Synergistic bioactive composition to improve joint health

Abstract

The present invention relates to the field of nutraceuticals, specifically to a synergistic bioactive composition designed to improve joint health. This composition comprises Palmitoylethanolamide (PEA) and Cucumis sativus, aimed at reducing joint pain and protecting cartilage. It addresses the complex pain components of osteoarthritis, including both nociceptive pain, which stems from ongoing joint inflammation and tissue damage, and neuropathic pain, which indicates nerve damage. This nutraceutical composition provides a novel solution for mitigating the debilitating effects of osteoarthritis through oral administration, utilizing pharmaceutically acceptable excipients to ensure efficacy and safety.

Description

[0001] SYNERGISTIC BIOACTIVE COMPOSITION TO IMPROVE JOINT

[0002] HEALTH

[0003] RELATED APPLICATION:

[0004] The present application claims benefit of the Indian Provisional Application No. IN202421054393 filed on, July 16th, 2024 the entire contents of which are hereby incorporated by reference.

[0005] FIELD OF THE INVENTION:

[0006] The present invention relates to the field of nutraceuticals, specifically to a synergistic bioactive composition designed to improve joint health. This composition comprises Palmitoylethanolamide (PEA) and Cucumis saiivus. aimed at reducing joint pain and protecting cartilage. It addresses the complex pain components of osteoarthritis, including both nociceptive pain, which stems from ongoing joint inflammation and tissue damage, and neuropathic pain, which indicates nerve damage. By leveraging the dual mechanisms of PEA and Cucumis saiivus. the invention offers a comprehensive approach to managing osteoarthritis, enhancing joint function, reducing stiffness, and improving overall physical mobility. This nutraceutical composition provides a novel solution for mitigating the debilitating effects of osteoarthritis through oral administration, utilizing pharmaceutically acceptable excipients to ensure efficacy and safety.

[0007] BACKGROUND OF THE INVENTION:

[0008] Osteoarthritis (OA) is one of the most common degenerative joint diseases, affecting millions of people worldwide, particularly the elderly. It is characterized by the breakdown of joint cartilage and underlying bone, leading to pain, stiffness, swelling, and reduced mobility. As the disease progresses, it results in significant disability and a diminished quality of life. The primary symptoms of OA include joint pain, inflammation, and loss of function, which severely impair daily activities.

[0009] The pain associated with osteoarthritis has both nociceptive and neuropathic components. Nociceptive pain is the result of ongoing inflammation and damage to tissues surrounding the joints. This type of pain is typically attributed to the sensitization of peripheral nociceptive receptors located in the synovium (joint lining) and subchondral bone. Nociceptive pain manifests as an intense, sharp, or throbbing pain during movement or pressure on the joint, coupled with a persistent aching pain at rest. Neuropathic pain, on the other hand, is related to nerve damage and is often described as burning, shooting, or tingling pain. This dual nature of pain in OA complicates its management and requires a multifaceted treatment approach.

[0010] IN382053 provide a synergistic composition using Tamarindus indica and Curcuma longa extracts for the prevention or treatment of inflammation, arthritis, joint pain, and related conditions, formulated with suitable carriers for effective application. The composition offers enhanced efficacy in treating arthritis conditions compared to traditional treatments, with specific benefits including potent inhibition of inflammatory mediators, improved joint health, and reduced side effects commonly associated with current pharmaceutical options. The patent focuses on a synergistic composition using Tamarindus indica and Curcuma longa extracts for inflammation and arthritis, but does not include or explore the benefits of Palmitoylethanolamide or Cucumis sativus extract.

[0011] KR101162336 discloses a health nutraceutical composition aimed at enhancing osteoarthritis. It consists of specific proportions of ogar, thaw, and depressant extracted in hot water. The invention addresses the need for effective osteoarthritis treatments with natural ingredients. The composition comprising 33% ogar, 34% thaw, and 33% depressant mixed in 10-fold hot water, ultrasonically extracted at 40°C for 3 hours, filtered, and concentrated under reduced pressure. The patent discloses a composition for osteoarthritis treatment using specific proportions of ogar, thaw, and depressant, without considering the synergistic potential of combining Palmitoylethanolamide with Cucumis sativus extract.

[0012] US20200268827 provides a method for treating osteoarthritis by administering an extract of Alpinia oxyphylla. The extract is prepared using specific solvents and is formulated in various types. The invention offers a natural approach for osteoarthritis treatment. This patent provides a method for treating osteoarthritis with Alpinia oxyphylla extract but does not incorporate a dual mechanism of action involving Palmitoylethanolamide and Cucumis sativus for enhanced efficacy.

[0013] W02024 / 019499 discloses a pharmaceutical composition and health functional food for osteoarthritis treatment, focusing on a Pomegranate Radix extract. The inventions aim to provide anti-inflammatory effects, cartilage protection, and inhibition of chondrolytic enzymes. The patent focuses on a composition using Pomegranate Radix extract for osteoarthritis, lacking the inclusion of Palmitoylethanolamide and Cucumis sativus extract to address both nociceptive and neuropathic pain components.

[0014] EP2240190 describes a method for modulating inflammation by administering Biota orientalis extract. It further includes additional extracts like mussel, abalone, or shark cartilage. The invention aims to provide a nutraceutical composition for treating inflammation and associated disorders. This patent describes a method for modulating inflammation with Biota orientalis extract and other marine extracts, but does not consider the combined effects of Palmitoylethanolamide and Cucumis sativus extract for comprehensive osteoarthritis treatment.

[0015] US 10500240 provides method for treating osteoarthritis using a Terminalia chebula extract with defined chebulagic acid and chebulinic acid percentages. The extract shows antiinflammatory effects and potential for pain reduction. The invention aims to provide an effective treatment for osteoarthritis. The patent provides a method for treating osteoarthritis using Terminalia chebula extract, focusing on its anti-inflammatory effects without exploring the synergistic benefits of Palmitoylethanolamide and Cucumis sativus extract for joint health.

[0016] Traditional treatments for osteoarthritis primarily focus on managing symptoms. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed to reduce inflammation and relieve pain. However, long-term use of NSAIDs lead to gastrointestinal issues, cardiovascular problems, and other adverse effects. Analgesics and opioids are used for pain relief, but these also come with significant side effects and the risk of dependency. Other treatments include physical therapy, lifestyle modifications, and in severe cases, surgical interventions such as joint replacement.

[0017] In recent years, there has been increasing interest in the use of nutraceuticals for the management of osteoarthritis. Nutraceuticals are food-derived products that provide medical or health benefits, including the prevention and treatment of disease. They offer a promising alternative to conventional medications, with fewer side effects and the potential for long-term benefits.

[0018] Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide that has gained attention for its anti-inflammatory, analgesic, and neuroprotective properties.

[0019] Cucumis sativus. commonly known as cucumber, is a plant that has been traditionally used for its anti-inflammatory and analgesic properties.

[0020] The present invention introduces a synergistic nutraceutical composition that combines Palmitoylethanolamide (PEA) and Cucumis sativus extract to provide comprehensive management of osteoarthritis. This innovative composition targets both nociceptive and neuropathic pain components, offering a dual mechanism of action for effective pain control. The synergistic effects of PEA and Cucumis sativus extract are designed to provide enhanced relief from joint pain, reduce inflammation, and protect cartilage.

[0021] The composition comprises of pharmaceutically acceptable excipients to ensure stability, efficacy, and ease of administration. The specific ratios of PEA to Cucumis sativus extract have been carefully formulated to maximize therapeutic benefits. The composition is administered orally, providing a convenient and non-invasive option for individuals with osteoarthritis.

[0022] The synergistic nutraceutical composition shall achieve the following outcomes:

[0023] • Significant reduction in joint pain and stiffness

[0024] • Improvement in physical function and joint mobility

[0025] • Protection and preservation of cartilage • Control of both nociceptive and neuropathic pain components of osteoarthritis

[0026] • Reduction of inflammation

[0027] This synergistic composition offers a promising solution for the comprehensive management of osteoarthritis, improving the quality of life for individuals suffering from this debilitating condition.

[0028] In conclusion, the present invention represents a significant advancement in the field of nutraceuticals for joint health. By combining Palmitoylethanolamide and Cucumis sativus extract, this synergistic composition addresses the complex nature of osteoarthritis pain and provides a holistic approach to improving joint health and function. The innovative dual mechanism of action offers an effective, safe, and convenient alternative to traditional osteoarthritis treatments, with the potential to transform the management of this chronic condition.

[0029] The ability of composition to work synergistically with existing pharmacological treatments further enhances its applicability and potential benefits in managing the joint health.

[0030] OBJECTIVE OF THE INVENTION:

[0031] The primary objective of the present invention is to provide a synergistic nutraceutical composition for improving joint health, particularly targeting osteoarthritis.

[0032] The Prime objective of the present invention is to combine Palmitoylethanolamide and Cucumis sativus extract to reduce joint pain and inflammation effectively.

[0033] One objective of the present invention is to address both nociceptive and neuropathic components of osteoarthritis pain through a dual mechanism of action.

[0034] One more objective of the present invention is to improve joint function and reduce stiffness in individuals suffering from osteoarthritis. Another objective of the present invention is to exert a neuroprotective effect, potentially preventing or reducing nerve damage associated with osteoarthritis.

[0035] Yet another objective of the present invention is to produce an anti-neuroinflammatory effect, thereby reducing overall inflammation in the joints.

[0036] One more objective of the present invention is to enhance physical function and joint mobility through the synergistic effects of Palmitoylethanolamide and Cucumis sativus extract.

[0037] Another objective of the present invention is to protect cartilage from degradation, thereby preserving joint structure and function.

[0038] One more objective of the present invention is to provide a composition which is administered orally for ease of use and patient compliance.

[0039] Yet another objective of the present invention is to formulate the composition with pharmaceutically acceptable excipients to ensure stability, efficacy, and safety.

[0040] One more objective of the present invention is to explore the optimal ratios of Palmitoylethanolamide and Cucumis sativus extract to maximize the synergistic effects on joint health.

[0041] One more objective of the present invention is to demonstrate the efficacy of the composition in suitable animal models for osteoarthritis, providing a basis for clinical application.

[0042] Another objective of the present invention is to offer a natural and safe alternative to conventional pharmaceutical treatments for osteoarthritis, with reduced side effects. Yet another objective of the present invention is to improve the quality of life for individuals suffering from osteoarthritis by providing a comprehensive and effective treatment option.

[0043] SUMMARY OF THE INVENTION:

[0044] The present invention relates to a synergistic nutraceutical composition aimed at improving joint health, particularly in individuals suffering from osteoarthritis. The composition comprises Palmitoylethanolamide and Cucumis sativus extract, which work together to provide pain relief and protect cartilage from degradation.

