Liposomal formulations that form drug nanocrystals after freeze-thaw

1. A formulation, comprising:

liposomes wherein the liposomes comprise:

a lipid bilayer comprised of sucrose and a phosphatidylcholine-enriched phospholipids present at a ratio between 1:10 to 10:1 (w/w);

a sucrose cryopreservative;

a polysorbate 20 in an amount of between 0.01% to 1%; and

nanocrystals of ciprofloxacin surrounded by the lipid bilayer wherein the nanocrystals have dimensions of 200 nm or less.

2. The formulation of claim 1 , further comprising:

a pharmaceutically acceptable carrier.

3. The formulation of claim 2 , wherein the ciprofloxacin is:

dissolved in the carrier.

4. The formulation of claim 1 , further comprising:

a liquid form of a pharmaceutically active drug in which the liposomes are dispersed.

5. The formulation of claim 4 , wherein the drug in liquid form is an anti-infective drug.

6. The formulation of claim 5 , wherein the anti-infective drug is selected from the group consisting of a quinolone, a sulfonamide, an aminoglycoside, a tetracycline, para-aminobenzoic acid, a diaminopyrimidine, a beta-lactam, a beta-lactam and a beta-lactamase inhibitor, chloramphenicol, a macrolide, lincomycin, clindamycin, spectinomycin, polymyxin B, colistin, vancomycin, bacitracin, isoniazid, rifampin, ethambutol, ethionamide, aminosalicylic acid, cycloserine, capreomycin, a sulfone, clofazimine, thalidomide, polyene antifungal, flucytosine, imidazole, triazole, griseofulvin, terconazole, butoconazole ciclopirax, ciclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine and combinations thereof;

wherein the lipid bilayer is comprised of a lipid selected from the group consisting of fatty acids; lysolipids; sphingolipids; sphingomyelin; glycolipids; glucolipids; glycosphingolipids; palmitic acid; stearic acid; arachidonic acid; oleic acid; lipids bearing sulfonated mono-, di-, oligo- or polysaccharides; lipids with ether and ester-linked fatty acids, polymerized lipids, diacetyl phosphate, stearylamine, cardiolipin, phospholipids, synthetic phospholipids with asymmetric acyl chains; and lipids bearing a covalently bound polymer; and

wherein the liposome comprises a phospholipid selected from the group consisting of phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, phosphatidylglycerols, phosphatidic acid, phosphatidylserines, and mixtures thereof; wherein said phospholipid is provided in admixtures with a modifying agent selected from the group consisting of cholesterols, stearyl amines, stearic acid, tocopherols, and mixtures thereof; and wherein the liposomes are unilamellar or multilamellar.

7. The formulation of claim 6 ,

wherein the nanocrystals have dimensions of 100 nanometers or less.

8. The formulation of claim 7 ,

wherein the nanocrystals have a dimension of 50 nanometers to 75 nanometers;

wherein 90% or more of the liposomes maintain structural integrity when liposome temperature is decreased to a reduced temperature in a range of −20° C. to −80° C.; and

stored at the reduced temperature for a period of one week or more at the reduced temperature; and

thawed by increasing the temperature to a temperature in a range of 5° C. to 30° C.

9. The formulations as claimed in claim 8 , wherein the formulation is aerosolized into particles having an aerodynamic diameter in a range of from 1 micron to 12 microns and liposomes having a diameter in a range of 20 nanometers to 1 micron, wherein at least 90% of the liposomes are comprised of a composition which allow the liposomes to maintain structural integrity after aerosolization.

10. A liposome formulation produced by a process comprising the steps of:

providing a solution of ciprofloxacin;

forming spherical lipid bilayers around the ciprofloxacin solution thereby encapsulating the solution in liposomes wherein the lipid bilayer is comprised of sucrose and a phosphatidylcholine-enriched phospholipids present at a ratio between 1:10 to 10:1 (w/w), and polysorbate 20 in an amount of between 0.01% to 1%;

freezing the liposomes;

maintaining the liposomes frozen over a period of time;

raising the temperature of the liposomes to a temperature above a freezing point of the solution to a temperature whereby nanocrystals of ciprofloxacin are formed wherein the nanocrystals have dimensions of 100 nanometers to 50 nanometers.

