DESC:FIELD OF INVENTION
The present invention relates to a stable injectable pharmaceutical composition comprising posaconazole or its pharmaceutically acceptable salts thereof. The invention particularly relates to a ready-to-dilute composition comprising posaconazole or its pharmaceutically acceptable salts 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 INVENTION
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 µg/mL in neutral and basic aqueous solutions. The solubility increases under acidic conditions (e.g., 3 µg/mL at pH 3 and 800 µg/mL at pH 1). Solubility and stability are long identified factors hindering the development of therapeutic agents. Conventional delivery systems for very insoluble drugs typically use a combination of specialized excipients like cyclodextrins, extreme pH conditions, all of which are detrimental and toxic, when ingested in large amounts.
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™ injection is available as a sterile solution in the concentration of 18mg/mL and is administered after dilution with compatible mixture of diluent. Owing to the limited water solubility of posaconazole, the Noxafil™ contains the excipient Sulfobutyl Ether Sodium (SBECD). SBECD is a large, cyclic oligosaccharide that is predominantly excreted through glomerular filtration with a t1/2 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 Betadex Sulfobutyl Ether Sodium (SBECD) occurs. Serum creatinine levels needs to be closely monitored in these patients, and, if this level increases, injection therapy is to be discontinued and patients need to be switched to oral therapy. However, this switch of injection therapy to oral is not possible in the case of patients who have difficulty in swallowing or who are unconscious.
Thus, there exists a need in the art to develop a ready-to-dilute composition comprising posaconazole or its pharmaceutically acceptable salts thereof, which is free of such excipients like SBEBCD. The present invention relates to stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof, wherein said composition is free of cyclodextrin.
Further, the marketed Noxafil product (18mg/ml posaconazole) must be diluted with compatible admixture diluent to achieve a final concentration of 1-2mg/ml posaconazole before administration. There is a reported risk of particulate formation especially after the dilution step is carried out. It is of utmost challenge for a formulator to develop a composition that is stable even after dilution with compatible admixture diluent, and the exclusion of extreme solubilizer and stabilizer like cyclodextrin makes it even more challenging. The present invention also addresses this unmet need and relates to an injectable composition which remains stable for a sufficiently long period of time after dilution with compatible admixture diluent to allow for safe infusion to a subject in need thereof.
Some attempts have been made to provide the 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 the use of cyclodextrin.
WO2005117831 discloses a suspension composition of posaconazole with specialized excipients like phospholipid.
However, all the prior attempts involve use of excipients which may interact with the active ingredient or such excipients either produce undesired side effect or such prior attempts involve a tedious process of manufacture. Also, such references do not teach any means for retaining stability after dilution with compatible admixture diluent.
The present invention addresses specific unmet needs in the art by eliminating the addition of undesired excipients such as SBECD, and yet imparting stability upon dilution with compatible admixture diluent. The stable injectable compositions thus allow administration to patients with renal impairment or patients who cannot take oral therapy, for example patients who are unconscious. The injectable composition of the present invention thus also eliminates the need to shift renally impaired patients to oral therapy such as oral Posaconazole, Isavuconazole, and Echinocandins.

OBJECT OF THE INVENTION
An object of the invention is to provide a stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof.
Another object of the invention is to provide a stable injectable composition comprising (a) posaconazole or its pharmaceutically acceptable salts thereof, (b) a solvent mixture comprising atleast one polymeric organic solvent and atleast one non-polymeric organic solvent, and (c) atleast one surfactant.
Another object of the invention is to provide a process for preparing a stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof.
One another object of the present invention is to provide safe, efficacious and easy to use injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide an injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof which is free of cyclodextrin.
Another object of the present invention to provide a method of treating fungal infections caused by Aspergillus and Candida species by administering a stable ready-to-dilute injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION
The present invention relates to stable injectable pharmaceutical composition comprising posaconazole or its pharmaceutically acceptable salts thereof. The invention particularly relates to a ready-to-dilute composition comprising posaconazole or its pharmaceutically acceptable salts 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.
One embodiment relates to a stable injectable composition comprising (a) posaconazole or its pharmaceutically acceptable salts thereof, (b) a solvent mixture comprising atleast one polymeric organic solvent and atleast one non-polymeric organic solvent, and (c) atleast one surfactant.
In one embodiment, the stable injectable composition of the present invention is free of cyclodextrin.
In another embodiment, the stable injectable composition of the present invention is non-aqueous.
