WO2023148763A1

WO2023148763A1 - Injectable pharmaceutical compositions of azole antifungal agents

Info

Publication number: WO2023148763A1
Application number: PCT/IN2023/050094
Authority: WO
Inventors: Pradeep Bhadauria; Tushar RAJYAGURU; Arnab Kumar SINGHADEO
Original assignee: Cipla Limited
Priority date: 2022-02-01
Filing date: 2023-02-01
Publication date: 2023-08-10

Abstract

: The present invention relates to stable injectable pharmaceutical composition comprising azole antifungal agent. The invention particularly relates to a ready-to- use composition comprising posaconazole or its pharmaceutically acceptable salts, derivatives thereof and pharmaceutically acceptable excipients, process of preparing the composition and its use in the treatment of fungal infections caused by Aspergillus and Candida species.

Description

“INJECTABLE PHARMACEUTICAL COMPOSITIONS OF AZOLE ANTIFUNGAL AGENTS”

FIELD OF INVENTION:

The present invention relates to stable injectable pharmaceutical composition comprising azole antifungal agent. The invention particularly relates to a ready -to- use composition comprising posaconazole or its pharmaceutically acceptable salts, derivatives thereof and pharmaceutically acceptable excipients, process of preparing the composition and its use in the treatment of fungal infections caused by Aspergillus and Candida species.

BACKGROUND OF THE INVENTION:

Posaconazole is a broad spectrum antifungal agent having the following structure:

Posaconazole is a weakly basic and poorly-aqueous soluble drug that has poor bioavailability and variable absorption. Posaconazole has a solubility of less than 1 pg/mL in neutral and basic aqueous solutions. The solubility increases under acidic conditions (e.g., 3 pg/mL at pH 3 and 0.8 mg/mL at pH 1).

Posaconazole is marketed as an oral suspension (40 mg/ml), delayed release tablets and injection under the trademark Noxafil™ in the United States by Merck. Noxafil™ (posaconazole) is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy. Noxafil™ (posaconazole) is also indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.

Noxafil™ is available as sterile solution in the concentration of 18mg/ mL and is administered after dilution with compatible mixture of diluent. To prepare the required dose, one vial of Noxafil™ injection needs to be transferred to intravenous bag of suitable diluent such as sodium chloride, potassium chloride, dextrose and their mixtures thereof to achieve a final concentration of posaconazole. There is a restriction on use of other diluents as they may result in particulate composition. Thus, marketed single dose injection solution composition is associated with certain limitations such as the cumbersome and time consuming aseptic dilution process, non- assurance of proper dilution, potential for dosing errors and wastage of remaining drug in vial after dose administration of diluted medication. It is evident that the dilution process is also time consuming and requires specific sterile diluent. It is advised that once admixed, the product should be used immediately and if not used immediately, the solution needs be stored up to 24 hours refrigerated 2-8°C (36-46°F). Noxafil™ injection is for single use only and any unused solution needs to be discarded. Also, it has to be taken care that diluted composition should not have developed particulate matter and it has to be inspected visually prior to administration, whenever solution and container permit. Thus, the diluted product should be utilized as early as possible to render them sterile and avoid stability concern. Thus there exists a need of a ready-to-use composition comprising posaconazole or its pharmaceutically acceptable salts, derivatives thereof, which eliminates the cumbersome and complex steps of dilution along with ensuring sterility of the product during this process.

Further, the Noxafil™ product contains inactive ingredients such as Betadex Sulfobutyl Ether Sodium (SBECD), edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection. Owing to the limited water solubility of posaconazole, the Noxafil™ contains the vehicle SBECD. SBECD is a large, cyclic oligosaccharide that is predominantly excreted through glomerular fdtration with a ti/2 elimination of 2 hours in patients with normal kidney function. Noxafil™ injection cannot be administered in patients with moderate or severe renal impairment (eGFR mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil™ injection. If Noxafil™ is administered to patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), then accumulation of the intravenous vehicle, (Betadex Sulfobutyl Ether Sodium (SBECD)) occurs. Serum creatinine levels needs to be closely monitored in these patients, and, if increases , injection therapy is to be discontinued and oral therapy has to be started. However, this switch of therapy from injection to oral is not possible in the case of patients who have difficulty in swallowing or who are unconscious. Thus injectable composition is preferred in such patients. At the same, time problem of renal impairment does not allow them to take injection therapy. Thus, there exists a need in the art to develop a ready-to-use composition comprising posaconazole or its pharmaceutically acceptable salts, derivatives thereof, which is free of SBEBCD.

Some attempts have been made to provide the stable posaconazole injectable compositions.

CN105287403 discloses a freeze-dried composition of a prodrug of posaconazole which is free of cyclodextrin.

US10517867 discloses posaconazole derivative/prodrugs having improved solubility. The reference further discloses that these prodrugs can be formulated into an injection dosage form without use of cyclodextrin.

W02005117831 discloses a suspension composition of posaconazole with specialized excipients like phospholipid. US10307418 discloses a composition of azole drug with polyethylene glycol and benzyl alcohol/acidifed ethanol, wherein such composition is diluted with infusion fluid containing a lipid-based infusion emulsion fluid.

US9364433 discloses a non-aqueous homogenous solution comprising azole drug and amphiphilic liquid polymeric solvent like polyethylene glycol, and composition is free of non-polymeric solvents and surfactants.

However, all the prior attempts to produce alternative injection of posaconazole involve use of excipients which may interact with active and produce undesired side effect or are produced by tedious process of manufacture. Some compositions which are to be diluted before administration require a process of dilution leading to error in dosing. Some compositions are also not stable for longer time and difficult to re-disperse or re-suspend.

Thus, there exists a need for improved methods of delivering posaconazole which is safe for administration to all categories of patients as well as which is cost effective, which can be produced by simple manufacturing techniques, which can be stored for long term and moreover which provides patient compliance as well as is free of side effects. Hence, there is a need to develop a stable injectable composition of posaconazole.

The present invention overcomes the drawbacks of commercially available posaconazole injectable composition which does not require dilution process before administration, is devoid of cyclodextrin to avoid the side effects and is stable during the prolonged shelf life. Additionally, the present invention uses simple and economical production process.

As posaconazole has limited solubility and the composition has limited stability, development of long term storage stable posaconazole injection composition devoid of cyclodextrin and thus with less side effects is very challenging as there are high chances of change in the physical and chemical properties, development of impurities, particulate formation when such products are stored for long time.

The present invention addresses the need for a pharmaceutically stable ready to use posaconazole injectable composition having long term storage stability, with regard to retaining the ready to use liquid dosage form, avoiding unacceptable degradation to undesired related substances, providing minimal or lower irritation at the site of administration and less side effects. Also, since the compositions provided herein do not need the cumbersome procedure of dilution, they are easy to administer and demonstrate reduction in dosing errors.

The inventors of present invention have provided stable ready to use posaconazole injectable composition of posaconazole having prolonged stability.

OBJECT OF THE INVENTION:

An object of the invention is to provide stabilized, ready-to-use posaconazole injectable compositions.

Another object of the invention is to provide ready-to-use composition comprising posaconazole or its pharmaceutically acceptable salts, surfactants and optionally pharmaceutically acceptable excipients.

Another object of the invention is to provide a process for preparing stabilized, ready-to-use posaconazole injectable compositions.

One another object of the present invention is to provide safe, efficacious and easy to use injectable compositions of posaconazole.

One object of the present invention is to provide posaconazole injectable compositions which are substantially free of cyclodextrin. Another object of the present invention is to provide posaconazole injectable compositions which do not contain any cyclodextrin compounds.

Another object of the present invention to provide a method of treating fungal infections caused by Aspergillus and Candida species by administering stable ready-to-use injectable compositions of Posaconazole.

SUMMARY OF THE INVENTION

According to some embodiments, the compositions can include Posaconazole or its pharmaceutically acceptable salts, surfactants and optionally pharmaceutically acceptable excipients

In some embodiments, the compositions of present invention are substantially free of cyclodextrin. In another embodiment, the composition of the present invention do not contain any cyclodextrin compounds. In an embodiment the compositions of present invention are in the form of ready-to-use compositions.

According to some embodiments of present invention, the ready-to-use composition comprising posaconazole or its pharmaceutically acceptable salts, surfactants and optionally pharmaceutically acceptable excipients is provided.

According to some embodiments, the composition can be a ready-to-use composition of posaconazole that can be directly administered to patient without first combining with a pharmaceutically acceptable diluent.

In some embodiments, the composition can be ready-to-use composition of posaconazole ready for direct administration using a pre-filled syringe.

