WO2013024495A1

WO2013024495A1 - Pharmaceutical formulations of cabazitaxel

Info

Publication number: WO2013024495A1
Application number: PCT/IN2012/000558
Authority: WO
Inventors: Chandrasekhar Kocherlakota; Nagaraju Banda; Tarun Singh; Prasad Vure; Moumita BISWAS; Harshal Prabhakar Bhagwatwar; Navin Vaya; Nirmal KHATI; Shaik Riyaz AHMED
Original assignee: Dr. Reddys Laboratories Limited
Priority date: 2011-08-18
Filing date: 2012-08-17
Publication date: 2013-02-21

Abstract

Aspects of the present application relate to pharmaceutical formulations comprising cabazitaxel or its pharmaceutically acceptable salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, polymorphs, and mixtures thereof. In embodiments, formulations are in the form of ready-to-use solutions or concentrates, or lyophilized forms. Further aspects relate to stable injectable compositions of cabazitaxel ready for direct dilution with infusion solution, without any need for preparation of premix solutions, and manufacturing processes thereof.

Description

PHARMACEUTICAL FORMULATIONS OF CABAZITAXEL

INTRODUCTION

The drug compound having the adopted name "cabazitaxel" has a chemical name (2α,5β,7β,10β, 13a)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl)amino]-2- hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11- en-2-yl benzoate and its structural formula is shown below.

Cabazitaxel has the empirical formula

its molecular weight is 835.93. Cabazitaxel is a white to off-white powder. It is lipophilic, practically insoluble in water, having solubility about 8 pg per mL, and is soluble in alcohol.

Cabazitaxel is the 7, 10-dimethoxy analogue of docetaxel, which is a member of the taxane family. It is a microtubule inhibitor, which binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions. It is indicated in combination with prednisone for treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

Cabazitaxel is the active ingredient in products sold as JEVTANA® Injection 60 mg/1.5 mL by Sanofi Aventis as a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution in single-use vials containing 60 mg cabazitaxel (calculated on an anhydrous and solvent free basis) and 1.56 g of polysorbate 80. Each ml contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80.

JE TANA Injection is a micellar formulation. Cabazitaxel shows polymorphism and polymorphic form A of the acetone solvate is known to offer manufacturing feasibility, reproducibility, and stability.

Due to stability issues, JEVTANA product requires two dilutions prior to intravenous infusion. First diluent for Jevtana is approximately 5.7 mL clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection. This pre-mix solution prepared by the first dilution is supersaturated by about 400% and is inherently physically unstable. It requires repeated inversions for at least 45 seconds to assure complete mixing of the concentrated drug solution and the diluent. The pre-mix solution, having a concentration of 10 mg of cabazitaxel per mL should be used immediately, preferably within 30 minutes and requires further dilution before administration. A volume of premix solution calculated based on a dose of 25 mg/m² is withdrawn and injected into a PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion: After this second dilution, concentrations of cabazitaxel in the infusion solution should be between 0.10 mg/mL and 0.26 mg/mL. Diluted infusion solution should be used for

intravenous administration immediately, within 8 hours, if stored at room

temperature, or within 24 hours, if stored under refrigerated conditions, including the 1-hour infusion period. As both the pre-mix solution and the second diluted infusion solution are supersaturated, the solutions may crystallize over time. The prescribing information for JEVTANA instructs that if crystals and/or particulates appear in the diluted infusion solution, it must not be used and should be discarded.

One of the difficulties with the commercially available JEVTANA formulation is that the administration process is complex and involves many steps. As described above, the person administering the drug must first create a premix solution and the subsequently transfer that premix solution into an infusion bag. As cabazitaxel is extremely toxic, strict precautions should be taken in order to minimize handling hazards involving dilution of JEVTANA Injection and subsequent preparation of an infusion solution. In making the premix solution, the medical practitioner must manually invert the vial for 45 seconds repeatedly. The prescribing information for JEVTANA gives very clear instructions not to shake the vial to avoid foaming or spillage. Foaming may result in potency loss. A further difficulty of the JEVTANA product is that the premix solution must be added to the infusion bag within 30 minutes of making such admixture. Further, once added to the infusion bag, it has a limited stability in the infusion bag.

U.S. Patent No. 5,438,072 discloses a two-part injectable composition, which involves preparing a premix solution by mixing the stock solution comprising taxane and surface active agent with a first diluent solution, prior to the addition of this premix solution to infusion bag. The first diluent solution contains an additive, which promotes the dissolution of taxane in the aqueous infusion solution in hospitals.

U.S. Patent Nos. 5,403,858; 5,698,582; 5,714,512; 5,750,561 are directed towards substantially reducing the concentration or completely removal of cremophor and ethanol from the perfusion fluid to reduce the chances of probable anaphylactic manifestations. The invention therefore consists in producing an intermediate premix solution prior to the addition of this premix solution to infusion bag. All these references, disclose formulations containing taxane derivative dissolved in a surfactant selected from polysorbate or polyethoxylated castor oil which are essentially free of ethanol (less than 5% by volume of ethanol). As described in the specification, the solutions of paclitaxel or docetaxel without ethanol have a physical stability ranging between 8 and 100 hours and several months. However, there is no single datum which mentions a physical and chemical stability of several months or even of one week of an injectable or perfusion composition comprising a taxane, ethanol and a surfactant in one container. Furthermore, as observed, the stability of an aqueous solution of cabazitaxel in ethanol and polysorbate 80 is only eight hours when stored between 2°C and 8° C or at room temperature.

U.S. Patent No. 7,241 ,907 discloses a process for preparing an acetone solvate of cabazitaxel by crystallization from an aqueous acetone solution.

U.S. Patent Application Publication No. 2009/0 8354 discloses a liquid pharmaceutical formulation for parenteral administration comprising docetaxel or a pharmaceutically acceptable salt thereof, one or more glycols, and a

pharmaceutically acceptable nonaqueous solvent system, wherein the formulation has a pH in the range of 2.5 to 7.

U.S. Patent Application Publication No. 2011/0130446 discloses

pharmaceutical compositions for parenteral administration, comprising a taxane, at least one surfactant, at least one alkyl ester of citric acid, and ethanol in an amount less than 15% by weight.

U.S. -Patent Application Publication Nos. 2010/0305202 and 2010/0267817 disclose lyophilized pharmaceutical composition comprising a water-insoluble taxoid, cyclodextrin, and at least one hydrophilic polymer selected from the group consisting of hydroxypropylmethyl cellulose (HPMC), polyethylene glycol (PEG), and

polyvinylpyrrolidone (PVP).

International Application Publication No WO 2010/023321 discloses liquid pharmaceutical formulations comprising: (a) a taxane derivative or a

pharmaceutically acceptable salt thereof, (b) a solvent consisting in the mixture of a pharmaceutically acceptable alcohol, a pharmaceutically acceptable polyethoxylated fatty acid ester and 30-50 % by weight of water based on the total weight of the solvent.

International Application Publication No WO 2009/1 5655 discloses solvates, heterosolvates, and hydrates of dimethoxydocetaxel.

There remains a need for improved formulations of cabazitaxel, whose administration involves simple one-step dilution procedure. Ideally, such formulations would be conveniently prepared for use and would exhibit enhanced storage stability at ambient conditions.

SUMMARY

In embodiments, the application provides single vial compositions of cabazitaxel, ready for direct introduction into an infusion bag or direct dilution with infusion solution.

In embodiments, pharmaceutical formulations of cabazitaxel of this

application, after dilution with infusion solution, are essentially free of crystals or other particles at preparation time or within 8 hours, if stored at room temperature, or within 24 hours, if stored at refrigerated conditions including the 1-hour infusion period.

In embodiments, the application includes pharmaceutical compositions comprising amorphous cabazitaxel.

In embodiments, the application includes pharmaceutical compositions comprising amorphous cabazitaxel containing acetone.

In embodiments, the present application relates to manufacturing processes of cabazitaxel compositions, wherein embodiments of such processes involve dissolving amorphous cabazitaxel in a solvent mixture comprising alcohol and at least one surfactant.

In embodiments, the present application includes cabazitaxel compositions having impurities within commercially acceptable limits, being maintained during storage for commercially relevant times.

In embodiments, the present application provides stable compositions of cabazitaxel suitable for use as a multi-dose product.

In embodiments, the application provides stable compositions of cabazitaxel with low foaming when preparing a product, minimizing the risk of potency loss.

DETAILED DESCRIPTION

Aspects of the present application relate to pharmaceutical formulations comprising cabazitaxel, or its pharmaceutically acceptable salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, polymorphs, and mixtures thereof, in the form of ready-to-use solutions or concentrates or lyophilized forms.

In embodiments, the present application relates to stable injectable compositions of cabazitaxel, ready for direct dilution with infusion solution without need for preparation of a premix solution, and manufacturing processes therefor.

As used herein, the term "cabazitaxel" includes the compound cabazitaxel, pharmaceutically acceptable salts of cabazitaxel, isomers, solvates, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof.

In embodiments, the application includes pharmaceutical compositions comprising amorphous cabazitaxel containing acetone. In further embodiments, the application includes pharmaceutical compositions comprising amorphous cabazitaxel containing about 5% of acetone.

In embodiments, the application includes pharmaceutical compositions comprising amorphous cabazitaxel, wherein processes for the preparation of amorphous cabazitaxel comprise:

a) providing a solution of cabazitaxel in a solvent; and

b) isolating an amorphous cabazitaxel.

Step a) involves providing a solution of cabazitaxel in a solvent. Providing a solution in step a) includes:

i) direct use of a reaction mixture containing cabazitaxel that is obtained in the course of its synthesis; or

ii) dissolving cabazitaxel in a suitable solvent.

Any physical form of cabazitaxel may be utilized for providing the solution of cabazitaxel in step a). Suitable solvents that may be used in step a) include, but are not limited to, polar aprotic solvents such as, for example, dimethyjsulphoxide, acetone, acetonitrile, and mixtures of any two or more thereof.

Step b) involves isolation of an amorphous form of cabazitaxel from the solution of step a). The isolation may be effected by removing solvent. Suitable techniques that may be used for the removal of solvent include using a rotational distillation device such as a Buchi® Rotavapor®, spray drying, thin-film drying, freeze drying (lyophilization), ball milling, and the like, and any other suitable techniques.

The term "stable compositions" refers to any preparation of cabazitaxel having sufficient stability to allow storage at a convenient temperature, such as between about 0°C and about 60°C, for a commercially reasonable period of time, such as at least about one week, at least about one month, at least about three months, at least about six months, at least about one year, or at least about 2 years.

The term "lyophilization" refers to processes, in which cabazitaxel, together with any desired pharmaceutical excipients, is dissolved in a solvent and then subjected to a procedure that involves placing into a dryer and establishing a low shelf temperature, e.g., from -30°C to 25°C, applying vacuum to obtain a powder residue, and subsequently drying under reduced vacuum to remove residual solvent. Lyophilization processing is suitable for injectables because it can be conducted under sterile conditions, which is a primary requirement for parenteral dosage forms. The term "dry powder filling" refers to processes including filling a solid particulate composition, such as a mixture of cabazitaxel and mannitol, into containers such as vials.

The term "user" refers to any qualified physician, nurse, or other practitioner who is experienced in the use of antineoplastic medicinal products.

