Title of Invention

"A PHARMACEUTICAL COMPOSITION BASED ON NANOPARTICLES OF POLYMERIC MICHELLES CONTAINING PACLITAXEL"

Abstract

The present invention provides a pharmaceutical composition based on nanoparticles of polymeric micelles containing Paclitaxel, its derivatives or analogs physically entrapped therein, essentially comprising of Paclitaxel, its derivatives or the analogs in a concentration ranging between 0.1 to 20 mg/ml, a co-polymer comprising of monomers selected from Vinylpyrrolidone, N-isopropyl acrylamide, and functionalized polyethylene glycol, in a concentration ranging between 0.01 to 20 mg/ml, a stabilizing surfactant in a concentration ranging between 0.01 to 20 mg/ml, an alcohol, an intravenous aqueous diluting fluid, and a conventional buffering agent in a concentration sufficient to bring pH between 6.0 to 7. 5. The present invention also provides a process for preparation of such composition.

Full Text

This invention relates to pharmaceutical compositions based on paclitaxel, its derivatives or analogs, which are entrapped into nanoparticles of co-polymeric micelles. The present invention also relates to a process for preparing said pharmaceutical composition. The compositions of the present invention are used for treatment of pathological conditions arising out of excessive proliferartion of cells and other cancerous conditions. 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. [G.S. Kwon et al, Adv. Drug Delivery Rev: 21, 107-116 (1996); G. S. Kwon et al Adv. Drug Delivery Rev: 16, 295-309 (1995); S. S Da\>is et al, Biomaterials, 9, 111-115 (1988)} 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. The use of polymeric micelles as carriers for anticancer and other hydrophobic drugs has been the subject of extensive study. [K. Kataoka et al, J. Control Release 24,119-132 (1993); M. Yokoyama et al, Macromol. Chem. 190, 2041-2054 (1989); M. Yokoyama et al, Cancer Res. 50, 1693-1700 (1990); M. Yokoyama et al, Cancer Res. 51, 3229-3236(1991); M. Yokoyama et al, Biconjugate Chem. 3, 295-301 (1992); G. Kwon et al,./. Contro Release, 29, 17-23 (1994); M. Yokoyama et al, .7. Control Release, 28, 59-65 (1994); M. Yokoyama et al, J. Control Release 32, 269-277 (1994); G. s Kwon et al, Pharm Res. 12, 192-195 (1995); M. Yokoyama et al, J. Control Release 39, 351-356 (1996); S.B. La et al, J. Pharma Sci. 85, 85-90 (1996); X, Zhang et al, J. Pharm. 132, 195-206(1996)}. 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. [T. Inoue et al, J. Control Release, 51, 221-229(1998); S. Y. Kim, J. Control Release 51, 13-22 (1998); B, G. Yu et al, J. Control Release, 53, 131-136(1998); G. Kwon et al, J, Control Release, 48, 195-201 (1997)]. Solubilization of pyrene, doxorobicine and indomethacin 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. [P. Jenkins et al, Chemistry in Great Britain (1996); S. G. Arbuch et al, Monogr. Natl. Cancer Inst. 15, 11-24 (1993); H. J. Long, Mayo Clin. Proc, 69, 341-345, (1994); R. Fao et al, Int. J. Clin Lah. Res. 24, 6-14 (1994)}. 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 composition 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. [R. B. Weiss et al, J. Clinical Oncology, 8, 1263-1268 (1990)}. Moreover, paclitaxel is a toxic drug and therefore, large doses may cause severe toxic reactions. Liposomal compositions may not be very effective because of low entrapment in the hydrophobic layer of liposomes in addition to the other inherent limitations of liposomal compositions. [(A. Sharma et al, Pharm. Res. 2, 889-896(1994)}. US Patent 5,684,169, describes a method of improving solubility of paclitaxel in water by adding an unbranched cyclodextrin or a branched cyclodextrin thererto at a molar ratio of 1-20 times with respect to paclitaxel. The applicants' co-pending Application No. 263/Del/99 filed on February 19, 1999 corresponding to their US. Patent Application No. 09/40l,927discloses a novel process for the preparation of nanoparticles of polymeric micelles and entrapping paclitaxel, its derivatives or analogs into these nanoparticles of polymeric micelles. The contents of these co-pending applications are deemed to have been incorporated herein by virtue of reference. These nanoparticles of polymeric micelles besides keeping the drug in aqueous solution also help in increasing the circulation time in blood, in vivo. In particular, the said co-pending applications disclose a novel process for the preparation of a pharmaceutical composition of paclitaxol entrapped into polymeric miscelles nanoparticles comprising 1. dissolving at least one type of amphiphilic monomer, preferably two types of amphiphilic monomers as herein described, in an aqueous medium to obtain micelles, 2. adding an aqueous solution of cross-linking agent, and optionally an activator and initiator as herein described to the micellar solution of the monomers, 3. subjecting the mixture to polymerization in the presence of an inert gas at 20°C to 80°C, preferably between 30°-40°C, until the polymerization of the micelles is complete, 4. purifying the nanoparticles of the co-polymeric micelles by dialysis to remove toxic monomers and other unreacted materials. 