In an embodiment, the polymeric organic solvent is selected from polyethylene glycol and polypropylene glycol. In a specific embodiment, the polymeric organic solvent is polyethylene glycol.
In another embodiment, the non-polymeric organic solvent is selected from pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane, methanol, ethanol, 2-methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, octanol, ethyl acetate, 2-methoxyethyl acetate, butyl acetate, benzyl benzoate, benzene, toluene, pyridine, xylene, diethyl ether, 2-ethoxyethyl ether, ethylene glycol dimethyl ether, methyl t-butyl ether, formaldehyde, glutaraldehyde, acetone, 3-pentanone (diethyl ketone), ethylene glycol, propylene glycol, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, acetic anhydride, piperidine, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), benzonitrile, acetonitrile, hydrazine, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichlorobenzene, 1,2-dichloroethane, tetrachloroethylene and 1-chlorobutane, tetrahydrofuran,1,4-dioxane; and glycerin/glycerol. In a specific embodiment, the non-polymeric organic solvent is ethanol.
In a further embodiment, the surfactant is selected from D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), polysorbate or polyethoxylated castor oil, Polyoxyl 20 stearate, Polyoxyl 35 castor oil, poloxamer, 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 desoxycholate, 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 Centrol 3F21B, POE 26 glycerin, Olepal isosteariques (PEG-6 isostearate), Plurol diisostearique (polyglycerol-3-diisostearate), Plurol Oleique CC, POE 20 Sorbitan trioleate, Tagat TO (polyoxyethylene glycerol trioleate), or Solutol (macrogol-15 hydroxystearate). In a specific embodiment, the surfactant is D-a-Tocopheryl polyethylene glycol 1000 succinate.
In a more specific embodiment, the solvent mixture comprises polyethylene glycol and ethanol.
In an embodiment, the present invention relates to a stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof, wherein the ratio of surfactant: solvent mixture is greater than about 0.20:1. In a specific embodiment, the ratio of surfactant: solvent mixture is about 0.27:1
In one embodiment, the stable injectable composition of the present invention comprises (a) about 150 mg to about 600 mg posaconazole or its pharmaceutically acceptable salts thereof, (b) a solvent mixture comprising about 5 grams to about 15 grams of atleast one polymeric organic solvent and about 2 grams to about 5 grams of atleast one non-polymeric organic solvent, and (c) about 2 grams to about 8 grams of atleast one surfactant.
In another embodiment, the stable injectable composition of the present invention comprises (a) about 150 mg to about 600 mg posaconazole (b) a solvent mixture comprising about 5 grams to about 15 grams polyethylene glycol and about 2 grams to about 5 grams ethanol and (d) about 2 grams to about 8 grams D-a-Tocopheryl polyethylene glycol 1000 succinate.
In a further embodiment, the present invention relates to a stable injectable composition comprising (a) about 300 mg posaconazole (b) a solvent mixture comprising about 11 grams polyethylene glycol and about 3.3 grams ethanol and (c) about 4 grams D-a-Tocopheryl polyethylene glycol 1000 succinate.
In one embodiment, the stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof remain stable for atleast 1 hour after dilution with compatible admixture diluent.
In some embodiments, the stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof can be ready-to-dilute composition for direct administration using a pre-filled syringe.
Also disclosed herein are processes for the preparation of a stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof. Also disclosed herein are method for treating fungal infections caused by Aspergillus and Candida species by administering stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof.

Other objects, features and advantages of the present invention will be apparent to those of ordinary skill in the art in view of the following detailed description of the invention and accompanying drawings.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to stable injectable pharmaceutical composition comprising posaconazole or its pharmaceutically acceptable salts thereof. The invention particularly relates to a ready-to-dilute composition comprising posaconazole or its pharmaceutically acceptable salts 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 is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy] phenyl] -1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:

Posaconazole has poor water solubility and thus is difficult to formulate it as a stable injectable composition. Owing to the limited water solubility of posaconazole, the marketed product Noxafil™ contains the excipient SBECD. SBECD is a large, cyclic oligosaccharide that is predominantly excreted through glomerular filtration with a t1/2 elimination of 2 hours in patients with normal kidney function. If Noxafil™ is administered to patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), then accumulation of Betadex Sulfobutyl Ether Sodium (SBECD) occurs. Serum creatinine levels needs to be closely monitored in these patients, and, if this level increases, injection therapy is to be discontinued and patients need to be switched to oral therapy. However, this switch of therapy to oral is not possible in the case of patients who have difficulty in swallowing or who are unconscious.
