PARENTERAL FORMULATIONS OF POSACONAZOLE
Background of the invention
Posaconazole is a potent broad-spectrum azole antifungal agent useful in the treatment of invasive fungal infections. Posaconazole is chemically described 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. The structure is depicted below:

Posaconazole was developed by Schering-Plough Pharmaceuticals, formerly known as SCH 56592. Posaconazole was approved by the United States Food and Drug Administration on March 13, 2014 under the brand name Noxafil® as an injection containing Posaconazole, betadex sulfobutyl ether sodium (SBECD), edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection. Noxafil® injection is indicated for prophylaxis of invasive aspergillus and candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant recipients with graft-versus-host disease or those with hematologic malignancies with prolonged neutropenia from chemotherapy, administered by slow intravenous infusion.
U.S. Pat Nos. 5,703,079 and 5,661,151 to Anil et al., discloses Posaconazole, a broad spectrum anti-fungal agent and process of preparation thereof.

U.S. Pat No. 9,023,790 to Susan et al., discloses aqueous pharmaceutical compositions of Posaconazole stabilized by substituted [beta]-cyclodextrin, wherein the pH of said composition is between about 2.0 and about 3.5.
U.S Patent Application 2006/160823 to Lakshmanan et al., describes a formulation consisting of an injectable suspension of Posaconazole.
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, and the solubility of Posaconazole increases under acidic conditions. Hence the commercially available formulations of Posaconazole have acidic pH range.
Commercially available formulation of Posaconazole has acidic pH, however acidic pH is a primary cause of infusion phlebitis. By increasing the pH value of the parenteral formulations, incidence of phlebitis can be reduced to some extent. The inventors of the present invention have developed stable Posaconazole formulations which are stable even at pH range of 4 to 8.
Summary of the invention
One aspect of the invention provides stable parenteral pharmaceutical formulation of Posaconazole, wherein the pH of the formulation ranges from about 4 to 8.
The present invention relates to stable parenteral pharmaceutical formulation of Posaconazole comprising of Posaconazole, cyclodextrins, buffering agents/pH adjusting agents, solvents and optionally other pharmaceutically acceptable excipients, wherein the pH of the said formulation ranges from about 4 to 8.
Another aspect of the present invention provides manufacturing process for preparing stable formulation of Posaconazole, wherein the pH of the said formulation ranges from about 4 to 8.

Detailed description of the invention
In the context of this invention “Posaconazole” refers to the pharmaceutically acceptable salts, solvates, hydrates, acids and anhydrous forms thereof.
The term “about” is meant to encompass a pH range of ± 0.5 from the specified value or range.
The parenteral pharmaceutical formulations of the present invention can be in the form of liquid formulations or lyophilized formulations.
The inventors of the present invention have surprisingly found that it is possible to develop stable parenteral pharmaceutical formulation of Posaconazole having a pH range of 4 to 8, despite Posaconazole being soluble at acidic pH only.
An embodiment of the invention provides stable parenteral pharmaceutical formulation of Posaconazole having a pH in the range of 4 to 8.
An embodiment of the invention provides stable parenteral pharmaceutical formulation comprising:
i. Posaconazole ii. cyclodextrin iii. buffering agents and/or pH adjusting agents iv. one or more solvents and optionally other pharmaceutically acceptable excipients, wherein the pH of the formulation ranges from about 4 to 8.
A preferred embodiment of the invention provides stable parenteral pharmaceutical formulation comprising i. Posaconazole ii. SBECD iii. buffering agents and/or pH adjusting agents

