WO2012156999A1

WO2012156999A1 - Ready to use docetaxel formulation

Info

Publication number: WO2012156999A1
Application number: PCT/IN2012/000358
Authority: WO
Inventors: Manu Chaudhary
Original assignee: Manu Chaudhary
Priority date: 2011-05-19
Filing date: 2012-05-21
Publication date: 2012-11-22
Also published as: WO2012156999A4

Abstract

A single vial stabilized liquid formulation of taxane derivative, adapted to be used directly to a perfusion/infusion solution for administration into a subject in need is provided. The formulation includes an effective amount of : docetaxel or a pharmaceutically acceptable salt thereof; one ore more surfactant; one or more co-surfactant; water for injection; and one or more organic acid. The particle size of the formulation is in a range of 20 nm to 100nm and the pH of the formulation is in a range of about 3.5 to 4.

Description

READY TO USE DOCETAXEL FORMULATION

FIELD OF THE INVENTION

[001] The embodiments herein generally relates to a stabilized formulation of taxen derivative such as docetaxel, in a single vial injectable pharmaceutical form . The formulation further comprises one or more aqueous solvents so as to result in a nano sized drug i.e docetaxel along with a pharmaceutically acceptable acid- (Stabilizer) to adjust the pH of the formulation. The present invention also relates to pharmaceutical formulations comprising docetaxel, a solubilizer, an organic acid, and a surfactant and co-surfactant. Furthermore, the present invention relates to methods for administering docetaxel to patients in need thereof. The present invention also provided a method of preparation of this formulation.

BACKGROUND OF THE INVENTION

[002] Docetaxel is an antineoplastic agent belonging to the taxoid family. It is a highly lipophilic semisynthetic taxoid and almost insoluble in water. It is prepared by semi-synthesis process, beginning with a precursor extracted from the renewable needle biomass of yew plants. Taxotere®(Sanofi-Aventis.) is sterile docetaxel injection concentrate, available in vials containing docetaxel and polysorbate 80, to be administered intravenously after diluting with a diluent like ethanol in water for injection and is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.

[003] Taxotere® has problems in that the drug administration is very complicated. TAXO- 40 TERE® is available as an injection concentrate in single-dose vials containing 40 mg/mL docetaxel (on an anhydrous basis) and polysorbate 80 (also known as TWEEN 80®). TAXOTERE® is provided as an injection concentrate and requires dilution to 10 mg/mL prior to use. Hence, a sterile, non-pyrogenic, single-dose diluent containing 13% ethanol in water for injection is supplied in a separate vial. After dilution, the required amount of docetaxel is then transferred from the 10 mg/mL initial diluted solution to an infusion bag or bottle of either 0.9% sodium chloride solution or 5% dextrose solution to produce a final dilution for infusion having a concentration of 0.3 to 0.74 mg/mL. The recommended therapy is six cycles of docetaxel given once every three weeks.

[004] Therefore, administration of Taxotere involves a multi step procedure which required skilled hands for administration.

[005] Furthermore, Taxotere® infusion solution, if stored between 2 and 25° C. (36 and 77° F.) is stable for 4 hours. Fully prepared Taxotere® infusion solution (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).

[006] TAXOTERE®, however, most often results in serious side effects. Such reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients. Hypersensitivity reactions require immediate discontinuation of the TAXOTERE® infusion and administration of appropriate therapy due to degradation of Taxotere in toxic compounds.

[007] In order to reduce the side effects induced by Taxotere for having high concentration of Polysorbate 80 and ethanol which lead to degradation of docetaxel , during administration, patients are treated with dexamethasone for three days prior to therapy. Dexamethasone is a steroid that suppresses the immune response in patients, which can be especially detrimental in cancer patients under chemotherapy, whose immunity may already be compromised due to the destruction of healthy cells by the chemotherapeutic treatment.

[008] Furthermore, due to the fact that docetaxel is practically insoluble in water, there have been a number of other attempts to develop appropriate injectable formulations. For example, docetaxel is known to be soluble- in ethanol and one of the first such other formulations was 50% ethanol and 50% Emulphor EL® (a non-ionic solubilizer and emulsifier manufactured by reacting castor oil with ethylene oxide).

