The present invention relates to a sustained release and long residing ophthalmic formulation.
Background of the invention
Medication of the eyes is done for two purposes - to treat the outside of the eyes for such infections as conjunctivitis, blepharitis, keratitis sicca etc and to provide intraocular treatment through the cornea for diseases such as glaucoma or uveitis. Most ocular diseases are treated with topical application of solutions administered as eye drops. One of the major problems encountered with the topical delivery of ophthalmic drugs is the rapid and extensive precorneal loss caused by drainage and high tear fluid turn over. After instillation of an eye-drop, typically less than 2-3% of the applied drug penetrates the cornea and reaches the intra-ocular tissue, while a major fraction of the instilled dose is often absorbed systematically via the conjunctiva and nasolacrimal duct. Another limitation is relatively impermeable corneal barrier that limits ocular absorption.
Because of the inherent problems associated with the conventional eyedrops there is a significant efforts directed towards new drug delivery systems for ophthalmic administration such as hydrogels, micro- and nanoparticles, liposomes and collagen shields. Ocular drug delivery is an approach to controlling and ultimately optimizing delivery of the drug to its target tissue in the eye. Most of the formulation efforts aim at maximizing oculai drug absorption through prolongation of the drug residence time in the cornea and conjunctival sac as well as to slow drug release from the delivery system and minimizing precorneal drug loss.
To solve the above mentioned problem associated with the ocular delivery of drugs, WO 9405257 Al 940317 discloses a method for preparing a bioerodible drug delivery vehicle composed of solid polymeric matrix formed from derivatised cellulose and methacrylic acid copolymer and incorporating ophthalmic drugs in it. The inventors have demonstrated that such formulation when instilled in eyes the polymeric materials bio-erodes and dispenses the incorporated drug on the cornea surface. However, the problem always associated with the use of such bulk gel is the blurring effect and biocompatibility of the polymeric material. Moreover, the long residence time and sustained release of drug have not been achieved.
There have been reported other studies on the use of copolymeric materials as carriers for ophthalmic drugs and particularly noteworthy are the attempts to incorporate hydrophobic drugs into the hydrophobic core of the copolymer micelles. The pharmaceutical efficacy of these formulations depends on the specific nature and properties of the copolymeric materials.
For example, EP 0744938 Al 961204 discloses sustained release liquid aqueous ophthalmic delivery system. The method provides a slow and sustained release of treating agents. The polymer used was chitosan and was applied in the form of bulk material. However, it is difficult for such bulk polymer to penetrate the corneal membrane and the liquid formulation remain in the liquid form even at body temperature so that there exists every possibility to be washed away by tears. There also exists a problem of this formulation. The acidic pH of the liquid, pH 3.0 to 6.2, is not very much patient compliance. The other patent with related formulation with chitosan is WO 9522315 Al 950824 and EP 0594760.
Al 940504 discloses a method for entrapping ophthalmic drugs in polyacryl acid polymer to obtain a fluid aqueous gel having a pH of between 6.5 and 8. The formulation is claimed to be useful for treating various pathological ocular conditions. This method, thus solves the potential mucoadhesive problem of the polymer by using polyacrylic acid gels. However, pure polyacryl acid is so much sticky that a permanent polymer layer on the cornea surface may cause blurred vision. Moreover, being bulk gel, these polymeric composition may not have sufficient penetration and subsequently less bio-availability. The same is the comment for other patents: WO 9300887 Al 930121 and WO 9922713 Al 19990514 and WO 9405257 Al 940317.
There are reported studies on formulations of non-steroidal antiinflammatory drugs using different carriers particularly directed towards oral delivery to avoid the adverse effects on the gastrointestinal tract.
A patent WO 93/25190 has disclosed surface modified NSAID nanoparticles by taking crystalline NSAID having surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400nm.
One patent EP 0274870 A2 880720, has disclosed the micelles containing polyethoxylated nonionic surfactant as carrier for certain NSAIDs. Other
patents, EP 0818992 Al 980121 and WO 9505166 Al 950223 disclose the similar type of micellar encapsulation of NSAIDs using cellular acetate phthalate and gelatin.
Another patent, WO 9702017 Al 970123 used hydrophilic poloxamer for encapsulating NSAIDs. These are some of the patents, which are mainly directed towards oral delivery formulations so that these NSAIDs cannot be exposed in GI tract. These formulations do not have any relevance to eye drop preparations.
