FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
NANODISPERSION
SUN PHARMA ADVANCED RESEARCH COMPANY LTD.
A company incorporated under the laws of India having their office at 17/B, MAHAL INDUSTRIAL ESTATE, MAHAKALI CAVES ROAD, ANDHERI (E), MUMBAI-400093, MAHARASHTRA, INDIA.
The following specification particularly describes the invention and the manner in which it is
to be performed.

The present invention relates to a 'nanodispersion' of one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative and process for its preparation.
BACKGROUND OF THE INVENTION
There are number of pharmaceutical drugs that are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges in terms of having poor oral bioavailability or in terms of formulating them for drug delivery especially through the intravenous route. If a drug is intravenously administered, particles must be small enough to safely pass through capillaries without causing emboli. For intravenous administration, it is recognized as safe to administer drugs in the form of solution, emulsion, liposomes, nanodispersions and the like. Another requirement that should be met while formulating a drug delivery system especially for hydrophobic drugs is that the formulation should be physically stable with no substantial aggregation or crystallization of the drug or change in appearance of the formulation on storage at room temperature for desired period of time.
An example of a poorly soluble drug includes taxane derivatives which are well known for their anticancer activity. A taxane derivative or a taxoid is a complex diterpenoid natural product derived principally from the bark of the Western Yew, Taxus brevifolia and essentially has a taxane skeleton. Taxanes have been used to produce various chemotherapeutic drugs. Currently two taxane derivatives paclitaxel and docetaxel are available commercially as potent anti-tumor agents.
The taxane derivatives exhibit very poor solubility in water and in most pharmaceutically acceptable solvents thus limiting their administration to patients. Due to this unfavorable intrinsic property, TAXOL injection, the commercially marketed paclitaxel injection is formulated as a non-aqueous solution in Cremophor TM EL (a polyethoxylated castor oil) and dehydrated alcohol. However, use of solubilizer like Cremophor TM EL in large amounts lead to various adverse effects such as serious or fatal hypersensitive and hypertensive reactions, bradyarrhythmia, anemia, neutropenia and/or peripheral neuropathy. Therefore all patients receiving paclitaxel are premedicated with steroids, antihistamines and H2 receptor antagonists and then paclitaxel is only infused very slowly over a period of at least 3 hours or more.
In view of these problems associated with Taxol formulations, researchers have tried to prepare taxol formulations without using Cremophor EL.
United States Patent no. 6537579 describes compositions of substantially water insoluble pharmacologically active agents such as paclitaxel, in which the pharmacologically active agent exists 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 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.
United States Patent no. 6017948 relates to a composition comprising paclitaxel in the form of a solution of paclitaxel in a pharmaceutically acceptable, water-miscible, non-aqueous solvent (like N-methyl pyrrolidone) and further comprising a pharmaceutically acceptable solubilizer (such as triacetin), with the provision that polyethoxylated castor oil (Cremophor) is excluded from the composition. In preferred embodiments, a large amount of solvent i.e. 4000 mg of NMP (example 1) or combination of 2000 mg of NMP and 2000 mg of ethanol (example2) were used to solubilize 10 mg of paclitaxel under moderate agitation. If therapeutically effective amount of drug is delivered through such compositions, it will be associated with entry of excessive amounts of ethanol, non-aqueous solvents or solubilizers in the body.
United States Patent no. 6046230 relates to a stable injection formulation containing paclitaxel and two solubilizers - oxyethylene sorbitol oleate and (oxyethylene glycol) 15.20 fatty acid monoester along with additional components such as povidone and polyethylene glycol. The main solubilizer used in the formulation polyethoxylated sorbitol oleic polyester which is an ethylene oxide addition product of palm olein-derived oleic acid has an inherent property of getting solidified at temperatures below 10°C, making it unsuitable for solubilizing paclitaxel when used alone. However when combined with an auxiliary solubilizer polyethylene glycol mono fatty acid ester, the two solubilizers together exhibit good solubility in water and in anhydrous alcohol and they stay in fluid phase even at low temperatures. So, use of the two solubilizers together is mandatory. Also it is an essential criterion that HLB value of the solubilizers which meet the desired characteristics should be as high as 15 but not less than 13. The resulting formulation is a solution.
PCT Application no. WO 2006/133510 discloses a liquid pharmaceutical formulation for parenteral administration comprising docetaxel or a pharmaceutically acceptable salt thereof; one or more glycols and a pharmaceutically acceptable non-aqueous solvent system, wherein the formulation has a pH meter reading in the range of from 2.5 to 7.0. The embodiments of the invention involve use of very high amount of surfactants (about 25%v/v of polysorbate 80 or 30 % v/v of Cremophor) which inturn can lead to toxic side effects. The application does not disclose the efficacy and toxicity profile of the formulations. Further the formulation disclosed by the '510 application is a solution of drug in a non-aqueous solvent system which on admixture with an infusion diluent (0.9% NaCl or 5% Dextrose solution) produces an infusion solution. A novel drug delivery system or nanodispersion is not formed anywhere in the process. Also the stability of the formulation solutions after diluting with infusion diluent is of very short period of about 4 to 6 hours which can limit its administration efficiency.
US2002/0058060 discloses liposomes containing hydrophobic substances and two phospholipids with different phase transition temperatures and liposome forming materials like cholesterol and hydrophilic polymer modified lipids. The ratio of the drug to the phospholipids and the liposome forming materials is varied to get different liposomal formulations. The patent application tried to formulate liposomes of

taxanes which have elevated drug: lipid ratio, by using two specified class of phospholipids, so that total amount of lipid used is reduced, as injection of excessive amount of lipids in the body leads to certain extent of toxicity.
Thus it is evident from the prior art that the major problem associated with formulating a taxane composition is hydrophobicity of taxanes, which
(a) makes it difficult to formulate a composition which contains solubilized form of the drug and which is stable, without any substantial aggregation or crystallization of the drug or change in appearance of the formulation till a desired period of time.
(b) necessitates the use of large amount of solubilizers, phospholipids and surfactants.
Also, toxicity studies of TAXOL (marketed solution of paclitaxel in Cremophor and Alcohol) shows a LD50 value of 7.5-12.0 mg/kg (Reference: (1) US Patent no. 6753006; (2) Chemwatch Material Safety Data Sheet, Rev no.2, Issue date: 1 l-Apr-2006, (Chemwatch name: PACLITAXEL INJECTION.)) which is low, indicating that the drug administered in the form of solution has very low therapeutic index and even a moderate dose may show serious side effects and toxic reactions. Thus there exists a need for an injectable formulation of a taxane derivative which
(a) avoids the use of large amount of excipients,
(b) avoids the use of Cremophor,
(c) delivers the drug through a novel delivery system, which shows increased LD50 value, minimizing the toxic side effects associated with the administration of the drug in solution form and
(e) overcomes the limitations of the drug associated with its hydrophobic nature and is stable with no substantial aggregation or crystallization of the drug or change in appearance of the formulation, for the desired period of time during administration and during storage. We have developed a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a non-aqueous solvent and water, said nanoparticles comprising one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof. The present invention provides a formulation which avoids the use of Cremophor, involves the use of much reduced amounts of additives (like surfactants, phospholipids) and delivers the drug in the form of nanoparticles, thus minimizing the toxic reactions and side effects associated with the administration of the drug. The LD50 value observed for formulations of the present invention is 342.5 mg/kg which is much greater than the LD50 value of 7.5-12.0 mg/kg of marketed TAXOL solution (Reference: (1) US Patent no. 6753006; (2) Chemwatch Material Safety Data Sheet, Rev no.2, Issue date: ll-Apr-2006, (Chemwatch name: PACLITAXEL INJECTION.)) of the drug. Also the formulation of the present invention is stable, with no substantial aggregation or crystallization of the drug or change in appearance of the formulation, for the desired period of time during administration and during storage.

OBJECTS OF THE INVENTION
It is an object of the present invention to provide a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a non-aqueous solvent and water, said nanoparticles comprising one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof.
It is a further object of the present invention to provide a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a non-aqueous solvent and water, said nanoparticles comprising paclitaxel, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof.
It is a further object of the present invention to provide a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a non-aqueous solvent and water, said nanoparticles comprising docetaxel, a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof.
It is a further object of the invention to provide a process for preparing the nanodispersion of the present invention, comprising dissolving one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof, in a non-aqueous solvent and adding an aqueous liquid vehicle to the above solution.
It is a further object of the invention to provide a process for preparing the nanodispersion of the present invention, comprising dissolving one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof, in a non-aqueous solvent and adding this solution to an aqueous liquid vehicle.
It is a further object of the invention to provide a nanodispersion of one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, which is devoid of toxic excipient like cremophor and involves the use of much reduced amounts of additives (like surfactants and phospholipids) required for formulating a stable composition thus minimizing the associated toxic reactions.
It is a further object of the invention to provide a nanodispersion of one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, which is stable for the desired period of time before and during administration and shows no sign of aggregation or change in appearance of the formulation on storage for 24-48 hours at room temperature.

