DESC:AN OPHTHALMIC COMPOSITION FOR GLAUCOMA AND METHOD OF PREPARATION THEREOF

FIELD OF THE INVENTION

The present invention relates to an ophthalmic composition for the treatment and prevention of glaucoma comprising Bimatoprost or pharmaceutically acceptable salts thereof and netarsudil or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients. It further relates to a method of preparing such compositions and their use for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension.

BACKGROUND OF THE INVENTION

Bimatoprost is chemically known as (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2- [(1E,3S)-3-hydroxy-5-phenyl1-pentenyl]cyclopentyl]-5-N ethylheptenamide. Bimatoprost is currently marketed in two strengths 0.03% w/v and 0.01% w/v concentration, under the brand name Latisse® and Lumigan® respectively. Both the formulations contain benzalkonium Chloride as preservative. Latisse® (bimatoprost ophthalmic solution) 0.03% is indicated to treat hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness; and Lumigan® (bimatoprost ophthalmic solution) 0.01% is indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension. Currently marketed 0.03% formulation contains 0.005 % w/v of benzalkonium chloride, while 0.01 % formulation contains 0.02% w/v of benzalkonium chloride.

Netarsudil is a Rho kinase inhibitor and is chemically known as is (S)-4-(3- amino-1-(isoquinolin-6-yl-amino)-1-oxopropan-2-yl) benzyl 2,4-dimethyl benzoate dimesylate. Netarsudil is currently marketed in the form of solution with strength EQ 0.02% Base ophthalmic drop under the brand name of Rhopressa. Rhopressa is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Marketed formulation of Rhopressa contains 0.2 mg of netarsudil (equivalent to 0.28 mg of netarsudil dimesylate) along with boric acid, mannitol, sodium hydroxide to adjust pH, and water for injection. Formulation also contains 0.015% of Benzalkonium chloride as a preservative.

Some of the patients require the better control of intra ocular pressure which is difficult with the use of individual drug. So, there is always a requirement of the combination of drugs for better efficacy and control of intra-ocular pressure.

In view of the above points, it is therefore needed to provide an ophthalmic composition comprising combination of netarsudil or its pharmaceutically acceptable salts and bimatoprost in the present invention which provides less side effects, better/comparable bioavailability and better stability when compared to the marketed formulation. The combination formulation shows synergistic effect as compared to the effects shown by the individual formulations.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients for the treatment and prevention of the open angle glaucoma or ocular hypertension.

In one of the aspects, the present invention provides an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the bimatoprost is in the range of 0.005- 0.05%w/v, and netarsudil is in the range of 0.005- 0.05% w/v.

In one of the aspects, the present invention provides an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the concentration of netarsudil base is 0.02% w/v.

In one of the aspects, the present invention provides an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, where in the composition comprises less than 0.05% w/v benzalkonium chloride.

In another aspect, the present invention provides an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of preservative.

In another aspect, the present invention provides an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of benzalkonium chloride.

In another aspect, the present invention provides an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of phosphate buffer.

In another aspect, the present invention provides an ophthalmic pharmaceutical composition comprising netarsudil or its pharmaceutically acceptable salts, and bimatoprost or its pharmaceutically acceptable salts, with one or more pharmaceutically acceptable excipients, wherein netarsudil or its pharmaceutically acceptable salts is in dissolved form and bimatoprost or its pharmaceutically acceptable salts is suspended or dissolved in the composition.

In another aspect, the present invention provides an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising buffers, tonicity agents, preservatives, chelating agents, antioxidants, surfactants, co-solvents, viscosity modifying agent, vehicles, pH adjusting agents and/ or combinations thereof.

In another aspect, the present invention provides an aqueous sterile, ophthalmic pharmaceutical composition for lowering intraocular pressure in a patient suffering from elevated intraocular pressure comprising netarsudil or its pharmaceutically acceptable salts thereof, bimatoprost or its pharmaceutically acceptable salts thereof, a polymer, a buffer, a preservative along with one or more pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of solution.

In another aspect, the present invention provides an aqueous sterile, ophthalmic pharmaceutical composition for lowering intraocular pressure in a patient suffering from elevated intraocular pressure comprising netarsudil or its pharmaceutically acceptable salts thereof, bimatoprost or its pharmaceutically acceptable salts thereof, a polymer, a buffer, a preservative along with one or more pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of suspension.

In another aspect, the present invention provides a method for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension, wherein the method comprises administering a pharmaceutical composition comprising netarsudil or pharmaceutically acceptable salts thereof and bimatoprost or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a process for preparing an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof and bimatoprost or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION

In main embodiment, the present invention provides an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof and bimatoprost or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable excipients.

Ophthalmic solutions are sterile, free form particles and especially prepared for instillation into the eye. Considerations in preparing ophthalmic solutions involve clarity, tonicity, pH/buffer, sterility, preservatives, antioxidants, viscosity enhancers and proper packaging.

Applicant has tried various excipients and combination of excipients to develop an ophthalmic pharmaceutical composition of netarsudil and bimatoprost along with one or more pharmaceutically acceptable excipients, which is not only stable but also provide sufficient efficacy. While working on the present application, applicant has found that the pharmaceutical composition of netarsudil and bimatoprost can be stabilized by using very less amount of antimicrobial agent.

Accordingly, applicant developes an ophthalmic pharmaceutical composition comprising netarsudil or its pharmaceutically acceptable salts, and bimatoprost or its pharmaceutically acceptable salts, with one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is optionally free of preservatives.

The terms “pharmaceutically acceptable salt” or “salt” are used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids and organic acid salts.

In another embodiment of the present invention, it is provided that an ophthalmic composition comprising bimatoprost and one or more pharmaceutically acceptable excipients, wherein the composition comprises from 0.005% w/v to 0.05% w/v bimatoprost or pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, it is provided that an ophthalmic composition comprising bimatoprost and one or more pharmaceutically acceptable excipients, wherein the bimatoprost concentration is 0.01% w/v or pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, it is provided that an ophthalmic composition comprising bimatoprost and one or more pharmaceutically acceptable excipients, wherein the bimatoprost concentration is 0.03% w/v or pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, it is provided that the ophthalmic composition comprising netarsudil and one or more pharmaceutically acceptable excipients, wherein the netarsudil is in the range of 0.005% w/v to 0.05% w/v or pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, it is provided that the ophthalmic composition comprising netarsudil and one or more pharmaceutically acceptable excipients, wherein the concentration of netarsudil is 0.02% w/v or pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, it is provided that an ophthalmic composition comprising netarsudil and bimatoprost, wherein the Netarsudil or its pharmaceutically acceptable salt and bimatoprost or its pharmaceutically acceptable salt is present in any known polymorphic form i.e. amorphous or crystalline form.

In another embodiment of the present invention, it is provided that the pharmaceutical composition, is having a pH in the range of 3 to 8.

In another embodiment of the present invention, it is provided that the composition is in the form of a clear solution, emulsion, suspension, dispersion, gel, or nano-dispersion having water as a major constituent.

Yet in another embodiment, the present invention provides a pharmaceutical composition, wherein the composition is free of benzalkonium chloride.

Yet in another embodiment, the present invention provides a pharmaceutical composition, wherein the composition comprises less than 0.05% w/v benzalkonium chloride.

Yet in another embodiment, the present invention provides a pharmaceutical composition, wherein the composition comprises less than 500 ppm benzalkonium chloride.

Yet in another embodiment, the present invention provides a pharmaceutical composition, wherein the composition is free of phosphate buffer.

In another embodiment, the present invention provides a pharmaceutical composition, wherein the composition is filled into a single-dose container or multi-dose container and wherein the suitable containers include, but not limited to, bottles, vials or ampoules.

In another embodiment of the present invention, it is provided that an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of preservative and wherein said composition is filled into a multi-dose container.

In another embodiment, the present invention provides a pharmaceutical composition, wherein the composition is filled in three piece bottle of suitable capacity plugged with nozzle and seal with cap. Pharmaceutically acceptable packaging materials include, but are not limited to, low density polyethylene ("LDPE"), high density polyethylene ("HDPE"), polypropylene, polystyrene, polycarbonate, polyesters (such as polyethylene terephthalate and polyethylene naphthalate), nylon, polyvinyl chloride, poly(vinylidine chloride), poly(tetrafluoroethylene) and other materials known in the literature.

Typically, the bottle may be made from Low Density Polyethylene (LDPE), Linear Low-Density Polyethylene (LLDPE), High Density Polyethylene (HDPE), Polypropylene (PP) and the like or a combination thereof. Typically, the nozzle/cap may be made of low-density polyethylene (LDPE), linear low-density polyethylene (LLDPE), high density polyethylene (HDPE), polypropylene (PP) and the like or a combination thereof. Alternatively, the nozzle may be made of a hydrophobic material or may be coated with a hydrophobic material such as a fluoropolymer like Teflon (polytetrafluoroethylene) and the like.

