FIELD OF INVENTION
The invention relates to a ready to use, non-aqueous pharmaceutical compositions comprising voriconazole or a pharmaceutically acceptable salt thereof. The invention also relates to a process for preparation of a ready to use, non-aqueous pharmaceutical compositions comprising voriconazole, wherein the composition is preferably administered intravenously.
BACKGROUND OF THE INVENTION
Voriconazole, (2R,3 S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl) -l-(lH-l,2,4-triazol-l-yl)-2-butanol, an anti-fungal agent, is disclosed in European patent no. EP 0 440 372 Bl and has following structure.
Drugs that are poorly soluble or insoluble in water provide challenges to their delivery. A problem associated with the use of voriconazole, however, is that voriconazole is practically insoluble in water (0.61 mg/ml at a pH 7; 0.2 mg/ml at a pH 3), due to which development of intravenous formulations, with a sufficient shelf life has proved to be difficult.
US Patent No. 6,632,803 describes pharmaceutical composition comprising voriconazole and sulfobutyl ether P-cyclodextrin (SBECD).
EP 2 018 866 Al describes a process for increasing solubility of voriconazole in aqueous solutions by complexation with beta-cyclodextrin.

EP 2 409 699 Al discloses pharmaceutical formulation comprising voriconazole, cyclodextrin and glycine, wherein glycine is present in a stabilizing amount.
WO 2012/171561 discloses pharmaceutical formulation comprising voriconazole, hydroxpropyl |3-cyclodextrin (HPPCD) and lactose, wherein lactose acts as a stabilizing agent.
Voriconazole is marketed as an intravenous solution, which is available as a lyophilized powder for solution for intravenous infusion and contains 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial. It is a single-dose, unpreserved product. Vials containing 200 mg lyophilized voriconazole are intended for reconstitution with water for injection to produce a solution containing lOmg/ml voriconazole and 160 mg/ml of sulfobutyl ether beta-cyclodextrin sodium.
It is desirable to provide a ready-to-use stable voriconazole composition that could be administered without the need for reconstituting lyophilized voriconazole available in market.
SUMMARY AND OBJECTIVES OF THE INVENTION
The invention relates to a ready to use, non-aqueous pharmaceutical composition comprising voriconazole or a pharmaceutically acceptable salt thereof.
An object of the invention is to provide a ready to use, non-aqueous pharmaceutical composition comprising voriconazole and atleast one solubilizer.
Yet another object of the invention is to provide a process for preparation of a ready to use, non-aqueous pharmaceutical composition comprising voriconazole and atleast one solubilizer.

Yet another object of the invention is to provide a ready to use, non¬aqueous pharmaceutical composition comprising voriconazole, for the treatment of a fungal infections to a person in need thereof.
DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION
The invention provides a ready-to-use, non-aqueous pharmaceutical composition comprising voriconazole a pharmaceutically acceptable salt thereof
Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".
The term "non-aqueous" as used herein refers to a composition which comprises less than 10% w/w water. In a more preferred embodiment, the composition according to the invention comprises less than 8% w/w water, in a more preferred embodiment less than 5% w/w water, in a more preferred embodiment less than 3% w/w water and in an even more preferred embodiment less than 2% w/w water.
In a preferred embodiment, the invention provides a ready to use, non¬aqueous pharmaceutical composition comprising voriconazole and atleast one solubilizer.
In accordance with the preferred embodiment of the invention, the pharmaceutically acceptable non-aqueous solvent system may comprise any pharmaceutically acceptable non-aqueous components known to persons skilled in the art, in which voriconazole is soluble, for example alcohols. Pharmaceutically acceptable alcohols for this application include, but are not limited to, ethanol, benzyl alcohol, tertiary-butyl alcohol, isopropyl alcohol, and suitable mixtures thereof.

