Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-09-11
2001-08-07
Nguyen, Dave Trong (Department: 1633)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S455000, C435S458000, C424S450000
Reexamination Certificate
active
06271206
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to the field of gene delivery to respiratory epithelial cells. The invention is more particularly related to compositions comprising a nebulized nucleic acid/stabilizing agent complex, and to methods employing such complexes for nucleic acid delivery to a patient.
BACKGROUND OF THE INVENTION
Gene delivery via inhalation is a technique that shows considerable promise for the treatment and prevention of a variety of diseases, but its application has been limited by practical difficulties. In particular, safety concerns have slowed the development of some methods of aerosol gene delivery, particularly those involving viral-based systems, and the application of other delivery methods has been limited by efficiency problems. One promising approach for gene delivery involves the use of lipid-based carriers, or liposomes. However, as with other carriers, liposomes have been inefficient for nucleic acid delivery using the drug delivery devices commonly employed.
Pharmaceutical devices that have been employed for aerosol drug delivery include metered dose inhalers (MDIs), dry powder inhalers (DPIs) and air-jet nebulizers. While such devices are suitable for the delivery of some therapeutic agents, gene delivery via these devices presents practical problems. MDIs have not been used for gene delivery because of the difficulty of formulating plasmids with propellant mixtures. DPIs are also not suitable for gene delivery because a prohibitively high inspiratory air flow rate is required to achieve effective dispersion of powder blends.
Currently, the most practical pharmaceutical device for gene delivery is the air-jet nebulizer. This device uses a compressed air source to deliver a high velocity air-jet through an orifice to create a venturi effect that draws liquid from a reservoir into an air flow stream. The differential velocity between the air and the liquid causes the liquid to break up into droplets, the majority of which are in the respirable range (1-5 &mgr;m). The jet nebulizer has been preferred for lipid-based gene delivery because of the comparative ease of formulation (e.g., often the parenteral formulation can be used directly), versatility in dose adjustment (concentration and frequency), affordability and time-proven delivery technology. The drug reservoir of the nebulizer can also be designed to administer high doses of aerosolized therapeutic agents to the lungs.
Significant drawbacks remain, however, with gene delivery using a jet nebulizer, including lack of portability, output variability between units, large dead volumes and variation in solution versus solvent output. The delivery efficiency (defined as the ratio of mass of drug nebulized to mass of drug deposited in the lower airways) is very low—less than 2%. This low delivery efficiency may be attributable to constant air flow through the system, resulting in continuous atomization and concomitant dilution of the output aerosol stream. Further, using a jet nebulizer, aerosols are generated even during exhalation, which accounts for 60% of the respiratory cycle.
Accordingly, there is a need in the art for improved methods of pulmonary gene delivery. The present invention fulfills these needs and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention provides compositions and methods for pulmonary gene delivery. In one aspect, the present invention provides a nucleic acid delivery apparatus. The apparatus comprises, in one embodiment, (a) a sonic nebulizer, (b) a nucleic acid and (c) a stabilizing agent, wherein the nucleic acid and stabilizing agent are contained within the sonic nebulizer. In a related embodiment, the nucleic acid(s) and stabilizing agent(s) are provided in a separate container, the sonic nebulizer being adapted to receive the container and produce an aerosol suitable for inhalation therefrom.
In another aspect, methods are provided for preparing a sonic nebulized nucleic acid/stabilizing agent complex, comprising the steps of: (a) combining at least one nucleic acid with at least one stabilizing agent to form a complex and (b) forming an aerosol of the complex with a sonic nebulizer.
In a related aspect, the present invention provides a sonic nebulized nucleic acid/stabilizing agent complex, wherein the complex comprises at least one nucleic acid and at least one stabilizing agent, and wherein the complex is sonic nebulized to form an aerosol.
In a further aspect, the present invention provides methods for treating a patient with a sonic nebulized nucleic acid/stabilizing agent complex, comprising the step of providing a sonic nebulized nucleic acid/stabilizing agent complex to a patient, wherein the complex is suitable for inhalation by said patient. In a related aspect, a method for treating a patient with a nucleic acid encoding a therapeutic protein is disclosed, comprising the step of providing a complex as discussed above to a patient, wherein the complex is suitable for inhalation by the patient.
In yet another related aspect, methods are provided for treating a patient with a sonic nebulized nucleic acid/stabilizing agent complex, comprising the steps of: (a) combining at least one nucleic acid with at least one stabilizing agent to form a complex; (b) forming an aerosol of the complex with a sonic nebulizer, and (c) providing the aerosol for inhalation by a patient.
In still further aspects, the present invention provides methods for treating a patient with a nebulized nucleic acid/stabilizing agent complex, comprising the step of providing a nebulized nucleic acid/stabilizing agent complex to a patient, wherein the stabilizing agent comprises a cationic lipid, has a net positive charge, and is suitable for inhalation by the patient.
In a related aspect, methods are provided for treating a patient with a nebulized nucleic acid/cationic lipid complex, comprising the steps of: (a) combining at least one nucleic acid with at least one cationic lipid to form a complex having a net positive charge; (b) forming an aerosol of the complex with a nebulizer; and (c) providing the aerosol for inhalation by a patient.
These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.
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Pillai Raviraj S.
Rolland Alain
Nguyen Dave Trong
Seed Intellectual Property Law Group PLLC
Valentis, Inc.
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