The pharmaceutical compositions or the active ingredient as per the present invention can be sterilized using any of the known methods of sterilization, such as filtration, moist heat, dry heat, gas sterilization or irradiation (gamma and electron beam) or combination thereof. The container in which composition is filled can be sterilized using gamma irradiation or ethylene oxide or pre-acetic acid or any other conventional method of sterilization. The compositions can be terminally sterilized also.

In another embodiment of the present invention, it is provided that an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the composition has total impurities less than the maximum allowed limit as per ICH guidelines.

In another embodiment of the present invention, there is provided an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising buffers, tonicity agents, preservatives, chelating agents, antioxidants, surfactants, co-solvents, viscosity modifying agent, vehicles, pH adjusting agents and/ or combinations thereof.

In another embodiment, the suitable preservatives used in the composition include cetrimide, polyquaternium-1, thiomersal or thimerosal, acids and their pharmaceutically acceptable salts such as sorbic acid, potassium sorbate, boric acid, borax, sodium perborate NaBO3, salicylic acid, benzoic acid, lactic acid, acetic acid; S.O.C (stabilized oxychloro complex)/purite, S.C.P (stabilized chlorite peroxide), phenylethanol, benzalkonium chloride, benzododecinium bromide (BDD), benzethonium chloride, cetrimonium chloride, methyl parahydroxybenzoate, polyquaternium ammonium chloride, polyaminopropyl, and hydrogen peroxide, parabens such as methyl paraben, propyl paraben, ethyl paraben, butyl paraben, perborates, phenol and its derivatives such as m-cresol and chlorocresol, benzyl alcohol, halogenated alcohols such as chloro-butanol and/or combinations thereof.

In another embodiment, the suitable viscosity modifying agent/suspending agents used in the composition include hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), cellulose and derivatives thereof, polycarbophil, polyoxyethylene glycol (PEG), hyaluronic acid (HA), amylase and derivatives thereof, amylopectins and derivatives thereof, dextran and derivatives thereof, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and acrylic polymers such as derivatives of polyacrylic or polymethacrylic acid including hydroxylmethyl methacrylate (HEMA), carbomer such as carbomer 974 P or a mixture thereof.

In another embodiment, the suitable buffering agents include, but are not limited to, phosphates, such as sodium phosphate monobasic, sodium phosphate dibasic, phosphoric acid, citric acid, citrates such as sodium citrate, borate, acetic acid, acetates such as sodium acetate, lactic acid, sodium lactate, tartaric acid, sodium tartrate, tartrates, succinates, amino acids such as L-arginine, tromethamine and/or combinations/mixtures thereof.

In another embodiment, the suitable osmotic/tonicity adjusting agents include propylene glycol, glycerol, sodium chloride, potassium chloride, sodium bromide, calcium chloride, mannitol, sorbitol, dextrose, sucrose, mannose and the like and mixtures thereof. The osmotic agent is used in an amount to maintain the solution’s osmolality compatible with respect to eye fluid.

In another embodiment, the suitable pH adjusting agents include acids and bases. Suitable acids to adjust the pH of the composition include, but are not limited to, hydrochloric acid, citric acid, sulfuric acid, nitric acid and/or combinations thereof.

In another embodiment, the suitable bases to adjust the pH of the composition include, but are not limited to, sodium hydroxide, potassium hydroxide, barium hydroxide, amino acid and/or combinations thereof.

In another embodiment, the suitable vehicles/diluents include water for injection, purified water, Ringer's solution, normal saline solution. Other vehicles may be chosen, as is known in the art, including but not limited to: water soluble polyethers such as polyethyene glycol, polyvinyls, such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.

In another embodiment, the suitable antioxidants include, but are not limited to, sodium thiosulfate, sodium bisulfite, acetone sodium bisulfite, gentisic acid, gentisic acid ethanolamide, sodium formaldehyde sulfoxylate, thiourea, butylated hydroxyanisole, butylated hydroxy toluene, esters of gallic acid, ascorbic acid, salts of ascorbic acids such as ascorbyl palmitate, sodium ascorbate, retinoids and derivatives of vitamin A, acetylcysteine, thioglycerol, Vitamin E and its derivatives e.g. Vitamin E TPGS and/or combinations thereof.

In another embodiment, the suitable surfactants include but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. The formulations can contain surface-active agents conventionally employed in topical formulations, such as oleic acid, lecithin, sorbitan trioleate, benzododecinium bromide, cetylpyridinium chloride, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan mono-oleate, polyoxypropylene/polyoxyethylene block copolymers, polyoxypropylene/polyoxyethylene/ethylene diamine block copolymers, ethoxylated castor oil and/or combinations thereof.

In another embodiment, the suitable co-solvents include propylene glycol, polyethylene glycol, glycerine, glycerol and the like or mixtures thereof.

In another embodiment, the suitable chelating agents include edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid and/or combinations thereof.

In another embodiment, the present invention provides a pharmaceutical composition, wherein netarsudil and bimatoprost is in dissolved form in the composition.

In another embodiment, the present invention provides a pharmaceutical composition, wherein netarsudil or its pharmaceutically acceptable salts is in dissolved form and bimatoprost or its pharmaceutically acceptable salts is suspended or dispersed in the composition.

In another embodiment, the present invention provides a pharmaceutical composition, wherein the particle size of bimatoprost is d90 less than 20µm.

In another embodiment, the present invention provides a pharmaceutical composition, wherein the viscosity of the suspension is less than 1000 cps, more preferably less than 500 cps and even more preferably less than 150 cps. Viscosity of the bimatoprost suspension is in the range of about 30 cps to about 120cps.

In another embodiment of the present invention, there is provided a method for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension, wherein the method comprises administering a pharmaceutical composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention, there is provided a method of reducing the side effect of benzalkonium chloride used in netarsudil and bimatoprost ophthalmic composition, said method comprises once-a-day topical instillation into the eye of a patient, an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts in an amount ranging from about 0.005% w/v to 0.05% w/v; bimatoprost or its pharmaceutically acceptable salt in an amount of 0.01% w/v and one or more pharmaceutically acceptable excipients, wherein the composition comprises preservative other than benzalkonium chloride in an amount to maintain the preservative efficacy throughout the shelf-life of the product.

In another embodiment of the present invention, there is provided a method of reducing the side effect of benzalkonium chloride used in netarsudil and bimatoprost ophthalmic composition, said method comprises once-a-day topical instillation into the eye of a patient, an ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts in an amount ranging from about 0.005% w/v to 0.05% w/v; bimatoprost or its pharmaceutically acceptable salt in an amount of 0.03% w/v and one or more pharmaceutically acceptable excipients, wherein the composition comprises preservative other than benzalkonium chloride in an amount to maintain the preservative efficacy throughout the shelf-life of the product.

In another embodiment of the present invention, there is provided a method of reducing the side effect of higher concentration of BKC (Benzalkonium Chloride) used in netarsudil 0.02% w/v and bimatoprost 0.01 % w/v ophthalmic composition, said method comprises once-a-day topical instillation into the eye of a patient, an ophthalmic composition comprising 0.02% w/v netarsudil or its pharmaceutically acceptable salt and 0.01 % w/v bimatoprost or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the composition comprises less than 0.015 % w/v of Benzalkonium chloride.

In another embodiment of the present invention, there is provided a method of reducing the side effect of higher concentration of BKC(Benzalkonium Chloride) used in netarsudil 0.02% w/v and bimatoprost 0.03 % w/v ophthalmic composition , said method comprises once-a-day topical instillation into the eye of a patient, an ophthalmic composition comprising 0.02% w/v netarsudil or its pharmaceutically acceptable salt and 0.03 % w/v bimatoprost or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the composition comprises less than 0.015 % w/v of Benzalkonium chloride.

The present invention further relates to a process for preparing an ophthalmic composition comprising netarsudil and bimatoprost and one or more pharmaceutically acceptable excipients, wherein said process involves adding of both drugs and other excipients to suitable vehicle to form final composition followed by filling in a suitable container.

In another embodiment of the present invention it relates to process for preparing an ophthalmic comprising by a adding the compounds selected from the below mentioned table 1-10 i.e. Boric acid, Mannitol, PEG 400, EDTA, Polyoxyl 40 Sterate and Cremophore RH 40, all were dissolved in water followed by addition of solution of benzalkonium chloride (optional depends on the formulation type) containing Bimatoprost and Netarsudil, further the pH adjusted to 3-8.

Alternatively, drugs can be sterilized separately either alone or with other excipients optionally followed by milling and then adding it to the remaining excipients to form final composition.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

The following examples will illustrate in more detail the various aspects of the present invention.

Table 1: Ophthalmic composition of Bimatoprost & Netarsudil

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Boric Acid 0.2-0.7
Mannitol 30-70
Benzalkonium chloride 0.01- 0.2
Polyoxyl 40 stearate 1-7
Cremophore RH 40 1-7
PEG 400 10-50
EDTA 0.01-0.5
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Table 2: Ophthalmic composition of Netarsudil & Bimatoprost

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Boric Acid 0.2-0.7
Mannitol 30-70
Benzalkonium chloride 0.01- 0.2
Cremophore RH 40 1-7
PEG 400 10-50
EDTA 0.01-0.5
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Table 3: Ophthalmic composition of Netarsudil & Bimatoprost

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Boric Acid 0.2-0.7
Mannitol 30-70
Benzalkonium chloride 0.01- 0.2
Polyoxyl 40 stearate 1-7
PEG 400 10-50
EDTA 0.01-0.5
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Table 4: Ophthalmic composition of Netarsudil & Bimatoprost

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Boric Acid 0.2-0.7
Mannitol 30-70
Benzalkonium chloride 0.01- 0.2
Polyoxyl 40 sterate 1-7
Cremophore RH 40 1-7
EDTA 0.01-0.5
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Table 5: Ophthalmic composition of Netarsudil & Bimatoprost

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Boric Acid 0.2-0.7
Mannitol 30-70
Polyoxyl 40 sterate 1-7
Cremophore RH 40 1-7
PEG 400 10-50
EDTA 0.01-0.5
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Table 6: Ophthalmic composition of Netarsudil & Bimatoprost

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Sodium Chloride 0.1-0.9
Sodium phosphate dibasic 0.1-0.9
Sodium phosphate Monobasic 0.1-0.9
Benzalkonium chloride 0.01- 0.2
EDTA 0.01-0.5
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Table 7: Ophthalmic composition of Netarsudil & Bimatoprost

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Boric Acid 0.2-0.7
Mannitol 30-70
Benzalkonium chloride 0.01- 0.2
EDTA 0.01-0.5
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Table 8: Ophthalmic composition of Netarsudil & Bimatoprost

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Boric Acid 0.2-0.7
Mannitol 30-70
Benzalkonium chloride 0.01- 0.2
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Table 9: Ophthalmic composition of Netarsudil & Bimatoprost

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Boric Acid 0.2-0.7
Sodium Borate 1-8
Glycerine 5-15
Benzalkonium chloride 0.01- 0.2
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Table 10: Ophthalmic composition of Netarsudil & Bimatoprost

Ingredient Mg/ml
Bimatoprost 0.1-0.3
Netarsudil 0.2
Sodium Chloride 0.1-0.9
Sodium phosphate dibasic 0.1-0.9
Citric Acid 0.1-0.9
Benzalkonium chloride 0.01- 0.2
Hydrochloric acid QS
Sodium hydroxide QS
Water for Injection QS

Process of preparation of Composition: All the composition can be prepared by the process described as follows:
a. One or more pharmaceutically acceptable excipients are dissolved in water.
b. The mixture formed in step (a) was added in the mixture of Bimatoprost & Netarsudil to obtained final composition.

It will be apparent to a person skilled in the art that the above description is for illustrative purposes only and should not be considered as limiting. Various modifications, additions, alterations, and improvements without deviating from the spirit and the scope of the invention may be made by a person skilled in the art.
,CLAIMS:We Claim:

1. An ophthalmic composition comprising netarsudil or pharmaceutically acceptable salts thereof; bimatoprost or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

2. The ophthalmic composition as claimed in claim 1, wherein the composition comprises from 0.005% w/v to 0.05% w/v bimatoprost or pharmaceutically acceptable salts thereof.

3. The ophthalmic composition as claimed in claim 1, wherein the composition comprises from 0.005%w/v to 0.05%w/v netarsudil or pharmaceutically acceptable salts thereof.

4. The ophthalmic composition as claimed in claim 1, wherein the composition further comprises benzalkonium chloride.

5. The ophthalmic composition as claimed in claim 4, wherein the composition comprises less than 0.05% w/v benzalkonium chloride.

6. The ophthalmic composition as claimed in claim 1, wherein the composition is free of phosphate buffer.

7. The ophthalmic composition as claimed in claim 1, wherein the pharmaceutical composition is having a pH in the range of 3 to 8.

8. The ophthalmic composition as claimed in claim 1, wherein the composition is in the form of a clear solution, emulsion, suspension, dispersion, gel, or nano-dispersion having water as a major constituent.

9. The ophthalmic composition as claimed in claim 1, wherein the composition is filled into a single dose container or multi-dose container

10. An ophthalmic pharmaceutical composition comprising netarsudil or its pharmaceutically acceptable salts, and bimatoprost or its pharmaceutically acceptable salts, with one or more pharmaceutically acceptable excipients, wherein netarsudil or its pharmaceutically acceptable salts is in dissolved form and bimatoprost or its pharmaceutically acceptable salts is suspended or dissolved in the composition.

Dated this, 29th Day of August 2024 For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer