Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
In accordance with the present invention, there are provided compositions and methods useful for the in vivo delivery of substantially water insoluble pharmacologically active agents (such as the anticancer drug paclitaxel) in which the pharmacologically active agent is delivered in the form of suspended particles coated with protein (which acts as a stabilizing agent). In particular, protein and pharmacologically active agent in a biocompatible dispersing medium are subjected to high shear, in the absence of any conventional surfactants, and also in the absence of any polymeric core material for the particles. The procedure yields particles with a diameter of less than about 1 micron. The use of specific composition and preparation conditions (e.g., addition of a polar solvent to the organic phase), and careful selection of the proper organic phase and phase fraction, enables the reproducible production of unusually small nanoparticles of less than 200 nm diameter, which can be sterile-filtered. The particulate system produced according to the invention can be converted into a redispersible dry powder comprising nanoparticles of water-insoluble drug coated with a protein, and free protein to which molecules of the pharmacological agent are bound. This results in a unique delivery system, in which part of the pharmacologically active agent is readily bioavailable (in the form of molecules bound to the protein), and part of the agent is present within particles without any polymeric matrix therein.
1 - 65 . (canceled)
66 . A composition comprising paclitaxel and an albumin,
wherein the weight ratio of the total amount of albumin to the total amount of the taxane in the composition is 9:1.
67 . The composition of claim 66 , comprising:
nanoparticles comprising
paclitaxel and albumin.
68 . The composition of claim 67 , wherein the nanoparticles have an average diameter of no greater than about 220 nm.
69 . The composition of claim 66 , further comprising a solvent for paclitaxel.
70 . The composition of claim 69 , wherein the solvent for paclitaxel comprises methylene chloride.
71 . The composition of claim 69 , wherein the solvent for paclitaxel comprises chloroform.
72 . The composition of claim 69 , wherein the solvent for paclitaxel comprises ethanol.
73 . The composition of claim 66 in the form of a lyophilized powder.
74 . The composition of claim 68 in the form of a lyophilized powder.
75 . A unit dose of the composition of claim 68 contained within a container.
76 . A unit dose of the composition of claim 73 contained within a container.
77 . The container of claim 75 , wherein the container is a sealed vial.
78 . The container of claim 76 , wherein the container is a sealed vial.
79 . The composition of claim 68 , wherein the nanoparticles comprise paclitaxel and have an albumin coating.
80 . The composition of claim 79 , wherein the nanoparticles have a core and the nanoparticle core is substantially free of a polymeric matrix.
81 . The composition of claim 79 , wherein the albumin coating has free albumin associated therewith, and wherein a portion of the paclitaxel is contained within the albumin coating and a portion of the paclitaxel is associated with the free albumin.
82 . The composition of claim 68 , wherein at least a portion of the albumin is crosslinked by disulfide bonds.
83 . The composition of claim 68 , wherein the paclitaxel is substantially amorphous.
84 . The composition of claim 66 , wherein the paclitaxel is substantially crystalline.
85 . The composition of claim 83 in the form of a lyophilized powder.
86 . A method of treatment, comprising administering an effective amount of the composition of claim 68 to a patient to treat a tumor.
87 . The method of claim 86 , wherein the composition is administered parenterally, orally, intravenously, subcutaneously, intraperitoneally, intrathecally, intramuscularly, by inhalation, topically, transdermally, rectally, or vaginally.
88 . The method of claim 87 , wherein the composition is administered intravenously.
89 . The method of claim 88 , wherein the pharmaceutical formulation is infused, and the infusion volume is no greater than 200 ml.
90 . A method of treatment, comprising administering an effective amount of the composition of claim 68 to a patient to treat rheumatoid arthritis.
91 . The method of claim 90 , wherein the composition is administered parenterally, orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intrathecally, intramuscularly, by inhalation, topically, transdermally, rectally, or vaginally.