As used herein, "substantially free" refers to the presence of a material in an amount less than about 5% (peak area %), or about 3%, or about 1 %, or about 0.5%, or about 0.1 %, or about 0% (i.e., totally free) as measured by HPLC with the UV detector set at a specific wavelength.

As used herein, "impurity" refers to any component of a drug product that is not the drug substance or an excipient in the drug product. See ICH Guidelines: Impurities in New Drug Products at 6. An impurity can include any degradant of a drug product.

Injectable formulations are typically formulated as aqueous or non-aqueous solutions or suspensions. Injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in a liquid prior to injection, or as emulsions. Sterile injectable formulations can be prepared according to techniques known in the art using suitable carriers, dispersing or wetting agents, and suspending agents. The injectable formulations may be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water for injection, isotonic dextrose solution, Ringer's solution, isotonic sodium chloride solution, and suitable non-aqueous solvents useful for parenteral administration. In addition, sterile fixed oils, fatty . esters, or polyols are conventionally employed as solvents or suspending media.

The formulations of the present application are particularly suited for use in parenteral administration, but it will be understood that the solutions may have alternative uses. Injectable formulations may take any route including intramuscular, intravenous, or subcutaneous.

The compositions according to an aspect of the application may be in the form of liquid concentrates, ready-to-use solutions, lyophilized powders, or physical admixtures for injection.

In embodiments, the present application provides pharmaceutical formulations comprising cabazitaxel at concentrations about 5 mg/mL to about 200 mg/mL. In embodiments, the concentrations of cabazitaxel are in the range of about 10 mg/mL to about 60 mg/mL, or about 15 mg/mL to about 50 mg/mL.

In embodiments, the pharmaceutical formulations of the application comprise aqueous or non-aqueous solvent systems, or suitable mixtures thereof.

The persons skilled in the art will understand that when the solvent system is described as nonaqueous, this merely indicates that water is not specifically added to the formulation. There can be some water present in the formulation due to its presence in some of the commercial components used (e.g., surfactants), and water may also be absorbed from the environment into the formulation. Formulations containing these incidental amounts of water are included within the scope of the application.

In embodiments, the pharmaceutical formulations of the application comprise lyophilized powders or physical admixtures for injection, co-packaged with a diluent for making a solution or suspension for injection.

Cabazitaxel is practically insoluble in water but has good solubility in alcohols.

However, usage of alcohols should be limited, because a large amount of alcohol associated with high dose requirement of cabazitaxel may result anaphylactic or alcoholism manifestations, resulting in serious adverse events. Pharmaceutically acceptable solubilizers should be also added into the composition in addition to alcohols.

In embodiments, the pharmaceutically acceptable non-aqueous solvent system may comprise any pharmaceutically acceptable non-aqueous components known to persons skilled in the art, in which the cabazitaxel is soluble, for example, ketones such as acetone, alcohols, solubilizers, or suitable mixtures thereof.

Pharmaceutically acceptable alcohols for this application include, but are not limited to, ethanol, benzyl alcohol, tertiary-butyl alcohol, isopropyl alcohol, and suitable mixtures thereof.

Ethanol is commonly used as a solvent, co-solvent, and anti-microbial preservative in parenteral compositions. Small quantities of ethanol may also act as an antifoaming agent. Although other alcohols may be effectively used in cabazitaxel compositions, ethanol has been found to be a good solvent for dissolving

cabazitaxel.

In embodiments, the non-aqueous solvent is about 10 to about 90% of the total volume of the formulation. In embodiments, an ethanol is present in amounts in the range of from about 5 to about 60% by volume of the formulation, or about 20 to about 45%, or about 30%.

In embodiments, pharmaceutically acceptable non-aqueous solvent systems comprise one or more alcohols and one or more non-ionic surfactants.

In embodiments, the solubilizer is about 10 to about 90% of the total volume of the formulation.

In embodiments, a nonionic surfactant is present in amounts in the range of about 20 to about 95% by volume of the formulation, or about 40 to about 80%, or about 70%.

In embodiments, an alcohol is ethanol and a solubilizer is a polysorbate. In such formulations, cabazitaxel is solubilized via the formation of micelles of polysorbate that trap cabazitaxel molecules. However, the resulting micellar solutions are supersaturated and may lead to crystallization of the drug product in the premix or the infusion bags. For reasons of safety, at the time of administration to the patient the infusion solution comprising cabazitaxel should be physically stable (absence of crystallization, precipitation, or any other particulate formation). Diluted infusion solution should be used for intravenous administration immediately, or within 8 hours if stored at room temperature, or within 24 hours if stored at refrigerated conditions (including the 1-hour infusion). Several factors may contribute to increased crystallization, such as manipulation of the premix and/or infusion bag, multiple injections in the infusion bag, solution concentrations, and temperatures.

A person skilled in the art preparing formulations according the application will understand that the proportions of components with respect to each other will vary depending on the specific components used. For example, the use of different surfactants and alcohols will require some straightforward modifications to the proportions, depending on the miscibility of a particular surfactant in a particular alcohol.

In embodiments, the excipients may be selected for the application form the range of pharmaceutically acceptable excipients, which are soluble in the nonaqueous solvent system and which are compatible with the active ingredient. The excipients selected for the purpose of the present application should not create any degenerative effect on the active ingredient such as cabazitaxel. In some instances the scope of this application also covers incorporation of pharmaceutically acceptable excipients useful to counteract the degenerative effect of any of the other excipients present in the formulation.

A person skilled in the art will be aware that pH is a measure of free hydrogen ions in a solution. For example, free hydrogen ions will exist in alcohol systems that contain acids. The pH may be measured by placing a pH meter electrode directly into liquid formulations, such pH meter having been calibrated for the appropriate pH range with standard aqueous buffers. Persons skilled in the art will know of other methods which may be used to measure pH. Such persons will further know that, while the pH meter reading obtained for a substantially non-aqueous formulation may not be a true reflection of the actual hydrogen ion concentration in the solution, it may nonetheless give a meaningful and reproducible measurement that indicates the relative acidity/basicity of the solution, as is the case for the cabazitaxel formulations disclosed herein. In instances, the pH meter reading will be in the range from about 3 to 9, or from about 3 to 6, or from about 4 to 6. These ranges are for measurements made at room temperature (20-25°C). A person skilled in the art will know that the pH meter reading will vary somewhat, depending on the temperature.

A person skilled in the art will recognize that the pH meter reading of the formulations according to the application can be achieved by acidifying the formulation itself, or by adjustment of the pH of any of the components of the formulation, for example by purification of a surfactant to remove basic contaminants or acidification of any of the components prior to the mixing of the formulation.

The acids may be any pharmaceutically acceptable acids known to those skilled in the art, which are soluble in a nonaqueous solvent system and are compatible with cabazitaxel. A person skilled in the art will know that certain strong acids may react with cabazitaxel, creating degradants, and to avoid such acids. For example, epimerization of the hydroxyl functionality of cabazitaxel is known to be facilitated by certain strong acids. In some instances, the use of a stabilizing agent may counteract any degradation effect of the acid. The acids may be inorganic or organic. In embodiments, a pharmaceutically acceptable acid is a carboxylic or dicarboxylic acid. Useful examples include, but are not limited to, citric acid, tartaric acid, acetic acid, and any mixtures thereof.

A person skilled in the art will know that the amount of pharmaceutically acceptable acid used will be limited by the particular acid's solubility in the pharmaceutically acceptable nonaqueous solvent system. The amount of acid required will also be further determined by the relative strength of the acid.

When the pharmaceutically acceptable acid is citric acid, in embodiments the citric acid is present at concentrations in the range of from about 1 to 8 mg/mL

In some instances the scope of this application also covers incorporation of antioxidants and/or chelating agents to reduce the chances of degradation of cabazitaxel or any other excipient present in the formulation. A person skilled in the art will know that the amount of parenterally acceptable antioxidant and/or chelating agent used will be limited by the particular excipient solubility and stability in the pharmaceutically acceptable nonaqueous solvent system. The amount of such excipient required will also be further determined by formulation requirements. When such antioxidant and/or chelating agent is incorporated in the formulation, pH should be adjusted accordingly to provide optimum stability or solubility of cabazitaxel and optimum antioxidant property required for the formulation.

In embodiments, an antioxidant is present in amounts in the range of about 1 to about 20% by weight of the formulation.

In embodiments, a chelating agent is present in amounts in the range of about 1 to about 20% by weight of the formulation.

In embodiments, the present application provides formulations comprising cabazitaxel and a glycol. The glycol can be a polyethylene glycol, propylene glycol, tetraglycol, or any mixtures thereof. Polyethylene glycols (e.g., PEG 300 and PEG 400) are excipients, which are widely used in pharmaceutical formulations. In embodiments, the polyethylene glycols have average molecular weights in the range from about 200 to 600, or about 300 (PEG 300).

Propylene glycols and tetraglycols are also used in pharmaceutical formulations as solvents and are approved for parenteral use by regulatory authorities around the world, including the U.S. Food and Drug Administration and the equivalent European authority. In embodiments, a glycol is present in the formulations in amounts in the range of about 10 to about 70% by volume.

Impurity Analysis

The analysis of the impurities can be undertaken using techniques such as high performance liquid chromatography (HPLC). HPLC is a technique that is widely used and well known in the art. HPLC can be used to measure the potency of the cabazitaxel, where potency is defined as a percentage of the initial (or label) concentration of cabazitaxel. HPLC can also be used to measure the relative proportions of identified and unidentified impurities in a cabazitaxel formulation. Any suitable HPLC method that will separate the impurities may be used. Impurity levels can be calculated by peak area normalization.

The processes for preparation of pharmaceutical liquid formulations of the application involve simple mixing steps known in the art. In embodiments, the processing steps involve preparation of a solution of cabazitaxel in the required amount of an alcohol, followed by addition of a surfactant, with or without stirring.

According to other embodiments, the drug may be dissolved in a surfactant and an alcohol is gradually added to the drug and surfactant mixture, with or without stirring.

Mixing should result in clear solution and desirably will involve limited foaming. The pH of the final liquid concentrate should be adjusted to be within the desired range. In order to maintain the sterility of the final formulation, proper aseptic conditions known in the general art should be maintained.

The cabazitaxel formulations prepared as per the invention are packaged in suitable container and stored at 40°C and 75% relative humidity condition over 1 week to 3 months, and/or are stored at 25°C and 60% relative humidity condition over 1 week to 3 months. After storage, stability of the formulations is tested using HPLC analysis. The pharmaceutical formulations will typically comply with the International Conference on Harmonization (ICH) Guidelines.

Suitable packaging materials:

The choice of suitable packaging materials useful for parenteral dosage forms are within the scope of the present application. Small vials, usually made up of glass, containers that are sealed with a suitable stopper and seal, and other suitable primary containers may be used, such as, but not limited to, pre-filled syringes. The application includes use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE), and/or polypropylene and/or glass, glassine foil, polyvinyl chloride, polyvinylidene dichloride, etc. Optionally, the packaging material may comprise a glass container having a transparent plastic inner lining. Examples of plastic materials which may be used for containers or inner lining of the container include: polysulfones, polycarbonates, polypropylenes, polyethylenes (LDPE or HDPE), ethylene/propylene copolymers, polyolefins, acrylic-imide copolymers, PVC, polyesters (e.g. PET, PEN and the like), Teflon, Nylon, acetal (Delrin), polymethylpentene, PVDC, ethylvinylacetate, AN- copolymer, etc. The plastic material can be transparent or translucent, to permit visual inspection of the contents.

In embodiments, the present application provides pharmaceutical formulations comprising cabazitaxel that can be administered to a patient in need thereof, as a subcutaneous injection. Such subcutaneous injection of cabazitaxel can be advantageous over intravenous infusion because it offers the possibility of self- administration.

In embodiments, the present application provides subcutaneous injections comprising cabazitaxel, non-aqueous solvents, and optionally water-miscible solvents, to enhance solubility and ensure syringeability. Non-aqueous solvents include substances such as corn oil, cottonseed oil, peanut oil, and sesame oil. Water-miscible solvents include glycerin, ethanol, glycofurol, propylene glycol, and polyethylene glycols. Optionally, such formulations may be buffered, in order to provide optimum pH values to minimize adverse skin manifestations. Hyaluronidase may be co-administered to increase absorption and to decrease tissue distension.

A skilled person will understand that the appropriate relative ratios of each of the excipients have been obtained when a homogeneous solution results from the admixture of all ingredients, and the cabazitaxel remains in solution.

The injectable pharmaceutical formulations of the present application may optionally include one or more additional pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include one or more of:

antibacterial preservatives, including one or more of phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, cresol and chlorobutanol; antioxidants, including one or more of ascorbic acid, sodium sulfite, sodium bisulfite and sodium metabisulfite; chelating agents, such as ethylene diamine tetra acetic acid (EDTA) and its derivatives; buffering agents, including one or more of carboxylic or dicarboxylic acid salts such as acetates, citrates, tartarate, phosphates, benzoates, and bicarbonates; tonicity contributors, including one or more of sodium chloride, potassium chloride, dextrose, mannitol, sorbitol, and lactose; and alkaline substances, including one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and meglumine. Nonaqueous Vehicles

Another class of nonaqueous vehicles, in addition to alcohols described above, for the purpose of the present application includes oils such as vegetable oils like sesame oil, corn oil, soybean oil, cottonseed oil, peanut oil, and hydrogenated castor oil. Oils of vegetable origin are useful because they can be metabolized, are liquid at room temperature, and will not rapidly become rancid.

Solubilizers

Pharmaceutically acceptable solubilizers for the present application may be defined as substances that maximize the solubility of a practically insoluble drug like cabazitaxel. Solubility enhancement with the incorporation of solubilizer may involve micellar solubilization, cosolvency, complexation, prodrug formation, or salt formation. Pharmaceutically acceptable solubilizers for this application include, but are not limited to, nonionic surfactants such as polyethoxylene sorbitan fatty acid esters (polysorbates), for example Tween® 20, Tween® 60, Tween® 80,

polyoxyethylene glycol esters, for example Emulphor®, polyethoxylated castor oils, for example Cremophor-EL®, and cosolvents such as polyethylene glycols, for example PEG 200, PEG 300, PEG 400, PEG 800, propylene glycol, tetraglycol, glycerol, amide solvents, and suitable mixtures thereof.

Polysorbates are a series of partial fatty acid esters of sorbitol and its anhydrides, co-polymerized with ethylene oxide. The resulting product is a mixture of molecules of different sizes. Polysorbates are used as solubilizing agents for a variety of substances and as wetting agents in the formulation of oral and parenteral suspensions. Polysorbate 80 is a yellow oily liquid having a HLB value of about 15. Another name for polysorbate 80 is polyoxyethylene 20 sorbitan monooleate, and its molecular weight is about 1310. Polysorbate 80 is available commercially as

Tween™ 80, Tego™ SMO 80, Tego SMO 80V, Durfax™ 80, Durfax 80K, E433, Emrite™ 6120, Eumulgin™ SMO, Glycosperse™ O-20, Hodag™ PSMO-20, Liposorb™ O-20, Liposorb O-20K, Montanox™ 80, etc. The U.S. Food and Drug Administration, European Medicines Agency, and Therapeutic Goods Administration, Australia, approve the use of polysorbate 80 for parenteral use.

Polyethylene glycols are widely used excipients in pharmaceutical

formulations and polyethylene glycols having molecular weights in the range from about 200 to about 600 are useful for the purposes of this application. Water-soluble polyoxyethylene derivatives of castor oil that are nonionic . surface-active agents can be used as solubilizers. Polyoxyethylene castor oil derivatives are complex mixtures of various hydrophobic and hydrophilic

components. Members within each range have different degrees of ethoxylation (moles)/PEG unit as indicated by their numerical suffix (n). Cremophor® EL is polyoxyl 35 castor oil and is the only grade currently approved for parenteral applications in humans. In polyoxyl 35 castor oil, the relatively hydrophobic constituents comprise about 83% of the total mixture, the main component being glycerol polyethylene glycol ricinoleate. Other hydrophobic constituents include fatty acid esters of polyethylene glycol along with some unchanged castor oil. The hydrophilic part (17%) consists of polyethylene glycols and glycerol ethoxylates. Cremophor ELP, a 'purified' grade of Cremophor EL is also a polyoxyl 35 castor oil; it has a lower content of water, potassium, and free fatty acids, and hence is claimed to have improved stability.

Polyethylene glycols (PEG) are polymers of ethylene oxide and usually designated by a numerical value, which is indicative of the average molecular weight for a given grade. Molecular weights below 600 are liquids, and molecular weights above 1000 are solids at room temperature. These polymers are readily soluble in water, which make them quite useful for parenteral products. Only PEG 400 and PEG 300 are currently utilized in parenteral products, typically at concentrations up to about 30% by volume. These polymers are generally regarded as nontoxic and nonirritant.

Propylene glycols (PG) are non-toxic, more hygroscopic than glycerin and have excellent solubilizing power for a wide variety of compounds. In addition, they have bactericidal and preservative properties.

Cyclodextrins (CD) are crystalline, non-hygroscopic, cyclic oligosaccharides derived from starch. Among the most commonly used forms are α-, β-, and γ- cyclodextrins, which have respectively 6, 7, and 8 glucose units. CDs can interact with poorly water-soluble drugs, giving rise to soluble inclusion complexes.

Sulfobutylether β-cyclodextrin (SBECD), commercially available as Captisol®, is included in intravenous and intramuscular injectable products that are currently approved and marketed in the U.S. and Europe. SBECD can form non-covalent complexes with many types of compounds, enhancing their solubility and stability in water. 2-Hydroxypropyl-P-cyclodextrin may also be used in parenteral formulations. The minimum amount required for solubilization is, in general, a cyclodextrin to drug molar ratio of approximately 1-5. The maximum use in a formulation may be limited by physicochemical constraints such as viscosity (e.g. syringeable concentrations may be considered up to 50% w/v), and tonicity.

Buffers

Pharmaceutically acceptable buffer systems may be used to maintain the pK_a of a system within one pH unit of the pH desired for the system. The selection of the product pH is based on the stability of the active drug. The buffer concentrations typically chosen for a product range from about 1-2%, although higher

concentrations of up to 5% may be chosen for citrate buffers.

Examples of buffer ingredients include acetic acid, citric acid, glutamic acid, phosphoric acid, benzoic acid, lactic acid, ascorbic acid, tartaric acid, succinic acid, glycine, triethanolamine, diethanolamine, tromethamine, and various salts.

Antimicrobials

Examples of useful antimicrobials include benzyl alcohol, chlorocresol, metacresol, phenol, methyl p-hydroxybezoate, propyl p-hydroxybezoate, and butyl p- hydroxybezoate.

Benzyl alcohol (BA) is a bacteriostatic agent used against gram-positive bacteria, yeasts, molds, and fungi, and it is commonly used as a preservative in parenteral products. It has anesthetic properties at levels of approximately 1%. It has good solubilizing power, and may be typically used in concentrations up to 2% as a preservative and up to 5% as a solvent.

Antioxidants and Chelating Agents

Antioxidants and chelating agents may be employed to protect the active agent from oxidative degradation, particularly under the rigorous conditions of thermal sterilization. The amounts to be employed can be determined using routine experimentation. As an alternative to the use of antioxidant compounds, an antioxidant effect can be achieved by displacing oxygen (air) from contact with the solution of active agent. This is usually carried out by purging a container holding the solution with an inert gas, e.g., nitrogen. Chelating agents are used to increase the solubility of a drug or to impart additional product stability.

Examples of antioxidants include sodium bisulfite, sodium metabisulfite, ascorbic acid, butylatedhydroxyanisole (BHA), butylatedhydroxytoluene (BHT), L- monothioglycerolcysteine, L-cysteine, thioglycolic acid, lipoic acid, dihydrolipoic acid, tocopherol, glutathione, monoethanolamine gentisate, sodium formaldehyde sulfoxylate and propyl gallate.

Examples of chelating agents include ascorbic acid, citric acid, lactobionic acid, ethylenendiaminetetraacetic acid and derivatives thereof, for example sodium ascorbate, sodium citrate, tribasic (trisodium citrate dihydrate), disodium edetate, trisodium edetate, tretrasodium edetate etc.

Tonicity agents

The drug and each excipient contribute to the tonicity of the formulation.

However, the tonic contribution of these combined ingredients may not be sufficient to provide an isotonic solution for administration. In such cases, isotonicity is assured with the incorporation of a tonicity agent such as dextrose, sodium chloride, sodium sulfate, or mannitol.

Certain specific aspects and embodiments of the application will be further described in the following examples, which are provided solely for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. -

Lyophilized Compositions

Lyophilization, freeze-drying, or vacuum drying are processes in which solvent is removed from a solution or dispersion after it is frozen and placed under a vacuum, allowing the solvent to change directly from a solid to a vapor without passing through a liquid phase. A process consists of three separate, unique, and interdependent phases: a freezing phase; a primary drying phase (sublimation); and a secondary drying phase (desorption). These processes may be optimized to enhance the product stability as well as decrease the manufacturing costs.

The advantages of lyophilization include ease of processing a liquid, which simplifies aseptic handling; enhanced stability of a dry powder; removal of solvent without excessive heating of the product; enhanced product stability in a dry state; and rapid and easy dissolution of reconstituted product. The product is dried without using elevated temperatures, thereby eliminating adverse thermal effects, and then is stored in the dry state in which there are relatively fewer stability problems.

Additionally, freeze dried products are often more soluble, dispersions are stabilized, and products subject to degradation by oxidation or hydrolysis are protected.

Aspects of the present application provide lyophilized cabazitaxel formulations comprising a bulking agent. As described herein, a lyophilized formulation of cabazitaxel is achieved following removal of a solvent system from a pre- lyophilization bulk solution. A typical example of solvents used to prepare this formulation includes acetone, acetonitrile, and water for injection, including suitable mixtures of two or more thereof. Suitable antioxidants and/or chelating agents can also be used in the above formulation to improve the stability and physiochemical characteristics of the product.

In embodiments of the present disclosure, an aqueous prervacuum dried solution or dispersion is first formulated. The solution is aseptically filtered into a sterile container, filled into an appropriate sized vial, loosely covered, and loaded into a vacuum dryer. Using vacuum drying techniques, such as those described herein, the solution is dried to obtain moisture contents in the range of about 0.1 to about 8 percent by weight. The resulting dried powder is stable as a powder, typically for about six months to more than about 2 years, or greater than about 3 years, when stored in a closed container at about 5°C to about 25°C, and can be readily reconstituted with sterile water for injection, or other suitable fluid, to provide liquid formulations of cabazitaxel, suitable for administration, e.g., by parenteral injection. For intravenous administration, a reconstituted liquid formulation, i.e., a

pharmaceutical composition that is a solution is used.

The lyophilized powder is reconstituted as close to the time of patient administration as possible, with 6 mL of diluent composition A required volume of reconstituted solution based on a dose of 25 mg/m² is withdrawn and injected into a PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion.

Diluent compositions for the purpose of the present invention comprise suitable alcohol, sterile water for injection, polysorbate 80, PEG 300, PEG 400, propylene glycol and suitable mixtures thereof. A person skilled in the art preparing formulations according the application will understand that the proportions of components with respect to each other in diluent composition will vary depending on the specific components used and solubility of cabazitaxel.

In embodiments, the present application provides pharmaceutical formulation comprising 35.4 % w/w ethanol in polysorbate 80.

In embodiments, the present application provides pharmaceutical formulation comprising cabazitaxel and one or more amphiphilic anionic compounds. As is employed herein, the term "amphiphilic" refers to a compound which has at least one hydrophilic moiety and at least one hydrophobic moiety. The amphiphilic anionic compound may comprise one or more anionic groups per molecule. Accordingly, in one embodiment, the amphiphilic anionic compound comprises a sulfonate group attached directly to an aliphatic hydrocarbon chain. The anionic agent is an alkanesulfonate containing between 10 and 18 carbon atoms. Such amphiphilic anionic compound includes but not limited to dodecylbenzenesulfonate, Caeliferin A, polysulfonated polyethylene, polysulfated polysaccharide, alcohol ether sulfate, glycolipid sulfate.

In embodiments, the present application provides pharmaceutical formulation comprising cabazitaxel and one or more amphiphilic cationic compounds. The amphiphilic anionic compound may comprise one or more anionic groups per molecule. The hydrophilic moiety of the amphiphilic compounds useful in the practice of this invention preferably comprises one or more tertiary amine or quartemary ammonium salts. Such cationic groups are typically in the form of a pharmaceutically acceptable salt. It is preferred that the salts are chlorides, sulfates, or sulfonates. The hydrophobic moiety of the amphiphilic compounds useful in the practice of the present invention comprises a hydrocarbon chain as its hydrophobic part. Such chain may be an aliphatic chain, or a mixed aliphatic-aromatic chain. The aliphatic chain can be linear or branched although it is preferred that the said chain is linear. Preferably, the hydrocarbon chain contains between 8 and 18 carbon atoms.

Preferred tertiary amines include N-alkyl-N,N-dimethylamines, N-alkyl-N,N- diethylamines, N-alkyl-N-N-diethanoloamines, N-alkylmorpholine, N-alkylpiperidine, and N-alkylpyrrolidine. Particularly preferred are sterically hindered tertiary amines, for example, N-alkyl-N-N-diisopropylamine, N-alkylmorpholine, N-alkylpiperidine, and N-alkylpyrrolidine, and other such amines known to those skilled in art.

Certain specific aspects and embodiments of the application will be further described in the following examples, which are provided solely for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

Example 1 : Cabazitaxel liquid concentrate.

Polysorbate 80 1560 mg

Dehydrated Ethanol 0.646 ml_

Manufacturing process:

Required amount of dehydrated alcohol is taken in a clean vessel.

2. Weighed quantity of cabazitaxel is completely dissolved in dehydrated alcohol by stirring.

3. Required amount of polysorbate 80 is added to Step-2 and stirred for 15 minutes.

4. The bulk solution prepared in step 2 is filtered using 0.22μ membrane filtration assembly.

5. The filtered bulk solution is filled in USP type-l glass vial and

immediately the vial head space was flushed with sterile nitrogen.

6. The vials are stoppered immediately and sealed with aluminum tear off seals.

7. Vials are cleaned and labeled.

Example 2-5: Cabazitaxel liquid concentrate.

Manufacturing process:

1. Required amount of dehydrated alcohol is taken in a clean vessel.

2. Weighed quantity of citric acid anhydrous and cabazitaxel are completely dissolved in dehydrated alcohol by stirring.

4. The bulk solution prepared in step 3 is filtered using 0.22 membrane filtration assembly. 5. The filtered bulk solution is filled in USP type-l glass vial and immediately the vial head space was flushed with sterile nitrogen.

6. The vials are stoppered immediately and sealed with aluminum tear off seals.

7. Vials are cleaned and labeled.

Example 6-8: Cabazitaxel liquid concentrate.

Manufacturing process:

1. Required amount of dehydrated alcohol is taken in a clean vessel.

4. Required quantity of PEG 300 is added to Step-3 and stirred for 15 minutes.

5. The bulk solution prepared in step 4 is filtered using 0.22μ membrane filtration assembly.

6. The filtered bulk solution is filled in USP type-l glass vial and

immediately the vial head space was flushed with sterile .nitrogen.

7. The vials are stoppered immediately and sealed with aluminum tear off seals.

8. Vials are cleaned and labeled.

Example 9-11: Cabazitaxel liquid concentrate.

Cabazitaxel 60 mg 60 mg 60 mg

Citric Acid 4 mg 4 mg 4 mg

Polysorbate 80 1560 mg 1560 mg 1560 mg

Propylene Glycol 0.5 mL 1 mL 2 mL

Dehydrated Ethanol 0.646 mL 0.646 mL 0.646 mL

Manufacturing process: Manufacturing process is same to that of example 6, except that propylene glycol is used instead of PEG 300 in step 4.

Example 12-14: Cabazitaxel liquid concentrate.

Manufacturing process: Manufacturing process is same to that of example 4

Example 15-16: Cabazitaxel liquid concentrate.

Manufacturing process: Manufacturing process of example 15 and 16 are same to that of example 6 and 9 respectively.

Example 17: Cabazitaxel liquid concentrate. Same composition of Exampli 13 and 14 are prepared using following process:

1. Required amount of dehydrated alcohol is taken in a clean vessel. 2. Weighed quantity of citric acid anhydrous and cabazitaxel are completely dissolved in dehydrated alcohol by stirring.

3. Required amount of polysorbate 80 is added to Step-2 and stirred for 15 minutes to prepare the bulk solution. During bulk solution preparation the headspace of the manufacturing vessel is replaced with nitrogen blanket.

4. The bulk solution prepared in step 4 is filtered using 0.22μ membrane filtration assembly.

5. The filtered bulk solution is filled in USP type-l glass vial and

immediately the vial head space was flushed with sterile nitrogen.

6. The vials are stoppered immediately and sealed with aluminum tear off seals.

7. Vials are cleaned and labeled.

Example 18-20: Cabazitaxel liquid concentrate.

Manufacturing process: Manufacturing process is same to that of example 4, except that disodium edetate is additionally dissolved in dehydrated alcohol in step 2.

Example 21-26: Cabazitaxel liquid concentrate.

Ethanol mL mL mL mL mL mL

Manufacturing process:

1. Required amount of dehydrated alcohol is taken in a clean vessel.

2. Weighed quantities of citric acid anhydrous, cabazitaxel and sodium ascorbate or monothioglycerol are completely dissolved in dehydrated alcohol by stirring.

5. The filtered bulk solution is filled in USP type-l glass vial and immediately the vial head space was flushed with sterile nitrogen.

6. The vials are stoppered immediately and sealed with aluminum tear off seals.

7. Vials are cleaned and labeled.

Example 27-34: Cabazitaxel lyophilized powder for injection

Manufacturing process: . Required quantity of cabazitaxel and optionally the tonicity agent (mannitol or sorbitol or sucrose) as per the examples are dissolved completely in required volume of solvent(s) as mentioned in specific examples.

2. The solution prepared in step 1 is kept under nitrogen blanket and finally filtered through 0.2 μηι sterile filter.

3. Required volume of the sterile bulk solution is filled into depyrogenated glass vials and stoppered partially with sterile bromobutyl stoppers.

4. Vials of step 3 are lyophilized in a freeze dryer as per lyophilization cycle of Table 1 :

Table 1 : Processing conditions used in lyophilization cycle 5. After completion of lyophilization cycle, the vacuum is released completely under nitrogen gas followed by complete stoppering.

6. Vials are unloaded from lyophilizer, sealed with flip-off seals, cleaned externally and inspected for any defects.

Diluent Composition:

Manufacturing process:

1. Required quantity of solvent as per the examples are taken and mixed under continuous stirring until solution is uniform.

2. The solution is kept Under nitrogen blanket and finally filtered through 0.2 μιη sterile filter.

3. Required volume of the sterile diluent solution is filled into the depyrogenated glass vials, the head space is flushed with sterile nitrogen and completely stoppered with sterile bromobutyl stoppers.

4. Vials are sealed with flip-off seals, cleaned externally and inspected for any defects.

Claims

WE CLAIM

1. A pharmaceutical formulation for parenteral administration, comprising cabazitaxel or a pharmaceutically acceptable salt thereof and at least one solubilizer.

2. A pharmaceutical formulation of claim 1 , wherein such formulation comprises amorphous cabazitaxel containing acetone.

3. A pharmaceutical formulation of claim 1 , wherein such formulation comprises amorphous cabazitaxel about 5% of acetone.

4. A pharmaceutical formulation of claim 1 , wherein the concentration of cabazitaxel is about 5 mg/ml to about 100 mg/ml.

5. A pharmaceutical formulation of claim 1, wherein the concentration of cabazitaxel is about 10 mg/ml.

6. A pharmaceutical formulation of claim 1 , wherein solubilizer is selected from the group comprising of polysorbates, polyethylene glycols, propylene glycol, tetraglycol, glycerol, ethanol and a mixture thereof.

7. A pharmaceutical formulation of claim 1, wherein such formulation further comprises at least one pharmaceutically acceptable acid.

8. A pharmaceutical formulation of claim 5, wherein such

pharmaceutically acceptable acid is selected from the group consisting of citric acid, tartaric acid, acetic acid and mixtures thereof.

9. A pharmaceutical formulation for parenteral administration, comprising cabazitaxel or a pharmaceutically acceptable salt thereof and at least one solubilizer which does not require prior dilution with a diluent and is ready to add to the infusion solution.

10. A ready to use pharmaceutical formulation for parenteral

administration, comprising or a pharmaceutically acceptable salt thereof atleast one solubilizer, alcohol & a pharmaceutically acceptable excipient or mixtures thereof

11. A lyophilized pharmaceutical formulation for parenteral administration, comprising cabazitaxel or a pharmaceutically acceptable salt thereof.

12. A liquid pharmaceutical formulation for parenteral administration, comprising: (a) a taxane derivative or a pharmaceutically acceptable salt thereof, (b) a solvent consisting of a pharmaceutically acceptable polyethoxylated fatty acid ester and 10-70 % by weight of alcohol based on the total weight of the solvent.

13. A liquid pharmaceutical formulation for parenteral administration comprising: (a) cabazitaxel or a pharmaceutically acceptable salt thereof; (b) one or more glycols; (c) an amount of one or more pharmaceutically acceptable acids sufficient to provide the formulation with a pH from 2.5 to 8; (d) one or more alcohols; and (e) one or more non-ionic surfactants.