Ethanol is commonly used as a solvent, co-solvent, and anti-microbial preservative in parenteral compositions. Small quantities of ethanol may also act as an antifoaming agent. Although other alcohols may be effectively used in voriconazole compositions, ethanol has been found to be a good solvent.
The term "stable" refers to any composition of voriconazole having sufficient stability to allow storage at a convenient temperature, such as 25°C/60%RH, more preferably between about 2°C and about 8°C, for a commercially reasonable period of time, such as at least about one week, at least about one month, at least about three months, at least about six months or at least about one year.
According to the present invention, voriconazole can be used as such or in form of pharmaceutically acceptable salts, solvates, or derivatives thereof. Pharmaceutically acceptable salts of voriconazole include the acid addition and base salts thereof. All references herein to voriconazole include references to salts or solvates thereof.
Pharmaceutically acceptable solubilizers according to the present invention include, but are not limited to, nonionic surfactants such as polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters (Polysorbates), polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxomers), and the like.
Polysorbates are a series of partial fatty acid esters of sorbitol and its anhydrides, co-polymerized with ethylene oxide. Polysorbates are used as solubilizing agents for a variety of substances and as wetting agents in the formulation of oral and parenteral suspensions. Polysorbate 80 is a yellow oily liquid having a HLB value of about 15. Polysorbate 80 is available commercially as Tween™ 80, Tego™ SMO 80, Tego SMO 80V, Durfax™ 80, Durfax 80K,

E433, Emrite™ 6120, Eumulgin™ SMO, Glycosperse™ O-20, Hodag™ PSMO-20, Liposorb™ O-20, Liposorb O-20K, Montanox™ 80, etc.
In a further embodiment, the present invention provides a ready to use, non-aqueous pharmaceutical composition comprising voriconazole, atleast one solubilizer and one or more pH regulating agents.
In a still preferred embodiment, for pH adjustment, one or more pH regulating agents include an acid, a base or a buffer or combinations thereof. The acid can be a mineral acid or an organic acid such as hydrochloric acid, nitric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, malic acid tartaric acid and the like.
In yet another embodiment, the present invention provides a process for preparation of a ready to use, non-aqueous pharmaceutical composition comprising voriconazole, according to the invention, comprising the steps of:
1. Adding batch quantity of dehydrated alcohol to a clean vessel.
2. Adding the pH regulating agent in the dehydrated alcohol under continuous stirring and mixing
3. Adding voriconazole and mixing until solution becomes clear.
4. Adding required quantity of solubilizer to above solution, mixing until solution becomes homogenous.
5. Aseptically filtering the drug product before filling in the glass vials.
6. Stopper and seal the vials.
In another embodiment, the suitable dose for the parenteral administration of voriconazole is between 0.1 to 25 mg/kg, preferably 0.5 to 20 mg/kg, more preferably 1 to 10 mg/kg.

In a yet another embodiment, the present invention provides suitable packaging materials useful for the pharmaceutical compositions according to the present invention. Small vials, usually made up of glass, containers that are sealed with a suitable stopper and seal, and other suitable primary containers may be used, such as, but not limited to, pre-filled syringes. The application includes use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and/or polypropylene and/or glass, glassine foil, polyvinyl chloride, polyvinylidene dichloride, etc. Optionally, the packaging material may comprise a glass container having a transparent plastic inner lining. Examples of plastic materials which may be used for containers or inner lining of the container include: polysulfones, polycarbonates, polypropylenes, polyethylenes (LDPE or HDPE), ethylene/propylene copolymers, polyolefins, acrylic-imide copolymers, PVC, polyesters (e.g. PET, PEN and the like), Teflon, Nylon, acetal (Delrin), polymethylpentene, PVDC, ethylvinylacetate etc. The plastic material can be transparent or translucent, to permit visual inspection of the contents.
In yet another embodiment, ratio of solubilizer to non-aqueous solvent as herein described is ranging from 10: 90 v/v to 90: 10 v/v. In yet another preferred embodiment, ratio of polysorbate 80 to dehydrated alcohol is 10: 90 v/v to 90: 10 v/v. More preferably ratio of polysorbate 80 to dehydrated alcohol is 50: 50 v/v.
Notwithstanding any other embodiments, the present invention also provides a ready to use, non-aqueous pharmaceutical composition comprising other triazole antifungal agents such as itraconazole.
In yet another embodiment, the present invention provides a method for treatment of a fungal infection comprising administration of an effective amount of a ready to use, non-aqueous pharmaceutical composition comprising voriconazole as per the present invention to the person in need thereof.
In a further embodiment of the invention, there is provided a pharmaceutical kit comprising a ready to use, non-aqueous pharmaceutical

composition comprising voriconazole and sterile infusion solutions such as Dextrose Injection, Sodium Chloride Injection, Lactated Ringer's Injection, or Water for Injection.
An appropriate dosage, frequency and duration of administration, i.e., treatment regimen, to be used in any particular situation will be readily determined by one skilled in the art without undue experimentation, the concentration of voriconazole in the composition will be about 1 mg/mL to about 25 mg/mL.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention.

