FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2003
(COMPLETE SPECIFICATION)
TITLE OF THE INVENTION- "An efficient intravenous administration for the treatment of bacterial infection."
NAME OF APPLICANT - Lincoln Pharmaceuticals Limited
ADDRESS OF APPLICANT - Lincoln Pharmaceuticals Limited
B/h. Satyam Complex, Lincoln House, Science City Road, Sola, Ahmadabad-380062; Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION- The present invention relates to efficient injectable pharmaceutical composition which comprises main active ingredient Ofloxacin in high concentration for treatment of bacterial infection.
BACKGROUND OF THE INVENTION
Ofloxacin is a quinolone/ fluoroquinolone broad spectrum antibiotic. Ofloxacin. (RS)-7-fluoro-2-methyl-6-(4-methylpiperazin-l-yl)-10-oxo-4-oxa-l-azatricyclo [7.3.1.05,13] trideca-5(13),6,8,ll-tetraene-ll-carboxylic acid is a racemic mixture, which consists of 50% levOfloxacin (the biologically active component) and 50% of its "mirror image" or enantiomer dextrOfloxacin and is represented below.

Ofloxacin is slightly soluble in water and is soluble in aqueous solutions with pH between 2 and 5.
Ofloxacin is active against both gram positive and gram negative bacteria and is used for the treatment of infections of respiratory tract, kidney, skin, soft tissue, urinary tract, urethral and cervical gonorrhea. The mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian.
Ofloxacin for systemic use is available as tablets (multiple strengths), oral solution (250 mg/ml), and injectable solution (multiple strengths). It is also used as eye drops (trade name Exocin, known as Ocuflox in the United States) and ear- drops (Floxin Otic). Ofloxacin Injection available in market contains in each ml Ofloxacin USP 2 mg, Sodium Chloride 0.9%w/v and water for injection q.s. The dosage for intravenous infusion is 2 mg/ml.

Further, Ofloxacin is available in the market by the brand name Floxin. In an article on Floxin I. V. from drugs.com, Floxin I.V in premixed bottles and in premixed flexible containers are disclosed which contain sterile, preservative-free aqueous solutions of Ofloxacin with pH ranging from 3.8 to 5.8. Floxin I.V. in single use vials contains Ofloxacin in water for injection. Floxin I.V in premixed bottles and in pre mixed flexible containers are dilute, non -pyrogenic, nearly isotonic pre-mixed solutions that contain Ofloxacin in 5% dextrose, hydrochloric acid and sodium hydroxide to adjust the pH. The therapeutic doses of 200mg or 400mg of Ofloxacin are administered intravenously for 60min to normal volunteers.
According to CN101693008 wherein said the invention discloses an Ofloxacin injection which is prepared by ofloxacin, acetic acid, disodium tetracemate, propylene glycol and water for injection. The invention solves the problem that an Ofloxacin injection hydro-acupuncture is easy to crystallize through adopting the acetic acid as co solvent and improving the dissolvability of Ofloxacin by adding the propylene glycol to regulate the polarity of solution. The injection provided by the invention has excellent quality stability, solves the problem of crystallization commonly existed in products of Ofloxacin injection hydro-acupuncture, solves the weaknesses of instability and short retention period of injection, reduces the number of insoluble particles in medicine solution, and provides the effective guarantee for the safe use in clinics.
According to CN101269010 wherein said the invention discloses an Ofloxacin injection and a preparation method thereof; every lOOmg of the Ofloxacin injection contains 200mg of ofloxacin, 0.1 to 0.2 ml of 8 to 9 percent of lactic acid, 4 to 7g mannite, and the rest is water for injection. The preparation method is that: the mannite is added into certain quantity of water for injection to be dissolved and then is added with active carbon to be filtered, so as to form solution A; the lactic acid and the Ofloxacin are slowly added into certain quantity of water for injection to be dissolved, so as to form solution B; the solution B is added into the solution A and added with the water for injection to total quantity, and the active carbon is added into the mixed solution again to be stirred and filtered, the pH value is controlled within 4.2-4.8, so as to form solution C, the qualified solution of which is carried out by secondary filter, encapsulation and sterilization to be packed into a finished product. The Ofloxacin injection of the invention has stable quality and is applicable to a crowd of people, and does not contain salt and sugar, so that all the people who are sensitive strain infected persons having hypertension and diabetes mellitus can use the Ofloxacin injection. The