To overcome the problem of blurred vision and poor bio-availability of drug by using bulk gel in ophthalmic formulations, it has been suggested that colloidal carriers would have better effect. Colloidal carriers which have been studied for ocular delivery are mainly liposomes and nanoparticles because of their extremely small size. The main limitation of liposomes as ocular drug delivery system is its surface charge. Positively charged liposomes seemed to be preferentially captured at the negatively charged corneal surface compared to neutral and negatively charged liposomes. Another limitation of liposomes is the instability of the lipid aggregates on the mucine surface. The vesicular aggregates of positively charged lipids are completely disintegrated on the negatively charged mucine membrane surface.
Nanoparticles as drug carriers for ocular delivery have been revealed to be more efficient than liposomes and in addition to all positive points of liposomes, these nanoparticles are exceptionally stable entity and the sustained release of drug can be modulated.
Some studies have been reported in the literature as well as patents on the use of nanoparticles carriers for encapsulating water insoluble drugs. For example, a US patent 5,510,103 disclose the entrapment of water-insoluble drugs including NSAIDs in the hydrophobic core of polymeric micelles of different block copolymers. Another similar US patent, US 5,449,513 has also disclosed the use of various amphiphilic copolymers in the form of micelles to physically entrap water-insoluble drugs. The other patents of similar type are US 5510103, US 5449513, US 5124151.
All these patents described the method of preparation of amphiphilic copolymers of random compositions of two or three different types of amphiphilic monomers and aggregating them in aqueous solutions and
dissolving the water-insoluble drugs inside the hydrophobic core of these polymeric micelles. The properties of these copolymers are governed by the composition of them. But none of the polymers could comply the overall requirements of best ophthalmic formulation - hydro gel formation, mucoadhesiveness, thermosensitivity and small particle size - in a single formulation.
The object of the present invention therefore is to obviate the above-
mentioned drawbacks and to provide a formulation having
thermosensitivity, mucoadhesiveness, hydro gel properties and small
particle size.
Still further object of this invention is to provide sustained release and long residing ophthalmic formulation, so that the release of the entrapped drug can be controlled.
To achieve the said objective, this invention provides a sustained release and long residing ophthalmic formulation comprising
micelle solution of block co-polymer having a hydrophobic component and the hydrophilic component of general formula -(X-Y-Z-)m, wherein
m is an integer greater than 2
X is a compound having hydrogel formation properties selected from vinyl group of compounds
Y is a compound having thermosensitivity properties having a general formula R1-R2N-(C=O)-CH=CH2, Ri= a proton or CnH2n+1 in which n may have the value from 3 to 6 and R2 = alkyl group having chain length of C3 to C6
Z is a compound having mucoadhesive and pH-sensitivity properties and is selected form acrylate based monomers.
and
at least one hydrophobic drug with the said block co-polymer solution;
The said vinyl group of compounds is selected from vinyl pyrrolidine, vinyl alcohol, vinyl chloride or vinyl acetate. Y is N-isopropyl acrylamide(NIPAAM)
The said acrylate based monomers is selected from acrylic acid or methyl methacrylate. m preferably lies in the range 10-4000.
The said drug is non steroidal anti inflammatory drug (NSAID) preferably selected from 5-benzoyl (2,3 dihydro-lH pyrrolizone-1 carboxylic acid); 1-(4 chlorobenzoyl)-5 methoxy -2- methyl-1 H-indole-3acetic acid or N-(4-nitro- 2 phenoxyphenyl) methanesulphonamide or a mixture of at least
The said hydrophobic drug used for entrapment is in solution or in powder form and is preferably in the form of free bases.
The said polymerized micelles containing the hydrophobic drug have a size in the range of 10nm-100nm diameter, preferably lOnm to 50nm.
The block copolymers made of amphiphilic monomers are biocompatible and non-antigenic materials.
The molar ratio of the combination of amphiphilic monomers X, Y and Z is preferably 9.5% : 85.7% : 4.8% respectively.
The block copolymer micelles composed of polyvinylpyirolidone (which produces hydrogel to ; reduce the irritability of the eye), poly-N-isopropylacrylamide (pNIPAAM) (which renders thermosensitivity) and polyacrylic acid (which renders mucoadhesiveness) to the polymeric micelles. The copolymer is having an inner hydrophobic core and an outer hydrophilic shell. To render the micellar aggregates more stable, cross-linking of the polymeric chain was done by using N,N'methylene bis acrylamide during the vinyl polymerization process. The resulting micellar aggregate is suitable of dissolving hydrophobic drugs such as ketorolac, indomethicin and nimesulide. These micellar aggregates are very small in size (<50nm diameter) and therefore, can easily penetrate the mucine membrane of the eye, have mucoadhesive properties and therefore, can adhere on the corneal surface so that the corneal penetration is an extremely slow process. At and above 35°C, these nanoparticles are desolvated and becomes hydrophobic due to the presence of NIPAAM unit. This results the
deposition of particles in the membrane pores and cause sustained release of the drug there.