It is a further object of the invention to provide a solution of one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof in a non¬aqueous solvent, which is stable, physically and chemically and shows no sign of aggregation or change in appearance of the formulation on storage for at least 3 months at room temperature and which on dilution with an aqueous liquid vehicle gives nanodispersion of the present invention.
It is yet another object of the present invention to provide a kit having two containers, the first container comprising a solution of one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof in a non-aqueous solvent, and a second container comprising an aqueous liquid vehicle, such that on addition of contents of second container to the contents of the first container or vice versa, with mild agitation or shaking, results in the formation of nanodispersion of the present invention and is suitable for intravenous administration.
It is yet another object of the present invention to provide a kit having two containers, the first container comprising a lyophilized form of the nanodispersion and a second container comprising an aqueous liquid vehicle such that on addition of contents of second container to the contents of the first container or vice versa, with mild agitation or shaking, results in the formation of nanodispersion of the present invention and is suitable for intravenous administration.
It is a further object of the invention to provide a method of treatment of various types of cancers known in the art, comprising administering the present nanodispersion compositions to patients in need thereof.
SUMMARY OF THE INVENTION
A nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a non-aqueous solvent and water, said nanoparticles comprising one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof
A solution comprising one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof in a non-aqueous solvent, which on dilution with an aqueous liquid vehicle gives a nanodispersion as claimed in claim 1.
A process for preparing nanodispersion, comprising dissolving one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a

surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof in a non-aqueous solvent and adding an aqueous liquid vehicle to the above solution.
A process for preparing nanodispersion, comprising dissolving one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof in a non-aqueous solvent and adding this solution to an aqueous liquid vehicle.
BRIEF DESCRIPTION OF FIGURES
FIGURE 1: It represents a comparative account of change in relative tumor volume (RTV cm3) with time (in days) of human breast tumor xenograft (MX-1) implanted in Balb/c female nude mice for control sample, reference sample (ABRAXANE) and test sample (Composition of example 12 of the present invention) as per the study detailed in Example 24.
FIGURE 2: It represents a comparative account of change in relative tumor volume (RTV cm3) with time (in days) of human breast tumor xenograft (MX-1) implanted in Athymic female nude mice for control sample, reference sample (ABRAXANE) and test sample (Composition of example 9 of the present invention) as per the study detailed in Example 25.
FIGURE 3: It represents a comparative account of change in relative tumor volume (RTV cm3) with time (in days) of human colon tumor xenograft (HT-29) implanted in Athymic male nude mice for control sample, test sample (Composition of example 9 of the present invention) and two reference samples (ABRAXANE and ONCOTAXEL) as per the study detailed in Example 26.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a 'nanodispersion' of one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative and process for its preparation.
The term nanodispersion as used herein mean a colloidal dispersion of nanoparticles having mean size less than 300 nm in a vehicle.
Nanoparticles are defined as particles with controlled dimensions of the order of nanometers. The nanoparticles as claimed in the invention can be a polymeric nanoparticle (matrix of polymer entrapping the drug) and/or a polymeric nanovesicle (polymer stabilized nano sized vesicle encapsulating the drug.) and/or a polymeric nanocapsule (polymeric membrane surrounding drug in core) and/or nano sized particles of the drug stabilized by surfactants, and the like having mean size less than 300 nm.

According to one embodiment of the present invention, the particle size of the nanoparticles is in the range of 10 nm to 275 nm. In preferred embodiments of the present invention, the particle size is less than 200 nm. In most preferred embodiments of the present invention, the particle size is in the range of 10 nm to 200 nm.
Nanoparticles or nanosized particles in themselves afford many advantages in terms of efficient drug delivery. It has been realized that either incorporation of a drug into a delivery vehicle or attachment of the drug to the vehicle can afford many advantages in comparison to the administration of the drug in its free form. Incorporation of drug in vehicle can affect tissue specific distribution, in particular preferential accumulation in a certain tissue of interest or at a disease site, targeting of drug to a particular cell type, decrease of interaction with blood components, enhanced protection of the drug from premature degradation and increase in circulation time. Nanoparticle is one such important drug delivery vehicle. Nanoparticles have engineered specificity, allowing them to deliver a higher concentration of pharmaceutical agent to a desired location or target site of action (Kayser et al, Current Pharmaceutical Biotechnology, 2005, 6, 3-5). Targeted drug delivery is important in many applications, especially when toxicity of the drug, if delivered systemically, is an issue. Targeted drug delivery may help eliminate or at least minimize toxic side effects and lower the required dosage amounts, among other beneficial features. There are different approaches to target drugs to the site of action. A very simple, but in its applicability limited approach is the direct injection at the target site, e.g. injection into tumor tissue. Another approach is to use specific carrier systems for different administration routes (e.g. transferosomes for topical delivery), microspheres or nanoparticles for oral and parenteral administration. Out of the parenteral routes, the intravenous injection is most frequently used. Upon i.v. administration, particles are recognized by liver and spleen macrophages and preferentially they are taken up by the liver macrophages. This effect can be exploited to target drug-loaded carriers to liver and spleen or generally to macrophages to treat infections of the MPS (mononuclear phagocytic system) or RES (Reticulo endothelial system) and this targeting phenomenon is often called "passive targeting"). Escaping the MPS/RES recognition is possible by modifying the surface of the carriers with polyethylene glycol (PEG) moieties or PEG chain containing polymer such as Poloxamine 908. This increases the period of circulation of the carrier in the blood-stream upon intravenous injection. The normal as well as long circulating carriers can be equipped with a targeting moiety (lectins or monoclonal antibodies or sugars like mannose/ galactose etc.) generally called as a ligand. These ligands direct the drug containing carriers to the desired target cells carrying the appropriate receptors for the ligands. This site specific delivery achieved by using a targeting ligand involves an active process; therefore it is also called as "active targeting".
Nanoparticles having specific size, can passively target solid tumors through a phenomenon which exploits the characteristic features of tumor biology. Tumor tissues have leaky blood vessels, enhanced permeability and poor lymphatic drainage. In contrast, vascular endothelial cells in normal tissue have a lower permeability for nanoparticles compared to tumor tissues. This allows nanocarriers to accumulate in the tumor. The effect is known as Enhanced Permeability and Retention Effect or EPR Effect (Maeda et al,

Bioconjugate Chem; 1992;3:351-361). Also, nanoparticles less than 200 nm more effectively evade the reticuloendothelial system and remain in circulation for long time (Litzinger et al; Biochim Biophys Acta 1994;1190:99-107).
The delivery of drug through nanodispersion comprising nanoparticles having mean size less than 300 nm, leads to enhanced internalization and accumulation of the drug in the target tumor tissues and cells. Such increased internalization levels provides a potent treatment strategy for curing tumors associated with cancer.
The nanodispersion of the present invention comprises nanoparticles dispersed in a vehicle comprising non¬aqueous solvent and water.
The non-aqueous solvent used in the compositions of the present invention is one in which the taxane derivative is relatively soluble and which is miscible with water or aqueous solvents. Examples of such solvents include, but are not limited to: alcohols such as ethanol, n-propanol, isopropanol; glycols such as ethylene glycol, propylene glycol, butylene glycol and its derivatives; polyethylene glycols like PEG 400 or PEG 3350; polyethylene glycol esters and euiers such as polyethylene 15 glycol sorbitans, polyethylene glycol monoalkyl ethers; polypropylene glycol and its derivatives such as PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PPG- 15 stearyl ether; glycerol; glycofurol; dimethylsulfoxide (DMSO); dimethylacetamide; dimethylformamide; 1,4-dioxane, and the like and mixtures thereof.
In one embodiment of the present invention, the non-aqueous solvent may be selected from alcohols, polyethylene glycols and/or mixtures thereof. In preferred embodiment of the present invention, a mixture of ethanol and PEG (polyethylene glycol) is used as the non-aqueous solvent. Ethanol is used in the nanodispersion composition of the present invention in an amount ranging from about 0.001% w/v to about 5% w/v, more preferably from about 0.05% w/v to about 0.5% w/v and most preferably from about 0.1% w/v to about 0.25% w/v. Polyethylene glycols which are used preferably, include PEG-400 and PEG-3350. PEG-400 is used in die embodiments of the present invention in an amount ranging from about 0.01% w/v to about 20.0% w/v, more preferably from about 0.05% w/v to about 5.0% w/v and most preferably from about 1.0% w/v to about 2.5% w/v. PEG-3350 is used in the embodiments of the present invention in an amount ranging from about 0.001% w/v to about 10.0% w/v, more preferably from about 0.05% w/v to about 5.0% w/v and most preferably from about 0.1% w/v to about 3% w/v.
The vehicle further comprises water as sterile water for injection or about 5% to about 10.0%w/v dextrose solution or about 0.45% to about 0.9% w/v normal saline solution or a combination of 2.5% dextrose and 0.9% NaCl solution or any other pharmaceutical^ acceptable intravenous aqueous liquid vehicle and mixtures thereof. The preferred embodiments of the present invention comprise 5% dextrose solution as the aqueous liquid vehicle.

