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1. (WO2019043723) EMULSIONS FOR OPHTHALMIC DELIVERY OF ANTIOXIDANTS
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EMULSIONS FOR OPHTHALMIC DELIVERY OF ANTIOXIDANTS

FIELD OF THE INVENTION

This invention relates to drug delivery dosage forms and methods to treat medical conditions of the eye. Specifically, this invention relates to emulsiondrug delivery dosage forms of antioxidants for drug delivery within the eye.

BACKGROUD

Age related macular degeneration (ARMD) is a severe problem of the eye which accounts for the loss of vision of huge number of elderly population across the globe. The disease which starts as a mild innocent problem of the eye, including occasional floaters and black dots in front of the eye gradually progresses to the loss of peripheral vision to complete loss of vision

Antioxidants are well known to slow down the progression of the ARMD disease. There are several formulations available in the market containing single or combination of antioxidants like Alpha Tocopherol, Lutein, Zeaxanthin, Beta Carotene, Selenium, etc for oral administration for slowing down the progression of the disease. There are several drawbacks with orally administered drugs or bioactivesas the drug does not reach the eye at appropriate concentrations and has either none or very poor pharmacological action in the eye when administered through oral route.

Hence, there is a need for a topical formulation of antioxidants for ocular administrationthat will release the drug in a sustained manner in the eye which on repeated administration will lead to a steady concentration of antioxidants in the aqueous and vitreous humor thereby increasing the macular pigment optical density (MPOD), which will be helpful for better management of Age Related Macular

Degeneration.

SUMMARY

Accordingly, the invention provides new topical drug delivery system that releases the active agent in a sustain manner to provide the desired therapeutic effects, and methods of making such systems. The topical drug delivery system of the invention as disclosed herein is an emulsion. The emulsion compositionas disclosed herein provides release of the active agent in sustained manner and repeated administration of the formulation several times a day will lead to a steady concentration of antioxidants in the aqueous &vitreous humor increasing the macular pigment optical density (MPOD), which will be helpful for better management of Age Related Macular Degeneration.

The emulsion composition as disclosed herein is a stable oil-in- water ophthalmic emulsion comprising one or more antioxidants, at least one oil from vegetable, mineral or animal origin, at least one surfactant and at least one pharmaceutically acceptable excipient, wherein the pH range is from about 4 to 8. The concentration of the antioxidant in the emulsion composition as disclosed herein is in the range of about 0.0003%-().3% w/v and the antioxidant is selected from the group comprising of lutein, zeaxanthin, tocopherol, beta carotene, selenium or a combination thereof.

The oil is a vegetable oil or mineral oil or animal oil or a combination thereof. The vegetable oil is selected from the group comprising of Castor Oil, Cotton seed Oil, Peanut Oil, Coconut oil, Rice bran oil, Sunflower oil. Sesame oil, Soyabeen oil, Flax oil, Canola oil, Olive oil. Mustard Oil, Jojoba oil or a combination thereof.The animal oil is selected from the group comprising of fish oil. shark liver oil, cod liver oil or a combination thereof.The mineral oil is Liquid Paraffin, .

The surfactant is selected from the group comprising of Polyoxyethylated nonionic surfactants like PoiysorhateSQ, Polysorbate 60, Polysorbate, 40, Polysorbate 20, Cremophors, Tyloxapols, Poloxamers, Benzaikoniurn chloride, Benzethonium chloride, Cetyi alcohol, Carbomer, Cholesterol, Cocamidopropyi betaine, glyceryl monostearate, lanolin alcohols, lauralkoniuni chlorides, N lauroylsarcosine, Nonoxynoi 9, Oetoxynol 40, Polyoxyl 35 castor oil, Poiyoxyi 40 hydrgenated castor oil. Polyoxyl 40 stearate, Sorbitanmonolaureate, Sorbitan monooleate, Sorbitanmonopalmitate, Polyoxyethylene (2) Steryl Ether, Polyoxyethylene (2) Cetyl Ether, Polyoxyethylene (2) Oleyl Ether, Polyeoxyethyllene (2) Nonylphenylether, Polyoxyethylene (2) isooctylphenyl ether, Polyoxyletheylene (4) lauryl ether, Polyoxylethylene (5) isooctylphenylether or a combination thereof.

The emulsion composition as described herein further comprises at least one pH adjusting agent, at least one buffering agent, at least one osmolality control agent and at least one antimicrobial preservative.

The pH adjusting agent selected from the group comprising of Hydrochloric Acid, Sodium Hydroxide, Sulphuric Acid, Sodium Sulphate, Acetic Acid, Sodium Citrate, Ammonium Hydroxide, Citric Acid, Diethanolarnine, Nitric Acid, Phosphoric Acid or a combination thereof.

The buffering agent selected from the group comprising of Acetic Acid, Boric Acid, Citric Acid, Phosphoric Acid, Potassium Acetate, Potassium Phosphate, Potassium Sulphate, Potassium Sorbate, Sodium Acetate, Sodium borate, Sodium Carbomate, Sodium Citrate, Sodium Phosphate, Sorbic Acid, Tromethamine or a combination thereof.

