FIELD OF INVENTION
The present invention relates to an ophthalmic composition for treatment of ophthalmic disorders, in particular for treatment of diabetic and non-diabetic ocular neovascular complications cataract and glaucoma.
PRIOR ART AND BACKGROUND OF THE INVENTION:
Diabetic Retinopathy (DR) is a major complication of diabetes and is a leading cause of blindness worldwide. DR has been considered a microvascular disease, and the blood-retinal barrier breakdown is a hallmark of this disease. The available treatments are scarce and not very effective. Despite the attempts to control blood glucose levels and blood pressure, many diabetic patients are affected by DR, which progresses to more severe forms of disease, where laser photocoagulation therapy is needed. DR has a huge psychological impact in patients and tremendous economic and social costs. The cellular and molecular mechanisms underlying the pathogenesis of DR had shown involvement of the polyol pathway, advanced glycation end products, protein kinase C and oxidative stress.
Similarly, the term glaucoma does not represent a single pathological entity but a large group of disorders with widely differing clinical features. In glaucomatous conditions, no specific cause can be identified or secondary where optic neuropathy follows a rise in IOP because of some condition in the eye, such as inflammation, trauma or abnormal pigment release into the anterior chamber. The glaucomatous disorders occur when the intraocular pressure (IOP) is too high for the normal functioning of the optic nerve head. The most common glaucomatous disorders are primary open angle glaucoma (POAG), also known as chronic simple glaucoma, and acute closed angle glaucoma (ACAG), also known as primary angle closure glaucoma. In POAG, a relative obstruction to the outflow of aqueous humor through the trabecular meshwork results in a rise in intraocular pressure to a level above the normal range of 10-21mmHg. The raised pressure leads to direct damage of retinal nerve axons. Anoxia of these cells occurs due to compression of blood vessels and results in loss of visual field. Many drugs such as Triamcinolone acetonide, topical beta-blockers such as Betalol, Timolol, and Metipranolol is used to treat this condition, including Calcium Dobesilate.
Szabo et al (2001) investigated the oral treatment of diabetic rats with calcium Dobesilate on the prevention of free radical-mediated retinal injury induced by ischemia/reperfusion. Finally, 100 mg/kg calcium Dobesilate significantly reduced retinal edema (measured by the thickness of the inner plexiform layer) in diabetic rats. From the results, the authors concluded that oral treatment with calcium Dobesilate significantly protected diabetic rat retina against oxidative stress induced by ischemia/reperfusion.
Rota et al (Eur J Pharmacol. 2004 Jul 14;495(2-3):217-24) investigated the action of calcium Dobesilate on retinal albumin leakage in streptozotocin-diabetic rats, together with relevant in vivo retinal antioxidant and permeability markers, i.e., carboxymethyl-lysine-advanced glycation end product (CML-AGE) formation and vascular endothelial cell growth factor (VEGF) over expression. These results strongly suggest that calcium Dobesilate stabilizes blood-retinal barrier in diabetic retinopathy via an in situ antioxidant action.
The antioxidant properties effect of calcium Dobesilate and its action on endothelium through the synthesis of nitric oxide causes the increased endothelium dependent relaxation. This effect was demonstrated in different in vitro and in vivo models by decreasing the peritoneal permeability in rats induced by pro-oxidant substances. Moreover, vascular leakage was also decreased by calcium dobesilate in a reperfusion model in streptozotocin induced diabetic rats after ischemia of the central artery of the retina. Calcium Dobesilate may also preserve vascular endothelial function by acting directly as antioxidant to protect lipid from peroxidation.
Calcium dobesilate has been shown to inhibit the formation of sorbitol, another factor related to the occurrence of diabetic retinopathy. The multiple effects of calcium dobesilate including decreasing intraocular pressure, enhancing outflow facility, reducing both retinal hemorrhages and blood hyper viscosity resulted in improvement of the retinal state and visual fields. These
findings in conjunction with good patient tolerability suggest that calcium dobesilate may be promising for the treatment of diabetic retinopathy (Vojnikovic (Ophthalmic Res. 1991 ;23(1): 12-20); Schmidt & Michal, Arzneimittelforschung. 1989 Apr;39(4):493-5).
It is the only angioprotective agent that reduces the progression of diabetic retinopathy. Recent studies have shown that calcium dobesilate is a potent antioxidant, particularly against the highly damaging hydroxyl radical. In addition, it improves diabetic endothelial dysfunction, reduces apoptosis, and slows vascular cell proliferation (Garay et al Treat Endocrinol. 2005;4(4):221-32. ).