The nanodispersion of the present invention comprises one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative.
The taxane derivative, as mentioned in die embodiments of the present invention are those compounds which essentially have a taxane skeleton and are complex diterpenoid natural product derived principally from natural sources such as bark of the Yew tree, taxus brevifolia or from cell culture, or chemically synthesized molecules. The principal mechanism of action of the taxane class of drugs is the inhibition of the microtubule function. It does this by stabilizing GDP-bound tubulin in the microtubule. Microtubules are essential to cell division, and taxanes therefore stop this - called a "frozen mitosis".
Most prominent representatives of this group which are used in the compositions of the present invention include paclitaxel and docetaxel and their pharmaceutically acceptable salts, derivatives, analogs and isomers such as 7-epipaclitaxel, t-acetyl paclitaxel, 10-desacetyl-paclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, and the like and mixtures thereof.
Paclitaxel is a natural product with antitumor activity. Paclitaxel is obtained via a semisynthetic process from taxus brevifolia and/or taxus baccata. The chemical name for paclitaxel is 5a,20-Epoxy-l,2a,4,7/3,10j3,13a-hexahydroxytax-ll-en-9-one 4, 10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. Paclitaxel is available in the United States of America as TAXOL Injection. Paclitaxel is indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, paclitaxel is indicated in combination with cisplatin. Paclitaxel is also indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. Paclitaxel is also indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Paclitaxel, in combination with cisplatin, is also indicated for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy. Paclitaxel is also indicated for the second-line treatment of AIDS-related Kaposi's sarcoma.
Docetaxel is another antineoplastic agent belonging to the taxoid family. It is prepared by a semisynthetic method beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butylester, 13-ester with 5/3-20-epoxy-l,2a,4,7/3,10/3,13o!-hexahydroxytax-ll-en-9-one 4-acetate 2-benzoate, trihydrate. Docetaxel is available in the United States of America as TAXOTERE Injection concentrate. Docetaxel as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy. Docetaxel in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition. Docetaxel in combination with prednisone is

indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer. Docetaxel in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotfierapy for advanced disease. Docetaxel in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with inoperable locally advanced squamous cell carcinoma of the head and neck. The embodiments of the present invention comprise paclitaxel in an amount ranging from about 0.001 mg/ml to about 15.0 mg/ml, more preferably from about 0.3 mg/ml to about 5.0 mg/ml and most preferably from about 1.5 mg/ml to about 5.0 mg/ml. Docetaxel is used in the embodiments of the present invention in an amount ranging from about 0.001 mg/ml to about 10.0 mg/ml, more preferably from about 0.3 mg/ml to about 0.7 mg/ml and most preferably from about 0.3 mg/ml to about 2.5 mg/ml.
The nanodispersion composition of the present invention containing the taxane derivative, may further comprise an additional therapeutically active agent selected from the group consisting of an anti¬inflammatory agent, an anti-histaminic agent, a 5-HT3 antagonist, a H2-receptor antagonist, a vitamin and mixtures thereof.
Anti-inflammatory agents that may be used in the compositions of the present invention may be selected from steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs. The embodiments of the present invention preferably comprise steroidal anti-inflammatory drugs such as glucocorticoids. Examples of glucocorticoids that may be used in the compositions of the present invention may be selected from Cortisol or hydrocortisone, prednisone, prednisolone, dexamethasone, betamethasone, budesonide, triamcinolone and the like and mixtures thereof. In a preferred embodiment of the present invention, dexamethasone is used as the anti-inflammatory agent.
Anti-histaminic agent or histamine antagonists that may be used in the compositions of the present invention may be selected from first generation anti-histaminic agents such as ethylenediamines (mepyramine, antazoline), ethanolamines (diphenhydramine, carbinoxamine, clemastine, dimenhydrinate), alkylamines (pheniramine, chlorpheneramine, dexchlorpheniramine, triprolidine), piperazines (cyclizine, chlorcyclizine, hydroxyzine, meclizine), tricyclics and tetracyclics (promethazine, alimemazine, cyproheptadine, azatadine, ketotifen) and the like; second generation anti-histaminic agents such as acrivastine, astemizole, cetirizine, loratidine, mizolastine, terfenadine, azelastine, levocabastine, olapatidine and the like; third generation anti-histaminic agents such as levocetrizine, desloratidine, fexofenadine and the like and mixtures thereof.
5-HT3 antagonist that may be used in the compositions of the present invention may be selected from ondansetron, granisetron, dolasetron, tropisetron, palonosetron, alosetron, cilansetron and the like and mixtures thereof.

H2-receptor antagonist or H2-antagonist that may be used in the compositions of the present invention may be selected from cimetidine, ranitidine, nizatidine, famotidine, roxatidine, burimamide, metiamide and the like and mixtures thereof.
Vitamins that may be used in the compositions of the present invention may be selected from fat soluble vitamins such as vitamin A, vitamin D, vitamin E and vitamin K and water soluble vitamins such as vitamin C and vitamin B including vitamin (Bl: thiamine; B2: riboflavin; B3: niacin; B5: pantothenic acid; B7: biotin; B9: folic acid; B12: cyanocobalamin) and mixtures thereof. In one embodiment of the present invention the vitamin used is Vitamin D.
The compositions of the present invention further comprise polymer(s) and surfactant(s). The polymer(s) that may be used in the composition of the present invention may be selected from tertiary amide polymers such as polyvinylpyrrolidone and the like (PVP-PEG conjugate); polyamino acids such as polyglutamic acid and poly-1-lysine; polysaccharide containing glycos-aminoglycans such as hyaluronan, heparin sulphate and chondroitin sulphate; natural polymers such as gelatin, chitosan, human serum albumin; and the like; polyanhydrides such as poly sebacic acid; polyamides such as polyglutamates; polyesters such as polylactides, polyglycolides, polylactide-co-glycolide, polycaprolactones; other biocompatible and biodegradable polymers and/or their derivatives or copolymers or any other such polymers known to one skilled in die art and mixtures thereof.
According to one embodiment of the present invention, the polymer used is polyglutamic acid sodium salt. According to another embodiment of the present invention, the polymer used is sodium hyaluronate. According to preferred embodiment of the present invention, the polymer used is polyvinylpyrrolidone.
Polyvinylpyrrolidone is a tertiary amide polymer having linearly arranged monomer units of l-vinyl-2-
pyrrolidone, hereinafter designated PVP, and also known as Povidone. It is commercially available as a
series of products having mean molecular weights ranging from about 10,000 to about 700,000. The
various products are marketed according to average molecular weights designated K-values; e.g. GAF
Corporation supplies PVP having the following K-values:
K-value Average Molecular Weight
15 about 10,000
30 about 40,000
60 about 160,000
90 about 360,000
The composition of this invention may contain various grades of polyvinylpyrrolidone, i.e. for example, PVP K-12, K-30, K-60 and K-90. The polyvinylpyrrolidone ingredient may be present as one specific grade or as a combination of two or more grades.


According to one embodiment of the present invention, the polymer may be used in the compositions in an amount ranging from about 0.001% w/v to about 20% w/v. The polymer is preferably used in an amount ranging from about 0.01% w/v to about 5.0% w/v. Most preferably, it is used in an amount ranging from about 0.03% w/v to about 1.0% w/v.
The compositions of the present invention further comprise surfactant(s). The term surfactant is a blend of "surface active agent". Surfactants are molecules, which comprises a water-soluble (hydrophilic) and a lipid-soluble (lipophilic) part. The surfactants that are used in the compositions of the present invention may be selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof.
The term fatty acids includes aliphatic (saturated or unsaturated) monocarboxylic acids derived from or contained in esterified form, in an animal or vegetable fat, oil or wax. Examples of fatty acids or its salts that may be used in the compositions of the present invention include but are not limited to fatty acids or its salts having 'n' number of carbon atoms wherein 'n' ranges from about 4 to about 28. The fatty acid may be a saturated fatty acid or an unsaturated fatty acid, and their salt and combinations thereof. The saturated fatty acid and its salts may be selected from butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, sodium caprylate, sodium laurate, sodium myristate, sodium palmitate and the like and/or mixtures thereof. The unsaturated fatty acid and its salts may be selected from myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, sodium oleate, sodium arachidonate and the like and/or mixtures thereof.
Examples of sterol or its derivative or its salts that may be used in the compositions of the present invention may be selected form cholesterol, phytosterols, ergosterol, bile acids and their derivatives, salts and mixtures thereof. Cholesterol its derivatives and salts include cholesteryl sulfate, cholesterol acetate, cholesterol chloroacetate, cholesterol benzoate, cholesterol myristate, cholesterol hemisuccinate, cholesterol cinnamate, cholesterol crotanoate, cholesterol butyrate, cholesterol heptanoate, cholesterol hexanoate, cholesterol octanoate, cholesterol nonanoate, cholesterol decanoate, cholesterol oleate, cholesterol propionate, cholesterol valerate, dicholesteryl carbonate, and the like. Phytosterols that may be used in the compositions of the present invention include sitosterol, campesterol, stigmasterol, brassicasterol and its derivatives, salts and mixture thereof. For example, Phytosterols* marketed by Sigma, U.S.A. containing bsitosterol, campesterol and dihydrobrassicasterol. Bile acids include cholic acid, chenodeoxycholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, ursodeoxycholic acid and its derivatives, salts and mixture thereof.
According to one embodiment of the present invention, the surfactant used is selected from saturated fatty acid and cholesterol salt and/or mixtures thereof. According to preferred embodiment of the present invention, the surfactant used is selected from caprylic acid and cholesteryl sulphate and/or mixtures thereof.