The present invention addresses the specific unmet need by eliminating the addition of toxic excipients such as SBECD, and thus, allowing administration to patients with renal impairment or patients who cannot take oral therapy for example patients who are unconscious. The injectable compositions of the present invention thus also eliminates the need to shift renally impaired patients to oral therapy such as oral Posaconazole, Isavuconazole, and Echinocandins.
The inventors of present invention have done rigorous experimentation to choose the excipients such as solvents, and surfactants to provide the stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof having desired optimum characteristics.
The stable injectable composition of the present invention comprises posaconazole or its pharmaceutically acceptable salts thereof alongwith excipients. In one embodiment, the stable injectable composition of the present invention is free of cyclodextrin. The stable injectable composition of the present invention may include pharmaceutically acceptable salts of posaconazole such as, maleate, sulphonate, succinate and hydrochloride. The particle size is a critical attribute for improving the solubilization of posaconazole. The particle size of posaconazole as per the present invention may have a D90 about 10 µm to about 200 µm, preferably from about 15 µm to about 100 µm. In some embodiments, the particle size of posaconazole or its pharmaceutically acceptable salt thereof may have a D90 of at least about 10 µm, 20 µm, 30 µm, 40 µm, 50 µm, 60 µm. In some embodiments, the composition contains at least about 150 mg to about 600 mg posaconazole or its pharmaceutically acceptable salt thereof, more preferably about 250 mg to about 350 mg. In a more specific embodiment, the composition contains about 300 mg posaconazole or a pharmaceutically acceptable salt thereof.
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.
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.
The stable injectable composition of the present invention comprises (a) posaconazole or its pharmaceutically acceptable salts thereof, (b) a solvent mixture comprising atleast one polymeric organic solvent and atleast one non-polymeric organic solvent, and (c) atleast one surfactant. In one embodiment, the stable injectable composition of the present invention is free of cyclodextrin. In another embodiment, the injectable composition of the present invention is non-aqueous.
The stable injectable composition of the present invention comprise a solvent mixture to allow for solubilization of posaconazole and surfactant, as well as impart stability to the composition after dilution with compatible admixture diluents for infusion. The solvent mixture for the stable injectable composition of the present invention comprise atleast one polymeric organic solvent as well as atleast one non polymeric organic solvent.
The stable injectable composition of the present invention comprises a solvent mixture which further comprises atleast one polymeric organic solvent. Non-limiting examples of polymeric organic solvent are Polyethylene glycol (PEG) eg: PEG 400 and Polypropylene glycol (PPG), e.g. PPG 400, PPG 1200 and PPG 2000.
The stable injectable composition of the present invention may contain about 5 grams to about 15 grams, more preferably about 9 grams to about 13 grams of the polymeric organic solvent. In a more specific embodiment, the stable injectable composition of the present invention may contain about 11 grams of the polymeric organic solvent.
The stable injectable composition of the present invention comprise a solvent mixture which further comprises atleast one non polymeric organic solvent. Non polymeric solvents include, but not limited to pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane, methanol, ethanol, 2-methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, octanol, ethyl acetate, 2-methoxyethyl acetate, butyl acetate, benzyl benzoate, benzene, toluene, pyridine, xylene, diethyl ether, 2-ethoxyethyl ether, ethylene glycol dimethyl ether, methyl t-butyl ether, formaldehyde, glutaraldehyde, acetone, 3-pentanone (diethyl ketone), ethylene glycol, propylene glycol, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, acetic anhydride, piperidine, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), benzonitrile, acetonitrile, hydrazine, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichlorobenzene, 1,2-dichloroethane, tetrachloroethylene and 1-chlorobutane, tetrahydrofuran,1,4-dioxane; and glycerin/glycerol. The stable injectable composition of the present invention may contain about 2 grams to about 5 grams, more preferably about 2.5 grams to about 3.5 grams of the non polymeric organic solvent. In a more specific embodiment, the stable injectable composition of the present invention may contain about 3.3 grams of the non-polymeric organic solvent.
