants, and in particular, gamma tocopherol is capable of preserving the elastase inhibitor capacity of the lower respiratory tract fluid of mammals exposed to harmful, chemical gases. Thus, it is believed that the direct delivery of antioxidants such as vitamin E, and particularly, gamma tocopherol directly to the airways of mammals, may reduce or treat the injury resulting from burn and smoke inhalation, as well as other pulmonary disorders.

Inhalation-based therapies have been extensively evaluated as site-specific method to treat pulmonary disorders due to their ability to rapidly and selectively deposit agents in the lung in greater amounts than can be readily achieved by other methods [see: Kuhn, R. J., Pharmacotherapy, Vol. 22: pp. 80S-85S (2002)]. Consequently, a variety of aerosolized compounds have been researched and their aerosolization attempted, including recombinant proteins, glutathione, and vitamins such as Vitamin E [Hybertson, B. M., et al., Free Radic. Biol. Med., Vol. 18: pp. 537-542 (1995)]. However, these attempts have been largely unsuccessful due to the substantial insolubility of these therapeutic agents and potential therapeutic agents in carrier systems that are suitable for use in aerosol therapeutic delivery systems. For example, many of the pharmaceutical compounds, vitamins, and biological agents that exhibit promise in the treatment of pulmonary diseases, disorders and damage that result from smoke inhalation are insoluble in water and other the carriers for aerosol formulation and for use in nebulizers. Further, these same compounds which exhibit potential therapeutic applicability in the pulmonary region of patients are often soluble only in oil-based solvents or compounds, and as such they are unable to be aerosolized by the current nebulizer systems available and in use. In the event that such oil-based formulations can be realized, and they can be transformed into an aerosol by a nebulizer, the exceedingly high flow rate required to aerosolize them, and the resultant particle size of the aerosols makes the formulations unsuitable for use in treatment. Consequently, not only are new formulations necessary, but a new nebulizer design is required in order to convert formulations of such therapeutic agents into aerosols having the desired particle size in the desired range of 2 μm to 12 μm.

The present invention meets these needs by providing novel, pharmaceutical compositions of tocopherols, such as gamma tocopherol, and tocopherol derivatives which are demonstrated herein to protect animals from cytotoxic injury and death, pulmonary injury, as well as other injuries and disease conditions, including inflammatory diseases, as well as methods and systems for delivering these compositions by way of nebulizing such water-insoluble drug formulations.

In one aspect of the present disclosure, an apparatus for nebulizing a non-aqueous liquid is described.

In accordance with another aspect of the present disclosure, a nebulization system comprising a nebulizing nozzle capable of nebulizing a composition comprising fatty acids or lipids is described, wherein the nebulizing nozzle comprises an outer gas-delivery tube and an inner microchannel delivery tube having a central fluid channel, wherein the outer delivery tube is concentrically configured around the inner delivery tube, such concentric configuration forming an annular intermediate space between the two tubes, and wherein the intermediate air space between the two tubes is the free air opening value, the value of which is the internal diameter of the outer gas-delivery tube minus the total inside diameter of the inner microchannel delivery tube.

In accordance with another aspect of the present disclosure, a pulmonary drug delivery system capable of nebulizing a composition comprising a water-insoluble or substantially water-insoluble drug and a fatty acid or lipid is described, wherein the system comprises a reservoir for containing the drug composition; a reservoir for containing a propellant gas; a mechanical control valve capable of regulating the flow of the propellant gas and the drug composition; and a nebulizing nozzle adapted to receive both the drug composition and the propellant gas, wherein the nebulizing nozzle can produce aerosol droplets having a particle size ranging from about 2 μm to about 12 μm in median mass aerodynamic size.

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