WO2020240451A1

WO2020240451A1 - In-situ gelling nanoemulsion of brinzolamide

Info

Publication number: WO2020240451A1
Application number: PCT/IB2020/055052
Authority: WO
Inventors: Hemant Hanumant BHALERAO; Sajeev Chandran
Original assignee: Lupin Ltd
Current assignee: Lupin Ltd
Priority date: 2019-05-29
Filing date: 2020-05-28
Publication date: 2020-12-03
Anticipated expiration: 2021-11-29
Also published as: MX2021014477A

Abstract

This invention relates to a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions of brinzolamide and/or in combination with other active ingredients. The invention provides a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising brinzolamide, an oil dispersed in an aqueous phase, a primary and/or a secondary surfactant and a thickener.

Description

IN-SITU GELLING NANOEMULSION OF BRINZOLAMIDE

Field of the Invention

This invention relates to a pharmaceutical in- situ gelling nanoemulsion ophthalmic compositions comprising brinzolamide as active ingredient alone and/or in combination with other active ingredients. The invention also relates to the processes for making such compositions and use of these compositions in patient populations including pediatric populations.

Background of the Invention

Conventional drops of prostaglandins, beta-blockers, carbonic anhydrase inhibitors, alpha- adrenergic agonist and their combinations are available for treatment of glaucoma. Amongst them, carbonic anhydrase inhibitor plays an important role in treatment of glaucoma for reduction of ocular hypertension.

One such carbonic anhydrase inhibitors (CAIs) is R 4-ethylamino-3,4-dihydro-2-(3- methoxy)propyl-2H-thieno [3,2-e]-1,2-thiazine-6-sulfonamide 1,1 dioxide, which is known as brinzolamide. This compound is disclosed in U.S. Pat. No. 5,378,703 (Dean, et al). Brinzolamide is highly specific, no-competitive, reversible and effective inhibitor of carbonic anhydrase II, able to suppress formation of aqueous humor which reduces intraocular pressure

It is a drug of choice in case of glaucoma patients with a vascular dysregulation, it has double effect of reducing elevated intraocular pressure (IOP) with improving ocular blood flow. Brinzolamide can be used as first line medication due to fewer side effects and as monotherapy in patients unresponsive to beta-blockers or in patients in whom beta-blockers are contra-indicated, or as adjunctive therapy to beta blockers and prostaglandins. However, because of the poor aqueous solubility of brinzolamide, the clinical application is extremely limited. US Pat. No. 6,071,904 discloses ophthalmic suspensions containing brinzolamide and processes for manufacturing the suspensions.

Azopt^® (brinzolamide) commercial preparation of Brinzolamide available in the market is an aqueous multiple use suspension composed of 1% w/v Brinzolamide. Unfortunately, this formulation is associated with side effects, such as blurred vision, pain, discomfort (stinging and burning), eye discharge, blepharitis, dry eye, and taste perversion and the limitations of requirement of multiple dosing required (3 to 4 time per day) and dosing inaccuracy.

It is well known in the art that, the bioavailability of the suspension formulation is reduced because of the fact that the drug must be dissolved in order to be absorbed before being eliminated from the eye surface. The suspension formulation also suffer the drawback that the particulates have a potential to cause irritation, increasing the likelihood that they would be rubbed or washed from the eye. Additionally, manufacturing of sterile suspension formulation for ophthalmic use has its own challenges like particle size reduction, degree of homogenization required and ability of the formulation to remains in to the suspended state without particle aggregation throughout the shelf life.

Other types of vehicles have been developed for the purpose of increasing the residence time of the drug on the eye surface. Among these are those that increase the bioavailability by means of an increase of the viscosity such as hydrogels or ophthalmic ointments. In the case of hydrogels, an important increase of the bioavailability of the drug has not been achieved. On their part, ophthalmic ointments have the large inconvenience of the awkwardness of their application and blurred vision that is produced after their application, the use thereof being more appropriate at night.

Likewise, a large number of novel vehicles have been developed such as liposomes, nanoparticles, etc., though most of them have problems of stability, tolerance, difficulties for industrialization thereof and limited success as far as the increase of bioavailability is concerned. The inventors of the present invention have developed the in-situ gelling nanoemulsion ophthalmic compositions of brinzolamide which can deliver drug at the right dosage to the eye with the convenience of dosing just like any other ophthalmic solution. Entrapment of drug in oil phase of nanoemulsion can protect it from degradation, metabolism and cellular efflux during the course of drug delivery. Application method of in-situ gelling nanoemulsion is simple like conventional drop and also avoids the discomfort associated with the other dosage forms.

Summary of the Invention

This invention relates to a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising brinzolamide and process of preparing the same.

In an embodiment the present invention provides a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising of oil in water type emulsion that increases the bioavailability of the drug. Said emulsion is stable during storage without the need of including in its composition the potentially irritating products and ones that can cause cataractogenic process.

In another embodiment the present invention provides a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising; brinzolamide; an oil dispersed in an aqueous phase; a primary and/or a secondary surfactant; and a thickener.

In another embodiment the present invention provides a pharmaceutical in-situ gelling nanoemulsion ophthalmic to be obtained with normal emulsification equipment, with a rotary agitator or a pressurized homogenizer.

Brief Description of the Accompanying Drawings

Fig. 1: Graph of Comparative DIOR (mm Hg) vs Time (h) profile for Example- A(0.5% w/v brinzolamide) and Example-C (1.0 % w/v brinzolamide) of brinzolamide in situ gelling nanoemulsion formulations in comparison with commercial eyedrops (Azopt® 1.0 % w/v brinzolamide) in glaucomatous rabbits.

Fig. 2 Graph of Comparative DIOR (mm Hg) vs Time (h) profile for Example-D (0.5% w/v brinzolamide) and Example-F (1.0 % w/v brinzolamide) of brinzolamide in situ gelling nanoemulsion formulations in comparison with commercial eyedrops (Azopt® 1.0 % w/v brinzolamide) in glaucomatous rabbits.

Detailed Description of the Invention

The invention relates to a pharmaceutical in- situ gelling nanoemulsion ophthalmic compositions comprising brinzolamide and process of preparing the same. Preferably the nanoemulsion ophthalmic compositions is a sterile composition.

The invention further relates to a pharmaceutical in- situ gelling nanoemulsion ophthalmic compositions comprising brinzolamide optionally in combination with other active ingredients and process of preparing the same.

Although the present invention is described with respect to brinzolamide, the invention is not limited thereto. The present invention can also be utilized for manufacturing the pharmaceutical ophthalmic compositions of the active ingredients having ophthalmic applications such as corticosteroid, anti-inflammatory, beta- adrenergic receptor agonist, beta-blockers, prostaglandins, carbonic anhydrase inhibitors, alpha 2 adrenergic receptor agonist, antibiotics, antibacterial, antihistaminic/ mast cell stabilisers or combination thereof.

In some embodiments, the corticosteroid is selected from the group consisting of prednisolone, methylprednisolone, difluprednate, prednisone acetate, prednisolone sodium phosphate, triamcinolone, fluocinolone; fluorometholone, betamethasone, medrysone, rimexolone, dexamethasone, hydrocortisone, loteprednol and a combination thereof. In other embodiments, the anti-inflammatory is selected from a group consisting of a corticosteroid, a non-steroidal anti-inflammatory drug (“NS AID”), thymosin beta 4, and a combination thereof. In one particular instances, the NSAID is selected from the group consisting of diclofenac, flubiprofen, ketorolac, ketorolac thromethamine, bromfenac, nepafenac, flurbiprofen, and a combination thereof. In yet another embodiment, the beta-adrenergic receptor agonist is selected from the group consisting of dopexamine, epinephrine, isoprenaline, isoproterenol, levalbuterol, salbutamol, albuterol, and a combination thereof. Still in other embodiments, the beta-blocker is selected from the group consisting of timolol, propranolo, sotalol, nadolol, betaxolol, levobetaxolol and a combination thereof. Yet still in other embodiments, the prostaglandins analog is selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, and a combination thereof. Yet in other embodiments, the carbonic anhydrase inhibitor is selected from the group consisting of dorzolamide, methazolamide, dichlorphenamide, and a combination thereof. Yet in other embodiments, the alpha 2 adrenergic receptor agonists include, but are not limited to, brimonidine, 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tizanidine, tolonidine, xylazine, xylometazoline, and the like including pharmaceutically acceptable salts thereof. Yet in other embodiments, antibiotics and/or antibacterial includes besifloxacin, neomycin; polymyxin b, tobramycin, sulfacetamide sodium, gentamicin, oxytetracycline, natamycin, chloramphenicol, tetracycline, gatifloxacin, moxifloxacin and a combination thereof. Yet in other embodiments, the antihistamine/mast cell stabiliser include, but are not limited to, levocabastine, alcaftadine, azelastine, bepotastine, emedastine, epinastine, ketotifen, olopatadine and a combination thereof.

The concentration of the brinzolamide present in the pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions according to the present invention is in the range of about 0.02% to 5% w/v of composition; preferably 0.01, 0.5, 0.75, 1, 2, 3, 4 or 5% w/v of composition or intermediate fraction thereof.

An emulsion refers to a liquid-liquid dispersion system in which at least one liquid is dispersed in another liquid with which it is immiscible, and the emulsion generally has a size distribution ranging from 0.1 to several tens of micrometers. In an oil in water type emulsion, the water is continuous phase and an oil is dispersed phase i.e. oil globules dispersed in the water.

Nanoemulsion are oil-in-water emulsions, the oil globules of which have a very fine particle size, i.e. a mean globule size of 50 nm to 250 nm. In accordance with the present invention the globule size were measured by using Delsa™ Nano C, Beckman Coulter connected with Delsa™ Nano UI software version 3.73.

In accordance with the present invention“In-situ gel emulsion” is an emulsion that undergoes gelation in situ (at physiological site of application), to form a gel within 30 seconds of administration. Wherein the viscosity of gel formed in-situ is at least twice of the initial formulation. In a preferred embodiment, viscosity of gel formed in-situ is increased at least 3 to 9 times of the initial formulation. In most preferred embodiment viscosity of gel formed in-situ is increased at least 5-7 times of initial formulation.

In accordance with the present invention, the nanoemulsion has a pH between 5 and 8 and an osmolality between 250 and 600 mOsm/kg. The appearance of these emulsions tends to be light milky.

In accordance with the present invention, the oil soluble or partly oil soluble drugs such as brinzolamide are included in an oil in water type emulsion to be administered in the eye thus increasing the bioavailability of the same with regard to other compositions. Said vehicle comprises an oil and a non-ionic surfactant, as well as enough preservative to meet the requirements of the pharmacopeia. The present invention can also be formulated as preservative free pharmaceutical composition when stored in specialized containers which prevent microbial ingress into the container and retains the sterility of the content during its shelf life and in-use period. The example of such specially designed container closure is NOVELIA® manufactured by Nemera.

The oil that forms part of the emulsion may be a vegetable oil, an animal oil, a mineral oil, fatty acids, a medium chain triglyceride, fatty alcohols or any combination of these oils and/or oily substances that are well tolerated at the eye level. The preferred oils are medium chain triglycerides, vegetable oils, olive oil, sunflower seed oil, sesame seed oil with an acid value less than 0.5, castor oil, mineral oil and glyceryl monostearate (GMS) or combination thereof. The more preferred oils are castor oil, mineral oil and glyceryl monostearate (GMS) or combination thereof.

In accordance with the present invention the oil phase contains the brinzolamide totally or partially solubilized in the oil.

In accordance with the present invention, oil is present in concentration preferably between 0.1% and 25% w/v of composition. In a preferred embodiment the oil present in 2% w/v to 20% w/v of composition. In most preferred embodiment oil component is present in 5% w/v to 10% w/v of composition.

In accordance with the present invention the aqueous phase includes water or water and glycerin mixture.

In accordance with the present invention, the surfactant may be primary or secondary surfactant. In accordance of present invention“primary surfactant” is surfactant used in to increase solubility of brinzolamide in oil. In accordance of present invention “secondary surfactant” is used as emulsifier in aqueous phase of emulsion. In a preferred embodiment primary surfactant and secondary surfactant are selected from the group consisting of, but not limited to, sorbitan esters (such as Span or Arlacel), glycerol esters (such as glycerin mono stearate), polyethylene glycol esters (such as polyethylene glycol stearate), block polymers (such as poloxamers (Pluronics®)), acrylic polymers (such as Pemulen®), ethoxylated fatty esters (such as polyoxyl 35 castor oil ,Cremophor® RH-40), ethoxylated alcohols (such as Brij®), ethoxylated fatty acids (such as polysorbate 80, Tween or Tween 20), monoglycerides, silicon based surfactants alone or in combination. In a preferred embodiment, the primary surfactant and secondary surfactant is polyoxyl 35 castor oil and polysorbate 80 used alone or in combination. In a preferred embodiment primary surfactant is polyoxyl 35 castor oil and secondary surfactant is polysorbate 80. In a preferred embodiment of the present invention the primary surfactant is ethoxylated fatty esters (polyoxyl 35 castor oil) and the secondary surfactant is ethoxylated fatty acids (polysorbate 80).

In preferred embodiment of the present invention the ratio of primary surfactant to secondary surfactant is 1:2, 1: 1.5, 1: 1, 1.5: 1, 2: 1, 2.5: 1, 3: 1 or fractions in between. In more preferred embodiment the ratio of primary to secondary surfactant is 1.5: 1.

In accordance with the present invention, the thickener is a polymer material having an ion-sensitive characteristics. In accordance with the present invention ionic strength dependent in-situ gel polymers are polymers that undergo a sol-gel transition upon contact with physiological ions (Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺ etc.) in the site of application or site of action. Example of ionic strength in-situ gel polymers include various types of sodium alginate, gellan gum, guar gum, pectin and sodium hyaluronate. In a more preferred embodiment the thickener is gellan gum. In an embodiment of present invention ionic strength in-situ gel polymer may be used alone or in combination. In further embodiment of the present invention in-situ gel polymer can be combined with other thickening polymers like one or more of hypromellose (HPMC), methyl cellulose (MC), polyvinyl pyrrolidone (PVP), polyvinylalcohol (PVA), and Poly(acrylic acid) polymers such as carbomers, and the like can also be added.

In accordance with the present invention, thickener is present in concentration preferably about 0.10% w/v to 0.50%w/v of the composition. In a preferred embodiment thickener is present in about 0.15% to 0.30% w/v of the composition. In most preferred embodiment thickener is present in about 0.20% to 0.25%w/v of the composition. In one of the most preferred embodiments the present invention comprises gellan gum as a thickener in concentration about 0.20% to 0.25% w/v of the composition.

In accordance with the present invention, the composition may optionally further comprise of one or more of the following components; isotonizing agents, stabilizers, buffers, preservatives and/or antioxidants. The composition of the present invention may include an isotonizing agent such as mannitol, glycerin, glycerol, sorbitol, glucose or combination thereof. In preferred embodiment the isotonizing agent is glycerin, glycerol or combination thereof. The composition of present invention may contain stabilizers such as sodium edatate, citric acid or combination thereof; buffers such as tris(hydroxymethyl)aminomethane, sodium phosphate and potassium phosphate, sodium citrate, sodium carbonate and sodium bicarbonate or combination thereof; preservatives such as quaternary ammonium compound like benzalkonium chloride, chlorobutanol, sodium perborate or combination thereof. In a preferred embodiment the preservative used is benzalkonium chloride.

The compositions of the present invention may be sterilized by filtration or they may be obtained by sterilization of the aqueous phase and the oily phase and subsequently mixing and emulsifying in aspectic conditions.

Accordingly, an embodiment discloses a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising;

brinzolamide;

an oil phase dispersed in an aqueous phase;

a primary and/or a secondary surfactant; and

a thickener.

Another embodiment disclose a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising;

brinzolamide;

about 0.1%-25% w/v of oil phase dispersed in an aqueous phase;

a primary and/or a secondary surfactant; and

a thickener,

wherein the oil phase includes oil globules having a mean globule size of less than 250 nm.

Another embodiment disclose a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising; brinzolamide;

about 0.1%-25% w/v of oil phase dispersed in an aqueous phase, wherein the an oil phase selected from the group comprising of castor oil, mineral oil, glyceryl monostearate or combination thereof;

a primary and/or a secondary surfactant selected from the group comprising of polyoxyl 35 castor oil, polysorabte 80 alone or combination thereof; and

about 0.20% to 0.25% w/v a thickener which is gellan gum;

wherein the oil phase includes oil globules having a mean globule size of less than 250 nm;

wherein all percentage are based on total weight of the composition.

brinzolamide;

0.1%-25% w/v of oil phase dispersed in an aqueous phase, wherein the an oil phase selected from the group comprising of castor oil, mineral oil, glyceryl monostearate or combination thereof;

0.20% to 0.25%w/v a thickener which is gellan gum;

wherein brinzolamide is dispersed in the oil phase with one or more primary surfactant;

wherein all percentage are based on total weight of the composition.

Another embodiment disclose a pharmaceutical preservative free in-situ gelling nanoemulsion ophthalmic compositions comprising;

brinzolamide;

an oil phase dispersed in an aqueous phase;

a primary and/or a secondary surfactant; and

a thickener;

wherein the composition is stored in specially designed container closure. Viscosity of the nanoemulsion was determined by Rheocalc T 1.2.19 (Brookfield Engineering Labs Inc) using spindly SC4-18 at 25.0 ± 0.5°C. The rotation speed was 50 rpm and the viscosity was determined in centipoise from rheogram plotted using shear stress (dyn/cm²) and shear rate (1/s).