The term “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 their polar head group. A non-ionic surfactant has no charged groups in its head. Non ionic 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 the 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, D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), polysorbate or polyethoxylated castor oil, Polyoxyl 20 stearate, Polyoxyl 35 castor oil, poloxamer, 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 desoxycholate, 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 Centrol 3F21B, POE 26 glycerin, Olepal isosteariques (PEG-6 isostearate), Plurol diisostearique (polyglycerol-3-diisostearate), Plurol 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 D-a-Tocopheryl polyethylene glycol 1000 succinate. The stable injectable composition of the present invention may contain from about 2 grams to about 8 grams, more preferably from about 3 grams to about 5 grams of the surfactant. In a more specific embodiment, the stable injectable composition of the present invention may contain about 4 grams of the surfactant.
The present invention relates to stable injectable composition comprising (a) posaconazole or its pharmaceutically acceptable salts thereof, (b) a solvent mixture comprising atleast one polymeric organic solvent and atleast one non-polymeric organic solvent, and (c) atleast one surfactant. In one embodiment, the polymeric organic solvent is polyethylene glycol. In another embodiment, the non-polymeric organic solvent is ethanol. In one more embodiment, the solvent mixture comprises polyethylene glycol and ethanol. In an embodiment, the surfactant is a non-ionic surfactant. In a specific embodiment, the surfactant is D-a-Tocopheryl polyethylene glycol 1000 succinate. In one embodiment, the stable injectable composition of present invention comprises (a) about 150 mg to about 600 mg posaconazole or its pharmaceutically acceptable salts thereof, (b) a solvent mixture comprising about 5 grams to about 15 grams of atleast one polymeric organic solvent and about 2 grams to about 5 grams of atleast one non-polymeric organic solvent, and (c) about 2 grams to about 8 grams of atleast one surfactant. In another embodiment, the stable injectable composition of present invention comprises (a) about 150 mg to about 600 mg posaconazole (b) a solvent mixture comprising about 5 grams to about 15 grams polyethylene glycol and about 2 grams to about 5 grams ethanol and (c) about 2 grams to about 8 grams D-a-Tocopheryl polyethylene glycol 1000 succinate.
The present invention also relates to a stable injectable composition comprising (a) about 300 mg posaconazole (b) a solvent mixture comprising about 11 grams polyethylene glycol and about 3.3 grams ethanol and (c) about 4 grams D-a-Tocopheryl polyethylene glycol 1000 succinate.
The marketed Noxafil product (18mg/ml posaconazole) must be diluted with compatible admixture diluent to achieve a final concentration of 1-2 mg/ml posaconazole before administration. There is a reported risk of particulate formation especially after the dilution step is carried out. It is of utmost challenge for a formulator to develop a composition which is stable even after dilution with compatible admixture diluent, and exclusion of extreme solubilizer and stabilizer like cyclodextrin makes it even more challenging.
The inventors of present invention have done rigorous experimentation to select the excipients such as solvents, and surfactants in optimized quantities so as to formulate an injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof having stability for a sufficiently long time after dilution with a compatible admixture diluent so as to allow for safe infusion to a subject in need thereof.
The stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof remain stable for atleast 1 hour after dilution with compatible admixture diluent. The inventors have found that the ratio of surfactant: solvent mixture is critical for maintaining the stability of the injectable composition upon dilution with the compatible admixture diluent. Preferably, injectable compositions having a ratio of surfactant: solvent mixture greater than 0.20:1 were found to remain stable upon dilution for a sufficiently long time so as to allow for safe infusion to a subject in need thereof. In one embodiment, the present invention relates to a stable injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof, wherein ratio of surfactant: solvent mixture is greater than about 0.20:1. In a specific embodiment, ratio of surfactant: solvent mixture in the stable injectable composition of the present invention is about 0.27:1.
The term "stable" refers to an injection composition of present invention which is physically as well as chemically stable as demonstrated by compliance with 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. The term “stable” also refers to an injectable composition as per the present invention which exhibits physical stability for a sufficiently long time to allow for infusion of the product upon dilution with compatible admixture diluent such as sterile water for injection, saline or dextrose. The injectable compositions of the present invention remain stable after dilution with a compatible admixture diluent for a sufficient time to allow for infusion to be completed. Suitably, the injectable 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 injectable 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 at least 12 months, preferably for 18 months, more preferably 24 months or longer. The injectable composition of the present invention remains stable for atleast 1 hour after dilution with a compatible admixture diluent.
