Provided herein is a method of treating primary lung cancer or metastatic cancer to the lung in an individual by delivering at least once to the respiratory tract of the individual via inhalation a nebulized liposomal aerosol comprising a dilauroylphosphatidylcholine liposome containing camptothecin or a derivative thereof in an amount sufficient to deliver a pharmacologically effective dose of the camptothecin or its derivative to treat the cancer. Also provided is a nebulized liposomal aerosol comprising the DLPC containing the camptothecin or its derivative and a method of making the liposome-drug comprising the aerosol.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention is directed to a method for treating a primary lung cancer or a metastatic cancer to the lung by delivering at least once to the respiratory tract of the individual via inhalation a nebulized liposomal aerosol comprising a dilauroylphosphatidylcholine liposome containing camptothecin or a derivative thereof in an amount sufficient to deliver a pharmacologically effective dose of the camptothecin or its derivative to treat the cancer.

The present invention is directed further to a nebulized liposomal aerosol comprising dilauroylphosphatidylcholine and camptothecin or a derivative thereof suitable for delivery of the camptothecin or its derivative to the respiratory tract of an individual upon inhalation of the nebulized liposomal aerosol. The concentration of the camptothecin or its derivative in the dilauroylphosphatidylcholine liposome does not exceed 1.0 mg/ml. The present invention is also directed to a method of producing the dilauroylphosphatidyl-camptothecin or derivative thereof liposome comprising the nebulized liposomal aerosol.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention there is provided a method for treating a primary lung cancer or a metastatic cancer to the lung by delivering at least once to the respiratory tract of the individual via inhalation a nebulized liposomal aerosol comprising a dilauroylphosphatidylcholine liposome containing camptothecin or a derivative thereof in an amount sufficient to deliver a pharmacologically effective dose of the camptothecin or its derivative to treat the cancer.

In an aspect of this embodiment the nebulized liposomal aerosol is delivered via an inhalation regimen comprising twice a day for 5 consecutive days within a week for one or more consecutive weeks. In an example of such a regimen the period of consecutive weeks is the first 8 weeks out of a ten week period. Further in this aspect the inhalation regimen may be repeated after week 10 of the regimen. Within this aspect the nebulized liposomal aerosol may be inhaled for 60 minutes during each period of inhalation in the regimen. In any described inhalation regimen the dose of camptothecin or it derivative delivered via inhalation may be about 0.26 mg/m.sup.2/day to about 1.04 mg/m.sup.2/day.

In all aspects of this embodiment the concentration of the camptothecin or its derivative in the dilauroylphosphatidylcholine liposome comprising the liposomal aerosol does not exceed 1.0 mg/ml. A representative example of such a concentration is 0.4 mg/ml. Also, in all aspects a weight ratio of camptothecin or its derivative to dilauroylphosphatidylcholine in the liposome comprising the liposomal aerosol is about 1:10 to about 1:50 wt:wt.

Additionally, in all aspects of this embodiment the camptothecin derivative may be 9-nitro-camptothecin, 9-amino-camptothecin or 10,11-methylenedioxy-camptothecin. The metastatic cancer may be a sarcoma, a melanoma, lung cancer endometrial cancer, cervical cancer, pancreatic cancer, thyroid cancer or trophoblastic cancer.

In another embodiment of the present invention there is provided a nebulized liposomal aerosol comprising dilauroylphosphatidylcholine and camptothecin or a derivative thereof suitable for delivery of the camptothecin or its derivative to the respiratory tract of an individual upon inhalation of the nebulized liposomal aerosol. The concentration of the camptothecin or its derivative in the dilauroylphosphatidylcholine liposome does not exceed 1.0 mg/ml. A representative example of concentration is 0.4 mg/ml. In all aspects of this embodiment the weight ratios of the camptothecins to dilauroylphosphatidylcholine, the camptothecin derivatives and the metastatic cancers are as described supra.

In an aspect of this embodiment a method of producing the dilauroylphosphatidyl-camptothecin or derivative thereof liposome comprising the nebulized liposomal aerosol is provided. The method comprises the steps of dissolving one of the camptothecins in a volume of DMSO to produced dissolved camptothecin or its derivative, dissolving the dilauroylphosphatidylcholine in an appropriate to solvent to produce dissolved dilauroylphosphatidylcholine and combining the dissolved constituents to produce a solution having a DMSO concentration not exceeding about 5% of the total volume of the solution. The weight ratio of the camptothecin or its derivative to the dilauroylphosphatidylcholine in the solution is in a range of about 1:10 wt:wt to about 1:50 wt:wt of the solution. The solvents are evaporated from the solution to form a powder. The powder is redissolved in sterile water to produce a suspension such that a concentration of the camptothecin or its derivative in the sterile water does not exceed 1.0 mg/ml.

The following terms shall be interpreted according to the definitions set forth below. Terms not defined infra shall be interpreted according to the ordinary and standard usage 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 (See Knight, V., Viral and Mycoplasmal Infections of the Respiratory Tract. 1973, Lea and Febiger, Phila. Pa., pp. 2). "Liposome aerosols" consist of 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 man or animals (32). 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 MMAD 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.

As used herein, the terms "20-S-camptothecin", "camptothecin" or "CPT" refers to a plant alkaloid with anti-cancer properties.

As used herein, the terms "9-nitro-camptothecin" or "9-NC", "9-amino-camptothecin" or "9-AC," and "10,11-methylenedioxy-camptothecin" or "MDC" refer to active anti-cancer drugs derived from 20-S-camptothecin that are insoluble in water but are soluble in certain lipid solvents.

As used herein, the terms "dilauroylphosphatidylcholine" or "DLPC" is a lipid used to formulate liposomes.

Provided herein is a method for treating a primary or metastatic lung cancer in an individual by delivering a nebulized DLPC-CPT or -CPT derivative liposomal aerosol to the respiratory tract of the individual via inhalation. A jet nebulizer nebulizes the DLPC-CPT or -CPT derivative liposomes to form a small particle aerosol comprising aqueous dispersions of the DLPC-CPT or -CPT derivative liposomes that subsequently are delivered to the individual upon inhalation. The present invention demonstrates that speedier and more efficient systemic absorption of camptothecin or a derivative thereof is actualized after pulmonary administration by aerosol than is actualized by intramuscular or oral administration. Although not limited to such, the present methods are effective in treating cancers such as sarcomas, melanomas, lung cancer, endometrial cancer, cervical cancer, pancreatic cancer, thyroid cancer or trophoblastic cancer.

It is contemplated specifically that the nebulized liposomal aerosols of the present invention be used for delivery via inhalation of aqueous dispersions of liposomes carrying camptothecin or a derivative thereof to the respiratory tract the individual. Examples of camptothecins used in the present invention are 20-S-camptothecin or camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin or 10,11-methylenedioxy-camptothecin. Camptothecin or its derivatives is delivered in a pharmacologically effective amount; i.e., a total amount that eliminates or reduces the tumor burden of the cancer. To be effective the concentration of the camptothecin or derivative in the dilauroylphosphatidylcholine liposome comprising the liposomal aerosol should not exceed 1.0 mg/ml and preferably is 0.4 mg/ml. Additionally, the weight ratio of the camptothecins to DLPC is within the range of about 1:10 wt:wt to about 1:50 wt:wt, preferably 1:50.

Although the dose and dosage regimen will depend upon the nature of the cancer, i.e., primary or metastatic, the characteristics of the particular camptothecin chosen, e.g., its therapeutic index, the patient, the patient's history and other factors, a person having ordinary skill in this art would readily be able to determine, without undue experimentation, the appropriate dosages. Typically, however, the amount of camptothecin or its derivative administered via inhalation may be in the range of about 0.26 mg/m.sup.2/day to about 1.04 mg/m.sup.2/day or about 6.7 .mu.g/kg/day to about 26.6 .mu.g/kg/day. The dosage or inhalation regimen may comprise one or two inhalation therapies per day using all or a divided daily dose over a period of consecutive days, e.g., 5, in a week additionally over a period of consecutive weeks such as 8 out of 10 weeks. It is also contemplated that a dosage or inhalation regimen may be repeated.

Treatment using a nebulized DLPC-9-nitro camptothecin (DLPC-9NC) aerosol has demonstrated a lack of hematologic toxicity. While the aerosol doses administered were 3 to 5 times lower than those administered orally, blood levels were close to those observed after oral ingestion (29). The aerosol droplet size or MADD of the DLPC-9NC liposome, as defined herein, is in the range that optimizes alveolar deposition. Alveolar-capillary exchange of 9NC through the pulmonary vein (30) makes inhalation therapy a method of rapid and efficient sustained arterial delivery through the lung parenchyma. This allows for first pass presentation of 9NC to the cancer site. It is demonstrated herein that high levels of 9NC are found in the lungs at the end of treatment and that clearance of 9NC from the lungs is slower than from the plasma.

Administration of the nebulized liposomal aerosol via inhalation is relatively easy using a jet nebulizer; patients can be trained to self-administer at home using a portable machine. Local pulmonary effects were bothersome in a few patients, but no incapacitating interference with pulmonary function was noted despite the presence of substantial primary or metastatic cancer in the lungs. Although chemical pharyngitis was the most prevalent dose-limiting side effect, the mucosa of the bronchus was spared significant toxicity despite a decrease in FEV1. Chemical pharyngitis increased during administration but disappeared at the conclusion of the treatment. Use of bronchodilators and steroid inhalers ameliorated this side effect. Additionally, bronchospasm was also more pronounced inpatients with extensive pulmonary involvement with cancer.

The methods of the present invention have demonstrated the systemic absorption of 9-nitrocamptothecin after pulmonary administration. Additionally, a partial remission of an endometrial cancer with metastases to the liver has been effected. As such, it is contemplated that systemic delivery of an anti-cancer drug, e.g., one of the camptothecins, via inhalation of a liposomal aerosol containing the drug can be used to treat other than pulmonary cancers.
 

Claim 1 of 11 Claims

1. A method for treating a primary lung cancer or a metastatic cancer to the lung in an individual comprising the step of: delivering at least once to the respiratory tract of the individual via inhalation a nebulized liposomal aerosol comprising a dilauroylphosphatidylcholine liposome containing camptothecin or a derivative thereof in an amount sufficient to deliver a pharmacologically effective dose of said camptothecin or derivative thereof to treat said cancer, wherein said dose of camptothecin or derivative thereof delivered via inhalation is about 0.26 mg/m.sup.2/day to about 1.04 mg/m.sup.2/ day.

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