In accordance of the present invention, the viscosity of the present invention is 5cps to 200cps. In preferred embodiment of the present invention, viscosity is 1Ocps to 100 cps. In preferred embodiment of present invention, the viscosity is 25cps to 75cps.

In accordance with the present invention the viscosity of gel formed in- situ is at least twice of the initial formulation. In a preferred embodiment viscosity of gel formed in-situ is increased at least 3 to 9 times of the initial formulation. In most preferred embodiment viscosity of gel formed in-situ is increased at least 5-7 times of initial solution.

In-situ gelling of the present invention was determined by in-vitro study by placing 4mL of brinzloamide formulation of present invention in a vial containing about 2mLof pH 7.4 stimulated tear fluid (STF). Viscosity of in-situ nanoemulsion gel was determined by Rheocalc T 1.2.19 (Brookfield Engineering Labs Inc) using spindly SC4-18 at 25.0 ± 0.5°C. The rotation speed was 50 rpm and the viscosity was determined in centipoise from rheogram plotted using shear stress (dyn/cm²) and shear rate (1/s).

In situ gelling time was determined by placing a drop of brinzolamide formulation of present invention in a vial containing about 2 mL of pH 7.4 stimulated tear fluid (STF).

The in-vivo pharmacodynamic studies were carried out using glaucomatous rabbits. The commercially available ophthalmic drops (Azopt^®) containing 1.0 % w/v (10 mg/mL) of brinzolamide were administered as a reference at the same dose as test formulation. IOP measurement carried out by using calibrated Schiotz tonometer at different time intervals. The change in IOP (DIOR) at each time point from the stabilised IOP (zero time) was determined by using following equation; Equation 1

The AUC (DIOP vs.t) of DIOP vs. time curve calculated using trapezoid rule and the AUC_Rel was calculated using the following equation;

Equation 2

In accordance with the present invention a pharmaceutical in- situ gelling nanoemulsion ophthalmic composition shows a decrease in elevated IOP in glaucomatous rabbits for a longer period of time as compared to reference formulation. The AUC (DIOP vs. t) of the present nanoemulsion was about 2-8 times higher than that of reference product.

Given below are the examples which merely as illustration of a pharmaceutical ophthalmic composition and do not restrict the general concept of the present invention.

EXAMPLES

Example- 1

** Polyoxyl 35 Castor Oil was obtained from BASF SE Germany which is manufactured in Germany.

Process:

In-situ gelling nanoemulsion was prepared by using combination of high speed and high pressure homogenization technique.

1. The drug solution phase (oil phase) was prepared by dissolving brinzolamide in mixture of castor oil and polyoxyl 35 castor oil preheated at 70-80°C under stirring using magnetic stirrer.

2. In aqueous phase; tris(hydroxymethyl)aminomethane (Tris buffer) was added in purified water and its pH was adjusted in between 6.8 to 7.2 using phosphoric acid.

3. The aqueous phase was then heated at 70-80°C and Polysorbate 80, Gellan gum, Glycerol and Benzalkonium chloride were added under stirring.

4. Drug solution phase was added drop wise in aqueous phase under homogenization at 12000 to 16000 RPM and homogenization continued for 45 minutes.

5. This micro emulsion then passed through high pressure homogenizer at 1000-1200 bar pressure for 30 minutes.

6. Prepared nanoemulsion filtered through 1.0 micron filter to remove particulate matter present in nanoemulsion.

7 Sterilization of above nanoemulsion was performed using filtration techniques using 0.45 micron followed by 0.22 micron filter.

The in-vivo pharmacodynamic studies were carried out using glaucomatous rabbits. The commercially available ophthalmic drops (Azopt^®) containing 1.0 % w/v (10 mg/mL) of brinzolamide were administered as a reference at the same dose as test formulation. The result of this study is shown in Table 1 and Fig 1.

TABLE 1: In-vivo Pharmacodynamic Study Results:

The pharmacodynamic studied conducted with optimized formulations of brinzolamide in-situ gelling nanoemulsion showed decrease in elevated IOP in glaucomatous rabbits for a longer period of time as compared to reference formulation. The AUC (DIOP vs. t) for the selected nanoemulsions were about 3-5 times higher than that of reference product.