11. The formulation of claim 10 , wherein freezing is to a temperature of from −20° C. to −80° C., and the freezing is maintained over a period of time of one week or more.

12. A method of treatment, comprising:

aerosolizing a formulation to create aerosolized particles having an aerodynamic diameter in a range of from 2 microns to 12 microns;

wherein the formulation comprises:

a pharmaceutically acceptable carrier;

ciprofloxacin; and

liposomes wherein the liposomes comprise:

a lipid bilayer comprised of sucrose and a phosphatidylcholine-enriched phospholipids present at a ratio between 1:10 to 10:1 (w/w);

a polysorbate 20 in an amount of between 0.01% to 1%;

nanocrystals of the ciprofloxacin surrounded by the lipid bilayer wherein the nanocrystals have dimensions of 200 nm or less;

wherein the liposomes are dispersed in a liquid form of a pharmaceutically active drug; and

inhaling the aerosolized particles.

13. The method of claim 4 , wherein the pharmaceutically active drug in liquid form is an anti-infective drug selected from the group consisting of a quinolone, a sulfonamide, an aminoglycoside, a tetracycline, para-aminobenzoic acid, a diaminopyrimidine, a beta-lactam, a beta-lactam and a beta-lactamase inhibitor, chloramphenicol, a macrolide, lincomycin, clindamycin, spectinomycin, polymyxin B, colistin, vancomycin, bacitracin, isoniazid, rifampin, ethambutol, ethionamide, aminosalicylic acid, cycloserine, capreomycin, a sulfone, clofazimine, thalidomide, polyene antifungal, flucytosine, imidazole, triazole, griseofulvin, terconazole, butoconazole ciclopirax, ciclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine and combinations thereof;

wherein the lipid bilayer is comprised of a lipid selected from the group consisting of fatty acids; lysolipids; sphingolipids; sphingomyelin; glycolipids; glucolipids; glycosphingolipids; palmitic acid; stearic acid; arachidonic acid; oleic acid; lipids bearing sulfonated mono-, di-, oligo- or polysaccharides; lipids with ether and ester-linked fatty acids, polymerized lipids, diacetyl phosphate, stearylamine, cardiolipin, phospholipids, synthetic phospholipids with asymmetric acyl chains; and lipids bearing a covalently bound polymer; and

wherein the liposome comprises a phospholipid selected from the group consisting of phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, phosphatidylglycerols, phosphatidic acid, phosphatidylserines, and mixtures thereof; wherein said phospholipid is provided in admixtures with a modifying agent selected from the group consisting of cholesterols, stearyl amines, stearic acid, tocopherols, and mixtures thereof; and wherein the liposomes are unilamellar or multilamellar.

14. The method of claim 4 ,

wherein the nanocrystals have dimensions of 100 nanometers or less and wherein;

the pharmaceutically active drug wherein in liquid form is ciprofloxacin; and

the aerosol is inhaled into a human patient's lungs.

15. A formulation, comprising:

a pharmaceutically acceptable carrier;

ciprofloxacin dissolved in the carrier;

liposomes dispersed in the carrier, wherein the liposomes comprise:

a lipid bilayer comprised of sucrose and a phosphatidylcholine-enriched phospholipids present at a ratio between 1:10 to 10:1 (w/w);

polysorbate 20 in an amount of between 0.01% to 1%; and

nanocrystals of ciprofloxacin having a dimension of 50 nanometers to 75 nanometers wherein the nanocrystals are surrounded by a solution of ciprofloxacin which is surrounded by the lipid bilayer;

wherein the lipid bilayer is comprised of polyol and phosphatidylcholine-enriched phospholipids present at a ratio between 1:1 and 5:1 (w/w).