The block copolymer micelles are made of mucoadhesive and thermosensitive polymer components, and when instilled, it penetrates the mucin membrane, adhere to the membrane pores and at body temperature, it becomes more hydrophobic to release the drug faster. These biodegradable block copolymer micelles nanoparticles having an average diameter of 20nm to 60nm are particularly suitable for formulating an ocular delivery composition of NSAIDs like ketorolac, indomethicin and nimesulide which are usually made soluble in water by making them salts in acidic medium.
The block copolymer of micelles of the present invention may be prepared by mixing monomers such as vinylpyrrolidone (VP), N-isopropyl acrylamide (NIPAAM) and acrylic acid(AA) in presence of NN methylene bis acrylamide (MBA) and polymerizing the mixture by free radical polymerization reaction using ammonium persulphate as catalyst. The hydrophobic moiety of the polymeric chain remain buried inside the micelles which help dissolution of drug and the hydrophilic moiety such as carboxylic acids are extended outside the surface of the micelles. The clear solution of the micellar dispersion in aqueous solution can be instilled in the patient's eyes much more effectively and the sustained release of the drug encapsulated inside the micelles enhances the therapeutic effect of the drug.
The block copolymer used in the drug composition of the present invention may be a random copolymer of eonstiuenf s VP, NIPAAM and AA.
(Formula Removed)
wherein,
m is an integer larger than 2, preferably from 10 to 4000.
In this copolymer, the VP, NIPAAM and AA components are responsible for hydrogel formation, thermosensitivity and mucoadhesiveness of the micelles respectively.
The monomers are not limited to only these three monomers only. Any monomer having these characteristics can be used for such micelles. As for
example, instead of NIPAAM, one can take N-alkylacrylamide of general formula
(Formula Removed)
Wherein Ri may be a proton or CnH2n+1 in which n may have any value from 3 to 6.
Instead of VP one can take vinylalcohol.
Suitable hydrophobic drugs, which may be incorporated into the block copolymer micelles of the present invention, are non-steroid antiinflammatory drugs such as ketorolac, indomethicin and nimesulide.
The combination of amphiphilic monomers is preferably VP, NIPAAM and AA in the molar ratio 9.5% : 85.7% : 4.8%
In order to incorporate one or more drugs mentioned above into the block copolymer micelles, various methods described below may be used alone or in combination.
(i) Stirring
A drug is added to an aqueous solution of a block copolymer, and stirred for 2 to 24 hours to obtain micelles containing drug.
(ii) Heating
A drug and an aqueous solution of a block copolymer are mixed and stirred at 30C to 80C for 5minutes to a couple of hours and then cooled to room temperature while stirring to obtain micelles containing the drug.
(iii) Ultrasonic treatment
A mixture of a drug and an aqueous solution of a block copolymer is subjected to an ultrasonic treatment for lOminutes to 30minutes and then stirred at room temperature to obtain micelles containing the drug.
(iv) Solvent evaporation
A drug is dissolved in an organic solvent such as chloroform and was added to an aqueous solution of micelles. Subsequently the organic
solvent was evaporated slowly while stirring, and then filtered to remove non-soluble drug.
(v) Dialysis
The polymeric micelles solution was added to an organic solution of drug and the mixture is dialyzed against a buffer solution and then water.
Preferably, the process for preparing a sustained release and long residing ophthalmic formulation comprising the steps of:
- preparing micelle solution of block co-polymer having a hydrophobic component and the hydrophilic component of general formula -(X-Y-Z-)m, wherein
m is an integer greater than 2
X is a compound having hydrogel formation properties selected from vinyl group of compounds
Y is a compound having thermosensitivity properties having a general formula R1-R2N-(C=O)-CH=CH2, wherein R1= a proton or CnH2n+1 in which n may have the value from 3 to 6 R2 = alkyl group having chain length of C3 to C6
Z is a compound having mucoadhesive and pH-sensitivity properties and is selected form acrylate based monomers.
mixing at least one hydrophobic drug with the said block copolymer solution;
subjecting the resulting mixture to stirring, heating, ultrasonic treatment, solvent evaporation or dialysis to physically incorporate the hydrophobic drug into the hydrophobic core of block co-polymeric micelle, and
purifying the mixture to recover the sustained release and long residing ophthalmic formulation.
