A synergistic bioactive composition for glaucoma

Abstract

The present invention relates to a synergistic bioactive pharmaceutical composition comprising Palmitoylethanolamide (PEA), Forskolin, and Rutin along with one or more pharmaceutically acceptable excipients for the treatment and management of glaucoma and related ocular disorders. The composition is suitable for formulation into various oral dosage forms for preventing disease progression and improving visual outcomes in patients with glaucoma.

Description

[0001] A SYNERGISTIC BIOACTIVE COMPOSITION FOR GLAUCOMA

[0002] RELATED APPLICATION:

[0003] The present application claims benefit of the Indian Provisional Application No. IN202521004135 filed on, January 17th, 2025 the entire contents of which are hereby incorporated by reference.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to a synergistic bioactive pharmaceutical composition comprising Palmitoylethanolamide (PEA), Forskolin, and Rutin along with one or more pharmaceutically acceptable excipients for the treatment and management of glaucoma and related ocular disorders. The composition exhibits a synergistic effect that is superior to the additive effects of its individual components and is suitable for formulation into various dosage forms, including sachets, tablets, capsules, suspensions, or ophthalmic preparations, thereby offering a comprehensive solution for preventing disease progression and improving visual outcomes in patients with glaucoma.

[0006] BACKGROUND OF THE INVENTION

[0007] Glaucoma represents a significant global health concern and is characterized by progressive degeneration to the optic nerve, which is responsible for transmitting visual signals from the retina to the brain. A principal factor contributing to the pathophysiology of glaucoma is elevated intraocular pressure (IOP), which, when inadequately controlled results in gradual and irreversible visual impairment and may ultimately lead to complete blindness. Glaucoma is widely recognized as the second leading cause of blindness worldwide, affecting millions of individuals and imposing a substantial clinical, socio-economic and healthcare burdens.

[0008] The management of glaucoma has historically focused on lowering IOP, as it remains the only modifiable risk factor identified to date. Existing therapeutic strategies include pharmacological agents, laser-based interventions,, and surgical procedures. However, despite the availability of these treatments, , a substantial proportion of patients continue to experience disease progression, attributable to suboptimal IOP control and, more critically, to the inability of current therapies to directly address the underlyingneurodegenerative mechanisms .. These limitations underscore a significant unmet medical need for therapeutic strategies capable of not only lowering IOP but also providing neuroprotective and antioxidative benefits, thereby preserving optic nerve integrity and maintaining retinal ganglion cell viability.

[0009] US4476140 discloses a method for treating elevated intraocular pressure or glaucoma by topically administering polyoxygenated labdane compounds, including forskolin and coleforsin.

[0010] EP3687526 discloses a composition comprising naturally occurring substances for the treatment of glaucoma, wherein the composition includes a synergistic combination of Crocus sativus extract, forskolin, and one or more additional active ingredients selected from citicoline, rutin, or combinations thereof.

[0011] IN245785 discloses a solubilized composition of forskolin, a diterpene compound, formulated using randomly-methylated P-cyclodextrins to enhance its solubility and bioavailability. The disclosed composition containing forskolin in concentrations up to 6%, is described as suitable for pharmaceutical applications, particularly ophthalmic preparations, and is reported to provide enhanced therapeutic efficacy without causing ocular irritation.

[0012] IN314665 discloses a pharmaceutical composition comprising forskolin in combination with co-crystal formers such as amino acids, sugars, or anti-oxidants, with the objective of enhancing solubility and bioavailability for ophthalmic applications. The disclosed composition is described as particularly effective for the treatment of glaucoma, wherein the formation of stable co-crystals through non-covalent interactions improves the pharmacological efficacy of forskolin.

[0013] WO2016063217 discloses a composition comprising Spirulinaand Palmitoylethanolamide (PEA) for treatment of tissue hyperactivation states, inflammatory pathologies, and various ophthalmic diseases.Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that has been reported to exert beneficial effects on intraocular pressure modulation, neuroprotection, and reduction of oxidative stress.

[0014] Rutin is a naturally occurring bioflavonoid known for its antioxidant properties, vascular protective effects, and its potential to support retinal integrity and optic nerve function. Forskolin, a diterpenoid obtained from Coleus species, is recognized for its ability to modulate intraocular pressure and influence cellular signaling pathways relevant to ocular health and function.

[0015] Glaucoma is a complex and multifactorial disease in which elevated intraocular pressure, retinal ganglion cell neurodegeneration, oxidative stress, and impaired ocular blood flow collectively contribute to progressive vision loss. Although existing therapies effectively reduce intraocular pressure, they frequently fail to adequately address the concomitant neurodegenerative and oxidative pathways involved in disease progression. Consequently, treatments directed towards a single mechanistic target provide only partial therapeutic benefit and are often insufficient to halt or significantly slow the disease progression of glaucoma in many patients.

[0016] Accordingly, there remains a continuing need for therapeutic strategies capable of acting on multiple pathways implicated in the pathophysiology of glaucoma, wherein such strategies combine effective intraocular pressure reduction with neuroprotective, antioxidative, and vascular protective effects. Such multi-modal approaches would provide more comprehensive and sustained management of the disease compared to existing monotherapies.

[0017] OBJECTIVE OF THE INVENTION

[0018] The main objective of the present invention is to provide a synergistic pharmaceutical composition comprising Palmitoylethanolamide, Forskolin, and Rutin, in combination with one or more pharmaceutically acceptable excipients, for the effective treatment and management of glaucoma and related ocular disorders.The primary objective of the present invention is to provide a pharmaceutical composition comprising Palmitoylethanolamide, Forskolin, and Rutin, in combination with one or more pharmaceutically acceptable excipients, for the use in the treatment and management of glaucoma.

[0019] Another objective of the present invention is to provide a pharmaceutical composition consisting essentially of Palmitoylethanolamide, Forskolin, and Rutin, in combination with one or more pharmaceutically acceptable excipients, for the treatment and management of glaucoma.

[0020] Another objective of the present invention is to provide the composition in which the ratio of Palmitoylethanolamide, Forskolin, and Rutin is maintained within defined ranges to achieve desired therapeutic activity.

[0021] A further objective of the invention is to provide the composition wherein Palmitoylethanolamide, Forskolin, and Rutin are present in specific weight percentages based on the total weight of the composition.

[0022] Another objective of the present invention is to provide the composition in which Palmitoylethanolamide, Forskolin, and Rutin are present in defined amounts (mg) suitable for therapeutic administration.

[0023] A further objective of the present invention is to provide a kit comprising Palmitoylethanolamide, Forskolin, and Rutin, either as a single composition or as separate compositions, together with one or more pharmaceutically acceptable excipients, for use in the treatment of glaucoma.

[0024] Another objective of the present invention is to provide the composition in which the pharmaceutically acceptable excipient is selected from diluents, disintegrants, binders, surfactants, lubricants, polymers, preservatives, antimicrobial agents, glidants, or mixtures thereof.Another objective of the present invention is to provide the composition in suitable dosage forms, including sachets, tablets, capsules, suspensions, or other pharmaceutically acceptable formulations.

[0025] A further objective of the present invention is to provide the composition for the treatment or prevention of ocular disorders including, but not limited to, glaucoma, ocular hypertension, age-related macular degeneration, diabetic retinopathy, cataract, retinal ischemia, and other degenerative or vascular diseases of the eye.

[0026] Another objective of the present invention is to provide a composition comprising defined amounts of Palmitoylethanolamide, Forskolin, and Rutin, wherein the combination exhibits a synergistic effect in the treatment of glaucoma.

[0027] Yet another objective of the present invention is to provide the composition in a form suitable for multiple routes of administration, including oral, ophthalmic, or parenteral formulations, thereby broadening its therapeutic applicability.

[0028] A further objective of the present invention is to provide the composition in stable, safe, and patient-compliant dosage forms, ensuring ease of manufacture, long shelf-life, and effective clinical use.

[0029] SUMMARY OF THE INVENTION

[0030] The present invention provides a synergistic pharmaceutical composition comprising Palmitoylethanolamide, Forskolin, and Rutin, in combination with one or more pharmaceutically acceptable excipients, for use in the treatment and management of glaucoma and related ocular disorders.

[0031] In one embodiment, the present invention provides a pharmaceutical composition in which the ratio of Palmitoylethanolamide, Forskolin, and Rutin is maintained within defined ranges to achieve optimal therapeutic efficacy. In another embodiment, the composition comprises Palmitoylethanolamide, Forskolin, and Rutin in specific weight percentages or amounts relative to the total weight of the composition.The present invention further provides a kit comprising Palmitoylethanolamide, Forskolin, and Rutin, either in a single composition or as separate compositions, together with one or more pharmaceutically acceptable excipients, intended for the treatment of glaucoma.

[0032] The composition may further comprise pharmaceutically acceptable excipients selected from diluents, disintegrants, binders, surfactants, lubricants, polymers, preservatives, antimicrobial agents, glidants, or mixtures thereof, and may be formulated in various dosage forms, including sachets, tablets, capsules, suspensions, or ophthalmic preparations.

[0033] In certain embodiments, the composition is suitable for use in the treatment or prevention of ocular disorders including glaucoma, ocular hypertension, age-related macular degeneration, diabetic retinopathy, cataract, retinal ischemia, and other degenerative or vascular diseases of the eye.

[0034] A further aspect of the invention relates to the synergistic effect exhibited by the combination of Palmitoylethanolamide, Forskolin, and Rutin in the treatment of glaucoma, wherein the combined activity provides therapeutic benefits superior to those obtained from the individual components or any known dual combinations thereof.

[0035] Accordingly, the present invention provides a composition that concurrently addresses multiple aspects of glaucoma pathology by combining intraocular pressure reduction, neuroprotective activity, antioxidative effects, and vascular support within a single formulation. The synergistic interaction of Palmitoylethanolamide, Forskolin, and Rutin results in a therapeutic profile that is broader and more efficacious than that of the individual components or any dual-component combinations, , thereby offering a comprehensive strategy for improved management of glaucoma and related ocular disorders.

[0036] BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure- 1: Reduction in intraocular pressure

[0038] Figure-2: Reduction in Malondialdehyde

[0039] Figure-3 : Increase in Superoxide Dismutase

[0040] Figure-4: Increase in Catalase levelsFigure-5: Increase in Glutathione peroxidase levels

[0041] Figure-6: Increase in Aqueous humor TNF-a levels

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] The following detailed description sets forth various embodiments of the present invention. These embodiments are described in sufficient detail to enable a person skilled in the art to practice the invention. It will be appreciated, however, that alternative embodiments may be utilized and modifications may be made without departing from the scope of the invention.

[0044] References herein to “an embodiment,” “one embodiment,” or “various embodiments” are not intended to be limiting and may refer to the same or different embodiments. The description that follows is, therefore, to be understood as illustrative and not restrictive, with the scope of the invention being defined solely by the appended claims and their legal equivalents.

[0045] The present invention provides a pharmaceutical composition comprising Palmitoylethanolamide (PEA), Forskolin, and Rutin in combination with one or more pharmaceutically acceptable excipients, for use in the treatment and management of glaucoma and related ocular disorders.

[0046] Glaucoma encompasses is a group of progressive ocular diseases characterized by optic nerve damage, which can lead to vision impairment or blindness. While elevated intraocular pressure constitute a primary risk factor, additional mechanisms including neurodegeneration, oxidative stress, and impaired ocular blood flow also contribute to disease progression. The present invention addresses these multifactorial aspects through a synergistic combination of bioactive components.

[0047] In one embodiment, the invention provides a composition in which Palmitoylethanolamide, Forskolin, and Rutin are present in defined ratios or concentrations to maximize therapeutic benefit. The synergistic interaction among these components results in enhanced efficacy compared to individual administration or known dual combinations, providing simultaneous intraocular pressure reduction, neuroprotection, and antioxidant activity.In another embodiment, the invention provides a pharmaceutical composition consisting essentially of Palmitoylethanolamide, Forskolin, and Rutin, in combination with one or more pharmaceutically acceptable excipients, for the treatment and management of glaucoma.

[0048] Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, which may be used in free form, micronized form, salts, esters, or other pharmaceutically acceptable derivatives. In the context of the invention, PEA contributes to intraocular pressure modulation, exhibits anti-inflammatory activity, and provides neuroprotection of retinal ganglion cells. Micronized or ultra-micronized forms may be utilized to enhanced bioavailability.

[0049] Rutin is a naturally occurring bioflavonoid that may be used in its free form, glycosidic forms, salts, hydrates, or pharmaceutically acceptable derivatives. Rutin may be derived from botanical sources including fruit peels or Cotinus bark or produced via fermentation or synthetic methods. Within the composition, Rutin contributes antioxidant activity, vascular protection, and improvement of ocular perfusion.

[0050] Forskolin is a diterpenoid compound that may be used in pure form, pharmaceutically acceptable derivatives, or extracts obtained from Coleus species including Coleus forskohlii, C. barbatus, C. aromaticus, or other suitable species. Forskolin functions to reduce aqueous humor secretion and intraocular pressure, while also exerting neuroprotective effects.

[0051] In one embodiment, the invention provides the composition in defined ratios of Palmitoylethanolamide, Forskolin, and Rutin, wherein the proportions are selected to optimize therapeutic effect. In another embodiment, the composition comprises defined weight percentages of each active ingredient relative to the total weight of the composition.

[0052] In yet another embodiment, the composition comprises defined amounts (mg) of each ingredient suitable for administration to a patient in need thereof. The ratio of Palmitoylethanolamide to Forskolin to Rutin may range from about 1:0.0006:0.0066 to 1:5:8, 1:0.0014:0.0179 to 1:3 6:6, 1:0.0023:0.0385 to 1:2.6667:4.6667, 1:0.0033:0.0625 to1:2:3.7143 and 1:0.005:0.1 to 1: 1.5:3 depending on the desired therapeutic effect. Within these ranges , sub-ranges may be selected to optimize intraocular pressure reduction, neuroprotection, or antioxidant activity.

[0053] The composition comprises Palmitoylethanolamide in an amount ranging from about 100 mg to 1500 mg, 125 mg to 1400 mg, 150 to 1300 mg, 175 to 1200 mg and 200 mg to 1000 mg based on the total weight of the composition.

[0054] The composition comprises Forskolin in an amount ranging from about 1 mg to 500 mg, 2 mg to 450 mg, 3 mg to 400 mg, 4 mg to 350 mg and 5 mg to 300 mg based on the total weight of the composition.

[0055] The composition comprises Rutin in an amount ranging from about 10 mg to 800 mg, 25 mg to 750 mg, 50 to 700 mg, 75 mg to 650 mg and 100 mg to 600 mg based on the total weight of the composition.

[0056] In certain embodiments, the amounts of active ingredients may be expressed as weight percentages relative to the total composition. For example, Palmitoylethanolamide from 2% to 99%, 3% to 98%, 4% to 97%, 5% to 96%, 6% to 95%, Forskolin from 0.02% to 81%, 0.03% to 79%, 0.04% to 78%, 0.05% to 77%, 0.06% to 76% and Rutin from 0.2% to 90%, 0.3% to 88%, 0.4% to 87%, 0.5% to 86%, 0.5% to 85%, relative to the total composition.

[0057] Fixed-dose unit formulations may be prepared in which the composition provides therapeutically effective amounts of Palmitoylethanolamide, Forskolin, and Rutin within the above-defined ranges. In certain embodiments, the composition may be formulated for once-daily dosing, sustained release, or immediate release, depending on clinical requirements.

[0058] The synergistic effect of the composition is demonstrated by enhanced in intraocular pressure reduction, improved retinal ganglion cell viability, and reduced oxidative stress, compared to the individual components or known dual combinations. The synergistic interaction provides a broader therapeutic profile, supporting the use of the combinationin long-term glaucoma. Together, all three active ingredients produce an effect greater than the additive effect of the individual components.

[0059] The pharmaceutical composition of the present invention may be formulated into dosage forms suitable for oral, ophthalmic, or parenteral administration. Oral dosage forms may include solid preparations such as tablets, capsules, granules, or sachets containing the active ingredients either as a simple blends, conventional tablets, granules, or as part of controlled release, sustained release, or delayed release formulations. Liquid oral preparations, including syrups, suspensions, or emulsions may also be prepared. Ophthalmic dosage forms may include sterile aqueous or oily solutions, suspensions, emulsions, or gels suitable for topical instillation into the eye, optionally comprising stabilizers, buffering agents, and preservatives to ensure safety and stability. Parenteral dosage forms may include sterile injectable solutions, suspensions, or lyophilized powders for reconstitution, prepared under aseptic conditions and optionally including solubilizers or stabilizing agents. In certain embodiments, the pharmaceutical composition is formulated as sachets containing premeasured doses of Palmitoylethanolamide, Forskolin, and Rutin, in defined amounts, providing convenient administration.

[0060] In another embodiment, the invention provides a kit comprising Palmitoylethanolamide, Forskolin, and Rutin, together with one or more pharmaceutically acceptable excipients. The kit may provide the active ingredients either in a single combined formulation or as separate compositions for sequential or simultaneous administration. The kit may include unit dosage forms such as sachets, tablets, or capsules containing the defined amounts of the active ingredients. Alternatively, the kit may include separate containers, each containing one of the active ingredients. Alternatively, the kit may include separate containers, each containing one of the active ingredient in suitable formulation , together with instruction for combined use. In certain embodiments, the kit may further comprise delivery devices such as droppers, applicators, or blister packs to facilitate accurate dosing and patient convenience. The kit format allows for flexibility in administration, improved stability of individual components, and enhanced patient compliance.

[0061] In one embodiment of the present invention, pharmaceutically acceptable excipients are incorporated into the formulation to enhance stability, solubility, bioavailability, andoverall performance of the active ingredients. The excipients are selected to be chemically and physically compatible with Palmitoylethanolamide, Forskolin, and Rutin, while also enhancing patient compliance and convenience of administration. The selection of excipients may vary depending on the intended dosage form, including tablets, capsules, sachets, suspensions, ophthalmic preparations, or injectable formulations. The use of excipients in the present invention follows established pharmaceutical practices to ensure that the final is safe, effective, and maintains stability throughout its shelflife.

[0062] Suitable examples of pharmaceutically acceptable excipients, categorized according to their primary function in the formulation, are provided below; however, these examples are not intended to be limiting and may be varied or substituted by equivalent excipients as would be recognized by a person skilled in the art.

[0063] Pharmaceutically acceptable excipients may be selected from diluents, binders, disintegrants, surfactants, lubricants, glidants, preservatives, antioxidants, stabilizers, polymers, sweeteners, flavoring agents, or mixtures thereof, depending on the intended dosage form is a tablet, capsule, sachet, suspension, or other pharmaceutical formulations.

[0064] Diluents suitable for use in the compositions described herein may be selected from microcrystalline cellulose, calcium carbonate, dicalcium phosphate, lactose, lactose monohydrate, sorbitol, mannitol, starch, maltodextrin, pregelatinized starch, croscarmellose sodium, guar gum, xanthan gum, sodium alginate, polyvinylpyrrolidone (PVP), sodium carboxymethyl cellulose (CMC), or mixtures thereof. The selected diluents may be incorporated into capsule formulations to facilitate powder filling, into sachets formulations to enhance flow properties, or into liquid or semi-solid compositions such as suspensions to promote uniform dispersion.

[0065] Binders suitable for use in the compositions described herein may be selected from starch, pregelatinized starch, polyvinylpyrrolidone (PVP), methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium alginate, xanthan gum, acacia, or mixtures thereof. Such binders may be employed to promote cohesion of powders in tablets, granules, and sachet formulations.Disintegrants suitable for use in the compositions described herein may be selected from croscarmellose sodium, sodium starch glycolate, crospovidone, starch, microcrystalline cellulose, or mixtures thereof. Such disintegrants may be incorporated into tablet, capsule, and sachet formulations to promote rapid disintegration upon administration.

[0066] Surfactants suitable for use in the compositions described herein may be selected from sodium lauryl sulfate, polysorbate 80, polysorbate 20, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, cetyltrimethylammonium bromide (CTAB), poloxamers, polyethylene glycol, sodium dodecylbenzene sulfonate, glycerol monostearate, Tween 80, or mixtures thereof. Such surfactant may be incorporated into suspension formulations to stabilize dispersed phases and into capsules or sachets formulations to enhance solubility of the active ingredients..

[0067] Lubricants and / or glidants suitable for use in the compositions described herein may be selected from magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene glycol, silicon dioxide, colloidal silica, hydrogenated vegetable oil, sodium benzoate, polyvinyl acetate, glyceryl behenate, or mixtures thereof. Such lubricants and / or glidants may be employed to facilitate tablet compression, capsule fdling , or to promote uniform flow and dispersion of powders in sachet formulations.

[0068] Preservatives suitable for use in the compositions described herein may be selected from parabens (methylparaben, propylparaben), benzalkonium chloride, benzyl alcohol, sodium benzoate, potassium sorbate, or mixtures thereof. Such preservatives may be incorporated, especially in suspension and ophthalmic dosage forms to maintain microbial stability throughout the product’s shelflife.

[0069] Antioxidants suitable for use in the compositions described herein may be selected from ascorbic acid, sodium metabisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherols, or mixtures thereof. Such antioxidants may be incorporated into suspension or sachet formulations to protect active ingredients from oxidative degradation.Polymers and stabilizers suitable for use in the compositions described herein may be selected from HPMC, HPC, carbomers, polyethylene glycols, polyvinyl alcohol, or mixtures thereof. Such polymers and stabilizers may function as film-forming agents in capsule formulations, as matrix-forming excipients in tablet or sachet compositions, or as stabilizing agents in suspension formulations.

[0070] Sweeteners and flavoring agents suitable for use in the compositions described herein may be included for oral formulations such as sachets, suspensions, or chewable dosage forms. Such agents may be selected from saccharin sodium, sucralose, aspartame, mannitol, sorbitol, fructose, menthol, or fruit flavoring agents or mixtures thereof, and may be employed to enhance palatability and thereby improve patient compliance.

[0071] Other pharmaceutically acceptable excipients known to a person skilled in the art may likewise be employed, provided that such excipients are compatible with the active ingredients and suitable for intended dosage form.

[0072] In certain embodiments, the formulation may comprise micronized Palmitoylethanolamide (PEA). Micronization of PEA increases its surface area and thereby enhancing its solubility, dissolution rate, and bioavailability permitting the administration of lower doses while maintaining therapeutic efficacy. The micronized PEA is uniformly dispersed within the formulation to ensure consistent dosing and optimal therapeutic outcomes. In further embodiments, forskolin and rutin may likewise be provided in micronized, nanoparticulate, encapsulated, or complexed forms, including but not limited to cyclodextrin inclusion complexes, liposomal formulations, or polymeric nanoparticles system, so as to improve stability, absorption and overall bioavailability.

[0073] The pharmaceutical composition of the present invention can be prepared using conventional formulation techniques known in the art for the manufacture of oral, ophthalmic, or parenteral dosage forms.

[0074] In one embodiment, the composition is prepared by direct compression, wherein Palmitoylethanolamide, Forskolin, and Rutin are blended with pharmaceutically acceptableexcipients such as diluents, binders, disintegrants, and lubricants, to form a uniform mixture, which is subsequently compressed into tablets.

[0075] In another embodiment, the composition is prepared by granulation methods, including wet granulation or dry granulation, to improve flowability and compressibility of the formulation. The resulting granulated material may be dried, sieved and blended with one or more lubricants, and thereafter compressed into tablets or filled into capsules. In certain embodiments, the composition may alternatively be prepared by directly filling a powder blend of the active ingredients and suitable excipients into capsules without prior granulation. Capsules may be provided as hard gelatin capsules, soft gelatin capsules, or hydroxypropyl methylcellulose (HPMC)-based vegetarian capsules, each containing the active ingredients in combination with one or more diluents, lubricants, stabilizers, or mixtures thereof.

[0076] In certain embodiments, the formulation may be supplied as sachets, wherein the active ingredients are blended with appropriate excipients such as diluents, flavoring agents, and sweeteners to ensure free flow, palatability, and stability. The sachets may contain powders or granules intended for direct oral administration or for reconstitution with an appropriate liquid vehicle to form an oral suspensions.

[0077] Suspensions may be prepared by dispersing the active ingredients in aqueous or nonaqueous vehicles together with suitable stabilizers, surfactants, suspending agents, and preservatives so as to maintain uniformity, stability, and patient compliance. Liquid oral dosage forms including syrups, emulsions, or reconstitutable powders for suspension may likewise be employed.

[0078] For ophthalmic preparations, the active ingredients may be dissolved or suspended in sterile aqueous or oily vehicles, optionally in combination with stabilizers, preservatives, buffering agents, tonicity adjusters, or viscosity enhancers. The resulting formulation may be subjected to sterile filtration and aseptically filling into suitable containers such as vials, droppers, or unit-dose packs.For parenteral dosage forms, the actives may be formulated into sterile injectable solutions, lyophilized powders for reconstitution, or nanoparticle dispersions, prepared under aseptic conditions using pharmaceutically acceptable carriers and stabilizers.

[0079] Forskolin may be obtained by extraction, isolation or purification from Coleus species, including but not limited to C. forskohlii, C. barbatus, C. aromaticus, and C. ettiveroides, or alternatively produced by fermentation or chemical synthesis. Rutin may be obtained from botanical sources such as fruit peels, flowers, or Cotinus bark, or prepared by fermentation or chemical synthesis. Palmitoylethanolamide (PEA) may be obtained by synthesis or derived from natural lipid sources. In certain embodiments, PEA is provided in micronized or ultramicronized form to enhance solubility and bioavailability.

[0080] The present invention provides a novel synergistic pharmaceutical composition comprising Palmitoylethanolamide, Forskolin, and Rutin, in combination with pharmaceutically acceptable excipients, for the treatment and management of glaucoma. In contrast to existing therapies that primarily reduce intraocular pressure, the invention addresses the multifactorial nature of glaucoma by concurrently lowering intraocular pressure, providing neuroprotection, and offering antioxidant and vascular support, thereby delivering a comprehensive therapeutic approach.

[0081] The synergistic interaction among Palmitoylethanolamide, Forskolin, and Rutin has been demonstrated to achieve superior outcomes compared to individual agents or known dual combinations. In particular, the composition produces greater reduction in intraocular pressure, enhanced preservation of retinal ganglion cells, attenuation of oxidative stress, and improved ocular blood flow, each of which contributes to slowing or preventing the progression of glaucoma-related vision loss.

[0082] From an economic standpoint , the synergistic interaction among the active components permits effective therapy at reduced individual doses,, thereby lowering treatment costs and minimizing the potential for side effects. The ability to formulate the composition into variety of table dosage forms, including tablets, capsules, sachets, suspensions, or ophthalmic preparations further enhances patient compliance, manufacturing scalability,and overall cost-effectiveness. Such attributes render the invention particularly suitable for large-scale management of glaucoma.

[0083] The studies and findings presented herein substantiate the superior efficacy of the composition, thereby paving the way for its application in clinical practice.

[0084] It will be understood by those skilled in the art that the embodiments described herein are illustrative and not limiting. Variations, modifications, or equivalents that achieve the same technical and economic effects in glaucoma management fall within the scope of the invention. The scope of protection is defined solely by the appended claims and their legal equivalents.

[0085] EXAMPLE-1: COMPOSITION

[0086] Following is a general composition formula as per the present invention:

[0087]

[0088] Process for preparation of example 1 :

[0089] 1. Accurately weigh each ingredient in separate containers.

[0090] 2. Sift the previously weighed active ingredients and excipients through a sieve. 3. Combine the contents from step 2 to prepare suitable oral dosage form.

[0091] TABLET EXAMPLE-2:

[0092]

[0093]

[0094] TABLET EXAMPLE-3:

[0095]

[0096] TABLET EXAMPLE-4:

[0097]

[0098]

[0099] General Procedure for preparation for Example- 2-4:

[0100] 1. All the active ingredients and excipients were accurately weighed as per the batch formula and passed through a #40 sieve to remove lumps and ensure uniform particle size.

[0101] 2. Palmitoylethanolamide, Forskolin, Rutin, Microcrystalline Cellulose, Half of the Croscarmellose Sodium, Colloidal Silicon Dioxide were blended for 10-15 minutes to achieve uniform mixture.

[0102] 3. A binder solution was prepared by dissolving Polyvinylpyrrolidone and Polysorbate in purified water and added to the blend while mixing to form uniform granules, which were passed through a suitable sieve and then dried.

[0103] 4. The dried granules were passed through a 30# mesh sieve to break lumps.

[0104] Croscarmellose Sodium, Talc, Magnesium Stearate and Zinc Stearate were added and blended gently for 3-5 minutes to avoid over-lubrication.

[0105] 5. The lubricated blend from Step 4 was compressed to form tablets and polymer solution uniformly was applied over compressed tablets using a coating pan. 6. The finished products were packed into moisture-protective packaging, labelled, and stored under recommended conditions.

[0106] SACHET EXAMPLE S:

[0107]

[0108]

[0109] SACHET EXAMPLE-6:

[0110]

[0111] General Procedure for preparation for Example- 5-6:

[0112] 1. All the active ingredients and excipients were accurately weighed as per the batch formula and passed through a #40 sieve to remove lumps and ensure uniform particle size.

[0113] 2. Palmitoylethanolamide, Forskolin, Rutin, Microcrystalline Cellulose, Lactose Monohydrate, Crospovidone, Hypromellose, Colloidal Silicon Dioxide were blended for 15-20 minutes to achieve uniform mixture.

[0114] 3. Talc, Magnesium Stearate and Zinc Stearate were added and blended gently for 3- 5 minutes to avoid over-lubrication.

[0115] 4. The blend of step-3 is filled in suitable sachets.

[0116] 5. The final product of step-4 were packed into suitable packs, labelled, and stored under recommended conditions.

[0117] CAPSULE EXAMPLE-7:

[0118]

[0119]

[0120] General Procedure for preparation for Example-7:

[0121] 1. All the active ingredients and excipients were accurately weighed as per the batch formula and passed through a #40 sieve to remove lumps and ensure uniform particle size.

[0122] 2. Palmitoylethanolamide, Forskolin, Rutin, Microcrystalline cellulose, Colloidal silicon dioxide, Polysorbate 80 were blended until a uniform mixture is achieved.

[0123] 3. Magnesium Stearate was added to blend and blended gently for 3-5 minutes to avoid over-lubrication.

[0124] 4. The blend from Step 4 the final blend into hard gelatin or HPMC capsules.

[0125] 5. The finished products were packed into moisture-protective packaging, labelled, and stored under recommended conditions.

[0126] SUSPENSION EXAMPLE S:

[0127]

[0128] SUSPENSION EXAMPLE-9:

[0129]

[0130]

[0131] General Procedure for preparation for Example-8 to 9:

[0132] 1. All the active ingredients and excipients were accurately weighed as per the batch formula.

[0133] 2. About 60-70% of the required purified water is added in a stainless steel mixing tank, Sorbitol solution, Citric acid, Sodium benzoate, Potassium sorbate, Sucralose, Ponceau 4R were added by stirring.

[0134] 3. In a separate container, slowly disperse Xanthan gum was slowly dispersed, in a separate container into a portion of water, colloidal silicon dioxide was added and mixed until a uniform suspension base is formed.

[0135] 4. Palmitoylethanolamide, Forskolin, and Rutin were blended separately in a container with a small quantity of water or polysorbate to form a slurry or paste and added to the pre -mix to the main batch under continuous stirring to avoid lump formation.

[0136] 5. Purified water was added to the main batch to make the final volume.

[0137] 6. After mixing the final product of step-5 is filled in suitable containers and sealed.

[0138] 7. The containers were packed, labelled, and stored under recommended conditions.EXAMPLE 10: Animal Study

[0139] Objective: To evaluate the synergistic therapeutic potential of palmitoylethanolamide, forskolin, and rutin in a dexamethasone -induced glaucoma model in rabbits.

[0140] Study design: Prior to the initiation of the study, male New Zealand White rabbits (animals) aged 8-9 weeks prior to the start of treatments were acclimatized to laboratory conditions for a minimum period of five days. They were divided into below mentioned groups: Group- 1: Normal control group, Group-2: Disease control group, Group-3: Standard group, Group-4: Palmitoyl ethanolamide group, Group-5: Forskolin group, Group-6: Rutin group and Group-7: Palmitoylethanolamide + Forskolin + Rutin group. Each group has 6 rats. Glaucoma was induced in all the groups except normal control group (Group- 1) through the topical administration of 0.1% dexamethasone sodium phosphate eye drops, applied twice daily for a period of four weeks. This regimen resulted in a progressive and sustained elevation of intraocular pressure (IOP), typically detectable from day 10, with peak values occurring between days 21 and 28. Upon confirmation of elevated IOP (>25 mmHg), animals in the treatment groups received the treatment as per the below:

[0141]

[0142]

[0143] *b.wt= body weight

[0144] Evaluation parameters:

[0145] • Intraocular pressure

[0146] 5 • Serum malondialdehyde (MDA) level

[0147] • Serum Superoxide dismutase (SOD) level

[0148] • Serum catalase level

[0149] • Serum glutathione peroxidase

[0150] • Aqueous humor levels of tumor necrosis factor alpha (TNF-a)

[0151] 10 All the data are expressed as mean ± standard deviation (SD) and were statistically analyzed using two-way analysis of variance (ANOVA), followed by Tukey’s post hoc multiple comparison test. A p-value of less than 0.05 was considered statistically significant.

[0152] Animal study results:

[0153] 15

[0154] Table 2:

[0155]

[0156]

[0157] Intraocular pressure: Intraocular pressure (IOP) plays a crucial role in the development and progression of glaucoma. Elevated IOP can damage the optic nerve, leading to irreversible vision loss. Monitoring and controlling IOP is essential to prevent or slow 5 disease progression. A reduction in intraocular pressure is desired to control glaucoma effectively, as it minimizes optic nerve damage. Moreover, a sustained decrease in IOP indicates the effectiveness of the chosen therapeutic intervention. Group-7 (Palmitoyl ethanolamide (PEA) + Forskolin + Rutin) showed a 21.31% greater reduction in intraocular pressure compared to the sum of their (G4, G5, G6) individual effects, 10 suggesting a synergistic effect of the combination in reducing elevated intraocular pressure and achieving better glaucoma control.

[0158] Table 3:

[0159]

[0160] 15

[0161] Malondialdehyde: Malondialdehyde (MDA) is a key biomarker of oxidative stress and lipid peroxidation, processes that contribute to retinal and optic nerve damage in glaucoma.

[0162] Elevated MDA levels indicate increased oxidative injury, which accelerates the progression of glaucomatous degeneration. Therefore, monitoring MDA provides valuable insight into 20 oxidative stress status in glaucoma patients. A decrease in malondialdehyde levels isdesired to control glaucoma, as it reflects reduced oxidative damage. Furthermore, a reduction in MDA levels suggests the effectiveness of the therapeutic intervention in mitigating oxidative stress and protecting ocular tissues. Group-7 (Palmitoylethanolamide (PEA) + Forskolin + Rutin) showed a 26.10% greater reduction in serum malondialdehyde 5 levels compared to the sum of their (G4, G5, G6) individual effects, suggesting a synergistic effect of the combination in controlling oxidative stress and offering better glaucoma management.

[0163] Table 4:

[0164] 10

[0165]

[0166] Superoxide dismutase: Superoxide dismutase (SOD) is a vital antioxidant enzyme that protects retinal and optic nerve cells from oxidative damage by neutralizing harmful superoxide radicals. In glaucoma, decreased SOD activity is associated with increased 15 oxidative stress, contributing to optic nerve degeneration and vision loss. Therefore, enhancing SOD levels is desirable to control glaucoma and preserve ocular health. An increase in SOD levels indicates effective mitigation of oxidative stress and reflects the protective impact of the therapeutic intervention on ocular tissues. Group-7 (Palmitoylethanolamide (PEA) + Forskolin + Rutin) demonstrated a 39.00% greater 20 increase in serum superoxide dismutase levels compared to the combined effects of G4, G5, and G6 individually, indicating a synergistic action of the combination in reducing oxidative stress and providing enhanced protection in glaucoma.Table 5:

[0167]

[0168] Catalase: Catalase is a key antioxidant enzyme that protects ocular tissues by breaking down hydrogen peroxide, a harmful reactive oxygen species, into water and oxygen. In glaucoma, reduced catalase activity contributes to oxidative stress, leading to optic nerve damage and vision loss. Therefore, increasing catalase levels is desirable to control glaucoma and protect retinal cells. Enhanced serum catalase levels indicate effective mitigation of oxidative stress. Moreover, a rise in catalase activity reflects the effectiveness of therapy in controlling glaucoma and preserving ocular health. Group-7 (Palmitoylethanolamide (PEA) + Forskolin + Rutin) demonstrated a 33.20% greater increase in serum catalase levels compared to the combined effects of G4, G5, and G6 individually, indicating a synergistic action of the combination in reducing oxidative stress and enhancing ocular protection in glaucoma.

[0169] Table 6:

[0170]

[0171]

[0172] Glutathione peroxidase: Glutathione peroxidase (GPx) is a crucial antioxidant enzyme that protects retinal and optic nerve cells by neutralizing hydrogen peroxide and lipid peroxides, preventing oxidative damage. In glaucoma, decreased GPx activity contributes 5 to increased oxidative stress, accelerating optic nerve degeneration and vision loss.

[0173] Therefore, increasing glutathione peroxidase levels is desirable to control glaucoma and safeguard ocular tissues. Enhanced serum GPx levels indicate effective reduction of oxidative stress. Moreover, a rise in GPx activity reflects the therapeutic efficacy in controlling glaucoma and preserving visual function. Group-7 (Palmitoylethanolamide, 10 Forskolin, and Rutin) produced a 25.56% greater increase in serum glutathione peroxidase levels compared to the combined effects of G4, G5, and G6, highlighting a synergistic effect in reducing oxidative stress and improving ocular protection in glaucoma.

[0174] Table 7:

[0175] 15

[0176]

[0177] Aqueous humor TNF-a: Tumor necrosis factor-alpha (TNF-a) in the aqueous humor is a pro-inflammatory cytokine that contributes to optic nerve damage and retinal ganglion cell death in glaucoma. Elevated levels of TNF-a are associated with increased inflammation 20 and accelerated progression of the disease. Therefore, reducing aqueous humor TNF-alevels is desirable to control glaucoma and protect ocular tissues. A decrease in TNF-a indicates effective suppression of inflammatory pathways. Moreover, reduced aqueous humor TNF-a levels reflect the therapeutic efficacy in managing glaucoma and preserving visual function. Group-7 (Palmitoylethanolamide, Forskolin, and Rutin) decreased aqueous humor TNF-a levels by 25.04% over the combined effects of G4-G6, demonstrating a synergistic effect in suppressing inflammation and enhancing ocular protection in glaucoma.

[0178] The results of the studies presented herein clearly demonstrate that the present invention provides a synergistic pharmaceutical composition comprising Palmitoylethanolamide, Forskolin, and Rutin, which represents a technical advance over existing approaches to glaucoma management. The combination exhibits an unexpected synergistic effect, achieving superior outcomes when compared to the individual components or their known dual combinations. The formulation can be developed in multiple dosage forms including tablets, capsules, sachets, suspensions, or ophthalmic preparations, thereby offering flexibility for clinical use and enhancing patient compliance.

[0179] The invention also demonstrates clear economic and industrial significance. By providing Palmitoylethanolamide, Forskolin, and Rutin together in a single synergistic composition, the invention offers a more convenient and cost-effective therapeutic option for glaucoma management compared to separate composition. Thus, the invention combines technical advantage with economic benefit and is capable of industrial application in the pharmaceutical sector, offering a practical, effective, and commercially viable solution for glaucoma management.

Claims

I / We claim:

1. A pharmaceutical composition comprising Palmitoylethanolamide, Forskolin, and Rutin, and one or more acceptable pharmaceutical excipient for the treatment of glaucoma.

2. The pharmaceutical composition as claimed in claim 1, wherein the ratio of Palmitoylethanolamide, Forskolin, and Rutin ranges from 1:0.0006:0.0066 to 1:5:8.

3. The pharmaceutical composition as claimed in claim 1, wherein:Palmitoylethanolamide is present in an amount ranging from 2 % to 99% w / w, Forskolin is present in an amount ranging from 0.02 % to 81% w / w, and Rutin is present in an amount ranging from 0.2 % to 90% w / w,based on the total weight of the composition.

4. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises:Palmitoylethanolamide in an amount ranging from 100 mg to 1500 mg, Forskolin in an amount ranging from 1 mg to 500 mg, andRutin in an amount ranging from 10 mg to 800 mg.

5. A kit comprising Palmitoylethanolamide, Forskolin, and Rutin, and one or more acceptable pharmaceutical excipient, wherein:Palmitoylethanolamide is present in an amount ranging from 100 mg to 1500 mg, Forskolin is present in an amount ranging from 1 mg to 500 mg, andRutin is present in an amount ranging from 10 mg to 800 mg,wherein Palmitoylethanolamide, Forskolin, and Rutin are either provided in a single composition or as separate compositions within the kit;and wherein the kit is intended for the treatment of glaucoma.

6. The pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipient is selected from diluents, disintegrants,binders, surfactants, lubricants, polymers, preservatives, antimicrobial agents, glidants, or mixtures thereof.

7. The pharmaceutical composition as claimed in claim 6, wherein the diluent is selected from microcrystalline cellulose, sucrose, lactose, lactose monohydrate, maltodextrin, calcium carbonate, mannitol, sorbitol, or mixtures thereof.

8. The pharmaceutical composition as claimed in claim 1, wherein the composition is fdled in a sachet or is formulated as a tablet, capsule, suspension, or any other suitable dosage form.

9. The pharmaceutical composition as claimed in claim 1, wherein the composition is intended for the treatment or prevention of ocular disorders selected from glaucoma, ocular hypertension, age-related macular degeneration, diabetic retinopathy, cataract, retinal ischemia, and other degenerative or vascular diseases of the eye.

10. A pharmaceutical composition for the treatment of glaucoma, comprising:Palmitoylethanolamide in an amount ranging from 100 mg to 1500 mg, Forskolin in an amount ranging from 1 mg to 500 mg, andRutin in an amount ranging from 10 mg to 800 mg,wherein the ratio of Palmitoylethanolamide, Forskolin, and Rutin ranges from 1:0.0006:0.0066 to 1:5:8,wherein the combination of Palmitoylethanolamide, Forskolin, and Rutin exhibits a synergistic effect in the treatment of glaucoma,wherein the composition is solid dosage form and for oral administration.

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