Pulmonary delivery of protonated/acidified nucleic acids

Details Pulmonary delivery of protonated/acidified nucleic acids Pulmonary delivery of protonated/acidified nucleic acids

1999-03-31

2001-04-03

Clark, Deborah J. R. (Department: 1633)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C424S001130, C435S006120, C536S023100, C536S025100, C536S025200

Reexamination Certificate

active

06211162

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to pulmonary delivery of antibiotics, and in particular delivery of antibiotics to alleviate respiratory infections.
BACKGROUND OF THE INVENTION
Bacterial respiratory infections are a major health problem in the United States, and especially amongst patients with compromised immunological defense mechanisms. Patients with Cystic Fibrosis (CF), Acquired Immune Deficiency Syndrome (AIDS), congestive heart failure, chronic lung disease, cancer, and the elderly population all possess an increased risk of respiratory infection. For example, the debilitation of the lungs in CF patients is associated with accumulation of purulent sputum produced as a result of chronic endobronchial infections caused by opportunistic infectious organisms. Nearly all individuals suffering from CF eventually die of respiratory failure.
P. aeruginosa
is a small, aerobic gram-negative rod that inhabits soil, water, plants, and animals, including humans. Although
P. aeruginosa
occasionally colonizes the skin, external ear, upper respiratory tract or large bowel of healthy humans, these infections are usually mild. Infection by
P. aeruginosa
can be much more serious in immunocompromised individuals, causing a number of complications including: chronic infections of the lower respiratory tract of CF patients; bacteremic pneumonia, which complicates hematopoetic malignancies following chemotherapy-induced severe neutropenia; and primary pneumonia in patients with AIDS, congestive heart failure, and chronic lung disease.
S. aureus
is a staphylococcal bacteria that is a major health problem due to its tenacity, potential destructiveness, and increasing resistance to antimicrobial agents. Pneumonia arising from
S. aureus
infection most commonly follows tracheal intubation during hospitalization or is secondary to a viral respiratory infection. Such infections are very common in patients who are elderly and/or institutionalized. In addition, respiratory infection of
S. aureus
may cause septic pulmonary embolization in settings such as right-sided endocarditis, which is common in intravenous drug users, and septic thrombophlebitis, which is oftentimes a complication of an indwelling venous catheter.
S. aureus
is also a health problem in immunocompromised patients, as it is often difficult to treat with conventional systemic antibiotics.
Current treatments for these and other pulmonary bacterial infections are often expensive, non-specific, and must use very large doses in order to be effective. In one example, the present treatment of choice for chronic bronchitis or bronchiectasis seen in CF patients is parenteral administration of an aminoglycoside and a beta-lactam active against
P. aeruginosa
. However, aminoglycoside penetration into the bronchial secretions is poor at approximately only about 12% of the peak serum concentration (
Rev. Infect. Dis
., 3:67 (1981)). According to
Advances in Pediafric Infectious Diseases
, 8:53 (1993), sputum itself is inhibitory to the bioactivity of aminoglycosides because of its high ionic strength and the presence of divalent cations. This inhibitory activity can be overcome by increasing the concentration of aminoglycosides in the sputum to ten times the minimum inhibitory concentration of the particular
P. aeruginosa
isolate (
J Infect. Dis
., 148:1069 (1983)), but this increases the risk of systemic toxicity including ototoxicity and nephrotoxicity. Intravenous therapy may increase hardship on the patient, and frequently requires hospitalization, which increases treatment costs and exposes the patient to other potential infections.
One of the first studies using aerosolized antibiotics for the treatment of CF was reported in
Lancet
, 22:1377-9 (1981). A controlled, double-blind study on twenty CF patients demonstrated that aerosol administration of carbenicillin and gentamicin can improve the health of CF patients. Unfortunately, the physical properties of many antibiotics, such as aminoglycosides require a relatively high dose of the drug for aerosolization and such treatment then becomes rather expensive.
There is a need in the art for a cost-effective and therapeutically efficacious treatment for bacterial respiratory infections, and especially for respiratory infections in immuno-compromised patients. There is also a need for an efficient method for specifically introducing antibiotic agents to the respiratory tract to the site of the infection.
SUMMARY OF THE INVENTION
The present invention provides a method of treating bacterial respiratory infections by pulmonary administration of protonated/acidified nucleic acids. These modified nucleic acids are effective as bactericidal and/or bacteriostatic agents without regard to the class of bacteria, so are especially useful when diagnosis is difficult or when multiple infectious organisms are present. The antibiotic activity of nucleic acids of the invention is not dependent on either the specific sequence of the nucleic acid or the length of the nucleic acid molecule. The nucleic acids of the invention are protonated/acidified to give a pH when dissolved in water of less than pH 7 to about 1, more preferably less than pH 4.5 to about 1, and even more preferably less than pH 2 to about 1. Formulations of aerosolized protonated/acidified nucleic acids are preferably aerosolized and administered via hand-held, self-contained, disposable units.
The nucleic acids of the invention may have nuclease resistant backbones, acid resistant backbones, and, in their preferred embodiment, have both acid resistant and nuclease resistant backbones.
The preferred method of treatment comprises aerosolized delivery of protonated/acidified nucleic acids to the bronchial tubes of an animal, and in particular humans, in an amount sufficient to inhibit or prevent bacterial growth, to alleviate the symptom of the bacterial growth, or in an amount effective for treatment of a bacterial infection.
In another embodiment, the invention provides for pulmonary delivery of protonated/acidified nucleic acids to treat or prevent a primary respiratory disease involving viral infection, inflammatory diseases, cancer, fungal infections, etc., wherein the nucleic acids targeted to treat these disorders are additionally protonated in order to simultaneously treat or prevent a bacterial infection. Preferably, nucleic acids of this embodiment control expression of a gene known to be involved in the primary respiratory disease, e.g., a gene encoding a viral structural protein or an endogenous gene involved in cancer, e.g., an oncogene.
The dose of nucleic acid administered varies with a number of factors, including the inspiratory rate of the patient, the location of the infected region (i.e., upper or lower respiratory tract), the extent of the infection, and the particular species of bacteria involved in the infection. It is often preferable to target the dosage to a particular area of the lungs to better treat an infected region. For example, to achieve deposition of particles in the lower respiratory tract, e.g., to treat pneumonia, it is desirable to get the aerosolized formulation deeply into the lung. Delivery of particles can be controlled, in part, by adjusting particle sizes. In addition to adjusting particle size, delivery of the protonated/acidified nucleic acids can be obtained by releasing an aerosolized dose at a desired point in a patient's respiratory cycle.
Another object is to provide a method of administering a protonated/acidified oligonucleotide formulation to a patient wherein the formulation is repeatedly delivered to a patient at the same measured inspiratory flow rate (in the range of 0.1 to 2.0 liters/second) and separately determined inspiratory volume (in the range of 0.15 to 1.5 liters). Preferably, the oligonucleotide is from 2 to 100 nucleic acids in length.
Another object is to provide a method of administering a protonated/acidified nucleic acid monomer formulation to a patient wherein the formulation is repeatedly delivered to a patient at the same measured ins

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