Micelle composition of polymer and passenger drug
Hydrophobic drugs become more practical for treatments by being encapsulated in micelle compositions for increasing solubility. Micelle compositions may include an excipient tocopherol and/or prodrug formulations of the drug. Micelles extend the time period the drug remains in the micelles to improve drug circulation time and thereby drug delivery. Hydrophobic drugs for micelle encapsulation may include rapamycin, geldanamycin, and paclitaxel. Administration of these micelle compositions does not require Cremophor EL or Tween 80, avoiding serious side effects associated with these products which would previously accompany such drug administration.
1. A micelle composition comprising a plurality of micelles, wherein the micelles comprise a pegylated phospholipid, Vitamin E, and a hydrophobic passenger drug;
wherein
the Vitamin E and the pegylated phospholipid are present at a mol % ratio of about 0.1:1 to about 3:1;
the concentration of the Vitamin E is about 2 mM to about 100 mM;
the Vitamin E and the hydrophobic passenger drug are located within the micelles;
the hydrophobic passenger drug is selected from the group consisting of rapamycin, paclitaxel, paclitaxel prodrugs comprising a carbonyloxy-linked or silyloxy-linked moiety at one or both of the paclitaxel positions C2 and C7, geldanamycin, geldanamycin prodrugs comprising a nitrogen-linked moiety at the geldanamycin C17 position in place of the C17 methoxy group of geldanamycin, and combinations thereof.
2. The micelle composition of claim 1 wherein the mol % ratio of the Vitamin E to the pegylated phospholipid is about 1:1 to about 3:1.
3. The micelle composition of claim 1 wherein the mol % ratio of the Vitamin E to the pegylated phospholipid is about 2:1 to about 3:1.
4. The micelle composition of claim 1 wherein the pegylated phospholipid is PEG-distearoylphosphatidyl ethanolamine (PEG-DSPE).
5. The micelle composition of claim 1 wherein the Vitamin E is selected from the group consisting of alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, and delta-tocotrienol.
6. The micelle composition of claim 1 wherein the concentration of the Vitamin E is about 2 mM to about 20 mM.
7. The micelle composition of claim 1 wherein the hydrophobic passenger drug is one or more of rapamycin, paclitaxel, or geldanamycin.
8. The micelle composition of claim 1 wherein said paclitaxel prodrug comprises in increased log Po/w as compared to paclitaxel and wherein the geldanamycin prodrug has an increased loci Po/w as compared to geldanamycin.
9. The micelle composition of claim 1 wherein the hydrophobic passenger drug is rapamycin and the rapamycin comprises at least 11 wt. % of the micelles.
10. The micelle composition of claim 1 wherein the hydrophobic passenger drug is rapamycin and the concentration of rapamycin is about 0.1 mg/mL to about 4 mg/mL.
11. The micelle composition of claim 1 wherein the pegylated phospholipid is PEG-DSPE and the molecular weight of the PEG block is about 2 kDa.
12. The micelle composition of claim 1 wherein the hydrophobic passenger drug is rapamycin and the CMC is about 3 μM to about 28 μM.
13. A micelle composition comprising a plurality of micelles, wherein the micelles comprise a pegylated phospholipid, Vitamin E, and a hydrophobic passenger drug;
wherein
the Vitamin E and the pegylated phospholipid are present in a mol % ratio of about 0.1:1 to about 3:1
the concentration of the Vitamin E is about 2 mM to about 100 mM;
the Vitamin E and the hydrophobic passenger drug are located within the micelles; and
the hydrophobic passenger drug is rapamycin.
14. The micelle composition of claim 13 wherein the rapamycin in the micelles is about 10% wt. drug/wt. micelles to about 20% wt. drug/wt. micelles.
15. A micelle composition comprising a plurality of micelles, wherein the micelles comprise a pegylated phospholipid, Vitamin E, and a hydrophobic passenger drug;
wherein
the Vitamin E and the pegylated phospholipid are present at a tool % ratio of about 0.1:1 to about 3:1;
the concentration of the Vitamin E is about 2 mM to about 100 raM;
the hydrophobic passenger drug is selected from the group consisting of rapamycin, paclitaxel, paclitaxel prodrugs comprising a carbonyloxy-linked or silyloxy-linked moiety at one or both of the paclitaxel positions C2 and C7, geldanamycin, eldanamycin prodrugs comprising a nitrogen-linked moiety at the geldanamycin C17 position in place of the C17 methoxy group of geldanamycin, and combinations thereof.
16. A process for forming a micelle composition of claim 1 comprising:
combining a pegylated phospholipid, Vitamin E, and a hydrophobic passenger drug, in an organic solvent to form a solution, wherein the hydrophobic passenger drug is selected from the group consisting of rapamycin, paclitaxel, paclitaxel prodrugs comprising a carbonyloxy-linked or silyloxy-linked moiety at one or both of the paclitaxel positions C2 and C7, geldanamycin, geldanamycin prodrugs comprising a nitrogen-linked moiety at the geldanamycin C17 position in place of the C17 methoxy group of geldanamycin, and combinations thereof;
removing substantially all of the organic solvent from the solution to leave a substantially solvent-free mixture; and
resuspending the substantially solvent-free mixture in water or buffer, to provide the micelle composition wherein
Vitamin E and the pegylated phospholipid are present at a mol % ratio of about 0.1:1 to about 3:1, the concentration of the Vitamin E is about 2 mM to about 100 mM, and the Vitamin E and the hydrophobic drug are located within the micelles.
17. The process of claim 16 wherein the hydrophobic drug is rapamycin, paclitaxel, or geldanamycin.