Novel cochleate formulations

Abstract

A process for producing a small-sized, lipid-based cochleates. Cochleates are derived from liposomes which are suspended in an aqueous two-phase polymer solution, enabling the differential partitioning of polar molecule based-structures by phase separation. The liposome-containing two-phase polymer solution, treated with positively charged molecules such as Ca 2+ or Zn 2+ , forms a cochleate precipitate of a particle size less than one micron. The process may be used to produce cochleates containing biologically relevant molecules.

1 . A cochleate composition comprising a population of cochleates, wherein the cochleates comprise: 
 a negatively charged first lipid    a divalent cation or higher valency cation and    an additional biologically relevant molecule,    wherein the mean particle size of the cochleates is less than one micron.    
     
     
         2 . The cochleate composition according to  claim 1 , wherein the biologically relevant molecule bears a charge.  
     
     
         3 . The cochleate composition according to  claim 2 , wherein the biologically relevant molecule is positively charged.  
     
     
         4 . The cochleate composition according to  claim 2 , wherein the biologically relevant molecule is negatively charged.  
     
     
         5 . The cochleate composition according to  claim 1 , wherein the biologically relevant molecule is amphiphilic.  
     
     
         6 . The cochleate composition according to  claim 1 , wherein the biologically relevant molecule is hydrophobic.  
     
     
         7 . The cochleate composition according to  claim 1 , wherein the biologically relevant molecule is at least one member selected from the group consisting of a drug, a polynucleotide, a polypeptide, an antigen, a nutrient and a flavor substance.  
     
     
         8 - 22 . (canceled)  
     
     
         23 . The cochleate composition according to  claim 1 , wherein the negatively charged lipid is comprised of phosphatidylserine.  
     
     
         24 . The cochleate composition according to  claim 1 , wherein the cochleates further comprise a minor amount of a second lipid.  
     
     
         25 . The cochleate composition according to  claim 24 , wherein the other lipid is a member selected from the group consisting of a zwitterionic lipid, a PEGylated lipid, a cationic lipid, or a polycationic lipid.  
     
     
         26 . The cochleate composition according to  claim 24 , wherein the second lipid comprises lipid capable of forming hydrogen bonds to the biologically relevant molecule.  
     
     
         27 . The cochleate composition according to  claim 1 , wherein the di- or higher-valent ions are metal ions.  
     
     
         28 . The cochleate composition according to  claim 27 , wherein the di- or higher-valent metal ions are selected from the group consisting of calcium, zinc, barium, and magnesium.  
     
     
         29 . A cochleate composition according to  claim 1  wherein the di-or higher-valent cation is a di or higher-valent cationic lipid.  
     
     
         30 - 63 . (canceled)  
     
     
         64 . A pharmaceutical composition comprising an effective amount of the cochleate composition of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         65 . (canceled)  
     
     
         66 . A method of treatment comprising administering to a human or animal host a pharmaceutically effective amount of the pharmaceutical composition according to  claim 64 .  
     
     
         67 . (canceled)  
     
     
         68 . The method of treatment according to  claim 66 , wherein the administration is by a mucosal or a systemic route.  
     
     
         69 . (canceled)  
     
     
         70 . The method of treatment according to  claim 66 , wherein the administration is a mucosal route selected from the group consisting of oral, intranasal, intraocular, intraanal, intravaginal, and intrapulmonary.  
     
     
         71 . (canceled)  
     
     
         72 . The method of treatment according to  claim 66 , wherein the administration is by a systemic route selected from the group consisting of intravenous, intramuscular, subcutaneous, transdermal and intradermal.  
     
     
         73 . The cochleate composition of  claim 7 , wherein the nutrient is a vitamin.  
     
     
         74 . The cochleate composition of  claim 73 , wherein the vitamin is at least one member selected from the group consisting of: vitamin D, vitamin E, and vitamin K.  
     
     
         75 . The cochleate composition of  claim 73 , wherein the vitamin is vitamin A.  
     
     
         76 . The cochleate of  claim 7 , wherein the nutrient is a second cation.  
     
     
         77 . The cochleate composition of  claim 76 , wherein the second cation is at least one member selected from the group consisting of: calcium, magnesium, barium, iron and zinc.  
     
     
         78 . The cochleate composition of  claim 7 , wherein the cochleate comprises at least one vitamin and at least one mineral.  
     