preparation method is simple and easy to bimplemented, and has lower cost and good economic benefit.
According to CN101843625 wherein said the invention discloses a compound Ofloxacin injection for livestock and a preparation method thereof. Each lOOmL of injection comprises the following components: l-4g of ofloxacin, 0.5-2g of acetylcysteine, 3g of polyethylene glycol 10000, 0.05-0.Ig of dexamethasone sodium phosphate, and the balance of water for injection, wherein, the mass ratio of Ofloxacin to acetylcysteine is 2:1. The preparation method comprises the following steps: dissolving acetylcysteine into part of water for injection, adding ofloxacin, stirring for dissolving to obtain solution A; dissolving lOOOOg of polyethylene glycol into part of water for injection; adding dexamethasone sodium phosphate, and stirring for dissolving to obtain solution B; mixing the solution A and the solution B; adding lOOmL of water for injection; evenly mixing, filtering, encapsulating, and sterilizing to obtain the compound Ofloxacin injection. The injection of the invention has the characteristics of high efficiency and long effect, simple preparation method and good product stability, and is especially suitable for livestock bacteria and mycoplasma severe infection.
According to CN101007164 wherein the invention disclosed a kind of complex Ofloxacin injection as well as preparing method. The injection contains 5-20 shares of ofloxacin, 5-25 shares of sulphuric acid colistin, 1-20 shares of trimethoprim and 50-300 shares of propylene glycol. The preparing procedure includes the following steps: (1) weighing materials; (2) putting the sulphuric acid colistin into injection water, stirring until it's all soluble; (3) heating propylene glycol to 75-85DEG C, adding trimethoprim, stirring to make it soluble;(4) putting together the solution of step (2) and (3), clarifying the solution, regulating the ph value of the solution, adding water to 1000 shares to get the preparation. Ofloxacin has the antibacterial activity of the third generation quinolones which can inhibit the bacteria prokaryotic cell DNA gyrase and DNA replication. Sulphuric acid colistin has no residue and side effects in animal bodies. The combination of the two medicines can widen the antibacterial spectrum and increase the curative effect.
The present inventor has now felt a need to provide a novel injectable pharmaceutical composition that is useful for the treatment of infections caused due to both gram positive and

gram negative bacteria. It provide safe and effective dosage form of medication selected from intravenous injectable forms or sprays; preferably I.V. infusion.
SUMMARY OF THE INVENTION
In one aspect, the invention is to provide commercially viable and efficient formulation.
In one aspect, the invention is to provide safe and effective dosage form of medication selected from intravenous injectable forms or sprays; preferably I.V. infusion.
In one aspect, the invention is to provide a pharmaceutical formulation which is less viscous (0.5 cps to 5.0 cps) contains high concentration of Ofloxacin (200 mg per 50 ml) in less volume of solvent, cause less pain to the patient, useful for effective treatment of bacterial infections.
In one aspect, the present invention contains the therapeutically active amount of different forms of Ofloxacin like R - Ofloxacin, S - Ofloxacin, Rac - Ofloxacin, D - Ofloxacin, L -Ofloxacin in unique blend of solvents.
In an aspect, the pharmaceutical composition is useful for the treatment of infections caused due to both gram positive and gram negative bacteria.
In another aspect, the present invention provides a method for the preparation of said pharmaceutical formulation.

DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail in connection with certain preferred and optional embodiments. So that various aspects thereof may be more fully understood and appreciated.
According to The present invention relates to a novel pharmaceutical formulation which is less viscous, contains high concentration of Ofloxacin in less volume of solvent, cause less pain to the patient, useful for effective treatment of bacterial infections.
In embodiment of the invention, the lower viscosity of the composition of present invention helps in faster diffusion of the drug from the site of action and also contributes to ease of administration resulting in lesser pain at the site of administration. Moreover, high concentration of the drug in less volume of solvent reduces the time of administration and enhances the effectiveness of the drug for the treatment of infections caused by sensitive organisms.
Accordingly, the viscosity of the pharmaceutical composition of the present invention is in the range of 1.0 cps to 5.0 cps .The formulation of the present invention contains the therapeutically active amount of different forms of Ofloxacin like R - Ofloxacin, S -Ofloxacin, Rac - Ofloxacin, D - Ofloxacin, L - Ofloxacin in unique blend of solvents. The active ingredient is present in an amount of 200 mg per 50 ml along with other pharmaceutic ally acceptable excipients and the concentration of the drug is in the range of 200 mg per 50ml. The maximum dose of 200 mg of ofloxcin by I.V. infusion is twice a day continue upto 1 to 14 days in adult/children. The therapeutic doses of 200 mg of Ofloxacin are administered intravenously for 30 min to 60 min to normal volunteers.
The pharmaceutically acceptable excipients are selected from osmotic agents, and pH adjusting agents.
In embodiment of the invention, the osmotic agent is selected from sodium chloride, dextrose anhydrous , mannitol, sorbitol, potassium chloride and like in amount of 0.1 % w/v to 10.00
% w/v.
In embodiment of the invention, the solubility enhancing agent is selected from lactic acid, glacial acetic acid and like in amount of 0.1 % w/v to 10.00 % w/v.