In most preferred embodiments, the surfactant used in the compositions of the present invention is a mixture of caprylic acid and cholesteryl sulfate. Caprylic acid may be used in the embodiments in an amount ranging from about 0.001% w/v to about 5.0% w/v, more preferably from about 0.01%w/v to about 1.0%w/v and most preferably from about 0.01%w/v to about 0.5%w/v. Cholesteryl sulfate is used in the embodiments of the present invention in an amount ranging from about 0.001% w/v to about 5.0% w/v, more preferably from about 0.01%w/v to about 1.0%w/v and most preferably from about 0.01%w/v to about 0.5 %w/v.
According to another embodiment of the present invention, the surfactant used is selected from unsaturated fatty acid and cholesterol salt and/or mixtures thereof. According to preferred embodiment, the surfactant used is selected from oleic acid and cholesteryl sulphate and/or mixtures thereof.
According to another embodiment of the present invention, the surfactant used is selected from saturated fatty acid and bile acid or bile salt and/or mixtures thereof. According to preferred embodiment, the surfactant used is selected from caprylic acid and sodium glycocholate or ursodeoxycholic acid and/or mixtures thereof
Bile salts when used are employed in an amount ranging from about 0.001% w/v to about 5.0% w/v, more preferably from about 0.01%w/v to about 1.0%w/v and most preferably from about 0.01%w/v to about 0.75 %w/v.
The compositions of the present invention may further comprise low amounts of lecithins/phospholipids and/or their derivatives. The lecithins that may be used can be a natural, partially hydrogenated or hydrogenated lecithin or sphingolipids. Natural lecithins inturn are mixtures of different phospholipids. The phospholipids that may be used in the compositions of the present invention is selected from phosphatidyl choline, (dimyristoylphosphatidyl choline, dipalmitotylphosphatidyl choline, distearyloylphosphatidyl choline, dioleoylphosphatidyl choline, dilauryloylphosphatidyl choline, 1-palmitoyl-phosphatidyl choline, l-myristoyl-2-palmitoyl phosphatidyl choline, l-palmitoyl-2-myristoyl phosphatidyl choline, l-stearoyl-2-palmitoyl phosphatidyl choline); phosphatidyl ethanolamine (dimyristoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidyl ethanolamine, distearoyl phosphatidyl ethanolamine, lysophatidylethanolamine); sphingomyelins (brain sphingomyelin, dipalmitoyl sphingomyelin); lysolecithin; cerebrosides and the like and mixtures thereof. Further polyethylene glycol derivatives of lipids such as polyethylene glycol-distearoyl phosphatidylethanolamine (PEG-DSPE), methoxypolyethylene glycol-distearoyl phosphatidylcholine m-PEG-DSPC and the like and mixtures thereof may also be used in the compositions of the present invention. Preferably, the phospholipid that may be used in the compositions of the present invention is m-PEG-DSPE (methoxy polyethylene glycol-disteroyl phosphatidyl ethanolamine).


In one embodiment of the present invention, the phospholipid used is - mPEG-DSPE. It is used in an amount ranging from about 0.001%w/v to about 10.0% w/v, more preferably from about 0.01%w/v to about 5.0%w/v and most preferably from about 0.03%w/v to about 0.5 %w/v.
The nanodispersion of taxane derivatives of the present invention may be typically prepared by any one of the processes listed below:
1) The therapeutically active ingredient (taxane derivative and/or other agents), polymer(s) and surfactant(s) selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof is dissolved in non-aqueous solvent (such as ethanol and/or PEG) along with stirring and heating to obtain a concentrated solution of the drug. The solution so obtained is filtered through a membrane filter. To this solution, an aqueous liquid vehicle (5% dextrose solution) is added slowly and the mixture is shaken/agitated, thus leading to the formation of die nanodispersion of the present invention. The nanodispersion so formed is optionally homogenized and/or sonicated, filtered or lyophilized. The lyophilized powder of the medicament can be reconstituted with the aqueous medium, reforming nanodispersion of the present invention, prior to administration to the patients.
2) The therapeutically active ingredient (taxane derivative and/or other agents), polymer(s) and surfactant(s) selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof is dissolved in non-aqueous solvent (such as ethanol and/or PEG) along with stirring and heating to obtain a concentrated solution of the drug. The solution so obtained is filtered through a membrane filter and is added to an aqueous medium (5% dextrose solution) and the mixture is shaken/agitated, thus leading to the formation of the nanodispersion of the present invention. The nanodispersion so formed is optionally homogenized and/or sonicated, filtered or lyophilized. The lyophilized powder of the medicament can be reconstituted with the aqueous medium, reforming nanodispersion of the present invention, prior to administration to the patients.
3) The therapeutically active ingredient (taxane derivative and/or other agents), and surfactant(s) selected
from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof, is dissolved in non¬
aqueous solvent (such as ethanol and/or PEG) by slightly warming at 40°C in a round bottomed flask, and the
solvent is evaporated to form a thin film of the drug. The polymer(s) is dissolved in required quantity of an
aqueous medium and this solution is added to die film with gentle agitation and shaking for 3-4 hours, thus
leading to the formation of the nanodispersion of the present invention. The nanodispersion so formed is
optionally homogenized and/or sonicated, filtered and lyophilized. The lyophilized powder of the
medicament can be reconstituted with die aqueous medium, reforming nanodispersion of the present
invention, prior to administration to the patients.
The compositions of the present invention thus provides nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a non-aqueous solvent and water, said nanoparticles comprising one or more therapeutically active ingredient wherein at least one therapeutically

active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof.
The nanodispersion so obtained is devoid of toxic excipients like cremophor and involves the use of much reduced amounts of additives (like surfactants and phospholipids) required for formulating a stable composition of the active agent thus minimizing the associated toxic reactions.
As the compositions of the present invention are colloidal nanodispersion of therapeutically active ingredient (taxane derivative and/or other agents) comprising nanoparticles having a mean size less than 300 nm, they were analyzed for physical and chemical stability. It was observed that the particles do not aggregate upon storage at room temperature for 24-48 hours and the formulation shows no sign of change in appearance, inferring that the composition is stable for the desired period of time before and during administration.
Also, when a solution of therapeutically active ingredient (taxane derivative and/or other agents) in non¬aqueous solvent was tested, it was observed that the solution remains physically and chemically stable for at least a period of 3 months, with no significant change in assay of the drug and no substantial aggregation or change in appearance of the formulation. The observations are illustrated in the upcoming examples.
The compositions of the present invention can be provided as a kit having two containers, the first container comprising a solution of one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof in a non-aqueous solvent, and a second container comprising an aqueous liquid vehicle, such that on addition of contents of second container to the contents of the first container or vice versa, with mild agitation or shaking, results in the formation of nanodispersion of the present invention and is suitable for intravenous administration.
The present invention also provides a kit having two containers, the first container comprising a lyophilized form of the nanodispersion and a second container comprising an aqueous liquid vehicle such that prior to administration to the patients, the contents of second container can be added to the contents of the first container or vice versa with mild agitation or shaking, resulting in the formation of nanodispersion of the present invention.
Administering the nanodispersion compositions of the present invention to patients in need thereof, will provide an efficient method of treatment of various types of cancers known in the art.
While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.

