FIELD OF THE INVENTION
The present invention relates to a stable ready to use liquid pharmaceutical composition comprising Ziprasidone or its pharmaceutically acceptable salts and cyclodextrin or its derivatives. The composition is useful for treating psychotic disorder.
BACKGROUND OF THE INVENTION
Ziprasidone (I) is an antipsychotic agent and is approved by US FDA and other drug regulatory agencies for treating schizophrenia and bipolar 1 disorder.
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The US patent 6,232,304 Bl, describes the composition comprising a pharmaceutically acceptable salt of ziprasidone and cyclodextrin wherein the said salt is selected from the tosylate, tartrate, napsylate, besylate, aspartate, esylate and mesylate salt; and wherein said cyclodextrin is selected from y-cyclodextrin. sulfobutyl ether p-cyclodextrin sodium (SBECD) and hydroxy propyl P-cyclodextrin (HPBCD). The example-1 and 2 disclose that the composition is served in the vial either in the form of solution or lyophilized powder.
The PCT publication WO 2004/037289 A2, describes the depot composition comprising a ziprasidone mesylate which is solubilized with SBECD; and a viscosity agent.
In US, ziprasidone is marketed under the brand name GEODON as an oral capsule and as an injectable drug. US FDA label mentions that GEODON for

SUMMARY OF THE INVENTION
One embodiment of the present invention provides a stable ready to use liquid pharmaceutical composition comprising ziprasidone or its pharmaceutical ly acceptable salts and cyclodextrin or its derivatives.
Another embodiment of the present invention provides a stable ready to use liquid pharmaceutical composition comprising ziprasidone or its pharmaceutically acceptable salts and cyclodextrin or its derivatives in prefilled syringe or suitable vial presentation.
Another embodiment of the present invention provides a stable ready to use liquid pharmaceutical composition comprising ziprasidone or its pharmaceutically acceptable salts and cyclodextrin or its derivatives wherein the fill volume of the composition is 1 mL.
Another embodiment of the present invention provides a process for the preparation of a stable ready to use liquid pharmaceutical composition comprising ziprasidone or its pharmaceutically acceptable salts and cyclodextrin or its derivatives.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention provides a stable ready-to-use liquid pharmaceutical composition comprising ziprasidone or its pharmaceutically acceptable salts and cyclodextrin or its derivatives.
The term stable as mentioned herein includes both physical and chemical stability. The stability parameters include but not limited to potency, related substances, constant pH value and other physic-chemical parameters.
The term ready to use as mentioned herein refers to a liquid pharmaceutical composition which does not require reconstitution or further dilution. The ready to use liquid pharmaceutical composition is administered as such to the patient in need thereof.
The liquid pharmaceutical composition as mentioned herein refers to aqueous solution which is free or substantially free of any organic solvent or aqueous solution

injection contains a lyophilized form of ziprasidone mesylate trihydrate. and contains 20 mg base equivalent of ziprasidone. The lyophilized powder has to be reconstituted with 1.2 mL of sterile water for injection for intramuscular injection. Further, the label mentions that to administer a 10 mg dose, draw up 0.5 mL of the reconstituted solution. To administer 20 mg dose, draw up 1.0 mL of the reconstituted solution. Any unused portion should be discarded which results in an inaccurate dosage administration to the patient.
Lyophilization involves complex manufacturing processes, which in turn results in. increasing manufacturing costs. Before administration to patients the lyophilized powder composition must be reconstituted with suitable fluids to achieve desired concentration for administration. Therefore, an additional step of reconstitution causes inconveniences raising safety issues and risks of contamination by microorganisms. In addition, improper reconstitution may lead to high or low dosing to the patient in need.
There is a need for stable ready to use (RTU) aqueous liquid composition comprising ziprasidone or its pharmaceutical^ acceptable salt. The RTU composition of the present invention avoids complex lyophilization process, reconstitution step, possible external contamination and medication error.
OBJECTIVE OF THE INVENTION
An objective of the present invention is to provide a stable ready to use liquid pharmaceutical composition.
Another objective of the present invention is to provide a stable ready to use liquid pharmaceutical composition which avoids complex lyophilization process, reconstitution step, possible external contamination and medication error.
Another objective of the invention is to provide a stable ready to use liquid pharmaceutical composition in prefilled syringe or in suitable vial.
Another object of the present invention is to provide a process for the preparation of a stable ready to use liquid pharmaceutical composition.