[009] U.S. Pat. No. 5,403,858 (AU 666,859; EP593 601; EP522 937) discloses a formulation for docetaxel which reduces the ethanol concentration, or eliminates the ethanol from the solution completely. The formulations comprise a surfactant, such as a polysorbate (eg Tween®), a polyoxyethylene glycol ester (eg. Emulphor®) or an ester of polyethylene glycol and castor oil (eg Cremophor EL®); and are virtually free from ethanol.

[0010] U.S. Pat. No. 5,714,512 is also part ofthis patent family and relates to formulations consisting essentially of docetaxel dissolved in a surfactant selected from polysorbate, polyoxyethylated vegetable oil and polyethoxylated castor oil which are essentially free of ethanol. U.S. Pat. No. 5,698,582 is also part of this patent family and relates to formulations comprising docetaxel dissolved in a surfactant selected from polysorbate or polyethoxylated castor oil which is essentially free of ethanol.

[0011] AU691476 (EP 0 671 912) discloses a two part injectable composition. This two part composition involves preparing an intermediate solution using the stock solution, prior to the addition of this intermediate solution to infusion bag. The intermediate solution contains an additive which promotes the dissolution of the stock solution in the aqueous infusion solution by breaking or avoiding the formation of a gelled phase between the surfactant in the stock solution and the water of the infusion solution. The additives have a molecular weight equal to or less than 200 and have at least one hydroxyl functional group or one amine functional group, for example, ethanol, glucose, glycerol, propylene glycol, glycine, sorbitol, mannitol, benzyl alcohol and polyethylene glycols. The additives may also be inorganic salts such as sodium chloride.

[0012] There are a number of other patent applications which have been made for formulations of docetaxel. However, none of these attempted formulations has resulted in a successful commercial product to compete with Taxotere® to date. There is thus still a need for alternative docetaxel formulations which have the necessary physicochemical properties, bioavailability and shelf life.

[0013] Accordingly, there is still a need for the development of a new pharmaceutical preparation that can offer improved storage stability with lesser degradation components and less toxicity. A stabilization strategy is needed to prevent the degradation of docetaxel in injectable pharmaceutical compositions.

OBJECT OF THE INVENTION

[0014] It is an objective of the present invention to provide a novel single vial ready to use stable injectable docetaxel formulation for the treatment of cancer including but not limited to non-small cell lung, breast, ovarian, head and cervical cancer.

[0015] Another object of the present invention is to formulate a (NDDS) based formulation where the active ingredient is in particle size range of20-100 nanometer.

[0016] Still another object of the present invention is to improve the drug penetration inside the cancerous cell.

[0017] Another object of the present invention is to provide an improved release profile of docetaxel.

[0018] Another object of the present invention is to improve storage stability of docetaxel which generates lesser degradation products as compared to those of conventional formulations.

[0019] Another objective of the present invention is to provide enhanced safety of the product by reduction in impurities of the docetaxel.

[0020] Another objective of the invention is reduction in constituent having adverse therapeutic effects.

[0021] Another object is to disclose compositions and method of manufacture of the said formulation.

[0022] Another object of the invention is to provide a single vial ready to use docetaxel formulation with higher efficacy, improved safety and lesser side effects.

[0023] Yet another object of the invention is to reduce the step of premixing the drug and the solvent before diluting with infusion solution.

SUMMARY OF THE INVENTION

[0024] In view of the foregoing, a single vial stabilized liquid formulation of taxane derivative, adapted to be used directly to a perfusion/infusion solution for administration into a subject in need is provided. The formulation includes an effective amount of : docetaxel or a pharmaceutically acceptable salt thereof; one or more surfactant; one or more co-surfactant; water for injection; and one or more organic acid. The particle size of docetaxel in the formulation is in a range of 20 nm to lOOnm and the pH of the formulation is in a range of about 3.5 to 4.

[0025] The formulation may be stable for a period of minimum 6 months to 24 months at a temperature of about 20±5°C .

[0026] The formulation may be stable for a period of more than 2 years at a temperature range of 2° C to 8° C.

[0027] Docetaxel may be present in a range of 20 mg/ml to 120mg/ml.

[0028] The amount of docetaxel may be 40mg/ml.

[0029] he surfactant may be polysorbate 80 and the surfactant may be present in an amount of 50% ± 5%, preferably 52.46% v/v.

[0030] The co-surfactant may be ethanol and the co-surfactant may be present in an amount of 40%± 5%, preferably 40.9% v/v.