The marketed product Noxafil™ needs to be stored at 2-8°C only, which implies that the product is only stable at 2-8°C. Further, upon dilution with compatible admixture diluents for infusion, the Noxafil™ solution can be stored for upto 24 hours only at 2-8°C. The injectable composition of the present invention was surprisingly found to be stable for atleast about 12 months at 25°C, which is a tremendous improvement over the marketed product. Further, the injectable composition when diluted with compatible admixture diluents for infusion has demonstrated satisfactory stability for atleast about 12 months at 25°C.
The injectable 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 injectable 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 ICH storage stability studies were performed on the injectable composition of the present invention 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 is 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 surfactants and solvent mixture in preparing injectable composition comprising posaconazole or its pharmaceutically acceptable salts thereof play a significant role in reducing the degradation of posaconazole thereby prolonging the shelf-life of said posaconazole compositions. It is also believed that the ratio of surfactant: solvent mixture is critical for the physical stability of the injectable compositions of the present invention when diluted with a compatible admixture diluent for infusion to a subject in need thereof.
The addition of the components for the preparation of stable injectable composition can be achieved by methods known in the art.
In an embodiment, the injectable composition of the present invention can be prepared by a process comprising (a) dissolving posaconazole in a polymeric organic solvent; (b) dissolving surfactant in a non polymeric organic solvent; (c) adding solution of step (b) to solution of step (a); (d) making up volume of solution of step (c) with polymeric organic solvent and (e) aseptically filtering the solution of step (d) followed by filling in an appropriate container.
In a specific embodiment, the injectable composition of the present invention can be prepared by a process comprising (a) dissolving posaconazole in polyethylene glycol; (b) dissolving D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) in ethanol; (c) adding solution of step (b) to solution of step (a); (d) making up volume of solution of step (c) with polyethylene glycol and (e) aseptically filtering the solution of step (d) followed by filling in appropriate container. 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 stable injectable compositions of the present invention can be packaged in any suitable sterile vial or prefilled syringe or container fit for the sterile storage of pharmaceuticals. The stable injectable composition of the 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 stable 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 shelf life. In another embodiment, the stable injectable composition of the present invention may be filtered by using an in-line 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:
Components Function Quantity per vial (in grams)
A B C D E
Posaconazole Active 0.3 0.3 0.3 0.3 0.3
D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) Surfactant 2.5 3.0 3.3 3.5 8
Ethanol Non polymeric organic solvent 2 2.4 2.65 2.8 6.42
Polyethylene glycol (PEG 400) Polymeric organic solvent 13 11.9 11.35 10.8 11
Ratio of surfactant: solvent mixture 0.16:1 0.20:1 0.23:1 0.25:1 0.45:1
Physical stability upon dilution with compatible admixture diluent for infusion Stable for 45 mins Stable for 60 mins Stable for 90 mins Stable for 120 mins Stable for 330 mins

Manufacturing process:
a. Posaconazole was dissolved in polyethylene glycol (PEG 400).
b. D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) was dissolved in ethanol.
c. Solution of step (b) was added to the solution of step (a) under stirring.
d. Volume of solution obtained in step (c) was made up with polyethylene glycol (PEG 400).
e. Solution of step (d) was filtered aseptically under nitrogen.
f. Solution obtained in step (e) was filled in glass vials under nitrogen followed by stoppering and labelling.

The physical stability of the compositions 1A to 1E was evaluated after these compositions were diluted in compatible admixture diluent for infusion. As illustrated above, the ratio of surfactant: solvent mixture is crucial for stability of the injectable composition when diluted in a compatible admixture diluent. It can also be seen from compositions 1A to 1E that the ratio of surfactant: solvent mixture is critical for maintaining the physical stability when diluted with compatible admixture diluent for infusion. Compositions 1A and 1B having ratio of surfactant: solvent mixture as 0.16:1 and 0.20:1 respectively demonstrated physical stability for 45 minutes and 60 minutes respectively. Considering an infusion time of 90 minutes required by the marketed Noxafil™ product, compositions 1A and 1B demonstrated poor physical stability upon dilution with compatible admixture diluents for infusion. Compositions 1C, 1D and 1E having ratio of surfactant: solvent mixture as 0.23:1, 0.25:1 and 0.45: 1 respectively demonstrated physical stability of 90 minutes, 120 minutes and 330 minutes respectively, which was sufficient enough to allow for a 90 minute infusion time. The above data showed that compositions having a ratio of surfactant: solvent mixture greater than 0.20:1 demonstrated physical stability for a sufficiently longer time when diluted with compatible admixture diluents for infusion, so as to allow complete infusion to a subject in need thereof.