Also disclosed herein are processes for preparation of ready-to-use composition of posaconazole. Also disclosed herein are method for treating fungal infections caused by Aspergiluus and Candida species by administering ready-to-use injectable composition of posaconazole.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to stable injectable pharmaceutical composition comprising azole antifungal agent such as posaconazole. The invention particularly relates to a ready-to-use composition comprising posaconazole or its pharmaceutically acceptable salts, derivatives thereof and pharmaceutically acceptable excipients, process of preparing the composition and its use in the treatment of fungal infections caused by Aspergillus and Candida species.

Posaconazole has poor water solubility and thus is difficult to formulate it as a stable injectable composition. In accordance with the present invention, the stable posaconazole composition composition has been manufactured as an aqueous injection by using co-solvent and surface active agent in optimum amount. Without being bound to any theory, it has been believed that co-solvent and surfactants form layers around posaconazole particles so that it remains in dissolved form in the composition. The inventors of present invention have done rigorous experimentation to choose the excipients such as co-solvents, surface active agent, electrolytes, pH adjusting agents and other excipients to provide the injectable composition of posaconazole with desired and optimum characteristics.

The ready to use pharmaceutical injectable composition of present invention comprises posaconazole or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients thereof. The present invention provides ready to use long term storage stable pharmaceutical composition comprising Posaconazole or its pharmaceutically acceptable salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, polymorphs, and mixtures thereof. In one embodiment, the injectable composition comprising posaconazole or its pharmaceutically acceptable salt thereof is substantially free of cyclodextrin. In another embodiment, the injectable composition comprising posaconazole or its pharmaceutically acceptable salt thereof does not contain any cyclodextrin.

The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

The term “substantially free of cyclodextrin” denotes that cyclodextrin may be present in a concentration less than 120 mg/ml based on total weight of composition or solution.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

Viscosity describes the resistance that a liquid system offers to flow when it is subjected to an applied shear stress. A more viscous system requires greater force or stress to make it flow at the same rate as a less viscous system. A liquid system will exhibit either Newtonian or non-Newtonian flow based on a linear or a nonlinear increase, respectively, in the rate of shear with the shearing stress. Structured vehicles used in suspensions exhibit non-Newtonian flow and are typically plastic, pseudoplastic, or shear-thinning with some thixotropy (exhibiting a decrease in viscosity with an increase in the rate of shear).

The posaconazole injectable composition of the present invention may include pharmaceutically acceptable salts of posaconazole such as, maleate, sulphonate, succinate and hydrochloride.

The pharmaceutically acceptable excipients included in composition of present invention include, not limited to, surfactant system, solvent system, pH adjusting agents, isotonicity agent, suspending agent, complexing agent, viscosity modifiers, buffer, and aqueous vehicle and the like.

The injectable composition of the present invention comprises a surfactant system. The surfactant system comprises of a combination of a surfactant and co-surfactant. The term “surfactant” or “co-surfactant” as used herein means agents that lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid. Surfactants are usually organic compounds that are amphiphilic, i.e., they contain both hydrophobic groups (tails) and hydrophilic groups (heads). Therefore, a surfactant contains both a water-insoluble (or oil- soluble) component and a water- soluble component.

Surfactants can be classified according to polar head group. A non-ionic surfactant has no charged groups in its head. Nonionic surfactants have covalently bonded oxygen-containing hydrophilic groups, which are bonded to hydrophobic parent structures. The head of an ionic surfactant carries a net positive, or negative charge. If the charge is negative, the surfactant is more specifically called anionic; if the charge is positive, it is called cationic. If a surfactant contains a head with two oppositely charged groups, it is termed zwitterionic. An ideal interaction of hydrophilic and lipophilic group of surfactant with particle surface could be reason for obtaining appropriate suspension stability. The surfactant can be a non-ionic surfactant, an ionic surfactant (anionic or cationic), or a zwitterionic surfactant. The surfactant reduces the interfacial tension between the solid particles and the liquid vehicle. Pharmaceutically acceptable surfactant for this application include, but are not limited to, polysorbate or polyethoxylated castor oil, Polyoxyl 20 stearate, Polyoxyl 35 castor oil, poloxamer, D-a-Tocopheryl polyethylene glycol 1000 succinate, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate, Polyoxyl 40 Hydrogenated castor oil, Polysorbate, Polysorbate 20, Polysorbate 40, Polyoxyl 60 stearate, Polysorbate 85, Polysorbate 60, poloxamer 331, polyoxyethylene fatty acid esters, Polyoxyl 40 castor oil, poloxamer 188, polyoxyethylene polyoxypropylene 1800, oleic acid, Sodium desoxy cholate, Sodium lauryl sulfate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan trioleate, N-Carbamoyl methoxypolyethylene glycol 2000-1,2-distearol, myristic acid, Steareth, Stearic acid, Polyoxyl 40 stearate, Sucrose stearate, Tocopherol, polyoxyl castor oil, Triglyceride synthetic, Trimyristin, Tristearin, magnesium stearate, lecithin, lauryl sulfate, Vitamin E, egg yolk phosphatides, docusate sodium, Polysorbate 80, dimyristoyl phosphatidylglycerol, dimyristoyl lecithin, Capryol 90 (propylene glycol monocaprylate), Capryol PGMC (propylene glycol monocaprylate), deoxycholate, cholesterol, Cremophor EL, Propylene glycol alginate, Croval A- 10 (PEG 60 almond glycerides), Labrafil 1944 (oleoyl macrogol-6 glycerides), Labrafil 2125 (linoleoyl macrogol-6 glycerides), Labrasol (caprylocaproyl macrogol-8 glycerides), Lauroglycol 90 (propylene glycol monolaurate), Lauroglycol FCC (propylene glycol laurate), calcium stearate, Lecithin Centromix E, Lecithin Centrophase 152, Lecithin Central 3F21B, POE 26 glycerin, Olepal isosteariques (PEG-6 isostearate), Plural diisostearique (polyglycerol-3 -diisostearate), Plural Oleique CC, POE 20 Sorbitan trioleate, Tagat TO (polyoxyethylene glycerol trioleate), or Solutol (macrogol-15 hydroxystearate). Preferred surfactants include Polysorbate 20, Polysorbate 80, sorbitan monolaurate, and poloxamer 188. In one embodiment, the surfactant is polysorbate, such as polysorbate 20 or polysorbate 80. In yet another preferred embodiment, the surfactant is sorbitan monolaurate. The concentration of surfactant can be from about 0.1 mg/mL to about 500 mg/mL, from about 0.5 mg/mL to about 350 mg/mL, from about 5 mg/mL to about 300 mg/mL, or from about 2 mg/mL to about 100 mg/mL.

The injectable composition of the present invention comprises D-a-Tocopheryl polyethylene glycol 1000 succinate as the co-surfactant. Preferably, the injectable composition of the present invention contains about Img/ml to about 300 mg/ml of D-a-Tocopheryl polyethylene glycol 1000 succinate.

It was observed by inventors that balancing between surfactant system and ionic species were helpful to obtain stabilized injectable composition of present invention, wherein posaconazole was present in solubilized form.

In one embodiment, the injectable pharmaceutical compositions comprising posaconazole or its salts thereof and a solvent system, wherein the surfactant and the co-surfactant are present in a ratio from about 1 : 10 to about 10: 1.

The injectable composition of the present invention comprises a solvent system. The solvent system of the present invention comprises combination of solvents and co-solvents. Suitable solvent/co-solvent include, but are not limited to water for injection, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide (DMSO), diethylene glycol monoethyl ethers, caprylocaproyl polyoxyl-8 glycerides, glycofurol, or mixtures thereof.

In a preferred embodiment, the co-solvent is selected from polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000), povidone, and combinations thereof. In preferred embodiment, the co-solvent is polyethylene glycol 400. For polyethylene glycol 400, the concentration can be from about 1 mg/mL to about 600 mg/mL, from about 20 mg/mL to about 500 mg/mL. In one embodiment, the injectable pharmaceutical compositions comprising posaconazole or its salts thereof and a solvent system, wherein the solvent and the co-solvent are present in a ratio from about 1: 10 to about 10: 1.

The pH may be adjusted by the addition of one or more pharmaceutically acceptable acids. Examples of suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and combinations thereof. Examples of other suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid or other than acid variants which comprises sodium hydroxide. In one embodiment, the pH is adjusted with one or more organic acids selected from ascorbic acid, fumaric acid and citric acid. The pH adjuster in the pharmaceutical composition may range from about 0. IN to about 5N of pH adjuster e.g. hydrochloric acid, sodium hydroxide.

