FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel 3)

1. TITLE OF THE INVENTION:
2. APPLICANT (S): (a) NAME. FDC Limited
"A NOVEL IN-SITU GEL FORMING SOLUTION FOR OCULAR DRUG DELIVERY"


(b) NATIONALITY: Indian company incorporated under the Companies
Act 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.


TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a novel in-situ gel forming solution for ocular drug delivery, comprising of natural polysaccharide with thixotropic behavior and thermoreversible polymers using one or more combination of mechanisms such as thermal gelation, corneal mucoadhesion, lysosomal interaction and ionic gelation. The combination of natural polysaccharide with thixotropic behavior and thermoreversible polymers, using the said mechanisms provides in-situ gel formation and leads to prolonged corneal residence time, improved corneal absorption, patient compliance and clinical success.
BACKGROUND AND PRIOR ART:
Topical drug delivery is a preferred method for the therapeutic treatment of most of the ocular problems and well-accepted route of administration for the treatment of various eye diseases. A major problem in conventional ophthalmic drug delivery systems is poor bioavailability due to ocular anatomical and physiological constraints, which include the poor permeability of cornea, nasolacrimal drainage and short retention time in the precorneal area. The bioavailability of topically administered drug in the anterior chamber is extremely low due to the protective barrier function of the cornea, its rapid clearance by the tear-fluid drainage, its absorption into the conjunctiva and its washout by aqueous humor from the anterior chamber. Topically applied drugs can reach the intraocular tissues by either the corneal and/or the non-corneal pathways. Under normal conditions, the eye can accommodate only a very small volume of administered drugs without overflowing.
Ocular disorders are mainly treated by using drug formulations in the form of eye drops. Eye drops are inefficient means of delivering ophthalmic drugs because of limited bioavailability and these can cause significant side effects due to systemic uptake of the drug, when the drug gets into the gastrointestinal tract through nasolacrimal drainage. The drug contained in the drops is lost due to absorption through the conjunctiva or


through the tear drainage. Attempts to improve ocular bioavailability have been focused on overcoming precorneal constraints through improving corneal penetration and prolonging the precorneal retention and reducing the nasolacrimal drainage.
EP Patent No. 424043 describes liquid ophthalmic composition comprising at least one active principle and a sulphated polysaccharide or sulphated polysaccharide derivative in aqueous solution which undergoes a liquid-gel phase transition on interaction of the said sulphated polysaccharide or one of its derivatives with the proteins of the lachrymal fluid.
US Patent No. 5422116 describes formulation of pH sensitive in-situ gel for ophthalmic application using chitosan as a polymer. The formulated ophthalmic solution consists of chitosen having the pH range in between 3 to 6.2. The acidic pH of these formulations may not be suitable for the drugs which are unstable at acidic aqueous environment.
Sci. Pharm. 2008; 76:515-532 describes in-situ gum based ophthalmic drug delivery system of linezolid, wherein hydroxypropyl guar and xanthan were used as gum with combination of hydroxyethyl cellulose, carbopol and sodium alginate as viscosity enhancing agents. The pH of the formulation in the said study is maintained at 7.4 because to retain the clarity of the formulation, however most of the drugs are stable in either weakly acidic and weakly basic drugs. The said article utilized more than 2 polymers in gel forming solutions and it leads to complication during manufacturing process.
WO 93/00887 demonstrates use of carbomer as an aqueous gel forming agent in ophthalmic preparations. Carbomer are acid insoluble polymers. These swell above their pKa value preferably at neutral pH. These formulations based on carbomers should be formulated with pH range of 6-7. These formulations are not suitable to load the drugs having physicochemical properties and chemical properties favorable to acidic environment.


Xanthan gum is a polysaccharide, which is known to be useful in many ophthalmic compositions as a viscosity enhancing agent. US Patent No. 3700451 discloses the gelable or gelled composition, which comprise a liquid medium, agar and a combination of natural gum gel-forming agents including xanthan gum and locust bean gum. The gelable dispersions are easily gelled by heating to the gel-critical temperature and subsequently cooling them below the setting temperature. However the time required for gelation is more than that of precorneal elimination time and hence this formulation is not suitable for retaining the drug in precorneal area at reproducible manner.
US Patent No. 4131677 describes ophthalmic composition containing echothiopate iodide and xanthan gum and xanthan gum is reported to enhance the treatment effect of echothiopate iodide. However patent does not describe any xanthan gum-containing compositions as capable of being administered as a liquid and gelling upon contact with the eyes.
US Patent No. 4136173 describes composition having a pH sensitive solution of a pharmaceutically acceptable vehicle of xanthan gum, locust bean gum and a pharmaceutically active drug in a said liquid vehicle. Moreover, solution containing combination of xanthan gum and locust bean gum does not show sufficient gelling and these solutions demonstrate pH sensitive liquid gel reversibility.
US Patent No. 6174524 discloses ophthalmic drug delivery systems using xanthan gum aqueous dispersion as vehicles which are administrable as a liquid and which gel upon contact with the eyes are disclosed. Xanthan gum when used alone in the ophthalmic formulation has the disadvantage that it requires lysosomal interaction to gel, which is a slow mechanism and therefore takes longer to form a gel. By this time the product solution may drain off. Moreover, being shear thinning polymer, the product may not attain viscosity due to shear generated through blinking.
Thus, there is a need to formulate ophthalmic solutions that are liquid in the container and can be instilled as eye drops but gel on contact with the tear fluid and provide increased


contact time with the possibility of improved drug absorption and increased duration of therapeutic effect.
For the present invention, sustained and controlled delivery of drugs to the ocular tissues is a main objective in light of major hurdles of optimum drug bioavailability including rapid turnover, lacrimal drainage, reflex blinking and drug dilution by tears.
OBJECT OF THE INVENTION:
The primary objective of the present invention is to provide a novel in-situ gel forming solution for ocular drug delivery comprising of natural polysaccharide with thixotropic behavior and thermoreversible polymer and process for preparation thereof.
Another objective of the invention is to provide in-situ gel formation by one or more combination of mechanisms such as thermal gelation, corneal mucoadhesion, lysosomal interaction and ionic gelation which provides prolonged corneal residential time, improved corneal absorption, patient compliance and clinical success.
Yet another objective of the invention is to provide a novel in-situ gel forming solution having longer duration of action and hence, improved patient compliance and therapeutic response.
SUMMARY OF THE INVENTION:
Accordingly, to meet the above stated objective, the present invention relates to a novel in-situ gel forming solution for ocular drug delivery, consisting of natural polysaccharide with thixotropic behavior and thermoreversible polymers using one or more combination of mechanisms such as thermal gelation, corneal mucoadhesion, lysosomal interaction and ionic gelation. The combination of natural polysaccharide with thixotropic behavior and thermoreversible polymers, using the said mechanisms provides in-situ gel formation


and leads to prolonged corneal residence time, improved corneal absorption, patient compliance and clinical success.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a novel in-situ gel forming solution for ocular drug delivery, comprising of natural polysaccharide with thixotropic behavior and thermoreversible polymers using one or more combination of mechanisms such as thermal gelation, corneal mucoadhesion, lysosomal interaction and ionic gelation. The combination of natural polysaccharide with thixotropic behavior and thermoreversible polymers, using the said mechanisms provides in-situ gel formation and leads to prolonged corneal residence time, improved corneal absorption, patient compliance and clinic success.
The present invention demonstrates the application of natural polysaccharide with thixotropic behavior as polymer of pseudo plasticity, which offers the shear thinning property to the system. The natural polysaccharide is selected from group consisting of but not limited to xanthan gum, locust bean gum, guar gum and tamarind seed polysaccaride The concentration of natural polysaccharide with thixotropic behavior in the present formulation is ranging 0.1 - 0.9 % w/v.
The thermoreversible polymers in the present invention are selected from the group consisting of but not limited to gelatin, polyvinyl chloride), poly(acrylonitrile), polystyrene (atactic), poly(vinyl alcohol), agarose, carrageenans, benzohydroxamic acid, cellulose derivatives, polaxomer and polysaccharides.
The present invention further describes the use of thermoreversible polymers as
rheological modifiers. The role of rheological modifiers is to retain the high viscosity of
the polymers in presence of shear stress at physiological conditions. The commonly used
rheological modifiers are natural and semi synthetic cellulose derivatives such as
methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose,


carboxymethylcellulose and its salts and polaxomer; preferably rheological modifiers are methylcellulose and polaxomer.
The role of thermoreversible polymers is to maintain the rigidity of gel or to retain the gel strength against shear stress and dilution, which is achieved through thermo-gelation properties of thermoreversible polymers at physiological pH. The optimal concentration of methylcellulose present in the formulation is 0.1 - 2.5% or the concentration of polaxomer used in the range of 2.0 to 20% w/v.
The active ingredient is useful for diagnosis or treatment of various eye disorders, whereas the formulation without active ingredient is used to treat the dry eyes. The active ingredient used optionally in the present invention is alone or in the combination and selected from the group consisting of ophthalmically acceptable agents, including pharmaceutical agents, diagnostic agents, vitamins, nutrients, and lubricants. The ophthalmically acceptable agents include without limitation thereto, from the categories of local anesthetics, antimicrobial agents, antifungals, anti-inflammatory, antiglucoma, steroids, (3-blocker, antihistamics, immunosuppressant, cycloplegics, mydriatics, vasodilators, vasoconstrictors and lubricants. The active ingredient used in the formulation is ranging from 0.00001% to 10% w/v
The compatible buffering system selected in the present invention is compatible with polymer as well as other excipients such as tonicity modifiers and preservatives. The buffering systems used in the formulation include but not limited to phosphate, citrate, citrophosphate and tris preferably buffering systems is phosphate and tris buffer ranging from 0.01 to 20% w/v.
The suitable preservatives used in the system include but not limited to benzalkonium chloride, thiomersol, chlorbutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate and polyquard. The most commonly used preservatives are sodium perborate and benzalkonium chloride ranging from 0.0001 to 1% w/v.


The osmolarity of the present invention is 260-340 mosm/s, the viscosity of the present invention is 20-1000 cps, pH of the present invention varies depending on the API used in the formulation.
The suitable tonicity agents used in the system include but not limited to sodium chloride, potassium chloride, mannitol, dextrose, sucrose, glycerin and polyethylene glycol.
According to the preferred emboidment, the ophthalmic gel forming solution prepared by using any one of the systems consisting of natural polysaccharide with thixotropic behavior and thermoreversible polymers that provide in-situ gel formation by one or more combination of mechanisms such as thermal gelation, corneal mucoadhesion, lysosomal interaction and ionic gelation provides prolonged corneal residence time, improved corneal absorption, patient compliance and clinical success.
Example Compositions consist of
• active pharmaceutical ingredient(s) optionally
• natural polysaccharide with thixotropic behavior
• thermoreversible polymer
• buffer
• preservative with or without stabilizer
• pH modifier(s)
• tonicity modifiers
• vehicle
Process
The inactive excipients are dissolved with or without active ingredient(s) in part quantity of aqueous vehicle. Natural polysaccharide with thixotropic behavior and thermoreversible polymer is dispersed in polyethylene glycol or aqueous vehicle and subjected to sterilization by suitable mean such as thermal sterilization and ionization


sterilization. The sterilized polymeric dispersion is mixed aseptically with the aqueous vehicle and pH adjusted if required. Both solutions or dispersions are mixed aseptically and filtered through sterile terylene cloth and filled in suitable container.
Example 1:

Sr. No. Ingredients Quantity
1 Tetracaine HC1 0.5 % w/v
2 Xanthan gum 0.15% w/v
3 Methylcellulose 0.5 % w/v
4 Tris buffer 0.2 % w/v
5 Sodium Perborate 0.03 % w/v
6 Diethyl triamine petamethylene phosphoric acid (50% w/v) 0.006%. w/v
7 Disodium Edetate 0.02 % w/v
8 Polyethylene Glycol 400 2 % w/v
9 Mannitol 2.5 % w/v
10 Hydrochloric Acid to adjust the pH 4.5
11 Aqueous vehicle q.s. to 100ml
Example 2:

Sr. No. Ingredients Quantity
1 Timolol Maleate (equal to timolol) 0.5 % w/v
2 Xanthan gum 0.1 %w/v
3 Polaxomer 2.5 % w/v
4 Boric Acid 0.3% w/v
5 Benzalkonium Chloride 0.02 % w/v
6 Polyethylene Glycol 400 1 % v/v
7 Mannitol 2.4 % w/v
8 Hydrochloric Acid to adjust the pH 6.8
9 Aqueous vehicle q.s. to 100ml
Example 3:

Sr. No. Ingredients Quantity
2 Xanthan gum 0.2 % w/v
3 Methylcellulose 0.5 % w/v
5 Benzalkonium Chloride 0.01 %w/v
6 Polyethylene Glycol 400 0.5 % v/v
7 Mannitol 4.5 % w/v
8 Hydrochloric Acid or Sodium to adjust the Ph 7.2


hydroxide
Aqueous vehicle

q.s.to 100ml

Example 4:

Sr. No. Ingredients Quantity
2 Tamarind seed polysaccaride 0.2 % w/v
3 Polaxomer 2.5 % w/v
5 Benzalkonium Chloride 0.01 % w/v
6 Polyethylene Glycol 400 0.5 % v/v
7 8 Sodium Chloride 0.75 % w/v

Hydrochloric Acid or Sodium hydroxide to adjust the pH 7.2
9 Aqueous vehicle q.s. to 100ml

Dr. Gopakumar G. Nair (Regn. No: IN/PA509) Agent for the applicant