FORM-2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION Sec 10-Rule 13
A STABLE GEL FORMING SOLUTION
INDOCO REMEDIES LIMITED
Indian
R-92-93, T.T.C Industrial Area, Thane Belapur Road, Rabale MIDC
Navi Mumbai- 400701
The following specification describes the invention and manner in which it is to be performed.

Technical Field:
The present invention relates to a stable ophthalmic gel forming solution with low preservative content. More particularly, the present invention relates to a stable ophthalmic gel forming solution comprising Lidocaine or its pharmaceutically acceptable salt, which forms gel on contact with tear fluid. The invention further relates to process for preparation of stable ophthalmic gel forming solution comprising low concentration of preservative.
Background of the Invention:
Lidocaine, 2-(diethylamino)-N-(2,6-dimethyl phenyl)-acetamide is amide derivative of drug, which anesthetize local site of administration. A medicinal practitioner prefers the Lidocaine (also known as "Lignocaine or Xylocaine") as a drug of choice to treat medicinal condition where prime necessities are to introduce safe local anesthesia & maintenance of same state for desired period of time. Lidocaine is BCS class I drug.
A number of dosage forms containing Lidocaine for eg. Injection, patch, gel, ointment, cream & suppository etc. are available commercially. In addition to this, some extended release dosage forms like dermal patch are also available in market.
There are many types of ocular disorders, which often require treatment applied directly to the eye. In such cases, it is desired that the formulations have a suitable surface retention properties such as viscosity, so that the formulation stay on the eye for a suitable period of time to deliver desire medication. The same applies during eye surgery. It is preferable that the eye is anaesthetized before surgery, that anaesthesia is maintained throughout surgery without additional application of the topical anaesthetic and to some extent, for a period of time after the surgery is completed.
The ophthalmic drug delivery dosage forms are preferred for treatment of various conditions of eyes. But absorption of drug after administration of drop in eye is

limited by unique mechanisms of eye & it's anatomy like drainage of the solutions, lacrimation, sensitive to foreign particle & metabolism etc. Such factors affects therapeutic efficacy of dosage form by causing low absorption of drug from administration site. Many times it has been observed that continuous blinking of eye, drains out instilled solution from the eye, & hence increase the treatment duration & cost associated with it.
Various kinds of Lidocaine formulation for ophthalmic delivery are proposed, where it could be formulation with single dose or multi dose provided in low density polyethylene (LDPE) or polypropylene container. The multiple dose dosage form contains higher concentration of preservative/s such as benzalkonium chloride, chlorobutanol, Cholhexidine acetate, phenyl mercuric nitrate etc. In chronic eye diseases or disorders treatment, ophthalmic drugs are administered on regular basis & repeatedly. Due to this, there is a continuous exposure of eye to preservatives. The preservative on higher concentration may damage epithelium layer & other essential cells as well as structure of eye.
US Patent 5958443 demonstrates an aqueous drug delivery composition capable of gelling in situ, comprises two part formulation system. Out of these two part system first part comprises an aqueous vehicle of polysaccharides whereas another part comprises aqueous solution of ionic polysaccharides.
A PCT application WO 1997010805 discloses a preserved ophthalmic composition comprising a cyclodextrin, a quaternary ammonium salt, an alkylene glycol and a pharmaceutically active compound.
EP 0678337 discloses an apparatus & a method for treatment of eye condition by spraying aqueous formulation to the eye.
US Patent 5858996 reveals polymer & chelating agent based stabilized composition for delivery of Lidocaine ophthalmic delivery.