Example-2

In-situ gelling nanoemulsion was prepared by using the method as disclosed in example 1. The result of this study is shown in Table 2 and Fig 2.

TABLE 2: In-vivo Pharmacodynamic Study Results:

Imax/ Dose is DIOR (mm Hg) normalized to dose, t_max time taken for DIOR (h). AUC (DIOP _{vs. t)}/Dose area under theDIOP vs. time curve normalized to dose, MRT is mean residence time. AUC_Rei ratio of AUC (DIOP _{vs. t)} test (designed formulations) to AUC (DIOP _{vs. t)} reference (marketed eyedrops).

The pharmacodynamic studied conducted with optimized formulations of brinzolamide in-situ gelling nanoemulsion showed decrease in elevated IOP in glaucomatous rabbits for a longer period of time as compared to reference formulation. The AUC (DIOP vs. t) for the selected nanoemulsion were about 4-8 times higher than that of reference product. Stability study:

The stability studies of selected in situ gelling nanoemulsion formulations were carried out as per International Conference on Harmonization guidelines after storage of the formulations for 6 months. The storage conditions employed were ambient (25°C±2°C/40±5% RH) and accelerated (40°C±2°C/25±5% RH) stability condition. The required volume of in-situ gelling nanoemulsion was stored in closed LDPE bottles and sealed tightly. At predetermined time intervals, samples were withdrawn and studied for the characteristics such as description, drug content, particle size, zeta potential, pH, osmolality, water loss and in vitro drug release profile.

TABLE 3: Stability study results of Example D and Example F at initial and 6 month, 25°C/40% RH and 40°C/25% RH condition

Example-3

** Polyoxyl 35 Castor Oil was obtained from BASF SE Germany which is manufactured in Germany. Example-4

In-situ gelling nanoemulsion of example 3 and 4 were prepared by using the method as disclosed in example 1.

All above examples were also prepared as preservative free in-situ gelling nanoemulsion formulation by using the method as disclosed in example 1 except the addition of preservative and stored in NOVELIA® containers.

Claims

WE CLAIM:

1. A pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising;

brinzolamide;

about 0.1%-25% w/v of oil phase dispersed in an aqueous phase;

a primary and/or a secondary surfactant; and

a thickener,

wherein the oil phase comprises oil globules having a mean globule size of less than 250 nm.

2. The nanoemulsion composition according to claim 1, wherein oil is selected from the group consisting of vegetable oil, an animal oil, a mineral oil, fatty acids, a medium chain triglyceride, fatty alcohols or combination thereof.

3. The nanoemulsion composition according to claim 1, wherein primary surfactant and secondary surfactant are selected from the group consisting of sorbitan esters, glycerol esters, polyethylene glycol esters, block polymers, acrylic polymers, ethoxylated fatty esters, ethoxylated alcohols, ethoxylated fatty acids, monoglycerides, silicon based surfactants or combination thereof.

4. The nanoemulsion according to claim 1, wherein thickener is a polymer material having an ion-sensitive characteristics.

5. The nanoemulsion according to claim 4, wherein the thickener is selected from the group consisting of, sodium alginate, gellan gum, guar gum, pectin, sodium hyaluronate, hydroxypropyl methylcellulose, methyl cellulose, polyvinyl pyrrolidone, polyvinylalcohol, poly(acrylic acid) polymers or combination thereof.

6. The nanoemulsion according to claim 1, wherein the viscosity of composition is about 10 cps to 100 cps.

7. The nanoemulsion according to claim 1, wherein the nanoemulsion has a pH between 5 and 8 and an osmolality betwee

n 250 and 600 mOsm/kg.

8. The nanoemulsion according to claim 1, further comprises one or more components selected from; isotonizing agents, viscosity modifying agents, stabilizers, buffers, preservatives and/or antioxidants.

9. A pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising;

brinzolamide;

about 0.1%-25% w/v of oil phase dispersed in an aqueous phase, wherein the oil phase is selected from the group consisting of castor oil, mineral oil, glyceryl monostearate or combination thereof;

a primary and/or a secondary surfactant selected from the group consisting of polyoxyl 35 castor oil, polysorabte 80 or combination thereof; and

about 0.20% to 0.25% w/v of gellan gum.

10. The nanoemulsion according to claim 9, further comprises one or more components selected from isotonizing agents, viscosity modifying agents, stabilizers, buffers, preservative and/or antioxidants.