[0045] The primary aspect of the present invention is to provide a nutraceutical composition that effectively improves joint health by combining Palmitoylethanolamide and Cucumis sativus extract. This combination has been found to reduce joint pain and inflammation while protecting cartilage.

[0046] One more aspect of the present invention is to address the nociceptive and neuropathic components of osteoarthritis pain. By targeting both types of pain, the composition offers comprehensive pain relief, addressing ongoing joint inflammation, tissue damage, and nerve damage.

[0047] Another aspect of the present invention is to enhance joint function and reduce stiffness. Palmitoylethanolamide and Cucumis sativus extract synergistically improve joint mobility and physical function, making daily activities easier for individuals with osteoarthritis.

[0048] Additionally, one aspect of the present invention is to leverage the neuroprotective and anti- neuroinflammatory effects of Palmitoylethanolamide. This compound helps to protect nerves from damage and reduce inflammation in the joints, contributing to overall joint health. One aspect of the present invention is to improve physical function and mobility with Cucumis sativus extract. This natural extract has been shown to reduce joint pain, making movement easier and less painful for osteoarthritis sufferers.

[0049] One more aspect of the present invention is to protect cartilage from degradation. The composition helps to preserve joint structure and function, preventing further damage and deterioration overtime.

[0050] An aspect of the present invention is to develop a composition which is administered orally. This ensures ease of use and better patient compliance, as taking an oral supplement is convenient and non-invasive.

[0051] One aspect of the present invention is to use pharmaceutically acceptable excipients to stabilize the composition. These excipients ensure the efficacy and safety of the nutraceutical product, making it suitable for long-term use.

[0052] Additionally, one more aspect of the present invention is to determine the optimal ratios of Palmitoylethanolamide and Cucumis sativus extract. By finding the best combination, the composition maximizes its synergistic effects on joint health.

[0053] One aspect of the present invention is to demonstrate the analgesic and cartilage-protective effects of the composition using suitable animal models for osteoarthritis. This provides a solid basis for the effectiveness of the treatment in clinical settings.

[0054] Another aspect of the present invention is to offer a natural and safe alternative to conventional pharmaceutical treatments for osteoarthritis. The composition reduces side effects commonly associated with pharmaceutical options while providing effective relief.

[0055] Yet another aspect of the present invention is to improve the overall quality of life for individuals suffering from osteoarthritis. By providing a comprehensive and effective treatment option, the nutraceutical composition helps individuals manage their condition and maintain an active lifestyle. One further aspect of the present invention is the use of pharmaceutically acceptable excipients to ensure the stability and effectiveness of the composition. These excipients include diluents, binders, surfactants, lubricants, glidants, additives, solvents, or mixtures thereof, all chosen to support the active ingredients and improve the overall formulation.

[0056] BRIEF DESCRIPTION OF THE DRAWINGS:

[0057] FIGURE-1: Study Results Comparative Graph for Evaluation of The Synergistic Effect of Palmitoylethanolamide and Cucumis Sativus Extract In Animal Model For Movement Evoked Pain

[0058] FIGURE-2: Study Results Comparative Graph for Evaluation of The Synergistic Effect of Palmitoylethanolamide and Cucumis Sativus Extract In Animal Model For Randall Selitto Test

[0059] FIGURE-3: Study Results Comparative Graph for The Synergistic Effect of Palmitoylethanolamide and Cucumis Sativus Extract In Animal Model For Weight Bearing capacity.

[0060] FIGURE-4: Study Results Comparative Graph for Evaluation of The Synergistic Effect of Palmitoylethanolamide and Cucumis Sativus Extract In Animal Model For Von Frey Test

[0061] FIGURE-5: Study Results Comparative Graph for Evaluation of The Synergistic Effect of Palmitoylethanolamide and Cucumis Sativus Extract In Animal Model For Serum II- ip

[0062] FIGURE-6: Study Results Comparative Graph for Evaluation of The Synergistic Effect of Palmitoylethanolamide and Cucumis Sativus Extract In Animal Model For Serum Mmp- 13

[0063] DETAIEED DESCRIPTION OF THE INVENTION: The following detailed description of the present subject matter the various embodiments. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present subject matter. Other embodiments may be utilized, and changes may be made without departing from the scope of the present subject matter.

[0064] References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.

[0065] The present invention relates to a synergistic nutraceutical composition designed to improve joint health, particularly targeting the symptoms and underlying causes of osteoarthritis. The composition consists primarily of Palmitoylethanolamide and Cucumis sativus extract, which work together to reduce joint pain and provide cartilage protection. This detailed description includes various embodiments of the invention, highlighting its unique properties and applications.

[0066] Osteoarthritis is a chronic joint disorder characterized by joint pain, inflammation, and cartilage breakdown. The pain associated with osteoarthritis includes both nociceptive and neuropathic components. Nociceptive pain results from ongoing joint inflammation and surrounding tissue damage, while neuropathic pain indicates a degree of nerve damage. This dual nature of pain in osteoarthritis necessitates a comprehensive treatment approach.