EXAMPLE 1 -5
Pharmaceutical compositions of the present invention are described in Table 1 below.
TABLE 1

s.
No. Ingredients Quantity (% w/v)

Example 1 Example 2 Example 3 Example 4 Example 5
1 Paclitaxel 0.15 0.15 0.15 0.15 0.15
2 Cholesteryl sulfate 0.01 0.01 0.01 0.02 0.04
r 3 Caprylic acid 0.0125 0.0125 0.0125 0.025 0.05
4 Polyvinylpyrrolidone (PVP) K-30 0.125 0.0625 0.0325 0.125 0.125
5 Ethanol 0.14825 0.14825 0.14825 0.14825 0.14825
6 PEG-400 2.0 2.0 2.0 2.0 2.0
7 Dextrose (5%) qs. 100.0 qs. 100.0 qs. 100.0 qs. 100.0 qs. 100.0
Procedure:
• Drug, cholesteryl sulfate, caprylic acid and PVP K-30 were weighed accurately in a vial.
• Contents were dissolved in the required quantity of absolute ethanol and PEG-400 with stirring and by heating at 45 °C to obtain a solution.
• The solution was filtered through 0.2 PVDF membrane filter.
• Dextrose solution (5%) was then added slowly to the vial containing the solution of drug and shaken gently to get a transparent to transluscent nanodispersion.
• pH of the nanodispersion is checked by using pH Meter (Mettler Toledo-seven easy).
• Particle size of the nanodispersion is measured by Particle size analyzer (Nano-ZS, Malvern)
The visual appearance, pH and the particle size of the compositions as observed are summarized in table 2 below.
TABLE 2

Observation
Example 1 Example 2 Example 3 Example 4 Example 5
Appearance
Initial Almost transparent to transluscent dispersion Almost transparent to transluscent dispersion Almost transparent to transluscent dispersion Almost transparent to transluscent dispersion Almost transparent to transluscent dispersion
24 hours at RT Almost transparent to transluscent Almost transparent to transluscent Almost transparent to transluscent Almost transparent to transluscent Almost transparent to transluscent

dispersion dispersion dispersion dispersion dispersion
3.86 4.0 4.0 4.0 4.0
Particle Size (nm)

Initial 127 146 179 136 122
3h 134 148 156 138 158
24h 128 154 158.2 169 i 169
It can be seen that the compositions of the present invention are physically stable, with no substantial aggregation or change in appearance of the formulation on storage for 24 hours at room temperature.
The nanodispersion composition of these examples contains 150 mg/100 ml of paclitaxel. For the human dose of approximately 300 mg of paclitaxel for a 70 kg person, 200 ml of the each nanodispersion composition can be administered to the patient. Thus 20 to 80 mg of the cholesteryl sulfate, 25 to 100 mg caprylic acid, 65 to 250 mg of PVP and about 300mg ethanol would be given with a single adult dose of paclitaxel composition of Examples 1 to 5. Thus the composition of the present invention provides nanosized particles with very low amounts of excipients co-administered with the active agent.
Pharmaceutical compositions as described in examples 6-7 below are concentrated solutions which have to be diluted several times with a diluent (5% w/v dextrose solution) to obtain a nanodispersion of the present invention before administration to the patient.
EXAMPLE 6-7
Pharmaceutical compositions of the present invention as concentrated solution of taxane derivative are described in Table 3 below.
TABLE 3

Sr.No. Ingredients Quantity (%w/w)

EXAMPLE 6 (Drug conc:60mg/gm) EXAMPLE 7 (Drug conc:100mg/gm)
1 Paclitaxel 6.0 10.0
2 Cholesteryl sulfate 0.400 0.66
3 Caprylic acid 0.500 0.830
4 Polyvinylpyrrolidone (PVP) K-30 5.0 4.16
5 Ethanol 6.0 10.0
6
L __ . ... . PEG-400 Qs to 100.0 Qs to 100.0
Procedure:
• Drug, cholesteryl sulfate, caprylic acid and PVP K-30 were weighed accurately in a glass vessel.
• Contents were dissolved in the required quantity of absolute ethanol and PEG-400 with stirring and by heating at 45°C to obtain a concentrated drug solution.

• The solution was filtered through 0.2u PVDF membrane filter.
• The solution of example-6 was filled in vials (1 gm per vials containing 60 mg drug) and charged for stability.
Stability samples were analyzed in the form of nanodispersion. Dextrose solution (5%w/v) (40 ml) was slowly added to the vial containing the drug concentrate (60 mg drug) with gentle shaking to get a transparent to transluscent nanodispersion of drug having dilution of 1.5 mg/ml. Nanodispersion was analyzed for the following tests: Appearance, Assay of Drug, pH (Mettler Toledo-seven easy, pH Meter) and Particle size (Nano-ZS, Malvern Particle size analyzer), described in table 4 below.
TABLE 4: Stability Data of Example-6

Concentrated drug solution Nanodispersion
Stability condition Appearance Appearance Assay of drug pH Particle size (nm)

Initial After 24h
Initial Clear, colorless, viscous liquid Almost transparent to transluscent nanodispersion 96.59 3.97 152 146
25°C/60% RH
1M -do- -do- 93.55 4.00 133 149
3M -do- -do- 94.07 4.00 165 162
Fridge 2-8°C
1M -do- -do- 94.86 3.96 132 127
3 M -do- -do- 94.47 3.99 159 165
There was no change in assay of paclitaxel over 3 months inferring that the formulation is chemically stable. Also, it can be seen that the compositions of the present invention are physically stable, with no substantial aggregation or change in appearance of die formulation on storage.
EXAMPLE 8
Pharmaceutical compositions of the invention using PVP K-12 are described in Table 5 below. The procedure for the preparation of nanodispersion is same as in example 1-5.
TABLE 5

S.No. Ingredients Quantity (% w/v)

Example 8
1 Paclitaxel 0.15
2 Cholesteryl sulfate 0.01
3 Caprylic acid 0.0125

S.No. Ingredients Quantity (% w/v)

Example 8
4 Polyvinylpyrrolidone (PVP) K-12 0.125
5 Ethanol 0.14825
6 PEG-400 2.0
7 Dextrose (5%) qs. 100.0
The visual appearance, pH and the particle size of the compositions were observed and are summarized in table 6 below.

It can be seen that the compositions of the present invention are physically stable, with no substantial aggregation or change in appearance of the formulation on storage for 24 hours at room temperature.
EXAMPLE 9
The compositions of the present invention as concentrated solution of taxane derivative is described in table 7 below.
TABLE 7

Sr. No. Ingredients Quantity (%w/w) (Drug conc:100mg/gm)
1 Paclitaxel 10.0
2 Cholesteryl sulfate 0.66
3 Caprylic acid 0.83
4 Polyvinylpyrrolidone (PVP) K-12 8.33
5 Ethanol 10.0
6 PEG-400 Qs to 100.0

Stability samples were analyzed as described below and stability data is provided in Table 8. Assay of drug was done in the concentrated drug solution. While for other observations, dextrose solution (5%w/v) (40 ml) was slowly added to the vial containing the drug concentrate (60 mg drug) with gentle shaking to get a transparent to transluscent nanodispersion of drug having dilution of 1.5 mg/ml. The nanodispersion was then analyzed for the following tests: Appearance, pH (Mettler Toledo-seven easy, pH Meter) and Particle size (Nano-ZS, Malvern Particle size analyzer)
TABLE 8: Stability Data of Example 9

Concentrated drug solution Nanodispersion
Stability condition Appearance Assay of drug in concentrated drug solution Appearance PH Particle size (nm)

Initial After 8h After 24h
Initial Clear, colorless, viscous liquid 97.02 Almost
transparent to
transluscent
nanodispersion 3.87 149 156 160
25°C/60% RH

1M -do- 97.81 -do- 3.90 159 225 246
3M -do- 99.08 -do- 3.74 146 153 160
Fridge 2-8°C
1M
1 -do- 98.02 -do- 3.92 140 i 150 150
3 M -do- 98.02 -do- 3.72 97.9 109 111
RH: Relative Humidity.
There was no change in assay of paclitaxel over 3 months inferring that the formulation is chemically stable on storage. Also, it can be seen that the compositions of the present invention are physically stable, with no substantial aggregation or change in appearance of the formulation on storage at various storage conditions.
EXAMPLE 10
A pharmaceutical composition of the present invention containing PEG-3350 is described in Table 9.
TABLE 9
Sr.No. Ingredients Quantity (% w/v)
1 Paclitaxel 0.15
2 Cholesteryl sulfate 0.01
3 Caprylic acid 0.0125
4 5 Polyvinylpyrrolidone (PVP) K-30 0.0625

Ethanol (%v/v) 2.5
6 PEG-3350 0.5
7 Dextrose (5%) Qs 100.0

Preparation:
• Drag, cholesteryl sulfate, caprylic acid, PVP K-30 and PEG 3350 were weighed in a vial.
• The contents of vial were dissolved in required quantity of absolute ethanol by stirring and heating at 45 °C until a clear solution is obtained.
• The above ethanolic solution was added slowly to dextrose solution (5%) with stirring to form a nanodispersion.
• pH of the nanodispersion is checked by using pH Meter (Mettler Toledo-seven easy).
• Particle size of the nanodispersion is checked by Particle size analyzer (Nano-ZS, Malvern Particle Size Analyzer.)
• The nanodispersion is filtered through 0.2u membrane filter.
• 20 ml of the above nanodispersion was filled into vial and lyophilized (Virtis).
The visual appearance and the particle size of the nanodispersion before lyophilization was observed immediately after the nanodispersion was prepared and at 24 and 48 hours after storage at room temperature (RT). These are summarized in Table 10 below:
TABLE 10

Observation Appearance Particle size (nm)
Initial Translucent nanodispersion 128
24 hours at RT 48 hours at RT Translucent nanodispersion Translucent nanodispersion 132 137
RT: room temperature
It can be seen that the composition of die present invention is physically stable with no substantial aggregation or change in appearance of the formulation on storage for 24 to 48 hours at room temperature.
Reconstitution of lyophilized cake: After lyophilization, cake obtained in the vial is dispersed by injecting in water for injection (20 ml) by gende shaking to obtain paclitaxel nanodispersion having concentration of 1.5 mg/ml.
The contents per vial and characteristics of reconstituted nanodispersion are given respectively in Table 11 and 12 below:
TABLE 11

Sr.No. Ingredients Quantity (mg/vial)
1. Paclitaxel 30.0
2. Cholesteryl sulphate 2.0
3. Caprylic acid 2.5
4. Polyvinylpyrrolidone (PVP) K-30 12.5
5. PEG-3350 100.0

Each vial contained 30 mg paclitaxel in the composition. For the human dose of approximately 300 mg of paclitaxel for a 70 kg person, 10 vials of the above composition can be taken and reconstituted in 60 to 600 ml of the diluent such as WFI to obtain 0.5 to 5.0 mg/ml of paclitaxel infusion. This diluted composition if administered to the patient will contain 20 mg of cholesteryl sulphate, 25 mg of caprylic acid and 125 mg of PVP.
TABLE 12

Observation after reconstitution. Appearance Particle size (nm)
Initial Translucent nanodispersion 217
24 hours at RT Translucent nanodispersion 225
It can be seen that the composition of the present invention is physically stable with no substantial aggregation and no change in appearance of the formulation, on storage for 24 hours at room temperature.
EXAMPLE 11
Pharmaceutical compositions of the present invention containing docetaxel are described in Table 13.
TABLE 13

Sr.No. Ingredients Quantity (%w/v)
1 Docetaxel 0.15
2 Cholesteryl sulfate 0.01
3 Caprylic acid 0.0125
4 Polyvinylpyrrolidone (PVP) K-30 0.125
5 Ethanol 0.14825
6 PEG-400 2.0
7 Dextrose (5%) qs. 100.0
The nanodispersion of this example was prepared by the procedure given in examples 1-5. The nanodispersion was white in color with a bluish tinge and had a mean particle size of 172 nm.
The composition contains 150 mg/100 ml of the docetaxel. For the human dose of approximately 180 mg of docetaxel for a 70 kg person, 120 ml of the nanodispersion composition can be used for administration to the patient, so that the composition contained 180 mg of docetaxel. The patient to whom the composition of this example is administered, receives 12 mg of cholesteryl sulfate, 15 mg of caprylic acid, 150 mg of PVP and about 180 mg of ethanol. Thus the composition of the present invention provides nanosized particles with minimum amount of excipients coadministered with the active agent. Ethanol, if any, is in nonaddictive amounts.

EXAMPLE 12
Pharmaceutical compositions of the invention are further described in Table 14 and the observation for various parameters is described in table 15.
TABLE 14

Sr. No. Ingredients EXAMPLES

EXAMPLE 12
Concentrated drug solution EXAMPLE 12a Nanodispersion

Quantity (%w/w)
(Drug concentration
:100mg/gm) Quantity (%w/v)
(Drug concentration
:1.5mg/ml)
1 Paclitaxel 10.0 0.15
2 Cholesteryl sulfate 0.66 0.01
3 Caprylic acid 0.830 0.0125
4 Polyvinylpyrrolidone (PVP) K-30 4.16 0.0625
5 mPEG-Distearoyl phosphatidyl ethanolamine (mPEG-DSPE) 4.16 0.0625
6 Ethanol 10.0 0.14825
7 PEG-400 Qs to 100 2.0
8 Dextrose (5% w/v) - q.s. To 100.0 ml
TABLE 15

Observations Formulations

Example 12 Example 12 a
PH - 4.0
Zeta Potential - -32.4
Appearance
Initial Clear colourless viscous liquid Almost transparent to
transluscent
nanodispersion
24 hours at RT Clear colourless viscous liquid Almost transparent to
transluscent
nanodispersion
Particle Size (nm)
Initial 146
lh 146
3h 146
5h 147
8h 147
24 h 130
EXAMPLE 13-14
Nanodispersion compositions of the present invention prepared by using oleic acid and stearic acid are described in Table 16 below:

TABLE 16

Sr.No Ingredients Quantity (%w/v)

EXAMPLE 13 (Drug cone: 1.5 mg/ml) EXAMPLE 14 (Drug cone: 1.5 mg/ml)
1 Paclitaxel 0.15 0.15
2 Cholesteryl sulfate 0.01 0.01
3 Oleic acid 0.0125 -
4 Stearic acid - 0.0125
5 Polyvinylpyrrolidone (PVP) K-30 0.0625 0.0625
6 Ethanol 0.14825 0.14825
7 PEG-400 2.0 2.0
8 Dextrose (5% w/v) q.s. To 100 ml q.s. To 100.0 ml
The procedure for the preparation of these compositions is same as in example 1-5. The nanodispersions so obtained were almost transparent to translucent and had a mean particle size of 134 nm and 155 nm respectively.
EXAMPLE 15
Pharmaceutical composition of the present invention, prepared by using cholesterol is described in table 17 below.
TABLE 17

Sr.No. Ingredients Quantity (%w/v)
1. Paclitaxel 0.15
2. Cholesterol 0.01
3. Caprylic acid 0.830
4. Polyvinylpyrrolidone (PVP) K-30 0.0625
5. Ethanol 0.14825
6. PEG-400 2.0
7. Dextrose (5% w/v) q.s. To 100.0 ml
Procedure:
• Drug, cholesterol, caprylic acid and PVP K-30 were weighed accurately in a glass vessel.
• Contents were dissolved in the required quantity of absolute ethanol and PEG-400 with stirring and by heating at 45°C to obtain a concentrated solution.
• The concentrated solution was filtered through 0.2u PVDF membrane filter.
• Dextrose solution (5%w/v) was slowly added to the vial containing the concentrated solution (100 mg drug) with gentle shaking to get a transparent to transluscent nanodispersion at the dilution of

1.5mg/ml.
• pH of the nanodispersion is checked by using pH Meter (Mettler Toledo-seven easy).
• Particle size of the nanodispersion is checked by Particle size analyzer (Nano-ZS, Malvern).
The nanodispersion composition of this example was almost transparent to translucent and had a mean particle size of 217 nm.
EXAMPLE 16
Pharmaceutical compositions of the invention prepared by using bile acids/salts (Sodium glycocholate and Ursodeoxycholic acid) is described in table 18 below.
TABLE 18

Sr.No. Ingredients Quantity (%w/v) (Drug concentration :1.5 mg/ml)

EXAMPLE 16 a EXAMPLE 16 b
1 Paclitaxel 0.15 0.15
2 Sodium glycocholate 0.75 -
3 Ursodeoxycholic acid - 0.01
4 Caprylic acid 0.0125 0.0125
5 Polyvinylpyrrolidone (PVP) K-30 0.0625 0.0625
6 Ethanol 0.14825 0.14825
7 PEG-400 2.0 2.0
8 Dextrose (5% w/v) q.s. To 100.0 ml q.s. To 100.0 ml
Procedure:
• Drug, bile acid/salt, caprylic acid, PVP K-30 were weighed accurately in a glass vessel.
• Contents were dissolved in the required quantity of absolute ethanol and PEG-400 with stirring and by heating at 45°C to obtain a concentrated solution.
• The concentrated solution was filtered through 0.2u PVDF membrane filter.
• Dextrose solution (5%w/v) was slowly added to the vial containing the concentrated solution (100 mg drug) with gentle shaking to get a transluscent nanodispersion at the dilution of 1.5mg/ml.
• pH of the nanodispersion is checked by using pH Meter (Mettler Toledo-seven easy).
• Particle size of the nanodispersion is checked by Particle size analyzer (Nano-ZS, Malvern).
The nanodispersion compositions so produced were almost translucent in appearance and had a mean particle size of 197 nm and 180 nm respectively.

EXAMPLE 17
Pharmaceutical compositions of the present invention containing PVP K-90 are described in Table 19.
TABLE 19

Sr.No. Ingredients Quantity (%w/v)
1. Paclitaxel 0.15
2. Cholesteryl sulfate 0.01
3. Caprylic acid 0.0125
4. Polyvinylpyrrolidone (PVP) K-90 0.0625
5. Ethanol 0.14825
6. PEG-400 2.0
7. Dextrose (5% w/v) q.s. To 100.0 ml
The procedure for the preparation is same as in example 1-5. The nanodispersion composition so produced was almost transparent to translucent in appearance and had a mean particle size of 207 nm.
EXAMPLE 18
Pharmaceutical composition of the present invention containing hyaluronic acid salt is described in Table 20.
TABLE 20

Sr.No. Ingredients Quantity (%w/v)
1 Paclitaxel 0.15
2 Cholesteryl sulphate 0.01
3 Caprylic acid 0.0125
4 Sodium hyaluronate 0.025
5 Ethanol 0.148
6 PEG-400 2.0
7 Dextrose (5% w/v) q.s. To 100.0 ml
Procedure:
• Drug, cholesteryl sulphate and caprylic acid were weighed accurately in a glass vessel.
• Contents were dissolved in the required quantity of absolute ethanol and PEG-400 with stirring and by heating at 45°C to obtain a concentrated drug solution.
• The solution was filtered through 0.2^ PVDF membrane filter.
• Sodium hyaluronate was dissolved in Dextrose solution (5%w/v) and was slowly added to the vial containing the concentrated drug solution (30mg), followed by the addition of remaining 5% w/v dextrose solution with gentle shaking to get a transluscent nanodispersion at the dilution of 1.5mg/ml.
• pH of the nanodispersion was checked by using pH Meter (Mettler Toledo-seven easy).