Example 2:
Components Function Quantity per vial
Posaconazole Active 300 mg
D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) Surfactant 4 g
Ethanol Non polymeric organic solvent 3.3 g
Polyethylene glycol (PEG 400) Polymeric organic solvent 11
Ratio of surfactant: solvent mixture 0.27:1

Manufacturing process:
The composition was manufactured in a similar manner as that of Example 1.
The above composition (undiluted) as well as after dilution with compatible admixture diluents for infusion was analysed for drug content (assay) and impurities and the data for the time points as per the ICH guidelines for stability is provided in the table below:
Condition Sample Assay Hydroxy triazole Des Hydroxy Posaconazole Benzylated Posaconazole Posaconazole N-Oxide-2 Impurity
Initial Initial
(undiluted) 98.4 ND ND < 0.1% (0.026%) ND
Initial (Diluted) 100.1 ND ND < 0.1% (0.025%) ND
90 min. (Diluted) 101 ND ND < 0.1% (0.024%) ND
180 min. (Diluted) 100.8 ND ND < 0.1% (0.025%) ND
25°C_
3M Initial (undiluted) 98.5 NA NA NA NA
Initial (Diluted) 100.3 ND ND < 0.1% (0.019%) ND
90 min (Diluted) 100.1 ND ND < 0.1% (0.019%) ND
180 min (Diluted) 100.3 ND ND < 0.1% (0.015%) ND
30°C_
3M Initial (undiluted) 98.7 NA NA NA NA
Initial (Diluted) 98.6 ND ND < 0.1% (0.018%) < 0.1% (0.018%)
90 min (Diluted) 98.7 ND ND < 0.1% (0.024%) ND
180 min (Diluted) 98.7 ND ND < 0.1% (0.021%) ND
40°C_
3M Initial (undiluted) 98.5 NA NA NA NA
Initial (Diluted) 97.2 ND ND ND ND
90 min (Diluted) 97.1 ND ND ND ND
180 min (Diluted) 97.2 ND ND ND ND
25°C_
6M Initial (undiluted) 101 < 0.1% (0.068%) ND < 0.1% (0.033%) ND
Initial (Diluted) 97.1 ND ND < 0.1% (0.022%) ND
90min (Diluted) 97.9 ND ND < 0.1% (0.040%) ND
180min (Diluted) 98.3 ND ND < 0.1% (0.078%) ND
30°C_
6M Initial (undiluted) 100.8 < 0.1% (0.049%) ND < 0.1% (0.039%) ND
Initial (Diluted) 98.8 ND ND < 0.1% (0.027%) ND
90min (Diluted) 98.3 ND ND < 0.1% (0.030%) ND
180min (Diluted) 98.6 ND ND ND ND
40°C_
6M Initial (undiluted) 100.3 ND ND < 0.1% (0.035%) ND
Initial (Diluted) 97.6 ND ND < 0.1% (0.026%) ND
90min (Diluted) 98.9 ND ND < 0.1% (0.035%) ND
180min (Diluted) 98.8 ND ND < 0.1% (0.046%) ND
25°C_
9M Initial (undiluted) 97.5 ND ND < 0.1% (0.033%) ND
Initial (Diluted) 97.0 ND ND < 0.1% (0.031%) ND
90min (Diluted) 99.2 ND ND < 0.1% (0.032%) ND
180min (Diluted) 99.4 ND ND < 0.1% (0.032%) ND
30°C_
9M Initial
(undiluted) 99.7 < 0.1% (0.018%) ND < 0.1% (0.033%) ND
Initial (Diluted) 99.3 ND ND < 0.1% (0.034%) ND
90min (Diluted) 99.1 ND ND < 0.1% (0.032%) ND
180min (Diluted) 99.7 ND ND < 0.1% (0.032%) ND
25°C_
12M Initial
(undiluted) 98.6 ND ND < 0.1% (0.026%) ND
Initial (Diluted) 99.9 ND ND < 0.1% (0.032%) ND
90min (Diluted) 99.5 ND ND < 0.1% (0.024%) ND
180min (Diluted) 100.6 ND ND < 0.1% (0.024%) ND
30°C_
12M Initial
(undiluted) 98.2 ND ND < 0.1% (0.044%) ND
Initial (Diluted) 99.5 ND ND < 0.1% (0.025%) ND
90min (Diluted) 98.9 ND ND < 0.1% (0.025%) ND
180min (Diluted) 99.5 ND ND < 0.1% (0.026%) ND