[0031] The organic acid may be selected from the group consisting of citric acid, tartaric acid, acetic acid or a combination thereof and the organic acid may be present in an amount about 9.5mM to adjust pH between 3.5 to 4.

[0032] The water for injection may be present in an amount preferably 5± 2% of the stabilized liquid formulation .

[0033] In another aspect a process of preparation of the single vial stabilized liquid formulation is provided. The process includes the step of : constant stirring of 50 ± 5% v/v of surfactant and 9.5mM citric acid solution at < 500 rpm for 20-30 minutes under inert gas atmosphere to obtain an initial solution. The temperature is maintained at 20±5° C . The citric acid solution is added to adjust the pH to about 3.5 to 4 ;addition of 40±5% v/v of co-surfactant with lowering of temperature to 2-8° C at < 500 rpm for 20-30 minutes under inert gas to obtain an intermediate solution; and addition of 20mg to 120 mg docetaxel into the intermediate solution under constant stirring until complete dissolution of docetaxel to obtain a clear solution of the single vial stabilized formulation.

[0034] The surfactant may be polysorbate 80;

[0035] The co-surfactant may be ethyl alcohol.

[0036] In one aspect, use of single vial stabilized formulation is provided for preparation of a medicament for treatment of disease condition selected from the group consisting of non-small cell lung, breast, ovarian, head cancer, cervical cancer and brain cancer.

[0037] The single vial stabilized formulation may used for preparation of a medicament for treatment of brain cancer, wherein said formulation is dragged into brain through traversing blood brain barrier.

[0038] In another aspect a method of treating disease condition selected from the group consisting of non-small cell lung, breast, ovarian, head cancer, cervical cancer and brain cancer comprising administering to a patient in need of such treatment is provided wherein an effective amount of single vial stabilized formulation is administered directly to an infusion/perfusion solution.

BREIF DESCRIPTION

[0039] FIG.l through FIG. 2 illustrate TEM (transmission electron microscope) studies to represent particle size of a stabilized liquid formulation of taxane derivative i.e. docetaxel.

[0040] FIG. 3 .Table 1 illustrates comparative impurity profile of the a stabilized liquid formulation to that of one marketed drug.

[0041] FIG. 4 , Table 2 illustrates various trial formulation of the stabilized liquid formulation and their relative stability.

[0042] FIG. 5, table 3 illustrates stability study of a formulation 3.

[0043] FIG. 6, table 4 illustrates a final dilution stability

[0044] FIG 7, table 5 illustrate a comparative percentage viability study report on a trial formulation 3 to that of a marketed formulation.

DETAILED DESCRIPTION OF THE INVENTION

[0045] The embodiments herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments that are illustrated in the accompanying figures & tables and detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein. [0046] According to one embodiment, the present invention provides a single vial stabilized liquid formulation of docetaxel injection that simplifies the preparation of the infusion solution by eliminating the first dilution step and hence offers ready to use solution.

[0047] In a preferred embodiment of the invention, the single vial the stabilized liquid formulation of docetaxel is a ready to use formulation and is directly diluted with suitable infusion solution such as 0.9% sodium chloride solution or 5% glucose solution and the like to prepare the solution for infusion.

[0048] In an embodiment of the invention, the single vial stabilized liquid formulation formulation of docetaxel comprises docetaxel or a pharmaceutically acceptable salt thereof. The docetaxel used to make the formulation of the invention may be in any form known to those skilled in the art including anhydrous forms, hydrated forms, polymorphs, derivatives and pro- drugswhich is preferably anhydrous docetaxel.

[0049] In another embodiment of the invention, the single vial stabilized liquid formulation of docetaxelis presented as a Docetaxel solution for infusion 20mg/0.5mL, 80mg/2.0mL and 120mg/3ml (corresponding to 40mg/ml base concentration) with the advantage of requiring a single dilution step in suitable infusion solutions prior to administration i. e. eliminating the first dilution step (the preparation of premix solution).

[0050] According to one embodiment, single vial stabilized formulation of docetaxel formulation for injection comprises docetaxel which is dissolved in a suitable hydrophobic solubilizer and is then stabilized using surfactant and co- surfactant and does not require an additional solvent preparation and it is meant for direct infusion in suitable infusion medium which give the same the final infusion solution concentration to that of docetaxel requiring intermediate dilution step.