iv. chelating agents selected from EDTA, DTPA, DOTA and salts thereof, and v. water, wherein the pH of the formulation ranges from about 4 to 8.
Suitable cyclodextrins include the following, but not limited to α, β, and γ-cyclodextrin and cyclodextrins modified with alkyl-, hydroxyalkyl-, dialkyl-, and preferably sulfoalkyl-ether modified cyclodextrins such as methyl or hydroxypropyl β-cyclodextrins (HPCD), methyl-and-ethyl-β-cyclodextrin, sulfoalkylether-substituted beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) and the like. Substituted beta-cyclodextrins include those substituted with one or more hydrophilic groups, such as monosaccharide (e.g., glucosyl, maltosyl), carboxyalkyl, hydroxyalkyl-substituted (e.g., hydroxyethyl, 2-hydroxypropyl) and the like. SBECD is the preferred cyclodextrin.
Suitable buffering agents include the following, but not limited to buffers such as phosphate, aconitic, citrate buffer, sodium carbonate, sodium bicarbonate, tartarate, benzoate, acetate buffer, lactate buffer, glutaric, malic, succinic and carbonic acid, alkali or alkaline earth salt of one of these acids, Tris buffer, histidine buffers, meglumine and amino acid buffers.
Particularly preferred amino acid buffers include lysine, arginine, histidine, alanine, glycine and the like. Analogs of amino acids may also be used. The amino acid in the formulation aids in the stabilization of the formulation, and to maintain the pH of the formulation in the range of 4 to 8.
pH adjusting agents which can be used as excipients in the present invention may be: acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and the like. Preferred pH adjusting agents are sodium hydroxide and hydrochloric acid.

The pharmaceutical formulations of the present invention contains chelating agents such as, but not limited to EDTA (Ethylenediaminetetraacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylenetriamine-N,N,N',N",N"-pentaacetate), EGTA (ethylene glycol-bis(β-aminoethyl ether)- N,N,N', N' tetraacetic acid); HEDTA (N (hydroxy ethyl) ethylenediaminetriacetic acid) and salts therof Preferred chelating agent is EDTA or salts thereof.
Suitable solvents include Ethanol, n-propanol, dimethylacetamide, dimethyl sulfoxide, tertiary butanol, glycerine, polyethylene glycols, propylene glycol, water and the like. Water is the preferred solvent.
The lyophilized product is reconstituted with a suitable diluent. Components of the diluent may be water, ethanol, buffers or agents to adjust solution osmolarity or other parenterally acceptable sugars, polyols, electrolytes or any suitable excipients.
The pharmaceutical formulations of the present invention may also contain anti¬oxidants, cryostabilizers, surfactants, tonicity modifiers, preservatives or any other suitable excipients.
Formulation of the present invention will have a pH from about 4 to 8. Preferably the pH would be from 4 to 7.
The most preferred embodiment of stable parenteral pharmaceutical formulation of Posaconazole comprises:
i) Posaconazole
ii) SBECD
iii) buffering agents and or pH adjusting agents, selected from the group comprising arginine, glycine, lysine, histidine, alanine, acetate salt, hydrochloric acid, sodium hydroxide and sodium phosphate.
iv) edetate sodium and
v) water, wherein pH of the formulation ranges from about 4 to 8.

The invention also provides process for preparing stable parenteral pharmaceutical formulation of Posaconazole. The process comprises:
i. Addition of chelating agent (if required) to the manufacturing vessel containing solvent and stirred till a clear solution is obtained. ii. Addition of cyclodextrin to the solution of step (i) followed by pH adjustment to around 1 to 3. iii. Addition of Posaconazole to another manufacturing vessel containing solvent or cyclodextrin solution, to get uniform wetting. The obtained suspension is slowly added to the solution of step ii, followed by stirring till a clear solution is obtained. iv. Finally pH of the solution is adjusted using suitable pH adjusting agent or buffering agent to around 4 to 8. v. Filtering and filling the solution in to suitable containers. vi. Optionally freeze drying the solution.
The following examples further describe certain specific aspects and embodiments of the present invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Manufacturing process
Water for injection was taken in a compounding vessel-I, edetate disodium was added and stirred. SBECD was added to the above solution and stirred till a clear solution was obtained. pH was adjusted using hydrochloric acid. Water for injection was taken in

another compounding vessel and Posaconazole was added to the water to form a suspension. The obtained suspension was slowly added to the solution present in compounding vessel-I and stirred till a uniform solution was obtained. Finally pH of the solution was adjusted using Arginine.
Manufacturing process
Water for injection was taken in a compounding vessel-I, edetate disodium was added and stirred. SBECD was added to the above solution and stirred till a clear solution was obtained. pH was adjusted using hydrochloric acid. Water for injection was taken in another compounding vessel and Posaconazole was added to the water to form a suspension. The obtained suspension was slowly added to the solution present in compounding vessel-I and stirred till a uniform solution was obtained. Finally pH of the solution was adjusted using glycine and sodium hydroxide.

