FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"NANODISPERSION OF POORLY WATER SOLUBLE DRTJG(S)"
2. APPLICANT (S):
(a) NAME: FDC Limited
(b)NATlONALITY: 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 particularly describes the invention and the manner in which it is to be performed

RELATED APPLICATION:
This application claims priority from our earlier Application No. 3064/MUM/2011 filed on 31/10/2011 and Application No.2021/MUM/2012 filed on 12/07/2012.
FILED OF INVENTION:
The present invention relates to a novel composition of nanodispersion for ocular drug delivery system comprising of poorly water-soluble drug(s).
BACKGROUND AND PRIOR ART:
Eye is the most vital and sensitive organ of the body. Eye ailments can cause distress and angst in patients. Many parts of the eye are relatively inaccessible to systemically administered drugs. Thus, topical drug delivery systems remain the preferred route in most of the ocular disorders and hence, a weil-accepted route of administration for the treatment of various eye diseases. Drugs may be delivered to treat the precorneal region for diseases namely conjunctivitis and blepharitis, or to provide intraocular treatment via the cornea for diseases such as glaucoma.
A major problem with conventional ophthalmic drug delivery systems is poor ocular bioavailability due to ocular anatomical and physiological constraints. The bioavailability of topically administered drug in the anterior chamber of eye is extremely low due to impermeable nature of the cornea. The physiological factors such as rapid clearance of the drug and/or dosage form by the tear-fluid drainage, absorption into the conjunctiva and washout by aqueous humor from the anterior chamber, are responsible for poor precorneal absorption. Topically applied drugs can reach the intraocular tissues by either the corneal and/or the non-cornea I pathways.
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 can cause significant side effects. Under normal conditions, an eye can accommodate very small volume of administered dosage form without overflowing. The drug contained in the eye 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, prolonging the precorneal retention, and reducing nasolacrimal drainage.
It is always a great challenge for formulation scientists to develop the dosage form for poorly water soluble drugs, especially in case of solution dosage form. Hence, there is a growing need for the development of unique strategies that can tackle the formulation-related problems associated with the delivery of hydrophobic drugs, in order to improve their clinical efficacy and optimize their therapy with respect to pharmacoeconomics. Nanodispersions are promising drug delivery technologies that can be used for enhancing the dissolution of poorly water-soluble drugs.
Dispersion associated with pharmaceutical products, such as suspension, emulsion and colloid, is a heterogeneous two phase system in which the internal phase (dispersed phase) is distributed or dispersed within external phase (dispersion medium). The dispersed phase and dispersion medium can be solid, liquid or gas.
US application no. 2008/0299206 discloses an ophthalmic formulation comprising, a) cyclosporine or a derivative thereof, b) at least one solvent, c) at least one oil selected from medium chain triglycerides, mineral oil, olive oil, peanut oil, wheat germ oil etc. d) surfactant, e) preservatives and (f) water or phosphate buffer. The said application also discloses a composition which comprises cyclosporine, a permeation enhancer and vitamin E TPGS. The said US application does not teach nanodispersion for ocular drug delivery and their potential advantages.
US application no. 2008/0102127 discloses a nanoparticulate colloidal delivery vehicle wherein nanoparticles are composed of water insoluble biocompatible polymer, solid lipid material, and outer layer comprising of surfactant, phospholipid, polymer etc. The said solid lipid includes tocopheryl esters such as tocopheryl succinate and tocopheryl palmitate. The said nanoparticle vehicle further contains surfactants, stabilizers, rheological modifiers, antioxidants and preservatives. The said invention describes the formulation of solid lipid nanoparticles, which consists of lipid material.

