Treatment of cancers by inhalation of stable platinum-containing formulations

Abstract

Disclosed are methods of treating cancers by inhalation of stable platinum-containing formulations.

Description

[0001] This Application claims benefit to a provisional application No. 60 / 313,528 filed on Aug. 20, 2001.[0002] The present invention relates to methods of treating cancers by administering stable platinum-containing formulations by inhalation into a subject's respiratory tract. More particularly, the present invention relates to methods of administration of cisplatin compounds by inhalation to treat lung cancers. [0003] Cisplatin has been used for the treatment of cancers since the 1970's. It is an antineoplastic, inhibiting cell division. Cisplatin has been particularly useful in treating testicular and ovarian cancers, with good results also shown for cancers of the head and neck, esophagus, bladder, and lung. Cisplatin converts to an ineffective form in aqueous solution, consequently, cisplatin solutions must be stabilized or the drug will lose its anti-tumor effectiveness. Cisplatin is associated with several adverse side effects, including nausea and vomiting, kidney damage, ...

AI Technical Summary

Benefits of technology

[0004] In comparison to injection or infusion, the administration of a drug by inhalation is attractive. For some cancers, inhalation can provide a more localized administration of the therapeutic agent and, therefore, can be more effective. The increased effectiveness of local administration will be seen most in the lungs and bronchial pathways, but as the platinum-containing drug is cleared from the lungs via cellular uptake and transfer to the lymphatic system, it can act on cancers affecting other areas, such as the liver, spleen, and bone marrow. With this local application approach, inhalation can reduce the side effects of cisplatin and other platinum-containing agents normally encountered after intravenous administration, due to limited bioavailability to tissues and organs via the blood stream. It can also be easier to administer therapeutics by inhalation. Cisplatin when administered intravenously is rapidly bound to various proteins found in the blood plasma, thus inactivating most of the intact platinum compound. In vivo studies indicate that this inactivation will not occur in the lung since the dose required to elicit a response in animal models is 10-100 fold more effective. Thus, the dose which is administered by inhalation can be 10-100 fold lower than the dose administered intravenously. Therefore the therapeutic index can be improved significantly. When appropriate medically, the drug can be self-administered, leading to better patient compliance and reduced cost.

[0006] The present invention can overcome the difficulties and disadvantages in current inhalation therapy and offer new advantages that can benefit the treatment of cancers by local administration. These methods minimize systemic exposure of non-cancerous cells in the body to the toxic effects of the platinum-containing drug. Less of a dose can be administered, since it is applied for local activity and is targeted to specific diseased cells in the lung rather than distributed throughout the body. The result can be an improved therapeutic index. In addition, formulations of the present invention can be prepared that will be absorbed systemically following inhalation. Such systemic absorption can occur with less toxicity. Furthermore, for some formulations, the release of the platinum can occur over a prolonged period of time. SUMMARY OF THE INVENTION

[0009] A stable platinum-based formulation can be produced by milling a platinum-based drug, such as cisplatin, to a powder and combining it with sodium chloride as a dry powder blend suitable for administration by inhalation. The resulting formulation can include one or more phospholipids or liposomes. The presence of extraneous chloride ions are known to prevent the cisplatin from degrading by loss of the chloride—constituents of the cisplatin molecule when the drug is dissolved in water. The extra chloride will protect the molecule from degrading as rapidly in the presence of the moisture in the lung. The added presence of lipids or liposomes can protect against hydration, permitting adherence to the lung surface, and provide sustained contact which can allow for longer release periods.

[0010] Alternatively, the platinum-containing drug can be combined with a sodium chloride solution, then the water removed from the solution by such methods as evaporation, freeze drying or spray drying, to form sodium chloride—platinum-containing drug combination, including, but not limited to, sodium chloride crystals which protect the platinum containing—drug from degradation. These crystals can then be precipitated in such a way that they are appropriate for administration by inhalation or milled to a powder suitable for administration by inhalation.

[0018]“Stabilizer” is an agent that prevents or slows the transformation or deactivation of a platinum-containing compound or ion in a platinum-containing formulation.

Problems solved by technology

Cisplatin converts to an ineffective form in aqueous solution, consequently, cisplatin solutions must be stabilized or the drug will lose its anti-tumor effectiveness.

Cisplatin is associated with several adverse side effects, including nausea and vomiting, kidney damage, and hearing loss.

With this local application approach, inhalation can reduce the side effects of cisplatin and other platinum-containing agents normally encountered after intravenous administration, due to limited bioavailability to tissues and organs via the blood stream.

Administration of therapeutic agents by inhalation does have drawbacks, however.

Due to the immune response of the lung and natural breathing parameters designed to expel foreign particles, drugs that are administered by inhalation quickly clear the lung and, therefore, often yield short-term therapeutic effects since they become subject to chemical and enzymatic in-vivo degradation and / or expulsion via the airways.

Furthermore, for some formulations, the release of the platinum can occur over a prolonged period of time.