5 dissolving paclitaxel, its derivatives, or analogs in a suitable solvent, generally an alcohol preferably ethanol and adding this solution under stirring to the nanoparticle solution, 6. optionally treating the nanoparticles containing entrapped paclitaxel, its derivatives or analogs with a stabilizer, optionally 7. lyophilizing the nanoparticles of co-polymerized micelles containing entrapped paclitaxel, its derivatives or analogs to obtain dry powder, and optionally 8. reconstituting the nanoparticles in suitable medium for human or mammalian administration. Tn step 3 of the process described above the completion of polymerization of the monomers is determined by monitoring the depletion of the monomers from the reaction mixture by HPLC. Dialysis is carried out for 2-4 hours to eliminate unreacted monomers. Nanoparticles of co-polymeric micelles are formed by the reaction/polymerization of the monomers in the reaction mixture. Random polymer chains are formed and are then cross-linked with each other with the help of a cross-linking agent. The amount of the cross-linking agent affects the amount of cross-linking in the polymer and which in turn affects the compactness of the network formed. The compactness of this network has a direct bearing on the drug entrapment and consequently drug release from these nanoparticles. The more compact the network, the more difficult it is for the drug to be released. The hydrophobic cores of these nanoparticles of co-polymeric micelles are composed of hydrophobic part of the block copolymers with hydrophilic part extended outside towards the aqueous medium. The nanoparticles of co-polymeric micelles prepared by the process of this invention may be used for the treatment of pathological conditions arising out of excessive proliferation of cells such as rheumatoid arthritis or cancer. The compositions can be used to treat ovarian cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, squamous cell cancer of the head and neck and malignant melanomas. Amphiphilic monomers, which form polymers through radical polymerization reaction, are preferred. Preferred monomers are vinyl pyrrolidone, acrylic acid, alkyl acrylates having a chain length of C3 to C6 and/or functionalsed polyethylene glycol of a molecular weight 2000 to 6000, N-alkylacrylamide having a chain length of C3 to C6, and alkylcyanoacrylate having a chain length of C3 to C6. Two or more amphiphilic monomers are used. A functionalized polyethyleneglycol is a polyethyleneglycol reacted to another organic compound containing a functional group. A preferred functionalized polyethylene glycol is polyethyleneglycol ester of maleic anhydride. Polyethyleneglycol is reacted with maleic anhydride to form polyethyleneglyol ester of maleic anhydride. Functionalized polyethyleneglycol may be covalently attached to the polymer chain of the nanoparticles of polymeric micelles with the polyethylene moiety protruding outside on the surface of the nanoparticles. A preferred combination of amphiphilic monomers is vinylpyrrolidone and N-isopropyl acrylamide in the molar ratio of 90-50 : 10-50. Another preferred combination of amphiphilic monomers is vinlypyrrolidone, N-isopropylacrylamide, and monoester of polyethylene glycol maleic anhydride. The initiators may be peroxide compounds, such as diacyl peroxide compounds such as benzoyl peroxide, diacetyl peroxide or dialkyl peroxides such as tertiary butyl peroxide and tertiary amyl peroxide or perdisulphate or 2,2'-azo bis isobutyronitrile (ALBN). Activators may be selected from tetramethylethylene diamine (TMED) and ferrous ammonium sulphate. Any combination of initiator and activator can be used. Two or more initiators can be used. Two or more activators can be used. The cross-linking agent whenever used is at least a bi-functional vinyl derivative. It can be more than bi-functional (i.e. it can have more than two reactive sites). A bi-functional vinyl derivative that can be used is N,N' methylene bis acrylamide. The inert gas may be a gas such as nitrogen or argon. Derivatives and analogs of paclitaxel include the derivative 2-debenzoyl-2-meta- azidobenzoylpaclitaxel and the analog taxotere. Other derivatives and analogs of paclitaxel include but are not limited to : i Ring A contracted Paclitaxel Derivatives ii. 10-Deacetyl Paclitaxel iii. 7-Deoxy Paclitaxel iv. Oxetane Ring (ring D) modified Paclitaxel v 2-Deoxy Paclitaxel vi 2-Aroyl-2-De Benzoyl Paclitaxel analogues I vii. N-Benzoyl Modified Paclitaxel analogues viii. 2,3 cyclohexyl Paclitaxel analogues ix. 4-Deacetyl Paclitaxel analogues x. 7,8-cyclopropane Paclitaxel xi 7-Fluoropaclitaxel Paclitaxel, its analogues or its derivatives can be added up to a maximum loading of 90% w/w in the nanoparticles of co-polymeric micelles. Now it has been well recognised that 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 & neck and malignant melanomas. It is also undergoing clinical trials against several other malignancies. Although Paclitaxel is now available for parenteral administration, there is only one approved composition for human use. Presently, the vehicle of the clinically used composition, besides the drug comprises 527 mg/ml polyoxyethylated castor oil (Cremophor EL) and 49.7% v/v absolute ethanol. Unfortunately, Cremophor has a potential to cause hypersensitivity reactions. The most common side effects of the available paclitaxel composition are severe hypotension, urticaria, angioedema and most notably anaphylactoid reactions with risk of a fatal outcome. These serious side effects from the current drug composition have made it necessary to pre-medicate the patients with H2-antagonists and even corticosteroids. Therefore, there is need, for alternate compositions of Paclitaxel, its derivatives or analogs without these dangerous side effects. OBJECTS OF THE INVENTION It is therefore, an object of the present invention to overcome the drawbacks of the prior art by providing alternate pharmaceutical composition based on paclitaxel, its derivatives or analogs entrapped in nanoparticles of polymeric micelles. Another important object of this invention is to provide a process for the preparation of a composition containing nanoparticles of polymeric micelles loaded with paclitaxel, its derivatives or analogs dispersed in aqueous solution, which can be diluted with aqueous intravenous fluids such as 10% dextrose solution. Yet, another object of this invention is to provide a process for the preparation of a pharmaceutical composition containing 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. SUMMARY OF THE INVENTION The applicants have surprisingly discovered that carbohydrates such as sucrose, mannitol, dextrose etc., have a synergistic stabilizing effect on the entrapment of drug inside the core of the nanoparticles. This stabilizing effect is further enhanced by the anionic surfactant sodium deoxycholate due to its contribution in enhancement of the hydrophobicity of the core of the micelles. A carbohydrate and sodium deoxycholate together can be used to stabilize the composition by facilitating the retention of the drug in the aqueous dispersion. Sodium deoxycholate and/or 5-10% dextrose can be used as stabilizers. The compositions of the present invention are synergistic in nature resulting in unexpected properties. The ingredients display synergistic interaction as opposed to chemical reaction. Accordingly the present invention provides a pharmaceutical composition based on nanoparticles of polymeric micelles containing Paclitaxel, its derivatives or analogs such as herein described physically entrapped therein, essentially comprising of Paclitaxel, its derivatives or the analogs in a concentration ranging between 0.1 to 20 mg/ml, a co-polymer comprising of monomers selected from Vinylpyrrolidone, N-isopropyl acrylamide, and functionalized polyethylene glycol, in a concentration ranging between 0.01 to 20 mg/ml, a stabilizing surfactant as herein described in a concentration ranging between 0.01 to 20 mg/ml, an alcohol as herein described, an intravenous aqueous diluting fluid as herein described, and a conventional buffering agent in a concentration sufficient to bring pH between 6.0 to 7. 