The commonly employed ophthalmic dosage forms are suspension, solution, ointment, gel, cream etc. Semi solid dosage forms are not preferred by user, due to disadvantages like staining, transportation issue, uneasy to apply to eye and deterioration due to temperature fluctuation not suitable to be used with contact lenses etc; on the other hand solution dosage form is easy to apply, convenient to carry & store.
Usually, incomplete product removal from pack of semisolid dosage form is experienced as one could not extract last portion of composition from pack eg. tube. This increases cost to medical treatment.
Thus there is an unmet need, to develop a stable ophthalmic gel forming liquid composition for safe and prolonged delivery of lidocaine as ophthalmic solution to ascertain safe delivery & optimum concentration of drug at absorption site.
Surprisingly, the inventors of present invention have found a novel ophthalmic solution that can transform conveniently to gel after administration to eye. This formulation aids to deliver drug substance via ophthalmic route.
Brief Description of the Drawing:
Fig I: Process flowchart for preparation of Gel Forming Solution containing active agent.
Object of the Invention:
The principal object of invention is to provide a stable ophthalmic gel forming solution comprising Lidocaine or its pharmaceutically acceptable salts, which on contact with tear fluids transforms to gel.
Another object of invention is to provide a stable ophthalmic gel forming solution comprising low concentration of preservative.

Yet another object of invention is to provide a stable ophthalmic gel forming solution comprising Lidocaine & low concentration of benzalkonium chloride.
Further object of invention is to provide a stable ophthalmic gel forming solution comprising low concentration of preservative, gelling agent & essential excipients.
Further object of invention is to provide a stable ophthalmic gel forming solution comprising Lidocaine, low concentration of benzalkonium chloride, gellan gum & other essential excipients.
Still further object of the present invention is to provide regional anaesthesia during ophthalmologic procedures by administering to the eye a stable ophthalmic gel forming solution comprising Lidocaine, low concentration of preservative, gelling agent & essential excipients.
Further object of invention is to provide a process for preparation of the stable ophthalmic gel forming solution.
Further object of the present invention is to provide a stable ophthalmic gel forming solution for use in treating ocular disorders or for providing anesthesia to patient before, during or after surgery or eye injuries.
Summary of the Invention:
The present invention relates to a stable ophthalmic gel forming solution comprising Lidocaine or pharmaceutically acceptable salts, which on contact with tear fluids transforms to gel.
The stable ophthalmic gel forming solution of the present invention is easy to administer, not easily expelled from the eye after administration and delivers a precise dosage as it forms gel when it comes in contact with tear fluid.

The present invention relates to a process for preparation of the stable ophthalmic gel forming solution, which comprises of following steps - A) Preparation of slurry of excipients, followed by sterilization, B) Preparation solution of active agent, followed by sterilization, C) Mixing of slurry of excipients and solution of API, under slow stirring, with pH adjustment, followed by making up of volume.
The present invention relates to provide a stable ophthalmic gel forming solution for use in treating ocular disorders or for providing anesthesia to patient before, during or after surgery or eye injuries.
Description of the Invention:
The present invention relates to stable ophthalmic gel forming solution which on contact with tear fluid transforms to gel. The stable ophthalmic gel forming solution asserts longer contact time for drug at site of absorption by transforming to gel and provides regional anaesthesia to eye. Thus ultimately such composition reduces treatment time by enhancing longer availability of drug at absorption site.
The composition is a clear, translucent solution in the form of a liquid before instillation into the eye which then undergoes a liquid-gel phase transition, and changes from the liquid phase to the gel phase. This is brought about by the ionic strength of the physiological fluid which is in this case is the tear fluid. The gel forming solution delivers benefit of both dosage form i.e liquid as well as gel dosage forms at a time to end users. The composition contains gelling agent that due to its unique mechanism responsible for liquid to gel transformation, without impairing viscosity.
The composition of present invention may comprise single or combination of active ingredient/s suitable for ophthalmic delivery, gelling agent, low concentration of preservative and essential excipients. The solution contains very low concentration of preservative which addresses eye protection by retarding overexposure of eye to