US 6114319 discloses ophthalmic emulsion comprising difluprednate, oil such as fatty acid ester of glycerol, water and an emulsifier, for the treatment of ocular inflammation. US 5556848 discloses an ophthalmic suspension comprising difluprednate, water soluble polymer selected from a group consisting of hydroxypropylmethyl cellulose and polyvinyl alcohol, and buffer selected from a group consisting of sodium acetate and □-aminocaproic acid, for the treatment of inflammation.
International Journal of Pharmaceutics 2007, 340(1-2); 126-33, discloses use of nanotechnology to formulate poorly water-soluble glucocorticoid drugs as nanosuspension for ophthalmic drug delivery system, and studies the effect of viscosity of the nanosuspension on the ocular bioavailability. The said invention is related to the development of ophthalmic nanosuspension for the delivery of Glucocorticoids. Nanosuspensions were formulated using 0.1% Pluronic as a surfactant.
International Journal of Pharmaceutics 301 (2005) 121-128, discloses preparation of oil-in-water type lipid emulsion for poorly water-soluble drug such as difluprednate, containing castor oil and polysorbate 80.
None of the aforementioned prior art discloses nanodispersion for ocular drug delivery comprising mineral oil. The mineral oil has the advantage of being inert and physic-chemically stable as compared to vegetable oils and other fatty esters of glycerol, which are prone to oxidation and rancidity on storage. The present invention discloses a cost effective and technically simple alternative for preparation of nanodispersion for ocular drug delivery of poorly water-soluble drugs(s). The nanodispersion of present invention exhibits improved corneal penetration, prolonged precorneal retention, reduced nasolacrimal drainage and enhanced magnitude of drug action.
SUMMARY OF THE INVENTION:
The present invention relates to nanodispersion formulation for ocular drug delivery comprising, poorly water-soluble drugs(s), mineral oil, surfactant(s), optionally permeation enhancer and other pharmaceutically acceptable excipients, with improved patient compliance, reduced dosing frequency, safety and better therapeutic efficacy. The invention further discloses a process for preparation of the nanodispersion.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1 relates to the size distribution of nanodispersion in Example 1, wherein the
extrapolated line indicates the average particle radius.
Figure 2 relates to the size distribution of nanodispersion in Example 2, wherein the
extrapolated line indicates the average particle radius.
Figure 3 relates to the size distribution of nanodispersion in Example 3, wherein the
extrapolated line indicates the average particle radius.
Figure 4 relates to the size distribution of nanodispersion in Example 4, wherein the
extrapolated line indicates the average particle radius.
Figure 5 relates to the size distribution of nanodispersion in Example 5, wherein the
extrapolated line indicates the average particle radius.
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.
The present invention provides nanodispersion for ocular drug delivery system comprising, poorly water-soluble drugs(s), mineral oil, surfactant(s), optionally permeation enhancer; and other pharmaceutically acceptable excipients.
Nanodispersion of present invention offers improved drug surface area and increased intraocular drug permeation. Moreover, nanosized dispersion of drug provides less mechanical irritation to the ocular tissue, when compared to microcrystals and coarse particles. The ocular irritation induces lachrymal fluid secretion, and hence results in drainage of the drug from the eye. The increased lachrymal secretion not only leads to precorneal elimination of the drug by draining out from the ocular cavity, but also causes dilution of the drug. The dilution of the drug in precorneal area, reduces the concentration gradient and hence reduces the rate of absorption of drug(s), which follows passive diffusion.
Ophthalmic solutions have been considered as the ideal choice of dosage form for ocular drug delivery because of their clarity, better biopharmaceutical properties and patient

