The small particle liposome aerosol compounds and methods of treatment of the present invention involve lipid- or water soluble anti-cancer drugs incorporated into liposomes. The liposomes are administered in aqueous dispersions from a jet nebulizer to the respiratory tract of an individual. Various anti-cancer drugs may be used, including 20-S-Camptothecin, 9-Nitro-camptothecin, 9-Amino-camptothecin, 10, 11-methylenedioxy-camptothecin and taxol or its derivatives. Administration of these drugs by inhalation provides faster and more efficient absorption of the anticancer drug than does intramuscular administration or oral administration.

Description of the Invention

SUMMARY OF THE INVENTION

The small particle liposome aerosol compounds and methods of treatment of the present invention involve lipid-soluble or water-soluble anti-cancer drugs incorporated into liposomes. The liposomes then are administered in aqueous dispersions from a jet nebulizer. The present invention demonstrates that speedier and more efficient systemic absorption of drug is actualized after pulmonary administration by aerosol than is actualized by intramuscular or oral administration.

One object of the present invention is to provide a method for treating cancer, comprising the step of delivering, via small particle aerosol, aqueous dispersions of anti-cancer drugs to the respiratory tract of an individual in need of such treatment. Examples of anticancer drugs available for use in this embodiment of the invention include, but are not limited to, 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, 10, 11-methylenedioxy-camptothecin, taxol, taxol-A, mitotane, methotrexate, mercaptopurine, lomustine, interferon, 5-fluorouracil and etopiside. In a more preferred embodiment of this object, the anti-cancer drug is selected from the group consisting of 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, 10, 11-methylenedioxy-camptothecin and taxol. Additionally, in a preferred embodiment of the present objective, the delivery of the anticancer drug is performed by a jet nebulizer.

In another object of the present invention, there is provided a liposome for delivery of anticancer drugs via small particle aerosols comprising an anticancer drug and a lipid, wherein the anticancer drug is at a concentration not exceeding about 10% of the total volume of the preparation and a ratio of the anticancer drug to the suitable solvent is in the range of about 1:1 to about 1:200, preferably in a range of about 1:10 to about 1:100, and most preferably in a range of about 1:10 to about 1:50 (wt:wt) of the preparation. One specific embodiment of this object includes 9-nitro-camptothecin and dilauroylphosphatidylcholine in a ratio of about 1:10 to 1:50 wt:wt; with a particularly preferred embodiment having a 9-nitro-camptothecin and dilauroylphosphatidylcholine of about 1:50 wt:wt. In another embodiment, there is provided a liposome for delivery of anticancer drugs via small particle aerosols comprising Taxol and dilauroylphosphatidylcholine in a ratio of about 1:30 wt:wt.

In yet another embodiment of the present invention, there is provided a liposome produced by the following steps: dissolving a lipid-soluble anticancer drug in a solvent suitable for dissolving the anticancer drug to produce dissolved anticancer drug; adding the dissolved anticancer drug to a dissolved lipid suitable for formulation and delivery of drugs by aerosol to produce a solution, wherein the dissolved anticancer drug is at a concentration not exceeding about 10% of the total volume of the solution and a ratio of the anticancer drug to the lipid is in the range of about 1:1 to about 1:200, preferably in a range of about 1:10 to about 1:100, and most preferably in a range of about 1:10 to about 1:50 (wt:wt) of the solution; and freezing and lyophilizing the solution. At this point, the solution may be stored frozen for later use or dissolved in sterile water for use, producing a suspension, wherein the concentration of the anticancer drug in the sterile water in the suspension is no more than about 5.0 mg/ml.

A preferred embodiment of the above object provides liposomal preparations of 20-S-camptothecin (CPT), 9-nitrocamptothecin (9-NC) and other lipid soluble camptothecin derivatives, produced by the following steps: preparing concentrated stock solutions of said 20-S-camptothecin (CPT), 9-nitrocamptothecin (9-NC) or other-lipid soluble camptothecin derivatives and lipids in compatible solvents; adding appropriate volumes of the 20-S-camptothecin (CPT), 9-nitrocamptothecin (9-NC) or other-lipid soluble camptothecin derivative and lipid concentrated stock solutions to a volume of t-butanol to form a second solution, wherein a concentration of said 20-S-camptothecin (CPT), 9-nitrocamptothecin (9-NC) and other lipid soluble camptothecin derivatives does not exceed 10% of said second solution and wherein a ratio of drug to lipid is in the range of about 1:1 to about 1:200, preferably in a range of about 1:10 to about 1:100, and most preferably in a range of about 1:10 to about 1:50 (wt:wt) in said second solution; freezing said second solution; and lyophilizing said second solution to produce a powder preparation. At this point, the powder preparation may be stored frozen for later use or dissolved in sterile water producing a suspension, wherein a concentration of said anticancer drug in said suspension is no more than about 5 mg/ml.