5. The present invention also provides a method of preparing a pharmaceutical composition of Paclitaxel for intravascular administration comprising the steps of: a) dissolving the co-polymer in the 10% dextrose solution; b) adding sodium deoxycholate to the solution of step a) ; c) adjusting the pH of the resulting solution with a conventional buffering agent in the pH ranging between 6 to 7.5; and d) adding an alcoholic solution of Paclitaxel, its derivatives or analogs, wherein the said Paclitaxel is dissolved in alcohol preferably ethanol, wherein concentration of Paclitaxel in the alcohol preferably ranges between 10 to 80 mg/ml, the composition essentially comprising of Paclitaxel, its derivatives or the analogs in a concentration ranging between 0.1 to 20 mg/ml, a co-polymer comprising of monomers selected from Vinylpyrrolidone, N-isopropyl acrylamide, and functionalized polyethylene glycol, in a concentration ranging between 0.01 to 20 mg/ml, a stabilizing surfactant as herein described in a concentration ranging between 0.01 to 20 mg/ml, an alcohol as herein described, an intravenous aqueous diluting fluid of the kind such as herein described, and a conventional buffering agent in a concentration sufficient to bring pH between 6.0 to 7. 5 Tn one embodiment, amphiphilic monomers such as vinyl pyrrolidone and N-alkylacrylamide were mixed together in water in molar ratios 90-50 : 10-50. A cross-linking agent such as N,N' methylene bis acrylamide and an initiator such as ammonium per disulphate is added in an atmosphere of nitrogen gas to polymerize the monomers. Accordingly, the present invention provides a pharmaceutical composition for the treatment of pathological conditions arising out of excessive proliferartion of cells comprising of paclitaxel, its derivatives or analogs physically, entrapped into nanoparticles of co-polymeric micelles a co-polymer, a stabilizing surfactant, a buffering agent and an intravenous aqueous diluting fluid. Tt is highly preferred that nanoparticles are formed by the co-polymer of vinylpyrrolidone, N-isopropyl acrylamide, functionalised polyethylene glycol. In a preferred embodiment, the drug Paclitaxel is at concentrations of about 0.1 to 20 mg/ml. The co-polymer is preferably, at a concentration of from about 0.01 to 20 mg/ml. The stabilizing surfactant is an anionic surfactant, preferably sodium deoxycholate. In another preferred embodiment, sodium deoxycholate is at concentrations of about 0.01 to 20 mg/ml In yet another embodiment of the invention, the pH of the final composition is between 6.0 to 7.5, which if necessary, is adjusted with a buffering agent suitable for intravenous administration, preferably sodium citrate. The intravenous aqueous diluting fluid is ideally a dextrose solution, preferably a 10% dextrose solution. The present invention also provide a method of preparing a pharmaceutical composition Paclitaxel composition for intravascular administration comprising the steps of: a). dissolving the co-polymer in the dextrose 10% solution. . b). adding sodium deoxycholate to the solution of step "a" c). adjusting the pH of the resulting solution, d). adding an alcoholic solution of Paclitaxel, its derivatives or analogs to the above solution. Preferably, said alcoholic solution of Paclitaxel has a concentration of 10 to 80 mg/ml. The composition of this invention may be used for the treatment of pathological conditions arising out of excessive proliferation of cells such as rheumatoid arthritis or cancer. The compositions can also be used to treat ovarian cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, squamous cell cancer of the head and neck and malignant melanomas. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS : The present invention provides a composition for the parenteral administration of poorly water soluble taxane analogs without the use of Cremophor. Parenteral administration is the preferred approach for taxane analogs as therapy for systemic malignancies. Unfortunately, most of these drugs have exceedingly low solubility in most physiologically acceptable aqueous solvents that would be compatible with intravascular administration. The current composition available in the market contains a large amount of alcohol and polyoxyethylated castor oil, which brings a potential for serious side effects. Paclitaxel in the marketed product has proven to have acute side effects of a primarily anaphylactoid nature, necessitating extensive premedication with diphenhydramine, histamine H2-antagonists and even corticosteroids. The current composition of Paclitaxel available in the market is a concentrate