preservative. Hence it prevents overexposure of eye tissues to preservatives, preventing damage to sensitive ocular tissues.
Another aspect of the present invention is to provide, method of inducing topical anaesthesia to the eye by topically administering an effective amount of the stable ophthalmic gel forming solution comprising Lidocaine or its pharmaceutically acceptable salt, preservative, gelling agents and pharmaceutically acceptable excipients. While the dosing regimen is left to the discretion of the clinician, it is recommended that the solution be topically applied by placing two drops to the ocular surface in the area of planned procedure. Additional drops of the solution can be applied as per requirement. An advantage of the ophthalmic gel forming solution of present invention is that it increases the residence time on the eye and which eventually gives long lasting anaesthetic activity.
According to one embodiment, stable ophthalmic gel forming solution would be useful for various medical conditions. The eye surgeries for which the stable ophthalmic gel forming solution of present invention can be used are cataract extraction, primary pterygium excision, sutureless vitrectomy, intravitreal injection, bilateral strabismus, chalazion excision and trabeculectomy.
Additionally, the stable ophthalmic gel forming solution of present invention may be used for laser eye surgery, refractive surgery, keratoplasty, keratotomy, keratomilleusis, glaucoma surgery, canaloplasty, kamra inlay, sclera reinforcement surgery, corneal surgery, vitreo retinal surgery, retinopexy, eye- musule surgery, surgery involving the lacrimal apparatus, insertion of implants into the eye & eye removal.
According to one embodiment, the present invention provides regional anaesthesia during eye operation or surgery by administering to the eye a stable ophthalmic gel forming solution comprising low concentration of preservative, gelling agent & essential excipients.

The present invention relates to a stable ophthalmic gel forming solution comprising of low concentration of preservative.
According to one embodiment, the concentration of preservative used is in the range of0.003 to 0.01%.
In an embodiment, the preservative used is benzalkonium chloride.
According to one embodiment, the concentration of gelling agent used is in the range ofO.l to 0.6%.
In an embodiment, the gelling agent used is gellan gum.
In further embodiment, the present invention provides a stable ophthalmic gel forming solution comprising Lidocaine or its acceptable salts as active ingredient.
Yet in further embodiment, invention relates to a stable ophthalmic gel forming solution comprising Lidocaine or its pharmaceutical salts, low concentration of benzalkonium chloride, gellan gum & other essential excipients.
According to one embodiment, the present invention provides a stable ophthalmic solution comprises of active agent & one or more preservatives, pH adjusting agents, gelling agents & buffering agents.
According to an embodiment, the present invention relates to an ophthalmic gel forming solution comprising of Lidocaine or its pharmaceutical acceptable salts. Other than lidocaine, active ingredients selected from group comprising of bupivacaine, mepivacaine, proparacaine, carbachol, cartedol, dichlorphenamide, pilocarpine or its pharmaceutically acceptable salts & combinations thereof can be used in the present invention.
Preservative is a vital excipient in multi dose formulation which prevents growth of microbes & warrant sterility to dosage form. The one or more preservative agent

include, but are not limited to benzalkonium chloride, benzethonium chloride and cetyl pyridinium chloride, benzyl bromide, EDTA, phenylmercury nitrate, phenylmercury acetate, thimerosal, merthiolate, acetate and phenylmercury borate, polymyxin B sulphate, chlorhexidine, methyl and propyl parabens, phenylethyl alcohol, quaternary ammonium chloride, sodium benzoate, sodium propionate and sorbic acid.
Gelling agent triggers solution to gel conversion of formulation after administration to eye. The one or more gelling agent include but are not limited to gellan gum, xanthan gum, guar gum, hydroxypropyl cellulose, ethyl methyl cellulose, hydroxy ethyl cellulose, various grades of carbopol and combinations thereof. Gelling agent converts solution to gel form due to change in conformation of polymers which occurs due to stimuli for eg - temperature, pH, ionic content and lacrimal fluid. Gellan gum converts into gel form on contact with tear fluid, by virtue of pH change.
Stable ophthalmic gel forming solution further comprises pH adjusting agents & buffering agents. This agent maintains pH of formulation to promote absorption of drug & prevent unwanted irritation at physiological site. pH adjusting agents according to present invention include but are not limited to sodium hydroxide, tromethamine, hydrochloric acid, potassium hydroxide, sodium carbonate, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydrogen carbonate, boric acid, borax and combinations thereof.
According to one embodiment of the present invention, the stable ophthalmic solution comprises 1 to 5% of active agent, 0.001 to 0.008% of preservative agent, 0.1 to 0.6% of gelling agent & 0.1 to 0.8% of buffering agent & essential quantity of pH adjusting agent.
According other embodiment of the present invention, the stable ophthalmic solution comprises 1 to 5% of Lidocaine hydrochloride, 0.001 to 0.008% of benzalkonium