A more particular embodiment provides liposomes produced by the following steps: preparing a concentrated stock solutions of anticancer drug, for example 100 mg CPT in 1 ml t-butanol or 100 mg 9-NC in DMSO, preparing a stock solution of lipid, for example, 100 mg DLPC in 1 ml butanol; adding appropriate volumes of said concentrated stock solutions to a volume of t-butanol to form a second solution wherein a final volume is about 10 ml, a volume of DMSO, if any, does not exceed 10% (vol:vol) of said final volume, a concentration of anticancer drug does not exceed 10% (wt:wt) of the total volume, and wherein a ratio of drug to lipid is in a range of about 1:1 to about 1:200, preferably in a range of about 1:10 to about 1:100, and most preferably in a range of about 1:10 to about 1:50 (wt:wt); freezing said second solution; and lyophilizing said frozen solution to produce a powder preparation. The powder preparation may then be stored frozen for later use or dissolved in sterile water producing a suspension. Generally, the concentration of the anticancer drug in the suspension is no more than about 5 mg/ml.

Another preferred embodiment of the object above provides a liposome produced by the following steps: mixing taxol with synthetic alpha lecithin: dilauroylphosphatidylcholine; dissolving the taxol-DLPC in t-butanol to produce a preparation; and freezing and lyophilizing the preparation. Liposomes are produced by adding sterile, pure water at a temperature above 25.infin. C., wherein the final concentration of taxol to dilauroylphosphatidylcholine is about 1:1 to about 1:200, preferably in a range of about 1:10 to about 1:100, and most preferably in a range of about 1:25 to about 1:40 (wt:wt). In addition to alpha lecithin, other natural or synthetic lecithins may be used, including but not limited to egg yolk phosphatidylcholine, hydrogenated soybean phosphatidylcholine, dimyristophosphatidylcholine, diolyeolyl-dipalmitoyleolylphospha-tidylcholine and dipalmitoyl phosphatidylcholine.

The efficiency of incorporation of 9-NC and other camptothecin derivatives and anticancer drugs into liposomes can be tested by layering an aqueous dispersion of lyophilized drug-liposome preparation over a Percoll % gradient and centrifuging. Unincorporated drug collects at the bottom of the tube, but drug incorporated into liposomes collects at the interface between the Percoll gradient and the water phase. One qualitative test of incorporation efficiency is the observation of drug crystals when the dispersion of drug-liposomes are examined by microscopy under polarized light. Other methods are also available, for example, analytical HPLC methods can be used to quantitatively assess non-encapsulated, crystalized drug.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a method for treating cancer, comprising the step of delivering, via small particle aerosol, aqueous dispersions of anti-cancer drugs to the respiratory tract of an individual in need of such treatment. In a preferred embodiment of this object, the anti-cancer drug is selected from the group consisting of 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin and 10, 11-methylenedioxy-camptothecin. Add-itionally, in a preferred embodiment of the present objective, the delivery of the anticancer drug is performed by a jet nebulizer.

Additionally, there is a liposome for delivery of anticancer drugs via small particle aerosols comprising an anticancer drug and a lipid, wherein the anticancer drug is at a concentration not exceeding about 10% of the total volume of the preparation and a ratio of the anticancer drug to the suitable solvent is in the range of about 1:1 to about 1:200, preferably in a range of about 1:10 to about 1:100, and most preferably in a range of about 1:10 to about 1:50 (wt:wt) of the preparation. One specific embodiment of this object includes 9-nitro-camptothecin and dilauroylphosphatidylcholine in a ratio of about 1:10 to 1:50 wt:wt; with a particularly preferred embodiment having a 9-nitro-camptothecin and dilauroyl-phosphatidylcholine of about 1:50 wt:wt.

Taxol is another anti-cancer drug that is lipid soluble and is incorporated easily into a liposome formulation. The optimal ratio for taxol and dilauroylphosphatidylcholine is a ratio of about 1:1 to about 1:200, preferably in a range of about 1:10 to about 1:100, and more preferably in a range of about 1:25 to about 1:40 (wt:wt). A most preferred embodiment provides a taxol to DLPC ratio of about 1:30. Taxol is directly dissolved in t-butanol without use of DMSO as is used for some camptothecins. The Taxol liposomal preparation is otherwise similar to that of the camptothecins.