containing 6 mg/ml of taxol in a solvent mixture composed of 50% by volume of ethanol 50% by volume of Cremophor EL, At the time of injection, this solution is mixed with a perfusion fluid containing sodium chloride or dextrose (glucose). To obtain a mixture which is stable from both a physical standpoint and a chemical standpoint it is necessary to limit the concentration of active principle in the perfusion solution to concentrations of approximately 0.3 to 1.2 mg/ml. Since the treatment often requires the administration of high doses of active principle (135 to 250 mg/m2), and since the concentration of the active principle in the solution is relatively low, the injection of a large volume has to be given. However, it also delivers concentrations of each of the following compounds, ethanol and most especially Cremophor, (approximately 20 g per 240 mg of drug), and this has the effect of causing, in addition to anaphylactic manifestations, manifestations of alcohol poisoning during the treatment. The present invention provides composition that makes it possible to reduce the ethanol concentration greatly, and to eliminate Cremophor completely from the perfusions. The composition disclosed herein, which is based on the nanoparticles of polymeric micelles has the ability to entrap/solubilize taxane analogs like paclitaxel without affecting their cytotoxic properties. The improved effect of the composition is due to the unexpected synergism envisaged between the components of the composition inter se. The following non-limiting examples are included to demonstrate preferred embodiments of the invention. EXAMPLES 1 - 9 The polymer (5mg) was dissolved in 5 ml of the diluting fluid followed by the addition of the anionic surfactant sodium deoxycholate (5mg) to get a clear solution. Paclitaxel solution in absolute alcohol (20 mg/ml) was then added to the solution of polymer and the surfactant to get drug concentrations of 0.1, 0.15 & 0.2 mg/ml. Different diluting fluids tried and the stability of the resulting drug solutions are tabulated below : (Table Removed) Dextrose had a stabilizing effect on the drug solubility as reflected in the stability of the drug solution. EXAMPLES 10 - 12 Effect of higher drug loading : The polymer (5mg) was dissolved in 5 ml of the diluting fluid followed by the addition of the anionic surfactant sodium deoxycholate (5mg) 40 get a clear solution. Paclitaxel solution in absolute alcohol (20 mg/ml) was then added to the solution of polymer and the surfactant to get drug concentrations of 0.2, 0.25 & 0.3 mg/ml. The stability of the resulting drug solutions are tabulated below : (Table Removed) More than 20% drug loading w.r.t. the polymer resulted in reduced stability of the drug solution EXAMPLES 13 -14 Effect of higher concentration of Dextrose : The polymer (5mg) was dissolved in 5 ml of the diluting fluid followed by the addition of the anionic surfactant sodium deoxycholate (5mg) to get a clear solution. Paclitaxel solution in absolute alcohol (20 mg/ml) was then added to the solution of polymer and the surfactant to get drug concentrations of 0.2 mg/ml. Different diluting fluids tried and the stability of the resulting drug solutions are tabulated below : (Table Removed) 10% dextrose had a more stabilizing effect on the solution as compared to 5% dextrose. The same was also reflected on the better solution clarity with 10% dextrose. EXAMPLES 15 - 17 Effect of pH on Solution Stability at 20% drug Loading : The polymer (5mg) was dissolved in 5 ml of the diluting fluid followed by the addition of the anionic surfactant sodium deoxycholate (5mg) to get a clear solution. pH of the resulting solution was adjusted with sodium citrate. Paclitaxel solution in absolute alcohol (20 mg/ml) was then added to the solution of polymer and the surfactant to get drug concentrations of 0.2 mg/ml. Results are tabulated below: (Table Removed) EXAMPLES 18 Determination of CMC of Polymer: Critical Micelle Concentration (CMC) of the polymer was determined using aqueous solutions of concentration ranging from 0.01 to 1.0 mg/ml. CMC was found to be in the range of 0.1 - 0.2 mg/ml as depicted in the graph shown in Figure 1 of the accompanying drawings EXAMPLES 19 - 23 Effect of reduction of Polymer/Sodium DOC on drug Loading : The requisite amount of polymer was dissolved in 5 ml of the diluting fluid followed by the addition of requisite amount of anionic surfactant sodium deoxycholate to get the concentrations shown in the table