Title:  Carbon dioxide enhancement of inhalation therapy

United States Patent:  6,440,393

Issued:  August 27, 2002

Inventors:  Waldrep; J. Clifford (The Woodlands, TX); Knight; J. Vernon (Houston, TX); Koshkina; Nadezhda (Houston, TX)

Assignee:  Research Development Foundation (Carson City, NV)

Appl. No.:  729468

Filed:  December 4, 2000

The present invention provides a method of increasing the deposition of aerosolized drug in the respiratory tract of an individual or animal, comprising the step of administering said aerosolized drug in an air mixture containing up to about 10% carbon dioxide gas.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of increasing the deposition of aerosolized drug in the respiratory tract of an individual or animal, comprising the step of administering said aerosolized drug in an air mixture containing up to about 10% carbon dioxide gas. Preferred concentrations include 2.5%, 5% and 7.5% carbon dioxide gas. The aerosol may be administered for 1 to 30 minutes or even longer.

The instant invention is directed to the aerosol delivery of a water soluble drug. Such a drug may be directly prepared as a water solution or a buffered solution and directly aerosolized. Representative water soluble drugs include antibiotics like tobramycin and pentamidine; muclolytics like acetyl cytsteine; bronchodilators like albuterol; parasympathetic agents like ipratropium bromide; enzymes like DNase; and anti-virals like ribavirin.

Alternatively, the instant invention may be used to deliver an insoluble drug that is associated with a carrier prior to aerosol delivery. Possible carriers include liposomes, slow release polymers and polycationic polymers. Lipsomes are an especially useful carrier for lipophilic drugs such as amphotericin B; nystatin; glucocorticoids; immunosuppressives like CsA, FK506, rapamycin or mycophenolate; and anti-cancer drugs like camptothecin, camptothecin derivatives, and paclitaxel. The liposomes may be formed from such lipids as the phospholipid dilauroylphosphatidylcholine (DLPC) or they may be sterically stabilized liposomes formulated with modified phospholipids such as dimyristylphosphoethanolamine poly(ethylene glycol) 2000. Slow release polymers, such as poly(lactic acid-co-glycolic acid) (PLGA), or polycationic polymers, such as polyethyleneimine (PEI), may be utilized.

The instant invention may also be applied to the delivery of therapeutic proteins, therapeutic peptides, DNA genes, sense oligonucleotides, anti-sense oligonucleotides, and viral vectors. Representative examples of DNA genes are the chloramphenical acetyl transferase gene (CAT) or the p53 gene. Preferably, these genes are delivered via a polycationic polymer carrier such as polyethylenimine. Cationic liposomes also may be utilized as carriers. The polyethylenimine may have a nitrogen:phosphate ratio from about 10:1 to about 20:1. In a preferred embodiment, the PEI nitrogen:phosphate ratio is about 10:1.

The following definitions are provided. Terms not specifically defined are meant to be interpreted as is customary in the art.

As used herein, the term "aerosols" refers to dispersions in air of solid or liquid particles, of fine enough particle size and consequent low settling velocities to have relative airborne stability (8).

As used herein, the term "liposome aerosols" refers to aqueous droplets within which are dispersed one or more particles of liposomes or liposomes containing one or more medications intended for delivery to the respiratory tract of humans or animals (9).

As used herein, the size of the aerosol droplets defined for this application are those described in U.S. Pat. No. 5,049,338, namely mass median aerodynamic diameter (MMAD) of 1-3 .mu.m with a geometric standard deviation of about 1.8-2.2. However, with low concentrations of 9-NC and possibly other camptothecin derivatives, the mass median aerodynamic diameter may be less than 1 .mu.m, such as 0.8 .mu.m. Based on the studies disclosed by the present invention, the liposomes may constitute substantially all of the volume of the droplet when it has equilibrated to ambient relative humidity.

As used herein, the "Weibel Lung Model" refers to a classification of the structure of the human lungs that recognizes 23 consecutive branchings of the airways of humans. The trachea is labeled 0, bronchi and bronchioles extend through branches 16. These portions of the airways contain ciliated epithelium and mucus glands. Together they constitute the mucociliary blanket. Branchings 17-23 compose the alveolar portion of the lung and do not have a mucociliary blanket. Thus, particles deposited here are not carried up the airway to be swallowed.

It is postulated herein that under controlled experimental conditions of hypercapnia, deposition of inhaled drug particles would greatly increase over levels observed during basal tidal breathing conditions. The use of carbon dioxide gas/air mixtures to drive continuous flow jet nebulizers could greatly increase the efficiency of the drug dose delivered to the peripheral lung (Weibel's generations 17-23). By analogy, this system could be effectively utilized to increase the biological efficiency of inhaled drugs. This concept could be theoretically employed with any drug, gene, oligonucleotide, or protein/peptide formulation (soluble, liposomal, crystalline, or polymer-based carrier such as polyethylenimine) and any gas or air driven jet nebulizer

The current invention is primarily directed toward the use of carbon dioxide gas to increase the depth and frequency of breathing during inhalation therapy with as aerosolized drug to result in increased minute volumes. The increased tidal lung volume results in enhanced pulmonary deposition of the inhaled drug particles, particularly in the lung periphery which may not be fully ventilated at low levels of breathing. The increased minute volume resulting from increased frequency and greater depth of breathing both contribute to the increased minute volume.

Administering an aerosolized drug in an air mixture containing up to about 10% carbon dioxide gas results in increased deposition of the drug in the respiratory system, measurably improving efficiency and therapeutic efficacy of the aerosol drug delivery. Preferred concentrations include 2.5%, 5% and 7.5% carbon dioxide gas. The aerosol may be administered for 1 to 30 minutes or even longer. The enhancing effect of the carbon dioxide is evident within 30 seconds. The respiratory effects of carbon dioxide are transient and can be employed repeatedly.

Claim 1 of 16 Claims

What is claimed is:

1. A method of increasing the deposition of a drug into the respiratory tract of an individual or animal during inhalation therapy, comprising the steps of:

mixing carbon dioxide gas with air to form a carbon dioxide-air mixture, said carbon dioxide-air mixture containing about 7.5% to about 10% by volume carbon dioxide gas;

aerosolizing said drug in said carbon dioxide-air mixture wherein prior to aerosolization said drug is a soluble drug dissolved in a buffered solution or water or, in the alternative, said drug is an insoluble or lipophilic drug carried by a liposome, a sterically stabilized liposome, a slow release polymer or a polycationic polymer; and

administering said aerosolized drug during inhalation therapy by continuously flowing said carbon-dioxide-air mixture wherein carbon dioxide in said mixture increases inhalation rate and inhaled volume of said aerosolized drug thereby increasing deposition of said aerosolized drug into the respiratory tract.
 

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