EXAMPLES
Preparation of ready to use, non-aqueous pharmaceutical composition comprising voriconazole:
Table 1: Voriconazole formulations
Method:
1. Batch quantity of dehydrated alcohol was added in to a clean vessel.
2. The pH regulating agent was added in the dehydrated alcohol under continuous stirring and mixed until dissolved.
3. Voriconazole was added and mixed until solution became clear.

4. Polysorbate 80 was added to the above solution and mixed until solution became homogenous.
5. The drug product was aseptically filtered and filled in the glass vials before stoppering and sealing them.
Table 2: Itraconazole formulation
Method:
1. Batch quantity of ethanol was added in to a clean vessel.
2. The pH regulating agent was added in the dehydrated alcohol under continuous stirring and mixed until dissolved.
3. Itraconazole was added and mixed until solution became clear.
4. Polysorbate 80 was added into above solution, mixed until solution became homogenous.
5. The drug product was aseptically filtered and filled in the glass vials before stoppering and sealing them.

Table 3: Formulations obtained by the above mentioned process were subjected to stability and analyzed for the assay and total.
Stability studies conducted for the exemplified formulations.

Results of the stability studies indicate that the exemplified formulations are stable at the given temperature conditions.
While the invention has been described in detail with respect to specific embodiments thereof, it will be apparent that numerous modifications and variations are possible without departing from the scope of the invention.

WE CLAIM
1. A ready to use, non-aqueous pharmaceutical composition comprising voriconazole or a pharmaceutically acceptable salt thereof and atleast one solubilizer.
2. A ready to use, non-aqueous pharmaceutical composition comprising voriconazole, according to claim 1, wherein atleast one solubilizer is a non-ionic hydrophilic surfactant.
3. A ready to use, non-aqueous pharmaceutical composition comprising voriconazole according to claim 2, wherein said non-ionic hydrophilic surfactant is selected from polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters (Polysorbates), polyoxyethylene fatty acid esters, sorbitan esters (Span), glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxomers), and the like.
4. A ready to use, non-aqueous pharmaceutical composition comprising voriconazole according to claim 3, wherein said non-ionic hydrophilic surfactant is polysorbate 80.
5. A ready to use, non-aqueous pharmaceutical composition comprising voriconazole according to claim 1, wherein ratio of solubilizer/non aqueous solvent is in the range of 10: 90 v/v to 90: 10 v/v.
6. A ready to use, non-aqueous pharmaceutical composition comprising voriconazole according to claim 1, wherein ratio of polysorbate 80/ dehydrated alcohol is in the range of 10: 90 v/v to 90: 10 v/v.
7. A ready to use, non-aqueous pharmaceutical composition comprising voriconazole according to claim 6, wherein ratio of polysorbate 80/ dehydrated alcohol is 50: 50 v/v.

8. A process for the preparation of a ready to use, non-aqueous
pharmaceutical composition comprising voriconazole according to claim 1,
comprises the steps of:
i). Adding batch quantity of dehydrated alcohol in to a clean vessel.
ii). Adding the pH regulating agent in the dehydrated alcohol under continuous stirring with mixing
iii). Adding voriconazole and mixing until solution becomes clear.
iv). Adding required quantity of solubilizer to above solution with mixing until solution becomes homogenous.
vi). Aseptically filtering the drug product before filling into the glass vials.
9. A method for treatment of a fungal infection in a mammal in need of such
treatment, comprising intravenously administering a ready to use, non¬
aqueous pharmaceutical composition according to claim 1 to such mammal.