DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(SECTION 10)

STABLE ANTIMICROBIAL INJECTABLE COMPOSITION

We, JODAS EXPOIM PRIVATE LIMITED.,
a company incorporated under the companies act, 1956 having address at H.No: 8-2-293/82/A/1359, 1st Floor, Road No.: 45, Jubilee Hills,
Hyderabad-500 033, Telangana, INDIA.

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF INVENTION
The present invention relates to parenteral preparations of antimicrobial agent. The present invention specifically relates to parenteral preparations of oxazolidinone antimicrobial agent. The present invention more specifically relates to linezolid injection composition comprising propylene glycol and/or polyethylene glycol as a water-miscible co-solvent.
BACKGROUND OF INVENTION
The first oxazolidinones were developed and synthesized by EI DuPont de Nemours & Co. Inc, in 1978 because of their activity against certain plant pathogens. In 1987, DuPont Pharmaceuticals made two antibacterial agents against human pathogens; however, because of the toxicity associated with these agents, their continued development was halted. In the early 1990s Upjohn Laboratories resumed the study of these agents leading to the delineation of a series of structure-activity relationships and, in 1996, developed two nontoxic derivatives of these drugs namely Linezolid and Eperezolid.
Linezolid is an antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to other antibiotics. The microbiological and clinical significance of linezolid is its spectrum of activity against gram-positive organisms, specifically methicillin-susceptible and resistant (MRSA) Staphylococcus aureus, Staphylococcus epidermidis and other coagulase-negative staphylococci vancomycin-susceptible and resistant (VRE) enterococci, and penicillin susceptible and resistant (PSRP) Streptococcus pneumoniae. In addition, bactericidal activity has been demonstrated against S. pneumoniae, Clostridium perfringens, and Bacteroides fragilis, an anaerobic gram negative organism.
Linezolid (CAS No. 60-00-4) is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is “(S)-N-[[3-[3-Fluoro-4-(4­morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide” has the empirical formula C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented as below:

5,688,792 disclose that the subject antibiotic oxazolidinone compounds, including linezolid, can be formulated as liquid form compositions including solutions. For example, it is disclosed therein that a solution can be provided of a subject oxazolidinone compound in water or in a water-propylene glycol or water-polyethylene glycol system, optionally containing conventional coloring agents, flavoring agents, stabilizers and thickening agents.
It is further disclosed in US 5,688,792 that the subject oxazolidinone compounds can be administered orally, parenterally and/or topically, and that parenteral administration can be by intravenous injection or other parenteral route. For parenteral administration, it is disclosed therein that a suitable composition will generally contain a pharmaceutically acceptable amount of a subject oxazolidinone compound as a soluble salt dissolved in a liquid carrier such as water for injection to form a suitably buffered isotonic solution. Such a solution is stated therein generally to contain a subject oxazolidinone compound dissolved in the carrier in an amount sufficient to provide an injectable concentration of about 1 to about 400 mg/ml of solution.
CN 104666241 discloses a method for preparing linezolid injection containing disodium hydrogen phosphate as pH adjusting agent, osmolality adjusting agent and stabilizers. This invention also discloses the process for preparing linezolid injection.
IN 209201 discloses a pharmaceutical composition for administrating to a subject having or at risk of infective disease containing oxazolidinone antimicrobial agent and cyclodextrin compound. This invention also discloses the compositions containing linezolid as oxazolidinone antimicrobial agent.
IN 2409/DELNP/2004 discloses a method of treating a diabetic foot infection in a mammal comprising parenterally administering to the mammal a pharmaceutically effective amount of an oxazolidinone antibiotic. This invention also discloses linezolid as oxazolidinone antibiotic.
IN 307/CHE/2011 discloses aqueous concentrated antibacterial formulation of linezolid comprising at least one solubilizer. This invention also discloses composition of linezolid injection concentrate.
IN 822/KOLNP/2012 discloses a pharmaceutical composition comprising an oxazolidinone antimicrobial agent or a pharmaceutically acceptable salt, ester, or prodrug thereof, buffer, pH modifier, and a solvent.
GR 1008260 discloses aqueous pharmaceutical composition for parenteral administration which contains linezolid or a pharmaceutically acceptable salt thereof as active ingredient, tonicity agent, buffering agent and a pH-adjusting agent.
All the prior art references shows the Linezolid has a potent range of activity against gram-positive microorganisms, including multi-resistant strains. Its unique mode of action to inhibit protein synthesis exhibits no cross-resistance with other agents that act on gram-positive bacteria. Compositions for preparing linezolid Injection contain linezolid as oxazolidinone antimicrobial agent, tonicity agent, buffering agent, a pH-adjusting agent and solvent. However, none of the references specifically discloses the use of propylene glycol and/or polyethylene glycol as water-miscible co-solvents for preparation linezolid compositions.
OBJECTIVE OF INVENTION
The objective of the present invention is to provide a parenteral composition comprising oxazolidinoneantimicrobial agent.
Another objective of the present invention is to provide stable Linezolid Injection composition comprising propylene glycol and/or polyethylene glycol as a water-miscible co-solvent.
Another objective of the present invention is to provide a composition which further contains sugar, buffering agents, pH modifier and water for injection.
Another objective of the present invention is the novel use of propylene glycol and/or polyethylene glycol in enhancing the solubility of linezolid injection and preventing crystallization of linezolid during storage.
SUMMARY OF INVENTION
Accordingly, the present invention provides a parenteral composition comprising oxazolidinones antimicrobial agent and propylene glycol as a water-miscible co-solvent.
Another embodiment of the present invention provides a parenteral composition comprising linezolid and propylene glycol as a water-miscible co-solvent.
Another embodiment of the present invention provides a parenteral composition comprising linezolid, propylene glycol and polyethylene glycol as a water-miscible co-solvent.
Yet another embodiment of the present invention provides a concentrated parenteral composition of Linezolid comprising propylene glycol as a water-miscible co-solvent.
Yet another embodiment of the present invention provides a concentrated parenteral composition of Linezolid comprising propylene glycol and or polyethylene glycol as a water-miscible co-solvent.
Yet another embodiment of the present invention provides a concentrated parenteral composition of Linezolid comprising 50% propylene glycol and 50% water as a solvent.
Yet another embodiment of the present invention provides a concentrated parenteral composition of Linezolid comprising 16.66% of propylene glycol, 33.33% of polyethylene glycol and 50% or quantity sufficient water as a solvent.
Yet another embodiment of the present invention provides a composition of linezolid injection further comprising Sugars, Buffering agents, pH modifiers, co-solvents which enhances the solubility of Linezolid and Aqueous Vehicle.
Yet another embodiment of the present invention provides a composition of linezolid injection for treating microbial infections which comprises dextrose, citric acid anhydrous, sodium citrate, Sodium hydroxide, Propylene glycol, polyethylene glycol and water for injection.
Yet another embodiment of the present invention provides a process for preparing linezolid injection for treating microbial infections which is prepared as follow:
(i) Adding and dissolving dextrose, citric acid, sodium citrate in water for injection and stir the solution till to get a clear solution,
(ii) Adding and dissolving Linezolid in propylene Glycol and stir the solution till to get a clear solution,
(iii) Adding step 1 solution to step 2 and stir the solution till to get a clear solution,
(iv) Adjusting the pH of step 3 solution to 4.4 – 5.5 and make the volume to 100%. Stirring the solution for 20 mins,
(v) Filtering the above solution through 0.22 micron PVDF membrane filter and fill into glass vials as per below target fill volumes,
(vi) Sterilizing the above filled and sealed vials by moist heat sterilization process for up to 15 mins at 121°C, and
(vii) Unloading the above sterilized vials, label it and pack the labeled vials in individual cartons.
Yet another embodiment of the present invention provides a process for preparing linezolid injection for treating microbial infections which is prepared as follow;
(i) Adding and dissolving dextrose, citric acid, sodium citrate in water for injection and stir the solution till to get a clear solution,
(ii) Adding and dissolving Linezolid in a mixture of propylene Glycol and PEG-300 (Propylene glycol previously dissolved in PEG-300) and stir the solution till to get a clear solution,
(iii) Adding step 1 solution to step 2 and stir the solution till to get a clear solution,
(iv) Adjusting the pH of step 3 solution to 4.4 – 5.5 and make the volume to 100%. Stirring the solution for 20 mins,
(v) Filtering the above solution through 0.22 micron PVDF membrane filter and fill into glass vials as per below target fill volumes,
(vi) Sterilizing the above filled and sealed vials by moist heat sterilization process for up to 15 mins at 121°C, and
(vii) Unloading the above sterilized vials, label it and pack the labeled vials in individual cartons.
Yet another embodiment of the present invention provides the use of propylene glycol and/or polyethylene glycol in linezolid injection in order to enhance solubility of linezolid and also to prevent crystallization upon storage.
Yet another embodiment of the present invention provides a parenteral composition containing Tedizolid and propylene glycol and/or polyethylene glycol as a water-miscible co-solvent.
DETAILED DESCRIPTION OF THE INVENTION
Many common gram-positive pathogens (eg, Staphylococcus aureus, Enterococcus spp, and Streptococcus pneumoniae) have become increasingly resistant to antimicrobial agents. The oxazolidinones, a new chemical class of synthetic antimicrobial agent, have a unique mechanism of inhibiting bacterial protein synthesis.
Antimicrobials of the present invention also include Penicillins, Cephalosporins, Monobactams, Carbapenems, Macrolide Antibiotics, Lincosamides, Streptogramins, Aminoglycoside Antibiotics, Quinolone Antibiotics, Sulfonamides, Tetracycline Antibiotics and Other Antibiotics or combinations thereof.
Oxazolidinones are a class of compounds containing 2-oxazolidine in the structure. Oxazolidinones represent a new class of synthetic antibacterial agents active against multiple-resistant gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci.
Oxazolidinones are a class of azoles, oxazolidines with the carbon between the nitrogen and oxygen oxidized to a ketone, hence oxazolidinone. The antibacterial oxazolidinone template has a common nomenclature specially for ‘aryl-5-(substituted) methyl-2-oxazolidinone’ and has a structural formula as follows:

Oxazolidinones used in the present invention is selected from the group consisting of Linezolid, Posizolid, Tedizolid and Radezolid.
The sugar used in the present invention selected from the group consisting of sugar is selected from the group consisting of galactose, dextrose, xylose, fructose, glucose, arabinose, ribose, lyxose, meso-erythritol, xylitol, dulcitol, myo-inositol, mannitol, sorbitol, adonitol, arabitol, cellobiose, maltose, raffinose, rhamnose, melibiose, fucose, maltodextrins, glucosamine, mannosamine, galactosamine, lactose, and sucrose, more specifically dextrose.
The pH adjusting agents and/or buffering agents used in the present invention is selected from the group consisting of 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 tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, citrate/phosphate, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in a physiologically acceptable range, particularly where the composition is intended for parenteral delivery.
The pH adjusting agent can be a Sodium Hydroxide and/or Hydrochloric acid solution ranging from 0.1N solution to 5N solution.
The combination of an aqueous solution and a water soluble organic solvent/surfactant (i.e., a cosolvent) is often used in parenteral compositions when pH adjustment alone is insufficient in achieving the desired solution concentration. The water-soluble organic solvents and surfactants used in present parenteral compositions include one or more of propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerin, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP; Pharmasolve), dimethylsulfoxide (DMSO), Solutol HS 15, Cremophor EL, Cremophor RH 60 and polysorbate 80.
Aqueous vehicle also includes Water for Injection (WFI), USP, Bacteriostatic Water for Injection (BWFI) and sterile water for injection (SWFI), USP.
The composition prepared in the invention can be easily diluted with any of the commonly available infusion solutions like Dextrose Injection, Sodium Chloride Injection, Lactated Ringer's Injection or others to the desired concentration prior to administration. Even Water for Injection can also be used to prepare the dilutions.
The term concentrated parenteral composition refers to an aqueous solution of Linezolid having a concentration of about 3 mg/ml to about 30 mg/ml. However, it was surprisingly found that concentrated liquid Linezolid compositions can be made by dissolving Linezolid in a buffered aqueous solution comprising at least one water-miscible co-solvent.
Various containers are known to hold aqueous solutions to be administered intravenously to a patient. The most common IV solution containers are glass and plastic bottles and plastic bags. Containers suitable for injection in connection with the invention refers to containers which do not interact physically or chemically with the preparation for injection in any manner to alter the strength, quality, or purity beyond the official requirements under the ordinary or customary conditions of handling, shipment, storage, sale and use. Suitable containers in accordance with the invention are for example made of glass. Particularly suitable are type 1 glass containers, which fulfills the criteria of type I glass containers according to European Pharmacopoeia, United States Pharmacopoeia and Japanese Pharmacopoeia. These vials with excellent barrier properties can be washed, autoclaved, sterilized, depyrogenated, filled, closed and inspected just like standard containers.
The container for injection according to the invention is closed or sealed with a suitable stopper in such a manner as to prevent contamination or loss of content.
In a preferred embodiment, the stoppers which can be used in the present invention include coated/laminated or uncoated Bromobutyl or Chlorobutyl or Fluoro butyl stoppers.
Sterilization methods that may be used in the present invention, include, but are not limited to, filtration sterilization, autoclaving, aseptically preparing and dispensing in the sterile containers or combination of one or more said methods.
In a preferred embodiment, the product of the present invention can be sterilized by aseptic filtration followed by moist heat sterilization up to 45 minutes, preferably up to 15 minutes or 30 minutes.
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, a daily dose for a human subject will typically be about 100 mg to about 1200 mg of Linezolid, administered in a composition of the invention.
The following examples describe the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative.
Example 1:
S.No Ingredients Qty/mL
1. Linezolid 10 mg
2. Dextrose Monohydrate 221.2 mg
3. Citric Acid Anhydrous 3.75 mg
4. Sodium Citrate Dihydrate 8.14 mg
5. Propylene Glycol 50%
6. NaOH/HCL q.s.
7. Water for Injection q.s to make 1 mL

Example 2:
S.No Ingredients Qty/mL
1. Linezolid 15 mg
2. Dextrose Monohydrate 326.6 mg
3. Citric Acid Anhydrous 5.525 mg
4. Sodium Citrate Dihydrate 12.02 mg
5. Propylene Glycol 50%
6. NaOH/HCL q.s.
7. Water for Injection q.s to make 1 mL
Example 3:
S.No Ingredients Qty/mL
1. Linezolid 20 mg
2. Dextrose Monohydrate 502.4 mg
3. Citric Acid Anhydrous 8.50 mg
4. Sodium Citrate Dihydrate 16.4 mg
5. Propylene Glycol 50%
6. NaOH/HCL q.s.
7. Water for Injection q.s to make 1 mL

Manufacturing procedure:
The aqueous concentrated composition according to invention was prepared by the process wherein sodium citrate, citric acid, dextrose are added to water for injection and stirred until dissolved to prepare a buffered solution with agitation. Separately Linezolid was added into Propylene Glycol solution and stirred to dissolve. To this solution the buffer solution was added further and heated up to 70-80° C until Linezolid fully dissolved. The pH of the solution was measured and adjusted if necessary. Final volume is made up with the water for injection. The mixture is filtered, filled into sterile vials. The filled vials are autoclaved at 121°C for 15 min.

Example 4:
S. No Ingredients Qty/mL
1. Linezolid 10 mg
2. Dextrose Monohydrate 251.2 mg
3. Citric Acid Anhydrous 4.25 mg
4. Sodium Citrate Dihydrate 8.2 mg
5. Propylene Glycol 16.66%
6. PEG-300 33.33%
7. NaOH/HCL q.s.
8. Water for Injection q.s to make 1 mL

Manufacturing procedure:
The aqueous concentrated composition according to invention was prepared by the process wherein sodium citrate, citric acid, dextrose are added to water for injection and stirred until dissolved to prepare a buffered solution with agitation. Separately Linezolid was added into a mixture of Propylene Glycol and PEG-300 solution and stirred to dissolve. To this solution the buffer solution was added further and heated up to 70-80° C until Linezolid fully dissolved. The pH of the solution was measured and adjusted if necessary. Final volume is made up with the water for injection. The mixture is filtered, filled into sterile vials. The filled vials are autoclaved at 121°C for 15 min. ,CLAIMS:We Claim:
1. A concentrated parenteral composition of Linezolid comprising propylene glycol as a water-miscible co-solvent.

2. A concentrated parenteral composition of Linezolid comprising 50% propylene glycol and 50% water as a solvent.

3. A concentrated parenteral composition comprising linezolid, propylene glycol and polyethylene glycol as a water-miscible co-solvent.

4. A concentrated parenteral composition of Linezolid comprising 16.66% of propylene glycol, 33.33% of polyethylene glycol and 50% of water as a solvent.

5. A parenteral composition according to claim 1 - 4, further comprising Sugars, Buffering agents, pH modifiers, co-solvents which enhances the solubility of Linezolid and Aqueous Vehicles.

6. A parenteral composition according to claim 5, wherein said sugar is selected from the group consisting of galactose, dextrose, xylose, fructose, glucose, arabinose, ribose, lyxose, meso-erythritol, xylitol, dulcitol, myo-inositol, mannitol, sorbitol, adonitol, arabitol, cellobiose, maltose, raffinose, rhamnose, melibiose, fucose, maltodextrins, glucosamine, mannosamine, galactosamine, lactose and sucrose or combinations thereof.

7. A parenteral composition according to claim 5, wherein said buffering agents used in the present invention is selected from the group consisting of 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 tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, citrate/phosphate, sodium bicarbonate and ammonium chloride.

8. A parenteral composition according to claim 5, wherein said pH adjusting agent can be a Sodium Hydroxide and/or Hydrochloric acid solution ranging from 0.1N solution to 5N solution.

9. A process for preparing linezolid injection for treating microbial infections which is prepared as follow:
(i) Adding and dissolving dextrose, citric acid, sodium citrate in water for injection and stir the solution till to get a clear solution,
(ii) Adding and dissolving Linezolid in propylene Glycol and stir the solution till to get a clear solution,
(iii) Adding step 1 solution to step 2 and stir the solution till to get a clear solution,
(iv) Adjusting the pH of step 3 solution to 4.4 – 5.5 and make the volume to 100%. Stirring the solution for 20 mins,
(v) Filtering the above solution through 0.22 micron PVDF membrane filter and fill into glass vials as per below target fill volumes,
(vi) Sterilizing the above filled and sealed vials by moist heat sterilization process for up to 15 mins at 121°C, and
(vii) Unloading the above sterilized vials, label it and pack the labeled vials in individual cartons.

10. A process for preparing linezolid injection for treating microbial infections which is prepared as follow;
(i) Adding and dissolving dextrose, citric acid, sodium citrate in water for injection and stir the solution till to get a clear solution,
(ii) Adding and dissolving Linezolid in a mixture of propylene Glycol and PEG-300 and stir the solution till to get a clear solution,
(iii) Adding step 1 solution to step 2 and stir the solution till to get a clear solution,
(iv) Adjusting the pH of step 3 solution to 4.4 – 5.5 and make the volume to 100%. Stirring the solution for 20 mins,
(v) Filtering the above solution through 0.22 micron PVDF membrane filter and fill into glass vials as per below target fill volumes,
(vi) Sterilizing the above filled and sealed vials by moist heat sterilization process for up to 15 mins at 121°C, and
(vii) Unloading the above sterilized vials, label it and pack the labeled vials in individual cartons.

Date this Ninth (09th) day of September, 2017.

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883