Manufacturing process
Water for injection was taken in a compounding vessel-I, edetate disodium was added and stirred. SBECD was added to the above solution and stirred till a clear solution was obtained. pH was adjusted using hydrochloric acid to around 1.3. Posaconazole was pre-wetted by adding Posaconazole to cyclodextrin solution and mixed well until a homogeneous suspension was formed. The remaining cyclodextrin solution was added to the pre-wetted posaconazole suspension and mixed well until a clear solution was obtained. pH of the solution was adjusted up to 4.5 with Glycine. The solution was filtered and filled into sterilized vials with nitrogen purging, followed by freeze drying. The freeze dried product can be reconstituted with water for injection.
Manufacturing process
Water for injection was taken in a compounding vessel-I, edetate disodium was added and stirred. SBECD was added to the above solution and stirred till a clear solution was obtained. pH was adjusted using hydrochloric acid to around 1.3. Posaconazole was pre-wetted by adding Posaconazole to cyclodextrin solution and mixed well until a homogeneous suspension was formed. The remaining cyclodextrin solution was added to the pre-wetted posaconazole suspension and mixed well until a clear solution was obtained. pH of the solution was adjusted up to 4.5 with sodium acetate. The solution was filtered and filled into sterilized vials with nitrogen purging, followed by freeze drying. The freeze dried product can be reconstituted with water.

Manufacturing process
Water for injection was taken in a compounding vessel-I, edetate disodium was added and stirred. SBECD was added to the above solution and stirred till a clear solution was obtained. pH was adjusted using hydrochloric acid to around 1.4. Posaconazole was Pre-wetted by adding Posaconazole to cyclodextrin solution and mixed well until a homogeneous suspension was formed. The remaining cyclodextrin solution was added to the pre-wetted posaconazole suspension and mixed well until get a clear solution. pH of the solution was adjusted using sodium hydroxide. The solution was filtered through and filled into sterilized vials with nitrogen purging, followed by freeze drying. The freeze dried product is to be reconstituted with glycine buffer diluent.
Manufacturing process
Water for injection was taken in a compounding vessel-I, edetate disodium was added
and stirred. SBECD was added to the above solution and stirred till a clear solution was

obtained. pH was adjusted using hydrochloric acid to around 1.3. Posaconazole was Pre-wetted by adding Posaconazole to cyclodextrin solution and mixed well until a homogeneous suspension was formed. The remaining cyclodextrin solution was added to the pre-wetted posaconazole suspension and mixed well until get a clear solution. pH of the solution was adjusted using sodium hydroxide. The solution was filtered and filled into sterilized vials with nitrogen purging, followed by freeze drying. The freeze dried product should be reconstituted with 16.5 ml of sodium acetate diluent.

We claim
Claim 1: A stable, parenteral pharmaceutical formulation of Posaconazole comprising of Posaconazole and pharmaceutically acceptable excipients, wherein pH of the said formulation ranges from about 4 to 8.
Claim 2: A stable, parenteral pharmaceutical formulation of Posaconazole of claim 1, wherein pH of the said formulation is between 4 and 7.
Claim 3: A stable, parenteral pharmaceutical formulation comprising
(i) Posaconazole
(ii) cyclodextrin
(iii) buffering agent/pH adjusting agent
(iv) one or more solvents and
optionally other pharmaceutically acceptable excipients, wherein pH of the formulation ranges from about 4 to 8.
Claim 4: A stable, parenteral pharmaceutical formulation of claim 3, comprising
(i) Posaconazole
(ii) SBECD
(iii) buffering agent/pH adjusting agent
(iv) chelating agents selected from EDTA, DTPA, DOTA and salts thereof,
and
(v) water,
wherein pH of the formulation ranges from about 4 to 7.
Claim 5: The stable, parenteral pharmaceutical formulation of claim 4, wherein the buffering agents or pH adjusting agents are selected from the group comprising arginine, glycine, lysine, histidine, alanine, acetate salt, hydrochloric acid sodium hydroxide and sodium phosphate.