The effect of calcium dobesilate as an antiangiogenic compound has been evaluated by Cuevas et al Eur J Med Res. 2005 Sep 12;10(9):369-72). Using gelatin sponge implantation method in mouse they have commented that calcium dobesilate may be having antiangiogenic property and that is responsible for its efficacy in treatment of vascular complications of diabetic retinopathy.
Schmidt & Michal, (Arzneimittelforschung. 1989 Apr; 39(4): 493-5) studied the effect of calcium dobesilate on aldose reductase and compared with tetramethylene glutaric acid (specific aldose reductase inhibitor) using human erythrocytes. In a 29 mM glucose medium, calcium dobesilate in concentrations of 2 and 10 mM caused, 50 and 100% inhibition of sorbitol formation, respectively, whereas TMGA completely inhibited sorbitol formation at a concentration of 0.1 mmol/1. These results suggest that calcium dobesilate may exert, at least in part, its beneficial effect on diabetic microangiopathy by inhibiting the formation of
sorbitol. The inhibition of sorbitol synthesis may be mediated by an inhibitory action of calcium dobesilate on aldose reductase.
Calcium Dobesilate is a vasoactive drug useful for treatment of venous disorders, diabetic retinopathy and other microvascular disorder. The drug acts by increasing endothelial nitric oxide levels by enhancing the activity of nitric oxide synthase and decreasing capillary hyperpermeability. Calcium Dobesilate is useful in treatment of diabetic retinopathy by playing its role of inhibiting the formation of sorbitol.
Various pharmaceutical formulations have been developed to evaluate the efficacy of calcium Dobesilate. As in Vojnikovic et al. Ophthalmic Res. 1984; 16(3)-150-62, 50 patients with diabetes mellitus of 2-7 years duration were divided by a random method into two equal groups, one of which received 1,500 mg of Calcium Dobesilate , daily for 3 months, the other group receiving a placebo. All the patients had diabetic retinopathy, open angle glaucoma, raised intraocular pressure and viscosity of whole blood, plasma and aqueous humor. Another study, Vojnikovic et al, Ophthalmic Res. 1991; 23(1):12-20, was carried outline the effect of oral treatment of Calcium Dobesilate. In a double-blind randomized clinical trial, 79 non-insulin-dependant diabetic subjects with early retinopathy and open -angle glaucoma received orally either three 500 mg capsules of Calcium Dobesilate daily for 6 months (41 patients) or three placebo capsules daily for the same period (38 patients).
Antioxidant properties of Calcium Dobesilate in ischemic/ reperfused diabetic rat retina was studied by Marta E, Szabo et al , European Journal of Pharmacology, Volume 428, Issue 2, 5 October 2001, Pages 277-286. Investigation was carried out on the oral treatment of diabetic rats with calcium Dobesilate on the prevention of free radical mediated retinal injury induced by ischemia/reperfusion.
Thus, as discussed above, most of the pharmaceutical compositions available in the market are administered through the oral route. The said compositions delivered through oral route have their own inherent disadvantages in that the active ingredient is prone to degradation on account of moisture and the tablets are not capable of long-term storage. Even if stored for long term, the efficacy is gradually diminished. Further, in many instances, only topical
effects are desired and drugs are administered for local effect without need for penetration onto the eyeball. For e.g., medication for superficial anti-infective effects as in inflammation of the conjunctiva. The blood aqueous/vitreous barriers and various thicknesses of the ocular tissues prevent certain drugs from reaching the anterior/posterior segments in the required therapeutic concentrations if administered systemically. Some drugs may do so only if administered systemically in quantities that would cause harm in other parts of the body. Therefore, potential adverse effects of these drugs can be avoided by administering them through the ocular route.
To overcome the aforesaid problems, the invention proposes a novel liquid composition comprising a Dobesilate salt of Calcium together with acceptable excipients.
Description of the invention:
Accordingly the invention provides a novel composition and comprising an active ingredient selected from calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate), diethylamine 2,5-dihydroxybenzenesulfonate (ethamsilate), and bis (diethylamine) 2,5-dihydroxybenzene-l, 4-disulfonate (bis (diethylamine) persilate); and pharmaceutically acceptable excipients. The excipients may include polymers, viscosity enhancer, preservatives, buffer, isosmotic agent and antioxidants.