It is important to note here that aqueous solution of posaconazole or its pharmaceutically acceptable salts at higher pH (1 to 7), preferably at pH of about 2 to about 5 remains stable without any physical instability. The composition of present invention is a ready-to-use composition that is stable at lower temperatures between 2° to 8°C for prolonged shelf life.

The injectable composition of the present invention also includes a buffering and/or isotonic agents. Examples of buffering agents include, without limitation, sodium dihydrogenphosphate, disodium hydrogenphosphate, sodium phosphate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate, citric acid, sodium hydroxide, hydrochloric acid or the combinations thereof. Preferably, the injectable composition of the present invention contains about ImM to about 10 mM of buffering agents. Suitable isotonicity agents that may be used include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other osmotic adjusting agents may also include, but are not limited to, mannitol, glycerol, propylene glycol, dextrose and mixtures thereof. Preferably, the injectable composition of the present invention contains about Img/ml to about 9 mg/ml sodium chloride.

Suitable complexing agents that may be used include, but are not limited to calcium disodium edetate, disodium edetate, sodium edetate, edetate acid, a-cyclodextrin, P-cyclodextrin, hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7-P-cyclodextrin. In an embodiment, the injectable composition of the present invention contains about 0.05 mg/ml to about 5 mg/ml disodium edetate. In another embodiment, the injectable composition of the present invention contains less than about 120 mg/ml of cyclodextrin or its derivatives thereof.

The term “suspending agent” as used herein refers to a pharmaceutical acceptable excipient that promotes particle suspension or dispersion and reduces sedimentation. Suspending agents retard settling and agglomeration of particles by minimizing interparticle attraction. Suspending agents include protective colloids and viscosity- inducing agents. Protective colloids differ from surfactants in that they do not reduce interfacial tension. Many agents that are protective colloids in low concentration (<0.1%) are viscosity builders in higher concentrations (>0.1%). The increase in viscosity of the solution is helpful to prevent sedimentation of the suspended particles. A suspension has well developed thixotropy. At rest the composition is sufficient viscous to prevent sedimentation and thus aggregation or caking of the particles. When agitation is applied, the viscosity is reduced and provide good flow characteristic.

Examples of suspending agents include polysaccharides, inorganic salts, and polymers. Specific examples of suspending agents include, without limitation, alginates, colloidal silicon dioxide, agar, calcium stearate, magnesium aluminium silicate, guar gum, acacia, tragacanth, xanthan gum, bentonite, carbomer, carageenan, gelatin, dextrin, medium-chain triglycerides, sucrose, chitosan, polyoxyethylene, polyoxy-propylene ethers and combinations thereof. The concentration of the suspending agent can generally be from about 0.1 mg/mL to about 200 mg/mL, or from about 0.5 mg/mL to about 100 mg/mL. In preferred embodiment, concentration of the suspending agent is from about 1 mg/mL to about 90 mg/mL.

The particle size is a critical attribute for improving the solubilisation of posaconazole. The particle size of posaconazole as per the present invention may have a D90 about 10 pm to about 200 pm, preferably from about 15 pm to about 100 pm. In some embodiments, the particle size of posaconazole or a pharmaceutically acceptable salt thereof may have a D90 of at least about 10 pm 20 pm., 30 pm, 40 pm, 50 pm, 60 pm.

In some embodiments, the composition contains at least about 1 mg/mL to about 20 mg/ml posaconazole or a pharmaceutically acceptable salt thereof. Preferably, the concentration of posaconazole in the composition of present invention is equal to 1 mg/ml or 2 mg/ml.

The physical properties critically impact the release behaviour of the drug product. Amorphous and crystalline nature of drug substance also play a major role for the suspension and colloidal solutions. Crystallinity of the drug substance i.e. posaconazole governs solubility in the composition. Preferably, posaconazole in the composition of present invention is of crystalline or amorphous or combination thereof in nature.

In one embodiment, the injectable composition of the present invention is a ready to use solution of Posaconazole. In another embodiment, the injectable composition of the present invention is a ready to use aqueous solution of Posaconazole.

In one embodiment, the injectable composition of the present invention is substantially free of cyclodextrin.

In another embodiment, the injectable composition of the present invention comprises posaconazole, chelating agent, solvent, co-solvent, and a pH adjusting agent.

In a further embodiment, the injectable composition of the present invention comprises posaconazole, disodium edetate, sulfobutyl ether beta cyclodextrin, polyethylene glycol and water.

In an embodiment, the injectable composition of the present invention comprises posaconazole, disodium edetate, sulfobutyl ether beta cyclodextrin, ethanol, polyethylene glycol and water.

In one embodiment, the injectable composition of the present invention is free of cyclodextrin.

In another embodiment, the injectable composition of the present invention comprises posaconazole, solvent, co-solvent, surfactant, a pH adjusting agent and optionally a chelating agent.

In a further embodiment, the injectable composition of the present invention comprises posaconazole, benzyl alcohol, Polysorbate 80, polyethylene glycol and water. In an embodiment, the injectable composition of the present invention comprises posaconazole, benzyl alcohol, Polysorbate 80, lecithin, polyethylene glycol and water.

In one more embodiment, the injectable composition of the present invention comprises posaconazole, benzyl alcohol, dimethyl acetamide, propylene glycol, polyethylene glycol and water.

In another embodiment, the injectable composition of the present invention comprises posaconazole, benzyl alcohol, dimethyl acetamide, polyethylene glycol and water.

In one embodiment, the injectable composition of the present invention comprises posaconazole, Polysorbate 80, dimethyl acetamide, polyethylene glycol and water.

In an embodiment, the injectable composition of the present invention comprises posaconazole, polyoxyl 15 hydroxystearate, dimethyl acetamide, polyethylene glycol and water.

In a further embodiment, the injectable composition of the present invention comprises posaconazole, benzyl alcohol, polyoxyl 15 hydroxy stearate, polyethylene glycol and water.

In another embodiment, the injectable composition of the present invention comprises posaconazole, disodium edetate, Polysorbate 80, Vitamin E TPGS, polyethylene glycol and water.

In one embodiment, the injectable composition of the present invention comprises posaconazole, Polysorbate 80, Vitamin E TPGS, polyethylene glycol and water. In another embodiment, the injectable composition of the present invention comprises posaconazole, disodium edetate, Vitamin E TPGS, polyvinyl pyrrolidone, polyethylene glycol and water.

In one embodiment, the injectable composition of the present invention is a ready to use suspension of Posaconazole.

In another embodiment, the injectable composition of the present invention comprises posaconazole, a surfactant, a solvent and optionally a pH adjusting agent.

In one more embodiment, the injectable composition of the present invention comprises posaconazole, Polysorbate 80, polyethylene glycol, phosphate buffer and water.

The term "stable compositions" refers to those posaconazole ready- to- use injection compositions of present invention which are physically as well as chemically stable as demonstrated by compliance to acceptable specification when the composition is stored at convenient temperature, such as between about 0°C and about 60°C, for a commercially reasonable period of time, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, or at least about 2 years. Suitably, the composition of posaconazole of present invention remains physically stable, with no precipitation or crystallization or color change upon storage and the shelf life period of 18-24 months when stored at 2-8° C. Suitably, the composition of posaconazole remains chemically stable when stored at 2-8° C., wherein various parameters such as the drug content (assay of Posaconazole) and content of related substances, i.e. known and unknown impurities remains within specified limits such as those specified according to ICH guidelines, upon storage for prolonged period of time such as for at least 12 months, preferably for 18 months, more preferably 24 months or longer. The composition of present invention is substantially free of impurities. For purposes of the present invention, "substantially free of impurities' shall be understood to include posaconazole containing compositions in which the amount of total impurities is less than about 5% of the sum of peak areas of all degradants, as calculated on a normalized peak area response ("PAR) basis as determined by high performance liquid chromatograph ("HPLC) after a period of about 18 months at a temperature of from about 2° C. to about 8° C. The amount of impurities is further calculated as being based upon the original amount of posaconazole (or salt thereof) being present in the composition. Preferably, the said stable compositions of posaconazole prevent degradation of posaconazole such that not more than 2 % , not more than 1% , not more than 0.4%, not more than 0.2% of posaconazole impurity or impurities are formed over the storage period. In yet another preferred embodiment the value of assay of posaconazole remains within the specified limit of 90-110% by weight of the label claim; the highest unknown impurity remains within the specified limit of not more than 0.2%; the known Impurities (Hydroxy Triazole, Deshydroxy Posaconazole, Benzylated posaconazole) remains within the specified limit of not more than 0.29%.