• Particle size of the nanodispersion was checked by Particle size analyzer (Nano-ZS, Malvern.
The nanodispersion composition so produced was almost translucent in appearance and had a mean particle size of 263 nm.
EXAMPLE 19
Pharmaceutical composition of the present invention containing polyglutamic acid salt is described in Table 21.
TABLE 21

Sr.No. Ingredients Quantity (%w/v)
1 Paclitaxel 0.15
2 Cholesteryl sulphate 0.01
3 Caprylic acid 0.0125
4 Polyglutamic acid, sodium salt 0.0625
5 Ethanol 0.148
6 PEG-400 2.0
7 Dextrose (5% w/v) q.s. To 100.0 ml
The procedure for the preparation of nanodispersion is same as in example 18. The nanodispersion composition so produced was almost translucent in appearance and had a mean particle size of 295 nm.
EXAMPLE 20
Pharmaceutical composition of the present invention containing an additional therapeutic agent Vitamin D is described in Table 22 below.
TABLE 22

Sr.No. Ingredients Quantity (%w/v)
1 Paclitaxel 0.15
2 Vitamin D 0.01
3 Caprylic acid 0.0125
4 Polyvinylpyrrolidone (PVP) K-30 0.0625
5 Ethanol 0.148
6 PEG-400 2
7 Dextrose (5% w/v) q.s. To 100 ml
Procedure:
• Paclitaxel, Vitamin D, Caprylic acid, PVP K-30 were weighed accurately in a glass vessel.
• Contents were dissolved in the required quantity of absolute ethanol and PEG-400 with stirring and by heating at 45°C to obtain the concentrated drug solution.
• The concentrated drug solution was filtered through 0.2u PVDF membrane filter.
• Dextrose solution (5%w/v) was slowly added to the vial containing the concentrated drug solution

(30 mg drag) with gentle shaking to get transluscent nanodispersion at the dilution of 1.5 mg/ml.
• pH of the nanodispersion is checked by using pH Meter (Mettler Toledo-seven easy).
• Particle size of the nanodispersion is checked by Particle size analyzer (Nano-ZS, Malvern).
The nanodispersion composition so produced was almost transparent to translucent in appearance and had a mean particle size of 158 nm.
EXAMPLE 21
Pharmaceutical composition of the present invention containing an additional therapeutic agent dexamethasone is described in Table 23 below. The procedure for the preparation of nanodispersion is same as in example 20.
TABLE 23

Sr.No. Ingredients Quantity (%w/v)
1 Paclitaxel 0.15
2 Dexamethasone 0.01
3 Caprylic acid 0.0125
4 Polyvinylpyrrolidone (PVP) K-30 0.0625
5 Ethanol 0.148
6 PEG-400 2.0
7 Dextrose (5% w/v) q.s. To 100 ml
The nanodispersion composition so produced was almost translucent in appearance and had a mean particle size of 185 nm.
EXAMPLE 22
Acute toxicity of Paclitaxel nanodispersion of the present invention in CD-I mice
Test Items:
1. Compositions of example 12 were used upon dilution with dextrose 5% w/v to l0mg/ml along with placebo
2. Compositions of example 9 were used upon dilution with dextrose 5% w/v to 8 mg/ml along with placebo and
3. ABRAXANE diluted with 0.9% sodium chloride to l0mg/ml.
CD-I mice were acclimatized to the conditions of individually ventilated cage system (IVC) in animal quarter number 2, for 5 days. After veterinary health check, 5 male and 5 female mice were allocated to each dose group. Mice had free access to water and feed throughout the experimental period. Test items and placebos of the below doses were administered intravenously, as such without any dilution with any vehicle, through caudal tail vein of mice using 26 gauge needle attached to a graduated syringe. Before injection, tail was swabbed with warm water to dilate the blood vessels. A total dose of 150, 200, 250, 300,

350 and 400mg/kg were tested for Paclitaxel nanodispersion (Example 12), doses of 250, 300 and 400mg/kg were tested for placebo (Placebo of example 12), doses of 200 and 250mg/kg were tested for Paclitaxel nanodispersion (Example 9), dose of 250mg/kg was tested for placebo (Placebo of example 9), and dose of 300mg/kg was tested for ABRAXANE. All these formulations were administered intravenously to CD-I mice via. 3 divided doses with a gap of one hour between two doses/injections. After last injection animals were observed twice daily for 1hour and between 4-6 hours post dosing. Thereafter, mice were observed twice daily to record toxic symptoms and mortality, if any, upto day 14.
TABLE 24

Test item Dose of Paclitaxel i.v. (mg/kg) % Mortality LD50
Paclitaxel Nanodispersion
(of Example 12) 150 0 ~342.5 mg/kg

200 0

250 0

300 0

350 60

400 90
Placebo of Example 12 250 0

300 0

400 0
Paclitaxel Nanodispersion
(of Example 9) 200 20 > 250mg/kg

250 20
Placebo of Example 9 250 0
ABRAXANE 300 90
The results indicated that Paclitaxel nanodispersion of example 12 showed 90% mortality at 400mg/kg and zero percent mortality at dose of 300mg/kg. No mortality observed with the placebo of example 12 at the highest dose tested (400mg/kg). On linear extrapolation of Paclitaxel nanodispersion, the LD50 and LD]0 values obtained were 342.5mg/kg and 310mg/kg respectively. Similarly, Paclitaxel nanodispersion of example 9 showed 20% mortality at 250mg/kg and LD50 for paclitaxel nanodispersion was >250mg/kg. No mortality observed with the placebo of example 9 at the highest dose tested (250mg/kg). The marketed nanoparticle formulation, ABRAXANE showed toxicity of 90% at 300mg/kg.
These data clearly shows that nanodispersion composition of the present invention is less toxic as compared to the marketed ABRAXANE composition.
Also, on comparison of LD50 value of nanodispersion composition of the present invention (342.5 mg/kg) with the LD50 value of marketed TAXOL formulation (7.5-12.0 mg/Kg; United States Patent No.-6753006), it is evident that the LD50 value observed for Paclitaxel nanodispersion of the present invention is much greater than the LD50 value of marketed TAXOL solution.

EXAMPLE 23
Acute toxicity of Paclitaxel nanodispersion of the present invention in SD rats. Test Items:
1. Composition of example 9 were used upon dilution with dextrose 5% w/v to 10 mg/ml along with
placebo, and
2. ABRAXANE diluted with 0.9% sodium chloride to 5mg/ml.
Rats were acclimatized to the conditions of individually ventilated cage system (IVC) in animal quarter number 3 for 5 days. After veterinary health check, 5 male and 5 female SD rats were allocated to each dose group. Rats had free access to water and feed throughout the experimental period. Test items and placebos of the below doses were administered intravenously, as such without any dilution with any vehicle, through caudal tail vein of rat using 26 gauge needle attached to a graduated syringe. Before injection, tail was swabbed with warm water to dilate the blood vessels. After injection animals were observed twice daily for 1 hour and between 4-6 hours post dosing. Thereafter, rats were observed twice daily to record toxic symptoms and mortality, if any, upto day 14.
TABLE 25

Acute Toxicity Studies in SD rats
Test Item Dose of Paclitaxel i.v. (mg/kg) % Mortality
Paclitaxel nanodispersion
(Example 9) 60 30

90 40
Placebo of example 9 90 0
LD50 in SD rats: > 90/mg/kg
ABRAXANE 70 100
The results indicate that Paclitaxel nanodispersion of the present invention of example 9 showed 40% mortality at 90mg/kg. No mortality observed with the placebo of example 9 at the highest dose tested (90mg/kg). The LD50 for paclitaxel nanodispersion of the present invention was >90mg/kg. The marketed nanoparticle formulation, ABRAXANE showed toxicity of 100% at 70mg/kg.
The observations and results of Examples 22 and 23 clearly indicate that nanodispersion composition of the present invention minimizes the toxicity associated with the drug and broadens the effective administrable therapeutic range of the drug and are less toxic than the existing marketed formulations such as TAXOL and ABRAXANE.
EXAMPLE 24
Antitumor efficacy (tumor regression) of paclitaxel nanodispersion (of composition of Example 12) in
nude mice implanted with MX-1 tumor xenografts.
Animals: Species: Mice, Strain: Balb/c nude, Sex: Female, Age: 6-8 weeks (21-25g)
Human Tumor Xenografts: MX-1 (breast)
Test sample: Composition of Example 12, diluted with dextrose 5% to 2mg/ml.

