A synergistic composition for controlling headache disorders

Abstract

The present invention relates to a synergistic composition for controlling headache disorders. The composition comprises Palmitoylethanolamide, Magnesium, and Ginkgolide B, along with pharmaceutically acceptable excipients. The invention addresses primary headache disorders, including migraine and tension-type headaches, which represent the majority of headache disorders. Palmitoylethanolamide exhibits analgesic and anti-inflammatory properties, down¬ regulating pro-inflammatory and nociceptive pathways. Magnesium contributes to the reduction of headache symptoms, while Ginkgolide B, derived from Ginkgo biloba, enhances the therapeutic effect. Animal studies have demonstrated the synergistic efficacy of this combination in reducing the frequency, duration, and severity of headache symptoms, both independently and when used with standard treatments.

Description

[0001] A SYNERGISTIC COMPOSITION FOR CONTROLLING HEADACHE DISORDERS

[0002] RELATED APPLICATION:

[0003] The present application claims benefit of the Indian Provisional Application No. IN202421081215 filed on, October 24th, 2024 the entire contents of which are hereby incorporated by reference.

[0004] FIELD OF THE INVENTION:

[0005] The present invention pertains to the field of pharmaceutical sciences, and more specifically, to pharmaceutical compositions for the prevention and / or treatment of headache disorders. The invention relates to a composition comprising Palmitoylethanolamide, Ginkgolide B, and Magnesium, optionally in combination with one or more pharmaceutically acceptable excipients, for use in the prophylaxis and / or management of headache disorders, including but not limited to primary and secondary headache types. Headache disorders, in particular migraines and tension-type headaches, constitute a predominant subset of neurological conditions that substantially impair the quality of life of affected individuals. These disorders not only result in significant morbidity but also contribute to a considerable economic and healthcare burden globally. There exists a continued need for safe and efficacious therapeutic formulations capable of mitigating the frequency, intensity, and associated symptoms of such headache disorders.

[0006] BACKGROUND OF THE INVENTION:

[0007] Headache disorders represent one of the most prevalent categories of neurological conditions globally, exerting a significant impact on individual quality of life and imposing substantial burdens on healthcare systems. These disorders affect individuals irrespective of age, gender, or socioeconomic background, with epidemiological data indicating a disproportionately higher prevalence among females. Among primary headache disorders, migraine, tension-type headache (TTH), and cluster headache collectively account for approximately 98% of diagnosed cases. Migraine, in particular, is recognized as a highly prevalent and debilitating neurological condition, typically presenting as a unilateral, pulsating or throbbing pain of moderate to severe intensity, with episodes lasting between approximately 4 to 72 hours. Migraine attacks are frequently associated with accompanying symptoms such as nausea, vomiting, photophobia (sensitivity to light), and phonophobia (sensitivity to sound). These recurrent episodes can re

[0008] Tension-type headaches (UH), while typically presenting with milder symptomatology compared to migraines, affect a substantial proportion of the general population. These headaches are characterized by a persistent, non-pulsatile (non-throbbing) pain, frequently described as a tightness or pressure around the head, which may persist for several hours or extend over multiple days, thereby impacting daily functioning. Cluster headaches, although relatively less prevalent, are recognized as one of the most severe forms of primary headache disorders. They are typified by sudden onset of excruciating unilateral pain, often localized in the orbital or temporal region. These headaches manifest in cyclical patterns or episodic clusters, frequently occurring at the same time each day or night, and are of such intensity that they commonly awaken individuals from sleep. The recurrent and disabling nature of cluster headaches necessitates effective therapeutic strategies for their prevention and management.

[0009] Tension-type headaches (UH), while typically presenting with milder symptomatology compared to migraines, affect a substantial proportion of the general population. These headaches are characterized by a persistent, non-pulsatile (non-throbbing) pain, frequently described as a tightness or pressure around the head, which may persist for several hours or extend over multiple days, thereby impacting daily functioning. Cluster headaches, although relatively less prevalent, are recognized as one of the most severe forms of primary headache disorders. They are typified by sudden onset of excruciating unilateral pain, often localized in the orbital or temporal region. These headaches manifest in cyclical patterns or episodic clusters, frequently occurring at the same time each day or night, and are of such intensity that they commonly awaken individuals from sleep. The recurrent and disabling nature of cluster headaches necessitates effective therapeutic strategies for their prevention and management.

[0010] Headache disorders impose a substantial economic burden on both individuals and healthcare systems, encompassing direct costs related to medical consultations, diagnostics, and pharmacological treatments, as well as indirect costs arising from absenteeism, reduced work efficiency, and lost productivity. Epidemiological and health economic studies have consistently demonstrated that headache disorders are significant contributors to global disability metrics. Notably, migraine has been identified as one of the leading causes of years lived with disability (YLDs) worldwide, underscoring the urgent need for effective and accessible therapeutic interventions to mitigate the personal, social, and economic impacts associated with such conditions.

[0011] European Patent Publication No. EP4331577 discloses a gastro-resistant tablet formulation comprising palmitoylethanolamide (PEA) as the active pharmaceutical ingredient. The disclosed formulation includes an enteric coating designed to delay the release of PEA, resulting in a sustained release profile wherein the active ingredient is released over a period exceeding 120 minutes.

[0012] European Patent Publication No. EP3130336 discloses a nutraceutical composition comprising palmitoylethanolamide (PEA) as a primary component. Specifically, the composition includes PEA in combination with at least one additional component selected from a second active ingredient and / or a release-modifying agent, thereby enabling modulation of the release profile of PEA within the organism.

[0013] International Patent Publication No. WO2011056174 discloses aqueous herbal supplement compositions intended for the relief of migraine headaches. The disclosed compositions are formulated using natural ingredients, including but not limited to Ubiquinone, Feverfew extract, and a Magnesium salt. In at least one embodiment, the composition further comprises additional components such as St. John's Wort extract, Butterbur Root extract, and Vitamin B2. The reference is directed specifically to aqueous formulations containing a combination of multiple herbal and nutritional ingredients for therapeutic benefit in migraine management.

[0014] Indian Patent Application No. 6486 / DELNP / 2012 discloses pharmaceutical compositions comprising a fatty acid amide hydrolase (FAAH) inhibiting compound of Formula I. The disclosed compositions are indicated for the treatment of a broad spectrum of conditions, including but not limited to pain, inflammation, neurological disorders, and gastrointestinal diseases. The inhibition of FAAH is described as a therapeutic mechanism for modulating endocannabinoid signalling pathways to achieve clinical benefit.

[0015] While the aforementioned references disclose the individual therapeutic potential of palmitoylethanolamide (PEA), magnesium, and various herbal or nutraceutical components in the management of neurological or pain-related conditions, none of these disclosures teach, suggest, or render obvious the synergistic combination of palmitoylethanolamide, Ginkgolide B, and magnesium. In particular, the prior art fails to recognize or anticipate the therapeutic advantage conferred by this specific combination in the comprehensive prevention and / or treatment of headache disorders, including both primary and secondary types.

[0016] Palmitoylethanolamide (PEA) is a bioactive lipid amide recognized for its antiinflammatory, analgesic, and neuroprotective properties, primarily mediated through modulation of mast cell activity and the endocannabinoid system. Ginkgolide B, a diterpenoid lactone derived from Ginkgo biloba. functions as a selective platelet-activating factor (PAF) antagonist and is known to exert neuroregulatory and vasodilatory effects, contributing to improved cerebral circulation and reduced neuroinflammation. Magnesium, an essential mineral, plays a critical role in neuromuscular transmission, mitochondrial function, and vascular tone regulation. Clinical and biochemical evidence suggests that magnesium deficiency is commonly associated with migraine pathophysiology, including cortical spreading depression, platelet aggregation, and altered neurotransmitter release.

[0017] Despite the acknowledged therapeutic benefits of palmitoylethanolamide (PEA), Ginkgolide B, and magnesium as individual agents, existing formulations fail to incorporate these compounds into a single, unified therapeutic strategy that leverages their distinct yet complementary mechanisms of action. The present invention addresses this unmet need by providing a synergistic composition comprising palmitoylethanolamide, Ginkgolide B, and magnesium. This combination offers enhanced efficacy in the management of headache disorders by targeting multiple biological pathways, including neuroinflammation, platelet-activating factor signalling, and vascular dysregulation, thereby affording improved and comprehensive control of headache symptoms through a multi-modal therapeutic approach.

[0018] OBJECTIVE OF THE INVENTION:

[0019] A principal object of the present invention is to provide a composition comprising palmitoylethanolamide (PEA), Ginkgolide B, and magnesium, optionally in combination with one or more pharmaceutically or nutraceutically acceptable excipients, for promoting neurological health and for the prevention and / or management of headache disorders. Such disorders include, but are not limited to, migraine, tension-type headache, cluster headache, medication-overuse headache, as well as other primary and secondary headache conditions.

[0020] Another object of the present invention is to provide a composition that exhibits a demonstrable synergistic effect, wherein the combination of palmitoylethanolamide (PEA), magnesium, and Ginkgolide B results in a significantly greater therapeutic benefit specifically, a marked reduction in the frequency, severity, and duration of headache episodes when compared to the administration of the individual components alone. This enhanced efficacy is supported by experimental evidence indicating a synergistic interaction among the active constituents.

[0021] A further object of the present invention is to provide a composition wherein the active components palmitoylethanolamide (PEA), Ginkgolide B, and magnesium are present in defined weight ratios, concentrations, or quantitative ranges, thereby optimizing therapeutic and / or prophylactic efficacy while concurrently minimizing the risk of adverse effects or undesirable interactions. The specified proportions are selected to enhance the synergistic interaction among the components and to ensure consistent clinical outcomes.

[0022] Another object of the present invention is to provide the aforementioned composition in a variety of pharmaceutically or nutraceutically acceptable dosage forms, including but not limited to sachets, tablets, capsules, and suspensions, in order to enhance formulation stability, facilitate ease of administration, and improve patient compliance. Yet another object of the present invention is to provide a therapeutic kit comprising palmitoylethanolamide (PEA), magnesium, and Ginkgolide B, optionally in combination with one or more pharmaceutically or nutraceutically acceptable excipients, wherein the active components may be formulated either as a single combined dosage form or as separate dosage units intended for concurrent or sequential administration. The kit is designed for use in the prevention and / or management of headache conditions.

[0023] An additional object of the present invention is to incorporate within the composition one or more pharmaceutically or nutraceutically acceptable excipients selected from the group consisting of diluents, disintegrants, binders, surfactants, lubricants, polymers, preservatives, antimicrobial agents, glidants, and combinations thereof. Exemplary diluents include, but are not limited to, microcrystalline cellulose, lactose, sucrose, maltodextrin, mannitol, sorbitol, and calcium carbonate.

[0024] Yet another object of the present invention is to provide a method of treatment that enhances patient compliance, attributable to the synergistic interaction among palmitoylethanolamide (PEA), magnesium, and Ginkgolide B. This synergistic effect contributes to improved therapeutic efficacy, enabling a reduction in the frequency of drug administration and simplification of the treatment regimen, thereby promoting adherence to therapy in patients suffering from headache disorders.

[0025] A further object of the present invention is to provide a composition that is suitable for long-term or routine administration, and which demonstrates an improved safety, tolerability, and efficacy profile. Such characteristics render the composition particularly appropriate for both prophylactic and symptomatic management of chronic or recurrent headache disorders.

[0026] In one embodiment, the present invention provides a composition that is suitable for use as either a nutraceutical or pharmaceutical product, depending on the specific formulation and applicable regulatory classifications within different jurisdictions. This versatility allows the composition to be employed across abroad spectrum of health-promoting applications, including both preventive and therapeutic indications. SUMMARY OF THE INVENTION:

[0027] The present invention provides a synergistic composition for the prevention and / or management of headache disorders. The composition comprises palmitoylethanolamide (PEA), magnesium, and Ginkgolide B, optionally in combination with one or more pharmaceutically or nutraceutically acceptable excipients. The combination of these active agents is designed to exert complementary and multi-modal biological effects, thereby enhancing therapeutic efficacy through synergistic mechanisms.

[0028] The present invention is directed toward the treatment and / or prevention of various headache disorders, including but not limited to migraine, tension-type headache, cluster headache, and other primary or secondary headache conditions. The combination of palmitoylethanolamide (PEA), magnesium, and Ginkgolide B has been demonstrated to produce a synergistic therapeutic effect, resulting in enhanced efficacy in reducing the frequency, severity, and duration of headache episodes when compared to the administration of any of the individual components alone. This synergistic interaction enables a multi-targeted approach to headache management, addressing underlying pathophysiological mechanisms such as neuroinflammation, vascular dysregulation, and neuromodulatory imbalance.

[0029] The invention further provides compositions wherein the active ingredients Palmitoylethanolamide (PEA), magnesium, and Ginkgolide B are present in defined weight ratios, percentages, or quantitative amounts that are optimized to enhance the observed synergistic interaction while maintaining a favorable safety and tolerability profile. The composition may be formulated in a variety of pharmaceutically or nutraceutically acceptable dosage forms, including but not limited to tablets, capsules, powders, suspensions, and sachets, and is preferably intended for oral administration.

[0030] In another embodiment, the present invention provides a therapeutic kit comprising palmitoylethanolamide (PEA), magnesium, and Ginkgolide B, wherein the active components are provided either in a single combined formulation or in separate dosage units intended for co-administration. The kit may further include instructions for use, and optionally one or more pharmaceutically or nutraceutically acceptable excipients, to facilitate effective administration for the prevention and / or management of headache disorders.

[0031] The present invention is to offer a composition that is used either as a standalone treatment or as an adjunct therapy alongside standard headache medications.

[0032] The invention also encompasses compositions comprising one or more pharmaceutically or nutraceutically acceptable excipients selected to facilitate formulation stability, enhance bioavailability, and improve manufacturability. Suitable excipients may include, but are not limited to, diluents, disintegrants, binders, surfactants, lubricants, polymers, preservatives, and glidants.

[0033] The composition is designed to be suitable for regular or long-term use, and may be classified and marketed either as a pharmaceutical or a nutraceutical product, depending on the specific formulation and the applicable regulatory framework in a given jurisdiction. This dual applicability allows for broad therapeutic and preventive utility across diverse healthcare settings.

[0034] In summary, the present invention provides a multi-component, synergistic composition that simultaneously targets multiple pathophysiological mechanisms implicated in headache disorders. By combining palmitoylethanolamide (PEA), magnesium, and Ginkgolide B, the composition offers enhanced symptom control, improved therapeutic efficacy, and superior patient outcomes compared to conventional single -agent therapies.

[0035] BRIEF DESCRIPTION OF THE DRAWINGS:

[0036] FIGURE-1: Study Results Comparative Graph for Evaluation of the synergistic effect of Palmitoylethanolamide (PEA), Magnesium, and Ginkgolide B in animal model for Hot plate tail flick test. FIGURE-2: Study Results Comparative Graph for Evaluation of the synergistic effect of Palmitoylethanolamide (PEA), Magnesium, and Ginkgolide B in animal model for Time in light chamber.

[0037] FIGURE-3: Study Results Comparative Graph for Evaluation of the synergistic effect of Palmitoylethanolamide (PEA), Magnesium, and Ginkgolide B in animal model for Time in dark chamber.

[0038] FIGURE-4: Study Results Comparative Graph for Evaluation of the synergistic effect of Palmitoylethanolamide (PEA), Magnesium, and Ginkgolide B in animal model for Forced swim test.

[0039] FIGURE-5: Study Results Comparative Graph for Evaluation of the synergistic effect of Palmitoylethanolamide (PEA), Magnesium, and Ginkgolide B in animal model for Photo actometer test.

[0040] FIGURE-6: Study Results Comparative Graph for Evaluation of the synergistic effect of Palmitoylethanolamide (PEA), Magnesium, and Ginkgolide B in animal model for Serum IL-6 levels.

[0041] FIGURE-7: Study Results Comparative Graph for Evaluation of the synergistic effect of Palmitoylethanolamide (PEA), Magnesium, and Ginkgolide B in animal model for Serum 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 provided in sufficient detail to enable those skilled in the art to make and use the invention. It should be understood, however, that alternative embodiments may be employed and various modifications and adaptations may be made without departing from the scope and spirit of the present invention, as defined by the appended claims. References to an, one, or various embodiments throughout this disclosure are not intended to be limiting or to refer to the same embodiment, and such references are intended to encompass one or more alternative embodiments. Accordingly, the following detailed description is not to be interpreted in a limiting sense, and the scope of the invention is defined solely by the appended claims and their full scope of legal equivalents.

[0044] The present invention provides a composition comprising palmitoylethanolamide (PEA), Ginkgolide B, and magnesium, optionally in combination with one or more pharmaceutically or nutraceutically acceptable excipients.

[0045] In one embodiment, the present invention provides a composition comprising palmitoylethanolamide (PEA), Ginkgolide B, and magnesium for use in the prevention and / or management of headache disorders.

[0046] In another embodiment, the present invention provides a composition comprising palmitoylethanolamide (PEA), Ginkgolide B, magnesium, and one or more pharmaceutically acceptable excipients for use in the prevention and / or management of headache disorders.

[0047] In another embodiment, the invention provides a composition comprising Palmitoylethanolamide, Ginkgolide B, Magnesium and optionally in combination with one or more pharmaceutically or nutraceutically acceptable excipients, for promoting neurological health and for the management or prevention of headache disorders.

[0048] According to the present invention, headache disorders include, but are not limited to, migraine, tension-type headache, cluster headache, medication-overuse headache, and other primary or secondary headache conditions as classified in accordance with standard clinical diagnostic criteria.

[0049] The present invention relates to a synergistic composition comprising palmitoylethanolamide (PEA), magnesium, and Ginkgolide B, in combination with one or more pharmaceutically or nutraceutically acceptable excipients, for use in the prevention and / or management of headache disorders. The composition is formulated to reduce the frequency, severity, and duration of various headache types, including but not limited to migraine, tension-type headache, cluster headache, medication-overuse headache, and other primary or secondary headache conditions.

[0050] In a further embodiment, the present invention provides a composition that exhibits a synergistic therapeutic effect. The combined administration of palmitoylethanolamide (PEA), magnesium, and Ginkgolide B results in a significantly greater reduction in headache -related parameters such as frequency, intensity, and duration compared to the administration of each component individually. This enhanced efficacy is indicative of a synergistic interaction among the active ingredients, providing superior clinical benefit in the management of headache disorders.

[0051] In another embodiment, the present invention provides a composition that exhibits a synergistic effect, wherein the combined administration of palmitoylethanolamide (PEA), magnesium, and Ginkgolide B results in a significantly greater reduction in the frequency, severity, and duration of headache episodes as compared to the administration of any of the individual components alone. This synergistic interaction contributes to the enhanced therapeutic efficacy of the composition in the prevention and / or management of headache disorders.

[0052] In another embodiment, the present invention provides a formulation that is suitable for preparation in various dosage forms, including but not limited to tablets, capsules, suspensions, sachets, or any other pharmaceutically or nutraceutically acceptable dosage form. The versatility of the formulation allows for adaptation to patient preferences and clinical requirements, thereby enhancing ease of administration, patient compliance, and therapeutic applicability.

[0053] In a further embodiment, the present invention provides a composition that is suitable and safe for long-term or chronic use. Conventional therapeutic agents for the treatment of headache disorders such as triptans and non-steroidal anti-inflammatory drugs (NSAIDs) are often associated with adverse effects when administered over extended periods, including but not limited to gastrointestinal irritation, cardiovascular risk, and renal impairment. In contrast, the present composition comprises naturally occurring compounds palmitoylethanolamide (PEA), magnesium, and Ginkgolide B with well -documented safety profiles, thereby offering a safer alternative for prolonged administration. The formulation is specifically designed for use in individuals experiencing frequent or chronic headache conditions, minimizing the risk of treatment-related complications.

[0054] In yet another embodiment, the present invention provides a nutraceutical composition formulated into various dosage forms, including but not limited to tablets, capsules, powders, or liquids, which may optionally be filled into sachets. The selection of dosage form may be tailored based on the preferences, age, and specific needs of the target population, thereby enhancing user compliance and therapeutic accessibility.

[0055] The present invention relates to a synergistic composition comprising Palmitoylethanolamide (PEA), Magnesium, and Ginkgolide B, in combination with one or more pharmaceutically or nutraceutically acceptable excipients. In one embodiment, the pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, surfactants, lubricants, glidants, or the like, or mixtures thereof. The inclusion of such excipients in the composition is intended to enhance formulation stability, improve bioavailability, and facilitate ease of administration.

[0056] Diluents are selected from one or more of microcrystalline cellulose, calcium carbonate, dicalcium phosphate, lactose, sorbitol, mannitol, starch, maltodextrin, pregelatinized starch, croscarmellose sodium, guar gum, xanthan gum, sodium alginate, polyvinylpyrrolidone (PVP), sodium carboxymethyl cellulose (CMC), or the like, or mixtures thereof.Binders are selected one or more from starch, pregelatinized starch, polyvinylpyrrolidone (PVP), methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium alginate, xanthan gum, acacia, or a like or a mixture thereof.

[0057] Surfactants are selected one or more from sodium lauryl sulfate, polysorbate 80, polysorbate 20, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, cetyltrimethylammomum bromide (CTAB), poloxamer, polyethylene glycol, sodium dodecylbenzene sulfonate, glycerol monostearate, tween 80 or a like or a mixture thereof.

[0058] Lubricants and / or glidants are selected from one or more of 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 the like, or mixtures thereof.

[0059] In another embodiment of the present invention, the composition comprises micronized Palmitoylethanolamide (PEA). Micronization of PEA enhances its surface area, thereby improving solubility and bioavailability. As a result, effective therapeutic outcomes can be achieved with lower dosages. The micronized PEA is uniformly dispersed within the composition to ensure consistent dosing and optimized efficacy.

[0060] A further embodiment of the present invention provides a synergistic composition comprising Palmitoylethanolamide, Magnesium, and Ginkgolide B, which may be administered alone or in combination with conventional headache therapies. The composition is intended to complement standard treatments, including but not limited to triptans and non-steroidal anti-inflammatory drugs (NSAIDs), by enhancing their therapeutic efficacy and potentially reducing the required dosage of such agents. This combinatorial approach facilitates improved management of headache symptoms while minimizing the adverse effects commonly associated with prolonged or high-dose use of conventional pharmacologic treatments.

[0061] Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that exhibits analgesic, anti-inflammatory, and neuroprotective properties. PEA used in the present invention may be obtained from natural, semi-synthetic, or synthetic sources. It may be derived from plantbased lipids, egg yolk, or soy lecithin, or synthesized chemically by known amide formation techniques. In one preferred embodiment, PEA is used in micronized or ultramicronized form to enhance its solubility, absorption, and bioavailability, enabling effective dosing at reduced quantities. The amount of PEA present in the composition may range from about 1.08% to 99.21% w / w or from about 50 mg to 2000 mg, 75 mg to 1900 mg, 100 mg to 1800 mg, 150 mg to 1700 mg, 175 mg to 1600 mg, 200 mg to 1500 mg, 200 mg to 1400 mg, 200 mg to 1300 mg, 200 mg to 1200 mg, 200 mg to 1100 mg, and 200 mg to 1000 mg per unit dose, depending on the formulation.

[0062] Magnesium used in the present invention may be present in any pharmaceutically acceptable salt form, including but not limited to magnesium oxide, magnesium citrate, magnesium bisglycinate, magnesium aspartate, magnesium malate, or magnesium L-threonate. The Magnesium may be derived from natural mineral sources, synthesized chemically, or isolated from plant-based inputs, and should comply with accepted pharmacopeial standards such as IP, USP, or Ph. Eur. The quantity of Magnesium present in the composition may range from about 0.06 % to 95.69% w / w or from about 3 mg to 1400 mg, 4 mg to 1300 mg, 5 mg to 1200 mg, 6 mg to 1100 mg, 7 mg to 1000 mg, 8 mg to 900 mg, 9 mg to 850 mg, and 10 mg to 800 mg per unit dosage, depending on the formulation.

[0063] Ginkgolide B used in the present invention may be extracted from Ginkgo biloba leaves using established methods such as solvent extraction, column chromatography, or supercritical fluid extraction. Alternatively, Ginkgolide B may be chemically synthesized or produced via fermentation using engineered microbial systems. The ingredient may be utilized either in its pure isolated form or as part of a standardized Ginkgo biloba extract with a defined Ginkgolide B content, in accordance with quality and consistency requirements. The quantity of Ginkgolide B in the composition may range from about 0.06 % to 95.01 % w / w or from about 3 mg to 1200 mg, 4 mg to 1100 mg, 5 mg to 1000 mg, 6 mg to 950 mg, 7 mg to 800 mg, 8 mg to 700 mg, 9 mg to 650 mg and 10 mg to 500 mg per unit dose, based on the total weight of the composition.

[0064] According to present invention, the active components may be present in various ratios depending on the intended use, target population, and desired release profile. In one embodiment, the ratio of Palmitoylethanolamide to Magnesium to Ginkgolide B may fall within a range of 1:0.0015:0.0015 to 1:28:24 by weight, although other ratios may be employed based on empirical optimization and stability criteria. In another embodiment, the present invention provides a kit comprising palmitoylethanolamide, magnesium, and Ginkgolide B, optionally in combination with one or more pharmaceutically or nutraceutically acceptable excipients, wherein the active components are provided either as a single combined formulation or as separate dosage units configured for concurrent or sequential administration in the prevention and / or treatment of headache disorders.

[0065] The synergistic bioactive composition as per the present invention helps to duration, frequency and severity of headache disorders.

[0066] The present invention provides a method of treatment that enhances patient compliance by virtue of the synergistic effects of palmitoylethanolamide, magnesium, and Ginkgolide B, wherein the combined action reduces the frequency of drug administration and simplifies treatment regimens.

[0067] Yet another embodiment of the present invention provides a pharmaceutical composition formulated in various dosage forms, including but not limited to powders, granules, pellets, tablets, mini-tablets, sachets, and solutions, thereby enhancing formulation versatility and patient compliance.

[0068] According to the present invention, the synergistic composition may be prepared utilizing various conventional and advanced pharmaceutical manufacturing techniques known in the art, including but not limited to direct compression, wet granulation, dry granulation, spray drying, and extrusion-spheronization. The composition may be formulated into a range of solid dosage forms, such as tablets, capsules, sachets, powders, granules, and orally disintegrating tablets (ODTs), with the choice of dosage form selected based on the intended therapeutic application and patient compliance considerations.

[0069] Additionally, the composition may be incorporated into liquid dosage forms, including but not limited to solutions, suspensions, emulsions, and syrups, to improve bioavailability and facilitate administration, particularly for patients who experience difficulty swallowing solid dosage forms. Furthermore, the composition may be formulated into semi-solid dosage forms such as gels, creams, or pastes, enabling alternative routes of administration as needed.

[0070] For controlled or targeted delivery, the composition may be formulated into sustained-release, delayed-release, or enteric-coated dosage forms to optimize absorption and enhance therapeutic efficacy. Additionally, other specialized delivery systems, including but not limited to orodispersible films, effervescent tablets, chewable formulations, and transdermal patches, may be developed to accommodate patient-specific requirements and improve compliance.

[0071] Thus, the present invention provides a versatile and adaptable formulation that may be customized into a wide range of pharmaceutical dosage forms to achieve optimal administration and enhanced therapeutic effectiveness.

[0072] Accordingly, the present invention provides a novel synergistic composition for the management and control of headache disorders. By combining palmitoylethanolamide, magnesium, and Ginkgolide B, the invention offers a comprehensive therapeutic approach targeting both neurological and vascular aspects of headache pathophysiology. The composition is formulated for long-term administration with minimal risk of adverse effects and may be provided in various pharmaceutically or nutraceutically acceptable dosage forms. The versatility, safety profile, and cost-effectiveness of the invention render it a valuable advancement in the field of headache treatment and management.

[0073] The present invention addresses an unmet medical need by providing a novel composition comprising palmitoylethanolamide, magnesium, and Ginkgolide B for the prevention and treatment of headache disorders, including migraine.

[0074] Thus, the present invention provides a unique and synergistic composition that is neither disclosed nor suggested by the prior art, thereby fulfilling a critical unmet need in the management of migraine. The invention described herein encompasses the various objects and embodiments as set forth above with respect to the described characteristics and methods. While particular aspects of the invention have been emphasized, it should be understood that variations and modifications within the scope of the appended claims and equivalents are contemplated and do not constitute a departure from the spirit or scope of the invention.

[0075] EXAMPLES:

[0076] GENERAL COMPOSITION - EXAMPLE-1: AS PER THE INVENTION Following is a general composition formula as per the present invention.

[0077] S. no Ingredients % w / w

[0078] 1 Palmitoylethanolamide 0.01 - 99 % WAV 2 Elemental magnesium 0.01 - 99 % WAV

[0079]

[0080] 3 Ginkgolide-B 0.01 - 99 % WAV

[0081] TABLET EXAMPLE-1:

[0082] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 300 63.56 2 Elemental magnesium 48 10.17 3 Ginkgolide-B 60 12.71 Microcrystalline

[0083] 4 24 5.08

[0084] cellulose

[0085] 5 Croscarmellose sodium 9 1.91 6 Polyvinylpyrrolidone 5 1.06 7 Polysorbate 7 1.48 8 Magnesium stearate 3 0.64 9 Talc 8 1.69 10 Zinc stearate 6 1.27 11 Colloidal silicon dioxide 2 0.42 Average weight 472 100

[0086]

[0087] TABLET EXAMPLE-2:

[0088] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 200 54.79 2 Elemental magnesium 48 13.15 3 Ginkgolide-B 60 16.44

[0089]

[0090] Microcrystalline

[0091] 4 19 5.21 cellulose

[0092] 5 Croscarmellose sodium 7 1.92 6 Polyvinylpyrrolidone 4 1.10 7 Polysorbate 8 2.19 8 Magnesium stearate 2 0.55 9 Talc 9 2.47 10 Zinc stearate 5 1.37 11 Colloidal silicon dioxide 3 0.82

[0093]

[0094] Average weight 365 100 TABLET EXAMPLE-3:

[0095] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 600 66.01 2 Elemental magnesium 96 10.56 3 Ginkgolide-B 120 13.20 4 Microcrystalline cellulose 28 3.08 5 Croscarmellose sodium 13 1.43 6 Polyvinylpyrrolidone 7 0.77 7 Polysorbate 14 1.54 8 Magnesium stearate 4 0.44 9 Talc 12 1.32 10 Zinc stearate 9 0.99 11 Colloidal silicon dioxide 6 0.66

[0096]

[0097] Average weight 909 100

[0098] TABLET EXAMPLE-4:

[0099] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 400 58.14 2 Elemental magnesium 96 13.95 3 Ginkgolide-B 120 17.44 4 Microcrystalline cellulose 22 3.20 5 Croscarmellose sodium 10 1.45 6 Polyvinylpyrrolidone 5 0.73 7 Polysorbate 12 1.74 8 Magnesium stearate 2 0.29 9 Talc 9 1.31 10 Zinc stearate 7 1.02

[0100]

[0101] 11 Colloidal silicon dioxide 5 0.73

[0102]

[0103] Average weight 688 | 100 | TABLET EXAMPLE S:

[0104] Quantity

[0105] S. No Ingredients

[0106] (mg) % w / w 1 Palmitoylethanolamide 600 77.72 2 Elemental magnesium 48 6.22 3 Ginkgolide-B 60 7.77 4 Microcrystalline cellulose 24 3.11 5 Croscarmellose sodium 9 1.17 6 Polyvinylpyrrolidone 5 0.65 7 Polysorbate 7 0.91 8 Magnesium stearate 3 0.39 9 Talc 8 1.04 10 Zinc stearate 6 0.78 11 Colloidal silicon dioxide 2 0.26

[0107]

[0108] Average weight 772 100

[0109] TABLET EXAMPLE-6:

[0110] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 300 57.69 2 Elemental magnesium 96 18.46 3 Ginkgolide-B 60 11.54 4 Microcrystalline cellulose 24 4.62 5 Croscarmellose sodium 9 1.73 6 Polyvinylpyrrolidone 5 0.96 7 Polysorbate 7 1.35 8 Magnesium stearate 3 0.58 9 Talc 8 1.54 10 Zinc stearate 6 1.15 11 Colloidal silicon dioxide 2 0.38

[0111]

[0112] Average weight 520 100

[0113] TABLET EXAMPLE-7:

[0114] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 300 56.39 2 Elemental magnesium 48 9.02 3 Ginkgolide-B 120 22.56 4 Microcrystalline cellulose 24 4.51 5 Croscarmellose sodium 9 1.69 6 Polyvinylpyrrolidone 5 0.94

[0115]

[0116] 7 Polysorbate 7 1.32 8 Magnesium stearate 3 0.56 9 Talc 8 1.50 10 Zinc stearate 6 1.13 11 Colloidal silicon dioxide 2 0.38

[0117]

[0118] Average weight 532 100 TABLET EXAMPLE S:

[0119] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 100 56.18 2 Elemental magnesium 10 5.62 3 Ginkgolide-B 5 2.81 4 Microcrystalline cellulose 18 10.11 5 Croscarmellose sodium 6 3.37 6 Polyvinylpyrrolidone 7 3.93 7 Polysorbate 9 5.06 8 Magnesium stearate 5 2.81 9 Talc 9 5.06 10 Zinc stearate 4 2.25 11 Colloidal silicon dioxide 5 2.81

[0120]

[0121] Average weight 178 100

[0122] TABLET EXAMPLE-9:

[0123] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 200 59.00 2 Elemental magnesium 50 14.75 3 Ginkgolide-B 30 8.85 4 Microcrystalline cellulose 13 3.83 5 Croscarmellose sodium 14 4.13 6 Polyvinylpyrrolidone 6 1.77 7 Polysorbate 9 2.65 8 Magnesium stearate 7 2.06 9 Talc 6 1.77 10 Zinc stearate 3 0.88 11 Colloidal silicon dioxide 1 0.29

[0124]

[0125] Average weight 339 100 TABLET EXAMPLE-10:

[0126] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 500 68.97 2 Elemental magnesium 100 13.79

[0127]

[0128] 3 Ginkgolide-B 60 8.28 4 Microcrystalline cellulose 18 2.48

[0129] 5 Croscarmellose sodium 11 1.52 6 Polyvinylpyrrolidone 3 0.41 7 Polysorbate 9 1.24 8 Magnesium stearate 5 0.69 9 Talc 7 0.97 10 Zinc stearate 8 1.10 11 Colloidal silicon dioxide 4 0.55

[0130]

[0131] Average weight 725 100 TABLET EXAMPLE-11:

[0132] S. No Ingredients Quantity (mg) % w / w

[0133] 1 Palmitoylethanolamide 750 65.62 2 Elemental magnesium 250 21.87 3 Ginkgolide-B 100 8.75 4 Microcrystalline cellulose 13 1.14 5 Croscarmellose sodium 5 0.44 6 Polyvinylpyrrolidone 4 0.35 7 Polysorbate 6 0.52 8 Magnesium stearate 1 0.09 9 Talc 7 0.61 10 Zinc stearate 4 0.35 11 Colloidal silicon dioxide 3 0.26

[0134]

[0135] Average weight 1143 100 General Procedure for preparation for Example-1-11:

[0136] Step-1) All ingredients were weighed individually using a calibrated balance and verified against the respective formulation table;

[0137] Step-2) The weighed materials as per step-1 were sifted through a appropriate mesh to remove foreign matter and ensure uniformity;

[0138] Step-3) The sifted ingredients obtained in step-2 were dry mixed;

[0139] Step-4) A binder solution was prepared by dissolving binder into suitable solvent. 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;

[0140] 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; Step-7) Oversized granules obtained in step-6 were milled and re-sifted through a #20 mesh. Lubricants and glidants were added to the sifted granules and blended for 5 minutes for lubrication;

[0141] 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;

[0142] Step-9) The coated tablets obtained in step-8 were sorted on an inspection belt, and defective units were removed manually;

[0143] 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.

[0144] SACHET EXAMPLE-12:

[0145] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 1000 43.99 2 Elemental magnesium 500 22.00 3 Ginkgolide-B 500 22.00 Microcrystalline

[0146] 4 112 4.93 cellulose

[0147] 5 Croscarmellose sodium 23 1.01 6 Polyvinylpyrrolidone 17 0.75 7 Polysorbate 28 1.23 8 Magnesium stearate 32 1.41 9 Talc 21 0.92 10 Zinc stearate 19 0.84 11 Colloidal silicon dioxide 21 0.92

[0148]

[0149] Average weight 2273 100 SACHET EXAMPLE-13:

[0150] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 1500 39.58 2 Elemental magnesium 1000 26.39 3 Ginkgolide-B 1000 26.39 Microcry stalline

[0151] 4 119 3.14 cellulose

[0152] 5 Croscarmellose sodium 27 0.71 6 Polyvinylpyrrolidone 21 0.55 7 Polysorbate 32 0.84

[0153]

[0154] 8 Magnesium stearate 38 1.00 9 Talc 18 0.47

[0155] 10 Zinc stearate 17 0.45 11 Colloidal silicon dioxide 18 0.47

[0156]

[0157] Average weight 3790 100 SACHET EXAMPLE-14:

[0158] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 1000 35.83 2 Elemental magnesium 750 26.87 3 Ginkgolide-B 750 26.87 Microcrystalline

[0159] 4 112 4.01 cellulose

[0160] 5 Croscarmellose sodium 17 0.61 6 Polyvinylpyrrolidone 26 0.93 7 Polysorbate 31 1.11 8 Magnesium stearate 45 1.61 9 Talc 26 0.93 10 Zinc stearate 19 0.68 11 Colloidal silicon dioxide 15 0.54

[0161]

[0162] Average weight 2791 100 General Procedure for preparation for Example-12 to 14:

[0163] Step-1) All ingredients were weighed individually using a calibrated balance and verified against the respective formulation table;

[0164] Step-2) The weighed materials as per step-1 were sifted through a appropriate mesh to remove foreign matter and ensure uniformity;

[0165] Step-3) The sifted ingredients obtained in step-2 were dry mixed;

[0166] Step-4) After mixing the product of step-3 is filled in suitable sachets

[0167] Step-5) The sachets obtained in step-5 were sorted on an inspection belt, and defective units were removed manually;

[0168] Step-6) The final product of step-5 were packed into suitable packs, labelled, and stored under recommended conditions.

[0169] CAPSULE EXAMPLE- 15:

[0170] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 220 72.85

[0171]

[0172] 2 Elemental magnesium 20 6.62 3 Ginkgolide-B 10 3.31 Microcrystalline

[0173] 4 12 3.97 cellulose

[0174] 5 Croscarmellose sodium 7 2.32 6 Polyvinylpyrrolidone 6 1.99 7 Polysorbate 7 2.32 8 Magnesium stearate 5 1.66 9 Talc 6 1.99 10 Zinc stearate 4 1.32 11 Colloidal silicon dioxide 5 1.66

[0175]

[0176] Average weight 302 100 General Procedure for preparation for Example-15:

[0177] Step-1) All ingredients were weighed individually using a calibrated balance and verified against the respective formulation table;

[0178] Step-2) The weighed materials as per step-1 were sifted through a appropriate mesh to remove foreign matter and ensure uniformity;

[0179] Step-3) The material was filled into appropriate size capsule.

[0180] SYRUP EXAMPLE-16:

[0181] S. No Ingredients Quantity (mg) % w / w 1 Palmitoylethanolamide 300 63.56

[0182] 2 Elemental magnesium 48 10.17

[0183] 3 Ginkgolide-B 60 12.71

[0184] Microcrystalline

[0185] 4 24 5.08 cellulose

[0186] 5 Silicon dioxide 9 1.91 6 Sucralose 5 1.06 7 Polysorbate 7 1.48 8 Magnesium stearate 3 0.64 9 Talc 8 1.69 10 Zinc stearate 6 1.27 11 Tartrazine 2 0.42

[0187]

[0188] Average weight 472 100 General Procedure for preparation for Example-16:

[0189] Step-1) All ingredients were weighed individually using a calibrated balance and verified against the respective formulation table; Step-2) The weighed materials as per step-1 were sifted through a appropriate mesh to remove foreign matter and ensure uniformity;

[0190] Step-3) A syrup base was prepared with purified water and sucrose;

[0191] Step-4) The syrup base was transferred in mixing vessel;

[0192] Step-5) All ingredients were added one by one in the syrup base and mixed for 60

[0193] minutes with stirrer;

[0194] Step-6) After mixing the final product of step-5 is filled in suitable containers and sealed;

[0195] Step-7) The containers were packed, labelled, and stored under recommended conditions.

[0196] Animal study Protocol

[0197] Objective: To Evaluate the Synergistic Effect of a combination of Palmitoylethanolamide, Magnesium and Ginkgolide B in a Nitroglycerin-induced Migraine Model in Wistar Rats.

[0198] Materials and Methods:

[0199] Animals:

[0200] • Female Wistar rats, acclimatized for 5 days.

[0201] Induction of Migraine:

[0202] All animals were divided into the groups mentioned below, each containing 6 animals.

[0203] Migraine was induced by intraperitoneal administration of nitroglycerin at a dose of 10 mg / kg with an injection volume of approximately 10 ml / kg body weight. Injections were administered on alternate days for a total five injections over a 2-week period (i.e. days 1,3, 5, 8 and 10), mimicking a chronic migraine-like condition. Control animals received an equivalent volume of the vehicle solution. Treatment was started for 28 days after confirmation of migraine was developed. Treatment as per below table was given from day 15 to day 42.

[0204] Treatment groups:

[0205] S. No Treatment groups Dose and Route (from week 0 to 6) mg / kg b.wt OD per oral)

[0206] 1 Normal group No Treatment

[0207] 2 Nitroglycerin 10 mg / kg b.w. / day i.p. on day 1,3, 5, 8 and 10

[0208] Control group followed by 0.5% CMC lOml / kg b.w. / day / oral from day

[0209]

[0210] 15 to 42 3 Nitroglycerin 10 mg / kg b.w. / day i.p. on day 1,3, 5, 8 and 10 Standard group

[0211] followed by propranolol 4.14 mg / kg body weight / day per (Propranolol)

[0212] oral from day 15 to 42

[0213] 4 Nitroglycerin 10 mg / kg b.w. / day i.p. on day 1,3, 5, 8 and 10 Palmitoylethanolamide followed by palmitoylethanolamide 62 mg / kg body weight / day per oral from day 15 to 42

[0214] 5 Nitroglycerin 10 mg / kg b.w. / day i.p. on day 1,3, 5, 8 and 10

[0215] Magnesium followed by magnesium 2.66 mg / kg body weight / day per oral from day 15 to 42

[0216] 6 Nitroglycerin 10 mg / kg b.w. / day i.p. on day 1,3, 5, 8 and 10

[0217] Ginkgolide-B followed by Ginkgolide B 12.4 mg / kg body weight / day per oral from day 15 to 42

[0218] 7 Nitroglycerin 10 mg / kg b.w. / day i.p. on day 1,3, 5, 8 and 10 Palmitoylethanolamide followed by palmitoylethanolamide 62 mg / kg body + Magnesium weight / day per oral + magnesium 2.66 mg / kg body weight / day per day from day 15 to 42

[0219] 8 Nitroglycerin 10 mg / kg b.w. / day i.p. on day 1,3, 5, 8 and 10

[0220] Magnesium + followed by Magnesium 2.66 mg / kg body weight / day per Ginkgolide-B oral + Ginkgolide B 12.4 mg / kg body weight / day per oral from day 15 to 42

[0221] 9 Nitroglycerin 10 mg / kg b.w. / day i.p. on day 1,3, 5, 8 and 10 followed by palmitoylethanolamide 62 mg / kg body Palmitoylethanolamide

[0222] weight / day per oral + Ginkgolide B 12.4 mg / kg body + Ginkgolide-B

[0223] weight / day per oral from day 15 to 42

[0224] 10 Nitroglycerin 10 mg / kg b.w. / day i.p. on day 1,3, 5, 8 and 10 Palmitoylethanolamide followed palmitoylethanolamide 62 mg / kg body weight / day + Magnesium + per oral+ magnesium 2.66 mg / kg body weight / day per oral + Ginkgolide-B Ginkgolide B 12.4 mg / kg body weight / day per oral from day

[0225]

[0226] 15 to 42

[0227] OD: Once in a Day

[0228] b.wt: Body weight

[0229] Outcome measures:

[0230] • Hot plate Tail flick latency test

[0231] • Time in Light chamber test

[0232] • Time in Dark chamber test

[0233] • Forced swim test Immobility time

[0234] • Photoactometer Movement in 5 mins

[0235] • Serum IL-6

[0236] • Serum TNF-a

[0237] Statistical Analysis:

[0238] All the data are represented as mean ± standard deviation and are statistically analysed by two-way ANOVA followed by Tukey’s multiple comparison test. Study Result 1: Hot plate Tail flick latency test (second)

[0239] Change % improvement in Change from Sum of change from group 9 compared S. No Groups Week 4 control from baseline of to Sum of change (All groups - group 4, 5 and 6 baseline in from baseline of Control group) group 10

[0240] (A) group 4,5 and 6

[0241] (B) (B / A) X 100-100 1 Normal group 10.52 ± 0.7071 8.02

[0242] 2 Control group 2.5 ± 0.79 0

[0243] 3 Standard group 7.4 ± 1.30 4.9

[0244] Palmitoylethanolamide

[0245] 4 3.9 ± 0.28 1.4

[0246] (PEA) group

[0247] 5 Magnesium (Mg) group 3.1 ± 0.30 0.6

[0248] Ginkgo biloba (Ginkgolide- 6 3.6 ± 0.54 1.1

[0249] B) group 3.1 4 29.03 7 PEA + Mg Group 4.7 ± 0.53 2.2

[0250] Mg + Ginkgo biloba

[0251] 8 4.4 ± 0.61 1.9

[0252] (Ginkgolide-B) group

[0253] PEA + Ginkgo biloba

[0254] 9 5.1 ± 0.41 2.6

[0255] group

[0256] 10 PEA + Mg + Ginkgo biloba 6.5 ± 0.40

[0257]

[0258] (Ginkgolide-B) group 4

[0259] The Hot Plate Tail Flick Latency Test is a key preclinical method used to evaluate analgesic 5 activity and central pain modulation, both essential for the development of migraine therapies. It measures the time an animal takes to respond to a painful heat stimulus, reflecting its pain sensitivity. Since migraines involve heightened sensitivity (hyperalgesia), an increased latency indicates analgesic efficacy by demonstrating delayed pain perception. All treatment groups showed a significant increase in Hot Plate Tail Flick 10 Latency compared to the control group, indicating the analgesic effects of each treatment.

[0260] Moreover, the combination of PEA, magnesium, and Ginkgolide B resulted in a 29.03% greater increase in latency compared to the sum of the individual effects of PEA, magnesium, and Ginkgolide B, suggesting a synergistic effect when administered in combination. The study results are provided in the above table and figure 1.

[0261] 15

[0262] Study Result 2: Time in Light chamber test (second)

[0263] % improvement in Change from Sum of change Change from group 9 compared S. No Groups Week 4 control from baseline of baseline in to Sum of change (All groups - group 4, 5 and 6 group 10 from baseline of Control group) (A) (B) group 4,5 and 6

[0264] (B / A) X 100-100 1 Normal group 1651 ± 32.29 1018

[0265] 448 597 33.26

[0266]

[0267] 2 Control group 633 ± 36.48 0 Standard group 1250 ± 39.30 617

[0268] Palmitoy lethano lamide

[0269] 797 ± 26.60 164

[0270] (PEA) group

[0271] Magnesium (Mg) group 769 ± 21.31 136

[0272] Ginkgo biloba (Ginkgolide- 781 ± 32.51 148

[0273] B) group

[0274] PEA + Mg Group 940 ± 27.23 307

[0275] Mg + Ginkgo biloba

[0276] 932 ± 24.42 299

[0277] (Ginkgolide-B) group

[0278] PEA + Ginkgo biloba group 946 ± 26.58 313

[0279] PEA + Mg + Ginkgo biloba

[0280] 0 1230 ± 31.00

[0281]

[0282] (Ginkgolide-B) group 597

[0283] The Time in Light Chamber Test is a preclinical model used to assess photophobia, a key symptom of migraine. Animals placed in a light-dark box exhibit light avoidance when experiencing migraine-like sensitivity. Reduced time spent in the light chamber indicates 5 heightened photophobia, while increased time following treatment suggests reduced light sensitivity, highlighting the compound’s therapeutic potential. All treatment groups showed a significant increase in time spent in the light chamber compared to the control group, indicating reduced light sensitivity with each treatment. Moreover, the combination of PEA, magnesium, and Ginkgolide B resulted in a 33.26% greater increase in time spent 10 in the light chamber compared to the sum of the individual effects of PEA, magnesium, and Ginkgolide B, suggesting a synergistic effect when administered in combination. The study results are provided in the above table and figure 2.

[0284] Study Result 3: Time in Dark chamber test (second)

[0285] 15

[0286] % improvement in Change

[0287] Change from Sum of change group 9 compared from

[0288] control from baseline of to Sum of change S. No Groups Week 4 baseline in

[0289] (All groups - group 4, 5 and 6 from baseline of group 10

[0290] Control group) (A) group 4,5 and 6

[0291] (B) (B / A) X 100-100 1 Normal group 3 ± 0.62 -24

[0292] 2 Control group 27 ± 2.11 0

[0293] 3 Standard group 6 ± 0.80 -21

[0294] Palmitoylethanolamide

[0295] 4 21 ± 1.20 -6

[0296] (PEA) group

[0297] 5 Magnesium (Mg) group 23 ± 0.72 -4 -15 -20 33.33 Ginkgo biloba (Ginkgolide- 6 22 ± 1.46 -5

[0298] B) group

[0299] 7 PEA + Mg Group 16 ± 1.26 -11

[0300] Mg + Ginkgo biloba

[0301] 8 17 ± 1.72 -10

[0302] (Ginkgolide-B) group

[0303]

[0304] 9 PEA + Ginkgo biloba group 16 ± 1.25 -11 PEA + Mg + Ginkgo biloba

[0305]

[0306] (Ginkgolide-B) group -20

[0307] The Time in Dark Chamber Test is a preclinical model used to evaluate photophobia, a key symptom of migraine. Animals are placed in connected light and dark compartments, and increased time spent in the dark reflects heightened light sensitivity. A reduction in time 5 spent in the dark chamber after treatment suggests the compound’s potential to alleviate migraine-related photophobia, making this test valuable for assessing migraine therapies targeting light sensitivity. All treatment groups showed a significant decrease in time spent in the dark chamber compared to the control group, indicating reduced photophobia with each treatment. Moreover, the combination of PEA, magnesium, and Ginkgolide B resulted 10 in a 33.33% greater decrease in dark chamber time compared to the sum of the individual effects of PEA, magnesium, and Ginkgolide B, suggesting a synergistic effect when administered in combination. The study results are provided in the above table and figure 3.

[0308] 15 Study Result 4: Forced swim test Immobility time (Second)

[0309] % improvement in group 9 Change from Sum of change Change from

[0310] compared to control from baseline of baseline in

[0311] S. No Groups Week 4 Sum of change (All groups - group 4, 5 and 6 group 10

[0312] from baseline of Control group) (A) (B) group 4,5 and 6

[0313] (B / A) X 100-100 1 Normal group 3 ± 0.58 -14

[0314] 2 Control group 17 ± 1.11 0

[0315] 3 Standard group 4 ± 0.57 -13

[0316] Palmitoylethanolamide

[0317] 4 13 ± 1.70 -4

[0318] (PEA) group

[0319] 5 Magnesium (Mg) group 14 ± 1.81 -3

[0320] Ginkgo biloba (Ginkgolide- 6 14 ± 1.48 -3 -10 -13 30.00 B) group

[0321] 7 PEA + Mg Group 10 ± 2.07 -7

[0322] Mg + Ginkgo biloba

[0323] 8 11 ± 1.40 -6

[0324] (Ginkgolide-B) group

[0325] 9 PEA + Ginkgo biloba group 10 ± 2.00 -7

[0326] PEA + Mg + Ginkgo biloba

[0327] 10 4 ± 0.57

[0328]

[0329] (Ginkgolide-B) group -13

[0330] The Forced Swim Test (FST) is a preclinical behavioral assay used to assess depressive- like behavior and fatigue symptoms often linked to chronic migraine. Rodents are placed 20 in an inescapable water container and immobility time is measured. Increased immobility reflects migraine-associated fatigue or despair, while reduced immobility after treatment suggests the compound's potential to alleviate these symptoms. Thus, FST offers insight into the neurobehavioral impact of migraine and the efficacy of treatments targeting mood and fatigue. All treatment groups showed a significant decrease in forced swim test 5 compared to the control group, indicating reduced fatigue and depressive like behavior with each treatment. Moreover, the combination of PEA, magnesium, and Ginkgolide B resulted in a 33.00% greater decrease in the Forced Swim Test compared to the sum of the individual effects of PEA, magnesium, and Ginkgolide B, suggesting a synergistic effect when administered in combination. The study results are provided in the above table and figure 10 4.

[0331] Study Result 5: Photoactometer Movement in 5 mins

[0332] % improvement in Change

[0333] Change from Sum of change from group 9 compared control from baseline of to Sum of change S. No Groups Week 4 baseline in

[0334] (All groups - group 4, 5 and 6 from baseline of group 10

[0335] Control group) (A) group 4,5 and 6

[0336] (B) (B / A) X 100-100 1 Normal group 351 ± 14.89 236

[0337] 2 Control group 115 ± 11.86 0

[0338] 3 Standard group 264 ± 23.19 149

[0339] Palmitoylethanolamide

[0340] 4 157 ± 21.86 42

[0341] (PEA) group

[0342] Magnesium (Mg)

[0343] 5 147 ± 17.97 32

[0344] group

[0345] Ginkgo biloba

[0346] 6 152 ± 17.87 37

[0347] (Ginkgolide-B) group 111 144 29.73 7 PEA + Mg Group 194 ± 18.05 79

[0348] Mg + Ginkgo biloba

[0349] 8 190 ± 19.70 75

[0350] (Ginkgolide-B) group

[0351] PEA + Ginkgo biloba

[0352] 9 196 ± 22.30 81

[0353] group

[0354] PEA + Mg + Ginkgo

[0355] 10 biloba (Ginkgolide-B) 259 ± 22.33

[0356]

[0357] group 144

[0358] 15 The photoactometer measures locomotor activity in animals, providing insights into motor function, fatigue, and behavioral changes associated with migraine. In preclinical migraine models, reduced movement detected by the photoactometer may reflect migraine- associated lethargy, fatigue, or malaise. Conversely, increased movement after treatment can indicate improved energy levels or reduced migraine-related discomfort, suggesting the 20 efficacy of the tested compound. Thus, the photoactometer serves as a valuable tool to evaluate general activity levels and behavioral improvements in migraine research. All treatment groups showed a significant increase in photoactometer movements compared to the control group, indicating reduced migraine-related lethargy or malaise with each treatment. Moreover, the combination of PEA, magnesium, and Ginkgolide B resulted in a 5 29.73% greater increase in photoactometer movements compared to the sum of the individual effects of PEA, magnesium, and Ginkgolide B, suggesting a a synergistic effect when administered in combination. The study results are provided in the above table and figure 5.

[0359] 10 Study Result 6: Serum IL-6 (ng / ml)

[0360] % improvement in Change

[0361] Change from Sum of change group 9 compared from

[0362] control from baseline of to Sum of change S. No Groups Week 4 baseline in

[0363] (All groups - group 4, 5 and 6 from baseline of group 10

[0364] Control group) (A) group 4,5 and 6

[0365] (B) (B / A) X 100-100 1 Normal group 3 ± 0.60 -26

[0366] 2 Control group 29 ± 1.67 0

[0367] 3 Standard group 7 ±0.19 -22

[0368] Palmitoy lethano lamide

[0369] 4 23 ± 2.16 -6

[0370] (PEA) group

[0371] 5 Magnesium (Mg) group 25 ± 1.4 -4

[0372] Ginkgo biloba

[0373] 6 24 ± 1.96 -5

[0374] (Ginkgolide-B) group -15 -21 40.00 7 PEA + Mg Group 17 ± 1.47 -12

[0375] Mg + Ginkgo biloba

[0376] 8 19 ± 2.34 -10

[0377] (Ginkgolide-B) group

[0378] PEA + Ginkgo biloba

[0379] 9 17 ± 0.95 -12

[0380] group

[0381] PEA + Mg + Ginkgo

[0382] 10 biloba (Ginkgolide-B) 8 ± 0.55

[0383]

[0384] group -21

[0385] Serum IL-6 is a key pro-inflammatory marker elevated during migraine attacks, reflecting neuroinflammation and central sensitization. Its reduction following treatment indicates 15 anti-inflammatory and therapeutic efficacy, making it a valuable biomarker for assessing migraine interventions. All treatment groups showed a significant decrease in IL-6 levels compared to the control group, indicating reduced migraine-related neuroinflammation with each treatment. Moreover, the combination of PEA, magnesium, and Ginkgolide B resulted in a 40.00% greater decrease in serum IL-6 compared to the sum of the individual 20 effects of PEA, magnesium, and Ginkgolide B, suggesting a synergistic effect when administered in combination. The study results are provided in the above table and figure 6.

[0386] Study Result 7: Serum TNF-a (ng / ml)

[0387] 5

[0388] % improvement in Change from Sum of change Change from group 9 compared control from baseline of baseline in to Sum of change S. No Groups Week 4

[0389] (All groups - group 4, 5 and 6 group 10 from baseline of Control group) (A) (B) group 4,5 and 6

[0390] (B / A) X 100-100 1 Normal group 98.11 ± 4.68 -304.69

[0391] 2 Control group 402.80 ± 11.02 0

[0392] 3 Standard group 159.11 ± 6.55 -561.91

[0393] Palmitoylethanolamide

[0394] 4 334.32 ± 4.14 -68.48

[0395] (PEA) group

[0396] Magnesium (Mg)

[0397] 5 342.38 ± 10.78 -60.42

[0398] group

[0399] Ginkgo bilob a

[0400] 6 338.35 ± 11.09 -64.45

[0401] (Ginkgolide-B) group -193.35 -238.96 23.59 7 PEA + Mg Group 271.60 ± 15.75 -131.2

[0402] 8 Mg + Ginkgo biloba 274.95 ± 13.33 -127.85

[0403] (Ginkgolide-B) group

[0404] PEA + Ginkgo biloba

[0405] 9 268.59 ± 16.03 -134

[0406] group

[0407] PEA + Mg + Ginkgo

[0408] 10 biloba (Ginkgolide-B) 163.84 ± 12.94

[0409]

[0410] group -238.96

[0411] Serum TNF-a (Tumor Necrosis Factor-alpha) is a pro-inflammatory cytokine closely linked to the pathophysiology of migraine. Elevated levels of TNF-a are associated with neuroinflammation, trigeminal nerve activation, and pain sensitization in migraine patients.

[0412] 10 Monitoring serum TNF-a helps assess the inflammatory burden during migraine attacks. A decrease in TNF-a following treatment suggests anti-inflammatory and potential antimigraine effects, making it a useful biomarker for evaluating therapeutic efficacy in preclinical and clinical studies. All treatment groups showed a significant decrease in serum TNF-a levels compared to the control group, indicating reduced migraine-related 15 neuroinflammation with each treatment. Moreover, the combination of PEA, magnesium,

[0413] and Ginkgolide B resulted in a 23.59% greater decrease in serum TNF-a compared to the sum of the individual effects of PEA, magnesium, and Ginkgolide B, suggesting a synergistic effect when administered in combination. The study results are provided in the above table and figure 7.

[0414] 20 The results of the study described above clearly establish that the present invention provides a pharmaceutical composition comprising Palmitoylethanolamide (PEA), Ginkgolide B, and Magnesium, which represents significant advancement over existing therapies for headache disorders. The synergistic combination produces enhanced therapeutic benefits that are significantly different and superior to those observed when the components are administered individually.

[0415] In addition to its technical advantages, the invention also provides substantial economic and industrial applicability. By reducing reliance on conventional pharmacological therapies that are often associated with adverse side effects, or risk of medication overuse or abuse, the composition offers a safer and more effective alternative for long-term management of headache disorders. Accordingly, the invention embodies a technical solution to an unmet medical need while simultaneously providing a commercially viable and industrially applicable composition for the treatment or prevention of headache disorders.

Claims

1. We Claim:

1. A pharmaceutical composition comprising an effective amount of Palmitoylethanolamide (PEA), Ginkgolide B, and Magnesium, together with one or more pharmaceutically acceptable excipients for the treatment or prevention of headache disorders.

2. The pharmaceutical composition as claimed in claim 1, wherein the ratio of Palmitoylethanolamide, Ginkgolide B, and Magnesium ranges from 1:0.0015:0.0015 to 1:24:

283. The pharmaceutical composition as claimed in claim 1, wherein:5.a) Palmitoylethanolamide is present in an amount ranging from 1.08% to 99.21% w / w,6.b) Ginkgolide B is present in an amount ranging from 0.06% to 95.01% w / w, and c) Magnesium is present in an amount ranging from 0.06 % to 95.69% w / w based on the total weight of the composition.

4. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises:8.a) Palmitoylethanolamide in an amount ranging from 50 mg to 2000 mg, b) Ginkgolide B in an amount ranging from 3 mg to 1200 mg, and9.c) Magnesium in an amount ranging from 3 mg to 1400 mg.

5. A kit comprising Palmitoylethanolamide, Ginkgolide B, and Magnesium, and one or more acceptable pharmaceutical excipient, wherein:11.a) Palmitoylethanolamide is present in an amount ranging from 50 mg to 2000 mg, b) Ginkgolide B is present in an amount ranging from 3 mg to 1200 mg, and c) Magnesium is present in an amount ranging from 3 mg to 1400 mg, wherein Palmitoylethanolamide, Ginkgolide B, and Magnesium are either provided in a single composition or as separate compositions within the kit;12.and wherein the kit is intended for the treatment of headache.

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 one or more headache disorders, including but not limited to migraine, tension-type headache, cluster headache, medication-overuse headache, and other primary or secondary headache disorders.

10. A pharmaceutical composition for the treatment of headache disorders, comprising:17.a) Palmitoylethanolamide is present in an amount ranging from 50 mg to 2000 mg, b) Ginkgolide B is present in an amount ranging from 3 mg to 1200 mg, and c) Magnesium is present in an amount ranging from 3 mg to 1400 mg, wherein the composition is supplied in a sachet.

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