chloride, 0.1 to 0.6% of gellan gum & 0.1 to 0.8% of tromethamine & essential quantity of hydrochloric Acid.
Still in further embodiment of the present invention, the stable ophthalmic solution comprises 3.5% of Lidocaine hydrochloride, 0.005%) of benzalkonium chloride, 0.45% of gellan gum, 0.5% of tromethamine & essential quantity of hydrochloric Acid.
According to an embodiment, the present invention also provides a process for preparation of stable ophthalmic solution comprising of following steps - A) Preparation of slurry of excipients, followed by sterilization, B) Preparation solution of active agent, followed by sterilization, C) Mixing of slurry of excipients and solution of API, under slow stirring, with pH adjustment, followed by making up of volume.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to person skilled in the art upon reference to the description. It is therefore contemplated that such modification can be made without departing from the spirit or scope of the present invention as defined.
The invention is further exemplified with following example and is not intended to limit the scope of the invention.

Example 1.

SrNo Ingredients % w/v
1. Lidocaine hydrochloride 3.5
2. Gellan gum 0.45
3. Tromethamine 0.5
4. Benzalkonium chloride 0.005
5. Hydrochloric Acid 0.1N q.s to adjust pH to 6.9
6. Water for injection q.s
Manufacturing Process:
1. In a clean S.S.Vessel Gellan gum was added in water under slow stirring.
2. Tromethamine was added to step 1 under stirring.
3. Benzalkonium chloride was dissolved in water and transferred to step 2 under slow stirring.
4. The Slurry from step 3 was sterilized by autoclave at 12° C for 30min.
5. The slurry from step 4 was cooled to room temperature
6. Lidocaine hydrochloride was dissolved in water and added it to the slurry from step 5 under slow stirring.
7. The volume was made up using water, and the solution was stirred for 15 minutes.
8. pH was checked & adjusted to 6.9.

Following tables represents results for stability studies performed at different set of temperature & relative humidity.
Table 1.
Name of product : Lidocaine Gel.
Fill Volume : 5ml
Batch No : LAS/D/012
Storage Condition : 40° C±2° C /25%± 5%RH

Tests Specification 40° C ± 2° C / 25% ± 5% RH

Initial 1 Month 3 Month
Description Clear, translucent solution Complies Complies Complies
Assay
Lidocaine hydrochloride 95-105% 99.1 98.2 98.3
Benzalkonium chloride 95-105% 103.4 102.8 103.9
pH Between 6.5-7.5 6.92 6.86 6.9
Conclusion: From the above data shows that the product is stable at 40° C / 25% RH for the period of 3 months in the recommended storage condition.

Table 2.
Name of product : Lidocaine Gel.
Fill Volume : 5ml
Batch No : LAS/D/012
Storage Condition: 30° C ± 2° C / 65% ± 5% RH

Tests Specification 30° C ± 2° C / 65% ± 5% RH

Initial 3 Month
Description Clear, translucent solution Complies Complies
Assay
Lidocaine hydrochloride 95-105% 99.1 96.2
Benzalkonium chloride 95-105% 103.4 102.8
pH Between 6.5-7.5 6.92 6.82
Conclusion: From the above data shows that the product is stable at 30° C / 65% RH for the period of 3 months in the recommended storage condition.

Tests
Specification 25° C ± 2° C / 40% ± 5% RH

Initial 3 Month
Description Clear, translucent solution Complies Complies
Assay
Lidocaine hydrochloride 95-105% 99.1 96
Benzalkonium chloride 95-105% 103.4 104
pH Between 6.5-7.5 6.92 6.98
Conclusion: From the above data shows that the product is stable at 25° C / 40% RH for the period of 3 months in the recommended storage condition.

Preservative Efficacy Test (PET)

B.No: LAS/D/012 ( Preservative 0.05mg/mL)
Label Claim:
Composition:
Lidocaine
%
Benzalkoniumchloride
0.005% Observation Incubation Period

Incubation Period 0 Hour 7 days 14 days 28 days
Name of Microbial Culture Limits NA No
increase from Log of Initial Calculated viable Count at "0"
Hour(Limi t NLT 1.0) Log reduction in viable count at 14 days from the initial calculated Viable count at "0"
Ho ur.( Limit NLT 3) Log of viable count at 28 days
(Limit:No increase from Log of Viable Count at 14 days) Remarks

Observation
↓




Bacteria Escherichia Coli Vial microbial count per mL of inoculated preparation 1.65xl05 cfu/mL 0.0 0.0 0.0

Log 10 viable microbial count per mL of inoculated preparation 0.0 5.2175 5.2175 0.0 Complies

Pseudomona s aeruginosa Vial microbial count per mL of inoculated preparation 4.8xl05 cfu/mL 0.0 0.0 0.0 Complies

Log 10 viable microbial count per mL of inoculated preparation 0.0 5.6812 5.6812 0.0

Staphylococc us aureus Vial microbial count per mL of inoculated preparation 1.73xl06 cfu/mL 0.0 0.0 0.0 Complies

Log 10 viable microbial count per mL of inoculated preparation 0.0 5.2372 6.2372 0.0

Candida albicans Initial Count:vial microbial count per mL of inoculated preparation 1.95xl05 cfu/mL 0.0 0.0 0.0 Complies
Yeast and
Log 10 viable microbial count per mL of inoculated preparation 0.0 0.0 0.0 0.0

Moulds Aspergillus brasiliensis Initial count: vial microbial count per mL of inoculated preparation 3.05xl05 cfu/mL 0.0 0.0 0.0 Complies

Log 10 viable microbial count per mL of inoculated preparation . 0.0 1.55xl02 cfu/mL 40 cfu/mL 0.0

The composition of the present invention was subjected to Presevative Efficacy Test (PET).
From the data of PET it is observed that viable microbial count on 'zero' day of the PET study do not increase during 28 day study cycle.
Moreover pharmaceutical limit of not less than 3 log reductions is achieved with the preservative system indicating the effectiveness of the preservative chosen. Effective log reduction during PET study is indicative of the fact that concentration of preservative used is adequate to impart desired microbial quality to the formulation. This is critical as the product is for ophthalmic application.
In short, PET data indicates that the choice and concentration of preservative is appropriate for the product.

We Claim,
1) A stable gel forming solution comprising of:
1% to 5% lidocaine or its pharmaceutically acceptable salts, 0.001% to 0.008% preservative, 0.1% to 0.6% gelling agent, 0.1% to 0.8% buffering agent.
2) The stable ophthalmic gel forming solution of claim 1, further comprises pH adjusting agent.
3) The stable ophthalmic gel forming solution of claim 1, wherein preservative is selected from benzalkonium chloride, benzethonium chloride and cetyl pyridinium chloride, benzyl bromide, EDTA, phenylmercury nitrate, phenylmercury acetate, thimerosal, merthiolate, acetate and phenylmercury borate, polymyxin B sulphate, chlorhexidine, methyl and propyl parabens, phenylethyl alcohol, quaternary ammonium chloride, sodium benzoate, sodium propionate, boric acid and sorbic acid or combination thereof.
4) The stable ophthalmic gel forming solution of claim 1, wherein the gelling agent is selected from gellan gum, xanthan gum, guar gum, hydroxypropyl cellulose, ethyl methyl cellulose, hydroxy ethyl cellulose, various grades of carbopol or combination thereof.
5) The stable ophthalmic gel forming solution of claim 1 & 2, wherein buffering agent & and pH adjusting agent is selected from sodium hydroxide, tromethamine, hydrochloric acid, potassium hydroxide, sodium carbonate, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydrogen carbonate, boric acid, borax and combinations thereof.

6) A process to prepare a stable ophthalmic gel forming solution of claim 1, comprising of following steps -
a) preparing an aqueous slurry comprising at least one gelling agent, at least one buffer and at least one preservative & water.
b) preparing an active agent solution comprising lidocaine and water.
c) individually sterilizing slurry and active agent solution.
d) mixing of sterilized slurry and active agent solution under stirring; adjusting pH of solution, followed by making up the volume.