Condition Sample Posaconazole N-Oxide-1 Impurity Des-Ethyl Posaconazole Single Maximum Impurity Total Impurity
Initial Initial (undiluted) ND ND < 0.1% (0.040%) < 0.1%
Initial (Diluted) ND ND < 0.1% (0.042%) < 0.1%
90 min. (Diluted) ND ND < 0.1% (0.041%) < 0.1%
180 min. (Diluted) ND ND < 0.1% (0.039%) < 0.1%
25°C_3M Initial (undiluted) NA NA NA NA
Initial (Diluted) ND ND < 0.1% (0.085%) < 0.1%
90 min (Diluted) ND ND < 0.1% (0.087%) < 0.1%
180 min (Diluted) ND ND < 0.1% (0.079%) < 0.1%
30°C_3M Initial (undiluted) NA NA NA NA
Initial (Diluted) ND < 0.1% (0.012%) < 0.1% (0.079%) < 0.1%
90 min (Diluted) ND < 0.1% (0.007%) < 0.1% (0.099%) < 0.1%
180 min (Diluted) ND < 0.1% (0.010%) < 0.1% (0.083%) < 0.1%
40°C_3M Initial (undiluted) NA NA NA NA
Initial (Diluted) ND ND 0.101 0.101
90 min (Diluted) ND ND 0.106 0.106
180 min (Diluted) ND ND 0.102 0.102
25°C_6M Initial (undiluted) ND < 0.1% (0.004%) < 0.1% (0.066%) < 0.1%
Initial (Diluted) ND ND 0.125 0.125
90min (Diluted) ND < 0.1% (0.003%) 0.104 0.104
180min (Diluted) ND < 0.1% (0.004%) 0.100 0.100
30°C_6M Initial (undiluted) ND ND 0.108 0.108
Initial (Diluted) ND < 0.1% (0.006%) 0.100 0.201
90min (Diluted) ND < 0.1% (0.004%) 0.101 0.101
180min (Diluted) ND < 0.1% (0.006%) 0.106 0.106
40°C_6M Initial (undiluted) ND < 0.1% (0.004%) 0.331 0.331
Initial (Diluted) ND < 0.1% (0.005%) 0.243 0.243
90min (Diluted) ND < 0.1% (0.005%) 0.248 0.248
180min (Diluted) ND < 0.1% (0.005%) 0.243 0.243
25°C_9M Initial (undiluted) ND ND 0.126 0.126
Initial (Diluted) ND < 0.1% (0.003%) 0.115 0.115
90min (Diluted) ND < 0.1% (0.005%) 0.123 0.123
180min (Diluted) ND < 0.1% (0.005%) 0.120 0.120
30°C_9M Initial
(undiluted) ND ND 0.168 0.308
Initial (Diluted) ND < 0.1% (0.003%) 0.167 0.307
90min (Diluted) ND < 0.1% (0.006%) 0.169 0.308
180min (Diluted) ND < 0.1% (0.006%) 0.168 0.302
25°C_12M Initial
(undiluted) ND ND 0.121 0.236
Initial (Diluted) ND ND 0.125 0.238
90min (Diluted) ND ND 0.120 0.231
180min (Diluted) ND ND 0.115 0.227
30°C_12M Initial
(undiluted) ND ND 0.230 0.338
Initial (Diluted) ND ND 0.231 0.347
90min (Diluted) ND < 0.1% (0.006%) 0.227 0.227
180min (Diluted) ND ND 0.234 0.348
The term diluted in the parenthesis means that the undiluted composition on stability was diluted with compatible admixture diluents for infusion and was tested for assay and impurity.

The stability data indicates that the injectable composition manufactured as per above example is stable and it has also demonstrated good physical and chemical stability after dilution with compatible admixture diluents for infusion.
The above composition had a ratio of surfactant: solvent mixture of 0.27:1 and demonstrated physical stability for around 240 minutes (4 hours) when diluted with compatible admixture diluents for infusion. This data again highlights the importance of the ratio of surfactant: solvent mixture in maintaining the stability of the injectable composition as per the present invention.
Further, the marketed product Noxafil™ needs to be stored at 2-8°C only, which implies that the product is only stable at 2-8°C. Further, upon dilution with compatible admixture diluents for infusion, the Noxafil™ solution can be stored for upto 24 hours only at 2-8°C. The injectable composition of the present invention was surprisingly found to be stable for atleast about 12 months at 25°C, which is a tremendous improvement over the marketed product. Further, the injectable composition when diluted with compatible admixture diluents for infusion has demonstrated satisfactory stability for atleast about 12 months at 25°C.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
,CLAIMS:1. A stable injectable composition comprising (a) posaconazole or its pharmaceutically acceptable salts thereof, (b) a solvent mixture comprising atleast one polymeric organic solvent and atleast one non-polymeric organic solvent, and (c) atleast one surfactant.
2. The injectable composition according to claim 1, wherein the polymeric organic solvent is selected from polyethylene glycol and polypropylene glycol.
3. The injectable composition according to claim 1, wherein the polymeric organic solvent is polyethylene glycol.
4. The injectable composition according to claim 1, wherein the non-polymeric organic solvent is selected from pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane, methanol, ethanol, 2-methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, octanol, ethyl acetate, 2-methoxyethyl acetate, butyl acetate, benzyl benzoate, benzene, toluene, pyridine, xylene, diethyl ether, 2-ethoxyethyl ether, ethylene glycol dimethyl ether, methyl t-butyl ether, formaldehyde, glutaraldehyde, acetone, 3-pentanone (diethyl ketone), ethylene glycol, propylene glycol, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, acetic anhydride, piperidine, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), benzonitrile, acetonitrile, hydrazine, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichlorobenzene, 1,2-dichloroethane, tetrachloroethylene and 1-chlorobutane, tetrahydrofuran,1,4-dioxane; and glycerin/glycerol.
5. The injectable composition according to claim 1, wherein the non-polymeric organic solvent is ethanol.
6. The injectable composition according to claim 1, wherein the surfactant is a non-ionic surfactant.
7. The injectable composition according to claim 1, wherein the surfactant is D-a-Tocopheryl polyethylene glycol 1000 succinate.
8. The injectable composition according to claim 1, wherein the solvent mixture comprises polyethylene glycol and ethanol.
9. The injectable composition according to claim 1, wherein the ratio of surfactant: solvent mixture is greater than about 0.20:1.
10. The injectable composition according to claim 1, wherein the ratio of surfactant : solvent mixture is about 0.27:1.
11. The injectable composition according to claim 1, wherein posaconazole is present in an amount of about 150 mg to about 600 mg.
12. The injectable composition according to claim 1, wherein posaconazole is present in an amount of about 300 mg.
13. The injectable composition according to claim 1, wherein the polymeric organic solvent is present in an amount of about 5 grams to about 15 grams.
14. The injectable composition according to claim 1, wherein the polymeric organic solvent is present in an amount of about 11 grams.
15. The injectable composition according to claim 1, wherein the non-polymeric organic solvent is present in an amount of about 2 grams to about 5 grams.
16. The injectable composition according to claim 1, wherein the non-polymeric organic solvent is present in an amount of about 3.3 grams.
17. The injectable composition according to claim 1, wherein the surfactant is present in an amount of about 2 grams to about 8 grams.
18. The injectable composition according to claim 1, wherein the surfactant is present in an amount of about 4 grams.
19. The stable injectable composition of claim 1, comprising (a) about 150 mg to about 600 mg posaconazole or its pharmaceutically acceptable salts thereof, (b) a solvent mixture comprising about 5 grams to about 15 grams of atleast one polymeric organic solvent and about 2 grams to about 5 grams of atleast one non-polymeric organic solvent, and (c) about 2 grams to about 8 grams of atleast one surfactant.
20. The stable injectable composition of claim 1, comprising (a) about 150 mg to about 600 mg posaconazole (b) a solvent mixture comprising about 5 grams to about 15 grams polyethylene glycol and about 2 grams to about 5 grams ethanol and (c) about 2 grams to about 8 grams D-a-Tocopheryl polyethylene glycol 1000 succinate.
21. A stable injectable composition comprising (a) about 300 mg posaconazole (b) a solvent mixture comprising about 11 grams polyethylene glycol and about 3.3 grams ethanol and (c) about 4 grams D-a-Tocopheryl polyethylene glycol 1000 succinate.
22. The injectable composition according to any of the preceding claims, wherein the said composition is stable for atleast 1 hour after dilution with a compatible admixture diluent.
23. The injectable composition according to any of the preceding claims, wherein the said composition is free of cyclodextrin.
24. The injectable composition according to any of the preceding claims, wherein the said composition is non-aqueous.