The micelle solution of block copolymers is prepared by dissolving amphiphilic monomers in an aqueous medium to obtain micelles, adding aqueous solutions of cross-linking agent, activator and initiator into the said micelles, subjecting the said mixture to polymerization in presence of an inert gas at 30°C- 40°C till the polymerization of micelles is complete.
The purification step is done by dialysis. The dialysis is carried out for 2-4 hours to eliminate unreacted monomers and free NSAID, if any, at the aqueous phase.
The organic solvents used for dissolving the drug is selected from
dimethylformamide (DMF), dimethylsulphoxide (DMSO), dioxane,
dhloroform, n-hexane, dichloromethane, ethylacetate, ethanol, ethanol and like.
The cross linking agent is a Afunctional vinyl derivative, preferably N,N' methylene bis acrylamide.
The initiators are peroxide derivatives, preferably benzoyl peroxide, or perdisulphate salts like ammonium perdisulphate or 2,2' - azo bis isobutyronitrile (AIBN).
The activator is tetramethyl ethylene diamine (TEMED). The inert gas is nitrogen or argon. The temperature at which polymerization is carried out ranges between 20°C-80°C, particularly between 30°C-40°C.
A hydrophobic drug may be incorporated into the polymeric micelles of the present invention during the time of polymerization wherein the drug is also dissolved into the micelles of the monomers in aqueous solution and the polymerization is done in presence of the drug. But one has to be very sure that the chemical structure of the drug is not affected by the ammonium persulphate added for polymerization.
As the drug held in the hydrophobic core of the micelles nanoparticles is released on the cornea surface in a controlled manner for a long time, the composition of the present invention is suitable for formulating drugs which are not amenable to conventional formulating techniques or using non mucoadhesive micelles.
The present invention thus provides a formulation which is therapeutically more effective, and toxicologically much safer, than conventional formulations of hydrophobic drugs.
The invention will now be described with reference to the following examples and the accompanying drawings.
Figure 1 - Typical size distribution of NIPAAM-VP-AA copolymeric micelles by dynamic light scattering measurement.
Figure 2 - Transmission electron microscope picture of keterolac loaded NIPAAM -VP-AA copolymeric micelles (scaleLlcm=50nm).
Figure 3 - Tear fluid PMN counts of keterolac formulation on PGE2 induced ocular inflammation in rabbits.
Figure 1 shows stable micelles having an average size of 30nm to 60nm diameter. Micelles of this size range are dispersed in water to give a transparent solution. The stability of the micelles is excellent as can be seen from the shelf life studies. The particle size was measured by Dynamic Light Scattering Experiment wherein the drug loaded lyophilized powder was dissolved in aqueous buffer to get about 5% solution. The solution was then filtered through 200nm Millipore filter and the particle size and size distribution of the polymeric micelles was determined using a Brookhaven BI8000 instrument with a BI200 SM goniometer. An aircooled argon ion laser operated at 488 nm was used as light source. The intensity of scattered light was detected at 90o to an incident beam. The measurement was done using a 128 channel digital correlator which derive the time dependent auto correlation function of the scattered intensity. The size of the particle was calculated from diffusion of the particles using Stoke-Einstein equation. The particle size and size distribution of ketorolac loaded polymeric micelles nanoparticles are shown this figure
Figure 2 shows the transmission Electron Microscopic (TEM) picture of the stained samples of polymeric micelles loaded with ketorolac. The TEM picture of the micellar nanoparticles was taken in a Philips EM 300 instrument using 14000 times magnification. A drop of aqueous solution of lyophilized powder (~ 5mg/ml) was placed on a membrane coated grid surface with a filter paper (Whatman #1). A drop of 1% phosphotungstic acid was immediately added to the surface of the grid. After 1 minute
excess fluid was removed and the grid surface was air dried at room temperature before loaded in the microscope. The micelles nanoparticles are all spherical in shape and nearly monodispersed.