The ready to use liquid pharmaceutical composition of the present invention is stable and is resistant to physical and chemical changes and hence ensures acceptable shelf life. Preferably, the pharmaceutical composition has sufficient stability to allow its storage at a convenient temperature, preferably between 0° C and 40° C; more preferably at 25°C; most preferably between 2°C and 8°C.
Another embodiment of the present invention provides a stable ready to use liquid pharmaceutical composition comprising ziprasidone or its pharmaceutically acceptable salts and cyclodextrin or its derivatives in prefilled syringe or suitable vial presentation.
The term stable as mentioned herein includes both physical and chemical stability. The stability parameters include but not limited to potency, related substances, constant pH value and other physic-chemical parameters.
The term ready to use as mentioned herein refers to a liquid pharmaceutical composition which does not require reconstitution or further dilution. The ready to use liquid pharmaceutical composition is administered as such to the patient in thereof.
The liquid pharmaceutical composition as mentioned herein refers to aqueous solution which is free or substantially free of any organic solvent or aqueous solution containing organic solvent. Aqueous solution as mentioned herein is water. Suitable organic solvent comprise, but not limited to, polar protic solvents and polar aprotic solvents or mixtures thereof. The polar protic solvents are known in the art and include alkyl alcohols, for example ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, isopropanol, tertiary butanol; acetic acid, alkyl glycols for example, ethylene glycol, propylene glycol and butylene glycol; glycerin; polyalkylene glycols, such as polyethylene glycol, polypropylene glycol, and polybutylene glycol, acetone, acetonitrile or mixtures thereof. The polar aprotic solvents are known in the art and include dimethyl acetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxone, acetonitrile, dimethyl formamide, propylene carbonate, chloroform,

containing organic solvent. Aqueous solution as mentioned herein is water. Suitable organic solvent comprise, but not limited to, polar protic solvents and polar aprotic solvents or mixtures thereof. The polar protic solvents are known in the art and include alkyl alcohols, for example ethanol. methanol, l-butanol, 2-butanol, 1-propanol, isopropanol, tertiary butanol; acetic acid, alkyl glycols for example, ethylene glycol, propylene glycol and butylene glycol; glycerin; polyalkylene glycols., such as polyethylene glycol, polypropylene glycol, and polybutylene glycol, acetone, acetonitrile or mixtures thereof. The polar aprotic solvents are known in the art and include dimethyl acetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1.4-dioxone. acetonitrile, dimethyl formamide, propylene carbonate, chloroform, dichloromethane, ethyl ether, l-methyl-2-pyrrolidione. l,3-dimethyl-2-imidazolidinone or mixtures thereof.
The pharmaceutical^ acceptable salts of Ziprasidone includes but not limited to tosylate, tartrate, napsytate, besylate, aspartate, esylate and mesylate salt; preferably mesylate.
The Cyclodextrin is selected from a-cyclodextrin, p-cyclodextrin and y-cyclodextrin; preferably p-cyclodextrin. The cyclodextin derivative is selected from hydroxylpropyl or sulfobutyl ether derivative; preferably hydroxy! propyl-p-cyclodextrin (HPBCD) and sulfobutyl ether-p-cyclodextrin sodium (SBECD); more preferably, the pharmaceutical composition comprises sulfobutyl ether-p-cyclodextrin sodium (SBECD).
The present invention provides a stable ready to ready to use liquid pharmaceutical composition having 1 mL fill volume. Use of 1 mL fill volume results in complete administration, 20 mg of Ziprasidone, of the drug product to the patient in need thereof.
The stable ready to use liquid pharmaceutical composition of the present invention optionally comprises antioxidants, tonicity adjuster, bulking agent, buffering agent, pH adjusting agent, solubilizer and stabilizer.