Among viscosity enhancers, compounds from the cellulose group like hydroxy propyl methyl cellulose (HPMC), Methyl cellulose, dextran and others are used. Carbomers like carbopol, Eudragit and others are used for the preparation of the controlled release dosage forms. Well known polymers like polyvinyl alcohol and polyvinyl pyrrolidone are utilized among others. Propylene glycol, glycerine and polyethylene glycol are examples of glycols used in the instant invention. Antioxidants could be selected from a wide range of well known excipients like Sodium metabisulphite, ascorbic acid, tocopherol, lycopene, quercetin, myrcetin, glutathione, pyruvate and ethyl pyruvate. To prepare in-situ gel compositions, aqueous gel vehicles like sterile water, propylene and/or polyethylene glycol are used along with carbopol or a cellulose derivative. Gelling agents used in these preparations may be non-ionic or anionic. Non-ionics include cellulose derivatives, such as methyl cellulose or hydroxy propyl
methyl cellulose whereas sodium carboxymethylcellulose is an ionic form of cellulose gelling agent. Preservatives are chosen from a wide range like polyquad, benzylkonium chloride, perborate, boric acid, thiomersal, phenylmercuric nitrite, chlorbutanol, zinc oxide and lactoferrin.
The amount of the active ingredient in the composition may be from 0.001% w/w to 20% w/w and the pharmaceutically acceptable excipients may be in the range of 30% to 99% w/w. Preferably, the composition may be formulated as a pourable liquid like solution, controlled release in-situ gels, eye spray, eyedrops, suspension, ointment, gels and ocular inserts.
It has surprisingly been found that when the active ingredient are formulated in the manner described above, the bio-availability of the said ingredient to the eye is far greater and has considerably better effect on diabetic retinopathy as compared to conventional products. An advantage of the composition is that the composition does not cause any irritation to the eye and is well tolerated. Further, the time of onset of action of the composition is far superior as compared to that of conventional compositions. It has been found that the composition of the invention delivers the active ingredient into the conjunctiva of the eye.
In another aspect, the invention also provides a method for preparation of the pharmaceutical composition, comprising the steps of mixing the active ingredient with the pharmaceutically acceptable excipients.
In another aspect, the present invention provides the dispensing of the composition in dosages of 0.05 ml to 50 ml.
A further aspect of the present invention provides a pharmaceutical kit comprising the composition in multidose vials or ophthalmic dispensers or a nebulizer aerosol or single dose sterile packings in polyethylene packing along with an optionally applicator together with an instruction manual.
The invention is now illustrated by various examples and accompanying drawings, which are not meant to limit the scope of the invention in any manner. All embodiments that may be obvious to a skilled person would fall within the scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS-
Figure 1 depicts the chromatogram showing the standard Calcium Dobesilate peak on aqueous spiking. The spiking was done by pippetting out 10 microlitres from the standard stock solution of 1 mg/1 ml Calcium Dobesilate and adding 90 microlitres of Distilled Water and Methanol. The vortexed and centrifuged solution was then injected to get the chromatogram.
Figure 2 depicts the processed biosample i.e. aqueous humor of the rabbit's eye after treatment of Calcium Dobesilate solution.
Figure 3 depicts the graphical representation in the form of a comparison of the intraocular penetration of topical calcium Dobesilate eye solution with and without Hydroxy Propyl Methyl Cellulose. It can be seen that the Formulation 2 which is developed with HPMC is having better penetration capacity than the Formulation 1 which was developed without HPMC.
Figure 4: Depict the stages of cataract at different treatment groups.
Figure 5: Depicts Anti-glaucoma activity (Intraocular pressure lowering property) of CDO in normotensive model in rabbits.
EXAMPLES:
Example 1-
Composition I - Eye Solution
The composition below was developed without Hydroxy Propyl Methyl Cellulose (HPMC).
CDO: -l%w/v
Sodium chloride - 0.76 % w/v
Sodium metabisulphite - 0.1% w/v
Water - q.s
The constitution of the composition was done mixing Calcium Dobesilate and Sodium Chloride in sterile injection water. Protection of light was carried out all through the mixing followed by addition of sodium metabisulphite. The thoroughly mixed solution was checked for clarity and was filtered.
Composition II - Eye Solution
The composition was developed incorporating Hydroxy Propyl Methyl Cellulose (HPMC) to enhance the viscosity.
CDO -l
Sodium chloride - 0.7 % w/v
Sodium metabisulphite - 0.1% w/v
HPMC - 0.4 % w/v
Water - q.s
The constitution of the composition was done mixing Calcium Dobesilate and Sodium Chloride in sterile injection water. Protection of light was carried out all through the mixing followed by addition of sodium metabisulphite. An even solution of HPMC was made in sterile injection water. All the ingredients are mixed evenly and the thoroughly mixed solution was checked for clarity and was filtered.