The ICH storage stability studies were performed on ready to use posaconazole composition packaged in the proposed commercial primary packaging and closure system. The stability study samples were stored at 2-8°C, 25°C, 30°C, and 40°C. The necessary parameters viz., assay, related substances, particle size distribution, pH, and osmolality were tested and found to be within specification at both stability conditions. The stability data suggested long term stability at 2-8°C.

In some preferred aspects of the invention, the time for which long term storage are contemplated include periods of at least about 24 months or longer with such that the composition is substantially free of impurities when stored at 2-8°C.

While not wishing to be bound by any theory whatsoever, it is believed that the use of excipients such as surfactant system and solvent systems in preparing posaconazole compositions of the invention play a significant role in reducing the degradation of posaconazole thereby prolonging the shelf-life of said posaconazole compositions. The addition of the components of the injection for the preparation of injection can be achieved by methods known in the art.

In one embodiment, the injectable composition can be prepared by a process comprising (a) dissolving posaconazole in pre-acidified water for injection; (b) adding chelating agents and solvents/co-solvents to the solution of step (a); (c) making up volume with water for injection followed by adjusting the pH of solution of step (b) and (d) filtering the solution of step (c). Preferably, the process of preparation of the composition of the present invention is carried out under nitrogen purging or blanketing. The injectable composition of the present invention may be sterilized under aseptic conditions well known in the art, preferably sterilization by filtration.

The compositions of the present invention can be packaged in any suitable sterile vial or prefilled syringe or container fit for the sterile storage of a pharmaceuticals. The composition of present invention can be provided in a kit or package that includes a container enclosing the composition. Suitable containers can be glass vials, i.e. Schott treated vials, molded glass vials, and CZ resin vials, polypropylene or polyethylene vials or other special purpose containers. Suitable containers can be prefilled syringe such as glass prefilled syringes, plastic prefilled syringes. Containers are of a size sufficient to hold one or more doses of posaconazole. The container may be part of a syringe or separate from the syringe. The kit or package also includes a needle that can be suitably mounted to the syringe. The size of the needle, in some embodiments, is equal to or smaller than 18G, 19G, 20G, 21G, 22G, 23G, 24G, or 25G. In one embodiment, the needle has a size that is 20G or smaller. In one embodiment, the needle has a size that is 21G or smaller. In one embodiment, the needle has a size that is 22G or smaller. In one embodiment, the needle has a size that is 23G or smaller. In one embodiment, the ready to use injectable composition of the present invention may be administered without the need of an in-line filter during administration, demonstrating the absence of particulate matter throughout its shelflife. In another embodiment, the ready to use injectable composition of the present invention need to be fdtered by using an inline filter before administration.

The present invention further provides methods of treating a patient suffering from fungal infections caused by Aspergillus and Candida species by injection of the composition of the present invention at a recommended dose of 300 mg to 600 mg.

EXAMPLES

The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever.

Example 1

Process:

1. Sulfo-Butyl Ether Beta-Cyclodextrin and Disodium Edetate was dissolved in sufficient quantity of water for injection.

2. Posaconazole was added to step 1 gradually under stirring, followed by Polyethylene glycol.

3. pH of the solution was adjusted between 1.5 to 4 with hydrochloric acid.

The below table depicts the analytical results of the composition of Example 1.

Example 2:

Process

2. Posaconazole was added to step 1 gradually under stirring, followed by Polyethylene glycol and ethanol.

3. pH of the solution was adjusted between 1.5 to 4 with hydrochloric acid. Example 3 :

Process

1. Posaconazole was dissolved in benzyl alcohol

2. Polysorbate 80 was added to step 1 under stirring, followed by Polyethylene glycol PEG400.

3. Pre-acidifed water for injection (pH 1.5 -6.5) was added to solution of step 2 and stirred.

Example 4:

Process

1. Posaconazole was dissolved in benzyl alcohol 2. Polysorbate 80 was added to step 1 under stirring, followed by lecithin and Polyethylene glycol PEG400.

3. Ethanol was added to solution of step 2

4. Pre-acidifed water for injection (pH 1.5 -6.5) was added to solution of step 3 and stirred

Example 5 :

Process

1. Posaconazole was dissolved in benzyl alcohol

2. Dimethyl acetamide was added to step 1 under stirring, followed by Polyethylene glycol PEG400 ad propylene glycol.

3. Ethanol was added to solution of step 2

4. Pre-acidifed water for injection (pH 1.5 -6.5) was added to solution of step 3 and stirred.

Example 6:

Process

1. Benzyl Alcohol, Dimethyl acetamide, PEG 400, PEG 300 were mixed under stirring to get clear solution

2. pH of step 1 was adjusted between 1.5 to 6.5, and the solution was heated to 60°C.