The stable ready to use liquid composition of the present invention optionally comprises antioxidants, tonicity adjuster, bulking agent, buffering agent, pH adjusting agent, solubilizer and stabilizer.
The ready to use liquid pharmaceutical composition of the present invention is stable and is resistant to physical and chemical changes and hence ensures acceptable shelf life. Preferably, the composition has sufficient stability to allow its storage at a convenient temperature, preferably between 0° C and 40° C; more preferably at 25°C; most preferably between 2°C and 8°C.
Another embodiment of the present invention provides a process for the preparation of a stable ready to use liquid pharmaceutical composition comprising;
a) dissolving cyclodextrin or its derivatives in required quantity of solvent for injection to obtain a solution
b) dissolving Ziprasidone or its pharmaceutically acceptable salts in the solution obtained in step (a) and
c) making the final volume into 100% .
The term stable as mentioned herein includes both physical and chemical stability. The stability parameters include but not limited to potency, related substances, constant pH value and other physio-chemical parameters.
The term ready to use as mentioned herein refers to a liquid pharmaceutical composition which does not require reconstitution or further dilution. The ready to use liquid composition is administered as such to the patient in need thereof.
Cyclodextrin or its derivatives is dissolved in suitable solvent at suitable temperature in the range of 10 to 80 °C; preferably 25- 650°C. The Cyclodextrin is selected from a-cyclodextrin, p-cyclodextrin and y-cyclodextrin; preferably p-cyclodextrin. The cyclodextin derivative is selected from hydroxy!propyl or sulfobutyl ether derivative; preferably hydroxylpropyl-p-cyclodextrin (HPBCD) and sulfobutyl ether-p-cyclodextrin sodium (SBECD); more preferably, the

dichloromethane, ethyl ether, l-methyl-2-pyrrolidione. l,3-dimethyt-2-imidazolidinone or mixtures thereof.
The pharmaceutical!)' acceptable salts of Ziprasidone includes but not limited to tosylate. tartrate, napsylate. besylate, aspartate, esylate and mesylate salt; preferably mesylate.
The Cyclodextrin is selected from a-cyclodextrin. p-cyclodextrin and y-cyclodextrin; preferably p-cyclodextrin. The cyclodextin derivative is selected from hydroxy Ipropyl or sulfobutyl ether derivative of cyclodextrin; preferably hydroxylpropyl-p-cyclodextrin (HPBCD) and sulfobutyl ether-p-cyclodextrin sodium (SBECD); more preferably, the composition comprises sulfobutyl ether-p-cyclodextrin sodium (SBECD).
A stable ready to use liquid pharmaceutical composition of the present invention is provided in pre-filled syringe (PFS) presentation or vial presentation. The PFS is selected from glass and plastic material; preferably glass PFS. The glass PFS is selected from USP Type I, Borosilicate glass syringe. The plastic PFS material is selected from cyclic olefin polymer, cyclic olefin copolymer and the like. The PFS is either staked with needle or stoppered. The PFS is used for self-administration or administration by another such as a medical professional. In certain embodiments, a prefllled syringe is provided in a sterile package. In some embodiments, such a package contains a plurality of prefllled syringes. In some embodiments, the prefllled syringe is substantially free of Tungsten. An advantage of using PFS presentation is that the dosing error is minimized or completely avoided. The vial presentation requires the physician or patient to withdraw the solution containing the drug product. Dosing error is likely to happen at the time of withdrawal of the solution. Hence, the necessary quantity of the drug product is not administered to the patient. In case of PFS, the solution containing drug product is administered as such and hence there will not be any dosing error.
The stable ready to use liquid pharmaceutical composition of the present invention also presented in vial which is selected from USP type I glass vial.

