Sustained release of antiinfectives

Abstract

Provided are lipid antiinfective formulations substantially free of anionic lipids with a lipid to antiinfective ratio is about 1:1 to about 4:1, and a mean average diameter of less than about 1 μm. Also provided is a method of preparing a lipid antiinfective formulation comprising an infusion process. Also provided are lipid antiinfective formulations wherein the lipid to drug ratio is about 1:1 or less, about 0.75:1 or less, or about 0.50:1 or less prepared by an in line fusion process. The present invention also relates to a method of treating a patient with a pulmonary infection comprising administering to the patient a therapeutically effective amount of a lipid antiinfective formulation of the present invention. The present invention also relates to a method of treating a patient for cystic fibrosis comprising administering to the patient a therapeutically effective amount of a lipid antiinfective formulation of the present invention.

What is claimed: 
     
         1 . A lipid antiinfective formulation comprising a lipid formulation and an antiinfective, wherein the lipid formulation is substantially free of anionic lipids, and wherein the weight ratio of lipid to antiinfective is 4:1 to 1:1, 3:1 to 1:1, 2:1 to 1:1, or 1:1. 
     
     
         2 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation is a liposome. 
     
     
         3 . The lipid antiinfective formulation of  claim 2 , wherein the liposome has a mean diameter of 0.1 μm to 1.0 μm, 0.2 μm to 0.5 μm, 0.2 μm to 0.4 μm, or 0.2 μm to 0.3 μm 
     
     
         4 . The lipid antiinfective formulation of  claim 1 , wherein the antiinfective is selected from the following: an aminoglycoside, a tetracycline, a sulfonamide, p-aminobenzoic acid, a diaminopyrimidine, a quinolone, a β-lactam, a β-lactam and a β-lactamase inhibitor, chloraphenicol, a macrolide, penicillins, cephalosporins, corticosteroid, prostaglandin, linomycin, clindamycin, spectinomycin, polymyxin B, colistin, vancomycin, bacitracin, isoniazid, rifampin, ethambutol, ethionamide, aminosalicylic acid, cycloserine, capreomycin, a sulfone, clofazimine, thalidomide, a polyene antifungal, flucytosine, imidazole, triazole, griseofulvin, terconazole, butoconazole ciclopirax, ciclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine, or combination thereof. 
     
     
         5 . The lipid antiinfective formulation of  claim 1 , wherein the antiinfective is an aminoglycoside. 
     
     
         6 . The lipid antiinfective formulation of claim wherein the antiinfective is amikacin. 
     
     
         7 . The lipid antiinfective formulation of claim wherein the antiinfective is tobramicin. 
     
     
         8 . The lipid antiinfective formulation of claim wherein the antiinfective is gentamicin. 
     
     
         9 . The lipid antiinfective formulation of claim, wherein the lipid formulation comprises neutral lipids. 
     
     
         10 . The lipid antiinfective formulation of  claim 1 , wherein the lipids that make up the lipid formulation are all neutral lipids. 
     
     
         11 . The lipid antiinfective formulation of  claim 1 , free of anionic lipids. 
     
     
         12 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation comprises a phospholipid. 
     
     
         13 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation comprises a steroid. 
     
     
         14 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation comprises a sterol. 
     
     
         15 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation comprises a phospholipid and a steroid. 
     
     
         16 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation comprises a phospholipid and a sterol. 
     
     
         17 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation comprises dipalmitoylphosphatidylcholine (DPPC) and cholesterol. 
     
     
         18 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation is a liposome with a mean diameter of 0.1 μm to 1.0 μm, 0.2 μm to 0.5 μm, 0.2 μm to 0.4 μm, or 0.2 μm to 0.3 μm; the antiinfective is amikacin; and the lipid formulation comprises a phospholipid and a steroid. 
     
     
         19 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation is a liposome with a mean diameter of 0.1 μm to 1.0 μm, 0.2 μm to 0.5 μm, 0.2 μm to 0.4 μm, is or 0.2 μm to 0.3 μm; the antiinfective is amikacin; and the lipid formulation comprises a phospholipid and a sterol. 
     
     
         20 . The lipid antiinfective formulation of  claim 1 , wherein the lipid formulation is a liposome with a mean diameter of 0.1 μm to 1.0 μm, 0.2 μm to 0.5 μm, 0.2 μm to 0.4 μm, or 0.2 μm to 0.3 μm; the antiinfective is amikacin; and the lipid formulation comprises DPPC and cholesterol. 
     
     
         21 . A method of preparing the lipid antiinfective formulation of  claim 1  comprising infusing an aqueous or alcoholic solution or mixture of the antiinfective with a lipid-alcohol solution or mixture at a temperature below the phase transition of at least one of the lipids, wherein infusing the aqueous or alcoholic solution or mixture of the antiinfective is done from above. 
     
     
         22 . The method of  claim 21 , wherein the lipid-alcohol solution or mixture has a concentration of 10 to 30 mg/mL. 
     
     
         23 . The method of  claim 21 , wherein the aqueous or alcoholic solution or mixture of the antiinfective has a concentration of 20 to 70 mg/mL. 
     