     
         79 . The cochleate composition according to  claim 7 , wherein the nutrient is at least one member selected from the group consisting of fatty acids, amino acids, and saccharides.  
     
     
         80 . The cochleate composition according to  claim 7 , wherein the nutrient comprises a fatty acid selected from the group consisting of polyunsaturated fatty acids and saturated fatty acids.  
     
     
         81 . The cochleate composition according to  claim 7 , wherein the nutrient comrpises a saccharide selected from the group consisting of glucose and sucrose.  
     
     
         82 . The cochleate composition of  claim 7 , wherein the drug is an antifungal agent.  
     
     
         83 . The cochleate composition of  claim 7 , wherein the drug is a non-steriodal anti-inflammatory agent.  
     
     
         84 . The cochleate composition of  claim 7 , wherein the drug is an anticancer agent.  
     
     
         85 . The cochleate composition of  claim 7 , wherein the drug is selected from the group consisting of an antiviral, an anesthetic, or an anti-infectious agent, an immunosuppressant, a steroidal anti-inflammatory, a tranquilizer, and a vasodilatory agent.  
     
     
         86 . The cochleate composition of  claim 7 , wherein the drug is Amphotericin B.  
     
     
         87 . The cochleate composition of  claim 7 , wherein the drug is naproxen.  
     
     
         88 . The cochleate composition of  claim 7 , wherein the drug is Vitamin A acid.  
     
     
         89 . The cochleate composition of  claim 7 , wherein the drug is at least one member selected from the group consisting of acyclovir, adriamycin, carbamazepine, melphalan, nifedipine, indomethacin, naproxen, phenytoin, ergotamines, rapamycin, propanidid, propofol, alphadione, echinomycine, miconazole nitrate, teniposide, taxol, taxotere, nystatin, and rifampin.  
     
     
         90 . The cochleate composition of  claim 7 , wherein the drug is at least one member selected from the group consisting of estrogens, testosterones, steroids, cannabinoids, and vitamin A acid.  
     
     
         91 . The cochleate composition of  claim 7 , wherein the polynucleotide is a deoxyribonucletic acid (DNA) molecule  
     
     
         92 . The cochleate composition according to  claim 91 , wherein the DNA is transcribed to yield a ribonucleic acid.  
     
     
         93 . The cochleate composition of  claim 7 , wherein the polynucleotide is a ribonucleic acid (RNA) molecule.  
     
     
         94 . The cochleate composition according to  claim 93 , wherein the ribonucleic acid is translated to yield a biologically active polypeptide.  
     
     
         95 . The cochleate composition of  claim 7 , wherein the polynucleotide is a plasmid or a ribozyme.  
     
     
         96 . The cochleate composition of  claim 7 , wherein the polynucleotide is an antisense molecule.  
     
     
         97 . The cochleate composition of  claim 7 , wherein the polypeptide is at least one member selected from the group consisting of cyclosporin, angiotensin I, II, or III, enkephalins and their analogs, ACTH, anti-inflammatory peptides I, II, or III, bradykinin, calcitonin, beta-endorphin, dinorphin, leucokinin, leutinizing hormone releasing hormone (LHRH), insulin, neurokinins, somatostatin, substance P, thyroid releasing hormone (TRH), and vasopressin.  
     
     
         98 . The cochleate composition of  claim 7 , wherein the antigen is at least one member selected from the group consisting of carbohydrates, envelope glycoproteins from viruses, polynucleotides, DNA, RNA, plasmid DNA, immunogens, ribozymes, and antisense molecules.  
     
     
         99 . The cochleate composition of  claim 7 , wherein the antigen is at least one member selected from the group consisting of animal cell membrane proteins, plant cell membrane proteins, bacterial membrane proteins, envelope glycoproteins from viruses, and parasitic membrane proteins.  
     
     
         100 . The cochleate composition of  claim 7 , wherein the flavor agent is a botanical essential oil or an extract.  
     
     
         101 . The cochleate composition of  claim 7 , wherein the flavor agent is at least one flavor agent selected from the group consisting of: a cinnamon oil, a vanillin, an herb, a citrus, a spice and a seed.  
     
     
         102 . A cochleate composition comprising a population of cochleates, wherein the cochleates comprise: 
 a negatively charged lipid;    a divalent cation or higher valency cation; and, optionally,    an additional biologically relevant molecule,    wherein the mean particle size of the cochleates is less than one micron.