[0067] The present invention provides a synergistic nutraceutical composition comprising Palmitoylethanolamide and Cucumis sativus extract along with their pharmaceutically acceptable salts, derivative, isomer, or metabolite thereof. The combination of these two bioactive compounds targets both nociceptive and neuropathic pain mechanisms, providing comprehensive relief from osteoarthritis symptoms. As per the present invention the composition is nutraceutical and / or pharmaceutical composition. The nutraceutical composition and pharmaceutical composition are used interchangeably.

[0068] Palmitoylethanolamide (PEA): PEA is a naturally occurring fatty acid amide that has shown significant potential in reducing inflammation and pain. It improves joint function, reduces joint pain and stiffness, exerts a neuroprotective effect, and produces an anti- neuroinflammatory effect.

[0069] Cucumis sativus Extract (Cucumber): Cucumber extract is rich in anti-inflammatory compounds and antioxidants. It reduces joint pain, improves physical functions, enhances joint mobility, and protects cartilage from degradation.

[0070] The synergistic action of Palmitoylethanolamide and Cucumis sativus extract addresses both nociceptive and neuropathic pain components of osteoarthritis:

[0071] Nociceptive Pain Control: The composition helps reduce inflammation in the joints, thereby decreasing the sensitization of peripheral nociceptive receptors in the synovium and subchondral bone.

[0072] Neuropathic Pain Control: Palmitoylethanolamide's neuroprotective properties help reduce nerve damage, while Cucumis sativus extract's anti-inflammatory effects contribute to overall pain relief.

[0073] The primary embodiment of the present invention is a synergistic nutraceutical composition for joint health improvement comprising Palmitoylethanolamide and Cucumis sativus extract in a specific ratio. This composition is designed to reduce joint pain, improve physical functions, enhance joint mobility, and protect cartilage from degradation, thereby providing comprehensive relief from osteoarthritis symptoms.

[0074] The synergistic nutraceutical composition of the present invention is used for the prevention, management, or treatment of joint disorders selected from one or more of the following: osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gouty arthritis, ankylosing spondylitis, or other degenerative or inflammatory joint conditions, and is effective in improving joint health and function.

[0075] One embodiment of the present invention is a synergistic nutraceutical composition for joint health improvement comprising Palmitoylethanolamide and Cucumis sativus extract in a ratio ranging from 1 :0.003 to 1 :200.

[0076] Another embodiment of the present invention is a synergistic nutraceutical composition wherein the amount of Cucumis sativus extract is present in the range of 0.5% to 200% of Palmitoylethanolamide .

[0077] Yet another embodiment of the present invention is a synergistic nutraceutical composition wherein the amount of Palmitoylethanolamide is present in the range of 50% to 20000% of Cucumis sativus extract.

[0078] One more embodiment of the present invention is a synergistic nutraceutical composition further comprising pharmaceutically acceptable excipients selected from a diluent, a binder, a surfactant, a lubricant, a glidant, an additive, a solvent, or mixtures thereof.

[0079] Another embodiment of the present invention is a synergistic nutraceutical composition wherein the Palmitoylethanolamide is present in a micronized form to enhance bioavailability.

[0080] Yet another embodiment of the present invention is a method for improving joint health comprising administering an effective dose of the synergistic nutraceutical composition orally.

[0081] One embodiment of the present invention is a method for reducing joint pain and osteoarthritis symptoms by administering an effective dose of the synergistic nutraceutical composition. Another embodiment of the present invention is a method for protecting cartilage from degradation by administering an effective dose of the synergistic nutraceutical composition.

[0082] Yet another embodiment of the present invention is a method for improving physical functions and reducing joint stiffness by administering an effective dose of the synergistic nutraceutical composition.

[0083] One more embodiment of the present invention is a method for controlling nociceptive and neuropathic pain components of osteoarthritis by administering an effective dose of the synergistic nutraceutical composition.

[0084] The synergistic nutraceutical composition is most effective when Palmitoylethanolamide and Cucumis sativus extract are present in specific ratios. The preferred ratio ranges from 1:0.003 to 1:200, with the amount of Cucumis sativus extract present in the range of 0.5% to 200% of Palmitoylethanolamide. Conversely, the amount of Palmitoylethanolamide is ranging from 50% to 20000% of Cucumis sativus extract.

[0085] To ensure stability, efficacy, and safety, the composition include pharmaceutically acceptable excipients such as diluents, binders, surfactants, lubricants, glidants, additives, solvents, or mixtures thereof.

[0086] The present invention offers several advantages over traditional osteoarthritis treatments:

[0087] • Comprehensive Pain Relief: By targeting both nociceptive and neuropathic pain components, the composition provides more effective pain relief.

[0088] • Cartilage Protection: The composition helps preserve joint structure and function, preventing further damage.

[0089] • Improved Joint Function: The composition enhances joint mobility and reduces stiffness, improving overall physical function.

[0090] • Natural and Safe: The use of natural bioactive compounds reduces the risk of side effects commonly associated with pharmaceutical treatments.

[0091] • Convenient Administration: The various formulations ensure ease of use and patient compliance. In one more embodiment of the present invention, the nutraceutical composition is formulated into various dosage forms, such as tablets, fdm -coated tablets, chewable tablets, effervescent tablets, dispersible tablets, orally disintegrating tablets, capsules including hard gelatin and soft gelatin capsules, powders, granules, sachets, pellets, oral liquids, syrups, suspensions, solutions, emulsions, caplets, mini-tablets, or any other pharmaceutically acceptable oral dosage form, depending on the preferences and needs of the target population.

[0092] Pharmaceutically acceptable excipients are included in the composition to ensure stability, efficacy, and ease of administration. These excipients include diluents, binders, surfactants, lubricants and glidants, or mixtures thereof.

[0093] Diluents are selected one or more from Microcrystalline cellulose, Calcium carbonate, Dicalcium phosphate, Lactose monohydrate, Sorbitol, Mannitol, Starch, Maltodextrin, Pregelatinized starch, Croscarmellose sodium, Guar gum, Xanthan gum, Sodium alginate, Polyvinylpyrrolidone (PVP), Sodium carboxymethyl cellulose (CMC), Ammonium alginate, Calcium lactate, Calcium phosphate dibasic anhydrous, Calcium phosphate dibasic dihydrate, Calcium phosphate tribasic, Calcium silicate, Calcium sulfate, Cellulose powdered, Cellulose silicified microcrystalline, Cellulose acetate, Com starch and Pregelatinized starch, Dextrates, Dextrin, Dextrose, Erythritol, Ethylcellulose, Fructose, Fumaric acid, Glyceryl palmito stearate, Isomalt, Kaolin, Lactitol, Lactose anhydrous, Lactose monohydrate and Com starch, Lactose monohydrate and Povidone, Lactose monohydrate and Lactose spray-dried, Lactose monohydrate and Microcrystalline cellulose, Magnesium carbonate, Magnesium oxide, Maltitol, Maltose, Polydextrose, Polymethacrylates, Simethicone, Sodium chloride, Starch sterilizable maize, Sucrose, Sugar compressible, Sugar confectioner’s, Sugar spheres, Sulfobutylether b- cyclodextrin, Sunflower oil, Talc, Tragacanth, Trehalose, Xylitol and mixtures thereof.

[0094] Binders are selected one or more from Starch, Pregelatinized starch, Polyvinylpyrrolidone (PVP), Methylcellulose, Hypromellose, Hydroxypropyl cellulose (HPC), Sodium alginate, Xanthan gum, Acacia. Agar, Alginic acid, Calcium carbonate, Calcium phosphate tribasic, Calcium lactate, Carbomer, Carboxymethylcellulose sodium, Carrageenan, Cellulose acetate phthalate, Ceratonia, Microcrystalline cellulose, Chitosan, Copovidone, Cottonseed oil, Dextrates, Dextrin, Dextrose, Ethylcellulose, Gelatin, Liquid glucose, Glyceryl behenate, Guar gum, Hydroxyethyl cellulose, Hydroxyethylmethyl cellulose, Hydroxypropyl starch, Lactose anhydrous, Spray-dried lactose, Low- substituted hydroxypropyl cellulose, Inulin, Monohydrate lactose, Magnesium aluminum silicate, Maltodextrin, Maltose, Methylcellulose, Pectin, Poloxamer, Polycarbophil, Polydextrose, Polyethylene oxide, Polymethacrylates, Povidone, Sucrose, Sunflower oil, Hydrogenated vegetable oil, Vitamin E, Polyethylene glycol succinate, Zein, Tragacanth, Polyethylene glycol, Polyvinylpyrrolidone, Stearic acid, Tricaprylin and mixtures thereof.

[0095] Surfactants are selected one or more from Sodium lauryl sulfate, Polysorbate 80, Polysorbate 20, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan monostearate, Cetyltrimethylammonium bromide (CTAB), Poloxamer, Polyethylene glycol, Sodium dodecylbenzene sulfonate, Glycerol monostearate, Tween 80. Benzalkonium chloride, Benzethonium chloride, Cetylpyridinium chloride, Docusate sodium, Glycine, Glycofurol, Hypromellose, Phospholipids, Polyoxyethylene alkyl ethers, Polyoxyethylene castor oil derivatives, Polyoxyethylene sorbitan fatty acid esters, Polyoxyethylene stearates, Sodium lauryl sulfate, Sorbitan esters (sorbitan fatty acid esters), Tricaprylin and mixtures thereof.

[0096] Lubricants and / or glidants are selected one or more from Magnesium stearate, Calcium stearate, Zinc stearate, Stearic acid, Sodium stearyl fumarate, Talc, Polyethylene glycol, Colloidal Silicon dioxide, Colloidal silica, Hydrogenated vegetable oil, Sodium benzoate, Polyvinyl acetate, Glyceryl behenate, Canola oil, Castor oil, Glyceryl monostearate, Glyceryl palmitostearate, Lauric acid, Leucine, Light mineral oil, Mineral oil, Magnesium lauryl sulfate, Myristic acid, Octyldodecanol, Palmitic acid, Poloxamer, Polyvinyl alcohol, Potassium benzoate, Sodium hyaluronate, Sodium lauryl sulfate, Spray-dried lactose, Starch sterilizable maize, Tricaprylin, Sodium chloride, Tribasic calcium phosphate, Powdered cellulose, Magnesium oxide, Magnesium trisilicate, Magnesium silicate, Silicon dioxide, and mixtures thereof. In one embodiment, a pharmaceutical composition for improvement in joint health comprising Palmitoylethanolamide, Cucumis sativus extract and one or more acceptable pharmaceutical excipients.

[0097] In another embodiment, the pharmaceutical composition further comprise one or more diluents, disintegrants, binders, surfactants, lubricants and glidants.

[0098] In another embodiment, the pharmaceutical composition contains Palmitoylethanolamide in range from 10 mg to 2000 mg per unit dose.

[0099] In another embodiment, the pharmaceutical composition contains Cucumis sativus extract in range from 10 mg to 1000 mg per unit dose.

[0100] In one embodiments of the present invention include process for preparation of composition having various steps including weighing of all ingredients individually using a calibrated balance and the weighed materials are sifted through a #40 mesh to remove foreign matter and ensure uniformity. The sifted ingredients obtained are transferred to a blender and mixed for 10 minutes to achieve homogeneity. A binder solution is prepared by dissolving the specified binder (either hypromellose or polyvinyl pyrrolidone) in purified water with continuous stirring until clear. The dry mix is then transferred to a rapid mixer granulator, and the binder solution is added gradually. Granulation continued until a uniform wet mass is obtained. The wet mass is dried in a fluid bed dryer at 60-65°C until the moisture content fall below 2.5% w / w. The dried granules are sifted through a #20 mesh and oversized granules obtained are milled and re-sifted through a #20 mesh. Magnesium stearate, Zinc stearate, talc and colloidal silicon dioxide are added to the sifted granules and blended for 5 minutes for lubrication. The lubricated blend is then compressed into tablets using rotary compression equipment. The core tablets are coated with a film using a perforated coating pan under controlled conditions. The coated tablets obtained are sorted on an inspection belt, and defective units are removed manually. The final tablets are packed into HDPE containers with desiccant or into Suitable packs, labelled, and stored under recommended conditions. The present invention provides a synergistic bioactive composition comprising of Palmitoylethanolamide and Cucumis sativus extract along with their pharmaceutically acceptable salts, derivative, isomer, or metabolite thereof to reduce joint pain & osteoarthritis wherein the composition provides cartilage protection.

[0101] The synergistic nutraceutical composition as per the present invention contains Cucumis sativus and Palmitoylethanolamide which are present in the ratio of 1:0.005 to 1:200

[0102] The synergistic nutraceutical composition as per the present invention comprise of Cucumis sativus which is present in the range of 0.5 to 200% of Palmitoyl ethanolamide.

[0103] The synergistic nutraceutical composition as per the present invention comprise of Palmitoylethanolamide which is present in the range of 50 to 20000 % of Cucumis sativus extract, wherein Palmitoylethanolamide is present in micronized form.

[0104] The synergistic nutraceutical composition as per the present invention is formulated with pharmaceutically acceptable excipients which are selected from a diluent, a binder, a surfactant, a lubricant, a glidant an additive, a solvent or mixtures thereof.

[0105] The synergistic nutraceutical composition as per the present invention is formulated for oral administration of an effective dose of the composition controls nociceptive and neuropathic pain component of osteoarthritis.

[0106] In one of the embodiments, the present invention provides a pharmaceutical composition for improving joint health, comprising Palmitoylethanolamide or a pharmaceutically acceptable salt, derivative, isomer, or metabolite thereof; Cucumis sativus or a pharmaceutically acceptable salt, derivative, isomer, or metabolite thereof; and one or more pharmaceutically acceptable excipients; wherein, upon oral administration, the combination of Palmitoylethanolamide and Cucumis sativus results in a synergistic effect, providing at least a 25% greater reduction in serum interleukin- 1 beta (IL-ip) levels compared to the combined effect of Palmitoylethanolamide and Cucumis sativus administered individually. In one another embodiment, the present invention provides a pharmaceutical composition comprising Palmitoylethanolamide in an amount ranging from 10 mg to 2000 mg per unit dose; and Cucumis sativus in an amount ranging from 10 mg to 1000 mg per unit dose; wherein the ratio of Cucumis sativus to Palmitoylethanolamide ranges from 1:0.005 to 1:200; wherein the composition is formulated for oral administration; wherein the composition is intended for the prevention, management, or treatment of joint disorders, including osteoarthritis; and wherein, upon oral administration, the combination of Palmitoylethanolamide and Cucumis sativus produces a synergistic effect, resulting in at least a 23.17% higher pain threshold, as assessed by the Randall-Selitto test, compared to the sum of effects observed when Palmitoylethanolamide and Cucumis sativus are administered individually.

[0107] The synergistic nutraceutical composition as per the present invention is formulated in oral administration of an effective dose of the composition improves joint function and reduces inflammation.

[0108] The composition of the present invention can be supplied as a kit comprising the individual composition. The composition of the present invention may also be provided as two separate compositions in a kit, wherein one composition comprises Palmitoylethanolamide, and another composition comprises Cucumis sativus extract, both compositions intended for simultaneous administration to a person in need thereof.

[0109] EXAMPLE-1: GENERAL COMPOSITION

[0110] Following is a general composition formula as per the present invention:

[0111] General Procedure for preparation for Example-1 to 6: Step-1) All ingredients were weighed individually using a calibrated balance and verified against the respective formulation table;

[0112] Step-2) The weighed materials as per step-1 were sifted through a #40 mesh to remove foreign matter and ensure uniformity;

[0113] Step-3) The sifted ingredients obtained in step-2 were transferred to a blender and mixed for 10 minutes to achieve homogeneity;

[0114] Step-4) A binder solution was prepared by dissolving the specified binder (Hypromellose or polyvinyl pyrrolidone) in purified water with continuous stirring until clear;

[0115] Step-5) The dry mix from Step-3 was transferred to a rapid mixer granulator, and the binder solution from Step-4 was added gradually. Granulation continued until a uniform wet mass was obtained;

[0116] Step-6) The wet mass from Step 5 was dried in a fluid bed dryer at 60-65°C until the moisture content fell below 2.5% w / w. The dried granules were sifted through a #20 mesh;

[0117] Step-7) Oversized granules obtained in step-6 were milled and re-sifted through a #20 mesh. Magnesium stearate, Zinc stearate, talc and colloidal silicon dioxide were added to the sifted granules and blended for 5 minutes for lubrication;

[0118] Step-8) The lubricated blend from Step-7 was compressed into tablets using rotary compression equipment. The core tablets were coated with a film using a perforated coating pan under controlled conditions;

[0119] Step-9) The coated tablets obtained in step-8 were sorted on an inspection belt, and defective units were removed manually;

[0120] Step- 10) The final tablets of step-9 were packed into HDPE containers with desiccant or into Suitable packs, labelled, and stored under recommended conditions.

[0121] EXAMPLE-2: COMPOSITION TRIAL NO. 1 to 3

[0122] EXAMPLE-3: COMPOSITION TRIAL NO. 4 to 5 EXAMPLE-4: COMPOSITION TRIAL NO. 6 to 8

[0123] EXAMPLE S: COMPOSITION TRIAL NO. 9 to 10

[0124] EXAMPLE-6: COMPOSITION TRIAL NO. 11 to 14 ANIMAL STUDY BRIEF:

[0125] Objective: Evaluation of the Synergistic Anti-Osteoarthritic Effects of Palmitoylethanolamide and Cucumis sativus in Monosodium lodoacetate (MIA)-Induced Osteoarthritis in Wistar Rats.

[0126] Materials and Methods: Animals: Female Wistar rats (180-270 g), acclimatized for 5 days.

[0127] Induction of osteoarthritis: All animals were divided into the groups mentioned below, each containing 6 animals. Osteoarthritis was induced by administering an intra-articular injection of MIA (2 mg in 25 pL saline) into the right knee joint of each animal in all groups except the normal group. Treatments were administered for 28 days as described below.

[0128] Treatment groups:

[0129] BID: Twice daily b.wt: Body weight

[0130] Outcome measures:

[0131] • Movement-evoked pain

[0132] • Randall-Selitto test

[0133] • Weight bearing capacity

[0134] • Von Frey test paw withdrawal threshold

[0135] • Serum IL- ip

[0136] • Serum MMP-13

[0137] Statistical Analysis: All measurements were statistically analyzed using one-way ANOVA followed by Dunnett's multiple comparison test.

[0138] The results of the study are presented in the examples below. EXAMPLE-7: STUDY RESULTS FOR EVALUATION OF THE SYNERGISTIC

[0139] EFFECT OF PALMITOYLETHANOLAMIDE AND CUCUMIS SATIVUS

[0140] EXTRACT IN ANIMAL MODEL FOR MOVEMENT EVOKED PAIN

[0141] 5

[0142] The combination of Palmitoylethanolamide and Cucumis sativus (S. no. 6) has shown a greater effect in reducing movement-evoked pain compared to the Palmitoylethanolamide alone group (S. no. 4) and the Cucumis sativus alone group (S. no. 5). This suggests a synergistic effect of the Palmitoylethanolamide and Cucumis sativus combination. All 10 treatment groups showed a reduction in movement-evoked pain compared to the control group.

[0143] EXAMPLE-8: STUDY RESULTS FOR EVALUATION OF THE SYNERGISTIC

[0144] EFFECT OF PALMITOYLETHANOLAMIDE AND CUCUMIS SATIVUS

[0145] 15 EXTRACT IN ANIMAL MODEL FOR RANDALL SELITTO TEST

[0146]

[0147] The combination of Palmitoyl ethanolamide and Cucumis sativus (S. no. 6) showed a higher pain threshold (pain-bearing capacity) compared to the Palmitoylethanolamide alone group (S. no. 4) and the Cucumis sativus alone group (S. no. 5), as assessed by the Randall-Selitto 5 test. This suggests a synergistic effect of the Palmitoylethanolamide and Cucumis sativus combination. All treatment groups showed a higher pain threshold compared to the control group.

[0148] EXAMPLE-9: STUDY RESULTS FOR EVALUATION OF THE SYNERGISTIC 10 EFFECT OF PALMITOYLETHANOLAMIDE AND CUCUMIS SATIVUS EXTRACT IN ANIMAL MODEL FOR WEIGHT BEARING CAPICITY The combination of Palmitoyl ethanolamide and Cucumis sativus (S. no. 6) showed a higher weight-bearing capacity compared to the Palmitoylethanolamide alone group (S. no. 4) and the Cucumis sativus alone group (S. no. 5). A higher weight-bearing capacity indicates lower pain. This suggests a synergistic effect of the Palmitoylethanolamide and Cucumis 5 sativus combination. All treatment groups showed a higher weight-bearing capacity compared to the control group.

[0149] EXAMPLE-10: STUDY RESULTS FOR EVALUATION OF THE SYNERGISTIC

[0150] EFFECT OF PALMITOYLETHANOLAMIDE AND CUCUMIS SATIVUS 10 EXTRACT IN ANIMAL MODEL FOR VON FREY TEST

[0151] The combination of Palmitoyl ethanolamide and Cucumis sativus (S. no. 6) showed a higher pain threshold (pain-bearing capacity) compared to the Palmitoylethanolamide alone group 15 (S. no. 4) and the Cucumis sativus alone group (S. no. 5), as assessed using the Von Frey test. This suggests a synergistic effect of the Palmitoylethanolamide and Cucumis sativus combination. All treatment groups showed a higher pain threshold compared to the control group.

[0152] 20 EXAMPLE-11: STUDY RESULTS FOR EVALUATION OF THE SYNERGISTIC EFFECT OF PALMITOYLETHANOLAMIDE AND CUCUMIS SATIVUS EXTRACT IN ANIMAL MODEL FOR SERUM IL-10

[0153] The combination of Palmitoylethanolamide and Cucumis sativus (S. no. 6) showed a greater reduction in serum IL-ip levels compared to the Palmitoylethanolamide alone 5 group (S. no. 4) and the Cucumis sativus alone group (S. no. 5). This suggests a synergistic effect of the Palmitoylethanolamide and Cucumis sativus combination. All treatment groups showed a reduction in serum IL- 1 p levels compared to the control group. Reduction in IL- ip indicates reduction in inflammation.

[0154] 10 EXAMPLE-12: STUDY RESULTS FOR EVALUATION OF THE SYNERGISTIC EFFECT OF PALMITOYLETHANOLAMIDE AND CUCUMIS SATIVUS EXTRACT IN ANIMAL MODEL FOR SERUM MMP-13

[0155] The combination of Palmitoylethanolamide and Cucumis sativus (S. no. 6) showed a greater reduction in serum MMP-13 levels compared to the Palmitoylethanolamide alone group (S. no. 4) and the Cucumis sativus alone group (S. no. 5). This suggests a synergistic effect of the Palmitoylethanolamide and Cucumis sativus combination. All treatment groups showed a reduction in serum MMP-13 levels compared to the control group. Reduction in MMP-13 indicates reduction in cartilage degradation.

[0156] The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasized in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.

Claims

We Claim:

1. A pharmaceutical composition for improving joint health, comprising: a) Palmitoylethanolamide or a pharmaceutically acceptable salt, derivative, isomer, or metabolite thereof; b) Cucumis sativus or a pharmaceutically acceptable salt, derivative, isomer, or metabolite thereof; and c) one or more pharmaceutically acceptable excipients; wherein the ratio of Cucumis sativus to Palmitoylethanolamide ranges from 1:0.005 to 1:200.

2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from diluents, disintegrants, binders, surfactants, lubricants, glidants, and mixtures thereof.

3. The pharmaceutical composition as claimed in claim 1 , wherein Palmitoylethanolamide is present in an amount ranging from 10 mg to 2000 mg per unit dose.

4. The pharmaceutical composition as claimed in claim 1, wherein Cucumis sativus is present in an amount ranging from 10 mg to 1000 mg per unit dose.

5. The pharmaceutical composition as claimed in claim 1, wherein: a) Cucumis sativus is present in an amount ranging from 0.5% to 200% relative to the amount of Palmitoylethanolamide; and b) Palmitoylethanolamide is present in an amount ranging from 50% to 20,000% relative to the amount of Cucumis sativus.

6. The pharmaceutical composition as claimed in claim 1, wherein the composition is indicated for the prevention, management, or treatment of joint disorders selected from one or more of the following: osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gouty arthritis, ankylosing spondylitis, or other degenerative or inflammatory joint conditions, and is effective in improving joint health and function.

7. The pharmaceutical composition as claimed in claim 1, wherein, upon oral administration, the combination of Palmitoylethanolamide and Cucumis sativus results in a synergistic effect, providing at least a 25% greater reduction in serum interleukin- 1 beta (IL- 1 P) levels compared to the combined effect of Palmitoylethanolamide and Cucumis sativus administered individually.

8. The pharmaceutical composition as claimed in claim 1, wherein the composition is formulated for oral administration and is presented in a dosage form selected from the group comprising tablets, fdm-coated tablets, chewable tablets, effervescent tablets, dispersible tablets, orally disintegrating tablets, capsules including hard gelatin and soft gelatin capsules, powders, granules, sachets, pellets, oral liquids, syrups, suspensions, solutions, emulsions, caplets, mini-tablets, or any other pharmaceutically acceptable oral dosage form.

9. A kit for improving joint health, comprising: a) Palmitoylethanolamide; and b) Cucumis sativus; or their pharmaceutically acceptable salts, derivatives, isomers, or metabolites thereof; wherein the Palmitoylethanolamide and Cucumis sativus are provided either in a single pharmaceutical composition or in separate pharmaceutical compositions.

10. A pharmaceutical composition comprising: a) Palmitoylethanolamide in an amount ranging from 10 mg to 2000 mg per unit dose; and b) Cucumis sativus in an amount ranging from 10 mg to 1000 mg per unit dose; wherein the ratio of Cucumis sativus to Palmitoylethanolamide ranges from 1:0.005 to 1:200; wherein the composition is formulated for oral administration; wherein the composition is intended for the prevention, management, or treatment of joint disorders, including osteoarthritis; and wherein, upon oral administration, the combination of Palmitoylethanolamide and Cucumis sativus produces a synergistic effect, resulting in at least a 23. 17% higher pain threshold, as assessed by the Randall-Selitto test, compared to the sum of effects observed when Palmitoylethanolamide and Cucumis sativus are administered individually.

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