Protein-Stabilized Liposomal Formulations of Pharmaceutical Agents

Abstract

The present invention relates to protein stabilized liposomes. Specifically, the present invention discloses compositions and methods for protein stabilized liposomes, the creation of protein stabilized liposomes, and the administration of protein stabilized liposomes.

1 .- 37 . (canceled)  
     
     
         38 . A protein-stabilized lipid nanoparticle formulation comprising at least one lipophilic pharmaceutical agent, one or more phospholipids and one or more emulsion-forming proteins, wherein the formulation includes liposomal nanoparticles having sizes below 400 nm and emulsion-forming protein adsorbed onto their surfaces.  
     
     
         39 . The formulation of  claim 38 , wherein the nanoparticle formulation further includes cholesterol.  
     
     
         40 . The formulation of  claim 38 , wherein the nanoparticle formulation includes a PEG-phospholipid.  
     
     
         41 . The formulation of  claim 40 , wherein said PEG-phospholipid comprises poly(ethylene glycol)-derivatized distearoylphosphatidylethanolamine (PEG-DSPE) and/or poly(ethylene glycol)-derivatized ceramides (PEG-CER)  
     
     
         42 . The formulation of  claim 38 , wherein the lipophilic pharmaceutical agent is further identified as a substantially water insoluble pharmaceutical agent.  
     
     
         43 . The formulation of  claim 38 , wherein said emulsion forming protein comprises an albumin, immunoglobulin, casein, insulin, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, vitronectin, fibrinogen, lipase, or enzyme.  
     
     
         44 . The formulation of  claim 43 , wherein the emulsion forming protein is an albumin.  
     
     
         45 . The formulation of  claim 38 , wherein the nanoparticle formulation is lyophilized to provide a powder suitable for reconstitution in an aqueous suspension.  
     
     
         46 . The formulation of  claim 38 , wherein the pharmaceutical agent comprises a cardiovascular drug, respiratory drug, sympathomimetic drug, cholinomimetic drug, adrenergic or adrenergic neuron blocking drug, analgesic/antipyretic, anesthetic, antiasthamatic, antibiotic, antidepressant, antidiabetic, antifungal agent, antihypertensive agent, anti-inflammatory, antineoplastic, antianxiety agent, immunosuppressive agent, antimigraine agent, sedatives/hypnotic, antianginal agent, antipsychotic agent, antimanic agent, antiarrhythmic, antiarthritic agent, antigout agent, anticoagulant, thrombolytic agent, antifibrinolytic agent, hemorheologic agent, antiplatelet agent, anticonvulsant, antiparkinson agent, antihistamine/antipruritic, agent useful for calcium regulation, antibacterial agent, antiviral agent, antimicrobial, anti-infective, bronchodialator, hormone, hypoglycemic agent, hypolipidemic agent, protein, nucleic acid, agent useful for erythropoiesis stimulation, antiulcer/antireflux agent, antinauseant/antiemetic, oil-soluble vitamin, mitotane, visadine, halonitrosourea, anthrocycline or ellipticine.  
     
     
         47 . The formulation of  claim 46 , wherein the pharmaceutical agent is Proscillaridin-A, oleandrin, digitoxin, digoxin, odoroside-A, colchicine, colchicine derivatives, ara-C derivatives, diphyllin, justicidin-A, diphyllin derivatives, cleistanthin A, chloroquine, amphotericin B, paclitaxel, docetaxel, cyclosporine, camptothecin, 7-ethyl-10-hydroxy-camptothecin, 10-hydroxy-camptothecin, a camptothecin derivative, podophyllotoxin, podophyllotoxin derivatives, vinblastine, vincristine, dihydroartemisinin, mitoxantrone, amphotericin B, epothilone-A, epothilone-B, epothilone-C, epothilone-D, an epothilone derivative, a benz[c]-phenanthridine alkaloid derivative, a chelerythrine alkaloid derivative or cisplatin.  
     
     
         48 . The formulation of  claim 38 , wherein said one or more phospholipids comprise one or more of hydrogenated soy phosphatidylcholine (HSPC), egg phosphatidylcholine (EPC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinsitol (PI), monosialogangolioside, spingomyelin (SPM), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), or dimyristoylphosphatidylglycerol (DMPG).  
     
     
         49 . The formulation of  claim 38 , wherein the ratio of pharmaceutical agent to lipid-protein ranges from about 0.0005 to about 1 (w/w).  
     
     
         50 . The formulation of  claim 49 , wherein the ratio of pharmaceutical agent to lipid-protein ranges from about 0.0005 to about 0.5 (w/w).  
     
     
         51 . The formulation of  claim 50 , wherein the ratio of pharmaceutical agent to lipid-protein ranges from about 0.001 to about 0.1 (w/w).  
     
     
         52 . The formulation of  claim 38 , wherein the lipid formulation is defined further as comprising nanoparticles having size less than about 220 nm.  
     
     
         53 . The formulation of  claim 52 , wherein the nanoparticles have a size of between about 80-160 nm.  
     
     
         54 . The formulation of  claim 53 , wherein the nanoparticles have a size of between about 100-120 nm.  
     
     
         55 . A method of treating a disease in a patient comprising: 
 (a) obtaining a formulation in accordance with claim  1  comprising a pharmaceutical agent drug indicated for treatment of the disease; and    (b) administering an amount of the lipid formulated pharmaceutical agent to said patient that is effective to treat the disease.    
     
     
         56 . The method of  claim 55 , wherein the disease is a hyperproliferative disease and the pharmaceutical agent is an anti-hyperproliferative agent.  
     
     
         57 . The method of  claim 55 , wherein the formulation is administered parenterally.  
     
     
         58 . The method of  claim 55 , wherein the formulation is administered by slow infusion or bolus injection.