Further, the present invention is directed to liposomes for delivery of anticancer drugs via small particle aerosols produced by the following steps: dissolving a lipid-soluble anticancer drug in a solvent suitable for dissolving the anticancer drug to produce dissolved anticancer drug; adding the dissolved anticancer drug to a dissolved lipid suitable for formulation and delivery of drugs by aerosol to produce a solution, wherein the dissolved anticancer drug is at a concentration not exceeding about 10% of the total volume of the solution and a ratio of the anticancer drug to the suitable solvent is in the range of about 1:1 to about 1:200 of the solution; and freezing and lyophilizing the solution. At this point, the solution may be stored frozen for later use or dissolved in sterile water to produce a suspension, wherein the concentration of the anticancer drug in the sterile water in the suspension is no more than about 5.0 mg/ml. A particular embodiment of the present invention provides a liposome produced by the following steps: dissolving a lipid-soluble anticancer drug selected from the group of 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin and 10, 11-methylenedioxy-camptothecin in 100% DMSO to produce dissolved anticancer drug; and adding said dissolved anticancer drug to dilauroylphosphatidylcholine dissolved in t-butanol to produce a solution, wherein the dissolved anticancer drug is at a concentration not exceeding about 5% of the total volume of the solution and the ratio of anticancer drug to dilauroylphosphatidylcholine is about 1:50 in the solution. The solution is frozen and lyophilized overnight. For use, the lyophilized solution is suspended in appropriate volumes of sterile, distilled water. In addition, other methods of liposome preparation known in the art may be utilized, for example, rotary evaporation can be used instead of lyophilization.

9-NC-DLPC aerosol is prepared by first dissolving the drug in DMSO; to do so, heating to 50-60.infin. C. may be required. This solution is added to a larger volume of t-butanol, such that the DMSO solution does not exceed 5-10% of the total t-butanol and DMSO volume combined. The organic solvents DMSO and t-butanol are evaporated from the solution on liquid nitrogen resulting in a slightly yellow powder. For use, distilled sterile water is added to the vials containing the drug at the appropriate concentration and added to the reservoir of the nebulizer. The Aerotech II % nebulizer CIS-USA, Inc., Bedford Mass. is currently employed, but other nebulizers with similar aerosol-generating properties may be used.

A particular embodiment of the present invention is directed to a liposome produced by the following steps: mixing taxol with synthetic alpha lecithin: dilauroylphosphatidylcholine; dissolving the taxol-DLPC in t-butanol to produce a solution; and freezing and lyophilizing the solution. Liposomes are produced by adding sterile, pure water at a temperature above 25.infin. C., wherein the final concentration of taxol to dilauroylphosphatidylcholine is about 1:1 to about 1:200, preferably in a range of about 1:10 to about 1:100, and more preferably in a range of about 1:25 to about 1:40 (wt:wt).

It is contemplated specifically that the pharmaceutical compositions of the present invention be used for aerosol delivery of aqueous dispersions of liposomes carrying anti-cancer drugs to the respiratory tract. A person having ordinary skill in this art would readily be able to determine, without undue experimentation, the appropriate dosages of these aerosol formulations. When used in vivo for therapy, the aerosol formulations of the present invention are administered to the patient in therapeutically effective amounts; i.e., amounts that eliminate or reduce the tumor burden. As with all pharmaceuticals, the dose and dosage regimen will depend upon the nature of the cancer (primary or metastatic), the characteristics of the particular drug (e.g., its therapeutic index), the patient, the patient's history and other factors. The amount of aerosol formulation administered will typically be in the range of about 8 mg/kg of patient weight/day to about 100 mg/kg of patient weight/day for 9-NC. Again, dose and dosage regimen will vary depending on a number of factors known to those skilled in the art. See Remington's Pharmaceutical Science, 17th Ed. (1990) Mark Publishing Co., Easton, Pa.; and Goodman and Gilman's: The Pharmacological Basis of Therapeutics 8th Ed (1990) Pergamon Press.

The small particle liposome aerosol compounds and methods of treatment of the present invention involve lipid- or water-soluble anti-cancer drugs incorporated into liposomes. The liposomes are administered in aqueous dispersions from a jet nebulizer. Various anti-cancer drugs may be used, including 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, 10, 11-methylenedioxy-camptothecin and taxol.

 

Claim 1 of 4 Claims

1. A method for treating cancer, comprising the step of delivering, via small particle aerosol, aqueous dispersions of camptothecin or a derivative thereof in dilauroylphosphatidylcholine liposomes to the respiratory tract of an individual in need of such treatment, wherein said camptothecin or derivative thereof is 20-S-camptothecin, 9-nitrocamptothecin or 10,11-methylenedioxy-camptothecin, and the dose of said camptothecin or derivative thereof is about 8 mg/kg/day to about 100 mg/kg/day.

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