compliance. However, it is very difficult to formulate ophthalmic solutions for poorly soluble drugs because of limited availability of non-toxic solubilizers for ophthalmic use. Hence, the present inventors have developed nanodispersion, as conventional ophthalmic formulations has problems associated with it, which include blurred vision, mechanical irritation of the eye caused by coarser particles, sedimentation of particles, agglomeration of the particles during storage and poor content uniformity. Such factors hinder the clinical performance of the ophthalmic formulations.
The present invention develops nanodispersion for ocular drug delivery of poorly water-soluble drug(s) to combat the problems associated with the conventional ophthalmic formulations and offer better biopharmaceutical and clinical outcomes. The present invention has used, mineral oil, surfactant(s), optionally permeation enhancer and other pharmaceutically acceptable excipients which are further processed through high pressure homogenizer to produce homogenous nanodispersion. Such nanodispersion enhances the magnitude of drug action along with drug absorption in ocular cavity with limited volume of lachrymal fluid. Moreover, increased saturation solubility of the drug has been achieved due to high surface area of drug particles which is offered by nanosizing process in combination with the surfactant. Further increased saturation solubility increases the concentration gradient of the drug across the ocular surface and hence improves the rate of absorption.
The poorly water soluble drugs used in the nanodispersion of the present invention, are selected from a group consisting of steroid anti-inflammatory agents, non-steroidal antiinflammatory agents, antimicrobial, anti-viral, anti-glaucoma, and drugs used in the treatment of cataract and dry eye syndrome preferably difluprednate, dexamethasone; ciprofloxacin, levofloxacin and chloramphenicol.
The poorly water soluble drugs used in the nanodispersion of the present invention are in the range of 0.005% to 2.0% of the total weight of the composition.
The mineral oil is used as an oil phase, and further increases the partition of drug in lipoidal biological membrane with the help of surfactant. The mineral oil used in the present invention is selected from a group consisting liquid paraffin such as light liquid

paraffin, heavy liquid paraffin and mixtures thereof, and is in the range of 0.5% to 10% w/w of the total weight of the composition.
The surfactants are wetting agents that lower the surface tension of a liquid, thus allowing easier spreading of the formulation on the ocular surface. They also lower the interfacial tension between two liquids and facilitate drug partitioning, thereby enhancing its absorption. Surfactants reduce the surface tension of water by adsorbing at the liquid-gas interface. They also reduce the interfacial tension between oil and water by adsorbing at the liquid-liquid interface.
The surfactant(s) used in the present invention, are preferably non-ionic surfactants selected from Polysorbate 80, Polysorbate 20, Polysorbate 60, Polyvinyl alcohol, Polyoxy 35 castor oil, polyoxy 40 stearate, polypropylene glycol or sorbitan esters of fatty acids such as monooleate, monolaurate, monopalmitate, monostearate and tristearate, and ranges from 0.0005% to 5.0% w/v of total weight of the composition.
The permeability enhancer(s) are used in the present invention to improve the transcorneal permeability of the drug, and hence increase the intraocular drug concentration. The permeation enhancer is preferably selected from tocophersolan (Vitamin E Tocopheryl Polyethylene Glycol 1000 Succinate (Vitamin ETPGS)) or polyethylene glycol glycerides.
The other pharmaceutically acceptable excipients used in the present invention, include but are not limited to tonicity modifiers, pH adjusting agents, buffers, preservatives, antioxidants, viscosity modifiers, stabilizers and chelating agents.
The tonicity modifier used in the present invention, is selected from but not limited to sodium chloride, glycerol, glucose, mannitol or sorbitol.
The buffer used in the present invention, is selected from but not limited to borate, acetate, phosphate, citrate, citrophosphate or TR1S buffer.

The preservatives used in the system are selected from but not limited to quaternary ammonium salts such as benzalkonium chloride; benzethonium chloride; benzdodecanium bromide; polyquaternium; cationic compound such as chlorhexidine gluconate; parahydroxy benzoates such as methyl paraben, propyl paraben; alcoholic compounds such as chlorobutanol, benzyl alcohol; sodium dehydroacetate; sorbic acid; thiomersol; sodium perborate or stabilized oxychloro complex.
The antioxidant is a molecule capable of inhibiting the oxidation of drug substances in the formulations. The antioxidants used in the present invention are selected from the group consisting of but not limited to sodium bisulphite, sodium metabisulphite, thiourea, tocophersoJan and ethylenediamine tetraacetic acid.
The size of the nanodispersion of the present invention is less than lOOOnm, preferably less than 200nm, more preferably less than 20nm.
The osmolarity of the nanodispersion of present invention is 250-400 mosm/s, and the viscosity of the nanodispersion of present invention is 1-1000 cps preferably 1-200 cps. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples: Example 1

SrNo. Ingredients Cone. (%w/v)
1 Difluprednate 0.05
2 Liquid paraffin 4.0
3 Polysorbate 80 4.0
4 Glycerin 2.2
5 Sodium acetate 0.05
6 Disodium Edetate 0.02
7 Boric acid 0.1

8 Sorbic acid 0.1
9 Vitamin E TPGS (Tocophersolan) 0.5
10 Purified water q.s. to 100
Process:
Aqueous Phase
1. Heating two third volume of purified water upto 80°C followed by adding and
dissolving sodium acetate, disodium edetate, boric acid and vitamin E TPGS
(Tocophersolan) into it.
Oil phase
2. Dissolving Difluprednate and Sorbic acid in liquid paraffin (80°C).
Homogenization
3. Adding liquid paraffin phase to step (1) phase under high speed homogenizer to get a dispersion.
4. Adjusting pH between 5.0-7.0.
5. Homogenizing the dispersion in high pressure homogenizer to obtain nanodispersion.
Example 2

SrNo. Ingredients Cone. (%w/v)
1 Difluprednate 0.025
2 Liquid paraffin 4.0
3 Polysorbate 80 4.0
4 Glycerin 2.0
5 Sodium acetate anhydrous 0.05
6 Disodium Edetate 0.02
7 Boric acid 0.1
8 Sorbic acid 0.1
9 Vitamin E TPGS (Tocophersolan) 0.1
!0 Purified water q.s. to 100

Process:
Aqueous Phase
1. Heating two third volume of purified water upto 80°C followed by adding and
dissolving sodium acetate, disodium edetate, boric acid and vitamin E TPGS
(Tocophersolan) into it.
Oil phase
2. Dissolving Difluprednate and Sorbic acid in liquid paraffin (80°C).
Homogenization
3. Adding liquid paraffin phase to step (1) phase under high speed homogenizer to get a dispersion.
4. Adjusting pH between 5.0-7.0.
5. Homogenizing the dispersion in high pressure homogenizer to obtain nanodispersion.
Example 3

SrNo. Ingredients Cone. (%w/v)
1 Difluprednate 0.025
2 Liquid paraffin 4.0
3 Polysorbate 80 4.0
4 Glycerin 2.2
5 Sodium acetate trihydrate 0.05
6 Disodium Edetate 0.02
7 Boric acid 0.1
8 Sorbic acid 0.1
9 Vitamin E TPGS (Tocophersolan) 0.4
10 Purified water q.s. to 100

Process:
Aqueous Phase
1. Heating two third volume of purified water upto 80°C followed by adding and
dissolving sodium acetate, disodium edetate, boric acid and vitamin E TPGS
(Tocophersolan) into it.
Oil phase
2. Dissolving Difluprednate and Sorbic acid in liquid paraffin (80°C).
Homogenization
3. Adding liquid paraffin phase to step (1) phase under high speed homogenizer to get a dispersion.
4. Adjusting pH between 5.0-7.0.
5. Homogenizing the dispersion in high pressure homogenizer to obtain nanodispersion.
Example 4

SrNo. Ingredients Cone. (%w/v)
1 Ciprofloxacin 0.3
2 Liquid paraffin 1.0
3 Polysorbate 80 1.25
4 Sodium Chloride 0.75
4 HPMC F4M 0.00006
5 Benzalkonium chloride 0.006
6 Purified water q.s.to 100
Process:
1. Heating two third volume of purified water up to 80°C followed by adding and dispersing HPMC F4M and homogenizing for five minutes
2. Dissolving Benzalkonium chloride in one tenth volume of purified water (55°C). Adding this solution and Polysorbate 80 to step 1, followed by liquid paraffin under homogenization.
3. Adding Ciprofloxacin and continue homogenization for one hour.
4. Check and adjust the pH to 5.0-7.0.