     
         24 . The method of  claim 21 , wherein the lipid-alcohol solution or mixture has a concentration of 10 to 30 mg/mL, and the aqueous or alcoholic solution or mixture of the antiinfective has a concentration of 20 to 70 mg/mL. 
     
     
         25 . The method of  claim 21 , wherein the antiinfective is selected from the following: an aminoglycoside, a tetracycline, a sulfonamide, p-aminobenzoic acid, a diaminopyrimidine, a quinolone, a β-lactam, a β-lactam and a β-lactamase inhibitor, chloraphenicol, a macrolide, penicillins, cepalosporins, corticosteroid, prostaglandin, linomycin, clindamycin, spectinomycin, polymyxin B, colistin, vancomycin, bacitracin, isoniazid, rifampin, ethambutol, ethionamide, aminosalicylic acid, cycloserine, capreomycin, a sulfone, clofazimine, thalidomide, a polyene antifungal, flucytosine, imidazole, triazole, griseofulvin, terconazole, butoconazole ciclopirax, ciclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine, or combination thereof. 
     
     
         26 . The method of  claim 21 , wherein the antiinfective is an aminoglycoside. 
     
     
         27 . The method of  claim 21 , wherein the antiinfective is amikacin. 
     
     
         28 . The method of  claim 21 , wherein the antiinfective is tobramycin. 
     
     
         29 . The method of  claim 21 , wherein the antiinfective is gentamicin. 
     
     
         30 . The method of  claim 21 , wherein the lipid-alcohol solution or mixture comprises a phospholipid. 
     
     
         31 . The method of  claim 21 , wherein the lipid-alcohol solution or mixture comprises a sterol. 
     
     
         32 . The method of  claim 21 , wherein the lipid-alcohol solution or mixture comprises DPPC and cholesterol. 
     
     
         33 . A lipid antiinfective formulation comprising a lipid formulation and an antiinfective, wherein the lipid to antiinfective ratio is 1:1 or less. 
     
     
         34 . The lipid antiinfective formulation of  claim 33 , wherein the lipid to antiinfective ratio is less than 0.75:1. 
     
     
         35 . The lipid antiinfective formulation of  claim 33 , wherein the lipid to antiinfective ratio is less than 0.5:1. 
     
     
         36 . The lipid antiinfective formulation of  claim 33 , wherein the antiinfective is an aminoglycoside. 
     
     
         37 . The lipid antiinfective formulation of  claim 33 , wherein the antiinfective is an aminoglycoside selected from the following: amikacin, gentamicin, or tobramycin. 
     
     
         38 . The lipid antiinfective formulation of  claim 33 , wherein the antiinfective is amikacin. 
     
     
         39 . The lipid antiinfective formulation of  claim 33 , wherein the antiinfective is gentamicin. 
     
     
         40 . The lipid antiinfective formulation of  claim 33 , wherein the antiinfective is tobramycin. 
     
     
         41 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation is a liposome. 
     
     
         42 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation comprises a phospholipid. 
     
     
         43 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation comprises a steroid. 
     
     
         44 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation comprises a sterol. 
     
     
         45 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation comprises dipalmitoylphosphatidylcholine (DPPC). 
     
     
         46 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation comprises cholesterol. 
     
     
         47 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation comprises a phospholipid and a steroid. 
     
     
         48 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation comprises a phospholipid and a sterol. 
     
     
         49 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation comprises DPPC and cholesterol. 
     
     
         50 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation is a liposome and the antiinfective is amikacin. 
     
     
         51 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation is a liposome, the antiinfective is amikacin, and the lipid formulation comprises a phospholipid and a sterol. 
     
     
         52 . The lipid antiinfective formulation of  claim 33 , wherein the lipid formulation is a liposome, the antiinfective is amikacin, and the lipid formulation comprises a DPPC and a cholesterol. 
     
     
         53 . A method of preparing a lipid antiinfective formulation comprising a lipid formulation and an antinfective comprising: mixing a stream of a lipid solution or mixture, with a stream of an antiinfective solution or mixture, wherein the two streams are mixed in line. 
     
     
         54 . The method of  claim 53 , wherein the two streams enter a Y-connector prior to mixing in line. 
     
     
         55 . The method of  claim 53 , wherein the solutions or mixtures are aqueous or alcoholic. 
     
     
         56 . The method of  claim 53 , wherein the lipid formulation is a liposome. 
     
     
         57 . The method of  claim 53 , wherein the antiinfective is an aminoglycoside. 
     
     
         58 . The method of  claim 53 , wherein the antiinfective is an aminoglycoside selected from the following: amikacin, gentamicin, or tobramycin. 
     
     
         59 . The method of  claim 53 , wherein the antiinfective is amikacin. 
     
     
         60 . The method of  claim 53 , wherein the antiinfective is gentamicin. 
     
     
         61 . The method of  claim 53 , wherein the antiinfective is tobramycin. 
     
     
         62 . The method of  claim 53 , wherein the stream of a lipid solution or mixture, and the stream of an antiinfective solution or mixture are mixed at a total flow rate of 700 to 900 mL/min. 
     