below. pH of the resulting solution was adjusted to 6.4 - 6.8 with sodium citrate. Paclitaxel solution in absolute alcohol (20 mg/ml) was then added to the solution of polymer and the surfactant to get drug concentrations of 0.2 mg/ml. Results are tabulated below: (Table Removed) EXAMPLES 24 - 27 Effect of reduction of Sodium DOC on drug Loading : The polymer (0.625 mg) was dissolved in 5 ml of the diluting fluid followed by the addition of the anionic surfactant sodium deoxycholate to get a clear solution. pH of the resulting solution was adjusted to 6.4 - 6.8 with sodium citrate. Paclitaxel solution in absolute alcohol (20 mg/ml) was then added to the solution of polymer and the surfactant to get drug concentrations of 0.2 mg/ml. Results are tabulated below: (Table Removed) EXAMPLES 28 - 35 Optimization of Drug Loading : The requisite amount of the polymer was dissolved in 5 ml of the diluting fluid followed by the addition of requisite amount of the anionic surfactant sodium deoxycholate to get the concentrations shown in the table below. pH of the resulting solution was adjusted to 6.4 - 6.8 with sodium citrate. Paclitaxel solution in absolute alcohol (20 mg/ml) was then added to the solution of polymer and the surfactant to get drug concentrations of 0.2, 0.5, 0.6, 0.7, 0.8, 2.4, 3.2, 4.0, & 10 mg/ml. Results are tabulated below: (Table Removed) EXAMPLES 36 - 40 Effect of reduction of Sodium DOC on drug Loading: The polymer (1.5 mg) was dissolved in 5 ml of the diluting fluid followed by the addition of the anionic surfactant sodium to get concentrations of 0, 0.10, 0.15, 0.20 & 0.25 mg/ml. pH of the resulting solution was adjusted to 6.4 - 6.8 with sodium citrate. Paclitaxel solution in absolute alcohol (20 mg/ml) was then added to the solution of polymer and the surfactant to get drug concentrations of 0.6 mg/ml. Results are tabulated below : (Table Removed) THE PREFERRED COMPOSITION Drug Solution is prepared by dissolving Paclitaxel (100 mg) in ethanol (5 ml) to obtain a clear solution having a concentration of 20 mg/ml and filtered through 0.2|i filter. Infusion Vehicle is obtained by separately dissolving 30 mg of the polymer, 30 mg of sodium citrate and 20 mg of the anionic surfactant sodium deoxycholate in 100 ml of Dextrose (10%) solution and filtering through 0.2u filter. Composition for Infusion: The required amount of the drug solution (3 ml) is added to the vehicle to obtain a drug concentration of 0.6 mg/ml. The perfusion fluid is stable for more than 12 hrs without any apparent signs of precipitation of drug. Stability is also indicated by the fact that more that 90% of the drug is available in solution form at the end of 24 hrs, when analysed by HPLC. IOSS OF DRUG DURING PASSAGE THROUGH 0.2 u IN-LINE FILTER IN A I.V. SET: A preferred composition (100 ml) as given above was passed through an infusion set containing 0.2µ in-line filter, at a flow rate of about 3 ml per minute to simulate the actual bedside situation. The loss of drug during passage through the 0.2µ in-line filter was not more than 5%. Advantages of the present invention: 1. The compositions of the present invention are pharmaceutically stable and parenterally acceptable novel composition of nanoparticles of taxane analogs, that can be utilized for the treatment of pathological conditions arising out of excessive proliferation of cells such as rheumatoid arthritis or cancer The composition can be used to treat ovarian cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, squamous cell cancer of the head and neck and malignant melanomas. 2. The composition can be administered parenterally with clinically acceptable, aqueous Dextrose infusion fluid as final solvent. 3. The composition retains full cy to toxic activity as assessed in xenographs of malignant cells in mice. 4. The present invention provides compositions and methods for the solubilization of taxane analogs (eg paclitaxel) in nanoparticles of polymeric micelles in a pharmaceutically acceptable liquid vehicle that avoids the use of polyoxylethylated castor oils such a Cremophor EL, such that the drugs remain physically and chemically stable and can be administered intravascularly without undue toxicity from the undissolved drug and/or from the solvent vehicle at drug doses contemplated to be effective to exhibit clinically significant anti-tumor activity. 5. The preferred compositions utilize ethanol as the primary solvent for the drug that is miscible in the vehicle comprising of 10% dextrose solution in water, the polymer and the anionic surfactant sodium deoxycholate. In this composition the taxane analogs, such as paclitaxel, are suitably entrapped in the nanoparticles of polymeric micelles and are safe for human administration. 6. The described composition may be utilized to dissolve paclitaxel in concentrations ranging from 0.1 to more than 18 mg/ml. This range is contemplated to cover the administration of dosages necessary to yield active cytotoxic concentrations, in vivo to treat malignancies sensitive to these drugs. The invention will therefore allow the introduction of paclitaxel and other taxane analogs in clinical practice for the therapy of malignant disease without exposing the patient to the serious and potentially deleterious effects of Cremophor EL. 7. In a broader sense, the present invention describes a method to administer poorly water-soluble taxane analogs such as Paclitaxel intravascularly. This embodiment circumvents the poor intestinal absorption of the drug. It also avoids the serious systemic adverse effects of Cremophor. We claim: 1. A pharmaceutical composition based on nanoparticles of polymeric micelles containing Paclitaxel, its derivatives or analogs such as herein described physically entrapped therein, essentially comprising of Paclitaxel, its derivatives or the analogs in a concentration ranging between 0.1 to 20 mg/ml, a co-polymer comprising of monomers selected from Vinylpyrrolidone, N-isopropyl acrylamide, and functionalized polyethylene glycol, in a concentration ranging between 0.01 to 20 mg/ml, a stabilizing surfactant of the kind such as herein described in a concentration ranging between 0.01 to 20 mg/ml, an alcohol such as herein described, an intravenous aqueous diluting fluid of the kind such as herein described, and a conventional buffering agent in a concentration sufficient to bring pH between 6.0 to 7.5. 2. A composition as claimed in claim 1, wherein the said stabilizing surfactant is an anionic surfactant, preferably Sodium deoxycholate. 3. A composition as claimed in claim 1, wherein said buffering agent is sodium citrate. 4. A composition as claimed in claim 1, wherein the intravenous aqueous diluting fluid is a dextrose solution, preferably 10% dextrose solution. 5. A method of preparing a pharmaceutical composition of Paclitaxel for intravascular administration comprising the steps of: a) dissolving the co-polymer in the 10% dextrose solution; b) adding sodium deoxycholate to the solution of step a) ; c) adjusting the pH of the resulting solution with a conventional buffering agent in the pH ranging between 6 to 7.5; and d) adding an alcoholic solution of Paclitaxel, its derivatives or analogs, wherein the said Paclitaxel is dissolved in alcohol preferably ethanol, wherein concentration of Paclitaxel in the alcohol preferably ranges between 10 to 80 mg/ml, said composition essentially comprising of Paclitaxel, its derivatives or the analogs in a concentration ranging between 0.1 to 20 mg/ml, a co-polymer comprising of monomers selected from Vinylpyrrolidone, N-isopropyl acrylamide, and functionalized polyethylene glycol, in a concentration ranging between 0.01 to 20 mg/ml, a stabilizing surfactant of the kind such as herein described in a concentration ranging between 0.01 to 20 mg/ml, an alcohol such as herein described, an intravenous aqueous diluting fluid of the kind such as herein described, and a conventional buffering agent in a concentration sufficient to bring pH between 6.0 to 7. 5 6. A method as claimed in claim 5 wherein said alcohol is ethanol. 7. A pharmaceutical composition based on nanoparticles of polymeric micelles containing Paclitaxel, its derivatives or analogs physically entrapped therein substantially as herein described with reference to the foregoing examples. 8. A method of preparation of pharmaceutical composition based on nanoparticles of polymeric micelles containing Paclitaxel, its derivatives or analogs physically entrapped therein substantially as herein described with reference to the foregoing examples.

Documents:

641-del-2000-abstract.pdf

641-del-2000-claims.pdf

641-del-2000-correspondence-others.pdf

641-del-2000-correspondence-po.pdf

641-del-2000-description (complete).pdf

641-del-2000-drawings.pdf

641-del-2000-form-1.pdf

641-del-2000-form-19.pdf

641-del-2000-form-2.pdf

641-del-2000-form-3.pdf

641-del-2000-gpa.pdf

641-del-2000-pct-210.pdf

641-del-2000-pct-409.pdf

641-del-2000-petition-137.pdf

641-del-2000-petition-138.pdf