Novel ophthalmic formulations

Abstract

The invention discloses an ophthalmic preparation / composition which comprises a single cinnamic acid compound or a derivative thereof, a single catechin compound or a derivative thereof, or a combination of the cinnamic acid compound and the catechin compound, and an acceptable excipient, the formulations / compositions are useful for the treatment / clearance / alleviation of conditions associated with cataract, intraocular pressure and glaucoma, lenticular degeneration, corneal epithelial hyperplasia and liquefaction, and inflammation.

Description

Technical Field

[0001] The present invention relates to an ophthalmic preparation / composition comprising a cinnamic acid compound or a derivative thereof, a catechin compound or a derivative thereof, or a combination thereof, and an acceptable excipient. The preparation / composition is used to treat / eliminate / alleviate conditions associated with cataractous lens, intraocular pressure, glaucoma, lenticular degeneration, and corneal epithelial hyperplasia / liquefaction / inflammation. Background of the Invention

[0003] Cataract, defined as any clouding of the lens of the eye caused by various etiological factors, is a leading cause of blindness and severely impairs vision and quality of life.

[0004] Glaucoma is a group of eye conditions that damage the optic nerve, which is crucial for vision. This damage is usually caused by abnormally high pressure inside the eye, called intraocular pressure (IOP). Glaucoma is the leading cause of irreversible blindness worldwide.

[0005] Cinnamic acid derivatives and some catechins exhibit antioxidant and anti-inflammatory activities and inhibit several important steps of angiogenesis, including proliferation, migration, and adhesion.

[0006] In an article published in Nature, titled "Rosmarinic acid restores full transparency of ultrasound-treated human cataracts in vitro and delays cataract formation in vivo," by MARINA CHEMEROVSKI-GLIKMAN1 et al., rats were treated with subcutaneous injections of rosmarinic acid. The article discloses that rats were treated with subcutaneous injections of high-concentration rosmarinic acid (40 mM in 500 μl, i.e., a 1.4% concentration, with a dose of 7 mg / 0.5 ml per injection) to treat cataracts.

[0007] PCT / EP94 / 03340 discloses that N-acetylcarnosine is a prodrug of L-carnosine and proposes a topical medicament containing N-acetylcarnosine which can be used for the prevention and treatment of cataracts.

[0008] N-acetylcarnosine drops are commonly administered to treat age-related cataracts.

[0009] US6194457 discloses a liquid ophthalmic composition comprising an isotonic solution of reduced glutathione, vitamin A, vitamin E and one or more buffers that produce a pH in the composition similar to that of mammalian ophthalmic fluid, wherein the reduced glutathione comprises glutamic acid, cysteine ​​and glycine.

[0010] The inventors believe that there is still a need in the art to provide effective ophthalmic preparations to increase the bioavailability of cinnamic acid compounds or their derivatives, catechin compounds or their derivatives, repair cataract crystallin, reduce intraocular pressure, and thus prevent the occurrence of glaucoma.

[0011] Purpose of the Invention

[0012] Therefore, an object of the present invention is to provide an ophthalmic preparation comprising a cinnamic acid compound or a derivative thereof, a catechin compound or a derivative thereof, or a combination thereof, and an acceptable excipient, wherein the ophthalmic preparation can effectively increase the intraocular absorption of the active ingredients, thereby treating / clearing / alleviating cataractous crystalline lens proteins.

[0013] A further object is to provide an ophthalmic formulation that treats / clears / reduces intraocular pressure, thereby treating glaucoma.

[0014] Another object of the present invention is to provide an intraocular formulation that is expected to protect the vision of glaucoma patients and improve the quality of life of glaucoma patients.

[0015] Another object of the present invention is to provide a method for preparing an intraocular preparation that is expected to protect the vision of glaucoma patients and improve the quality of life of glaucoma patients. SUMMARY OF THE INVENTION

[0017] According to the above objectives, the present invention provides an ophthalmic preparation / composition comprising a cinnamic acid compound or a derivative thereof, a catechin compound or a derivative thereof, or a combination thereof; and an acceptable excipient.

[0018] Accordingly, the present invention provides an ophthalmic preparation comprising:

[0019] i. cinnamic acid compounds or their derivatives as active ingredients in a concentration range of 0.01% to 5.0% w / w; and / or

[0020] ii. catechin compounds or their derivatives as active ingredients, with a concentration range of 0.01% to 5.0% w / w;

[0021] and acceptable excipients.

[0022] In one aspect, the formulation is a powder, liquid, or gel.

[0023] In one aspect, the cinnamic acid compound is selected from cinnamic acid, coumaric acid, caffeic acid, rosmarinic acid, ferulic acid, and the like.

[0024] In one aspect, the derivatives of cinnamate are selected from alkyl / aralkyl alcohols esterified with appropriate cinnamate, which have the following general formula;

[0025] CA-CO-OR(I)

[0026] Wherein, CA = cinnamic acid, and R = C1-C22 alkyl, aryl, heteroaryl,

[0027] Ar-CH2-CH2-, carbohydrates, lipids, and CA-CO-O(CH)nO-CO-CA

[0028] Wherein, n=2-10.

[0029] The derivatives of cinnamate are selected from ethyl cinnamate, ethyl p-methoxycinnamate, butyl cinnamate, amyl cinnamate, benzyl cinnamate, phenylethyl cinnamate, tyrosol Cinnamate), hydroxy-p-hydroxyphenylethyl cinnamate, isobutyl cinnamate, cinnamyl cinnamate, phenylethyl coumarate, p-hydroxyphenylethyl coumarate, hydroxy-p-hydroxyphenylethyl coumarate, N-hexadecyl coumarate, N-octadecyl coumarate, N-docosyl coumarate, phenylethyl ferulate, p-hydroxyphenylethyl ferulate, hydroxy-p-hydroxyphenylethyl ferulate, N-hexadecyl ferulate, N-octadecyl ferulate, N-docosyl ferulate, caffeic acid phenethyl ester (CAPE), p-hydroxyphenylethyl caffeate, hydroxy-p-hydroxyphenylethyl caffeate, N-hexadecyl caffeate, N-octadecyl caffeate, N-docosyl caffeate, rosmarinic acid, cinnamic acid, coumaric acid, ferulic acid, dimer esters of caffeic acid, wherein the dimer esters are derived from C2 to C 10 Diols, etc.

[0030] In another aspect, the derivative of cinnamic acid amide is selected from amides having the following general formula;

[0031] CA-CO-NHR(II)

[0032] Wherein CA = cinnamic acid and R is C1-C22 alkyl, aryl, heteroaryl, aralkyl, lipid and carbohydrate.

[0033] The derivatives of cinnamic acid amide are selected from cinnamoyl phenethylamine, cinnamoyl p-hydroxyphenethylamine, cinnamoyl 5-hydroxytryptamine, cinnamoyl dopamine, coumaroyl phenethylamine, coumaroyl p-hydroxyphenethylamine, coumaroyl dopamine, coumaroyl 5-hydroxytryptamine, feruloyl phenethylamine, feruloyl p-hydroxyphenethylamine, feruloyl 5-hydroxytryptamine, feruloyl dopamine, caffeic acid phenethylamide (CAPA), caffeoyl p-hydroxyphenethylamine, caffeoyl 5-hydroxytryptamine, caffeoyl dopamine and the like.

[0034] In a preferred aspect, the cinnamic acid derivative is selected from cinnamic acid, caffeic acid, rosmarinic acid, ferulic acid, caffeic acid phenethylamide (CAPA), caffeic acid phenethyl ester (CAPE), feruloyl-4-hydroxyphenylethylamine, caffeoyl-4-hydroxyphenylethylamine, caffeoyl dopamine, feruloyl dopamine, alone or as a mixture thereof.

[0035] In another aspect, the catechin compound or its derivative is selected from (a) catechin: (2R,3S)-(+)-catechin; (2R,3S)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol; (b) EC: (2R,3S)-(–)-epicatechin; 2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-1-chromene-3,5,7-triol; (c) ECG: (2R,3R)-(–)-epicatechin gallate; (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-chromene-3,5,7-triol 3-(3,4,5-trihydroxybenzoate); (d)EGC: (2R,3R)-(–)-epigallocatechin; (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3 ,4-dihydro-1(2H)-benzopyran-3,5,7-triol; (e)GC: (2S,3R-(–)-gallocatechin; (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol; (f)EGCG: (2R,3R)-(–)-epigallocatechin gallate; (2R,3R)-2 -(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-chromene-3,5,7-triol 3-(3,4,5-trihydroxybenzoate); (g)GCG: (2S,3R)-(–)-gallocatechin gallate; (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-chromene-3,5,7-triol 3-(3,4,5-trihydroxybenzoate).

[0036] In one aspect, the active ingredient in the ophthalmic formulation of the present invention may be in encapsulated form or in free form.

[0037] In another aspect, acceptable excipients are selected from antioxidants, vitamins, stability enhancers / preservatives, solubilizers, buffers, isotonic pH adjusters, viscosity enhancers or modifiers, diluents, etc., which are present in appropriate proportions, with or without appropriate proportions of antioxidants and vitamins.

[0038] Accordingly, a stability enhancer / preservative selected from 2-hydroxypropyl β-cyclodextrin, a polysorbate surfactant including polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20); ethanol, benzyl alcohol, propylene glycol, polyvinyl pyrrolidone (PVP), ethylenediaminetetraacetic acid (EDTA); a buffer selected from phosphate and citrate buffers, ascorbic acid or sodium metabisulfite; a viscosity enhancer or modifier selected from carboxymethylcellulose (CMC) or an acceptable salt thereof, hyaluronic acid or an acceptable salt thereof, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), glycerol, polyethylene glycol ( PEG), xanthan gum, guar gum, gellan gum, carbomer, such as polyacrylic acid; borate buffers, such as potassium borate and potassium carbonate; phosphate buffers, including sodium phosphate and potassium phosphate, citrate buffers, such as sodium citrate or citric acid; acetate buffers, such as sodium acetate, Tris buffers, such as Tris (tris (hydroxymethyl) aminomethane; HEPES buffers, such as (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid; antioxidants selected from glutathione, N-acetylcarnosine, vitamins selected from vitamin A, vitamin E. The buffer helps maintain a pH range suitable for eye comfort and stability of the active ingredient.

[0039] In a preferred aspect, the acceptable excipients comprise a viscosity enhancer, which is carboxymethylcellulose or an acceptable salt thereof, in an amount ranging from 0.05% to 3.0% w / w, preferably, in a range of 0.2% to 2.0% w / w; or hyaluronic acid or an acceptable salt thereof, in a range from 0.05% to 1.5% w / w, preferably, in a range from 0.05 to 0.3% w / w; 2-hydroxypropyl β-cyclodextrin as an encapsulating agent or as a stabilizer, in an amount ranging from 0.1% to 15% w / w, preferably, from 1 to 5% w / w, glutathione or N-acetylcarnosine (NAC), as an antioxidant, in an amount ranging from 0.1 to 5% w / w; a surfactant selected from Tween 80, in an amount ranging from 1-10%, preferably, from 3-6% w / w, and vitamins, which are present in suitable amounts based on the total weight of the composition.

[0040] In another aspect, the present invention provides an ophthalmic formulation comprising a cinnamic acid derivative in combination with sodium hyaluronate, 2-hydroxypropyl-β-cyclodextrin, carboxymethylcellulose or an acceptable salt, potassium carbonate and potassium borate buffer, optionally containing N-acetylcarnosine or glutathione and vitamins, which are present in suitable amounts.

[0041] In another aspect, the present invention provides an ophthalmic formulation comprising rosmarinic acid in combination with 2-hydroxypropyl β-cyclodextrin, sodium hyaluronate, carboxymethylcellulose or a suitable salt, potassium carbonate and potassium borate buffer, optionally containing N-acetylcarnosine or glutathione and vitamins, which are present in suitable amounts.

[0042] In another aspect, the present invention provides an ophthalmic formulation comprising caffeic acid in combination with 2-hydroxypropyl-β-cyclodextrin, hyaluronic acid or a suitable salt, carboxymethylcellulose or a suitable salt, potassium carbonate and potassium borate buffer, optionally containing N-acetylcarnosine or glutathione and vitamins, present in suitable amounts.

[0043] In another aspect, the present invention provides an ophthalmic formulation comprising caffeic acid phenethylamide (CAPA) in combination with 2-hydroxypropyl-β-cyclodextrin, sodium hyaluronate, carboxymethylcellulose or a suitable salt, potassium carbonate and potassium borate buffer, optionally containing N-acetylcarnosine or glutathione and vitamins, which are present in suitable amounts.

[0044] In another aspect, the present invention provides an ophthalmic formulation comprising caffeic acid phenethyl ester (CAPE) in combination with 2-hydroxypropyl-β-cyclodextrin, hyaluronic acid or a suitable salt, carboxymethylcellulose or a suitable salt, potassium carbonate and potassium borate buffer, optionally containing N-acetylcarnosine or glutathione and vitamins, which are present in suitable amounts.

[0045] In another aspect, the present invention provides an ophthalmic formulation comprising caffeoyl-p-hydroxyphenylethylamine in combination with 2-hydroxypropyl-β-cyclodextrin, hyaluronic acid or a suitable salt, carboxymethylcellulose or a suitable salt, potassium carbonate and potassium borate buffer, optionally containing N-acetylcarnosine or glutathione and vitamins, which are present in suitable amounts.

[0046] In another aspect, the present invention provides an ophthalmic formulation comprising ferulic acid in combination with 2-hydroxypropyl-β-cyclodextrin, hyaluronic acid or a suitable salt, carboxymethylcellulose or a suitable salt, potassium carbonate and potassium borate buffer, optionally containing N-acetylcarnosine or glutathione and vitamins, which are present in suitable amounts.

[0047] In another aspect, the present invention provides an ophthalmic formulation comprising feruloyl-p-hydroxyphenylethylamine in combination with 2-hydroxypropyl-β-cyclodextrin, hyaluronic acid or a suitable salt, carboxymethylcellulose or a suitable salt, potassium carbonate and potassium borate buffer, optionally containing N-acetylcarnosine or glutathione and vitamins, which are present in suitable amounts.

[0048] In another aspect, the present invention provides an ophthalmic formulation comprising epigallocatechin gallate (EGCG) in combination with 2-hydroxypropyl-β-cyclodextrin, hyaluronic acid or a suitable salt, carboxymethylcellulose or a suitable salt, potassium carbonate and potassium borate buffer, optionally containing N-acetylcarnosine or glutathione and vitamins, which are present in suitable amounts.

[0049] In another aspect, the present invention provides a method for preparing an ophthalmic preparation, comprising the following steps:

[0050] i. at a temperature range of 25-75°C, containing cinnamic acid compounds or their derivatives and / or catechin compounds

[0051] The active ingredient of or its derivatives is dissolved in sterile water;

[0052] ii. At 25-75 ° C, an acceptable excipient is added to the solution of step (i) and the mixture is stirred;

[0053] iii. Adjust the isotonic pH to within the range of 6.2-7.6 with a mixture of alkali and buffer; and stir to form a clear, homogeneous

[0054] a homogeneous mixture; and

[0055] iv. Packing and storing the ophthalmic grade formulation of step (iii) at 2 to 40°C.

[0056] In one aspect, the active ingredient used in the method of preparing the ophthalmic formulation can be in encapsulated form or in free form. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 Representative images of histopathology results are depicted:

[0058] 1a) Cornea (uninduced, untreated, right eye): 1b) Cornea (induced, untreated, left eye, G1); 1c) Cornea (induced, treated, left eye, G2); 1d) Cornea (induced, treated, left eye, G3); 1e) Cornea (induced, treated, left eye, G4); 1f) Cornea (induced, treated, left eye, G5): 1g) Lens (uninduced, untreated, right eye); 1h) Lens (induced, untreated, left eye, G1): 1i) Lens (induced, treated, left eye, G2); 1j) Lens (induced, treated, left eye, G3); 1k) Lens (induced, treated, left eye, G4): 1l) Lens (induced, treated, left eye, G5):

[0059] Figure 2 Representative images of cataracts from two animals per group during induction and treatment are shown: 2a&2b) uninduced, untreated, right eye; 2c&2d) induced, untreated, G1, left eye; 2e&2f) induced, treated, G2, left eye; 2g&2h) induced, treated, G3, left eye; 2i&2j) induced, treated, G4, left eye; 2k&2l) induced, treated, G5, left eye.

[0060] Detailed Description of Preferred Embodiments

[0061] The invention will now be described in detail in conjunction with certain preferred and optional embodiments so that its various aspects may be more fully understood and appreciated.

[0062] The present invention provides an ophthalmic formulation that can be applied to the eye or taken in the form of an injection or oral administration. The formulation / composition is used to treat / clear / reduce cataracts, intraocular pressure, and glaucoma. The ophthalmic formulation of the present invention allows the active ingredient to directly penetrate the corneal and conjunctival epithelium, thereby reducing the required dosage and making it a patient-friendly option. The formulation / composition is used to treat / clear / reduce cataracts, intraocular pressure, and glaucoma.

[0063] In one embodiment, the present invention relates to an ophthalmic formulation comprising;

[0064] i. cinnamic acid compounds or their derivatives as active ingredients; and / or

[0065] ii. catechin compounds or their derivatives as active ingredients.

[0066] The active ingredient in the ophthalmic formulations of the present invention is present in an amount between 0.01% and 5.0% w / w.

[0067] The ophthalmic preparation of the present invention may further comprise an acceptable excipient.

[0068] In another embodiment, the present invention relates to an ophthalmic composition / formulation comprising

[0069] i. cinnamic acid compounds or their derivatives as active ingredients in a concentration range of 0.01% to 5.0% w / w; and / or

[0070] ii. catechin compounds or their derivatives as active ingredients, with a concentration range of 0.01% to 5.0% w / w;

[0071] and acceptable excipients.

[0072] In one aspect, the cinnamic acid compound is selected from cinnamic acid, coumaric acid, caffeic acid, rosmarinic acid, ferulic acid, and the like.

[0073] In one embodiment, the ophthalmic formulations of the present invention are administered topically, orally, or by injection.

[0074] In one embodiment, the formulation of the invention is a powder, liquid or gel.

[0075] In one embodiment, the cinnamate derivatives are selected from alkyl / aralkyl alcohols esterified with appropriate cinnamate and having the general formula

[0076] CA-CO-OR(I)

[0077] Wherein, CA = cinnamic acid, and R = C1-C22 alkyl, aryl, heteroaryl,

[0078] Ar-CH2-CH2-, carbohydrates, lipids, and CA-CO-O(CH)nO-CO-CA

[0079] Wherein, n=2-10.

[0080] The derivatives of cinnamate are selected from ethyl cinnamate, ethyl p-methoxycinnamate, butyl cinnamate, amyl cinnamate, benzyl cinnamate, phenylethyl cinnamate, p-hydroxyphenylethyl cinnamate, hydroxy-p-hydroxyphenylethyl cinnamate, isobutyl cinnamate, cinnamyl cinnamate, phenylethyl coumarate, p-hydroxyphenylethyl coumarate, hydroxy-p-hydroxyphenylethyl coumarate, N-hexadecyl coumarate, N-octadecyl coumarate, N-behenyl coumarate, phenylethyl ferulate, ferulic acid p-Hydroxyphenyl ethyl ester, hydroxy-p-hydroxyphenyl ethyl ferulate, N-hexadecyl ferulate, N-octadecyl ferulate, N-behenyl ferulate, caffeic acid phenylethyl ester (CAPE), caffeic acid p-hydroxyphenyl ethyl ester, hydroxy-p-hydroxyphenyl ethyl ferulate, caffeic acid N-hexadecyl ester, caffeic acid N-octadecyl ester, caffeic acid N-behenyl ester, rosmarinic acid, cinnamic acid, coumaric acid, ferulic acid, dimer esters of caffeic acid, wherein the dimer esters are derived from C2 to C 10 Diols, etc.

[0081] In yet another embodiment, the derivatives of cinnamic acid amide are selected from amides having the general formula

[0082] CA-CO-NHR(II)

[0083] in,

[0084] CA = cinnamic acid, and R is C1-C22 alkyl, aryl, heteroaryl, aralkyl, lipid, and carbohydrate.

[0085] The derivatives of cinnamic acid amide are selected from cinnamoyl phenethylamine, cinnamoyl p-hydroxyphenethylamine, cinnamoyl 5-hydroxytryptamine, cinnamoyl dopamine, coumaroyl phenethylamine, coumaroyl p-hydroxyphenethylamine, coumaroyl dopamine, coumaroyl 5-hydroxytryptamine, feruloyl phenethylamine, feruloyl p-hydroxyphenethylamine, feruloyl 5-hydroxytryptamine, feruloyl dopamine, caffeic acid phenethylamide (CAPA), caffeoyl p-hydroxyphenethylamine, caffeoyl 5-hydroxytryptamine, caffeoyl dopamine and the like.

[0086] In a preferred embodiment, the cinnamic acid derivative as an active ingredient is selected from rosmarinic acid, caffeic acid, ferulic acid, isoferulic acid, homoferulic acid, coumaric acid, 4-methyl-cinnamic acid, 4-aminocinnamic acid, 4-methoxy-cinnamic acid, caffeic acid, 3-hydroxy-4-n-propoxycinnamic acid, sinapinic acid, chlorogenic acid, syringic acid, p-coumaric acid and the like.

[0087] In another embodiment, the catechin compound or its derivative is selected from (a) catechin: (2R,3S)-(+)-catechin; (2R,3S)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol; (b) EC: (2R,3S)-(–)-epicatechin; 2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7 -triol; (c) ECG: (2R,3R)-(–)-epicatechin gallate; (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-chromene-3,5,7-triol 3-(3,4,5-trihydroxybenzoate); (d) EGC: (2R,3R)-(–)-epigallocatechin; (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3 ,4-dihydro-1(2H)-benzopyran-3,5,7-triol; (e)GC: (2S,3R-(–)-gallocatechin; (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol; (f)EGCG: (2R,3R)-(–)-epigallocatechin gallate; (2R,3R)-2-(3,4,5 -trihydroxyphenyl)-3,4-dihydro-1(2H)-chromene-3,5,7-triol 3-(3,4,5-trihydroxybenzoate); (g)GCG: (2S,3R)-(–)-gallocatechin gallate; (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-chromene-3,5,7-triol 3-(3,4,5-trihydroxybenzoate).

[0088] In one embodiment, the active ingredient in the ophthalmic preparation of the present invention may be in encapsulated form or in free form.

[0089] Acceptable excipients are selected from stability enhancers / preservatives, solubilizers, buffers, isotonic pH adjusters, viscosity enhancers or modifiers, diluents, encapsulating agents, antioxidants, vitamins, etc., which are present in appropriate proportions.

[0090] Accordingly, a stability enhancer / preservative selected from 2-hydroxypropyl-β-cyclodextrin, a polysorbate surfactant including polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20), ethanol, benzyl alcohol, propylene glycol, polyvinyl pyrrolidone (PVP), ethylenediaminetetraacetic acid (EDTA); a viscosity enhancer or modifier selected from carboxymethylcellulose (CMC) or an acceptable salt thereof, hyaluronic acid or an acceptable salt thereof, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), glycerol, polyethylene glycol (PEG), xanthan gum, guar gum, gellan gum , carbomer, such as polyacrylic acid; a buffer selected from phosphate buffers, including sodium phosphate and potassium phosphate; a citrate buffer selected from sodium citrate or citric acid; a borate buffer, such as potassium borate; an acetate buffer, such as sodium acetate, a Tris buffer, such as Tris (tris (hydroxymethyl) aminomethane; a HEPES buffer, such as (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid; ascorbic acid; sodium metabisulfite; potassium carbonate; an antioxidant selected from glutathione and N-acetylcarnosine. The buffer helps maintain an isotonic pH range suitable for eye comfort and stability of the active ingredient.

[0091] In a preferred aspect, the acceptable excipients comprise a viscosity enhancer consisting of carboxymethylcellulose or an acceptable salt thereof in an amount ranging from 0.05% to 5.0% w / w, preferably, ranging from 0.2% to 2.0% w / w; or hyaluronic acid or an acceptable salt thereof in an amount ranging from 0.05% to 1.5% w / w, preferably, ranging from 0.05 to 0.3% w / w; glutathione or N-acetylcarnosine (NAC) as an antioxidant in an amount ranging from 0.1 to 5% w / w; 2-hydroxypropyl-β-cyclodextrin as an encapsulating agent or as a stabilizer in an amount ranging from 0.1% to 15% w / w, preferably, from 1 to 5% w / w; a surfactant selected from Tween 80 in an amount ranging from 1-10% w / w, preferably, from 3-6% w / w, vitamins 0.5-6% w / w, etc., which are present in a suitable proportion based on the total weight of the composition.

[0092] According to the present invention, one of the suitable formulations advantageously comprises the following ingredients in the given amounts: rosmarinic acid 0.5% w / w; sodium carboxymethylcellulose 0.3% w / w; sodium hyaluronate 0.1% w / w; 2-hydroxypropyl-β-cyclodextrin 1% w / w; and sodium borate, potassium bicarbonate, or any other suitable buffer required to adjust the pH value of the ophthalmic formulation to a pH range of 6.2 to 7.6, sterile water.

[0093] In one embodiment, the present invention relates to an ophthalmic formulation comprising:

[0094] i. 0.5% w / w rosmarinic acid;

[0095] ii. 0.3% w / w sodium carboxymethylcellulose, 0.1% w / w sodium hyaluronate; 1% w / w 2-hydroxypropyl-β-cyclodextrin;

[0096] iii. Sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic preparation to a pH range of 6.2 to 7.6

[0097] within; and

[0098] iv. Sterile water.

[0099] In another embodiment, the present invention relates to an ophthalmic formulation comprising;

[0100] i. 0.5% w / w caffeic acid;

[0101] ii. 0.3% w / w sodium carboxymethylcellulose; 0.1% w / w sodium hyaluronate; 1% w / w 2-hydroxypropyl-β-cyclodextrin;

[0102] iii. Sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic preparation to a pH range of 6.2 to 7.6

[0103] within; and

[0104] iv. Sterile water.

[0105] In a further embodiment, the present invention relates to an ophthalmic formulation comprising;

[0106] i. 0.5% w / w of encapsulated feruloyl-4-hydroxyphenylethylamine,

[0107] ii. 0.3% w / w sodium carboxymethylcellulose; 0.1% w / w sodium hyaluronate; 2.32% w / w 2-hydroxypropyl-β-cyclodextrin;

[0108] iii. sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic preparation to a pH range of 6.2 to 7.6;

[0109] iv. 6% w / w Tween 80; and

[0110] v.Sterile water.

[0111] In another embodiment, the present invention discloses an ophthalmic formulation comprising:

[0112] i. 0.5% w / w ferulic acid;

[0113] ii. 0.3% w / w sodium carboxymethylcellulose, 0.1% w / w sodium hyaluronate, 1% w / w 2-hydroxypropyl-β-cyclodextrin;

[0114] iii. Sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic preparation to a pH range of 6.2 to 7.6

[0115] within; and

[0116] iv. Sterile water.

[0117] In another embodiment, the present invention relates to an ophthalmic formulation comprising;

[0118] i. 0.5% w / w caffeic acid phenethyl ester (CAPE),

[0119] ii. 0.3% w / w sodium carboxymethylcellulose; 0.1% w / w sodium hyaluronate; 2.05% w / w 2-hydroxypropyl-β-cyclodextrin;

[0120] iii. Sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic preparation to a pH range of 6.2 to 7.6

[0121] within; and

[0122] iv. Sterile water.

[0123] In another embodiment, the present invention relates to an ophthalmic formulation comprising:

[0124] i. 0.5% w / w caffeic acid phenethylamide (CAPA);

[0125] ii. 0.3% w / w sodium carboxymethylcellulose; 0.1% w / w sodium hyaluronate; 2.16% w / w 2-hydroxypropyl-β-cyclodextrin;

[0126] iii. sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic formulation to a pH within the range of 6.2 to 7.6; and

[0127] iv. Sterile water.

[0128] In another embodiment, the present invention relates to an ophthalmic formulation comprising;

[0129] i. 0.5% w / w rosmarinic acid;

[0130] ii. 0.25% w / w caffeic acid;

[0131] iii. 0.3% w / w sodium carboxymethylcellulose, 0.1% w / w sodium hyaluronate, 1% w / w 2-hydroxypropyl-β-cyclodextrin;

[0132] iv. sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic formulation to a pH within the range of 6.2 to 7.6; and

[0133] v.Sterile water.

[0134] In one embodiment, the present invention relates to an ophthalmic formulation comprising;

[0135] i. 0.15-0.5% w / w rosmarinic acid;

[0136] ii. 0.25-0.5% w / w caffeic acid;

[0137] iii. 0.15-0.5% w / w feruloyl-4-hydroxyphenylethylamine;

[0138] iv. 0.3% w / w sodium carboxymethylcellulose, 0.1% w / w sodium hyaluronate, 1% w / w 2-hydroxypropyl β-cyclodextrin;

[0139] v. sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic preparation to a pH within the range of 6.2 to 7.6;

[0140] vi. 6% Tween 80; and

[0141] vii. Sterile water.

[0142] In another embodiment, the present invention relates to an ophthalmic formulation comprising;

[0143] i. 0.15-0.5% w / w rosmarinic acid;

[0144] ii. 0.15-0.5% w / w caffeic acid;

[0145] iii. 0.15-0.5% w / w feruloyl-4-hydroxyphenylethylamine;

[0146] iv. 0.15-0.5% w / w epigalactocatechin gallate;

[0147] v.0.3% w / w sodium carboxymethylcellulose, 0.1% w / w sodium hyaluronate, 1% w / w 2-hydroxypropyl β-cyclodextrin;

[0148] vi. sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic preparation to a pH within the range of 6.2 to 7.6;

[0149] vii. 8% Tween 20; and

[0150] viii. Sterile water.

[0151] In one embodiment, the present invention relates to an ophthalmic formulation comprising:

[0152] i. 0.25-0.5% w / w epigalactocatechin gallate;

[0153] ii. 0.3% w / w sodium carboxymethylcellulose, 0.1% w / w sodium hyaluronate, 1% w / w 2-hydroxypropyl-β-cyclodextrin;

[0154] iii. Sodium borate and potassium bicarbonate in appropriate proportions to adjust the pH of the ophthalmic preparation to a pH range of 6.2 to 7.6

[0155] within; and

[0156] iv. Sterile water.

[0157] In one embodiment, the ophthalmic composition / formulation of the present invention enhances the absorption of the active ingredient in the eye, thereby treating / clearing / reducing cataract crystal protein, intraocular pressure and glaucoma

[0158] In one embodiment, the ophthalmic preparation of the present invention comprises rosmarinic acid used at a much lower concentration than compositions / preparations known in the art. MARINA CHEMEROVSKI-GLIKMAN1 et al. published an article in the journal Nature entitled "Rosmarinic acid restores complete transparency of ultrasound-treated human cataracts in in vitro experiments and delays cataract formation in in vivo experiments", June 2018, pages 6-7, in which rats were treated with subcutaneous injections of rosmarinic acid. The article discloses subcutaneous injection of high concentrations of rosmarinic acid (40mM, 500μl, i.e., 1.4% concentration, with a dose of 7mg / 0.5ml per injection) in rats to treat cataracts, while the ophthalmic preparation provided in the present invention comprises a significantly lower concentration of 0.5% rosmarinic acid, and the dose for ocular administration is 0.5mg / 100μl.

[0159] In one embodiment, the ophthalmic preparation of the present invention enhances the intraocular absorption of the active ingredient, thereby treating / eliminating / alleviating cataract protein. In addition, it helps to reduce intraocular pressure, providing an effective method for treating / eliminating / eliminating glaucoma.

[0160] In one embodiment, encapsulation of rosmarinic acid with 2-hydroxy-β-cyclodextrin improves stability, solubility, and gradual release, lowering intraocular pressure, increasing aqueous humor outflow, and potentially treating glaucoma.

[0161] In yet another embodiment, the present invention discloses a general method for preparing an ophthalmic formulation, comprising the following steps:

[0162] i. at a temperature range of 25-75°C, containing cinnamic acid compounds or their derivatives and / or catechins

[0163] The active ingredient of the compound or its derivative is dissolved in sterile water;

[0164] ii. At 25-75 ° C, an acceptable excipient is added to the solution of step (i) and the mixture is stirred;

[0165] iii. Adjust the pH to within the range of 6.2-7.6 with a mixture of base and buffer; and stir to form a clear and uniform mixture

[0166] things; and

[0167] iv. Packing and storing the ophthalmic grade formulation of step (iii) at 2 to 40°C.

[0168] In one embodiment, the active ingredient may be in encapsulated form or in free form.

[0169] Accordingly, the present invention provides a method for preparing an ophthalmic preparation, which comprises dissolving an active ingredient comprising a cinnamic acid compound or its derivative and / or a catechin compound or its derivative in free form in 100 mL of sterile water while stirring at a temperature range of 25-75° C. A suitable active excipient is then added to the solution and the suspension is stirred continuously at room temperature for 2 hours. Subsequently, the pH value of the resulting suspension is carefully adjusted to within the range of 6.2-7.6 using a mixture of potassium carbonate and potassium borate buffer. After achieving the desired pH, the solution is stirred continuously for an additional 30 minutes until a clear and uniform consistency is achieved. The final ophthalmic grade sterile preparation is packaged, labeled, and stored under controlled conditions at a temperature range of 2-40° C.

[0170] In another embodiment, the present invention discloses a method for preparing an ophthalmic formulation, comprising adding an encapsulated active ingredient to 100 mL of sterile water at a controlled temperature of 65-75°C. The formulation excipients are then added to the solution. The resulting suspension is stirred at 65-75°C for 12 hours. The pH of the suspension is then adjusted to a range of 6.2-7.6 using a mixture of potassium carbonate and potassium borate buffers. pH adjustment is a critical step to ensure the stability of the ophthalmic formulation. To aid in the dissolution of the encapsulated feruloyl-4-hydroxyphenylethylamine, 6.0 g of Tween 80 is introduced into the sterile water. The solution is then stirred at 65-75°C for 30 minutes until the desired clarity and homogeneity are achieved. Upon successful completion of the process, the solution is cooled to room temperature, and the sterile encapsulated feruloyl-4-hydroxyphenylethylamine-based formulation is packaged, labeled, and stored at 2-40°C.

[0171] In yet another embodiment, the present invention provides an ophthalmic preparation / composition comprising a cinnamic acid compound or a derivative thereof, a catechin compound or a derivative thereof, or a combination thereof as an active ingredient, and an acceptable excipient, wherein the preparation enhances the absorption of the active ingredient in the eye, thereby helping to treat / clear / mitigate crystalline proteins affected by cataracts, helping to reduce intraocular pressure, and effectively preventing glaucoma.

[0172] In one embodiment, the present invention discloses an ophthalmic formulation, wherein the formulation / composition is used to treat / eliminate / reduce: cataractous lens, intraocular pressure, glaucoma, lenticular degeneration, corneal epithelial hyperplasia / liquefaction / inflammation.

[0173] In another embodiment, the present invention relates to a method for treating / removing / reducing cataractous lens, intraocular pressure, glaucoma, lenticular degeneration, corneal epithelial hyperplasia / liquefaction / inflammation and their occurrence / recurrence, which method comprises applying / administering an ophthalmic preparation to a subject in need thereof.

[0174] The ophthalmic preparation of the present invention comprises an active ingredient selected from cinnamic acid compounds or their derivatives alone; or catechin compounds or their derivatives alone; or a combination thereof, and the preparation provides the following benefits:

[0175] Increased aqueous humor outflow and lowered intraocular pressure (IOP): By promoting efficient drainage of aqueous humor, these preparations target the regulation of intraocular pressure (IOP).

[0176] Reduced ocular inflammation: One of the expected effects is a reduction in intraocular inflammation, particularly when associated with elevated IOP.

[0177] Providing neuroprotection to retinal ganglion cells: These agents are designed to provide neuroprotection to retinal ganglion cells, which are critical for supporting vision and may help lower IOP to prevent glaucoma.

[0178] Antioxidant properties: Their mechanism of action includes protecting trabecular meshwork cells from oxidative damage, thereby maintaining normal fluid drainage and removing cataract-forming proteins, offering further potential benefits for ocular health.

[0179] Reduce lenticular degeneration.

[0180] Reduce epithelial proliferation.

[0181] Reduce corneal liquefaction.

[0182] The following examples, including preferred embodiments, will illustrate the practice of the invention, it being understood that the details shown are by way of example and for purposes of illustrative discussion of preferred embodiments of the invention.

[0183] Example 1:

[0184] The following table describes various ophthalmic formulations of the present invention.

[0185] (Table: 1)

[0186]

[0187]

[0188]

[0189] Example 2:

[0190] A: General method for the preparation of ophthalmic formulations as disclosed in Table 1.

[0191] An appropriate amount of the active ingredient is dissolved in 100 mL of sterile water at a temperature of 25-30°C while stirring. The appropriate proportions of excipients are then added to the solution, and the suspension is stirred continuously at room temperature for 2 hours. Subsequently, the pH of the resulting suspension is carefully adjusted to a range of 6.2-7.6 using a mixture of a base and a buffer. After achieving the desired pH, the solution is stirred for an additional 30 minutes until it reaches a clear and uniform consistency. The final sterile formulation is packaged, labeled, and stored under controlled conditions at a temperature of 2-40°C.

[0192] B: General method for the preparation of ophthalmic formulations containing encapsulated active ingredients.

[0193] 2-Hydroxypropyl-β-cyclodextrin is added to the active ingredient and ground to obtain the encapsulated active ingredient. The encapsulated active ingredient is then added to 100 mL of sterile water at a controlled temperature of 65-75°C. Appropriate formulation excipients are then added to the solution. The resulting suspension is stirred at 65-75°C for 12 hours. The pH of the suspension is then adjusted to a range of 6.2-7.6 using a mixture of an appropriate base and buffer. pH adjustment is a critical step to ensure the stability of the ophthalmic formulation. To aid in dissolving the encapsulated active ingredient, an appropriate amount of surfactant is added to the sterile water. The solution is then stirred at 65-75°C for an additional 30 minutes until the desired clarity and homogeneity are achieved. Upon successful completion of the process, the solution is cooled to room temperature, and the sterile encapsulated active base formulation is packaged, labeled, and stored at 2-40°C.

[0194] Illustrative ophthalmic formulations for treating eye diseases are as follows: The formulations provided below were tested in New Zealand rabbits with induced cataracts and the results are discussed below.

[0195] The following preclinical studies were conducted in a rabbit model to test the efficacy of various active ingredients.

[0196] Cataract induction and increased intraocular pressure leading to glaucoma

[0197] Cataracts were induced by injecting 0.5% methylcellulose, which replaces the aqueous humor in the rabbit eyes (i.e., 0.2 mL of aqueous humor was removed and the same 0.2 mL of 0.5% methylcellulose was injected as a replacement). Cataracts were observed within 3-4 days after 0.5% methylcellulose replacement. Cataracts were induced in the left eye, and the right eye served as a control.

[0198] Cataract and glaucoma induction and confirmation

[0199] The rabbits were observed every three days using an ophthalmoscope and a slit lamp to confirm the presence of cataracts, and the intraocular pressure was measured every three days using a tonometer to confirm the presence of glaucoma.

[0200] Preparation details: (Table: 2)

[0201]

[0202]

[0203] NOTE: Inject 50 μL into each left eye and, after an interval of 3-5 minutes, instill 50 μL into the same eye again.

[0204] Route and principle of administration

[0205] The test article formulations were administered via the ocular route. The ocular route was chosen because it is the intended route of administration in humans.

[0206] Dosage

[0207] All test formulations provided above were applied topically as therapeutic treatment. A total of 100 μL / rabbit of placebo or rosmarinic acid formulations (F1, F2, F3 and F4) were instilled twice at 50 μL / eye (left) for 28 days.

[0208] Macroscopic observation:

[0209] The following observations were made during the study.

[0210] (Table: 3)

[0211]

[0212] Note: Cataracts were induced only in the left eye of all animals; the right eye was completely normal. The conclusions presented in the table above refer to the left eye in which cataracts were induced. Cataract development was monitored based on lenticular degeneration and epithelial hyperplasia.

[0213] Microscopic observation (histopathology):

[0214] All surviving animals were euthanized on day 29 by an overdose of sodium thiopental. Prior to planned euthanasia, animals were fasted overnight (water was allowed) and final body weights were recorded. Detailed macroscopic observations of the animals were performed during necropsy. Right eyes (untreated / uninduced) and left eyes (treated / induced) were collected and the corneas and lenses were isolated and preserved in Davidson's fixative. The corneas and lenses selected for histopathological evaluation were processed, embedded, and sections were cut at a thickness of 3-5 μm, placed on grease-free slides, and stained with hematoxylin and eosin. Microscopic findings were ranked using a 5-level grading system of minimal, mild, moderate, significant, and severe for comparison between groups. Data were compiled according to the occurrence and severity of the changes.

[0215] Main group / formulation: G1 / placebo control (I072 / 001-I072 / 006) / sex: male (Table: 4)

[0216]

[0217]

[0218] Main group / formulation: G2 / F1 (I072 / 007-I072 / 012) (Table: 5)

[0219]

[0220] Main group / formulation: G3 / F2 (I072 / 013-I072 / 018) (Table: 6)

[0221]

[0222] Main group / formulation: G4 / F3 (I072 / 019-I072 / 024) (Table: 7)

[0223]

[0224]

[0225] Main group / formulation: G5 / F4 (I072 / 025-I072 / 030) (Table: 8)

[0226]

[0227] Right eye - uninduced / untreated; left eye - induced / treated Key: W = severity of lesion within normal histological limits - 1+ - minimal, 2+ - mild, 3+ - moderate, 4+ - marked, 5+ - severe.

[0228] Intraocular pressure: Sex: Male Animal number / Group: (Table: 9)

[0229]

[0230]

[0231] NIL = not statistically significant, ↑ = significantly higher, P ≤ 0.05, ↓ = significantly lower, P ≤ 0.05, ↓↓ = significantly lower, P ≤ 0.01, ↑↑ = significantly higher, values ​​are means and mean % difference compared with corresponding controls.

[0232] Preparation details: (Table: 10)

[0233]

[0234] Macroscopic examination: (Table 11)

[0235]

[0236]

[0237] Microscopic observation (histopathology): (Table: 12)

[0238]

[0239] Intraocular pressure

[0240] Intraocular pressure (IOP) was measured every three days in each group of animals using a tonometer. Readings were recorded for each eye. Intraocular pressure (IOP) was significantly reduced (P ≤ 0.01) on day 36 in all animals treated with the cinnamic acid derivative.

[0241] Sex: Male, Animal No. / Group 6 (Table: 13)

[0242]

[0243]

[0244] NIL = not statistically significant, ↑ = significantly higher, P ≤ 0.05, ↓ = significantly lower, P ≤ 0.05, ↓↓ = significantly lower, P ≤ 0.01, ↑↑ = significantly higher, P ≤ 0.01 Values ​​are means and mean % difference compared to corresponding controls.

[0245] Preparation details: (Table: 14)

[0246]

[0247] Macroscopic examination: (Table 15)

[0248] Overall results G1 G2 G3 G4 G5 G6 Right eye (uninduced) No abnormalities detected 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 Left eye (cataract induced) No abnormalities detected 0 / 6 4 / 6 6 / 6 6 / 6 6 / 6 6 / 6 Turbidity, cornea, diffuse lightest - 2 / 6 - - - - slight 3 / 6 - - - - - medium 3 / 6 - - - - -

[0249] Microscopic examination (histopathology): (Table: 16)

[0250] Histopathological results G1 G2 G3 G4 G5 G6 Right eye - uninduced No abnormalities 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 6 / 6 Left eye - induced No abnormalities 0 / 6 1 / 6 1 / 6 - 1 / 6 - lens liquefaction lightest - 2 / 6 5 / 6 - 2 / 6 1 / 6 slight 2 / 6 - - 6 / 6 1 / 6 4 / 6 medium - 2 / 6 - - 1 / 6 1 / 6 significant - - - - - - serious 4 / 6 1 / 5 - - 1 / 5 - Epithelial hyperplasia serious 4 / 6 - - - 1 / 5 - cornea edema slight - 1 / 6 - - - - inflammation lightest 1 / 6 - - - - - slight - - - 1 / 6 - - medium 1 / 6 - - - - -

[0251] Intraocular pressure: Sex: Male\Animal number / Group 6 (Table: 17)

[0252]

[0253]

[0254] NIL = not statistically significant, ↑ = significantly higher, P ≤ 0.05, ↓ = significantly lower, P ≤ 0.05, ↓↓ = significantly lower, P ≤ 0.01, ↑↑ = significantly higher, P ≤ 0.01, values ​​are means and mean % difference compared with corresponding controls.

[0255] Detailed description of efficacy study:

[0256] Macroscopic examination showed no abnormalities in all six animals treated with 0.5% rosmarinic acid (Table 3, Group G5).

[0257] Microscopic examination showed that liquefaction in the lens was within histological limits in 4 animals, while minimal liquefaction was observed in 2 animals. In 5 animals, epithelial hyperplasia of the lens was within histological limits, indicating a positive effect. In this case, only one animal showed minimal epithelial hyperplasia (Table 8, Group G5).

[0258] Furthermore, when the cornea was evaluated, corneal edema was found to be within histological limits in 5 animals and minimal corneal edema was observed in 1 animal (Table 8, Group G5).

[0259] In the glaucoma-induced left eye, the intraocular pressure was initially measured at 59.72 mmHg within 6 days, while the uninduced right eye maintained a normal intraocular pressure of 19.11 mmHg (Table 9, G5 group). This was in stark contrast to the untreated placebo group, in which the intraocular pressure remained unchanged. After a 28-day treatment regimen with 0.5% rosmarinic acid, the intraocular pressure of the induced left eye decreased dramatically from 59.72 mmHg to 20.06 mmHg (Table 9, G5 group). This significant reduction in intraocular pressure demonstrates the efficacy of rosmarinic acid in controlling intraocular pressure and preventing glaucoma.

[0260] Rosmarinic acid (0.5%) as an active ingredient is effective not only in preventing lens liquefaction, epithelial hyperplasia and corneal edema and treating cataracts, but also in reducing intraocular pressure.

[0261] Further efficacy studies involve investigating the efficacy of rosmarinic acid, caffeic acid, caffeic acid phenethyl ester (CAPE), caffeic acid phenethylamide (CAPA), caffeoyl-p-hydroxyphenylethylamine, a combination of rosmarinic caffeic acid, epigallocatechin gallate, encapsulated feruloyl-p-hydroxyphenylethylamine, and ferulic acid.

[0262] 0.5% rosmarinic acid in group G2 and 0.25% caffeic acid in group G6 proved optimal. In group G2, macroscopic examination revealed minimal corneal opacity in some animals, while one animal showed no abnormalities (Table 11, G2). Histopathology revealed that all animals were within histological limits. However, lens studies revealed minimal lenticular degeneration in four animals, as well as varying levels of epithelial hyperplasia and liquefaction (Table 12, G2).

[0263] In the G6 group, animals treated with 0.25% caffeic acid showed similar results for corneal opacity, but a higher incidence of lentiform degeneration (Table 12, G6). The study concluded that 0.5% rosmarinic acid demonstrated excellent efficacy, while 0.25% caffeic acid also showed promise, prompting plans to increase its concentration in further studies.

[0264] Caffeic acid (Group G3): This preparation showed the best results, with significant efficacy not only in alleviating cataracts but also in resolving glaucoma.

[0265] Cataract Efficacy: Macroscopic observation showed that all six animals had fully recovered, with no cataracts observed (Table 15, G3). Histopathology showed that in five of the six animals, the cells in the lens that had undergone degeneration due to cataract induction had completely regenerated, ranging from severe degeneration to the mildest grade. One animal showed complete recovery, with the eye appearing normal, similar to the uninduced right eye (Table 16, G3).

[0266] IOP and Glaucoma Efficacy: In the IOP-induced left eyes, the initial intraocular pressure (IOP) of 6 animals was measured to be 41.5 mmHg within 3 days, while the uninduced right eyes maintained a normal IOP of 16.83 mmHg, compared to an initial IOP of 73.22 and a final IOP of 57.00 mmHg in the untreated placebo group. However, after a 28-day treatment regimen of 0.5% caffeic acid, the IOP of the induced left eyes dropped dramatically from 41.50 mmHg to 21.11 mmHg. This significant reduction in IOP demonstrates the significant efficacy of caffeic acid in the direct treatment of glaucoma (Table 17, G3).

[0267] In summary, caffeic acid (G3) not only performs well in alleviating cataracts but also demonstrates a remarkable ability in lowering intraocular pressure, thereby preventing glaucoma, making it a promising drug candidate for both ocular conditions.

[0268] Epigallocatechin gallate (Group G4): This formulation demonstrated excellent efficacy in alleviating cataracts and also showed a significant ability to address glaucoma.

[0269] Cataract Efficacy: Macroscopic observation showed that all 6 animals recovered completely, with no cataracts observed (Table 15, G4). Histopathological results showed that in all 6 of the 6 animals, the lens cells initially affected by cataract induction fully recovered or regenerated, transitioning from a severe degeneration to a mild state. Only one animal showed mild corneal inflammation, which was a relatively minor problem given the overall reduction in cataract severity (Table 16, G4).

[0270] IOP and Glaucoma Efficacy: In the glaucoma-induced left eyes, the mean intraocular pressure of 6 animals was initially measured as high as 29.72 mmHg over 3 days, while the uninduced right eyes maintained a normal intraocular pressure of 18.11 mmHg. However, after a 28-day treatment regimen with 0.5% epigallocatechin gallate, the intraocular pressure in the induced left eyes dropped dramatically from 29.72 mmHg to 20.00 mmHg. This significant reduction in intraocular pressure demonstrates the impressive efficacy of epigallocatechin gallate in the direct treatment of glaucoma (Table 17, G4).

[0271] In summary, epigallocatechin gallate not only performs well in alleviating cataracts but also demonstrates remarkable ability to treat glaucoma, making it a promising drug candidate for both conditions.

[0272] Encapsulated feruloyl-4-hydroxyphenylethylamine (Group G5): This formulation showed significant effectiveness in alleviating cataracts and demonstrated significant efficacy in resolving glaucoma.

[0273] Cataract Efficacy: Macroscopic examination revealed complete recovery in all six animals, with no detectable cataracts (Table 15, G5). Histopathological analysis indicated that the formulation effectively regenerated lens cells in four of the six animals, reversing the severity of degeneration to a moderate grade. In addition, epithelial hyperplasia was observed in one animal, indicating a moderate level of efficacy in alleviating cataracts (Table 16, G5).

[0274] IOP and Glaucoma Efficacy: In the glaucoma-induced left eyes, the initial intraocular pressure of the six animals increased significantly within 3 days to 50.33 mmHg, while the non-induced right eyes maintained a normal intraocular pressure of 18.39 mmHg. However, after a 28-day treatment regimen with 0.5% encapsulated feruloyl-p-hydroxyphenylethylamine, the intraocular pressure of the induced left eyes decreased dramatically from 50.33 mmHg to 23.33 mmHg. This dramatic reduction in intraocular pressure demonstrates the impressive efficacy of encapsulated feruloyl-p-hydroxyphenylethylamine in the direct treatment of glaucoma (Table 17, G5).

[0275] In summary, encapsulated feruloyl-4-hydroxyphenylethylamine (G5) not only effectively alleviates cataracts but also shows great potential in the treatment of glaucoma, making it a promising drug candidate for both conditions.

[0276] Ferulic acid (Group G6): In all six animals, this formulation completely reversed the cataracts and caused minimal to moderate lentiform degeneration, showing a moderate level of cataract reduction.

[0277] IOP, Glaucoma Efficacy: In the glaucoma-induced left eyes, the initial intraocular pressure (IOP) was significantly elevated to a mean of 30.39 mmHg within 3 days, while the non-induced right eyes maintained a normal IOP of 17.28 mmHg. However, after a 28-day treatment regimen of 0.5% ferulic acid, the IOP of the induced left eyes decreased dramatically from 30.39 mmHg to 23.67 mmHg, demonstrating impressive efficacy in treating glaucoma (Table 17, G6).

[0278] Rosmarinic acid + caffeic acid (Group G2): Four of six animals fully recovered from cataracts (Table 15), but variable results were observed with some animals exhibiting minimal to severe lenticular degeneration and corneal edema, indicating relatively low efficacy (Table 16, G2).

[0279] Glaucoma efficacy: In the glaucoma-induced left eyes, the initial mean intraocular pressure increased significantly to 57.56 mmHg within 3 days, while the non-induced right eyes maintained a normal intraocular pressure of 16.44 mmHg. After a 28-day treatment regimen of 0.5% rosmarinic acid + caffeic acid, the intraocular pressure of the induced left eyes decreased dramatically from 57.56 mmHg to 23.22 mmHg, demonstrating impressive efficacy in treating glaucoma (Table 17, G2).

[0280] Therefore, the ranking of efficacy in alleviating cataracts and reducing intraocular pressure from highest to lowest is: caffeic acid G3 > epicatechin gallate G4 > encapsulated feruloyl-4-hydroxyphenylethylamine G5 > ferulic acid G6 > rosmarinic acid + caffeic acid G2.

[0281] The formulation of the present invention achieves complete cataract recovery and significant reduction of intraocular pressure in glaucoma-induced eyes and has complementary properties.

[0282] Although the present invention has been described in detail above for purposes of illustration, it should be understood that such details are for illustrative purposes only and variations may be made therein by those skilled in the art without departing from the spirit and scope of the invention, unless it may be limited by the claims.

Claims

1. An ophthalmic preparation comprising: i. cinnamic acid compounds or their derivatives as active ingredients; and / or ii. catechin compounds or their derivatives as active ingredients.

2. The ophthalmic preparation as claimed in claim 1, wherein the concentration of each active ingredient ranges from 0.01% to 5.0% w / w.

3. An ophthalmic formulation as claimed in claim 1, wherein the formulation comprises an acceptable excipient.

4. An ophthalmic preparation as claimed in claim 1, wherein the preparation is administered topically and / or by injection and / or orally.

5. The ophthalmic preparation as claimed in claim 1, wherein the preparation is in the form of powder, liquid, gel or the like.

6. An ophthalmic preparation as claimed in claim 1, wherein the cinnamic acid derivative is encapsulated or free.

7. The ophthalmic formulation as claimed in claim 1, wherein the cinnamic acid includes but is not limited to cinnamic acid, coumaric acid, caffeic acid, rosmarinic acid, ferulic acid, and combinations thereof.

8. The ophthalmic preparation as claimed in claim 1, wherein the cinnamate derivative comprises an ester of formula (I); CA-CO-OR(I) Where CA = cinnamic acid, and R = C1-C22 alkyl, aryl, heteroaryl, Ar-CH2-CH2-, carbohydrates, lipids, and CA-CO-O(CH)nO-CO-CA Where n=2-10.

9. The ophthalmic preparation as claimed in claim 8, wherein the cinnamate includes but is not limited to ethyl cinnamate, ethyl p-methoxycinnamate, butyl cinnamate, amyl cinnamate, benzyl cinnamate, phenylethyl cinnamate, p-hydroxyphenylethyl cinnamate, hydroxy-p-hydroxyphenylethyl cinnamate, isobutyl cinnamate, cinnamyl cinnamate, phenylethyl coumarate, p-hydroxyphenylethyl coumarate, hydroxy-p-hydroxyphenylethyl coumarate, N-hexadecyl coumarate, N-octadecyl coumarate, N-eicosyl coumarate Carbohydrate or lipid esters of cinnamic acid, dialkyl esters, phenethyl ferulate, p-hydroxyphenyl ethyl ferulate, hydroxy-p-hydroxyphenyl ethyl ferulate, N-hexadecyl ferulate, N-octadecyl ferulate, N-docosyl ferulate, phenethyl caffeate (CAPE), p-hydroxyphenyl ethyl caffeate, hydroxy-p-hydroxyphenyl ethyl caffeate, N-hexadecyl caffeate, N-octadecyl caffeate, N-docosyl caffeate, rosmarinic acid, cinnamic acid, and combinations thereof.

10. The ophthalmic preparation as claimed in claim 1, wherein the cinnamic acid derivative comprises an amide of the general formula (II); CA-CO-NHR(II) Wherein CA = cinnamic acid, and R is C1-C22 alkyl, aryl, heteroaryl, aralkyl, lipid and carbohydrate.

11. The ophthalmic formulation as claimed in claim 10, wherein the cinnamic acid amide includes but is not limited to cinnamoyl phenethylamide, cinnamoyl p-hydroxyphenylethylamine, cinnamoyl 5-hydroxytryptamine, cinnamoyl dopamine, coumaroyl phenethylamide, coumaroyl p-hydroxyphenylethylamine, coumaroyl dopamine, coumaroyl 5-hydroxytryptamine, feruloyl phenethylamide, feruloyl p-hydroxyphenylethylamine, feruloyl 5-hydroxytryptamine, feruloyl dopamine, caffeic acid phenethylamide (CAPA), caffeoyl p-hydroxyphenylethylamine, caffeoyl 5-hydroxytryptamine, caffeoyl dopamine, carbohydrate or lipid amides of cinnamic acid, and combinations thereof.

12. The ophthalmic formulation as claimed in claims 1 to 11, wherein the cinnamic acid derivatives include but are not limited to cinnamic acid, coumaric acid, caffeic acid, rosmarinic acid, ferulic acid, caffeic acid phenethylamide (CAPA), caffeic acid phenethyl ester (CAPE), feruloyl-4-hydroxyphenylethylamine, caffeoyl-4-hydroxyphenylethylamine, caffeoyl dopamine, caffeoyl 5-hydroxytryptamine, feruloyl dopamine, and feruloyl 5-hydroxytryptamine, alone or in combination.

13. The ophthalmic preparation as claimed in claim 1, which comprises a catechin compound or an ester, amide, glycoside, sulfonate, phosphate or the like thereof.

14. The ophthalmic preparation as claimed in claim 1, wherein the catechin derivatives include but are not limited to catechin compounds or their derivatives selected from the group consisting of: (a) catechin: (2R,3S)-(+)-catechin; (2R,3S)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol; (b) EC: (2R,3S)-(–)-epicatechin ; 2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7-triol; (c) ECG: (2R,3R)-(–)-epicatechin gallate; (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxy-benzoate); (d) EGC: (2R,3R)-(–)-Epigallocatechin; (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol; (e)GC: (2S,3R-(–)-Epigallocatechin; (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol; (f)EGCG: (2R,3R)-(–)-Epigallocatechin Gallate; (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-chromene-3,5,7-triol 3-(3,4,5-trihydroxybenzoate); (g)GCG: (2S,3R)-(–)-gallocatechin gallate; (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-chromene-3,5,7-triol 3-(3,4,5-trihydroxybenzoate).

15. The ophthalmic formulation as claimed in claim 3, wherein the excipients include but are not limited to stability enhancers / preservatives, solubilizers, buffers, surfactants, pH adjusters, viscosity enhancers or modifiers, diluents, encapsulating agents, antioxidants, vitamins, etc., which are present in appropriate proportions.

16. The ophthalmic formulation as claimed in claim 15, wherein the excipients include but are not limited to 2-hydroxypropyl-β-cyclodextrin, polysorbate surfactants including polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20), ethanol, benzyl alcohol, propylene glycol, polyvinyl pyrrolidone (PVP), ethylenediaminetetraacetic acid (EDTA); viscosity enhancers or modifiers selected from carboxymethylcellulose (CMC) or an acceptable salt thereof, hyaluronic acid or an acceptable salt thereof, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), glycerol, polyethylene glycol (PEG), xanthan gum, guar gum. Gum, gellan gum, carbomer, such as polyacrylic acid; a buffer selected from phosphate buffers, including sodium phosphate and potassium phosphate; a citrate buffer selected from sodium citrate or citric acid; a borate buffer, such as potassium borate; an acetate buffer, such as sodium acetate, a Tris buffer, such as Tris (tris (hydroxymethyl) aminomethane; a HEPES buffer, such as (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid; ascorbic acid; sodium metabisulfite; potassium carbonate; an antioxidant selected from glutathione and N-acetylcarnosine; a vitamin selected from vitamin E or vitamin A, which are present in various combinations and ratios.

17. The ophthalmic formulation as claimed in claims 15 and 16, wherein the excipients include, but are not limited to, viscosity enhancing agents including carboxymethylcellulose or an acceptable salt thereof in an amount ranging from 0.05% to 3.0% w / w, preferably in a range of 0.2% to 2.0% w / w; or hyaluronic acid or an acceptable salt thereof in an amount ranging from 0.05% to 1.5% w / w, preferably in a range of 0.05 to 0.3% w / w; glutathione / N-acetylcarnosine (NAC) as an antioxidant in an amount ranging from 0.1 to 5% w / w; 2-hydroxypropyl-β-cyclodextrin as an encapsulating agent or as a stabilizer in an amount ranging from 0.1% to 15% w / w, preferably from 1 to 5% w / w, based on the total weight of the composition; a surfactant selected from Tween 80 in an amount ranging from 1-10% w / w, preferably from 2-6% w / w.

18. An ophthalmic formulation as claimed in any one of claims 1 to 17 comprising: i. Active ingredient: 0.01% w / w to 5% w / w of cinnamic acid and / or its derivatives and / or catechin compounds and / or its derivatives (wherein, active ingredient is encapsulated or in a free state); ii. appropriate excipients; iii. Appropriate pH; as well as iv. Sterile water.

19. An ophthalmic formulation as claimed in any one of claims 1 to 18 comprising: i. Active ingredient: 0.1 to 2% w / ww / w of caffeic acid and / or rosmarinic acid ester thereof and / or ferulic acid and / or feruloyl-4-hydroxyphenylethylamine and / or caffeic acid phenethyl ester and / or caffeic acid phenethylamide and / or epigallocatechin gallate and / or epicatechin gallate and / or epigallocatechin, etc. (wherein the active ingredient is encapsulated or free); ii. Excipient: 0.3% w / w sodium carboxymethylcellulose; 0.1% w / w sodium hyaluronate; 1-5% w / w 2-hydroxypropyl-β-cyclodextrin; 6% w / w Tween 80, sodium borate, potassium bicarbonate, with or without antioxidants and vitamins, They are present in proper proportions; iii. Appropriate pH, between 6.2 and 7.6; iv. isotonic solution; i. Sterile water.

20. An ophthalmic formulation as claimed in any one of the preceding claims 1 to 19, wherein the formulation is prepared by a process comprising the steps of: i. dissolving the active ingredient comprising cinnamic acid and / or its derivatives and / or catechins and / or its derivatives in sterile water at an appropriate temperature, including but not limited to a temperature range of 25-75°C; ii. adding a suitable excipient to the solution of step (i) at an appropriate temperature and stirring the mixture; iii. adjusting the pH to within a certain range with a mixture of a base and a buffer; and stirring to form a clear and homogeneous mixture; and iv. packaging and storing the ophthalmic formulation of step (iii) at an appropriate temperature, including but not limited to a temperature of 2 to 40°C.

21. An ophthalmic preparation as claimed in claim 20, wherein the active ingredient is in an encapsulated or free state.

22. The ophthalmic formulation as claimed in claim 20, wherein the excipients include, but are not limited to, stability enhancers / preservatives, solubilizers, buffers, surfactants, pH adjusters, viscosity enhancers or modifiers, diluents, encapsulating agents, antioxidants, vitamins, etc., which are present in appropriate proportions.

23. Use of an ophthalmic preparation as claimed in any one of the preceding claims 1 to 22 for treating / clearing / reducing cataractous lens, intraocular pressure, glaucoma, lenticular degeneration, corneal epithelial hyperplasia / liquefaction / inflammation.

24. A method for treating / clearing / reducing cataractous lens, intraocular pressure, glaucoma, lenticular degeneration, corneal epithelial hyperplasia / liquefaction / inflammation and their occurrence / recurrence, which comprises applying the ophthalmic preparation claimed in any one of the preceding claims 1 to 23.

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