The solubility enhancer and inclusion complexes include but not limited to hydroxypropyl alpha-cyclodextrin, hydroxypropyl beta-cyclodextrin, hydroxypropyl gamma-cyclodextrin in an amount of 0.001 % w/v to 90.00 % w/v.
In embodiment of the invention, the chelating agent used in the present formulation is disodium edetate in concentration of 0.001 % w/v to 8.00 % w/v.
In embodiment of the invention, the pH adjusters include hydrochloric acid, glacial acetic acid, and phosphoric acid in the concentration of 0.01 % v/v 0.5 %v/v to and it was adjusted between 2.0 to 8.0.
It is a less viscous solution and maintained at a viscosity in the range of 1.0 cps to 5.0 cps.
In an embodiment, the pharmaceutical formulation of the invention can be in a form of medication is selected from intravenous injectable forms i.e preferably I.V. infusion which leads to direct availability of drug to systemic circulation which provides faster onset of action compared to other forms of known administration such as tablets, syrups, capsules or suspensions.
The pharmaceutical composition is useful for the treatment of infections caused due to both gram positive and gram negative bacteria and is useful for the treatment of infections of respiratory tract, kidney, skin, soft tissue, urinary tract, urethral and cervical gonorrhea.
In another embodiment, the present invention provides a method for preparation of said pharmaceutical formulation. Accordingly, the process of preparation comprises;
a) Dissolving osmotic agent in 25 ml of water for injection;
b) Adding Ofloxacin in to step (a) solution under continuous stirring and dissolving Ofloxacin using a mechanical sifter;
c) Adding lactic acid in to step (b) solution continuous stirring and dissolving Ofloxacin using a mechanical sifter;
d) Maintaining the pH using 35 %v/v HCL solution; checking the clarity and
e) Making the final volume by adding water for injection followed by filtering.

In another embodiment, the present invention provides a method to prepare the said pharmaceutical formulation. Accordingly, the process of preparation comprises;
1. Dissolving osmotic agent, chelating agent, and a solubility enhancer in 25 ml of water for injection;
2. Adding Ofloxacin in to step (1) solution under continuous stirring and let it get dissolved using a mechanical sifter;
3. Maintaining the pH using 10%v/v hydrochloric acid solution and check the clarity for the same.
4. Making the final volume by adding water for injection followed by filtering.
The pharmaceutical formulation of the present invention consisting of higher concentration of Ofloxacin as active ingredient while being useful for the effective treatment of bacterial infections also has the following advantages;
• Being less viscous reduces phlebitis, swelling, erythema at site of injection and causes less pain;
• Reduces the time of administration; and
• I.V infusion leads to direct availability of the drug to systemic circulation thereby providing faster onset of action, also is well suited for challenging patient who is unable to take orally.
The present investigation is more specifically explained by following examples. However, it will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present may be embodied in other specific forms without departing from the essential attributes thereof, and it is thereof desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing description, and all charges which come within the meaning and range of equivalency, of the -claims are therefore intended to be embraced therein.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the invention.

Example 1

SR.NO INGREDIENTS LABEL CLAIM
(Quantity/50 ml)
1 Ofloxacin 200 mg
2 Dextrose anhydrous 2500 mg
3 Lactic acid 40 mg
4 Hydrochloride acid (35% v/v) 5 ml
5 Water for injection Q.S.to50ml
Example 2

SR.NO INGREDIENTS LABEL CLAIM
(Quantity/50 ml)
1 Ofloxacin 200 mg
2 Dextrose anhydrous 2500 mg
3 Lactic acid 70 mg
4 Water for injection Q.S. to 50 ml

Example 3

SR.NO INGREDIENTS LABEL CLAIM
(Quantity/50 ml)
1 Ofloxacin 200 mg
2 Dextrose anhydrous 2500 mg
3 Lactic acid 50 mg
4 Hydrochloride acid (35% v/v) 10 ml
5 Water for injection Q.S. to 50 ml
Example 4

SR.NO INGREDIENTS LABEL CLAIM (Quantity/50 ml)
1 Ofloxacin 200 mg
2 Sodium chloride 450 mg
3 Hydroxypropyl beta-cyclo dextrin 50 mg
4 Disodium EDTA 20 mg
5 10% V/V Hydrochloric Acid 0.4 ml
6 Water for injection Q.S. to 50 ml

Example 5

SR.NO INGREDIENTS LABEL CLAIM
(Quantity/50 ml)
1 Ofloxacin 200 mg
2 Sodium chloride 390 mg
3 Hydroxypropyl beta-cyclodextrin 75 mg
4 Disodium EDTA 55 mg
5 10% V/V Hydrochloric Acid 0.4 ml
6 Water for injection Q.S. to 50 ml
Example 6

SR.NO INGREDIENTS LABEL CLAIM
(Quantity/50 ml)
1 Ofloxacin 200 mg
2 Sodium chloride 470 mg
3 Hydroxypropyl beta-cyclodextrin 40 mg
4 Disodium EDTA 10 mg
5 10% V/V Hydrochloric Acid 0.3 ml
6 Water for injection Q.S. to 50 ml

CLAIMS,
We claim,
(1) An efficient injectable formulation comprises of Ofloxacin along with other
pharmaceutical acceptable excipients and the process of preparation comprises;
(a)Dissolving osmotic agent in 25 ml of water for injection;
(b) Adding Ofloxacin in to step (a) solution under continuous stirring and dissolving Ofloxacin using a mechanical sifter;
(c) Adding lactic acid in to step (b) solution continuous stirring and dissolving Ofloxacin using a mechanical sifter.
(d) Maintaining the pH using 35 %v/v HCL solution; checking the clarity and
(e) Making the final volume by adding water for injection followed by filtering. And /or
1. Dissolving osmotic agent, chelating agent, and a solubility enhancer in 25 ml of water
for injection;
2. Adding Ofloxacin in to step (1) solution under continuous stirring and let it get
dissolved using a mechanical sifter;
3. Maintaining the pH using 10%v/v hydrochloric acid solution and check the clarity for the same.
4. Making the final volume by adding water for injection followed by filtering.

(2) An efficient injectable formulation as claimed in claim 1 wherein the therapeutically active amount of different forms of Ofloxacin like R - Ofloxacin, S - Ofloxacin, Rac -Ofloxacin, D - Ofloxacin, L - Ofloxacin in unique blend of solvents.
(3) An efficient injectable formulation as claimed in claim 1 wherein is less viscous, contains high concentration of Ofloxacin in less volume of solvent, cause less pain to the patient, useful for effective treatment of bacterial infections such as infections of respiratory tract, kidney, skin, soft tissue, urinary tract, urethral and cervical gonorrhoea thereof.

(4) An efficient injectable formulation as claimed in claim 1 wherein it provide safe and effective dosage form of medication selected from intravenous injectable forms or sprays; preferably I.V. infusion.
(5) An efficient injectable formulation as claimed in claim 1 wherein Being less viscous reduces phlebitis, swelling, erythema at site of injection and causes less pain, Reduces the time of administration; and I.V infusion leads to direct availability of the drug to systemic circulation thereby providing faster onset of action, also is well suited for challenging patient who is unable to take orally.
(6) An efficient injectable formulation as claimed in claim 1 wherein I.V. infusion which leads to direct availability of drug to systemic circulation which provides faster onset of action compared to other forms of known administration such as tablets, syrups, capsules or suspensions.
(7) An efficient injectable formulation as claimed in claim 1 wherein , the osmotic agent is selected from sodium chloride, dextrose anhydrous , mannitol, sorbitol, potassium chloride and like in amount of 0.1 % w/v to 10.00 % w/v.
(8) An efficient injectable formulation as claimed in claim 1 wherein the solubility enhancing agent is selected from lactic acid, glacial acetic acid and like in amount of 0.1 % w/v to 10.00
% w/v.
(9) An efficient injectable formulation as claimed in claim 8 wherein the solubility enhancer
and inclusion complexes include but not limited to hydroxypropyl alpha-cyclodextrin.
hydroxypropyl beta-eye lodextrin, hydroxypropyl gamma-cyclodextrin in an amount of 0.001
% w/v to 90.00% w/v.
(10) An efficient injectable formulation as claimed in claim 1 wherein the chelating agent
used in the present formulation is disodium edetate in concentration of 0.001 % w/v to 8.00 %
w/v.
(11) An efficient injectable formulation as claimed in claim 1 wherein the pH adjusters
include hydrochloric acid, glacial acetic acid, and phosphoric acid in the concentration of
0.01 % v/v 0.5 %v/v to and it was adjusted between 2.0 to 8.0.

(12) An efficient injectable formulation as claimed in claim 1 wherein It is a less viscous solution and maintained at a viscosity in the range of 1.0 cps to 5.0 cps .