LIPOSOMES COMPRISING A CALCIUM PHOSPHATE-CONTAINING PRECIPITATE

• US 20120201872A1
• Filed: 08/03/2010
• Published: 08/09/2012
• Est. Priority Date: 08/03/2009
• Status: Active Grant

• Current Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Original Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Inventors: Huang, Leaf, Li, Jun
• Granted Patent: US 9,937,128 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 48/0025 wherein the non-active part clearly interacts with the delivered nucleic acid
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C12N 15/111 : General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 2310/14 : interfering N.A.
• CPC Class Codes: C12N 2310/3515 : Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2320/32 : Special delivery means, e.g. tissue-specific

Abstract

Provided herein are methods and compositions for the delivery of bioactive compounds to a cell, tissue, or physiological site. The compositions comprise delivery system complexes comprising liposomes encapsulating a biodegradable ionic precipitate having incorporated therein a bioactive compound and delivery system complexes comprising a biodegradable ionic precipitate ionically bound to a surrounding lipid bilayer, wherein the biodegradable ionic precipitate comprises a bioactive compound. Also provided herein are methods for the treatment of a disease or an unwanted condition in a subject, wherein the methods comprise administering the delivery system complexes comprising bioactive compounds that have therapeutic activity against the disease or unwanted condition to the subject.

Claims

1-25. -25. (canceled)

26. A delivery system complex comprising a biodegradable ionic precipitate comprising a bioactive compound, wherein said biodegradable ionic precipitate is encapsulated by a lipid bilayer membrane, wherein;

said lipid bilayer membrane comprises an inner leaflet and an outer leaflet, wherein said inner leaflet comprises a first lipid and said outer leaflet comprises a second lipid, wherein;

said first lipid is capable of forming ionic interactions with said biodegradable ionic precipitate, and wherein;

said outer leaflet further comprises a lipid-polyethylene glycol (PEG) conjugate.

27. The delivery system of claim 26, wherein said lipid-PEG conjugate comprises PEG in an amount between about 12 mol % to about 50% of total surface lipid.

28. The delivery system of claim 26, wherein said bioactive compound is selected from the group consisting of antimicrobials, antibiotics, antimycobacterials, antifungals, antivirals, neoplastic agents, agents affecting the immune response, blood calcium regulators, agents useful in glucose regulation, anticoagulants, antithrombotics, antihyperlipidemic agents, cardiac drugs, thyromimetic and antithyroid drugs, adrenergics, antihypertensive agents, cholinergics, anticholinergics, antispasmodics, antiulcer agents, skeletal and smooth muscle relaxants, prostaglandins, general inhibitors of the allergic response, antihistamines, local anesthetics, analgesics, narcotic antagonists, antitussives, sedative-hypnotic agents, anticonvulsants, antipsychotics, anti-anxiety agents, antidepressant agents, anorexigenics, non-steroidal anti-inflammatory agents, steroidal anti-inflammatory agents, antioxidants, vaso-active agents, bone-active agents, antiarthritics, and diagnostic agents.

29. The delivery system of claim 26, wherein said bioactive compound is an antiviral or anticancer drug.

30. The delivery system of claim 26, wherein said bioactive compound is gemcitabine monophosphate.

31. The delivery system of claim 26, wherein said biodegradable ionic precipitate is selected from the group consisting of a divalent cation and a trivalent cation, or mixtures thereof.

32. The delivery system of claim 26, wherein said biodegradable ionic precipitate is a calcium phosphate precipitate.

33. The delivery complex of claim 26, wherein said bioactive compound is phosphorylated.

34. The delivery system complex of claim 26, wherein said bioactive compound is mono phosphorylated.

35. The delivery system complex of claim 26, wherein said bioactive compound comprises a polynucleotide or a polypeptide.

36. The delivery system complex of claim 35, wherein said polynucleotide comprises an interfering RNA.

37. The delivery system complex of claim 35, wherein said polynucleotide comprises an siRNA.

38. The delivery system complex of claim 35, wherein said polynucleotide is a plasmid DNA.

39. The delivery system complex of claim 26, wherein said lipid-PEG conjugate comprises a PEG molecule having a molecular weight of about 2000-5000 g/mol.

40. The delivery system complex of claim 39, wherein said lipid-PEG conjugate comprises a 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy-polyethylene glycol₂₀₀₀ (DSPE-PEG₂₀₀₀).

41. The delivery system complex of claim 26, wherein said outer leaflet comprises a targeting ligand.

42. The delivery system complex of claim 41, wherein said targeting ligand is selected from the group consisting of asialoglycoprotein, insulin, low density lipoprotein (LDL), folate, benzamide derivatives, peptides comprising the arginine-glycine-aspartate (RGD) sequence, and monoclonal and polyclonal antibodies directed against cell surface molecules or mixtures thereof.

43. The delivery system complex of claim 42, wherein said benzamide derivative comprises anisamide.

44. The delivery system complex of claim 26, wherein said delivery system complex has a diameter of about 15 to about 120 nm.

45. The delivery system complex of claim 26, wherein said delivery system complex has a diameter of about 25 to about 30 nm.

46. The delivery system complex of claim 26, wherein said outer leaflet comprises a cationic lipid.

47. The delivery system complex of claim 46, wherein said cationic lipid is DOTAP.

48. A method of making the delivery system complex of claim 26, comprising

a) mixing a first reverse microemulsion comprising a metal chloride and a second reverse microemulsion comprising a metal phosphate and said first lipid having a free phosphate group to form said biodegradable ionic precipitate, wherein said precipitate is substantially encapsulated by said first lipid, wherein said bioactive compound is present in said first reverse microemulsion or said second reverse microemulsion;

b) washing said biodegradable ionic precipitate;

c) solubilizing said biodegradable ionic precipitate in a volatile, organic solvent to form a biodegradable ionic precipitate/solvent mixture;

d) adding said second lipid to said biodegradable ionic precipitate/solvent mixture; and

e) evaporating said volatile organic solvent to produce said delivery system complex.