FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[See Sections 10 and rule 13]
TITLE: Injectable Benzodiazepine Composition
Applicant: (a) Intas Pharmaceuticals Limited
(b) Nationality: Indian
(c) 2nd Floor, Chinubhai Centre, Ashram Road Ahmedabad- 380009 Gujarat. India.
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the invention
The present invention relates to stable, ready to use injectable benzodiazepine composition of drug which is class of psychoactive drugs having properties like sedative, hypnotic, anxiolytic and others. This ready to use injectable benzodiazepine composition comprises active pharmaceutical ingredient of benzodiazepine class, pharmaceutically acceptable solvent and optionally other pharmaceutically acceptable excepients. The preferable benzodiazepine drug is Olanzapine or its pharmaceutically acceptable salts.
Background
Drug of benzodiazepine class preferably, Olanzepine have affinity for both 5-HT2 serotonin receptor and D2 dopamine receptor and is used for the treatment of schizophrenia, acute manic episode in bipolar disorder, mild anxiety state and other psychotic disorders. Olanzapine, commonly used as antipsychotic drug, is recommended to be taken once a day before bed as it has high sedative effect.
In acute condition of psychotic disorder, Olanzapine is required to reach immediately at the site of action and thereby to provide quick relaxation to the patient. This result can be achieved by making use of injectable composition of Olanzapine. The present invention provides ready to use injectable composition of Olanzapine to provide quick relaxation in acute psychotic condition.
Prior Art
US 5229382 have disclosed the dosage forms of olanzapine, which may be tablet, capsule or injection for the treatment of schizophrenia, acute manic episode in bipolar disorder mild anxiety state and other disorder. As per the disclosure, dosage forms are coated or uncoated tablet and lyophilized injection.
It has been discovered about the discoloration property of olanzapine at the time of contact with other excipients. It is also observed about discoloration of olanzapine tablet by ambient air conditions, at elevated temperatures and by moist environments. This
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discoloration property leads to development of browning and mottling appearance on the tablet, which is not acceptable pharmaceutically. Further discoloration property may disturb a psychotic patient and cause trouble due to change in appearance of their medication.
To overcome discoloration problem, US 5919485 have disclosed solid oral composition comprising film coated tablet of Olanzapine. Although the film coated tablet has solve the discoloration problem of uncoated tablet, its oral administration may not be convenient for the psychotic patient.
Now a day, development of parenteral drug, preferably intramuscular or intravenous, olanzapine composition are of great importance on the ground of less time in the attainment of a therapeutically effective blood serum concentration of the drug as compared with administration by oral dosage form. Such intramuscular or intravenous composition are lyophilized form or ready to use form wherein the development of lyophilized injection has been resulted into an expensive and time consuming manufacturing process.
As in the treatment of psychotic patient, main aim in acute agitation is sedation so it is deemed necessary for the development of ready to use injectable composition of olanzapine. Hence through present invention, ready to use injectable benzodiazepine composition is developed which comprises olanzapine or its pharmaceutically acceptable salts and other pharmaceutically acceptable excipients.
Object of the Invention
The main object of the invention is to provide stable, ready to use injectable composition of benzodiazepine preferably olanzapine.
Further object of the invention is to get rapid control of agitation or aggressive behavior associated with an acute psychotic condition in patient by making use of stable, ready to use injectable composition of olanzapine.
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Another object of the invention is to provide rapid tranquilization to psychotic patients with acute schizophrenia.
Another object of the invention is to provide cost effective composition by reduction in the expanse of manufacturing process for making composition and thereby reduce health cost of patient.
Still another object of the invention is to develop ready to use injectable composition for single dose or multi dose.
Summary of the Invention
The present invention relates to stable, ready to use injectable composition of benzodiazepine drug, class of psychoactive drugs, having the properties like sedative, hypnotic, anxiolytic and others, comprising olanzapine or its pharmaceutically acceptable salt, pharmaceutically acceptable solvent and optionally other pharmaceutically acceptable excepients.
This invention also relates to stable; ready to use injectable composition of Olanzapine for multi dose and process for preparation thereof.
Detailed Description of the Invention
According to the present invention stable, ready to use injectable composition of benzodiazepine comprises olanzapine or its pharmaceutically acceptable salts, pharmaceutically acceptable solvent and optionally other pharmaceutically acceptable excipients. This injectable composition can be used as single dose or multi dose.
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'Multi dose' herein defined as dosage form intended to be administered on more than one occasion. This multi dose is stable and remains uncontaminated from microorganisms for prolonged duration. The multi does comprise at least 2 doses.
The preferable benzodiazepine drug, olanzapine or its pharmaceutically acceptable salt in injectable composition of the present invention is in amounts ranging from 2 mg to 20 mg/ml, more preferably 5 mg/ml.
The pharmaceutically acceptable solvent, used in the present invention, is in amounts maximum up to 1 ml, wherein solvent is selected from the group consisting of polyethylene glycol(s), glycerides, alcohols and the like or mixtures thereof.
The pharmaceutically acceptable glycerides are selected from the group comprising PEG-6 caprylic/capric triglyceride, caprylic/capric diglyceryl succinate, polyglycolysed glycerides, medium chain triglycerides, vegetable or synthetic fatty acid esters of polyhydric alcohols, Sorbitan fatty acid esters, penta erythritol fatty acid and polyalkylene glycol ethers.
Alcohol used in the present invention are selected from the group, but not limited to benzyl alcohol, ethanol, glycol, glycerol and the like or mixtures thereof.
The other pharmaceutically acceptable excipients, optionally used in the present invention, are selected from the group consisting of an antioxidant and/or a preservative.
Antioxidant or preservative, optionally used in the present invention, for prevention of oxidation of API and thereby to provide chemical stability to the composition, are selected from the group, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, sodium bisulfite, benzyl alcohol, sodium metabisulfite, monothioglycerol, ethyleneamine acetic acid salts and the like.
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Antioxidant or preservative used in this pharmaceutical^ composition is in amounts 0.01-2.5 %w/v.
Optionally other pharmaceutical^ acceptable excipients like surface active agent, stabilizers etc can be used in the present invention, which may be in amount ranging from 0.01-0.5 %w/v.
The present ready to use injectable composition is prepared by dissolving olanzapine in to solvent as disclosed in this invention by continuous stirring till it become clear yellow solution. Then optionally antioxidant and/or preservatives are added to mixture solution. Finally mixture volume is made up with solvent and spurge nitrogen gas to the solution and fills the solution into 2 ml clear glass ampoule
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Example
The ready to use injectable composition of the present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of this specification, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention.
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Sr.No Ingredients Range
1. Olanzapine 2-20 mg/ml
2. Solvent q.s to 1 ml
3. Anti-oxidant/preservative 0 - 0.5 % w/v
1. Take 70 mL of solvent in a beaker
1. Add olanzapine and stir till it dissolves to give clear yellow solution
2. Add optionally antioxidant or preservative to step 2 solutions and stir till the antioxidants or preservative dissolve completely.
3. Make up the volume to 100 mL with solvent
4. Spurge nitrogen gas to the solution of step 4
5. Fill the solution of step 4 into 2 ml clear glass ampoule
The present invention can be illustrated by but not limited to following example(s).
Example 1

