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...

1999-09-23

2001-11-27

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S486000, C424S487000, C424S501000, C514S772300

Reexamination Certificate

active

06322817

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
In the last two decades research has focused on the development of efficient systems for site specific delivery of drugs by the use of appropriate carriers, which include liposomes, micelles, polymeric nanoparticles and nanoparticles made of hardened micelles (popularly known as polymeric micelles). The use of liposomes as drug targeting agents is found to be limited mainly due to the problems of low entrapment efficiency, drug instability, rapid drug leakage and poor storage stability. With the aim of overcoming these problems, the use of polymeric nanoparticles and polymeric micelles have been investigated by many scientists during the last two decades.
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.
Among the nanometer size hydrophilic drug carriers mentioned above, polymeric micelles, although the least studied, have the potential to deliver hydrophobic drugs. In recent papers and review articles, water-soluble biocompatible polymeric micelles as drug delivery vehicles have been reported.
1-3
A polymeric micelle usually consists of several hundred block copolymers and has a diameter of about 20 nm-50 nm. There are two spherical co-centric regions of polymeric micelles, a densely packed core of hydrophobic material which is responsible for entrapping the hydrophobic drug and an outer shell made of hydrophilic material for evasion of body's RES which permits circulation in the blood for a longer period of time.
Kataoka and his colleagues
4-15
have extensively studied polymeric micelles as carriers for anticancer and other hydrophobic drugs. They synthesized AB block copolymers of amphiphilic monomers that formed micelles with diameters in a range of several tens of nanometers. In most of these studies the anticancer drug molecules were covalently linked within the micellar core. When the drug was covalently linked within the polymeric micelles, it was difficult to control the cleavage rate of the drug linkage. Some studies have also been reported on the physical entrapment of hydrophobic drugs in these micellar nanoparticles
16-19
. Solubilization of pyrene, doxorubicine and indomethacine into polymeric micelles and their use in vivo studies have been reported in the literature.
Paclitaxel is the first of a new class of anticancer drugs and has been investigated in human trials, in particular for ovarian, breast, colon, non-small cell lung and head and neck cancer
20-23
. Paclitaxel causes stabilization of microtubules and thus interferes with cellular progress through mitosis and arresting cell replication. One problem associated with the use of paclitaxel is its poor solubility in water and in most pharmaceutically acceptable solvents.
Presently, the vehicle of the clinically used formulation comprises 527 mg/ml polyoxyethylated castor oil (Cremophor EL) and 49.7% v/v absolute ethanol. Unfortunately, Cremophor causes hypersensitivity reactions especially in some young children
24
. Moreover, paclitaxel is a toxic drug and therefore, large doses may cause severe toxic reactions
24
. Liposomal formulations may not be very effective because of low entrapment in the hydrophobic layer of liposomes in addition to the other inherent limitations of liposomal formulations
25
.
U.S. Pat. No. 5,684,169, describes a method of improving solubility of paclitaxel in water by adding an unbranched cyclodextrin or a branched cyclodextrin thereto at a molar ratio of 1-20 times with respect to paclitaxel. This is totally different from the present invention-preparation of nanoparticles of polymeric micelles and entrapping paclitaxel, its derivatives or analogs into these nanoparticles of polymeric micelles. 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 of this invention is a process for preparing nanoparticles of polymeric micelles which contain paclitaxel, its derivatives or analogs.
A further object of this invention is a process for the preparation of nanoparticles of polymeric micelles constituted of block copolymers that can entrap paclitaxel, its derivatives or analogs to the maximum extent possible.
Another object of this invention is a process for the preparation of nanoparticles of polymeric micelles having intercross-linked polymeric chains so that the release of the entrapped paclitaxel, its derivatives or analogs encapsulated in these micelles can be controlled.
Yet another object of this invention is a process for the preparation of nanoparticles of polymeric micelles loaded with paclitaxel, its derivatives or analogs with polyethyleneglycol chains at the outer surface of the nanoparticle. The polyethyleneglycol chains help the particles to circulate in the blood for a relatively long time.
Still another object of this invention is a process for the preparation of nanoparticles of polymeric micelles loaded with paclitaxel, its derivatives or analogs dispersed in aqueous solution, which are free from unwanted and toxic materials like unreacted monomers.
Another object of this invention is a process for the preparation of nanoparticles of polymeric micelles containing paclitaxel, its derivatives or analogs which can be used for in vivo experiments with a purpose to target maximum amounts of drug to tumors and only negligible amounts to other tissues, which obviates the disadvantages associated with the prior art.
A still further object of this invention is the use of nanoparticles of polymeric micelles loaded with paclitaxel, its derivatives or analogs prepared according to the process of this invention for the treatment of conditions arising out of excessive proliferation of cells.


REFERENCES:
patent: 5648090 (1997-07-01), Rahman et al.
patent: 5648506 (1997-07-01), Desai et al.
patent: 5684169 (1997-11-01), Hamada et al.
Kwon et al., “Polymeric Micelles as New Drug Carriers” Advanced Drug Delivery Rev., vol. 21 pp. 107-116 (1996).*
Kwon, G.S. et al.“ Polymeric Micelles as New Drug Carriers”Advanced Drug Delivery Rev., vol. 21 (1996) pp. 107-116.
Kwon, G.S. et al. “Block Copolymer Micelles as Long-Circulating Drug Vehicles”Advanced Drug Delivery Rev.vol. 16 (1995) pp. 295-309.
Kataoka K. et al. “Block Copolymer Micelles as Vehicles for Drug Delivery”Journal of Controlled Release, vol. 24 (1993) pp. 119-132.
Yokoyama, M. et al. “Characterization and Anticancer Activity of the Micelle-Forming . . . ”Cancer Researchvol. 50 (1990) pp. 1693-1700.
Yokoyama, M. et al. “Toxicity and Antitumor Activity Against Solid Tumors of Micelle-Forming . . . ”Cancer Researchvol. 51 (1991) pp. 3229-3236.
Yokoyama, M. et al. “Preparation of Micelle-Forming Polymer-Drug Conjugates”Bioconjugate Chem.vol. 3 (1992) pp. 295-301.
Kwon, G. et al. “Enhanced Tumor Accumulation and Prolonged Circulation Times of Micelle . . . ”Journal of Controlled Release. vol. 29 (1994) pp. 17-23.
Yokoyama, M. et al. “Influencing Factors on In Vitro Micelle Stability of Adriamycin-Block . . . ”Journal of Controlled Releasevol. 28 (1994) pp. 59-65.
Yokoyama, M. et al. “Improved Synthesis of Adriamycin-Conjugated Poly (Ethylene Oxide) . . . ”Journal of Controlled Release.vol. 32 (1994) pp. 269-277.
Kwon G.S. et al. “Physical Entrapment of Adriamycin in AB Block Copolymer Micelles”Pharmaceutical Researchvol. 12 No. 2 (1995) pp. 192-195.
Yokoyama, M. et al. “Introduction of Cisplatin into Polymeric Micelle”Journal of Controlled Releasevol. 39 (1996) pp. 351-356.
La, S.B. et al. “Preparation and Characterizati

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