     
         63 . The method of  claim 53 , wherein the stream of a lipid solution or mixture, and the stream of an antiinfective solution or mixture are mixed at a total flow rate of 800 mL/min. 
     
     
         64 . The method of  claim 53 , wherein the stream of a lipid solution or mixture is added at a flow rate of 200 to 400 mL/min. 
     
     
         65 . The method of  claim 53 , wherein the stream of a lipid solution or mixture is added at a flow rate of 300 mL/min. 
     
     
         66 . The method of  claim 53 , wherein the stream of an antiinfective solution or mixture is added at a flow rate of 400 to 600 mL/min. 
     
     
         67 . The method of  claim 53 , wherein the stream of an antiinfective solution or mixture is added at a flow rate of 500 mL/min. 
     
     
         68 . The method of  claim 53 , wherein the stream of a lipid solution or mixture is added at a flow rate of 300 mL/min, and the stream of an antiinfective solution or mixture is added at a flow rate of 500 mL/min. 
     
     
         69 . The method of  claim 53 , wherein the temperature of the combined streams is 30-40° C. 
     
     
         70 . The method of  claim 53 , wherein the temperature of the lipid solution or mixture is 30° C., and the temperature of the antiinfective solution or mixture is 30° C. 
     
     
         71 . The method of  claim 53 , wherein the temperature of the lipid solution or mixture is 50° C., and the temperature of the antiinfective solution or mixture is room temperature. 
     
     
         72 . The method of  claim 53 , further comprising the step of diluting the combined streams with water at least 20 seconds after mixing. 
     
     
         73 . The method of  claim 53 , wherein the concentration of the antiinfective solution or mixture is 30 to 50 mg/mL. 
     
     
         74 . The method of  claim 53 , wherein the concentration of the antiinfective solution or mixture is 40 to 50 mg/mL. 
     
     
         75 . The method of  claim 53 , wherein the stream of a lipid solution or mixture is added at a flow rate of 300 mL/min, and the stream of an antiinfective solution or mixture is added at a flow rate of 500 mL/min; the temperature of the combined streams is 30-40° C.; the combined streams are diluted with water at least 20 seconds after mixing; and the concentration of the antiinfective solution or mixture is 40 to 50 mg/mL. 
     
     
         76 . The method of  claim 53 , wherein the lipid comprises a phospholipid. 
     
     
         77 . The method of  claim 53 , wherein the lipid comprises a steroid. 
     
     
         78 . The method of  claim 53 , wherein the lipid comprises a sterol. 
     
     
         79 . The method of  claim 53 , wherein the lipid comprises DPPC. 
     
     
         80 . The method of  claim 53 , wherein the lipid comprises cholesterol. 
     
     
         81 . The method of  claim 53 , wherein the lipid comprises a phospholipid and a sterol. 
     
     
         82 . The method of  claim 53 , wherein the lipid comprises DPPC and cholesterol. 
     
     
         83 . The method of  claim 53 , wherein the lipid formulation is a liposome and the antiinfective is amikacin. 
     
     
         84 . The method of  claim 53 , wherein the lipid formulation is a liposome, the antiinfective is amikacin, and the lipid comprises a phospholipid and a sterol. 
     
     
         85 . The method of  claim 53  wherein the lipid formulation is a liposome, the antiinfective is amikacin, and the lipid comprises DPPC and cholesterol. 
     
     
         86 . The method of  claim 53 , wherein the lipid to antiinfective ratio is 1:1 or less. 
     
     
         87 . The method of  claim 53 , wherein the lipid to antiinfective ratio is 0.75:1 or less. 
     
     
         88 . The method of  claim 53 , wherein the lipid to antiinfective ratio is 0.5:1 or less. 
     
     
         89 . The method of  claim 53 , wherein the lipid formulation is a liposome, the antiinfective is amikacin, the lipid comprises DPPC and cholesterol, and the lipid to antiinfective ratio is 1:1 or less. 
     
     
         90 . A method of treating a patient for a pulmonary infection comprising administering to the patient a therapeutically effective amount of the lipid antiinfective formulation of  claim 1  or  33 . 
     
     
         91 . The method of  claim 90 , wherein the pulmonary infection is a  pseudomonas, P. aeruginosa, P. paucimobilis, P. putida, P. fluorescens , and  P. acidovorans , staphylococcal, Methicillinresistant  Staphylococcus aureus  (MRSA), streptococcal,  Streptococcus pneumoniae, Escherichia coli, Klebsiella, Enterobacter, Serratia, Haemophilus, Yersinia pesos, Burkholderia pseudomallei, B. cepacia, B. gladioli, B. multivorans, B. vietnamiensis, Mycobacterium tuberculosis, M. avium  complex (MAC),  M. avium, M. intracellulare, M. kansasii, M. xenopi, M. marinum, M. ulcerans, M. fortuitum  complex,  M. fortuitum , or  M. chelonei  infection. 
     
     
         92 . A method of treating a patient for a pulmonary infection caused by cystic fibrosis comprising administering to the patient a therapeutically effective amount of the lipid antiinfective formulation of  claim 1  or  33 .