Sr.No Ingredients Qty (mg/mL)
1. Olanzapine 5.0
2. Medium chain Triglycerides q.s to 1 mL
Procedure for a batch size of 100 mL:
1. Take 70 mL of Medium chain Triglycerides in a beaker
2. Add Olanzapine and stir till it dissolves to give clear yellow solution.
3. Make up the volume to 100 mL with Medium chain Triglycerides
4. Spurge nitrogen gas to the solution of step 3
5. Fill the solution of step 4 into 2 ml clear glass ampoule
Example 2

Sr.No Ingredients Qty (mg/mL)
1. Olanzapine 5.0
2. Butylated Hydroxytoluene 0.3
3. Butylated Hydroxyanisole 0.3
4. Medium chain Triglycerides q.s to 1 mL
Procedure for a batch size of 100 mL:
1. Take 70 mL of Medium chain Triglycerides in a beaker
2. Add Olanzapine and stir till it dissolves to give clear yellow solution
3. Add Butylated Hydroxyanisole and Butylated Hydroxytoluene to step 2 solution and stir till the antioxidants dissolve completely..
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4. Make up the volume to 100 mL with Medium chain Triglycerides
5. Spurge nitrogen gas to the solution of step 4
6. Fill the solution of step 4 into 2 ml clear glass ampoule
Example 3

Sr.No Ingredients Qty (mg/mL)
1. Olanzapine 5.0
2. Sodium metabisulfite 0.1 mL
3. Ethanol q.s to 1 mL
Procedure for a batch size of 100 mL:
1. Take 70 mL of Ethanol in a beaker
2. Add Olanzapine and stir till it dissolves to give clear yellow solution
3. Add Sodium metabisulfite and mix for 5-min and stir till it dissolves completely.
4. Make up the volume to 100 mL with Ethanol
5. Spurge nitrogen gas to the solution of step 4
6. Fill the solution of step 4 into 2 ml clear glass ampoule.
Example 4

Sr.No Ingredients Qty (mg/mL)
1. Olanzapine 5.0
2- j Butylated Hydroxytoluene 0.3
3. Butylated Hydroxyanisole 0.3
4. Benzyl Alcohol 0.1 mL
5. Medium chain Triglycerides q.s to 1 mL
Procedure for a batch size of 100 mL:
1. Take 70 mL of Medium chain Triglycerides in a beaker
2. Add Olanzapine and stir till it dissolves to give clear yellow solution
3. Add Butylated Hydroxyanisole and Butylated Hydroxytoluene to step 2 solutions and stir till the antioxidants dissolve.
4. Add Benzyl Alcohol to the solution of step 3 and mix for 5 min and stir till it dissolves completely.
5. Make up the volume to 100 mL with Medium chain Triglycerides
6. Spurge nitrogen gas to the solution of step 5
7. Fill the solution of step 6 into 2 ml clear glass ampoule
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Example 5

Sr.No Ingredients Qty (mg/mL)
1. Olanzapine 5.0
2. PEG 300 :PEG 400 (1:1) q.s to l mL
Procedure for a batch size of 100 mL:
1. Take 70 mL of Medium chain Triglycerides in a beaker
2. Add Olanzapine and stir till it dissolves to give clear yellow solution.
3. Make up the volume to 100 mL with PEG 300 : PEG 400 (1:1).
4. Spurge nitrogen gas to the solution of step 4
5.Fill the solution of step 4 into 2 ml clear glass ampoule.
Example 6

Sr.No Ingredients Qty (mg/mL)
1. Olanzapine 5.0
2. Tween 80 :PEG 400 (l : l) q.s to 1 mL
Procedure for a batch size of 100 mL:
1. Take 70 mL of Medium chain Triglycerides in a beaker
2. Add Olanzapine and stir till it dissolves to give clear yellow solution.
3. Make up the volume to 100 mL with Tween 80: PEG 400 (1:1).
4. Spurge nitrogen gas to the solution of step 4
5. Fill the solution of step 4 into 2 ml clear glass ampoule.
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We Claim,
1. Ready to use injectable benzodiazepine composition comprises Olanzapine or pharmaceutically acceptable salts, pharmaceutical^ acceptable solvent and optionally other pharmaceutically acceptable excipient.
2. Ready to use multi dose injectable benzodiazepine composition comprises olanzapine or pharmaceutically acceptable salts, pharmaceutically acceptable solvent and optionally other pharmaceutically acceptable excipient.
3. Injectable composition as claimed in claim 1 and 2, wherein solvent is selected from the group consisting of polyethylene glycol(s), glycerides, alcohol and the like or mixtures thereof.
4. Injectable composition as claimed in claim 1 and 2, optionally comprises antioxidant and / or preservative.
5. Injectable composition as claimed in claim 4, antioxidant or preservative can be selected from the group comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, sodium bisulfite, benzyl alcohol, sodium metabisulfite, monothioglycerol, ethyleneamine acetic acid salts.
6. Injectable composition as claimed in claim 3, alcohol can be benzyl alcohol, ethanol, glycol, glycerol or mixtures thereof.
7. Ready to use injectable composition of olanzapine as claimed in claim 1 and 2, wherein, olanzapine 2-20 mg/mL, solvent up to 1 ml, and antioxidant/ preservative 0 - 0.5 % w/v.
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8. Ready to use injectable composition as claimed in claim 2, can be in the form of multi dose comprises at least two doses.
9. A process for preparation of stable, ready to use injectable composition of olanzapine for single dose or multi dose comprises olanzapine 2-20 mg/mL, solvent up to 1 ml, antioxidant/preservative 0 - 0.5 %w/v.
10. Stable ready to use injectable benzodiazepine composition of olanzapine for single dose or multi dose as herein described with foregoing description and examples.