Example -1
Polymeric nanoparticles containing ketorolac:
To 900mg NIPAAM, 100µl freshly distilled VP and 50µl freshly distilled AA in 100ml water, 300/d MBA ([MBA]=O.049gm/ml) was added to crosslink? the polymer chain,. The dissolved oxygen was removed by passing nitrogen gas for 30mins. 50µl of 0.5% w/v ferrous ammonium sulphate d(FAS) and 50µl saturated ammonium persulphate" (APS) solutions were, then, added to initiate the polymerization reaction. The polymerization was done at 30°C for 24 hrs in nitrogen atmosphere. Total aqueous solution of polymer was then dialyzed for overnight using a spectrapore membrane dialysis bag (12kD cut off). The dialyzed aqueous solution of polymeric micelles was frozen in liquid nitrogen and was lyophilized immediately to obtain dry powder for subsequent use. The yield of micelles nanoparticles was more than 80%. The lyophilized powder is easily redispersible in aqueous buffer. 100mg of lyophilized powder of polymeric micelles was dispersed in 10ml of water and was stirred well to constitute the micelles. The free acid form of ketorolac was dissolved in absolute ethanol ([ketorolac]=50mg/ml) and the alcoholic solution was added in polymeric micelles slowly with constant stirring. Ketorolac got directly loaded into "hydrophobic core of micelles. The drug loaded polymeric micelles were then lyophilized to get dry powder for subsequent use.
Example -2
Polymeric nanoparticles containing Indomethacin:
In 100mg of the lyophilized powder of the polymeric micelles nanoparticles, an alcoholic solution of indomethacin ([Indomethacin]=33mg/ml) was added with constant stirring to get clear solution of polymeric micelles containing the drug of desired concentration dispersed in aqueous buffer. Maximum 10% w/w of the drug could be dissolved in polymeric micelles at room temperature. The drug loaded polymeric micelles was then lyophilized to get dry powder for subsequent use.
Example — 3
Polymeric micelles containing Nimesulide:
In 100mg of dry powder of polymeric micelles, an alcoholic solution of nimesulide ([nimesulide]=10mg/ml) was added with constant stirring to get clear solution. Maximum 8% w/w of nimesulide could be dissolved in polymeric micelles at room temperature. The drug loaded micelles was then lyophilized to get dry powder for subsequent use.
Example - 4
Shelf life of the drug loaded polymeric micelles nanoparticles:
The shelf life of drug loaded polymeric micelles was determined by
dissolving certain amount of drug loaded lyophilized powder in water and
the solution was kept in incubator at 25C. The solution was clear at the time
of loading (zero time). The time when the solution became just turbid was
noted. The shelf life of ketorolac loaded nanoparticles, for example, is
shown in the table 1. The table shows that while 5% w/w ketorolac in
polymeric micelles keeps the solution clear for more than 15 days, a
solution containing nanoparticles of 30% loading gives turbidity within 24
hours. This shows that these drugs entrapped in polymeric micelles can not
be used as aqueous solution for a very long time and has to be kept as a
lyophilized powder.
Clinical Trials:
In vitro transcorneal permeation studies:
The experiment was carried out using freshly excised rabbit corneas. Albino rabbit weighing 1.5 to 2kg was sacrificed with an intravenous lethal dose of phenobarbitone sodium injection (200mg/ml) and eye balls were removed. The corneas were dissected along with 2-4mm of surrounding scleral tissue and washed with cold normal saline water. Cornea was mounted between the donor and receptor chambers of a modified version of Franz all glass diffusion cell. Cornea area available for permeation was 0.64cm2. The receptor was filled with 12ml of bicarbonate ringer and all air bubbles were
removed. 1ml of formulation was placed in the donor chamber i.e. on the top of the cornea. The entire set up was thermostated at 37°C. 2ml sample was withdrawn at 60 and 120 mins from the receptor chamber through the sample port and was diluted with 0.1N HCl , and the drug content was determined spectrophotometrically by measuring the absorbance at 313nm, 319nm or 301nm for ketorolac, indomethacin or nimesulide respectively. Bicarbonate ringer replaced the quantity of samples withdrawn. At the end, cornea was freed of scleral ring and weighed. The cornea was then dried at 80°C to constant weight to determine the corneal hydration. Corneal hydration level was found to be between 79% and 80% as shown in table 2, indicating no corneal damage has taken place due to addition of keterolac formulation.