[0051] According to an preferred embodiment, the present invention discloses single vial docetaxel formulation containing anhydrous docetaxel. The anhydrous docetaxel is formulated as a liquid aqueous solution for infusion requiring a single dilution step direct in suitable infusion solutions prior to administration. Since taxanes are cytotoxic, these compounds must be diluted before administrating to patients. Thus, a formulator's challenge not only encompasses solubilizing the taxane, but also includes preventing the taxane from precipitating after it is diluted for intravenous ("IV") infusion and during administration into the patient's bloodstream. Due to such challenges, formulator has selected NDDS which is self nanoemulsifying drug delivery system that solubilizes the taxane and prevent it from precipitating even with the addition of water in the formulation and upon subsequent dilution thereof. Furthermore, the selected concentration of excipients allow the taxane an improved stability and lesser degradation at the time of administration by the IV route to a patient safely and effectively, with minimal side effects and maximizing efficacy.

[0052] For the purpose of different embodiments of the present invention, a self nanoemulsifying drug delivery system/formulation refers a drug delivery system/formulation that uses a collide/nanoemulsion achieved by chemical rather than mechanical means. That is, by an intrinsic property of the drug and excepients used during the formulation, rather than by special mixing and handling.

[0053] To this end, applicant sought to develop a formulation that is self nano emulsifying, stablized and delivers docetaxel in nanoparticle form in first step and making the formulation easy to withdraw and ready for use. Additionally formulation prevented its precipitation upon dilution, has lesser impurity generation on storage and further dilution in infusion solution. Further, it incorporates at least 40 % lesser amount of solubilizers used in taxotere formulation there by reducing the adverse drug reaction drastically. Additionally the formulation is pH sensitive and is stable at a pH of 3.5 to 4.0 achieved by adding suitable organic acid as pH modifying component, which additionally acts as chelator to remove toxic chemicals from the formulation which are generated over a period of time. The organic acid also demonstrate antioxidant properties and is preferably citric acid or a pharmaceutically acceptable salt thereof according to an embodiment herein.

[0054] In one embodiment, the minimum single dose of the formulation is 20mg/0.5ml.

[0055] In one aspect of the invention, it has surprisingly been found that the stabilized docetaxel which is ready to use formulation has the following advantages:

a) comparatively improved/ enhanced stability of the formulation at room temperature when compared to the Taxotere® concentrate (ie pre-dilution) which is stable only at refrigerated conditions of 2-8 degree Celsius temperature;

b) suitable for use as a multi-dose product due to ease of withdrawal in syringe of formulation content;

c) it is a single vial product ready for introduction directly into the infusion bag without the need for any intermediate solution, therefore requiring less handling by the medical practitioner prior to administration to a patient; d) more accurate dosage of the drug as a consequence of the reduced foaming when preparing the product minimizing the risk of potency loss; e) comparatively enhanced stability once the formulation is introduced to the infusion solution because lesser impurities are generated; particle size in nano meters which enables quick on set of action solubilized drug in nanometric scale enables quick onset of action further decreasing the Reticuloendothelial uptake of the drug there by enhancing the amount of free drug present for therapeutic action. f) lmproved safety because the toxic effect due to higher solvent concentration are reduced up to > 40 % in comparison to TAXOTERE g) Ease of formulation as lesser time and energy is required

[0056] In a preferred embodiment, a single vial stabilized liquid formulation of taxane derivative such as decetaxel, adapted to be used directly to a perfusion/infusion solution for administration into a subject in need is provided in a nano scale. The single vial stabilized liquid formulation includes an effective amount of: docetaxel or a pharmaceutically acceptable salt thereof; one or more surfactant; one or more co-surfactant; water for injection and one or more organic acid, wherein particle size of docetaxel stabilized formulation is in a range of 20 nm to lOOnm; and pH of the stabilized liquid formulation is in a range of about 3.5 to 4.

[0057] In one embodiment, the stabilized liquid formulation is stable for a period of minimum 6 months to 24 months at a temperature of about 20°C 5°C. However, the stabilized liquid formulation remain stable for a period of more than 2 years when the temperature is kept at a range of 2° C to 8° C.

[0058] In another embodiment, in the single vial stabilized liquid formulation, Docetaxel is present in a range of 20 mg/ml to 120mg/ml, preferably 40 mg/ml

[0059] The surfactants include: Gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, microcrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidene (PVP). [0060] In a preferred embodiment, the surfactant is polysorbate 80 and is present in a range of 50±5% according to an embodiment herein. The amount of polysorbate used 80 is thus reduced to more than 45% in comparison to concentration present in Taxotere formulation in 2 vial.

[0061] In another embodiment, the co-surfactant is ethanoi and is present in a range of 40±5%. The amount of co-surfactant used is thus reduced to more than 80% in comparison to concentration present in Taxotere formulation in 2 vial.

[0062] The amount of surfactant is higher than co surfactant and the ratio of surfactant : co-surfactant is in range of 1.28:1 according to an embodiment herein.

[0063]The ratio of the surfactant: co-surfactant and amount of surfactant is atleast 25 to 30% higher than co-surfactant according to an embodiment herein.

[0064] The organic acid is selected from the group consisting of citric acid, tartaric acid, acetic acid or a combination thereof. The organic acid is present 9.5 mM to adjust pH of the stabilized formulation between 3.5 to 4. The organic acid is preferably citric acid which has antioxidant effect and chelation properties to make the single vial stabilized formulation of docetaxel more safe and stable according to an embodiment herein.

[0065] In another embodiment, the water for injection is present in an amount 5±2% which constitutes the aqueous phase of the formulation.

[0066] The single vial stabilized liquid formulation of taxane derivative in a nano sized form is established based on a peculiar concentration of the surfactant and the co-surfactants used therein. In self nanoemulsifying system in presence of 5±2% water. Herein the water insoluble drug i.e Docetaxel is solubilized in presence of water using self nanoemulsifying drug delivery system ethanoi and polysorbate 80 to yield a clear, transparent and a stable system according to an embodiment herein.

[0067] In one embodiment, the single vial stabilized formulation of doceatxel is present in the form that includes micronized nanao particles, self- nanoemuslsifying formulation, miceller nano particle.

[0068] In preferred embodiment, Polysorbate 80 is used in a concentration range of 50±5% while ethanol being the co-surfactant is incorporated in the stabilized liquid formulation in a range of 40±5%. Ethanol is chosen as the co- surfactant because of its excellent dilution ability on usage. Polysorbate 80 also called polyoxyethylene sorbitan monooleate is used both as solublizer and as the surfactant because it well stabilizes and forms clear dispersed system.

[0069] In another embodiment, a process of preparation of the stabilized liquid formulation is provided. The process includes the step of : constant stirring of 50 ± 5% v/v of surfactant and 9.5mM citric acid solution at 500 rpm for 20-30 minutes under inert gas atmosphere to obtain an initial solution. The temperature for the entire process is maintained at 20+5° C and the citric acid solution is added to adjust the pH to about 3.5 to 4 which is kept in this range for the rest of the processing ; addition of 40±5% v/v of co-surfactant with lowering of temperature to 2-8° C at < 500 rpm for 20-30 minutes under inert gas to obtain an intermediate solution; and addition of 20mg to 120 mg docetaxel into the intermediate solution under constant stirring until complete dissolution of docetaxel to obtain a clear solution of the single vial stabilized formulation of docetaxel. The surfactant is polysorbate 80 and the co-surfactant is ethyl alcohol.

[0070] FIG.l through FIG 2, TEM studies are illustrated for the stabilized liquid formulation to observed the particle size and morphology of the nanosized system. The TEM micrographs clearly depict the size of the particles to be less than lOOnm and > 20nm. The particles were spherical in shape. The nano sized docetaxel in the form of the stabilized liquid formulation has higher penetration resulting in better bio-availability profile. Further the drastically reduced concentration of Polysorbate 80 and ethanol provides substantial reduction in drug related toxicity. Furthermore and most importantly the stabilized liquid formulation can be directly used to a perfusion solution without requiring an intermediate dilution. Thus, the nano sized stabilized formulation thus can be used multiple times.

[0071] In another embodiment, the stabilized liquid formulations has improved impurity profile while compared with that of the commercially available Taxotere. FIG. 3 .Table 1 illustrates comparative impurity profile of the a stabilized liquid formulation to that of one marketed drug.

[0072] FIG. 4 , Table 2 illustrates various trial formulation of the stabilized liquid formulation and their relative stability. It was found that formulation 3 was most appropriate for prolong stability according to an embodiment herein.

[0073] FIG. 5, table 3 illustrates stability study of a formulation 3.

[0074] FIG. 6, table 4 illustrates a final dilution stability of formulation 3.

[0075] FIG.7, table 5 illustrates Comparative Percentage Viability study report on trial formulation 3 of current invention. It was observed that trial formulation 3 has faster penetration and achieves 9% more cell killing at 0.5mcg concentration in first 24 hrs compared to TAXOTERE.

[0076] With the advent of the nanosized drug being dispersed in the system, there would be enhanced solubilization of the drug as a result of improved stability.

[0077] The stabilized liquid formulation Docetaxel is presented as a single vial formulation as concentrate for solution for infusion for parenteral administration from which the active ingredient is absorbed through perfusion.

[0078] The total percentage of unknown impurities is found to be less than about 75% as measured by high performance liquid chromatography ("HPLC") after storage at 40° C. for 6 months according to an embodiment herein. The stabilized liquid formulation as formed herein above has a stability up to 2 years at 20 ± 5°C and more than 2 years at 2°-8°C and up to 6 months at 40° C.

[0079] In another embodiment, the polysorbates are amphipathic, nonionic surfactants composed of fatty acid esters of polyoxyethylene sorbitan being polyoxyethylene sorbitan monolaurate for polysorbate 20 and polyoxyethylene sorbitan monooleate for polysorbate 80. The polysorbates used in the single vial formulation of docetaxel are mixtures of different fatty acid esters with the monolaurate fraction of polysorbate 80 making up > 58% of the mixture. The polysorbates undergo autooxidation, cleavage at the ethylene oxide subunits and hydrolysis of the fatty acid ester bond. Autooxidation results in hydroperoxide formation, side-chain cleavage and eventually formation of short chain acids such as formic acid. Autooxidation in current invention is prevented by use of antioxidant. This antioxidant is a weak organic acid which is citric acid.

[0080] In an preferred embodiment of the invention, content of polysorbate used in the stabilized liquid formulation in a single vial ready to use formulation is remarkably lower (45% lesser) when compared to Taxotere®. The co- surfactant used includes ethanol or any other equivalent co surfactant.

[0081] In another aspect of the invention, the acid may be selected from the range of pharmaceutically acceptable acids known to those skilled in the art, which are compatible in the nonaqueous solvent system and which are compatible with docetaxel. A person skilled in the art will know that certain strong acids may react with docetaxel generating higher degradation products and to avoid such acids. For example, epimerisation of the hydroxyl functionality of docetaxel is known to be facilitated by certain strong acids. In some instances, the use of a stabilizing agent may counteract any degradative effect of the acid. The acid may be inorganic or organic. Preferably, the pharmaceutically acceptable acids are organic acids. More preferably, the pharmaceutically acceptable acid is selected from carboxylic and dicarboxylic acids, preferably a weak organic acid.

[0082] According to another aspect of the invention, the applicant determined that the drug-to-solvent ratio is very specific, and adversly affects the solution stability of docetaxel. As such, applicant surprisingly observed that the stabilization effects of a weak organic acid acting as an antioxidant at 9.5mM concentration when added after pre dissolution in 5±2 % of water for injection to form self nano emulsifying formulation of 40mg/ml concentration ofdocetaxel which is ready to use single vial stable formulation having lesser adverse effects , higher penetration rate and improved efficacy with improved stability is achieved.

[0083] In one embodiment, the single vial stabilized formulation is used for preparation of a medicament for treatment of disease condition selected from the group consisting of non-small cell lung, breast, ovarian, head cancer, cervical cancer and brain cancer.

[0084] In another embodiment, the single vial stabilized formulation of claim 1 used for preparation of a medicament for treatment of brain cancer, wherein said formulation is dragged into brain through traversing blood brain barrier.

[0085] In yet another embodiment, a method of treating disease condition selected from the group consisting of non-small cell lung, breast, ovarian, head cancer, cervical cancer and brain cancer is provided . The method includes administering to a patient in need of such treatment an effective amount of single vial stabilized formulation of claim 1, wherein said formulation is administered directly to an infusion/perfusion solution.

[0086] Applicant studied the impurity profile for making comparison of stabilized liquid formulation against TAXOTERE® ((presentation 20 mg/0.5 ml)) which is presented in FIG 3, TABLE 1 according to an embodiment herein.

ILLUSTRATIVE EXAMPLES

Each single vial stabilized liquid formulation of Docetaxel formulation include:

l.Docetaxel 20-120 mg/ml, preferably 40 mg/ml

2.Anhydrous ethanol 40+5%

3. Polysobate-80 50+5%

4.Citric acid monohydrate 9.5m M of 1 Molar Citric Acid(to adjust

pH between 3.5 to 4.0)

5. Water for injection 5+2 %

Above disclosure describe a manner and method of making using the invention and sets forth the best mode contemplated by the inventor for carrying out his invention but is not to be construed as limiting. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention should not be unduly limited to such specific embodiments and claims. Indeed, various modifications and equivalents of the described modes for carrying out the invention that are obvious to those skilled in formulation development or related fields are intended to be within the scope of the invention. The foregoing description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the accompanied claims.

Claims

We Claim:

1. A single vial stabilized liquid formulation of taxane derivative, adapted to be used directly to a perfusion/infusion solution for administration into a subject in need, said formulation comprising an effective amount of :

docetaxel or a pharmaceutically acceptable salt thereof;

at least one surfactant;

at least one co-surfactant;

water for injection; and

at least one organic acid,

wherein particle size of docetaxel is in a range of 20 nm to lOOnm;

wherein pH of the formulation is in a range of about 3.5 to 4.

2. The single vial stabilized liquid formulation of claim 1,

wherein said formulation is stable for a period of more than 6 months at a temperature of about 40°C .

wherein said formulation is stable for a period of minimum 6 months to 24 months at a temperature range of 15° C to 25 ⁰ C. .

wherein said formulation is stable for a period of more than 2 years at a temperature range of 2° C to 8° C.

3. The single vial stabilized liquid formulation of claim 1, wherein amount of docetaxel is

40mg/ml.

4. The single vial stabilized liquid formulation of claim 1,

wherein said surfactant is polysorbate 80; and

wherein said surfactant is present in an amount of 50 ± 5% v/v , preferably 52.46% v/v.

5. The single vial stabilized liquid formulation of claim 1,

wherein said co-surfactant is ethanol; and

wherein said co-surfactant is is present in a range of 40±5% v/v, preferably 40.9% v/v.

6. The single vial stabilized liquid formulation of claim 1,

wherein said organic acid is selected from the group consisting of citric acid, tartaric acid, acetic acid or a combination thereof ; and

1 wherein said organic acid is present in an amount preferably 9.5mM to adjust pH between 3.5 to 4.

7. The single vial stabilized liquid formulation of claim 1, wherein said organic acid is citric acid.

8. The single vial stabilized liquid formulation of claim 1, wherein water for injection is present in an amount preferably 5±2%.

9. The single vial stabilized formulation of claim 1, wherein said formulation is present in the form of micronised nanao particles, self- nanoemuslsifying formulation, miceller nano particle or a colloidal form.

10. A process of preparation of the single vial stabilized liquid formulation of claim 1, said process comprising the step of :

constant stirring of 50 ± 5% v/v of surfactant and 9.5mM citric acid solution at < 500 rpm for 20-30 minutes under inert gas atmosphere to obtain an initial solution,

wherein temperature is maintained at 20±5° C till the end of the processing; and wherein citric acid solution is added to adjust maintain pH to about 3.5 to 4 till the end of the processing;

addition of 40+5% v/v of co-surfactant with lowering of temperature to 2-8° C at < 500 rpm for 20-30 minutes under inert gas to obtain an intermediate solution; and

addition of 20mg to 120 mg docetaxel into the intermediate solution under constant stirring until complete dissolution of docetaxel to obtain a clear solution of formulation.

11. The process of preparation of claim 1,

wherein said surfactant is polysorbate 80;

wherein said co-surfactant is ethyl alcohol.

12. Use of single vial stabilized formulation of claim 1 for preparation of a medicament for

treatment of disease condition selected from the group consisting of non-small cell lung, breast, ovarian, head cancer, cervical cancer and brain cancer.

13. A method of treating disease condition selected from the group consisting of non-small cell lung, breast, ovarian, head cancer, cervical cancer and brain cancer comprising administering to a patient in need of such treatment an effective amount of single vial stabilized formulation of claim 1, wherein said formulation is administered directly to an infusion/perfusion solution.

2