Formulations of paclitaxel, its derivatives or its analogs...

Details Formulations of paclitaxel, its derivatives or its analogs... Formulations of paclitaxel, its derivatives or its analogs...

2000-09-21

2002-04-02

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S078080, C424S078170, C424S450000, C424S451000, C424S501000, C514S449000

Reexamination Certificate

active

06365191

ABSTRACT:

This invention relates to pharmaceutical formulations of paclitaxel, its derivatives or analogs entrapped into nanoparticles of co-polymeric micelles, a process for preparing the same and the use thereof.
BACKGROUND OF THE INVENTION
Amongst the chemotherapeutic agents that have entered clinical testing in the last decade paclitaxel is one of the most promising candidates. It has shown impressive activities against ovarian cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, squamous cell cancer of the head and neck and malignant melanomas. It is also undergoing clinical trials against several other malignancies.
It is preferred that paclitaxel be administered parenterally. Unfortunately, paclitaxel and many of its derivatives and analogs have exceedingly low solubilities in most physiologically acceptable aqueous solvents that would be compatible with intravascular administration.
There is one approved formulation of paclitaxel for parenteral administration in humans. This formulation contains the drug, 527 mg/ml of polyoxyethylated castor oil (Cremophor EL) and 49.7% v/v of absolute ethanol. Unfortunately, Cremophor has a potential to cause hypersensitivity reactions. The most common side effects of the available paclitaxel formulation are severe: hypotension, urticaria, angioedema and most notably anaphylactoid reactions with a risk of a fatal outcome. These serious side effects from the current drug formulation have made it necessary to pre-medicate the patients with diphendydramine, histamine H
2
antagonists or even corticosteroids.
Therefore, there is need for alternate formulations of paclitaxel, its derivatives or analogs. The present invention provides composition that makes it possible to reduce the ethanol concentration greatly, and to eliminate Cremophor completely from the formulations.
The formulations disclosed herein, contain nanoparticles of polymeric micelles that entrap/solubilize taxane analogs like paclitaxel without affecting their cytotoxic properties.
Nanometer size drug carriers with hydrophilic surfaces are found to evade recognition and uptake by the reticulo-endothelial systems (RES) and thus can circulate in the blood for a long time. Another advantage of these hydrophilic nanoparticles is that, due to their extremely small size, the particles extravasate at the pathological sites such as solid tumors through passive targeting mechanism.
These nanoparticles of polymeric micelles besides keeping the drug in aqueous solution also help in increasing the circulation time in blood, in vivo.
SUMMARY OF THE INVENTION
The object if this invention is to overcome the drawbacks in the prior art by providing alternate formulations of paclitaxel, its derivatives or analogs by entrapping the drug in nanoparticles of polymeric micelles.
An important object of this invention is a process for the preparation of formulations of nanoparticles of polymeric micelles loaded with paclitaxel, its derivatives or analogs dispersed in aqueous solution, which can be diluted with aqueous intravenous fluids.
A further object of this invention is the use of formulations of this invention for the treatment of conditions arising out of excessive proliferation of cells.
Another object of this invention is the use of the formulations of this invention to target maximum amounts of drug to tumors and only negligible amounts to other tissues, which obviates the disadvantages associated with the prior art.
The formulations of this invention contain nanoparticles of polymeric micelles which contain paclitaxel, a derivative or analog thereof entrapped therein. The formulations contain paclitaxel, a derivative or analog thereof, a co-polymer, an anionic surfactant, a buffering agent and an intravenous aqueous diluting fluid.


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