Patent Application: US-89973610-A

Abstract:
the present invention provides a method of inhibiting cancer growth in the lungs of a mammal through the inhalation administration of aerosol particles of an anti - cancer drug formulation . further , the present invention provides a formulation for aerosol delivery that comprises a combination of paclitaxel , α - tocopheryl succinate ; sorbitan trioleate , ethanol , and carbon dioxide . prior studies have indicated that aerosol administration of cancer drugs holds great potential as a treatment modality , both for lung cancer and for lung metastases of other cancers . practice of the invention has been demonstrated using a mouse model of lung cancer , in which intrapulmonary deposition of paclitaxel by aerosol inhalation reduced lung tumor size and increased body weight in tumor - bearing mice .

Description:
one of ordinary skill in the art will be able to envision and practice the invention as described or in related , alternative embodiments . in one embodiment , the invented formulation comprises 60 mg paclitaxel , 0 . 3 g α - tocopheryl succinate ( αts ), 0 . 66 g sorbitan trioleate ( span85 ), 5 . 8 g ethanol ( etoh ), and 230 g of co 2 enclosed in a 48 ci pressure vessel , then pressurized to 1600 psig with helium gas . broadly , the invented lung cancer therapeutic formulation includes paclitaxel , solubility enhancing agents αts , span85 , and etoh , and carbon dioxide as the solvent and propellant . the ratios of paclitaxel to the solubility enhancing agents and pressurized solvent is not firmly fixed , but can be varied . by mass , the formulation can be described as as noted , these relative ratios are not fixed , but can be adjusted to meet the paclitaxel delivery needs . for example , for a given amount of paclitaxel the relative amounts of the solubility enhancing agents αts , span85 , and ethanol can be adjusted , as well as the amount of carbon dioxide solvent needed to dissolve the resultant mixture . in such a case , one of many permutations would be that the use of additional span85 could decrease the amount of αts needed in the formulation . depending on the desired amount of paclitaxel delivered , the formulation can include , minimally , paclitaxel and carbon dioxide alone . therefore , the invention description can be described as ranges of concentrations used to create a suitable paclitaxel formulation for aerosol delivery , as low as zero for individual solubility enhancing agents depending on the amounts used of the others , and a range of carbon dioxide solvent for dissolving the resultant paclitaxel - containing mixture : in other embodiments , other agents are added to improve the formulation effectiveness against lung tumors that exhibit resistance to paclitaxel . a variety of mechanisms may be involved . in the case of multidrug resistance gene upregulation , agents can be added to interfere with the expression and activity of p - glycoprotein transport of paclitaxel out of the targeted cells . in other words , in addition to the paclitaxel , the formulation can include active agents to decrease drug resistance to paclitaxel . for example , the formulation can include cyclosporin , quinidine , biricodar , or other agents to decrease paclitaxel efflux from tumor cells . other lung cancer drugs can be utilized in the supercritical fluid formulation in addition to paclitaxel . this would include , but not be limited to , other taxanes such as docetaxel , topoisomerase inhibitors such as etoposide , camptothecin , or doxorubicin , dna crosslinking agents such as cisplatin , and other agents active against lung tumors . we demonstrated the use of an aerosol formulation of 60 mg paclitaxel , 0 . 3 g αts , 0 . 66 g span85 , 5 . 8 g etoh , and 230 g of co 2 , pressurized to 1600 psi with helium gas headspace and released through a high pressure nozzle to form respirable , airborne paclitaxel aerosol particles , deposit relevant doses in mouse lungs , and inhibit lung tumor growth in a mouse model of nonsmall cell lung cancer . fig1 shows the particle size distribution after collection of said paclitaxel aerosol on anderson cascade impactor and quantitative analysis of paclitaxel on the stages by hplc - ms / ms . the mass median aerodynamic diameter is 1 . 2 μm which is ideal for particle inhalation : aerosol delivery of the paclitaxel formulation to mice gave a per - mouse , lung - specific dose of 30 ± 5 ng paclitaxel , an amount calculated to be appropriate for further study in a lung tumor model . a mouse model of lung cancer was used for further testing of the paclitaxel aerosol formulation . briefly , athymic nude mice were injected with human nonsmall cell lung cancer a549 cell line cell stably transfected with the firefly luciferase gene ( a549 - luc cells ). on day 12 , mice verified to have lung tumor formation in vivo by luciferin - dependent chemiluminescence were divided into two groups , one untreated control tumor group and one aerosol - treated tumor group , receiving 30 ng of paclitaxel by inhalation of the aforementioned aerosol formulation 3 × per week , with monitoring of body weights . at day 33 , the experiment was ended , body weights assessed and excised lung tumor volumes measured . it was determined that tumor - bearing mice treated by inhalation of the paclitaxel aerosol formulation gained weight , but untreated tumor - bearing mice lost weight , an indication that the overall health of the treated mice was better than that of the untreated mice . the mean body weight was higher in the paclitaxel aerosol - treated mice than the untreated mice at day 31 after a549 lung tumor cell injection ( p & lt ; 0 . 05 ) as shown in fig2 . notably , there was also a decrease in lung tumor volume in the mice treated with inhaled paclitaxel aerosol formulation compared to the untreated mice . the total number of lung tumors per mouse was not different between the two groups , but the lung tumor volume was significantly lower in the mice that were treated with the inhaled paclitaxel aerosol formulation ( p & lt ; 0 . 05 ), as shown in fig3 . 1 . anderson p m , markovic s n , sloan j a , clawson m l , wylam m , arndt c a , smithson w a , burch p , gornet m , and rahman e . aerosol granulocyte macrophage - colony stimulating factor : a low toxicity , lung - 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