5. Homogenizing the dispersion in high pressure homogenization to obtain the nanodispersion,
Example 5

SrNo. Ingredients Conc (%w/v)
1 Chloramphenicol 1.0
2 Dexamethasone 0.1
3 Heavy Liquid paraffin 1.5
4 Polysorbate 80 4.0
5 HPMC F4M 0.00006
6 Sodium Chloride 0.8
7 Phenyl mercuric nitrate 0.002
8 Disodium Edetate 0.02
9 Polysorbate 80 3.0
10 Vitamin E TPGS (Tocophersolan) 0.5
11 Purified water q.s. to 100
Process:
1. Heating two third volume of purified water up to 80°C followed by adding and dispersing HPMC F4M and homogenizing for five minutes followed by adding and dissolving Disodium edetate, Phenyl mercuric nitrate and Polysorbate 80 into it.
2. Adding and dissolving vitamin E TPGS in one tenth volume of purified water (SOX). Cooling to room temperature and adding to the solution of step 1.
3. Adding Liquid paraffin to the above solution under homogenization
4. Adding Chloramphenicol, Dexamethasone and continue homogenization for one hour.
5. Adjusting the pH to 5.0 -7.0.
6. Homogenizing the dispersion in high pressure homogenization to obtain the nanodispersion.

Table 1 includes evaluation parameters of nanodispersion
• Average particle size of nanodispersion measured using Malvern zetasizer
• Polydispersity index (PDI) is a measurement of distribution of particle sizes in the formulation (measured using Malvern zetasizer)
• Viscosity
• Osmolarity
Table: 1

Example Size analysis Viscosity (cps) Osmolarity

Average particle size radius (nm) PDI % Peak 1 %
Peak 2
(mosm)
1 1.413 0.207 100 0.00 2.0 334
2 6.627 0.249 100 0.00 2.1 304
3 6.473 0.243 100 0.00 2.4 341
4 3.033 0.209 100 0.00 1.9 298
5 2.751 0.237 100 0.00 2.0 308

We claim:
1. A nanodispersion for ocular drug delivery comprising poorly water-soluble drug(s), mineral oil, surfactant(s), optionally permeation enhancer and other pharmaceutically acceptable excipients, and process for preparation of said pharmaceutical composition.
2. The nanodispersion according to claim 1, wherein the poorly water soluble drugs are selected from a group consisting of steroid anti-inflammatory agents, non-steroidal anti-inflammatory agents, antimicrobial, anti viral, anti glaucoma, and drugs used in the treatment of cataract and dry eye syndrome preferably difluprednate, dexamethasone; ciprofloxacin, ievoftoxacin and chloramphenicol.
3. The poorly water-soluble drugs according to claim 2, wherein the said drugs are in the range of 0.005% to 2.0% of the total weigth of the composition.
4. The nanodispersion according to claim 1, wherein the mineral oils are selected from a group consisting of light liquid paraffin, heavy liquid paraffin and mixtures thereof, present in an amount of 0.5% to 10% w/w of total weight of the composition.
5. The nanodispersion according to claim 1, wherein the surfactant(s) are non-ionic surfactant(s) selected from polysorbate 80, polysorbate 20, polysorbate 60, polyvinyl alcohol, polyoxy 35 castor oil, polyoxy 40 stearate, polypropylene glycol or sorbitan esters of fatty acids such as monooleate, monolaurate, monopalmitate, monostearate and tristearate, present in an amount of 0.0005% to 5.0% w/v of total weight of the composition.
6. The nanodispersion according to claim 1, wherein the permeation enhancers are selected from tocophersolan or polyethylene glycol glycerides.
7. The nanodispersion according to claim 1, wherein the size of nanodispersion is less than lOOOnm, preferably less than 200 nm, more preferably less than 20 nm.

8. The nanodispersion according to claim 1, wherein the osmolarity of the nanodispersion is 250-400 mosm/s, and the viscosity of the nanodispersion is 1-1000 cps preferably 1 -200 cps.
9. The nanodispersion according to claim 1, wherein the pharmaceutically acceptable excipients comprises tonicity modifiers, pH adjusting agents, buffers, preservatives, antioxidants, viscosity modifiers, stabilizers and chelating agents.