High delivery rates for lipid based drug formulations, and methods of treatment thereof

Abstract

Provided is a method of preparing lipid based drug formulations with low lipid/drug ratios using coacervation techniques. Also provided are methods of delivering such lipid based drug formulations at high delivery rates, and methods of treating patients with pulmonary diseases comprising administering such lipid based drug formulations.

1 .- 25 . (canceled) 
     
     
         26 . A lipid antiinfective formulation comprising an antiinfective complexed to or encapsulated by a lipid component, wherein the lipid component is net neutral and comprises a phospholipid and a sterol, and the lipid component to antiinfective weight ratio in the formulation is 0.40:1 to 0.49:1. 
     
     
         27 . The lipid antiinfective formulation of  claim 26 , wherein the phospholipid is dipalmitoylphosphatidylcholine (DPPC). 
     
     
         28 . The lipid antiinfective formulation of  claim 26 , wherein the sterol is cholesterol. 
     
     
         29 . The lipid antiinfective formulation of  claim 27 , wherein the sterol is cholesterol. 
     
     
         30 . The lipid antiinfective formulation of  claim 26 , wherein the lipid component is present as liposomes and the antiinfective is encapsulated by the liposomes. 
     
     
         31 . The lipid antiinfective formulation of  claim 27 , wherein the lipid component is present as liposomes and the antiinfective is encapsulated by the liposomes. 
     
     
         32 . The lipid antiinfective formulation of  claim 28 , wherein the lipid component is present as liposomes and the antiinfective is encapsulated by the liposomes. 
     
     
         33 . The lipid antiinfective formulation of  claim 29 , wherein the lipid component is present as liposomes and the antiinfective is encapsulated by the liposomes. 
     
     
         34 . The lipid antiinfective formulation of  claim 26 , wherein the antiinfective is 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, a penicillin, a cephalosporin, 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 a combination thereof. 
     
     
         35 . The lipid antiinfective formulation of  claim 33 , wherein the antiinfective is 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, a penicillin, a cephalosporin, 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 a combination thereof. 
     
     
         36 . The lipid antiinfective formulation of  claim 26 , wherein the antiinfective is an aminoglycoside. 
     
     
         37 . The lipid antiinfective formulation of  claim 27 , wherein the antiinfective is an aminoglycoside. 
     
     
         38 . The lipid antiinfective formulation of  claim 28 , wherein the antiinfective is an aminoglycoside. 
     
     
         39 . The lipid antiinfective formulation of  claim 29 , wherein the antiinfective is an aminoglycoside. 
     
     
         40 . The lipid antiinfective formulation of  claim 30 , wherein the antiinfective is an aminoglycoside. 
     
     
         41 . The lipid antiinfective formulation of  claim 31 , wherein the antiinfective is an aminoglycoside. 
     
     
         42 . The lipid antiinfective formulation of  claim 32 , wherein the antiinfective is an aminoglycoside. 
     
     
         43 . The lipid antiinfective formulation of  claim 33 , wherein the antiinfective is an aminoglycoside. 
     
     
         44 . The lipid antiinfective formulation of  claim 36 , wherein the aminoglycoside is amikacin. 
     
     
         45 . The lipid antiinfective formulation of  claim 37 , wherein the aminoglycoside is amikacin. 
     
     
         46 . The lipid antiinfective formulation of  claim 38 , wherein the aminoglycoside is amikacin. 
     
     
         47 . The lipid antiinfective formulation of  claim 39 , wherein the aminoglycoside is amikacin. 
     
     
         48 . The lipid antiinfective formulation of  claim 40 , wherein the aminoglycoside is amikacin. 
     
     
         49 . The lipid antiinfective formulation of  claim 41 , wherein the aminoglycoside is amikacin. 
     
     
         50 . The lipid antiinfective formulation of  claim 42 , wherein the aminoglycoside is amikacin. 
     
     
         51 . The lipid antiinfective formulation of  claim 43 , wherein the aminoglycoside is amikacin. 
     
     
         52 . A method of treating a pulmonary infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a lipid antiinfective formulation comprising an antiinfective complexed to or encapsulated by a lipid component, wherein the lipid component is net neutral and comprises a phospholipid and a sterol, and the lipid component to antiinfective weight ratio in the formulation is 0.40:1 to 0.49:1. 
     
     
         53 . The method of  claim 52 , wherein the administering occurs via nebulizing the lipid antiinfective formulation at a rate of 10 to 25 mg/min. 
     
     
         54 . The method of  claim 52 , wherein the lipid component is present as liposomes and the antiinfective is encapsulated by the liposomes. 
     
     
         55 . The method of  claim 52 , wherein the phospholipid is dipalmitoylphosphatidylcholine (DPPC). 
     
     
         56 . The method of  claim 53 , wherein the phospholipid is dipalmitoylphosphatidylcholine (DPPC). 
     
     
         57 . The method of  claim 54 , wherein the phospholipid is dipalmitoylphosphatidylcholine (DPPC). 
     
     
         58 . The method of  claim 55 , wherein the sterol is cholesterol. 
     
     
         59 . The method of  claim 56 , wherein the sterol is cholesterol. 
     
     
         60 . The method of  claim 57 , wherein the sterol is cholesterol. 
     
     
         61 . The method of  claim 58 , wherein the pulmonary infection is a  Pseudomonas  infection. 
     
     
         62 . The method of  claim 59 , wherein the pulmonary infection is a  Pseudomonas  infection. 
     
     
         63 . The method of  claim 60 , wherein the pulmonary infection is a  Pseudomonas  infection. 
     
     
         64 . The method of  claim 58 , wherein the pulmonary infection is a mycobacterial infection. 
     
     
         65 . The method of  claim 59 , wherein the pulmonary infection is a mycobacterial infection. 
     
     
         66 . The method of  claim 60 , wherein the pulmonary infection is a mycobacterial infection. 
     
     
         67 . The method of  claim 52 , wherein the antiinfective is 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, a penicillin, a cephalosporin, 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 a combination thereof. 
     
     
         68 . The method of  claim 54 , wherein the antiinfective is 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, a penicillin, a cephalosporin, 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 a combination thereof. 
     
     
         69 . The method of  claim 60 , wherein the antiinfective is 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, a penicillin, a cephalosporin, 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 a combination thereof. 
     
     
         70 . The method of  claim 67 , wherein the antiinfective is an aminoglycoside. 
     
     
         71 . The method of  claim 68 , wherein the antiinfective is an aminoglycoside. 
     
     
         72 . The method of  claim 69 , wherein the antiinfective is an aminoglycoside. 
     
     
         73 . The method of  claim 70 , wherein the aminoglycoside is amikacin. 
     
     
         74 . The method of  claim 71 , wherein the aminoglycoside is amikacin. 
     
     
         75 . The method of  claim 72 , wherein the aminoglycoside is amikacin.