Reference: Marketed formulation, ABRAXANE, diluted to 2mg/ml. Dose: 20 mg/kg, once daily for 5 consecutive days, i.v., 10 ml/kg body wt.
Study Design:
1. Tumor was implanted by subcutaneous route on the right flank of the animal as 30 to 40mg fragments.
2. The tumor was allowed to increase to a median size of ~160 mg before initiation of treatment.
3. The tumor bearing animals were divided in groups consisting often animals.
4. The animals were administered doses as described above and tumor was evaluated as below.
Tumor Evaluation: Tumors are evaluated for Relative Tumor Volume (RTV) with respect to time in
days. The data for 18 days is given in Table 26 and represented graphically in Fig 1.
TABLE 26

Relative Tumor Volume (RTV cm3) Data
Days Control Reference Test
1 1 1 1
3 1.83 1.04 1.16
5 2.97 0.64 0.76
7 4.38 0.46 0.46
9 5.82 0.52
11 7.38 0.37
14 9.38 0.28
16 13.12 0.23
18 14.79 0.14
The above data, shows that when test composition i.e. the Paclitaxel nanodispersion of die present invention is administered to the tumor bearing experimental mice, a linear regression in tumor volume is observed with time, thus proving the efficacy of the nanodispersion composition of the present invention in treating cancerous tumors.
EXAMPLE 25
Antitumor efficacy (tumor regression) of paclitaxel nanodispersion (of composition of Example 9) in nude mice implanted with MX-1 tumor xenografts.
Animals: Species: Mice, Strain: Athymic nude, Sex: Female, Age: 6-8 weeks (21-25g) Human Tumor Xenografts: MX-1 (breast)
Test sample: Composition of Example 9, diluted with dextrose 5% to 2mg/ml. Reference: Marketed formulation, ABRAXANE diluted to 2mg/ml. Dose: 20 mg/kg, once daily for 5 consecutive days, i.v., 10 ml/kg body wt.
Study Design:
1. Tumor was implanted by subcutaneous route on the right flank of the animal as 2 x 2 x 2 mm fragments.
2. The tumor was allowed to increase to a size of 5 x5 x 5mm before initiation of treatment.

3. The tumor bearing animals were divided in groups consisting often animals.
4. The animals were administered doses as described above and tumor was evaluated as below.
Tumor Evaluation: Tumors are evaluated for Relative Tumor Volume (RTV) with respect to time (in days). The data for 15 days is given in Table 27 and represented graphically in Fig 2.
TABLE 27

Relative Tumor Volume (RTV cm3) Data
Days Control Reference Test
0 1.0 1.0 1.0
2 1.06 0.91 0.63
4 1.31 0.48 0.47
7 2.07 0.18 0.17
9 2.09 0.13 0.15
12 2.21 0.06 0.08
15 3.08 0.02 0.07
The above data, shows that when test composition i.e. the Paclitaxel nanodispersion of the present invention is administered to the tumor bearing experimental mice, a linear regression in tumor volume is observed with time, thus proving the efficacy of the nanodispersion composition of the present invention in treating cancerous tumors.
EXAMPLE 26
Antitumor Efficacy (tumor regression) of Paclitaxel nanodispersion (of composition of Example 9) in Nude Mice implanted with HT-29 Human Colon Tumor Xenografts.
Animals: Species: Mice, Strain: Athymic nude, Sex: male, Age: 6-8 weeks (21-25g)
Human Tumor Xenografts: HT-29 Human Colon.
Test sample: Composition of Example 9, diluted with dextrose 5% to 2mg/ml.
Dose: 20 mg/kg, once daily for 5 consecutive days, i.v., 10 ml/kg body wt.
Reference:
(a) Marketed formulation, ABRAXANE diluted to 2mg/ml.
Dose: 20 mg/kg, once daily for 5 consecutive days, i.v., 10 ml/kg body wt.
(b) Marketed formulation, ONCOTAXEL.
Dose: 13.4 mg/kg once daily for 5 consecutive days, i.v. Study Design:
1. Tumor was implanted by subcutaneous route on the right flank of the animal as 2 x 2 x 2 mm fragments.
2. The tumor was allowed to increase to a size of 5 x5 x 5mm before initiation of treatment.
3. The tumor bearing animals were divided in groups consisting often animals.

4. The animals were administered doses as described above and tumor was evaluated as below.
Tumor Evaluation: Tumors are evaluated for Relative Tumor Volume (RTV) with respect to time in days. The data for 12 days is given in Table 28 and represented graphically in Fig 3.
TABLE 28 Relative Tumor Volume (RTV cm3) Data
Days Control Test Reference

Abraxane Oncotaxel
0 1 1 1 1
2 1.17 0.74 0.79 0.68
4 1.17 0.51 0.64 0.46
6 1.43 0.40 0.43 0.50
9 1.55 0.34 0.31 0.32
12 1.80 0.26 0.27 0.28
The above data shows that when test composition i.e. the Paclitaxel nanodispersion of the present invention is administered to the tumor bearing experimental mice, a linear regression in tumor volume is observed with time, thus proving the efficacy of the nanodispersion composition of the present invention in treating cancerous tumors.
In all, it can be concluded that nanodispersion compositions of me present invention is on one hand, efficacious in treating cancerous tumors and on other hand is less toxic than the existing marketed formulations such as TAXOL and ABRAXANE.
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of me invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

We claim:
1) A nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle
comprising a non-aqueous solvent and water, said nanoparticles comprising one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof.
2) A nanodispersion as claimed in claim 1, wherein the mean size of the nanoparticles is in the range of
about 10 nm to about 200 nm.
3) A nanodispersion as claimed in claim 1, wherein the non-aqueous solvent is selected from alcohols,
glycols and its derivatives, polyalkylene glycols and its derivatives, glycerol, glycofurol, dimethylsulfoxide (DMSO), dimethylacetamide, dimethylformamide, 1,4-dioxane and combinations thereof.
4) A nanodispersion as claimed in claim 3, wherein the non-aqueous solvent is alcohol and polyethylene
glycol (PEG).
5) A nanodispersion as claimed in claim 4, wherein the non-aqueous solvent is ethanol and PEG-400 or
PEG-3350.
6) A nanodispersion as claimed in claim 1, wherein the taxane derivative is selected from paclitaxel,
docetaxel and their pharmaceutically acceptable salts, derivatives, analogs and isomers.
7) A nanodispersion as claimed in claim 6, wherein paclitaxel is used in an amount ranging from about
0.001 mg/ml to about 15.0 mg/ml and docetaxel is used in an amount ranging from about 0.001 mg/ml to about 10.0 mg/ml.
8) A nanodispersion as claimed in claim 1, wherein the polymer is selected from the group comprising
tertiary amide polymers, polyamino acids, polysaccharide containing glycosaminoglycans, natural polymers, polyanhydrides, polyamides, polyesters and mixtures thereof.
9) A nanodispersion as claimed in claim 8, wherein the tertiary amide polymer is polyvinylpyrrolidone.
10) A nanodispersion as claimed in claim 9, wherein polyvinylpyrrolidone is used in an amount ranging from about 0.001% w/v to about 20% w/v.

11) A nanodispersion as claimed in claim 1, wherein the fatty acid or its salt may be selected from caprylic acid, stearic acid, oleic acid and mixture thereof.
12) A nanodispersion as claimed in claim 1, wherein the sterol or its derivatives including salts may be selected from cholesterol, cholesteryl sulfate, phytosterols, bile acids, their derivative, salts and mixtures thereof.
13) A nanodispersion as claimed in claim 1, wherein the surfactant comprises a mixture of fatty acid or its salts and sterol or its derivatives including salts.
14) A nanodispersion as claimed in claim 13, wherein the surfactant is a mixture of caprylic acid and cholesteryl sulphate.
15) A nanodispersion as claimed in claim 14, wherein the surfactant is used in an amount ranging from about 0.001% w/v to about 5.0 % w/v.
16) A nanodispersion as claimed in claim 1, wherein the therapeutically active ingredient comprises a mixture of a taxane derivative and a second therapeutically active ingredient selected from the group consisting of an anti-inflammatory agent, an anti-histaminic agent, a 5-HT3 antagonist, a H2-receptor antagonist, and a vitamin.
17) A solution comprising one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof in a non-aqueous solvent, which on dilution with an aqueous liquid vehicle gives a nanodispersion as claimed in claim 1.
18) A process for preparing nanodispersion, comprising dissolving one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof in a non-aqueous solvent and adding an aqueous liquid vehicle to the above solution.
19) A process for preparing nanodispersion, comprising dissolving one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof in a non-aqueous solvent and adding this solution to an aqueous liquid vehicle.

20) A process for preparing nanodispersion as claimed in claim 18-19, wherein the composition further is optionally homogenized, sonicated, filtered and lyophilized.

ABSTRACT
The present invention provides a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a non-aqueous solvent and water, said nanoparticles comprising one or more therapeutically active ingredient wherein at least one therapeutically active ingredient is a taxane derivative, a polymer and a surfactant selected from fatty acids or its salts, sterol or its derivatives including salts and mixtures thereof.
To
The Controller of Patents, The Patent Office, Mumbai - 400 037