Phospholipid-coated therapeutic agent nanoparticles and related methods

Abstract

Phospholipid-coated nanoparticles containing a therapeutic agent, compositions that include the nanoparticles, and methods for making and using the nanoparticles and compositions.

1 - 20 . (canceled) 
     
     
         21 . A method for preparation of a phospholipid-coated therapeutic agent nanoparticle, comprising:
 subjecting an organic phase containing a therapeutic agent dispersed therein and an aqueous medium containing a phospholipid to high shear conditions in a high pressure homogenizer to provide a homogenized phospholipid-coated therapeutic agent nanoparticle mixture,   wherein the mixture comprises phospholipid-coated therapeutic agent nanoparticles are stable in aqueous delivery vehicles and release the therapeutic agent substantially instantaneously upon exposure to or contact with a physiological fluid.   
     
     
         22 . The method of  claim 21 , wherein subjecting to high shear conditions comprises using a high pressure homogenizer at a pressure in the range of about 3,000 up to 30,000 psi. 
     
     
         23 . The method of  claim 21  further comprising removing the organic phase from the mixture. 
     
     
         24 . The method of  claim 21  further comprising removing the aqueous medium from the mixture. 
     
     
         25 . The method of  claim 21 , wherein the organic phase comprises a mixture of a substantially water immiscible organic solvent and a water soluble organic solvent. 
     
     
         26 . The method of  claim 21 , wherein said aqueous medium is selected from water, buffered aqueous media, saline, buffered saline, solutions of amino acids, solutions of sugars, solutions of vitamins, solutions of carbohydrates, or combinations thereof. 
     
     
         27 . The method of  claim 21 , wherein the phospholipid-coated therapeutic agent nanoparticle has an average diameter of from about 30 nm to about 300 nm. 
     
     
         28 . The method of  claim 21  further comprising sterile filtering the mixture. 
     
     
         29 . The method of  claim 24 , wherein removing the aqueous medium from the mixture comprises lyophilizing the mixture to provide a nanoparticle powder. 
     
     
         30 . The method of  claim 21 , wherein the therapeutic agent is therapeutic agent having an octanol/water partition coefficient greater than 2.0. 
     
     
         31 . The method of  claim 21 , wherein the therapeutic agent is selected from the group consisting of analgesics/antipyretics, anesthetics, antiasthamatics, antibiotics, antidepressants, antidiabetics, antifungal agents, antihypertensive agents, anti-inflammatories, antineoplastics, antianxiety agents, immunosuppressive agents, antimigraine agents, sedatives/hypnotics, antianginal agents, antipsychotic agents, antimanic agents, antiarrhythmics, antiarthritic agents, antigout agents, anticoagulants, thrombolytic agents, antifibrinolytic agents, hemorheologic agents, antiplatelet agents, anticonvulsants, antiparkinson agents, antihistamines/antipruritics, agents useful for calcium regulation, antibacterial agents, antiviral agents, antimicrobials, anti-infectives, bronchodialators, hormones, hypoglycemic agents, hypolipidemic agents, proteins, nucleic acids, agents useful for erythropoiesis stimulation, antiulcer/antireflux agents, antinauseants/antiemetics, and oil-soluble vitamins. 
     
     
         32 . The method of  claim 21 , wherein the therapeutic agent is an antineoplastic selected from adriamycin, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, interferon, camptothecin, phenesterine, paclitaxel, docetaxel, epothilones, vinblastine, vincristine, tamoxifen, etoposide, or piposulfan. 
     
     
         33 . The method of  claim 21 , wherein the therapeutic agent is paclitaxel. 
     
     
         34 . The method of  claim 21 , wherein the phospholipid is a mono-acylphospholipid selected from the group consisting of lysophosphatidylcholines, lysophosphatidylethanolamines, lysophosphatidylglycerols, lysophosphatidylserines, lysophosphatidylinositols, lysophosphatidic acids, and mixtures thereof. 
     
     
         35 . The method of  claim 21 , wherein the phospholipid is a mixture of a mono-acylphospholipid and a diacylphospholipid. 
     
     
         36 . A method for preparation of a phospholipid-coated therapeutic agent nanoparticle, comprising:
 dissolving a therapeutic agent and a phospholipid in an organic phase to provide a solution;   concentrating the solution to dryness to provide a film; and   hydrating the film with water to provide an aqueous suspension of phospholipid-coated therapeutic agent nanoparticles,   wherein the phospholipid-coated therapeutic agent nanoparticles are stable in aqueous delivery vehicles and release the therapeutic agent substantially instantaneously upon exposure to or contact with a physiological fluid.   
     
     
         37 . A method for preparation of a phospholipid-coated paclitaxel nanoparticle, comprising:
 dissolving paclitaxel and a phospholipid in an organic phase to provide a solution;   concentrating the solution to dryness to provide a film; and   hydrating the film with water to provide an aqueous suspension of phospholipid-coated paclitaxel nanoparticles,   wherein the phospholipid-coated paclitaxel nanoparticles are stable in aqueous delivery vehicles for administration and release paclitaxel substantially instantaneously upon exposure to or contact with a physiological fluid.   
     
     
         38 . The method of  claim 37 , wherein the phospholipid is a mono-acylphospholipid selected from the group consisting of lysophosphatidylcholines, lysophosphatidylethanolamines, lysophosphatidylglycerols, lysophosphatidylserines, lysophosphatidylinositols, lysophosphatidic acids, and mixtures thereof. 
     
     
         39 . The method of  claim 37 , wherein the phospholipid is a mixture of a mono-acylphospholipid and a diacylphospholipid.