As described herein, Ziprasidone or its pharmaceutically acceptable salts is prepared according to the known methods available in the literatures such as US patent 4:831,031; US patent 5,359,068 and US patent 6,399,777.
The following example further describes certain specific embodiments of the invention and demonstrates 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. Experimental Section:

Manufacturing process:
1. SBECD was dissolved in required quantity of water at 45-55°C under
stirring.
2. The required quantity of Ziprasidone mesylate trihydrate was dissolved in
the solution obtained in step-1 under stirring at 45-55°C.
3. The final volume was made up to of 100% with water for injection and the
bulk solution was filtered.
4. The solution obtained in step-3 was filled into a prefilled syringe or a
suitable vial which was stoppered and sealed after filling.
The below Table-I describes stability of the ready to use liquid pharmaceutical composition of the present invention. Based on the 12 months stability data, the appropriate storage condition proposed for the ready to use liquid composition is 2-8°C.

pharmaceutical composition comprises sulfobutyl ether-|3-cyclodextrin sodium (SBECD).
The solvent is selected from aqueous and non aqueous solvent. The solvent is preferably aqueous solvent, i.e., water which is free or substantially free of any organic solvent. The water may contain any other organic solvent. The organic solvent comprises, but not limited to. polar protic solvents and polar aprotic solvents or mixtures thereof. The polar protic solvents are known in the art and include alkyl alcohols, for example ethanol. methanol, l-butanol. 2-butanol, l-propanol. isopropanol, tertiary butanol; acetic acid, alkyl glycols for example, ethylene glycol, propylene glycol and butylene glycol; glycerin; polyalkylene glycols, such as polyethylene glycol, polypropylene glycol, and polybutylene glycol, acetone, acetonitrile or mixtures thereof. The polar aprotic solvents are known in the art and include dimethyl acetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1.4-dioxone, acetonitrile, dimethyl formamide, propylene carbonate, chloroform, dichloromethane, ethyl ether, l-methyl-2-pyrrolidione, l,3-dimethyl-2-imidazolidinone or mixtures thereof.
Ziprasidone or its pharmaceutically acceptable salts is dissolved in the solution containing cyclodextrin or its derivative at suitable temperature in the range of I0-80°C; preferably 25-60°C. The pH of the solution obtained in step (b) is in the range of 3 to 5; preferably 3.5 to 4.6.
The solution comprising cyclodextrin or its derivatives and ziprasidone or its pharmaceutically acceptable salts, obtained in step (b), is made up to 100%. The bulk solution is optionally filtered through 0.2 micron or 0.4 micron PVDF filter; preferably 0.2 micron. The stable ready to use liquid pharmaceutical composition is packed in prefllled syringe or suitable vial which is stoppered and sealed after filling.
The stable ready to use liquid pharmaceutical composition of the present invention is optionally subjected to autoclave at about 12I°C for a period of between 5 to 15 minutes; preferably 12 minutes; more preferably 7 minutes.

Claims:
1. A stable ready to use liquid pharmaceutical composition comprising Ziprasidone or its pharmaceutically acceptable salts and cyclodextrin or its derivatives.
2. The composition of claim 1. wherein the cyclodextrin derivatives are selected from hydroxypropyl-P-cyclodextrin (HPBCD) and sulfobutylether-p-cyclodextrin sodium (SBECD).
3. The composition of claim 1, wherein the pharmaceutically acceptable salts are selected from hydrochloride, tosylate, tartrate, napsylate. besylate, aspartate, esylate and mesylate.
4. The composition claim 1. wherein the liquid pharmaceutical composition is an aqueous solution.
5. The composition of claim I, wherein fill volume of the liquid pharmaceutical composition is I mL.
6. A prefilled syringe comprising a stable ready to use liquid pharmaceutical composition of claim 1.
7. A prefilled syringe comprising a stable ready to use liquid pharmaceutical composition of claim I wherein the fill volume is 1 mL.
8. A process for the preparation of a ready to use liquid pharmaceutical composition comprising;

a) dissolving cyclodextrin or its derivatives in water for injection to obtain a solution,
b) dissolving Ziprasidone or its pharmaceutically acceptable salts in the solution obtained in step (a) and
c) making the final volume into 100%.

Tablc-II: Stability evaluation of ready to use liquid pharmaceutical composition under various conditions: