FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
STABILIZED PHARMACEUTICAL COMPOSITION CONTAINING LORAZEPAM OR SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a stabilized pharmaceutical composition for the parenteral administration comprising Lorazepam or pharmaceutically acceptable salts thereof wherein the composition comprises sparged/purged carbon dioxide that imparts better stability and significant reduction in the impurity level as compared to the use of nitrogen gas.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. Description
The present invention provides a stabilized pharmaceutical composition for the parenteral administration comprising Lorazepam or pharmaceutical^ acceptable salts thereof wherein the composition comprises sparged/purged carbon dioxide that imparts better stability and significant reduction in the impurity level as compared to the use of nitrogen gas.
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Lorazepam is a benzodiazepine derivative with antianxiety and sedative effects. Chemically Lorazepam is 7-chloro-5-(0-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzo-diazepin-2-one (Formula I). It is commercially available under the trade name of Ativan®. Lorazepam is indicated in adult patients for preanesthetic medication, producing sedation (sleepiness or drowsiness), relief of anxiety, and a decreased ability to recall events related to the day of surgery. It is most useful in those patients who are anxious about their surgical procedure and who would prefer to have diminished recall of the events of the day of surgery.


US Patent No. 4,017,616 discloses a non-aqueous parenteral dosage forms of benzodiazepine compounds comprise from about 10% to about 65% polyethylene glycol, from about 35% to about 90% propylene glycol, from 0% to about 10% benzyl alcohol, and 1 mg. to 15 mg. of benzodiazepine compound per ml.
U.S. Pat. No. 3,123,529 describes partially aqueous parenteral formulations for the benzodiazepine drug (e.g. diazepam) and provides solutions of the subject benzodiazepine, which are highly unstable.
U.S. Pat. No. 3,228,834 describes partially aqueous parenteral formulations for the benzodiazepine drug (e.g. chlorodiazepoxide) and describes a diluent, which is mixed with the benzodiazepine compound only shortly before administration.
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Use of inert gases like nitrogen, carbon dioxide, helium, or argon to stabilize the parenteral formulation is well known in the prior art. Also, it is well known that Lorazepam upon storage losses a molecule of water and rearranges to form 6-chloro-4-(o-chlorophenyl)-2-quinazoline carboxaldehyde (Impurity C).


In the light of the prior and the problem exemplified above, the present inventors while developing a stable parenteral formulation of Lorazepam or salt thereof have individually studied the effect of inert gases like carbon dioxide and nitrogen on the stability of Lorazepam injection at accelerated condition. While working, inventors have surprisingly found that the when carbon dioxide is sparged/purged into the Lorazepam injection it imparts better stability and significant reduction in the level of impurity C (6-chloro-4-(o-chlorophenyl)-2-quinazoline carboxaldehyde) by preventing the loss of water molecule, which further prevents the rearrangement of diazepine ring that leads to the formation of impurity C.
The inventors have surprisingly found that carbon dioxide, as an inert gas is more effective in reducing the level of impurity C as compared to nitrogen as an inert gas. The present inventors have also surprisingly found that the level of impurity C is reduced in carbon dioxide sparged/purged Lorazepam injection when compared to commercially available ATIVAN® injection (Lorazepam injection) after 3 months of storage at accelerated condition.
In one of the aspects of the present invention there is provided a stable pharmaceutical composition comprising Lorazepam or pharmaceutically acceptable salts thereof in admixture with pharmaceutically acceptable excipients wherein the said pharmaceutical composition is stabilized by sparging/purging carbon dioxide gas.
In yet another aspect of the present invention there is provided a method of stabilizing pharmaceutical composition comprising Lorazepam or pharmaceutically acceptable salts thereof in admixture with pharmaceutically acceptable excipients wherein the said method comprise the step of sparging/purging carbon dioxide as an inert gas.
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The pharmaceutical composition contains Lorazepam as an active ingredient. The composition can be prepared by cooling propylene glycol in a jacketed manufacturing vessel and then mixing it with polyethylene glycol 400 and sparging/purging inert gas (carbon dioxide or nitrogen) for sufficient time. Lorazepam is added into Benzyl alcohol and transferred to the solution of polyethylene glycol 400 and propylene glycol. The resultant solution is again sparged/purged with inert gas (carbon dioxide or nitrogen) for sufficient time. The resultant solution is then filtered through 5-inch glass fiber cartridge filter (pore size 2-20 m) followed by a 5-inch PVDF cartridge filter (pore size 0.2 u). Solution is then filled into suitable vial and purged with carbon dioxide. The composition is meant for parenteral administration.
The method of stabilizing pharmaceutical composition comprising Lorazepam as an active ingredient involves the step of sparging/purging carbon dioxide gas. Sparging/purging of carbon dioxide imparts better stability after 3 months of storage at accelerated condition and reduces the level of impurity C upto 25% when compared to Lorazepam injection sparged/purged with nitrogen gas. Also, when the composition of the present invention (sparged/purged with carbon dioxide) was compared with commercially available ATIVAN® injection (Lorazepam injection), it showed a decrease of about 25% in the level of impurity C after 3 months of storage at accelerated condition. Moreover, the level of total impurities is reduced upto 25% after 3 months of storage at accelerated condition.
Impurity C refers to 6-chloro-4-(o-chlorophenyl)-2-quinazoline carboxaldehyde.
Accelerated condition refers to the storage of composition at temperature of 25°C and 60% Relative Humidity.
Pharmaceutically acceptable excipients can be selected from a group comprising of one or more of solubilizing agent, preservatives, non-aqueous vehicle,
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chelating agents, antioxidants and reducing agent, buffers and pH adjusting agents, tonicity adjustors and the like.
Suitable solubilizing agent includes one or more of polyethylene glycol, polysorbates, sodium lauryl sulfate and the like.
Suitable preservatives include one or more of benzyl alcohol, methyl paraben, propyl paraben, benzyl paraben and the like.
Suitable non-aqueous vehicles include one or more of polysorbates, cremophore, polyethylene glycols, oils like castor oil or sesame oil, ethanol, benzyl alcohol, propylene glycol and the like.
Suitable chelating agents include one or more of ethylenediaminetetraacetic acid, diethylene triamine pentaacetic acid, dimercaptosuccinic acid, deferoxamine and the like.
Suitable antioxidants and reducing agents include one or more of ascorbic acid, gentisic acid tocopherol-derived compounds, butylated hydroxyanisole, butylated hydroxytoluene, citric acid and the like.
Suitable buffers and pH adjusting agents include one or more of hydrochloric acid, sulphuric acid ascorbic acid, aspartic acid, benzoic acid, potassium dihydrogen phosphate, sodium hydrogen phosphate and the like.
Suitable tonicity adjustors include one or more of sodium chloride, dextrose and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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Example 1
Table 1: Composition of Lorazepam Injection 2 mg/mL and 4 mg/mL

S.No. Ingredients Quantity
2 mg/mL 4 mg/mL
1. Lorazepam 2mg 4mg
2. Polyethylene glycol 400 0.18 mL 0.18 mL
3. Benzyl alcohol 2.0 % 2.0 %
4. Propylene glycol q.s. to 1 mL q.s. to 1 mL
Procedure: Collect the propylene glycol in a jacketed manufacturing vessel and cool it to a temperature below 10°C. Add and mix homogenously, the polyethylene glycol 400 with continuous stirring and sparge/purge inert gas. Add Lorazepam into Benzyl alcohol, and transfer the resultant suspension to the solution of polyethylene glycol 400 and propylene glycol and stir till clear solution is obtained. Make up the volume and sparge/purge inert gas. Filter the obtained solution through suitable filter. Filtered solution is filled into suitable vials and vial headspace is purged with inert gas. Stopper the vial with suitable stoppers.
Table 2 Data showing effect of purged carbon dioxide and nitrogen on the stability of Lorazepam Injection (4 mg/mL) done at accelerated condition for 3 months.

Stability Condition Impurity C (%) Total Impurities (%)
Nitrogen Carbon Dioxide Nitrogen Carbon Dioxide
Initial 0.000 0.000 0.039 0.039
1M/25°C 2.905 (Up)* 2.944 (Inv)* 2.435 (Up) 2.311 (Inv) 2.929 (Up) 2.968 (Inv) 2.460 (Up) 2.331 (Inv)
2M/25°C 6.325 (Up) 6.328 (Inv) 5.115 (Up) 4.862 (Inv) 6.372 (Up) 6.384 (Inv) 5.205 (Up) 4.904 (Inv)
3M/25°C 8.526 (Up) 8.349 (Inv) 6.626 (Up) 6.546 (Inv) 8.611 (Up) 8.440 (Inv) 6.685 (Up) 6.614 (Inv)
* Upright positi on "Inverted Po sition

Table 3 Stability data showing percentage of impurity C and total impurities in ATIVAN® injection (4 mg/mL) and Lorazepam injection (4 mg/mL) purged with carbon dioxide done at accelerated condition for 3 months.

Stability Condition Impurity C (%) Total Impurities (%)
ATIVAN® injection Lorazepam injection purged with Carbon Dioxide ATIVAN® injection Lorazepam injection purged with Carbon Dioxide
Initial 1.976 0.000 2.840 0.039
1M/25°C 5.775 2.435 (Up)* 2.311 (Inv)* 6.923 2.460 (Up) 2.331 (Inv)
2M/25°C 7.576 5.115 (Up) 4.862 (Inv) 8.703 5.205 (Up) 4.904 (Inv)
3M/25°C 9.054 6.626 (Up) 6.546 (Inv) 9.950 6.685 (Up) 6.614 (Inv)
* Upright po sition "Invert ed Position

WE CLAIM:
1. A stable pharmaceutical composition comprising Lorazepam or pharmaceutical^ acceptable salts thereof in admixture with pharmaceutical^ acceptable excipient wherein the said composition is stabilized by sparging/purging carbon dioxide gas
2. A method of stabilizing pharmaceutical composition comprising Lorazepam or pharmaceutically acceptable salts thereof in admixture with pharmaceutically acceptable excipients wherein the said method comprise the step of sparging/purging carbon dioxide as an inert gas.
3. As per claim 1 and 2, a stable pharmaceutical composition has reduced level of impurity C.
4. As per claim 3, impurity C is 6-chloro-4-(o-chlorophenyl)-2-quinazoline carboxaldehyde.
5. As per claim 3, the level of impurity C is reduced to 25% or less when compared to Lorazepam injection composition sparged/purged with nitrogen after 3 months of storage at accelerated conditions.
6. As per claim 1 and 2 pharmaceutically acceptable excipient is selected from a group comprising of one or more of solubilizers, preservatives, non-aqueous vehicles and the like.
7. As per claim 6, solubilizer is PEG 400
8. As per claim 6, preservative is benzyl alcohol

9. As per claim 6, non-aqueous vehicle is propylene glycol
10. A stable pharmaceutical composition of claim 1 wherein said composition is administered by parenteral route.