The osmolality control agent selected from the group comprising of Sodium Chloride, Sodium Sulphate, Sodium Nitrate, Sorbitol, Mannitol, Calcium Chloride,

Glycerine, Magnesium Chloride, PEG 300, PEG 400, Potassium Chloride, Propylene Glycol or a combination thereof.

The antimicrobial preservative selected from the group comprising of Quaternary ammonium compounds selected from Benzalkonium Chloride, Benzethonium chloride, Benzododecinium bromide or Polyquatermium-1 ; or Acid/Base compounds selected from Boric acid, sodium acetate or sodium borate; or Alcohols selected from chlorobutanol or Phenylethyl alcohol; or Organic Mercuric compounds selected from Phenyl mercuric acetate, Phenyl mercuric nitrate or Thimerosai; or Parabens selected from methyl paraben or Propyl Paraben; or Oxidizing agent sodium chlorite; or Metal salt Zinc Chloride or a combination thereof.

DETAILED DESCRIPTION

As described herein, the disclosure provides emulsion compositions for ocular delivery of antioxidants that releases the active agent in sustained manner and repeated administration of the formulation several times a day will lead to a steady concentration of antioxidants in the aqueous and vitreous humor increasing the macular pigment optical density (MPOD), which will be helpful for better management of Age Related Macular Degeneration.

The emulsion composition as disclosed herein is a stable oil -in- water ophthalmic emulsion comprising one or more antioxidants, at least one oil from vegetable, mineral or animal origin, at least one surfactant and at least one pharmaceutically acceptable excipient, wherein the pFI range is from about 4 to 8.

The antioxidant is selected from the group comprising of lutein, zeaxanthin, tocopherol, beta carotene, selenium or a combination thereof. The concentration of the antioxidant in the emulsion composition as disclosed herein is in the range of about 0.0003 %-0.3% w/v.

The emulsion composition as described herein further comprises at least one pH adjusting agent, at least one buffering agent, at least one osrnolarity control agent and at least one antimicrobial preservative.

The oil is a vegetable oil or mineral oil or animal oil or a combination thereof. The vegetable oil is selected from the group comprising of Castor Oil, Cotton seed Oil, Peanut Oil, Coconut oil, Rice bran oil, Sunflower oil, Sesame oil, Soyabeen oil, Flax oil, Canola oil, Olive oil, Mustard Oil, Jojoba oil or a combination thereof.The animal oil is selected from the group comprising of fish oil, shark liver oil, cod liver oil or a combination thereof.The mineral oil is Liquid Paraffin.

The surfactant is selected from the group comprising of Polyoxyethylated nonionic surfactants like PolysorbateSO, Polysorbate 60, Polysorbate, 40, Polysorbate 20, Cremophors, Tyloxapols, Poloxamers, Benzalkonium chloride, Benzethonium chloride, Cetyl alcohol, Carbomer, Cholesterol, Cocarnidopropyl betaine, glyceryl monostearate, lanolin alcohols, lauralkonium chlorides, N lauroylsarcosine, Nonoxynol 9, Octoxynol 40, Poiyoxyl 35 castor oil, Polyoxyl 40 hydrgenated castor oil. Polyoxyl 40 stearate, Sorbitanmonolaureate, Sorbitan monooleate, Sorbitanmonopalmitate, Poiyoxyethyiene (2) Steryl Ether, Polyoxyethylene (2) Cetyl Ether, Polyoxyethylene (2) Oleyl Ether, Polyeoxyethyllene (2) Nonylphenylether, Polyoxyethylene (2) isooctylphenyl ether, Polyoxyletheylene (4) lauryl ether, Polyoxylethylene (5) isooctylphenylether or a combination thereof.

In one embodiment, the topical ocular suspension comprises the antioxidants lutein and zeaxanthin and pharmaceutical excipients.

Example: 1

Lutein + ZeaxanthinOphthalmic Emulsion

Process: Seasame oil was heated to about 70° C and to it was added Lutein & Zeaxanthin and stirred to completely dissolve the same in the oil phase. Sterile purified water was heated to about 70° C,and to it polysorbate 80, Sodium citrate, Benzalkonium Chloride and HPMC was added and mixed to form the aqueous phase. The oil phase was added while stiring the aqueous phase with a high shear mixerto form the emulsion. This crude emulsion was finely divided in a high pressure homogenizer and the volume was made up with sufficient quantity of water for injection and the pH was adjusted using either sodium hydroxide/ hydrochloric acid and sterilized by filtration through 0.22 μm membrane filter to form the sterile ophthalmic emulsion of antioxidants, which is filled into containers aseptically and sealed.

In another embodiment, the ophthalmic emulsion comprises the antioxidants lutein, zeaxanthin, alpha tocopherol, and selenium and pharmaceutical excipients.

Example: 2

Lutein , Zeaxanthin, Alpha Tocopherol & SeleniumOphthalmic Emulsion

Process: Peanut oil was heated to about 70° C and to it was added Lutein, Zeaxanthin and alpha tocopherol and stirred to completely dissolve the same in the oil phase. Sterile purified water was heated to about 70° C ,and to it Selenium, Poloxamer 188, Polyethylene Glycol (PEG) 400, Sodium Chloride, and Phenyl mercuric nitrate was added and mixed to form the aqueous phase. The oil phase was added while stirring the aqueous phase with a high shear mixerto form the emulsion. This crude emulsion was finely divided in a high pressure homogenizer to form a stable emulsion of antioxidants and the volume was made up with sufficient quantity of water for injection and the pH was adjusted using either sodium hydroxide/ hydrochloric acid and sterilized by filtration through 0.22 μm membrane filter to form the sterile ophthalmic emulsion of antioxidants, which is filled into containers aseptically and sealed.

In another embodiment of the invention, the ophthalmic emuslioncomprises lutein, alpha tocopherol and pharmaceutical excipients.

Example: 3

Lutein + AlphaTocopherolOphthalmic Emulsion

Process: Medium Chain Triglycerides was heated to about 70° C and to it was added Lutein, and alpha tocopherol and stirred to completely dissolve the same in the oil phase. Sterile purified water was heated to about 70° C,and to it Poloxamer 407, Sodium Citrate, Citric Acid, and Benzalkonium Chloride was added and mixed to form the aqueous phase. The oil phase was added while stirring the aqueous phase with a high shear mixerto form the emulsion. This crude emulsion was finely divided in a high pressure homogenizer to form a stable emulsion of antioxidants and the volume was made up with sufficient quantity of water for injection and the pH was adjusted using either sodium hydroxide/ hydrochloric acid and sterilized by filtration through 0.22 μm membrane filter to form the sterile ophthalmic emulsion of antioxidants, which is filled into containers aseptically and sealed.

In another embodiment of the invention, the ophthalmic emuslion comprises of beta carotene and pharmaceutical excipients.

Example: 4

Beta Carotene Ophthalmic Emulsion

Process: Fish Oil was heated to about 70° C atto it was added Beta carotene and stirred to completely dissolve the same in the oil phase. Sterile purified water was heated to about 70° C,and to it Kolliphor EL, Sodium Citrate, Citric Acid, and Benzalkonium Chloride were added and mixed to form the aqueous phase. The oil phase was added while stirring the aqueous phase with a high shear mixerto form the emulsion. This crude emulsion was finely divided in a high pressure homogenizer to form a stable emulsion of antioxidants and the volume was made up with sufficient quantity of water for injection and the pH was adjusted using either sodium hydroxide/ hydrochloric acid and sterilized by filtration through 0.22 μm membrane filter to form the sterile ophthalmic emulsion of antioxidants, which is filled into containers aseptically and sealed.

In another embodiment of the invention, the ophthalmic emuslion comprises of zeaxanthin and pharmaceutical excipients.

Example: S Zeaxanthin Ophthalmic Emulsion

Process: Liquid Paraffin was heated to about 70° C and to it was added Zeaxanthin and stirred to completely dissolve the same in the oil phase. Sterile purified water was heated to about 70° C,and to it Polyethylene glycol oleyl ether (Brij® 93), Sodium Borate, Boric Acid, Sorbitol and Benzalkonium Chloride was added and mixed to form the aqueous phase. The oil phase was added to the aqueous phase while stirring the aqueous phase with a high shear mixerto form the emulsion. This crude emulsion was finely divided in a high pressure homogenizer to form a stable emulsion of antioxidants and the volume was made up with sufficient quantity of water for injection and the pH was adjusted using either sodium hydroxide/ hydrochloric acid and sterilized by filtration through 0.22 μm membrane filter to form the sterile ophthalmic emulsion of antioxidants, which is filled into containers aseptically and sealed.

In another embodiment of the invention, the ophthalmic emuslion comprises of lutein and pharmaceutical excipients.

Example:6 Lutein Ophthalmic Emulsion

Process: Liquid Paraffin was heated to about 70° C and to it was added Lutein and stirred to completely dissolve the same in the oil phase. Sterile purified water was heated to about 70° C,and to it Polyethylene glycol oleyl ether (Brij® 93), Sodium Borate, Boric Acid, Sorbitol and Benzalkonium Chloride were added and mixed to form the aqueous phase. The oil phase was added to the aqueous phase while stirring the aqueous phase with a high shear mixerto form the emulsion. This crude emulsion was finely divided in a high pressure homogenizer to form a stable emulsion of antioxidants and the volume was made up with sufficient quantity of water for injection and the pH was adjusted using either sodium hydroxide/ hydrochloric acid and sterilized by filtration through 0.22 μm membrane filter to form the sterile ophthalmic emulsion of antioxidants, which is filled into containers aseptically and sealed.

The method for preparing the topical ocular suspension according to the disclosure described herein is not limited to the above methods. The ophthalmic emulsion for ocular delivery of antioxidants according to the disclosure described herein can be prepared by using various other techniques.