Composition HI: Water Insoluble Eye Ointment
CDO -l%w/v
Oleaginous Base - Q.S.
(White Petrolatum, Mineral oil preferably with Mineral oil gel) Antimicrobial Preservative - - 0.01% w/v

The Oleaginous base is melted to liquid form and then basic active ingredient CDOB (micronized powder form) is dispersed and/or dissolved with stirring. The preservative and the buffer are mixed to the above mass with thoroughly and continuous stirring until a smooth semisolid mass is achieved. The final product is an ointment, which is subjected to the testing of grittiness.
Composition IV: Water Soluble Eye Ointment
CDO -l%w/v
Polyethylene Glycols - Q.S.
Antimicrobial Preservative - 0.001%w/v
The Oleaginous base is melted to liquid form and then basic active ingredient CDOB (micronized powder form) is dispersed and/or dissolved with stirring. The preservative and the buffer are mixed to the above mass with thoroughly and continuous stirring until a smooth semisolid mass is achieved. The final product obtained is a water soluble eye ointment.
Composition V: Controlled Release in-situ gel forming composition
CDO -l%w/v
Sterile water - Q.S.
Sodium Metabisulphite - 0.2 % w/v
Gel forming polymer - Q.S
The active ingredient, Calcium Dobesilate is dissolved in sterile water and is made solution by controlling the pH with gel forming polymer at neutral pH. The final product obtained is an in-situ gel forming composition.
Example 2: Eye irritation test
The compositions prepared in the Example 1 are adjusted to physiological values of osmolarity, pH and other parameters.
While on application to the rabbit eye for intraocular penetration study, any significant ocular manifestations were not observed indicating ocular irritation. There was no swelling of eyelids, no tearing due to irritation, no abnormal eye blinking was observed.
Example 3: Testing on Rabbit eyes METHODOLOGY:
New Zealand albino rabbits of either sex having 2-2.5 kg body weight were included in this study. Fifty micro liters of topical formulations of CDO were instilled into the cul-de-sac of each rabbits using calibrated micro pipette.50-100 microlitres of aqueous humor was withdrawn through the limbus under topical 4% xylocaine at different time intervals. Three eyes were used for each time point. The collected samples were stored at -70 °C till analysis by HPLC.
INSTRUMENTATION:
A reverse phase HPLC method was developed for the quantification of CDO in biological samples with HPLC system. This system consists of a quaternary gradient Surveyor HPLC pump connected to Symmetry shield CIS column (4.6 X 150 mm, 3|am particle size). The spectral analysis of CDO was done at SOOnm using PDA detector. For data acquisition and interpretation, ChromQuest software was used.
Various formulations consisting of Calcium Dobesilate and along with pharmaceutically acceptable excipients were developed. The active ingredient used was Calcium Dobesilate. Sodium Chloride was used to control the tonicity of the eye solution. To maintain the viscosity of the dosage form, hydroxyl propyl methylcellulose was incorporated. Suitable amount of NaCl added to make the formulation isotonic with blood and tears.
ASSAY CONDITION:
Best analytical separation was achieved with 20 mM potassium hydrogen phosphate adjusted to pH 3 and acetonitrile in the ratio of 90:10 (v/v) and was degassed in the inbuilt degasser
present in the system. The flow rate was adjusted to 1 ml/min. The run time optimized for total elution was 10 minutes. The temperature was maintained at 25+1° C.
STOCK SOLUTION & STANDARD SAMPLES PREPARATION:
A standard solution of CDOB was made in 1:1 methanol-water (by dissolving Img /I ml solution of Calcium Dobesilate in 50 % methanol) & stored at -70 °C. Since, Calcium Dobesilate is prone to photo-oxidation; therefore it is protected from light. Serial dilutions were made from the stock solution to give a concentration range of 0.108, 1.08 and 5.4 ug/ml.
PROCESSING AND ANALYSIS OF BIOSAMPLES:
The Biosamples were prepared by extracting aqueous humor taken from rabbit eyes and adding 100 uL MeOH. Biosamples were subjected to direct deproteination with methanol, vortexed and centrifuged at 5000g for 10 minutes. Twenty microlitres of supernatant was injected into the HPLC column for estimation. Results were calculated evaluating the mean concentration of Calcium Dobesilate as depicted in Table 1 and 2 in aqueous humor of Rabbit eyes.

(Table Removed)
Table 1 showing the mean concentration of CDC (Formulation I without HPMC) in aqueous humor

(Table Removed)
Table 2 showing the mean concentration of CDO
(Formulation II with HPMC) in aqueous humor
STABILITY STUDIES OF CALCIUM DOBESILATE EYE DROPS:
The stability of calcium dobesilate eye drop was studied for the extended period of 3 months using accelerated stability testing protocol according ICH guidelines. The formulation was subjected for quantification in 40 Deg C, 25 Deg C, 4 Deg and -20 Deg C. The formulation was quantified for the presence of CDO at different time intervals by using High Performance Liquid Chromatography.
Result: At the end of the 3 months CDO formulation stored at-20 Deg C showed percentage purity of 94%, CDO stored at 4 Deg C showed a percentage purity of 100.5%. At 25 Deg C it showed percentage purity of 93.8% and at 40 Deg C it showed 91.0%.

Conclusion: CDO topical formulation would be having required shelf life for the intended usage of topical application.
Efficacy of CDO in the diabetic model of cataract in albino rats
The efficacy of CDO was evaluated in invivo galactose-induced cataract in rats (n=10 eyes). Rats weighing 70-100g were fed for 1 month 30% galactose and water ad libitum. Each group having 10 rats were randomized. Experimental rats received CDO 1% (topical drug treated), CDO orally treated animal received calcium dobesilate (150mg/kg) and normal saline (control group) was administered topically three times a day . Evaluation of grade of cataract was done as per Sipple's grading at 0, 7th, 14th, 21st and 28th day of administering CDO and normal saline using slit lamp.
Results: At the end of study in the control group 50% of eyes were in grade III and 50% eyes in grade IV cataract. However, in CDO 1% (twice daily topical instillation) group 80% of eyes were in grade 'IF, 10% in grade III and 10% in grade IV as compared to control group.
Conclusion: Topical administration of CDO (Figure 4) delays the progression of cataract and up to the studied period of 28th day 80 % of the eyes were in stage II cataract and 10% of eyes were at stage III and 10 % of them reached stage IV. Where as in control group 50% of eyes reached stage III and 50% reached stage IV (full form of cataract. In calcium dobesilate orally treated group 50 % of the eyes reached stage II and 50 % of them were in stage III. This study ensures the equivalent or higher efficacy of calcium dobesilate eye drops that of oral calcium dobesilate.
Calcium dobesilate 1% topical drops can be used in the conditions of cataract of diabetic in origin or oxidative in origin and can also be used in other ocular conditions warrants topical antioxidant therapy.
Antiangiogenic property of CDO topical drops in the corneal neovascularization (new blood vessel formation or angiogenesis)
Wistar rats weighing 150-200gms were used for this study. They were anesthetized using sodium pentobarbitone anesthesia. With the help of corneal anesthesia (lignocaine) silver potassium cautery was be placed in the centre of the cornea for 2 sec. They were divided into two groups viz control and experimental. Each group contained 5 rats. Control animals received saline eye drops and experimental animals were received one drop of 1% CDO three times a day. At the end of the experiment (8l day) the cornea was be subjected for evaluation under slit lamp for the formation newer blood vessels in the cornea. Topical calcium dobesilate drug therapy would be initiated after potassium cautery and its effect on controlling corneal neovascularization would be evaluated in this model.
Results: Corneal blood vessel density was counted as 26± 5.13 in the control animals (n=5) and CDO treatment comparatively decreased the blood vessel density to 18.13± 4.2 (Figure 5).
Conclusion: Topical CDO can be used effectively for the ocular angiogenesis conditions such as corneal neovascularization, diabetic retinopathy, and age related macular-degeneration. Anti-glaucoma activity (Intraocular pressure lowering property) of CDO in normotensive model in rabbits
Rabbits weighing 2-2.5 Kg were used for this study. The rabbits were randomized intro two groups on the day of study. Each group consisted of 4 rabbits (4 eyes). One eye served as control and other eye served as experimental. In the control group rabbits received one drop of normal saline and in the experimental group rabbits received 50 ul of CDO 1%. . Intraocualr pressure (IOP) was measured by Schiotz tonometer at different time intervals.
Results: CDO 1% showed IOP reduction of 15% to 20% over the time period of 2-4 hours. Conclusion: CDO topical eye drops have the capability of antiglaucoma property.
ADVANTAGES:
Some of the advantages of ophthalmic dosage forms for the treatment of Diabetic or non-diabetic ocular neovascular conditions, cataract and glaucoma in comparison to oral dosage forms are -
1. Ophthalmic dosage forms are capable of having more ocular bioavailability than the oral
dosage forms such as tablets and capsules.
2. In case of ophthalmic dosage forms there is rapid onset of action as compared to that of
oral dosage forms.
3. The pharmaceutical excipients used in the formulation of the eye solutions are
economical, easy to administer, no or very minimal systemic side effects and easy to procure.
4. There are significant metabolic and bioavailability differences on utilization of
ophthalmic dosage forms as compared to oral dosage forms.
5. The presence of Viscosity enhancers enables the formulation to remain in the eye longer
and gives more time for the drug to exert its therapeutic activity or undergo absorption unlike the less resident physiological time of the oral dosages.
6. Systemic administration like oral administration in general does not accomplish as much
as topical administration in the treatment of the anterior segment of the eye.

We Claim:
1. A pharmaceutical composition for treatment of diabetic and non-diabetic ocular
neovascular complications cataract and glaucoma, said composition comprising :
a) an active ingredient, selected from calcium benzene sulfonate salt compounds,
in an amount such as herein described; and
b) pharmaceutically acceptable excipients.

2. A composition as claimed in claim 1, wherein the calcium benzene sulfonate salt is
selected from a group of calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate),
diethylamine 2,5-dihydroxybenzenesulfonate (ethamsilate), and bis (diethylamine) 2,5-
dihydroxybenzene-1, 4-disulfonate (bis (diethylamine) persilate).
3. A composition as claimed in claim 2, wherein the calcium benzene sulfonate salt is
calcium Dobesilate.
4. A composition as claimed in claim 1, wherein pharmaceutically acceptable excipients
are selected from a group of polymer, viscosity enhancer, preservative, buffer, isosmotic
agent, anti-oxidant, aqeous gel-vehicles and gelling agents.
5. A composition as claimed in claim 4, wherein the viscosity enhancer is selected from a
group of hydroxy propyl methyl cellulose (HPMC), Methyl cellulose and dextran.
6. A composition as claimed in claim 4, wherein the polymer is selected from a group of
polyvinyl alcohol, polyvinyl pyrrolidone, propylene glycol, glycerine and polyethylene
glycol.
7. A composition as claimed in claim 4, wherein the anti-oxidant is selected from Sodium
metabisulphite, ascorbic acid, tocopherol, lycopene, quercetin, myrcetin, glutathione,
pyruvate and ethyl pyruvate.
8. A composition as claimed in claim 4, wherein the aqueous gel-vehicle is selected from a
group of sterile water, propylene and/or polyethylene glycol, carbopol or a cellulose
derivative.
9. A composition as claimed in claim 4, wherein the gelling agent is selected from a group
of non-ionic or anionic agents.
10. A composition as claimed in claim 9, wherein the non-ionic gelling agent is selected
from a group of cellulose derivatives, such as methyl cellulose or hydroxy propyl
methyl cellulose.
11. A composition as claimed in claim 9, wherein the ionic gelling agent is sodium
carboxymethylcellulose.
12. A composition as claimed in claim 4, wherein the preservative is selected from
polyquad, benzylkonium chloride, perborate, boric acid, thiomersal, phenylmercuric
nitrite, chlorbutanol, zinc oxide and lactoferrin.
13. A composition as claimed in claim 1, wherein the amount of active ingredient is in a
range of 0.001% w/w to 20% w/w of the total composition.
14. A composition as claimed in claim 1, wherein the amount of active ingredient is in a
range of 0.1 % w/w to 2% w/w of the total composition.
15. A composition as claimed in claim 1, wherein the pharmaceutically acceptable
excipients are in a range of 30% w/w to 99% w/w of the total composition.
16. A composition as claimed in claim 1, wherein the said composition is formulated in the
form of pourable liquid like solution, controlled release in-situ gels, eye-spray, eye-
drops, suspension, ointment, gels and ocular inserts.
17. A pharmaceutical kit comprising the composition as claimed in Claim 1 in a container
such as herein described, along with an instruction manual, optionally with an
applicator.
18. A pharmaceutical kit as claimed in Claim 17, wherein the container is selected from
multi-dose vials, ophthalmic dispensers, nebulizer aerosol or single dose sterile packings
in a polyethylene packing.
19. A pharmaceutical composition and a kit substantially herein described with reference to the examples and drawings.