3. Posaconazole was added to solution of step 2 and stirred to get a clear solution, volume was made up with water for injection.

Example 7 :

Process

1. Posaconazole was dissolved in Dimethyl acetamide and PEG 400 mixture to get a clear solution. 2. Polysorbate 80 was added under stirring to solution of step 1.

3. Volume was made up with water for injection (pre-acidified to pH 1.5-6.5).

Example 8:

Process

1. Posaconazole was dissolved in mixture of Dimethyl acetamide and Polyethylene glycol PEG 400

2. Kolliphor HS 15 was added to solution of step 1 under stirring.

3. Volume was made up with water for injection (pre-acidified to pH 1.5-6.5).

Example 9:

Process

1. Posaconazole was added in a mixture of benzyl alcohol and Polyethylene glycol PEG 400.

2. Kolliphor HS15 was added to solution of step 1.

3. Volume was made up with water for injection (pre-acidified to pH 1.5-6.5).

Example 10

Process

1. Posaconazole was added under stirring to pre acidified water for injection (pH 1.5 to 6.5).

2. Polyethylene glycol 400 and disodium edetate were added under stirring to solution of step 1.

3. Polysorbate 80 and Vitamin E TPGS were added to solution of step 2.

4. pH was adjusted with tromethamine solution and volume was made up with water for injection.

The below table depicts the analytical results of the composition of Example 10.

Example 11 :

Process

3. Vitamin E TPGS was added to solution of step 2.

The below table depicts the analytical results of the composition of Example 11.

Example 12:

Process

3. Vitamin E TPGS and Polyvinyl pyrrolidone PVP K12 were added to solution of step 2.

Example 13:

Process

1. Polysorbate 80/Poly sorbate 20 was dissolved in water for injection

2. Posaconazole was added to solution of step 1 slowly under stirring to get a homogenous slurry.

3. The slurry of step 2 was wet milled till a desired particle size was obtained.

4. Polyethylene glycol was added to solution of step 3 under stirring

5. Volume was made up with phosphate buffer.

Claims

We claim:

1. An injectable composition comprising (i) Posaconazole or its pharmaceutically acceptable salts thereof, (ii) solvent, (iii) co-solvent, and optionally one or more excipients selected from chelating agent, surfactants and pH adjusting agents.

2. The injectable composition according to claim 1, wherein the composition is an aqueous composition.

3. The injectable composition according to claim 1, wherein the composition is substantially free of cyclodextrin.

4. The injectable composition according to claim 1, wherein the composition does not contain cyclodextrin.

5. The injectable composition according to claim 1, wherein the composition is a solution.

6. The injectable composition according to claim 1, wherein the composition is a suspension.

7. The injectable composition according to claim 1, wherein the solvent and the co-solvent are present in a ratio from about 1 : 10 to about 10: 1.

8. The injectable composition according to claim 1 comprising posaconazole, disodium edetate, sulfobutyl ether beta cyclodextrin, polyethylene glycol and water.

9. The injectable composition according to claim 1 comprising posaconazole, benzyl alcohol, Polysorbate 80, polyethylene glycol and water.

10. The injectable composition according to claim 1 comprising posaconazole, benzyl alcohol, Polysorbate 80, lecithin, polyethylene glycol and water.

11. The injectable composition according to claim 1 comprising posaconazole, benzyl alcohol, polyoxyl 15 hydroxy stearate, polyethylene glycol and water.

12. The injectable composition according to claim 1 comprising posaconazole, disodium edetate, Polysorbate 80, Vitamin E TPGS, polyethylene glycol and water.

13. The injectable composition according to claim 1 comprising posaconazole, Polysorbate 80, Vitamin E TPGS, polyethylene glycol and water. The injectable composition according to claim 1 comprising posaconazole, disodium edetate, Vitamin E TPGS, polyvinyl pyrrolidone, polyethylene glycol and water. The injectable composition according to claim 1 comprising posaconazole, Polysorbate 80, polyethylene glycol, phosphate buffer and water.