In vitro studies of keterolac formulation on PGE2 induced ocular inflammation in rabbits:
Eight albino rabbits of either sex were divided randomly into two groups of four each. Each rabbit received 50ul of keterolac formulation in left eye and 50 µl of control vehicle (distilled water) in the contra lateral eye. Ten minutes late 50ul of PGE2 was instilled in both eyes. All eyes were then evaluated for parameters of inflammation i.e, lid closure and polymorphonuclear leucocyte (PMN) migration. Lid closure parameter was scored as follows:
0. Ml open,
1. one third open,
2. two third open,
3. fully closed.
Normal saline (100/d) was instilled in the inferior cul de sac of the rabbit eye and after quick and gentle mixing 50ul of the tear fluid was withdrawn at 1,2,3,4 and 5 hours following PGE2 instillation. Tear fluid PMN was counted in Neubaner haemocytometer. The result as shown in figure 3 of the accompanying drawing, indicated that the lid closure was prominent upto three hours after which it subsided. The lid closure was found to be more in all control eyes as compared to the eyes treated with nanoparticle formulations. Also the lid closure in case of eyes treated with nanoparticle formulations was very less compared to that observed with suspension of keterolac
of same concentration (table-3). PMN counts in the tears of rabbit increased upto three hours and afterward it decreased. In case of nanoparticle formulation , the PMN counts were observed to be less than the control throughout the five hour study. The percentage inhibition on PMN migration with nanoparticle formulations was found to be much higher and longer lasting than that observed with aqueous suspension containing equivalent amount of keterolac.
Tablel: Shelf-life studies of drug loaded polymeric micelles
with varying amount of ketorolac
(Table Removed)
Table2: Comparison of permeation of ketorolac from NIPAAM-VP-AA copolymenc micelle formulation with aqueous suspension
of dmg of same concentration (0.7 mg/ml) through rabbit cornea

(Table Removed)
Table3: Comparison of effect of ketorolac loaded NIPAAM-VP-AA copolymeric micelle formulation with
aqueous suspension of drug of same concentration on PGE2 induced lid closure in rabbit eye

(Table Removed)

We claim:
1. A sustained release and long residing ophthalmic formulation
comprising:
micelle solution of block co-polymer having a hydrophobic component and the hydrophilic component of general formula -(X-Y-Z-)m, wherein
m is an integer greater than 2
X is a compound having hydrogel formation properties selected from vinyl group of compounds
Y is a compound having thermosensitivity properties having a general formula R1-R2N-(C=O)-CH=CH2, R1= a proton or CnH2n+1 in which n may have the value from 3 to 6 and R2 = alkyl group having chain length of C3 to C6
Z is a compound having mucoadhesive and pH-sensitivity properties and is selected form acrylate based monomers.
and
at least one hydrophobic drug with the said block co-polymer solution;
2. A formulation as claimed in claim 1 wherein, said vinyl group of compounds is selected from vinyl pyrrolidine, vinyl alcohol, vinyl chloride or vinyl acetate.
3. A formulation as claimed in claim 1 wherein, Y is N-isopropyl acrylamide(NIPAAM)
4. A formulation as claimed in claim 1 wherein said acrylate based monomers is selected from acrylic acid or methyl methacrylate.
5. A formulation as claimed in claim 1 wherein, m preferably lies in the range 10-4000.
7. A formulation as claimed in claim 1 wherein, the said drug is non steroidal anti inflammatory drug (NSAID).
8. A formulation as claimed in claim 7 wherein, the said NSAID drug is selected from 5-benzoyl (2,3 dihydro-1H pyrrolizone-1 carboxylic acid); l-(4 chlorobenzoyl)-5 methoxy -2- methyl-1H-indole-3acetic acid or N-(4-nitro- 2 phenoxyphenyl) methanesulphonamide or a mixture of at least any two inereof.
9. A formulation as claimed in claim 1 or 7 and 8 wherein, the said drug used for entrapment is in solution or in powder form.
10. A formulation as claimed in claim 1 or 7-9 wherein, the said drug is in the form of free bases.
11. A formulation as claimed in claim 1 wherein, the said polymerized micelles containing the hydrophobic drug have a size in the range of 10nm-100nm diameter, preferably 10nm to 50nm.
12. A formulation as claimed in claim 1 or 11 wherein, the block copolymers made of amphiphilic monomers are biocompatible and non-antigenic materials.
13. A formulation as claimed in one of the preceding claims 1 wherein the molar ratio of the combination of amphiphilic monomers X, Y and Z is 9.5% : 85.7% : 4.8% respectively.
14. A sustained release and long residing ophthalmic formulation substantially as herein described with reference to the accompanying. drawings and foregoing examples.